CN1008093B - Process for preparation of isothiuronium salts compounds - Google Patents
Process for preparation of isothiuronium salts compoundsInfo
- Publication number
- CN1008093B CN1008093B CN85103160A CN85103160A CN1008093B CN 1008093 B CN1008093 B CN 1008093B CN 85103160 A CN85103160 A CN 85103160A CN 85103160 A CN85103160 A CN 85103160A CN 1008093 B CN1008093 B CN 1008093B
- Authority
- CN
- China
- Prior art keywords
- compound
- general formula
- formula
- amino imino
- imino methyl
- 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.)
- Expired
Links
- -1 isothiuronium salts compounds Chemical class 0.000 title claims abstract description 75
- 238000000034 method Methods 0.000 title claims description 27
- 238000002360 preparation method Methods 0.000 title claims description 22
- 230000008569 process Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 150000002500 ions Chemical class 0.000 claims description 9
- 230000002152 alkylating effect Effects 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 230000008859 change Effects 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 2
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims description 2
- 150000003573 thiols Chemical class 0.000 claims description 2
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 abstract description 15
- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- 125000003118 aryl group Chemical group 0.000 abstract description 6
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 150000001449 anionic compounds Chemical class 0.000 abstract 1
- 229910001412 inorganic anion Inorganic materials 0.000 abstract 1
- 150000002891 organic anions Chemical class 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 52
- 210000004027 cell Anatomy 0.000 description 36
- 210000002700 urine Anatomy 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 30
- 238000012360 testing method Methods 0.000 description 30
- 239000005864 Sulphur Substances 0.000 description 29
- 239000000203 mixture Substances 0.000 description 24
- 206010028980 Neoplasm Diseases 0.000 description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 16
- 238000009835 boiling Methods 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 238000002425 crystallisation Methods 0.000 description 15
- 230000008025 crystallization Effects 0.000 description 15
- 150000001298 alcohols Chemical class 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 12
- 229920002554 vinyl polymer Polymers 0.000 description 12
- MBFMRQGVTCPUQA-UHFFFAOYSA-N C[S]=NN Chemical compound C[S]=NN MBFMRQGVTCPUQA-UHFFFAOYSA-N 0.000 description 11
- 239000000178 monomer Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 230000000259 anti-tumor effect Effects 0.000 description 10
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 10
- 206010003445 Ascites Diseases 0.000 description 9
- 125000001246 bromo group Chemical group Br* 0.000 description 9
- 238000000151 deposition Methods 0.000 description 9
- 210000004698 lymphocyte Anatomy 0.000 description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 210000004881 tumor cell Anatomy 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 7
- 230000005012 migration Effects 0.000 description 7
- 238000013508 migration Methods 0.000 description 7
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000003708 ampul Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 206010025323 Lymphomas Diseases 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000000824 cytostatic agent Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000005934 immune activation Effects 0.000 description 5
- 210000000822 natural killer cell Anatomy 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- YBMRDBCBODYGJE-UHFFFAOYSA-N germanium dioxide Chemical compound O=[Ge]=O YBMRDBCBODYGJE-UHFFFAOYSA-N 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 230000002269 spontaneous effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 210000003714 granulocyte Anatomy 0.000 description 3
- 230000003308 immunostimulating effect Effects 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 230000000527 lymphocytic effect Effects 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000003448 neutrophilic effect Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000002516 radical scavenger Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- 229920000936 Agarose Polymers 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 239000000910 agglutinin Substances 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 230000005961 cardioprotection Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 229910052804 chromium Inorganic materials 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 239000002619 cytotoxin Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 230000005965 immune activity Effects 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 231100000636 lethal dose Toxicity 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000005395 methacrylic acid group Chemical group 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004089 microcirculation Effects 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 229960005485 mitobronitol Drugs 0.000 description 2
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 2
- 229950010913 mitolactol Drugs 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 210000001519 tissue Anatomy 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
- 230000009466 transformation Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 1
- TVDCSPSRGSLXOV-UHFFFAOYSA-N 1-bromo-3-chloropropan-2-ol Chemical class ClCC(O)CBr TVDCSPSRGSLXOV-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical class CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101710186708 Agglutinin Proteins 0.000 description 1
- 206010004173 Basophilia Diseases 0.000 description 1
- 241000219198 Brassica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010062580 Concanavalin A Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical group ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101710146024 Horcolin Proteins 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical class ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 241001480843 Ixodes ricinus Species 0.000 description 1
- 101710189395 Lectin Proteins 0.000 description 1
- GBKLAYXZNQSPBS-XYSQQLOGSA-N Mannomustine dihydrochloride Chemical compound Cl.Cl.ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl GBKLAYXZNQSPBS-XYSQQLOGSA-N 0.000 description 1
- 101710179758 Mannose-specific lectin Proteins 0.000 description 1
- 101710150763 Mannose-specific lectin 1 Proteins 0.000 description 1
- 101710150745 Mannose-specific lectin 2 Proteins 0.000 description 1
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical class CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 description 1
- QCEONQZIKPZQEZ-UHFFFAOYSA-N NN(C(=S)N=N)C Chemical compound NN(C(=S)N=N)C QCEONQZIKPZQEZ-UHFFFAOYSA-N 0.000 description 1
- MIEJJJFWLXJGEI-UHFFFAOYSA-N NN(C(SC)=[N+]=N)C Chemical class NN(C(SC)=[N+]=N)C MIEJJJFWLXJGEI-UHFFFAOYSA-N 0.000 description 1
- CXZHZFFSYJALGA-UHFFFAOYSA-N NN(C(SCC1CO1)=[N+]=N)C Chemical class NN(C(SCC1CO1)=[N+]=N)C CXZHZFFSYJALGA-UHFFFAOYSA-N 0.000 description 1
- KWYTWCXMRMXEJN-UHFFFAOYSA-N NN(C(SCCCl)=[N+]=N)C Chemical class NN(C(SCCCl)=[N+]=N)C KWYTWCXMRMXEJN-UHFFFAOYSA-N 0.000 description 1
- VHUWALJGGCVOMT-UHFFFAOYSA-N NN(C(SCCO)=[N+]=N)C Chemical class NN(C(SCCO)=[N+]=N)C VHUWALJGGCVOMT-UHFFFAOYSA-N 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 240000000528 Ricinus communis Species 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 150000005524 benzylchlorides Chemical class 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- FGPOJOPWLREKNC-UHFFFAOYSA-N chloric acid thiourea Chemical compound Cl(=O)(=O)O.NC(S)=N FGPOJOPWLREKNC-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- OKGXJRGLYVRVNE-UHFFFAOYSA-N diaminomethylidenethiourea Chemical compound NC(N)=NC(N)=S OKGXJRGLYVRVNE-UHFFFAOYSA-N 0.000 description 1
- 238000001965 diffuse reflectance infrared spectroscopy Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000020187 evaporated milk Nutrition 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 210000000224 granular leucocyte Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000001435 haemodynamic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000005246 left atrium Anatomy 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229940077810 liceall Drugs 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000029052 metamorphosis Effects 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N methyl monoether Natural products COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 231100001224 moderate toxicity Toxicity 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 230000000590 parasiticidal effect Effects 0.000 description 1
- 239000002297 parasiticide Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000000191 radiation effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004202 respiratory function Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000005477 standard model Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 238000004073 vulcanization Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings 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, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Abstract
The Isothiuronium salts of the general formula (I), can be prepared by reacting a compound of the general formula (II), with an agent capable of introducing a R<1> group. wherein, R<1> is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, aralkyl or aryl, the said groups being optionally substituted by one or more hydroxy, mercapto and/or halogen; R<2> stands for hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or C3-6 cycloalkyl; X represents an organic or inorganic anion.
Description
The present invention relates to isothiuronium salts, its preparation method, and the medicinal compositions that contains this salt.The major part of said isothiuronium salts is new compound.This compound has useful antitumor action and anti-excitation, and can be used in the treatment of human and beasts.
Generalformula is known (French Patent No.788,429 and Dos No.2,426,683),
R wherein
1Be methyl, ethyl or benzyl; R
2Represent H.But in these publications, said compound is only mentioned as intermediate, does not mention any biological activity or the purposes of these compounds aspect treatment of this compound fully.
One aspect of the present invention provides the salt and the new compound of generalformula.
