SE460198B - PROCEDURES FOR THE PREPARATION OF 5'-DEOXI-5'-METHYLTIOADENOSINE - Google Patents
PROCEDURES FOR THE PREPARATION OF 5'-DEOXI-5'-METHYLTIOADENOSINEInfo
- Publication number
- SE460198B SE460198B SE8102489A SE8102489A SE460198B SE 460198 B SE460198 B SE 460198B SE 8102489 A SE8102489 A SE 8102489A SE 8102489 A SE8102489 A SE 8102489A SE 460198 B SE460198 B SE 460198B
- Authority
- SE
- Sweden
- Prior art keywords
- mta
- aggregation
- formula
- same
- induced
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 3
- WUUGFSXJNOTRMR-UHFFFAOYSA-N 5alpha-Hydroxy-3abeta,5beta,8-trimethyl-1-(1,5-dimethyl-hexen-(4)-yl)-4abetaH,7abetaH-dicyclopentano[a.d]cyclooctaen-(8) Natural products OC1C(O)C(CSC)OC1N1C2=NC=NC(N)=C2N=C1 WUUGFSXJNOTRMR-UHFFFAOYSA-N 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- WUUGFSXJNOTRMR-WOIOKPISSA-N 5'-deoxy-5'-methylthioadenosine Chemical compound O[C@@H]1[C@@H](O)[C@H](CSC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 WUUGFSXJNOTRMR-WOIOKPISSA-N 0.000 claims 2
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 claims 1
- 229960001570 ademetionine Drugs 0.000 claims 1
- WUUGFSXJNOTRMR-IOSLPCCCSA-N 5'-S-methyl-5'-thioadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CSC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 WUUGFSXJNOTRMR-IOSLPCCCSA-N 0.000 description 42
- 238000012012 milestone trend analyses Methods 0.000 description 42
- 238000012360 testing method Methods 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 14
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 12
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 10
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 10
- 102000008186 Collagen Human genes 0.000 description 10
- 108010035532 Collagen Proteins 0.000 description 10
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 10
- 229920001436 collagen Polymers 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 230000002776 aggregation Effects 0.000 description 7
- 238000004220 aggregation Methods 0.000 description 7
- 230000002744 anti-aggregatory effect Effects 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 229960000905 indomethacin Drugs 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 5
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 229940114079 arachidonic acid Drugs 0.000 description 5
- 235000021342 arachidonic acid Nutrition 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 230000001754 anti-pyretic effect Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
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- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- IYSNPOMTKFZDHZ-KQYNXXCUSA-N 5'-chloro-5'-deoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O IYSNPOMTKFZDHZ-KQYNXXCUSA-N 0.000 description 2
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 241000207199 Citrus Species 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- -1 aliphatic alcohols Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229960000212 aminophenazone Drugs 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 235000020971 citrus fruits Nutrition 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 210000000416 exudates and transudate Anatomy 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 229960004194 lidocaine Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- IOYQOOUTHXXDIC-UHFFFAOYSA-N CSc1cccc(CC(C)N)c1 Chemical compound CSc1cccc(CC(C)N)c1 IOYQOOUTHXXDIC-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 101000862089 Clarkia lewisii Glucose-6-phosphate isomerase, cytosolic 1A Proteins 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000003835 adenosine derivatives Chemical class 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 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
- 239000006227 byproduct Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- QXUAFCKBYYPTPQ-ZWKAXHIPSA-L magnesium (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol octadecanoate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O QXUAFCKBYYPTPQ-ZWKAXHIPSA-L 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000009864 tensile test Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
460 198 2 vilken föreligger i vattenhaltig lösning, underkastas följande behandlingssteg: 1) koncentrering av den vattenhaltiga lösningen genom upphettning under vakuum till 35-40°C 5 2) upphettning av lösningen under åtcrflöde 3) neutralisering av reaktionsblandningen 4) avskiljning av bildat 5'-deoxi-5'metyltio- adenosin genom kylning till 0-5°C. 460 198 2 which is present in aqueous solution, is subjected to the following treatment steps: 1) concentration of the aqueous solution by heating under vacuum to 35-40 ° C 2) heating the solution under reflux 3) neutralizing the reaction mixture 4) separating the formed 5 ' -deoxy-5'methylthio- adenosine by cooling to 0-5 ° C.
Föreningen enligt uppfinningen med formeln (I) 10 kan dessutom omvandlas till syraadditionssalterna: klorid, sulfat, fosfat, formiat, acetat, citrat, tartrat, metansulfonat eller p-toluensulfonat.The compound of the invention of formula (I) may additionally be converted into the acid addition salts: chloride, sulphate, phosphate, formate, acetate, citrate, tartrate, methanesulfonate or p-toluenesulfonate.
För framställning av gruppen av föreningar med formeln: 15 NH2 / |\ \\ 20 CH2-S- R (la) 25 OHH i vilken R är en linjär eller förgrenad alkylgrupp med 30 l-18 kolatomer eller fenylalkylen, där alkylenkedjan har 1-6 kolatomer; R1 är H, en alifatisk acylgrupp med 1-6 kolatomer eller en aromatisk acylgrupp; R2 är H, en alifatisk acylgrupp med l-6 kolatomer 35 eller en aromatísk acylgrupp, eller alternativt bildar grupperna R2 tillsammans en isopropylidenkedja, och n är O eller l, 10 20 25 30 Lu' (_11 460 198 3 har Legraverand-metoden (Legraverand M. Ibanez S., et al. (1977) Eur. J. Med. Chem. 12, 105-108), där adenosin omvandlas till 5'-kloro-5'~deoxiadenosin genom reaktion med tionylklorid i hexametylfosforamid, använts. 5'-kloro-5'-deoxiadenosin omvandlas sedan till erforderliga tioetern genom reaktion med motsvarande merkaptan i en 2n natriumhydroxidlösning vid 80°C.To prepare the group of compounds of the formula: NH 2 / CH 2 -S-R (1a) 25 OHH in which R is a linear or branched alkyl group having 30 to 18 carbon atoms or phenylalkylene, wherein the alkylene chain has 1- 6 carbon atoms; R 1 is H, an aliphatic acyl group having 1-6 carbon atoms or an aromatic acyl group; R 2 is H, an aliphatic acyl group having 1-6 carbon atoms or an aromatic acyl group, or alternatively the groups R 2 together form an isopropylidene chain, and n is 0 or 1. Lu '(the Legraverand method ( Legraverand M. Ibanez S., et al. (1977) Eur. J. Med. Chem. 12, 105-108), where adenosine is converted to 5'-chloro-5'-deoxyadenosine by reaction with thionyl chloride in hexamethylphosphoramide. 5'-Chloro-5'-deoxyadenosine is then converted to the required thioether by reaction with the corresponding mercaptan in a 2N sodium hydroxide solution at 80 ° C.
De erhållna tioetrarna renas genom omkristallísa- tion ur vatten eller ur lägre alifatiska alkoholer.The thioethers obtained are purified by recrystallization from water or from lower aliphatic alcohols.
Föreningarna (Ia) kan sedan saltbildas med den stökiometriska mängden av den erfordrade syran.The compounds (Ia) can then be salted with the stoichiometric amount of the required acid.
Föreningar med den allmänna formeln NH-R1 1” nu) CH -S- R (lb) OR R i vilken R, Rl förutsatt att Rl och R och R2 är samma som ovan definierats, 2 är annat än väte eller en isopropylidenkedja, har framställts genom Satom och Makinometoden (Satom K, Makino K (1951) Nature 167, 238) genom att de motsvarande föreningarna med formeln (la) bringas att reagera med den erfordrade acylklo- riden i vattenfri pyridin. Produkterna omkristalliseras företrädesvis ur en 1:1-blandning av k1oroform/petroleum- Gtêl' . 460 198 4 Föreningar med formeln Hz-S-R (IC) 10 15 \C/ / \ CHB CHB 20 i vilken R och RI är samma som ovan definierats, fram- ställs genom att motsvarande föreningar med formeln NH2 25 u/ p ' \ \ o (u)n CH2-S-R 30 ORZORZ 35 där R2 är H, och R, RI och n har ovan definierad betydel- se, bríngas att reagera med aceton i närvaro av ZnC12, 10 15 20 25 30 460 198 5 återigen enligt Satom och Makino-metoden (till vilken ovan refererats). De erhållna produkterna renas före- trädesvis genom kristallisation ur en 1:1 blandning av kloroform/petroleumeter.Compounds of the general formula NH-R 1 1 "now) CH -S- R (1b) OR R in which R 1, R 1 provided that R 1 and R 2 and R 2 are the same as defined above, 2 prepared by Satom and the Makino method (Satom K, Makino K (1951) Nature 167, 238) by reacting the corresponding compounds of formula (Ia) with the required acyl chloride in anhydrous pyridine. The products are preferably recrystallized from a 1: 1 mixture of chloroform / petroleum. 460 198 4 Compounds of the formula Hz-SR (IC) 10 15 \ C / / \ CHB CHB 20 in which R and R 1 are the same as defined above, are prepared by corresponding compounds of the formula NH o (u) n CH 2 -SR 30 ORZORZ 35 where R 2 is H, and R, R 1 and n have the meaning defined above, are reacted with acetone in the presence of ZnCl 2, again according to Satom and the Makino method (referred to above). The products obtained are preferably purified by crystallization from a 1: 1 mixture of chloroform / petroleum ether.
Föreningar med formeln NH-R1 N/ N li» 0 CH 2-š-R (id) N) och R är samma som ovan definicrats, 1 2 framställs genom oxidation av motsvarande tioetrar, i vilken R, R vilka erhållits genom de ovan angivna metoderna, medelst brom eller väteperoxid i vattenhaltig lösning (Green Stein J.P., Winitz M. (1961)-Chemistry of the amino acids - John Wiley & Sons Inc. 2146). De erhållna produkterna renas genom omkristallisation ur vatten.Compounds of the formula NH-R 1 N / N (CH 2 -S-R (id) N) and R are the same as defined above, are prepared by oxidation of the corresponding thioethers, in which R, R methods, by means of bromine or hydrogen peroxide in aqueous solution (Green Stein JP, Winitz M. (1961) -Chemistry of the amino acids - John Wiley & Sons Inc. 2146). The products obtained are purified by recrystallization from water.
Den enligt uppfinningen framställda föreningen 5'-deoxi-5'-metyltioadenosin (MTA) med formeln 460 198 10 15 20 25 30 35 (I) OH H är en fysiologisk förening, som redan förekommer i levande organismer.The compound 5 '-deoxy-5'-methylthioadenosine (MTA) of the formula (I) OH H is a physiological compound which already exists in living organisms.
Man har nu funnit ett sätt att framställa denna produkt, vilket är särskilt enkelt och ekonomiskt ur industriell synvinkel. Det nya förfarandet består väsentligen av att hydrolys av S-adcnosylmetionin (SAME) utföres under strängt reglerade kritiska be- tingelser, vilka leder till praktiskt taget total hydrolys och fullständig kristallisation av MTA. 10 15 20 25 30 35 460 198 NH2 // t” \\ š §H2 H20 ___---.___.í__) cflz I cflz CH2 CH coon CHB on H ,/ t” cflz-s-CH3 til» + + Ho-CHZ-cnz-cH~CooH + H on H Det reglerade hydrolysförfarandet kan tillämpas NH2 på SAME som framställts pà vilket som helst sätt.A way has now been found to produce this product, which is particularly simple and economical from an industrial point of view. The new process essentially consists of hydrolysis of S-adnosylmethionine (SAME) being carried out under strictly controlled critical conditions, which lead to practically total hydrolysis and complete crystallization of MTA. 10 15 20 25 30 35 460 198 NH2 // t ”\\ š §H2 H20 ___ --- .___. Í__) c fl z I c fl z CH2 CH coon CHB on H, / t” c fl z-s-CH3 til »+ + Ho-CHZ-cnz-cH ~ CooH + H on H The controlled hydrolysis process can be applied NH2 to SAME prepared by any means.