Wherein,
R
1Be C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl,
C
3-6Cycloalkyl, aralkyl or aryl, said group can be arbitrarily by one or more hydroxyls, and sulfydryl and/or halogen replace; R
2Represent H, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or C
3-6Cycloalkyl;
X represents a kind of organic or inorganic negatively charged ion, but R
2When representing H, R
1Can not be methyl, ethyl or benzyl.
" C
1-6Alkyl " speech means the saturated aliphatic alkyl of straight key or key (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-etc.)." C
2-6Thiazolinyl " speech comprises straight key or key olefinic unsaturation base (for example vinyl, allyl group, methylallyl etc.)." C
2-6Alkynyl " speech means straight key or Zhi Jian, the aliphatic group that contains one three key at least is (for example: propargyl etc.)." C
3-6Cycloalkyl " speech means annular representative examples of saturated aliphatic alkyl (for example, cyclobutyl, cyclopentyl, cyclohexyl etc.)." aryl " speech comprises monocycle or Ppolynuclear aromatic alkyl (for example, phenyl, naphthyl etc.)." aralkyl " speech means the alkyl (as benzyl, beta-phenyl-ethyl etc.) that is replaced by an aryl at least." halogen " speech comprises fluorine, chlorine, bromine, iodine atom.
Said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl and aralkyl can have one or more hydroxyls, sulfydryl or halogen substituent arbitrarily.The for example following group that is substituted: 2-chloro-ethyl, 3-bromo-propyl group, 2-hydroxyl-ethyl, 3-chloro-2 hydroxyls-propyl group etc.
One group of compound with formula I is R preferably
1It is allylic derivative.
Better one group of compound with formula I is R
2It is the derivative of 2-halo-ethyl.
R
2Be preferably hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, allyl group or cyclohexyl.
X is preferably halid negatively charged ion, particularly muriate, the negatively charged ion of bromide or iodide.
Particularly preferred compound with formula I is the salt of pharmaceutically useful following derivative:
N-amino imino methyl-S-methyl-isothiuronium salts;
N-amino imino methyl-S-propyl group-isothiuronium salts;
N-amino imino methyl-S-allyl group-isothiuronium salts;
N-amino imino methyl-S-(2-chloroethyl)-isothiuronium salts;
N-amino imino methyl-S-(1-chloro-2-hydroxyl-propyl group)-isothiuronium salts;
N-amino imino methyl-S-(3-chloro-propyl group)-isothiourea;
N-amino imino methyl-S-(2-hydroxyethyl)-isothiuronium salts;
N-amino imino methyl-S-glycidyl-isothiuronium salts;
Better having generalformula is: N-amino imino methyl-N '-alkyl-S-allyl group-isothiuronium salts particularly has N '-methyl, N '-ethyl, the corresponding compounds of N '-n-propyl and N '-sec.-propyl.The present invention has further proposed to prepare the method for generalformula and its esters, and this method comprises:
A) will have the compound of general formula II or its suitable salt and can introduce R
1The alkylating reagent reaction of group:
(R wherein
2As above-mentioned), preferably with have general formula R
1The alkylating reagent reaction of-Y, wherein R
1As above-mentioned, Y representative residue base, preferably halogen; Perhaps
B) compound and the general formula with the general formula II is R
1The compound reaction of-SH:
(wherein, R
1As above-mentioned) if necessary, product that obtains thus and the acid (wherein X is the negatively charged ion of organic acid or mineral acid) with general formula HX are reacted, make it change salify.
Isothiuronium salts forms in said reaction.The general generation of this reaction with the N-alkylate by-product.
According to method a), situation is preferably, and the raw material with general formula II does not use with the form of free alkali, but uses with the form of its suitable salt, particularly carbonate.Therefore, will carry out quenching when generating the N-alkyl derivative, this may be because the carbonic acid gas of emitting has reduced the pH value of strong alkali medium.
As alkylating reagent preferably, can use corresponding haloalkane or dialkyl sulfate, other alkylating reagent also can use.
Gram molecular weights such as reactant can be also can add excessive alkylating reagent.For reaction medium, can use inert organic solvents, preferably pure, aliphatic ketone, aliphatic nitrile or ether.
Reaction can be under atmospheric pressure, carries out under 20～80 ℃ of temperature.
According to method a), situation is preferably, and the mole ratio that the raw material of general formula II and alkylating reagent react is 1: 1 to 1: 1.8, and organic solvent is a dehydrated alcohol, acetonitrile, and dimethyl formamide, acetone or ether, temperature is 20 ℃ and 30 ℃.
According to method b), be R with the compound and the general formula of general formula III
1The thiol reactant of-SH can prepare the compound with general formula IV.
(above-mentioned general formula is a narrower branch of generalformula, R
2Being hydrogen) reactant gram molecular weight such as can be, also can make general formula is R
1The mercaptan of-SH is excessive.As reaction medium, the most handy alcohol, particularly ethanol.If necessary, reaction can be carried out under pressure.Its pressure is preferably 1 to 5 crust, and temperature is preferably 20 ℃ to 100 ℃.
The raw material of general formula II is known, and can be by on record method preparation.Dicyano hydrazine and hydrogen sulfide reaction can easily be prepared N-amino imino methylthiourea (Houben-Weyl VII, 214).Guanidine alkali and corresponding alkyl isothiocyanic acid reactant salt can be prepared the N-amino imino methyl-N '-alkyl-thiourea derivative (U.S. Patent No. 4,009,163) with general formula II.
The raw material of general formula III can be prepared by currently known methods.
The product that obtains thus can be converted into pharmaceutical salts with organic acid or mineral acid.When generating salt, the most handy formic acid, lactic acid, citric acid, toxilic acid or sulfuric acid, hydrochloric acid, phosphoric acid or Hydrogen bromide.
Generalformula has antitumor, the character of antiparasitic immuno-stimulating.The active intensity of compound and direction and toxicity all depend on the substituent of this compound.
Know, gutimine relevant with generalformula on the structure is in pharmacology and clinical detection, as the material that causes the microcirculation illness (Gematol.Transfusiol.(1984), 29(1), 49-52) the same as agent detects that (C-A-66 452,929(1972) as anti-hypoxia; Patho phys-Exp.Ther, 10, (6)).
Have been found that the compound with formula I can make lowered body natural immune system return to normal value, perhaps increases to more than the normal value.
The organism of animal and human's class has immunity system (for example, eliminating the tumour system).In case the activity of this system reduces or stops its function, will produce multiple disease and tumour, and show.The compound activating of formula I natural immune system, therefore, in all cases, when needs improve lowered immune system activity, or when further improving immune normal activity, this compound is useful.
The compound of formula I also shows more useful biological effect, and for example, treatment microcirculation illness in conjunction with the group of insalubrity, is improved the hypoxic cell biological function and prolonged its life-span.
Following test will show the biological activity of generalformula.But, whole effects of high-activity compound are not shown here.
The special effects experiment
Immunity test
Lymphocyte, to the blood donor and the malignant lymphoma patient of health, the venous blood that the hard tumour patient of transitivity entity is extracted carries out lymphocyte Ficoll-Hypaque gradient separations (Boyum 1968) respectively.When selected patient belongs to the back one group the time, ADCC(is relied on the antibody killer cell) and the NK(natural killer cell) situation of active minimizing will take in, the tongue phagocyte is handled with iron powder and magnet.
ADCC measures ADCC with the white Germania method that changes slightly and white Germania (1970) method people such as (, 1981) Lang.Chicken red blood cell is with 10
5 51Cr mark and the erythrocytic cell of anti-chicken
Serum reaches lymphocyte together 37 ℃ of insulations 4 hours, and behind the stopped reaction, the activity of the cell conditioned medium liquid of centrifugation is measured with gamma counter.The release rate of chromium is represented with cytotoxin index (CI%).The method of saying in the article that this value was published in the past by us people such as (, 1980) Lang is calculated.(seeing Table I)
The activity of NK natural killer cell: NK is measured with the Jiang Daer-Pu Lusifa (goudal-pross) (1975) that changes slightly people 1981 such as () Lang.The K-562 tumour cell with
51Cr mark and effector cell one reinstate TC 199 liquid nutrient media and cultivate, and nutrient solution contains the calf serum of 10% decomplementation.After reaction stopped, the radioactivity of centrifugal separating cell supernatant liquor can (discharging chromium) be measured with gamma counter.The killer cell toxin index % of target cell) represents with the difference of test burst size and spontaneous burst size.