Förfarandet för framställning av SAME-lösningen är även en pâvcrkande faktor vid utförandet av det nya förfarandet på ett ekonomiskt lämpligt sätt.The process for preparing the SAME solution is also a influencing factor in carrying out the new process in an economically appropriate manner.
Följande arbetssteg ger den mest ekonomiska ut- föringsformen av förfarandet: 460 198 10 15 20 25 30 35 8 a) Normal brödjäst berikas med SAME genom behand- ling med metionin i enlighet med Schlenk-metoden (Schlenk F. (1965) Enzymologie 29, 283). b) Jästcellerna suspenderade i vatten underkas- tas lysis genom behandling med etyl- eller metylacetat vid omgivningstemperatur (DT-OS P23 3640l.4).The following work steps provide the most economical embodiment of the process: 460 198 10 15 20 25 30 35 8 a) Normal bread yeast is enriched with SAME by treatment with methionine according to the Schlenk method (Schlenk F. (1965) Enzymologie 29, 283). b) The yeast cells suspended in water are subjected to lysis by treatment with ethyl or methyl acetate at ambient temperature (DT-OS P23 3640l.4).
Genom reglering av pH-värdet till mellan 4 och 6 samt filtrering erhålles en vattenhaltig lösning, vilken innehåller praktiskt taget all SAME, som fanns i den ursprungliga jästen. c) Lösningen koncentreras under vakuum vid 35-40°C till ca 1/10 av dess begynnelsevolym. d) Koncentratet kokas under áterflöde i ca 30 min och pH-värdet justeras till 7 med soda. e) Lösningen får stå vid 0-5°C och utfällda MTA uppsamlas praktiskt taget fullständigt och vid god renhet.By adjusting the pH to between 4 and 6 and filtering, an aqueous solution is obtained, which contains practically all SAME, which was present in the original yeast. c) The solution is concentrated in vacuo at 35-40 ° C to about 1/10 of its initial volume. d) The concentrate is boiled under reflux for about 30 minutes and the pH is adjusted to 7 with soda. e) The solution is allowed to stand at 0-5 ° C and precipitated MTAs are collected practically completely and in good purity.
Stegen c, d och e, vilka såsom angivits är kritiskt nödvändiga för erhållande av fullständig, selektiv hydrolys av SAME till MTA utan bildning av biproduk- ter, är nya.Steps c, d and e, which as indicated are critically necessary for obtaining complete, selective hydrolysis of SAME to MTA without the formation of by-products, are new.
Framställningen av produkten enligt föreliggande uppfinning beskrives nedan.The preparation of the product of the present invention is described below.
EXEMPEL Erëæëzëllninsuëyjkéeeëtâlæstyltieëêeaeëirilßlïêl ll liter etylacetat och ll liter vatten vid omgiv- ningstemperatur, sattes till 90 kg brödjäst, som hade berikats med SAME genom tillsättning av metionin tills SAME-halten var 6,88 g/kg.EXAMPLES 1 liter of ethyl acetate and 11 liters of water at ambient temperature were added to 90 kg of bread yeast, which had been enriched with SAME by adding methionine until the SAME content was 6.88 g / kg.
Efter omsorgsfull omröring i 30 min justerades pH-värdet till 4,5 med utspädd HZSO4. Blandningen filtrcrades och återstoden tvättades med vatten för att go 140 liter av lösning med en SAME-halt av 4,40 g/litcr, vilket motsvarar 99,5 % av SAME som fanns i begynnclscmaterialet.After careful stirring for 30 minutes, the pH was adjusted to 4.5 with dilute H 2 SO 4. The mixture was filtered and the residue was washed with water to give 140 liters of solution with a SAME content of 4.40 g / liter, which corresponds to 99.5% of the SAME present in the starting material.
Det sålunda erhållna lysatet koncentrerades under vakuum (30 mm Hg; 35-40°C) till en volym av ca 14 \\v 10 15 20 25 MTA MTA 460 198 9 liter. Den koncentrerade lösningen kokades under åter- flöde vid normalt tryck i 30 min. Den kyldes till 20°C, pH-värdet justerades till 7 med 40 % soda och den lämnades över natten i en kylrumscell (+3°C).The lysate thus obtained was concentrated in vacuo (30 mm Hg; 35-40 ° C) to a volume of about 14 μl of MTA MTA 460 198 9 liters. The concentrated solution was refluxed at normal pressure for 30 minutes. It was cooled to 20 ° C, the pH was adjusted to 7 with 40% soda and it was left overnight in a cold room cell (+ 3 ° C).
En vit fällning bildades, vilken filtrerades, löstes i 10 liter kokande destillerat vatten och kristal- liserades genom kylning av denna lösning. _ 410 g av kristallint MTA av hög renhetsgrad erhölls, vilket motsvarar ett utbyte av 90 % med hänsyn till SAME som underkastades hydrolys.A white precipitate formed which was filtered, dissolved in 10 liters of boiling distilled water and crystallized by cooling this solution. 410 g of high purity crystalline MTA were obtained, which corresponds to a yield of 90% with respect to SAME which was subjected to hydrolysis.
Den erhållna produktens karaktäristika sammanfal- ler med dem för rent MTA som erhållits på annat sätt.The characteristics of the product obtained coincide with those of pure MTA obtained in another way.
Såsom inledningsvis angavs har man funnit att föreningen med formeln I besitter stark antiinflamma- torisk aktivitet, àtföljd av analgetisk och antipyre- tisk verkan.As initially stated, it has been found that the compound of formula I possesses strong anti-inflammatory activity, as a result of analgesic and antipyretic action.