Statistical computation is calculated with single sample test method.Several compounds of general formula I show very good immune activation effect.(for example by the prepared compound of example 11,12 and 16) said these compounds increase Normocellular activity significantly and significantly reduce NK cell and K cell activity, even also can paranormal level.Said this effect is very strong so that can make the cell toxicant disposition reduce to 1/10th of original numerical value, has to return to previous level (table II).
In the dosage range of human plasma concentration, the size that the compound of general formula I will be distinguished according to dosage increases human lymphocytic NK and K(killer cell) activity, and the reaction that improves NCMC and ADCC.To increase the conversion and the migration of lymphocyte (Bastos) from this compound of PRELIMINARY RESULTS of further immunological testing.
With mol proportional immune activation effect generally all reduce relevant when doing nitrogen-atoms replacement test with toxin.
Owing to the cytotoxic activity of tumour patient with stadium is proportional reduces, in addition owing to stop the treatment of cell growth, cytotoxic activity also can further reduce, significantly, the compound of formula I has strong immune activation effect, and do not suppress immune effect, may be even more important for decubation.
Leukocytic migration
Migration for white corpuscle spontaneous (at random) is (the Kalmar and Gergely 1982) that measures with the agarose droplet by the people's methods (1977) such as MC Coy that change a little.2 milliliters of agarose drops (0.2%) drop in the mobile plate (the federal Greiner of Germany) and add the TC199 nutritional medium again, and plate is hermetically enclosed, carries out migration circle with dissecting microscope after 24 hours and measures moving range mm
2Represent.
Leukocytic moving
Direct (at any time) of the polymorphonuclear cell of healthy human body migration can use-case 11,12 and 14 compound make it to increase.Using dosage can reach 1.0 μ g(micrograms)/(milliliter)
Ml(10 μ g(microgram)/ml(milliliter when using heavy dose)), its effect reduces, (table III).
Promote the lymphocyte transformation that the cell fission agent causes
Lymphocyte is incubated at the TC199 substratum, is added with the calf serum of 10% decomplementation in the solution, the HEPES(Serva of microbiotic and 25mH).To contain 2 * 10
5Individual lymphocytic 200 microlitres (μ l) cell suspension is coated in (Great Britain Sterilm manufacturing) on the microgram; Each adds the vegetalitas homo agglutinin (leuko-agglutinin of 2 and 10 micrograms (μ g)/milliliter (ml) respectively five parallel laboratory tests, Sweden Pharmacie factory makes) and the Jacr concanavalin A (Carbiochem) of 25 micrograms (μ g)/milliliter (ml) in nutrient solution, above data are for ultimate density.At 37 ℃, cultivated 72 hours.8 hours before incubation period finishes with 0.5 μ Ci
3The thymus nucleoside of H microcurie (Chemapol Czech Slav) adds in the sample.Freezing nutrient solution mixes with termination.After dissolving, (Scintillator counts sample with scintillometer shaking on the storage the penetrating property of quilt of filtering (Dynatech) sample certainly.Radiological performance is represented it (table IV and table V) with C.P.m..
Statistical study
The meaning of test-results is determined with single sample 2T2 test method.The result of example 11 acquisition of getting is illustrated in the table I, in II and the III.
The preliminary short-time test of antitumor and immune activation effect
This is a method of a large amount of samples being made short-time test in our testing laboratory.4,000,000 ascites lymphoma cells of inoculation in the male mouse of CELP (mean body weight 30 grams) peritoneal cavity.
Used mouse was promptly obviously seen tumour-be glue-generation at the 4th day in this test.Test 10 mouse of minimum use for every group, and the oral LD of mouse
50The dosage of medium lethal dose 1/10th.
On the cell analysis basis, come evaluation effect with Giemsa dyeing ascites smear after oral 24 hours, the mouse number of control group and treatment group is identical.
To the destruction of tumour cell, the activation of body and have toxic effect all to make evaluation at last.
When anti-tumour effect was evaluated, mortality ratio and intact tumor cells percentage were all taken into account, and its result represents in following ratio:
The tumor cell destruction effect
0-30% to no effect
The medium effect of 30-70%
The 70-100% effect significantly (has
Restraining effect)
According to appearing at ascites cells and participate in immune neutrophilic granulocyte, the quantity of lymphocyte and scavenger cell and the active enhancing of evaluating body immune system.Immune activity also can be represented with the ratio of oncocyte formation blood plasma-bridge in ascites by above-mentioned cell.By this assessment method,, so then the control treatment will there be any enhancing if what difference these cells do not have on quantity and activity.
If cell quantity or active enhancing surpass control group 20%, then can be observed medium curative effect.If it then is produce effects that immune system cell quantity and active increase surpass the words of control group more than 20%.(table VII)
Toxicity is by neutrophil granule sexual cell and lymphocytic metamorphosis, the Vasquolizationization of blood plasma, and the nucleus fragmentation, more piece and malicious granulation form to determine.Toxicity is represented it by following form:
Observations toxicity
Be difficult to change nontoxicity in the cell
20% variation moderate toxicity
Change and surpass 20% high toxicity
The antitumous effect test
1, in vitro tests
The K-562 people's who cultivates red white blood cell and mouse P-388 lymphoma cell are handled with the substances of 1-100 microgram (μ g)/milliliter (ml).
2, in vivo test
A) NK-Ly-ascites lymphoma
1,000,000 N é meth-Kellner ascites lymphoma cells are implanted into the intraperitoneal (mean body weight 30 grams) of 20 CFLP male mouses; Adopted a kind of new mouse ascites fluid knurl as the means of screening.Tumour 8,337(1961), the animal of half is organized in contrast.Half is with 1/10th LD in addition
50The formula I all cpds of quantity at one day and continuous five days, carries out oral and intraperitoneal injection respectively.If (1/10th LD
50Dosage is effectively talked about, and then can reduce dosage).After 24 hours, carry out the cellular form of ascites smear for the test group of single administration respectively and observe and measure damage rate and mortality ratio, calculate survival rate for five days administration batch totals.
B) L
1210Tumour
10
5Individual L
1210Tumor cell transplantation is gone into 20 BDF, female mouse (body weight 20(g) gram) abdominal cavity.Begin administration in tumour transplatation after 24 hours, and continued 8 days, each group have five female mouse day oral dosage be 5,50 and 500 milligrams (mg)/kilogram (kg).Control group also is five mouse; Observe its survival rate.
C) LewisShi bearing tumor
Each group is 5 and 50 milligrams (mg)/kilogram (kg) with 6 mouse, dosage.Control group is six mouse, and that this test is used is C
57B
2Female mouse/weigh 20 to restrain (g).
Tumour is gone in the right leg as subcutaneous transplantation.Do the leg amputation after 10 days, the beginning oral administration also continued 9 days, killed female mouse, calculates tumour cell and shift quantity under dissecting microscope.
D) dog of different varieties suffers from spontaneous gland tumor/conduit CC.(dnctus CC.)/oral 1-10 milligram (mg)/kilogram (kg) test medicine treatment do test all around resection operation, sample of tissue is carried out uterus pathology check analysis.
Example 11,13,14,15,27,28,34,35,36,38 compound has remarkable antitumous effect.Example 11 compounds 4 micrograms/ml can suppress the K-562 human erythroleukemia cell of tissue culture, and on the other hand, and this compound could suppress P-388 hyperplasia when concentration 40 micrograms (μ g)/milliliter (ml).Activity does not strengthen when concentration increases to 400 micrograms (μ g)/milliliter (ml).Effectively significant compound exists effect relevant with pharmaceutical quantities in concentration is 0.5-5 microgram (μ g)/milliliter (ml) scope, and poor efficiency compound and dosage are irrelevant.According in vivo test, this compounds is for L
1210Knurl is absolutely void or effect is very little.
This compound can reduce LewisShi bearing tumor lung significantly and shift quantity.Compound 11,13,14,15,22,27,28,45 at the LD that is lower than 1/10th
50Be effective during dosage.The compound of example 14 can make the tumour lung shift number minimizing 50% with the dosage of 5 milligrams (mg)/kilogram (kg).According to LD
50=2380 milligrams (mg)/kilogram (kg) this fact, this result is very significant.
We find repetitive therapy and more can heighten the effect of a treatment than improving dosage.
The compound of example 11,13,14,20,22,27,45 is lower than LD in concentration
50Ten of dosage/one is o'clock effective to NK-Ly-glue tumour, and situation that compound uses according to dosage is planted and in various degree increase survival rate and prolong life in the back.These compounds low doses have the immuno-stimulating effect when using.Then show its direct antitumous effect when heavy dose is used, example 11 and 22 compound demonstrate the immuno-stimulating effect respectively when dosage is 25 milligrams (mg)/kilogram (kg) and 20 milligrams (mg)/kilogram (kg).Example 11 and 12 compound have cell toxicant respectively when dose is 250-500 milligram (mg)/kilogram (kg) and 40-160 milligram (mg)/kilogram (kg).Use the S-allyl group, S-1-chloro-2-hydroxyl-propyl group-or the compound of the formula I of S-1-bromo-2-hydroxyl-propyl group-replacement be very high for the anti-knurl validity of the spontaneous mastadenoma of dog.Treatment 3-4 makes biopsy and can find in tumour that cellular infiltration (conduit CC.(ductas CC) also has eosinophil once in a while comprising lymphocyte and neutrophilic granulocyte scavenger cell after week.Can observe decline on tumour cell changes and the intensive disintegration.
NK cell and tumour cell form the blood plasma bridging and connect.This just causes the degeneration of tumour cell blood plasma cavity, and thinning thin at nucleus DNS clump place.The relation of the nucleus-blood plasma nucleus high level expansion that changes, the basophilia of blood plasma lowers.
In above-mentioned 1/4th example, white cell oozes profit and can ignore tumour; Tumour cell expands and the bleach decline on the other hand, and a large amount of transparent coloring matter depositions are arranged between cell and cell.
For compound oral 30-120 milligram every day (mg)/0.5-2 milligram (the mg)/kilogram of example 11/after 6 to 12 months, in people's breast tumor, ovarian tumor, the bone of pancreatic neoplasm etc. shifts can see tangible improvement or recovery respectively.
Drug combination is treated antitumor test
1, with known cytostatic agent combined treatment
There are the cytostatic agent of biological alkylating and generalformula to merge with various, treat for the CFLP mouse of NK-Ly-ascites tumour.Cytostatic agent is oral by 1/5 or 1/10 medium lethal dose or aforementioned best significant quantity, abdominal injection or intravenous injection.Take cytostatic agent oral generalformula after 48 hours, its dosage is 1/10th or twentieth LD
50Amount is taken once or several.It is endoxan on the one hand that merging makes in the medication, amino acid mustard (Carnomustine) granulation scavenging agent (Degranol) mitolactol (Dibromo dulcitol) and mitobronitol (Dibromo mannitol) are example 11,13 compounds and 14,15,16,27,28,45 on the other hand.When doing to compare with the contrast treatment group of only taking known cytostatic agent, anti-tumour effect strengthens, and immunosuppression reduces.
2) and known VITAMIN drug combination test
The isothiuronium salts of formula I can be effectively and the vitamin A of median dose and D
3Merge to use, or with the vitamins C coupling of heavy dose.In pharmacological testing and clinical case, all can obtain effect.
3) and known hormone drug combination test
It is all effective at pharmacological testing and clinical case to merge result's proof of using when treating the tumour relevant with hormone.
4) surgery is used
The success once of the compound of formula I to be applied to solid tumor/NK-Ly rigid, the pharmacological testing in the operating preoperative and postoperative treatment of Yosida/.Result according to pharmacological testing shows that the compound of formula I may also be applicable to the treatment of patient's surgical operation preoperative and postoperative.
The parasiticide effect test
Infect ixodes Ricinus(castor-oil plant Dou Lice for Ba Jiao Lice) the compound three days of dog clothes formula I, instructions of taking to N-amido imide ylmethyl-S-allyl group-isothiourea oxymuriate is oral dosage 1-2 milligram (mg)/kilogram (kg), and the kill ratio of record Ba Jiao Lice.After taking the active effective dose of formula I six to eight hours, the intravital Ba Jiao of all dogs Lice all is killed.
With combining of free radical
Example 9,10,11,16,23 and 29 compound can highly significant the attenuating hydrogen peroxide, organo-peroxide, and biological alkyl forms the toxicity (LD of change thing such as thing (free radical formations)
50).According to the compound of their the suitableeest toxicity data formula I be more suitable in and combined with radical, than the known more effective defence radiation effect of derivative by the different sulphur urine that corresponding thiocarbamide obtained.So then example 23 is better than the result of treatment of beta-aminoethyl-different sulphur urine hydrochloride.
The cardioprotection downright bad to cardiac stimulation agent (causing)
The cardioprotection of p-isopropyl suprarenin necrosis
Dosage by 5 milligrams (mg)/kilogram (kg), cardiac stimulation agent (isop-roterenol) is restrained the heavy 250-300 of male home mouse CFY() abdominal injection, every group is used ten mouse, one group of mouse is organized in contrast, another group No. 14 compound intraperitoneal injections of 1-5 milligram (mg)/kilogram (kg), or No. 14 compounds of oral 10-50 milligram (mg)/kilogram (kg).Heart is done ventricular systolic inspection evaluation after two weeks.Determine the ratio of the downright bad and complete section of heart, what we found that all N-amido imide ylmethyl-S-allyl groups by formula I-different sulphur urine hydrochloride treats can both reduce necrosis greatly.
The compound of testing in the zone of damage may be by showing its effect in conjunction with the hydrogen peroxide that neutrophilic granulocyte produced.By this pattern, the combination of other free radical and oxidation inhibitor molecule etc. will produce same effect.
Effect to circulation and breathing aspect
When intravenously administrable 10mg/kg, the cat that the compound of example 11 cuts and sews up the thoracic cavity does not have unusual effect on blood flow hydrotechnics parameter and the respiratory function.Once done following parameter test: ventricle and pressure on every side thereof, heart rate/function/electrocardiogram(ECG, circulation volume/minute, shrink respiratory capacity, respiration rate and resistance thereof etc.When intravenous injection dosage surpassed 10 milligrams/kilogram, the pressure and the frequency of left atrium went down.When dosage was 50 milligrams/kilogram, this effect was remarkable and lasting permanent.When intravenous injection dosage is 100 milligrams/kilogram, can be observed the obvious change of haemodynamics aspect, but the unlikely death of cat.N-(amino imino methyl)-effect of S-allyl group-isothiourea salt (halogenide).(compd A)
The table I
To the effect of ADDC dependence antibody killer cell, cytotoxic index (%)
The effector cell leads: target cell=5: 1.Be incubated 4 hours.
On average: ± S.E
X: effectively (P＜0.05)
The table II
To the NK(natural killer cell) active effect
Effector cell: target cell=50: 1.Be incubated 4 hours.
Cytotoxic index (%).Mean value: ± S.E
X: effectively (P＜0.05)
The table III
The effect of human polymorphonuclear leukocyte external directly (at random) migration.
Migration area (mm
2).The mean value of seven normal healthy controls is: ± S.E.M.
The table IV
By the external lymphocyte transformation effect of people's quasi-lymphocyte that PHA and ConA excite, the normal healthy controls of normal activity,
n＝6。Average C.P.m. ± S.E.m.
The table V
The external LT effect of people's quasi-lymphocyte that excites by PHA and ConA.The patient (tumour and SLE) that reaction reduces;
Average C.P.m. ± the S.E.m. of n=6
The table VI
24 hours acute toxicity of generalformula
Example R
2R
1LD
50Milligram/kilogram
P.O.
9 H methyl 2320 ± 220
23 H ethyls 3080 ± 290
10 H propyl group 2800 ± 260
25 H butyl 2700 ± 310
24 H i-propyl group 2260 ± 210
26 H i-amyl groups 2260 ± 241
13 H 2-chloroethyls 1120 ± 140
27 H 2-bromotrifluoromethanes 1050 ± 280
14 H 1-chloro-2-1240 ± 160
The OH-propyl group
15 H 3-chloropropyls 1210 ± 180
28 H 3-bromopropyls 980 ± 640
16 H 2-hydroxyl-ethyls 3280 ± 460
1680±210（i.P.）
29 H 1-oxygen-propyl group 2860 ± 180
11 H allyl groups 2380 ± 320
320±30（i.P.）
44 H methylallyls 1640 ± 210
18 H benzyls 2420 ± 260
17 H propargyls 90 ± 7.6
The table VI
Example R
2R
1LD
50Milligram/kilogram
P.O. i.p.