Den antiinflammatoriska aktiviteten visades inled- ningsvis för föreningen enligt uppfinningen ooh indome- tacin genom test av experimentellt ödem förorsakat av karragen i råttor, genom bestämning av procent skydd enligt Winter-metoden (J. Pharm. Exper. Therap. 141, 369 1963)- De erhållna värdena visas i Tabell 1. ggßßrr 1 % Skydd, be- räknat på ödemutveck- ling administrerad dos, mg/kg 37 50 (oralt) 23 50 (intramusku- lärt) lndometacin 9 50 (oralt) 460 198 10 15 20 25 30 35 10 Såsom framgår ur Tabell l är ED50 för MTA 37 mg/kg, vid oral administrering.The anti-inflammatory activity was initially demonstrated for the compound of the invention and indomethacin by testing experimental edema caused by carrageenan in rats, by determining percent protection according to the Winter method (J. Pharm. Exper. Therap. 141, 369 1963). The values obtained are shown in Table 1. ggßßrr 1% Protection, calculated on edema development administered dose, mg / kg 37 50 (oral) 23 50 (intramuscular) indomethacin 9 50 (oral) 460 198 10 15 20 25 As shown in Table 1, the ED50 for MTA is 37 mg / kg, when administered orally.
Vid samma test var ED50 för indometacin 9 mg/kg.In the same test, the ED50 for indomethacin was 9 mg / kg.
Vid dessa doser förekommer allvarliga gastriska lesioner, då däremot vid EDSO-dosernaMTAinte ger upphov till några sekundära effekter på gastro~intestinalsystemet. Det bör även noteras att LD för indometacin i råttor är 12 mg/kg (Martelli A. i Aspetti di farmacologia dell'- infiammazione, sid 73, publiserad av Tamburini-Milan 1973), då däremot LD50 för MTA i råttor är > 200 mg/kg vid oral administrering.At these doses, severe gastric lesions occur, whereas at the EDSO doses, MTA does not give rise to any secondary effects on the gastrointestinal tract. It should also be noted that the LD for indomethacin in rats is 12 mg / kg (Martelli A. in Aspetti di Pharmacologia dell'-infiammazione, page 73, published by Tamburini-Milan 1973), whereas the LD50 for MTA in rats is> 200 mg / kg when administered orally.
Följande terapeutiska index erhölls sålunda: Indometacin TI 1,3 MTA TI = > 54,05 Föreningen, vilken framställts med hjälp av för- farandet enligt uppfinningen underkastades även en serie farmakologiska test i avsikt att bekräfta dess antiinflammatoriska aktivitet och Visa dess analgetiska samt antipyretiska aktivitet.The following therapeutic indices were thus obtained: Indomethacin TI 1.3 MTA TI => 54.05 The compound prepared by the method of the invention was also subjected to a series of pharmacological tests in order to confirm its anti-inflammatory activity and show its analgesic and antipyretic activity. .
De erhållna resultaten med MTA qes nedan.The results obtained with MTA are given below.
Ur industriell framställningssynpunkt är förfarandet för framställning av MTA från SAMB, såsom upptäckts, det absolut enklaste och mest ekonomiska, och gör det möjligt att marknadsföra det till ett synnerligen lågt pris.From an industrial manufacturing point of view, the process for producing MTA from SAMB, as discovered, is by far the simplest and most economical, and makes it possible to market it at an extremely low price.
A - Antiinflammatorisk aktivetet.A - The anti-inflammatory activity.
Produkterna testades genom pleurit, som inducerats i råtta medelst karragen i enlighet med Velo-metoden (Velo G.P., DUNN C.J. et al. (1973) J. Path. lll, 149).The products were tested by pleurisy induced in rat by the carrageenan according to the Velo method (Velo G.P., DUNN C.J. et al. (1973) J. Path. Lll, 149).
MTA vid en dos av 75 mg/kg gav genom oral administrering ett skydd av 42,4 %, beräknat på volymen av exudatet, och 48,8 %, beräknat på totala antalet celler som fanns i exudatet. .MTA at a dose of 75 mg / kg gave by oral administration a protection of 42.4%, calculated on the volume of the exudate, and 48.8%, calculated on the total number of cells present in the exudate. .
Ett jämförbart skydd erhölls med l0 mg/kg indometa- cin, dvs vid en dos som var mycket närmare LD50.A comparable protection was obtained with 10 mg / kg indomethacin, ie at a dose that was much closer to LD50.
W 10 15 20 25 30 35 460 198 11 B - Antiinflammatorisk aktivitet Vid granulomtestet hos råtta genom bomullspelletar (Winter C.A., Riseley E.A. et al (1963) J. Pharm. Exper.W 10 15 20 25 30 35 460 198 11 B - Anti-inflammatory activity In the granuloma test in rats through cotton pellets (Winter C.A., Riseley E.A. et al (1963) J. Pharm. Exper.
Ther. 141, 369), som är signifikant för kronisk inflam- mation, gav MTA ett skydd av 30 % vid en oral dos av 9 mg/kg, med ett terapeutiskt index av 222.Ther. 141, 369), which is significant for chronic inflammation, gave MTA 30% protection at an oral dose of 9 mg / kg, with a therapeutic index of 222.
C - Den analgetiska aktiviteten hos produkterna bestäm- des genom två test, vilka ansågs vara mycket signifi- kanta.C - The analgesic activity of the products was determined by two tests, which were considered to be very significant.
~ Vid test av mus på het platta enligt Roberts (Roberts E. Simonsen D.G. (1966) Biochem. Pharmac. 15, 1875) gav MTA ett skydd av 50 % vid en oral dos av 37 mg/kg. Ett ungefär ekvivalent skydd av 58 % erhölls med l00 mg/kg amidopyrin vid oral administrering.~ When testing mice on Roberts' hot plate (Roberts E. Simonsen D.G. (1966) Biochem. Pharmac. 15, 1875), MTA provided 50% protection at an oral dose of 37 mg / kg. An approximately equivalent protection of 58% was obtained with 100 mg / kg amidopyrine when administered orally.