20 methacrylic 600 ± 54 75 ± 6.3
34 allyl ethyl 780 ± 62 84 ± 7.6
22 cyclohexyl allyl group 450 ± 51 65 ± 5.1
21 sec.-propyl allyl group 280 ± 26 32 ± 4
45 allyl group allyl group 380 ± 41 36 ± 4
22 cyclohexyl allyl group 400 ± 38 40 ± 6
The table VII
The test compound antineoplastic immune activates toxic effect
Example effect effect
In in 9
Strong by 0 in 23
In in 10 0
In in 25 0
In in 24 0
In in 26 0
13 powers 0
27 powers 0
The table VII
Test compound antineoplastic immune exitotoxicity
Example effect effect effect
14 powers 0
15 powers 0
28 powers 0
Strong by 0 in 16
In in 29 0
The last 11 is strong by 0
In in 44 0
18 increase by 00
In a little less than a little less than in the of 17
20 powers 0
In in 34 0
22 powers 0
21 powers 0
45 powers 0
22 weak 0
Another feature of the present invention provides and contains a kind of medicinal compositions with generalformula (as active ingredient) at least.Wherein:
R
1Be C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
3-6Cycloalkyl, aralkyl or aryl, these groups can be arbitrarily by one or more hydroxyls, and sulfydryl and/or halogen are replaced;
R
2Expression H, C
1-6Alkyl, C
2-3Thiazolinyl, C
2-6Alkynyl or C
3-6Cycloalkyl;
X represents a kind of organic or inorganic negatively charged ion.
Medicinal compositions of the present invention can be by the on record method preparation of medicine industry.Active constituent with formula I preferably mixes with general auxiliary (as lubrication prescription) commonly used, makes capsule; This capsule can be manufactured by automatic encapsulate capsule machine.This medicinal compositions also can be made the outer powder ampoule of the intestines that are used to inject and infuse, and these compositions also can be by on record method preparation.Can use solvent, as distilled water or normal saline solution.
Active ingredient with formula I also can be made ointment form, particularly lyophily ointment.The active ingredient with formula I that smell is stronger is preferably made microcapsule, promptly forms the mixture that is surrounded by cyclodextrine.
Medicinal compositions of the present invention except that the compound that contains formula I, also can contain one or more known biologically active substances as active ingredient.
Medicinal compositions of the present invention can be used for the treatment of human and beasts.When it was used as immunoactivator, oral or rectal dose preferably was about 0.5～25 milligram/kilogram.For topical therapeutic, preferably use bigger dosage.
Industrial applicibility
The present invention relates to many antitumor and new compounds immune activation effect of having.
Implement mode of the present invention
To be described in further detail the present invention among the embodiment, but protection scope of the present invention is not limited on the example.
Raw material
Example 1
N-amino imino methyl-sulphur urine carbonate
With 84.0 gram (1.0 moles) Dyhard RU 100s and the 300 ml waters autoclave of packing into.Add 34.0 gram (1 mole) gas vulcanization hydrogen in the autoclave of sealing by following mode again: under 20 ℃ of temperature, add hydrogen sulfide, make the pressure of autoclave reach 1.5 crust.After stopping air feed, autoclave slowly is heated to 80 ℃.The speed that adds gaseous hydrogen sulfide during this period should make the pressure of autoclave maintain 1.5 crust.After hydrogen sulfide all added, keeping the temperature of autoclave was 80 ℃, dropped to 0.3～0.4 crust until pressure.Reaction mixture is cooled to 20 ℃, uses nitrogen wash, filter then.Clear filtrate is cooled to 0 ℃, feeds carbon dioxide.Leach sedimentary white crystals N-(amino imino methyl)-sulphur urine carbonate, use cold water washing, and dry down at 60 ℃～80 ℃.Obtain 100 gram required compounds thus, productive rate 67%, fusing point (mp): 127～129 ℃.
The IR(of products obtained therefrom is infrared) the IR spectrum of the standard model of spectrum and this compound compares.
Example 2
N-amino imino methyl-N '-methyl-sulphur urine carbonate
The methylisothiocyanate salts solution that will contain 7.3 grams (0.1 mole) in 10 milliliters of acetone joins in the solution that contains 30 milliliters of acetone and 5.9 gram (0.1 mole) guanidine alkali.The speed that this isothiocyanate is joined in the guanidine solution should make the temperature of this mixture be no more than 40 ℃, and reaction mixture left standstill under 40 ℃ 4 hours, shifted out solvent then under vacuum.Remaining light yellow oil is suspended in the water, produces a kind of milky white solution.Carbon dioxide is fed in the solution that obtains thus, and required compound then is precipitated out with the white crystal form.Productive rate: 12.0 grams (73.5%), fusing point (mp): 132～134 ℃.
Example 3-8
According to the mode of example 2, the preparation following compounds:
3, N-amino imino methyl-N '-ethyl-sulphur urine-carbonate
4, N-amino imino methyl-N '-n-propyl-sulphur urine-carbonate
5, N-amino imino methyl-N '-sec.-propyl-sulphur urine-carbonate
6, N-amino imino methyl-N '-normal-butyl-sulphur urine-carbonate
7, N-amino imino methyl-N '-allyl group-sulphur urine-carbonate
8, N-amino imino methyl-N '-cyclohexyl-sulphur urine-carbonate
Following Example will illustrate the preparation of the finished product of formula I.
Example 9
N-amino imino methyl-S-methyl-different sulphur urine hydriodate
14.9 gram (0.05 mole) N-amino imino methyl-sulphur urine carbonate is suspended in 50 milliliters of dehydrated alcohols, again to the methyl iodide that wherein adds 17.0 grams (0.12 mole).Reaction mixture slowly is heated to boiling, and this moment, carbonic acid gas was overflowed.Reaction mixture was heated to boiling after 30 minutes, with its cool to room temperature, filtered, so that shift out last crystalline deposit thing.The clear filtrate vaporising under vacuum, remaining oil crystallization once more from vinyl acetic monomer.Leach yellow crystals, and dry down at 40 ℃～50 ℃.Obtain the required compound of 22.1 grams thus, productive rate is 85%, and fusing point (mp) is 124～125 ℃.
Example 10
N-amino imino methyl-S-n-propyl group-different sulphur urine hydrobromate
14.9 gram (0.05 mole) N-amino imino methyl-sulphur urine carbonate is suspended in 50 milliliters of dehydrated alcohols, adds 14.8 gram (0.12 mole) n-propyl bromides to this suspension.Under agitation slowly heated mixt is to boiling, and this moment, carbonic acid gas was overflowed.Reaction mixture was heated to boiling after 45 minutes, was cooled to room temperature.Filter this mixture then, shift out final throw out.With clear filtrate vaporising under vacuum, and make the crystallization in vinyl acetic monomer of oily raffinate.Again the white crystals that obtains is filtered, and dry under 40～50 ℃ of temperature.Obtain the required compound of 19.5 grams thus, productive rate 81%, fusing point: 122～124 ℃.
Example 11
N-amino imino methyl-S-allyl group-different sulphur urine hydrobromate
14.9 gram (0.05 mole) N-amino imino methyl-sulphur urine carbonate is joined in 50 milliliters of dehydrated alcohols, and in the suspension that generates, add 14.5 gram (0.12 mole) bromo allyl alkane.Under violent stirring, reaction mixture slowly is heated to boiling.With 30 minutes postcooling of reaction mixture refluxed to room temperature.Filter this mixture then, so that shift out final throw out.The filtrate vaporising under vacuum, the crystallization in vinyl acetic monomer of the residual thing of oily.The crystallisate of filtering-depositing, and dry down at 40～50 ℃.Obtain 19.6 gram required compounds thus, productive rate: 52%, 123～125 ℃ of fusing points.