- Vid sträckningstestet med fenylkinon (Siegmund E., Cadmus R., GO-LU (1957) Proc. Soc. Exp. Bio. Med. 95, 729), gav MTA ett skydd av 51 % vid en oral dos av 37 mg/kg.- In the tensile test with phenylquinone (Siegmund E., Cadmus R., GO-LU (1957) Proc. Soc. Exp. Bio. Med. 95, 729), MTA gave a protection of 51% at an oral dose of 37 mg / kg.
Vid samma test har MTA-sulfoxid en EDSO av 10 mg/kg vid intramuskulär administrering.In the same test, MTA sulfoxide has an EDSO of 10 mg / kg when administered intramuscularly.
D - Antipyretisk aktivitet Denna mättes för dennya produkten medelst feber, som inducerats i råtta med öljäst (Winter C.V. et al (1961) J. Pharmacol. Exp. Thet. 133, ll7).D - Antipyretic activity This was measured for this new product by fever induced in rat yeast (Winter C.V. et al (1961) J. Pharmacol. Exp. Thet. 133, 17).
Den antipyretiska effekten som värderades l h efter oral administrering av MTA vid en dos av 300 mg/kg, gav en temperaturminskning av 4,59 % med hänsyn till kontrollerna, vilka endast behandlats med jäst. Denna procentsats motsvarande en temperatursänkning från 3a,s°c till 37,4°c.The antipyretic effect, which was evaluated 1 hour after oral administration of MTA at a dose of 300 mg / kg, resulted in a temperature reduction of 4.59% with respect to the controls treated only with yeast. This percentage corresponds to a temperature decrease from 3a, s ° c to 37.4 ° c.
Jämförelsevis gav amidopyrin, som administrerades oralt vid en dos av 200 mg/kg, en temperaturminskning av 4,69 %, och intramuskulär administrering av MTA vid en dos av 80 mg/kg gav en temperaturminskning av 2,35 %.In comparison, amidopyrine administered orally at a dose of 200 mg / kg gave a temperature decrease of 4.69%, and intramuscular administration of MTA at a dose of 80 mg / kg gave a temperature decrease of 2.35%.
E - Aktivitet av antiaggregation av blodplättar.E - Platelet anti-aggregation activity.
Föreningen enligt uppfinningen värderades även med hänsyn till deras eventuella kapacitet avseende antiaggregation av blodplättar. 460 198 10 15 20 25 30 35 12 Det är känt att blodplättsaggregation är ett kom- plextfenomen, som kan uppdelas i ett primärt stadium beroende på den direkta verkan av en stimulus (exempel- vis adenosindifosfat, dvs ADP, eller epinefrin) och ett sekundärt stadium beroende på aggregationen, som inducerats av blodplättarnas frigöring av ADP. I detta hänseende, när blodplättarna kommer i kontakt med subendotelt kollagen, initierar kollagenet en hel serie reaktioner, vilka leder till blodplättarnas frigöring av ADP. Det är denna ADP som förorsakar den andra vågen av blodplättsaggregation. Följande test utfördes för att utvärdera de nya föreningarnas anti- aggregationseffekt: 1) "in vitro" test på blodplättsaggregation, inducerat av ADP samt kollagen, i närvaro av dennya produkten; 2) "in vitro“ test på blodplättsaggregation, inducerat av arakidonsyra (AA); 3) "in vivo" test pá blodplättsaggregation, inducerat av ADP och kollagen i personer som behandlats med -den nya produkten. v I detta fall erhölls återigen de mest signifikanta resultalten med MTA, varför de med användning av denna produkt erhållna resultaten ges som indikation på hela klassens beteende. l) "in vitro“ test Blod tappades utan stas,ochett antikoagulationsmedel (3,8 % natriumcitrat) tillsattes för att ge ett blodz- citrat-förhållande av 9:1. Plasma rikt på blodplättar och plasma fattigt på blodplättar erhölls genom centri- fugering vid omgivningstemperatur. Blodplättsaggrega- tion uppskattades med användning av metoden enligt Born & Cross (G.V.R. Born och M.J. Coss, J. Physiol., Lond. l68, 178, 1963) på plasmafraktionen som var rik på blodplättar- Aggregeríngsmedlen användes i följande koncen- trationer: adP (Sigma) 1 UM; kollagcn (Horn) S pg/ml; arakidonsyra 4x10_4M. i ß MJ' 10 15 20 25 30 35 460 198 13 Adenosin vid en koncentration av lxl0_5M användes som referenssubstans för antiaggregationsaktivitet.The compound of the invention was also evaluated in view of their possible capacity for platelet anti-aggregation. 460 198 10 15 20 25 30 35 12 It is known that platelet aggregation is a complex phenomenon, which can be divided into a primary stage depending on the direct action of a stimulus (for example adenosine diphosphate, ie ADP, or epinephrine) and a secondary stage due to the aggregation induced by platelet release of ADP. In this regard, when the platelets come in contact with subendothelial collagen, the collagen initiates a whole series of reactions, which lead to the platelets' release of ADP. It is this ADP that causes the second wave of platelet aggregation. The following tests were performed to evaluate the anti-aggregation effect of the new compounds: 1) "in vitro" test for platelet aggregation, induced by ADP and collagen, in the presence of this new product; 2) "in vitro" test for platelet aggregation, induced by arachidonic acid (AA); 3) "in vivo" test for platelet aggregation, induced by ADP and collagen in persons treated with -the new product. significant results with MTA, therefore the results obtained using this product are given as an indication of the behavior of the whole class. l) "in vitro" test Blood was drawn without stasis, and an anticoagulant (3.8% sodium citrate) was added to give a blood citrate ratio of 9: 1. Platelet-rich plasma and platelet-poor plasma were obtained by centrifugation at ambient temperature. Platelet aggregation was estimated using the Born & Cross method (GVR Born and MJ Coss, J. Physiol., Lond. L68, 178, 1963) on the platelet-rich plasma fraction. The aggregating agents were used in the following concentrations: adP ( Sigma) 1 UM; collagen (Horn) S pg / ml; arachidonic acid 4x10_4M. Adenosine at a concentration of 1x10 -5 M was used as a reference substance for anti-aggregation activity.
MTA minskar starkt primär blodplättsaggregation beroende pà ADP och inhiberar som en följd härav den andra aggregationsvàgen.MTA greatly reduces primary platelet aggregation depending on ADP and consequently inhibits the second pathway of aggregation.
Samma test utförda med kollagen gav negativa resultat. Dvs MTA uppvisade ingen inhiberande verkan gentemot blodplättsaggregation som inducerats av kol- lagen, vilket var värt att notera. 2) Effekterna av olika MTA-koncentrationer pà blodplättsaggregation som inducerats av AA vid en koncentration av 4xl0_4M testades. Den blodplättsag- gregationsinhíberande effekten av MTA är proportionell mot dess koncentration. MTA:s kapacitet att öka prosta- cyklinets (PGI2) inhiberande effekt vid aggregation inducerat av AA undersöktes även. När föreningarna användes i blandning uppstår en stark ökning av anti- aggregationsverkan vid koncentrationer som i sig själva är overksamma. 3) "in vivo" test.The same test performed with collagen gave negative results. That is, MTA did not show an inhibitory effect against platelet aggregation induced by the collagen, which was worth noting. 2) The effects of different MTA concentrations on platelet aggregation induced by AA at a concentration of 4x10 -4 M were tested. The platelet aggregation inhibitory effect of MTA is proportional to its concentration. The ability of MTA to increase the inhibitory effect of prostacyclin (PGI2) in AA-induced aggregation was also examined. When the compounds are used in admixture, a strong increase in the anti-aggregation effect occurs at concentrations which are in themselves ineffective. 3) "in vivo" test.
Tre till synes friska försökspersoner 35, 42 resp 48 år gamla, vilka inte intagit något läkemedel under minst 15 dygn, underkastades aggregatíonstest före och efter intagning av de nya produkterna vid en dos av 100 mg var 8 h i 3 dygn, varefter dessa test utvärderades.Three apparently healthy subjects aged 35, 42 and 48 years, respectively, who had not taken any drug for at least 15 days, were subjected to aggregation tests before and after taking the new products at a dose of 100 mg every 8 hours for 3 days, after which these tests were evaluated.
Blodprovet för bestämning av blodplättsaggregation togs 2 h före intagning av den sista dosen av produkten som testades.The platelet aggregation blood sample was taken 2 hours before taking the last dose of the product tested.
MTA inhiberar starkt blodplättsaggregation som inducerats av ADP (1 uM) "in vivo".MTA strongly inhibits platelet aggregation induced by ADP (1 μM) "in vivo".
Samma test upprepades med tillsättníng av 5 ng/ml kollagen till blodet visade att MTA inte är verksamt vid inhibering av blodplättsaggregation som inducerats av kollagen, utan förlänger endast fenomenets latens- tid. 460 198 10 15 20 25 30 w u1 14 Det faktum att MTA (och1påettmer eller mindre jäm- förbart sätt de andra produkterna i samma klass) starkt inhiberar blodplättsaggregation som inducerats av ADP, då däremot det praktiskt taget saknar effekt på aggre- gation som inducerats av kollagen, indikerar att MTA inhiberar den första aggregationsvågen, då den däremot har en negligêrbar direkt verkan på den andra aggrega- tionsvågen.The same test was repeated with the addition of 5 ng / ml collagen to the blood showed that MTA is not effective in inhibiting platelet aggregation induced by collagen, but only prolongs the latency of the phenomenon. 460 198 10 15 20 25 30 w u1 14 The fact that MTA (and more or less comparably the other products in the same class) strongly inhibits platelet aggregation induced by ADP, as it has virtually no effect on aggregation induced of collagen, indicates that MTA inhibits the first wave of aggregation, as it, on the other hand, has a negligible direct effect on the second wave of aggregation.
Dess användning i association med andra kända anti- aggregationsläkemedel, vilka i allmänhet är aktiva gentemot den andra vågen och endast i ringa grad verk- samma gentemot den första vågen, är därför särskilt intressant.Its use in association with other known anti-aggregation drugs, which are generally active against the second wave and have little effect against the first wave, is therefore of particular interest.
Den visade aktiviteten föreslår att användningen av MTA icke endast som ett blodplättsantiaggregations- läkemedel, utan även som ett antitrombotiskt och anti- aterosklerotiskt läkemedel, ty det förändrade förhål- landet mellan blodplättar och kärlväggar spelar även en primär roll vid aterosklerotisk sjukdom förutom att det är en bas för trombogenesmekanismerna.The activity shown suggests that the use of MTA not only as a platelet anti-aggregation drug, but also as an antithrombotic and anti-atherosclerotic drug, because the altered relationship between platelets and vessel walls also plays a primary role in atherosclerotic disease in addition to being a basis for the thrombogenesis mechanisms.
F - Sömninducerande aktivitet Morris-testet användes (Morris R.W. (1966) Arch. int.F - Sleep-inducing activity The Morris test was used (Morris R.W. (1966) Arch. Int.
Pharmacodyn 161, nr 2, 380) Vid detta test ökade MTA med 87 % varaktigheten av sömn, som induceratsmedpentobarbital i en mus, vid en intramuskulär dos av 20 mg/kg.Pharmacodyn 161, No. 2, 380) In this test, MTA increased by 87% the duration of sleep, induced by pentobarbital in a mouse, at an intramuscular dose of 20 mg / kg.
G - Akut toxicitet Föreningarna enligt föreliggande uppfinning är praktiskt taget fria frånakuttoxicitet när de admini- streras oralt. De är praktiskt taget fria från toxicitet vid de terapeutiska doserna för alla administrerings- sätt.G - Acute toxicity The compounds of the present invention are practically free of acute toxicity when administered orally. They are practically free from toxicity at the therapeutic doses for all modes of administration.