Example 12
N-amino imino methyl-S-allyl group-different sulphur urine hydrogen chlorate
14.9 gram (0.05 mole) N-amino imino methyl-sulphur urine carbonate is joined in 50 milliliters of dehydrated alcohols, and add 9.18 gram (0.12 mole) chloro allyl alkane to the suspension that generates.Slowly reacting by heating is to boiling under violent stirring, and 1 hour postcooling of reaction mixture refluxed is to room temperature.This mixture is filtered, so that shift out final throw out.The filtrate vaporising under vacuum, the crystallization in vinyl acetic monomer of the residual thing of oily.The crystallization that filtering-depositing goes out, it is dry under 40 ℃～50 ℃, obtain the required compound of 15.7 grams thus, productive rate 81%, fusing point (mp), 125～127 ℃.
Example 13
N-amino imino methyl-S-(2-chloroethyl) different sulphur urine hydrobromate
14.9 gram (0.05 mole) N-amino imino methyl-sulphur urine carbonate is joined in 50 milliliters of dehydrated alcohols, and add 17.2 gram (0.12 mole) 1-bromo-2-monochloroethane to the suspension that generates.Reaction mixture is heated to boiling under violent stirring.90 minutes postcooling of reaction mixture refluxed are to room temperature.Filter this mixture, so that shift out final throw out.Clear filtrate vaporising under vacuum, the crystallization in vinyl acetic monomer of oily raffinate.The white crystals of filtering-depositing, and dry under 40 ℃～50 ℃, obtaining the required compound of 17.2 grams thus, productive rate is 66%, fusing point (mp) is 142～143 ℃
Example 14
N-amino imino methyl-S-(1-chloro-2-hydroxyl-propyl group) different sulphur urine hydrobromate
14.9 gram (0.05 mole) N-amino imino methyl-sulphur urine carbonate is joined in 50 milliliters of dehydrated alcohols, and add 20.8 gram (0.12 mole) 1-bromo-2-hydroxyl-3-chloropropanes to the suspension that generates.Under violent stirring, reaction mixture slowly is heated to boiling.This reaction mixture refluxed was cooled to room temperature after 90 minutes.Then mixture is filtered, so that shift out final throw out.The clear filtrate vaporising under vacuum, the crystallization in vinyl acetic monomer of the residual thing of oily.Filter out sedimentary evaporated milk oil colours crystallisate, it is dry down at 40～50 ℃.Obtain the required compound of 17.8 grams thus, productive rate is 61%, and fusing point is 118～119 ℃.
Example 15
N-amino imino methyl-S-(3-chloropropyl) different sulphur urine hydrobromate
14.9 gram (0.05 mole) N-amino imino methyl-sulphur urine carbonate is joined in 80 milliliters of acetonitriles, and add 18.9 gram (0.12 mole) 1-bromo-3-chloropropanes to the suspension that generates.Slowly this reaction mixture of heating arrives boiling under violent stirring.Reaction mixture refluxed 90 minutes is filtered thermal reaction mixture, shifts out solid matter, and filtrate is cooled to room temperature.The white crystals of filtering-depositing, and dry down at 40～50 ℃.The required compound of 17.3 grams that obtains thus, productive rate is 65%, fusing point is 129～131 ℃.
Example 16
N-amino imino methyl-S-(2-hydroxyethyl)-different sulphur urine hydrogen chlorate
14.9 gram (0.05 mole) N-amino imino methyl-sulphur urine carbonate is joined in 50 milliliters of dehydrated alcohols, and add 9.7 gram (0.12 mole) ethylene chlorhydrins to the suspension that generates.Under violent stirring, reaction mixture slowly is heated to boiling, reaction mixture refluxed was cooled to room temperature after 90 minutes.Filter this mixture, so that shift out final throw out.Clear filtrate vaporising under vacuum, this crystallisate is filtered in the crystallization in vinyl acetic monomer of the residual thing of oily, and dry down at 40 ℃ to 50 ℃.Obtain the required compound of 13.5 grams thus.Productive rate is 68%, and fusing point is 134～136 ℃.
Example 17
N-amino imino methyl-S-glycidyl-different sulphur urine hydrobromate
14.9 gram (0.05 mole) N-amino imino methyl-sulphur urine carbonate is joined in 80 milliliters of acetonitriles, and add 16.5 gram (0.12 mole) epibromohydrins to the suspension that generates.Under violent stirring, reaction mixture slowly is heated to boiling.After the reaction mixture refluxed 2 hours, filter under the situation of heat, clear filtrate is cooled to room temperature.The white crystals of filtering-depositing, and dry down at 40 ℃～50 ℃.Obtain the required compound of 13.5 grams thus.Productive rate is 53%, and fusing point is 138～139 ℃.
Example 18
N-amino imino methyl-S-benzyl-different sulphur urine hydrogen chlorate
14.9 gram (0.05 mole) N-amino imino methyl-sulphur urine carbonate is joined in 50 milliliters of dehydrated alcohols, and add 15.2 gram (0.12 mole) benzyl chlorides to the suspension that generates.Under violent stirring, reaction mixture is heated to boiling.After the reaction mixture refluxed 1 hour, be cooled to room temperature.Filter this mixture, so that shift out final throw out, clear filtrate vaporising under vacuum, the crystallization in vinyl acetic monomer of the residual thing of oily.The white crystal of filtering-depositing, and it is dry down at 40～50 ℃.Obtain the required compound of 19.1 grams thus, productive rate is 78%, and fusing point is 159～161 ℃.
Example 19
If desired, can be by the isothiuronium salts of example 9～18 preparations by the crystallization once more of following method.This process is used N-amino imino methyl-S-allyl group-different sulphur urochloralic acid salt.
The ratio that 10 gram N-amino imino methyl-S-allyl group-different sulphur urochloralic acid salt are joined 60 milliliters of ethanol and methyl alcohol is in 5: 1 mixtures.Filtering heat mixture shifts out a small amount of undissolved crystallisate.The words that need are clarified filtrate with gac.Clear filtrate is cooled to room temperature, and this moment, white crystals was precipitated out.Again this mixture is cooled to 0～5 ℃, and under this temperature, places 1 hour after-filtration.With freezing washing with alcohol crystal, and it is dry down at 40 ℃～50 ℃.Obtain the required compound of 8.1 grams thus, productive rate is 81%.
Example 20
N-amino imino methyl-N '-methyl-S-allyl group-different sulphur urine hydrogen chlorate
The N-amino imino methyl-N '-methyl-sulphur urine carbonate of 16.3 grams (0.05 mole) by example 2 preparations is joined in 50 milliliters of dehydrated alcohols, and add 9.18 gram (0.12 mole) chloro allyl alkane to the suspension that generates.Under violent stirring, reaction mixture is heated to boiling.After the reaction mixture refluxed 1 hour, cool to room temperature filters this mixture, so that shift out final throw out.The clear filtrate of vaporising under vacuum, the white crystals that obtains is filtered in the crystallization in vinyl acetic monomer of the residual thing of oily, and it is dry down at 40～50 ℃.Obtain the required compound of 13.6 grams thus.Productive rate is 61%, and fusing point is 137～139 ℃.
Example 21
The different sulphur urine of N-amino imino methyl-N '-sec.-propyl-S-allyl group hydrogen chlorate
The N-amino imino methyl-N '-sec.-propyl-sulphur urine carbonate of 19.1 grams (0.05 mole) by example 5 preparations is joined in 50 milliliters of dehydrated alcohols, and add 9.18 gram (0.12 mole) chloro allyl alkane to the suspension that generates.Under violent stirring reaction mixture is heated to boiling, 1 hour postcooling of reaction mixture refluxed is to room temperature.Filter this mixture, so that shift out final throw out.Clear filtrate vaporising under vacuum, the crystallization in vinyl acetic monomer of the residual thing of oily.The white crystals of filtering-depositing, and it is dry down at 40～50 ℃.Obtain the required compound of 13.3 grams thus.Productive rate is 56%, and fusing point is 134～135 ℃.
Example 22
N-amino imino methyl-N '-cyclohexyl-S-allyl group-different sulphur urine hydrogen chlorate
The N-amino imino methyl-N '-cyclohexyl sulphur urine carbonate of 23.1 grams (0.05 mole) by example 8 preparations is joined in 50 milliliters of dehydrated alcohols, and in the suspension that generates, add 9.18 gram (0.12 mole) chloro allyl alkane.Under violent stirring, reaction mixture is heated to boiling, reaction mixture refluxed was cooled to room temperature after 1 hour.Filter this mixture, so that shift out final throw out.Clear filtrate vaporising under vacuum, the crystallization in vinyl acetic monomer of the residual thing of oily, the white crystals of filtering-depositing, and it is dry down at 40 ℃～50 ℃.Obtain the required compound of 20.85 grams thus.Productive rate is 85%, and fusing point is 129～130 ℃.
Example 23-31
According to the similar approach of example 12, prepare isothiuronium salts compound 23, the N-amino imino methyl-S-ethyl-isothiourea hydrobromate of following formula I
Fusing point: 123～124 ℃;
24, N-amino imino methyl-S-sec.-propyl-isothiourea hydrobromate,
Fusing point: 120～122 ℃;
25, N-amino imino methyl-S-normal-butyl-isothiourea hydrobromate,
Fusing point: 116～118 ℃;
26, N-amino imino methyl-S-isopentyl-isothiourea hydrobromate,
Fusing point: 111～113 ℃;
27, N-amino imino methyl-S-(2-bromo-ethyl)-the isothiourea hydrobromate
Fusing point: 129～131 ℃;
28, N-amino imino methyl-S-(3-bromo-propyl group)-the isothiourea hydrobromate
Fusing point: 127～129 ℃;
29, N-amino imino methyl-S-(3-hydroxyl-propyl group)-the isothiourea hydrobromate
Fusing point: 132～135 ℃;
30, N-amino imino methyl-S-(3-sulfydryl-propyl group)-the isothiourea hydrobromate
Fusing point: 141～142 ℃;
31, N-amino imino methyl-S-propargyl-isothiourea hydrobromate,
Fusing point: 131～133 ℃.
Example 32-40
According to the similar approach of example 20, the preparation following compounds:
32, N-amino imino methyl-N '-methyl-S-(2-hydroxyethyl)-and the isothiourea hydrobromate, fusing point: 147～148 ℃;
33, N-amino imino methyl-N '-ethyl-S-(2-chloroethyl)-and the isothiourea hydrobromate, fusing point: 143～144 ℃;
34, N-amino imino methyl-N '-ethyl-S-allyl group-isothiourea hydrogen chlorate
Fusing point: 138～139 ℃;
35, N-amino imino methyl-N '-sec.-propyl-S-(3-chloropropyl)-and the isothiourea hydrogen chlorate, 140～142 ℃ of fusing points;
36, N-amino imino methyl-N '-sec.-propyl-S-methylallyl-isothiourea hydrogen chlorate, fusing point: 138～139 ℃;
37, N-amino imino methyl-N '-cyclohexyl-S-n-propyl-isothiourea hydrobromate, fusing point: 133～135 ℃;
38, N-amino imino methyl-N '-cyclohexyl-S-methylallyl-isothiourea hydrogen chlorate, fusing point: 130～132 ℃;
39, N-amino imino methyl-N '-cyclohexyl-S-glycidyl-isothiourea hydrobromate, fusing point: 143～145 ℃;
40, N-amino imino methyl-N '-cyclohexyl-S-benzyl-isothiourea hydrogen chlorate, fusing point: 147～149 ℃.
The fusing point of the compound of formula I and infrared (IR) spectrum are summarised in down in the tabulation VIII.
The table VIII
R
2R
1X mp(℃) the diffuse reflectance infrared spectroscopy peak
H methyl I 124～125 3300,3120,
1685，1570
H n-propyl Br 122～124 3300,3120,
2925，2850，
1685，1570，
730
H allyl group Br or 123～125 3290,3260,
Cl 3160，3105，
1640，1605，
1550，1375，
1090，980，
910，705，
650
H 2-chlorine Br 142～143 3300,3110,
Ethyl 2925,1640,
1920，720
H 1-chloro-Br 118～119 3300,3110,
The 2-hydroxyl-
Propyl group 3000,2850,
1685，1610，
720
H 3-chlorine Br 129～131 3300,3275,
Propyl group 3165,3105,
2900，2825，
1680，695
H 2-hydroxyl-Cl 143～136 3310,3280,
Ethyl 3110,3000,
2990，1675，
1610
H sweet Br 138～139 3300,3275 of shrinking,
Oil base 3110,3000,
1690，1600，
865
H benzyl Cl 159～161 3290,3285,
3115，3005，
1680，1590，
1485，755
H ethyl Br 123～124 3300,3120,
1685，1570
H sec.-propyl Br 120～122 3300,3120
1680，1380，
1365
H normal-butyl Br 116～118 3315,3300,
3210，3180，
2850，1690，
1450
H isopentyl Br 111～113 3305,3300,
3205，3175，
2960，2845，
1695，1470
H 2-bromo-Br 129～131 3300,3205,
Ethyl 2910,1670,
1090，715
H 3-bromo-Br 127～129 3305,3215,
Propyl group 2920,1665
H 3-hydroxyl-Br 132～135 3590,3300
Propyl group 3220,2925,
1680
H 3-sulfydryl-Br 141～142 3320,3305,
Propyl group 3210,3180,
2920，2570，
1690
H propargyl Br 131～133 3310,3300,
3200，2180，
1680
Methacrylic Cl 137～139 3305,3290,
2960，2690，
1640
Methyl 2-hydroxyl-Br 147～148 3585,3300,
Ethyl 3285,1680,
1375，1360
Ethyl 2-chloro-Br 143～144 3305,3285,
Ethyl 2965,1660,
765
Allyl ethyl Cl 138～139 3310,3300,
3210，3180，
1650，990，
905
Sec.-propyl allyl group Cl 134～135 3305,3295,
3200，3170，
1655，985，
895
The sec.-propyl first is for alkene Cl 138～139 3305, and 3295,
Propyl group 3200,3175,
1650，890
Sec.-propyl 3-chloro-Br 140～142 3320,3300,
Propyl group 3195,3160,
1690，775
Cyclohexyl allyl group Cl 129～130 3315,3305,
3200，3170，
2830，1695，
985，900
Cyclohexyl n-propyl Br 133～135 3320,3300,
3210，3175，
2925
The cyclohexyl first is for alkene Cl 130～132 3315, and 3300,
Propyl group 3215,3180
885
Cyclohexyl sweet Br 143～145 3325,3315 of shrinking,
Oil base 3210,3190,
1690，870
Cyclohexyl benzyl Cl 147～149 3300,3275,
3120，3000，
1675，1590，
750
Example 41
The preparation of tablet and dragee.
Tablet and dragee prepare with the tabletting machine that has self-feeder.By doing or wet method, in advance with active ingredient and proper assistant granulation.If it is make wet medicament grain, preferably that it is dry in a vacuum.
The particle of preparation tablet and dragee core is pressed through a suitable metal-free sieve.In order to prepare this particle, preferably adopt the single component prescription of pharmacopeia regulation, or adopt other suitable prescription.Preparation contains the tablet core and the dragee core of 30 milligrams of active ingredients, adds 70 milligrams of vehicle (for example simple grain agent) (granulatum simplex).
Example 42
The preparation capsule
Preferably use automatic filling machine.With proper auxiliary agent (for example simple grain agent) or any other inert additwe granulation, preparation is the particle of size suitably with active ingredient.Sieve then, incapsulate.Active component content in the capsule reaches 30 milligrams.
Example 43
Preparation powder ampoule
During preparation powder ampoule, no longer add auxiliary agent.The content of active constituent will reach 10 and 20 milligrams respectively in the powder ampoule.The solvent ampoule contains 1 or 2 ml distilled water or normal saline solutions.The most handy at least 100 milliliters preserved material dilution, and after dissolving, directly use the thing in the ampoule.
Example 44
N-(amino imino methyl)-S-methylallyl-isothiourea hydrobromate
With 14.9 gram N-(amino imino methyl)-thiocarbamide carbonate is suspended in 50 milliliters of dehydrated alcohols, and adds 16.1 gram bromo first for allyl alkane.With reaction mixture refluxed 30 minutes.After the filtration, under vacuum, steam the sample solvent.Obtain the product of 21 grams, then separate out crystallization during placement as honey.