Följande värden erhölls för MTA: > 2000 mg/kg 360 m9/k9 MTA - LDSO 1 mus oralt intravenöst 10 15 20 30 460 198 Adenosinderivaten med formeln (I) kan administreras utspädda med lämpliga farmakologiskt acceptabla tillsats- medel, i varje terapeutiskt användbar form, såsom oralt, parenteralt eller på venöst eller rektalt sätt. De kan även användas i produkter för utvändigt bruk genom topisk applikation.The following values were obtained for MTA:> 2000 mg / kg 360 m9 / k9 MTA - LDSO 1 mouse orally intravenously The adenosine derivatives of formula (I) may be administered diluted with appropriate pharmacologically acceptable additives, in any therapeutically useful form. , such as orally, parenterally or by venous or rectal means. They can also be used in products for external use through topical application.
Vissa exempel på typiska farmaceutiska kompositioner med MTA ges nedan i belysande syfte: - 100 mg kagslar MTA Mannitol Magnesiumstearat - 50 mg kagslar MTA Mannitol Magnesiumstearat - 100 mg tabletter MTA Stärkelse Magnesiumstearat Laktos - 50 mg tabletter MTA Stärkelse Magnesiumstearat Laktos 100,2 mg 195,0 mg 5,0 mg 300,2 mg 50,1 mg 100,0 mg 3,0 mg 153,1 mg 100,2 mg 100,0 mg 15,0 mg 85,0 mg 300,2 mg 50,1 mg 120,0 mg 15,0 mg 115,0 mg 300,1 mg 460 198 lO 15 20 25 30 35 16 - 100 mg suppositoria MTA 100,2 mg Suppositoriummassa l700,0 mg l800,2 mg - 50 mg suppositoria MTA ' 50,1 mg Suppositoriummassa l450,0 mg l500,l mg - 50 mg injektionsflaska MTA _ HCl (56,l5 mg huvud- sakligen ekvivalent) 50 mg Lidokain . HCl 25 mg Vatten upp till 3 ml - 25 mg injektionsflaska MTA . HCl (28,07 mg huvud- sakligen ekvivalent) 25 mg Lidokain . HCl 20 mg Vatten upp till 2 ml - l00 mg oral dos MTA . HCl (ll2,3 mg huvud- sakligen ekvivalent) 100 mg Citrussmaktillsats 0,025 mg Socker l g Antifermenteringsmedel 50 mg Vatten upp till 5 ml - 50 mg oral dos MTA . HCl (56,l5 mg huvud- sakligen ekvivalent) 50 mg Citrussmaktillsats 0,015 mg Socker 0,5 g Antifermenteringsmedel 30 mg Vatten upp till 5 ml hf 460 198 17 - 100 g salva MTA 5 g Bas för vattenlöslig salva, upp till 100 g Antioxidationsmedel 0 , l g.Some examples of typical pharmaceutical compositions with MTA are given below for illustrative purposes: - 100 mg capsules MTA Mannitol Magnesium Stearate - 50 mg capsules MTA Mannitol Magnesium Stearate - 100 mg tablets MTA Starch Magnesium Stearate Lactose - 50 mg tablets MTA Starch Magnesium Stearate 195 Lactose 100 Lactose 100 Lactose 0 mg 5.0 mg 300.2 mg 50.1 mg 100.0 mg 3.0 mg 153.1 mg 100.2 mg 100.0 mg 15.0 mg 85.0 mg 300.2 mg 50.1 mg 120.0 mg 15.0 mg 115.0 mg 300.1 mg 460 198 10 15 20 25 30 35 16 - 100 mg suppositories MTA 100.2 mg Suppository mass l700.0 mg l800.2 mg - 50 mg suppositories MTA '50 , 1 mg Suppository mass l450.0 mg l500, 1 mg - 50 mg vial MTA _ HCl (56, 1.5 mg mainly equivalent) 50 mg Lidocaine. HCl 25 mg Water up to 3 ml - 25 mg vial MTA. HCl (28.07 mg mainly equivalent) 25 mg Lidocaine. HCl 20 mg Water up to 2 ml - 100 mg oral dose MTA. HCl (ll2.3 mg mainly equivalent) 100 mg Citrus flavor 0.025 mg Sugar 1 g Antifermenting agent 50 mg Water up to 5 ml - 50 mg oral dose MTA. HCl (56, 15 mg mainly equivalent) 50 mg Citrus flavor 0.015 mg Sugar 0.5 g Antifermenting agent 30 mg Water up to 5 ml hf 460 198 17 - 100 g ointment MTA 5 g Base for water-soluble ointment, up to 100 g Antioxidant 0.1 g.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT21550/80A IT1193529B (en) | 1980-04-22 | 1980-04-22 | ADENOSINIC DERIVATIVES FOR ANTI-INFLAMMATORY AND ANALGESIC ACTIVITIES AND THERAPEUTIC COMPOSITIONS THAT CONTAIN THEM AS AN ACTIVE PRINCIPLE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SE8102489L SE8102489L (en) | 1981-10-23 |
| SE460198B true SE460198B (en) | 1989-09-18 |
Family
ID=11183457
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE8102489A SE460198B (en) | 1980-04-22 | 1981-04-21 | PROCEDURES FOR THE PREPARATION OF 5'-DEOXI-5'-METHYLTIOADENOSINE |
| SE8700914A SE464635B (en) | 1980-04-22 | 1987-03-04 | USE OF AN ADENOSIN DERIVATIVE FOR THE PREPARATION OF A MEDICINE FOR TREATMENT OF INFLAMMATION, PAIN AND FEBRUARY |
| SE8700913A SE466238B (en) | 1980-04-22 | 1987-03-04 | THERAPEUTIC COMPOSITION CONTAINING ADENOSIN DERIVATIVES |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE8700914A SE464635B (en) | 1980-04-22 | 1987-03-04 | USE OF AN ADENOSIN DERIVATIVE FOR THE PREPARATION OF A MEDICINE FOR TREATMENT OF INFLAMMATION, PAIN AND FEBRUARY |
| SE8700913A SE466238B (en) | 1980-04-22 | 1987-03-04 | THERAPEUTIC COMPOSITION CONTAINING ADENOSIN DERIVATIVES |
Country Status (17)
| Country | Link |
|---|---|
| JP (2) | JPS56166117A (en) |
| AR (1) | AR231144A1 (en) |
| BE (1) | BE888472A (en) |