Example 45
N-(amino imino methyl)-N '-allyl group-S-allyl group-isothiourea hydrobromate
With 17.6 gram N-(amino imino methyl)-N '-allyl group-isothiourea carbonate is suspended in 50 milliliters of dehydrated alcohols, and adds 14.5 gram bromo allyl alkane.Under violent stirring, reaction mixture refluxed 1 hour, and this mixture of after-filtration steams solvent under vacuum.Obtain 23 gram oily viscous products.
Example 46
N-amino imino methyl-S-allyl group-isothiourea hydrogen chlorate
To contain 4.2 the gram Dyhard RU 100s, 20 milliliters with the saturated ethanol of hydrochloric acid think 3.7 the gram allyl sulfhydrates mixtures under violent stirring, slowly be heated to boiling.3 hours postcooling to 0 of reaction mixture refluxed ℃.Filter out sedimentary crystallization, use washing with alcohol again.Obtain the required compound of 7 grams thus, fusing point is 125～127 ℃.
Claims (5)
1, preparation has the method for the salt of formula I,
Wherein: R
1Be can be by hydroxyl, the C that sulfydryl and/or halogen replace arbitrarily
1-6Alkyl, C
2-6Thiazolinyl is by C
1-4Phenyl or glycidyl that alkyl replaces, R
2Expression hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or C
3-6Cycloalkyl; X represents halid negatively charged ion, if but R
2Be hydrogen, R then
1Can not be methyl, ethyl or benzyl, this method comprises:
With the acceptable acid addition salts and the general formula of general formula II compound is R
1-Y (R wherein
1As above-mentioned definition, Y represents halogen) alkylating reagent reaction,
(R wherein
2As above-mentioned definition)
HX (wherein X the is halid negatively charged ion) acid that the compound that obtains thus and general formula are II is reacted, change the salt of formula I compound into.
2, preparation has the method for the salt of formula I,
(R wherein
1Be C
3-6Alkenyl, R
2Be hydrogen, X is halid negatively charged ion), this method comprises that with formula III compound and general formula be R
1-SH(R
1Be C
3-6Alkenyl) thiol reactant, acid (X the is halid negatively charged ion) reaction that the compound that obtains and general formula are HX again changes the salt of accepted way of doing sth I.
3, according to the described method of claim 1, wherein raw materials used is the carbonate of general formula II compound.
4, according to the described method of claim 1, wherein this is reflected under the existence of organic solvent and carries out, and preferably at alcohol, aliphatic ketone carries out under the existence of nitrile and/or ether.
5, according to the described method of claim 2, reactant wherein is to wait mol, or the excessive general formula that uses is R
1The mercaptan of-SH.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU841324A HU196745B (en) | 1984-04-03 | 1984-04-03 | Process for producing n-/amino-imino-methyl/-isothiuronium derivatives with immunostimulant and cytostatic effect |
| HU132485 | 1985-03-19 | ||
| HU1324/84 | 1985-03-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85103160A CN85103160A (en) | 1986-09-17 |
| CN1008093B true CN1008093B (en) | 1990-05-23 |
Family
ID=26317358
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN85103160A Expired CN1008093B (en) | 1984-04-03 | 1985-04-24 | Process for preparation of isothiuronium salts compounds |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPH0825992B2 (en) |
| CN (1) | CN1008093B (en) |
| DE (1) | DE3590133T1 (en) |
| FI (1) | FI80259C (en) |
| GB (1) | GB2167750B (en) |
| IL (1) | IL74743A (en) |
| NZ (1) | NZ211639A (en) |
| PL (1) | PL145636B1 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR788429A (en) * | 1934-12-14 | 1935-10-10 | Ig Farbenindustrie Ag | Production of combinations of guanyl and biguanyl |
| DE2426683A1 (en) * | 1974-06-01 | 1975-12-18 | Boehringer Mannheim Gmbh | BIGUANID AND METHOD FOR MANUFACTURING THEREOF |
-
1985
- 1985-03-27 IL IL74743A patent/IL74743A/en not_active IP Right Cessation
- 1985-03-29 NZ NZ211639A patent/NZ211639A/en unknown
- 1985-04-02 GB GB08529529A patent/GB2167750B/en not_active Expired
- 1985-04-02 DE DE19853590133 patent/DE3590133T1/en not_active Withdrawn
- 1985-04-02 JP JP60501619A patent/JPH0825992B2/en not_active Expired - Lifetime
- 1985-04-03 PL PL1985252744A patent/PL145636B1/en unknown
- 1985-04-24 CN CN85103160A patent/CN1008093B/en not_active Expired
- 1985-12-03 FI FI854790A patent/FI80259C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FI80259B (en) | 1990-01-31 |
| DE3590133T1 (en) | 1986-06-26 |
| FI854790A0 (en) | 1985-12-03 |
| JPS61501849A (en) | 1986-08-28 |
| GB8529529D0 (en) | 1986-01-08 |
| GB2167750A (en) | 1986-06-04 |
| GB2167750B (en) | 1988-04-27 |
| IL74743A (en) | 1992-09-06 |
| JPH0825992B2 (en) | 1996-03-13 |
| IL74743A0 (en) | 1985-06-30 |
| FI854790A (en) | 1985-12-03 |
| NZ211639A (en) | 1989-03-29 |
| PL145636B1 (en) | 1988-10-31 |
| FI80259C (en) | 1990-05-10 |
| CN85103160A (en) | 1986-09-17 |
| PL252744A1 (en) | 1986-08-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1033299C (en) | Method for immured plant from disease | |
| CN1214011C (en) | Meta-azacyclic amino benzoic acid compound and derivatives thereof being integrin antagonists | |
| CN1259950A (en) | Pyrrolo [2,3D] pyrimidines and their use as tyrosine kinase inhibitors | |
| CN1655804A (en) | Method and composition for treating cardiovascular diseases by employing neuroregulation protein | |
| CN1560035A (en) | 5-hydroxylic indole-3-carboxylic ester kind derivantion | |
| CN1157225C (en) | Lectin compositions and uses thereof | |
| CN1031532A (en) | Heterogeneous ring compound | |
| CN1683317A (en) | Ester compound of thymol and/or carvacrol, preparing method and its medicinal active composition | |
| CN1480134A (en) | Amino acid iodine composition and preparation method and application thereof | |
| CN1081564A (en) | The composition pesticide of 3-hydroxy-5-methyl-isoxazole and using method | |
| CN1256347C (en) | Fusion protein of kininogen D5 and tumor necrosis factor related apoptosis-inducing ligand(D5-TRAIL), its preparation and use thereof | |
| CN1166637C (en) | Antibacterial activity, induction, separation and synthesis of N-acyltryptamine derivative as plant protecting chemical | |
| CN1566054A (en) | Resveratrol oligo cattail compounds, its manufacturing process, pharmaceutical combination and uses thereof | |
| CN1272340C (en) | Oleanolic acid couple derivatives and their pharmaceutical use | |
| CN1133611C (en) | Substances capable of inducing appotosis | |
| CN101058573A (en) | 2-hydrazone substituted triazine compound, preparation method thereof, and medicinal composition and use using same as active component | |
| CN1008093B (en) | Process for preparation of isothiuronium salts compounds | |
| CN1372556A (en) | Heterocyclic compounds for inhibiting angiogenesis | |
| CN1177354A (en) | Pyrimido [4, 5 -b] indoles | |
| CN1942430A (en) | 5-aminolevulinic acid phosphate, method for producing the same and use thereof | |
| CN1025617C (en) | Pyrimidine derivatives and pharmaceutically acceptable salt thereof | |
| CN1024277C (en) | Pyrimidine derivatives | |
| CN1251677C (en) | Anti-cancer assistant medicine contg. 20(S)-protopanaxadiol as effective component, and its application | |
| CN1856491A (en) | Imidazopyridine derivatives as inducible NO synthase inhibitors | |
| CN1673228A (en) | Substituted phenoxy acetoxyl aromatic heterocyclic alkyl phosphonate with bactericidal and herbicidal activity and its prepn |
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 | ||
| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Address after: Washington, USA Applicant after: Sai Rios Co. Address before: Hungary Applicant before: Peremartoni Vegyipari Vallalat |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: DIANNASI MARIA LUOBEIKE TO: THYRIOLS CO.,LTD. |