| CA (1) | CA1198105A (en) |
| CH (2) | CH645544A5 (en) |
| DE (1) | DE3116067A1 (en) |
| DK (1) | DK159453C (en) |
| ES (2) | ES501539A0 (en) |
| FI (1) | FI70227C (en) |
| FR (1) | FR2491761A1 (en) |
| GB (3) | GB2074446B (en) |
| IT (1) | IT1193529B (en) |
| LU (1) | LU83307A1 (en) |
| MX (1) | MX9203630A (en) |
| NL (1) | NL192111C (en) |
| NO (1) | NO150515C (en) |
| SE (3) | SE460198B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1177373B (en) * | 1984-12-06 | 1987-08-26 | Bioresearch Spa | SALTS OF 5'-METHYLLIUM-5'-DEOXYDENOSINE WITH LONG ALCHYLIC CHAIN SULPHONIC ACIDS |
| IT1227049B (en) * | 1988-07-29 | 1991-03-14 | Bioresearch Spa | USE OF ADENOSINIC DERIVATIVES FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS HAVING IMMUNOSTIMULATING ACTIVITIES. |
| JPH0497287A (en) * | 1990-08-10 | 1992-03-30 | Nec Ic Microcomput Syst Ltd | Picture display integrated circuit |
| ES2259552B1 (en) * | 2005-03-17 | 2007-06-16 | Proyecto De Biomedicina Cima, S.L. | EMPLOYMENT OF 5'-METHYLTIOENENINE (MTA) IN THE PREVENTION AND / OR TREATMENT OF AUTOIMMUNE DISEASES AND / OR REPLACEMENT OF TRANSPLANTS. |
| HRP20090646T1 (en) | 2005-03-17 | 2010-01-31 | Proyecto De Biomedicina Cima | Use of 5'-methylthioadenosine (mta) in the prevention and/or treatment of autoimmune diseases and/or transplant rejection |
| DE102010027595A1 (en) * | 2010-07-23 | 2012-01-26 | Helmut Vorbrüggen | Clinical application of adenosine derivative, preferably (dihydroxyphenyl)ethyl-amino-purin-9-yl-(hydroxymethyl)oxolane-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks |
| DE102011005232A1 (en) * | 2011-03-08 | 2012-09-13 | AristoCon GmbH & Co. KG | Adenosine and its derivatives for use in pain therapy |
| CN105102609B (en) * | 2013-04-05 | 2018-07-20 | 狮王株式会社 | Yeast culture and internal composition |
| JP6214628B2 (en) * | 2013-04-05 | 2017-10-18 | ライオン株式会社 | Oral composition |
| WO2014163152A1 (en) * | 2013-04-05 | 2014-10-09 | ライオン株式会社 | Non-rem sleep-promoting agent, deep sleep-promoting agent and natural sleep-inducing agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1259341B (en) * | 1962-12-22 | 1968-01-25 | Boehringer & Soehne Gmbh | Process for the preparation of new 5'-sulfoxides of nucleosides |
| DE1545645A1 (en) * | 1965-12-06 | 1969-08-21 | Boehringer Mannheim Gmbh | Process for the preparation of disubstituted adenosine derivatives |
| FR2252405B1 (en) * | 1973-11-27 | 1978-04-28 | Ajinomoto Kk | |
| FR2313937A1 (en) * | 1975-06-09 | 1977-01-07 | Anvar | DRUG BASED ON 5 'THIOETHERS OF ADENOSINE |
| FR2424027A1 (en) * | 1978-04-28 | 1979-11-23 | Merieux Inst | NEW MEDICINAL PRODUCT, IN PARTICULAR SEDATIVE AND SLEEP INDUCER AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT |
-
1980
- 1980-04-22 IT IT21550/80A patent/IT1193529B/en active
-
1981
- 1981-04-17 BE BE0/204529A patent/BE888472A/en not_active IP Right Cessation
- 1981-04-21 JP JP5930181A patent/JPS56166117A/en active Granted
- 1981-04-21 ES ES501539A patent/ES501539A0/en active Granted
- 1981-04-21 SE SE8102489A patent/SE460198B/en not_active IP Right Cessation
- 1981-04-21 AR AR285020A patent/AR231144A1/en active
- 1981-04-21 CA CA000375784A patent/CA1198105A/en not_active Expired
- 1981-04-21 LU LU83307A patent/LU83307A1/en unknown
- 1981-04-21 NO NO811346A patent/NO150515C/en unknown
- 1981-04-21 DK DK176481A patent/DK159453C/en not_active IP Right Cessation
- 1981-04-22 DE DE19813116067 patent/DE3116067A1/en active Granted
- 1981-04-22 CH CH263281A patent/CH645544A5/en not_active IP Right Cessation
- 1981-04-22 CH CH4716/84A patent/CH650514A5/en not_active IP Right Cessation
- 1981-04-22 GB GB8112428A patent/GB2074446B/en not_active Expired
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- 1981-04-22 NL NL8101984A patent/NL192111C/en not_active IP Right Cessation
- 1981-04-22 FI FI811249A patent/FI70227C/en not_active IP Right Cessation
-
1982
- 1982-04-01 ES ES511039A patent/ES8306378A1/en not_active Expired
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1983
- 1983-08-15 GB GB08321947A patent/GB2144409B/en not_active Expired
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1984
- 1984-05-25 GB GB08413454A patent/GB2144038B/en not_active Expired
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1987
- 1987-03-04 SE SE8700914A patent/SE464635B/en not_active IP Right Cessation
- 1987-03-04 SE SE8700913A patent/SE466238B/en not_active IP Right Cessation
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1989
- 1989-02-02 JP JP1022771A patent/JPH01301692A/en active Granted
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1992
- 1992-06-26 MX MX9203630A patent/MX9203630A/en unknown
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