NO751157L - - Google Patents
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- Publication number
- NO751157L NO751157L NO751157A NO751157A NO751157L NO 751157 L NO751157 L NO 751157L NO 751157 A NO751157 A NO 751157A NO 751157 A NO751157 A NO 751157A NO 751157 L NO751157 L NO 751157L
- Authority
- NO
- Norway
- Prior art keywords
- compound
- phthalazone
- formula
- compounds
- tert
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 16
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical class C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 9
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 8
- 229940095074 cyclic amp Drugs 0.000 description 8
- 238000004220 aggregation Methods 0.000 description 7
- 230000002776 aggregation Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 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 6
- 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 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 206010020772 Hypertension Diseases 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 5
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 5
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- 210000001772 blood platelet Anatomy 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 230000001077 hypotensive effect Effects 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 231100000820 toxicity test Toxicity 0.000 description 3
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- 229930182837 (R)-adrenaline Natural products 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- -1 cancer Chemical compound 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229960005139 epinephrine Drugs 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 101000909851 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) cAMP/cGMP dual specificity phosphodiesterase Rv0805 Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 208000028831 congenital heart disease Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000009399 inbreeding Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
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- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000009394 selective breeding Methods 0.000 description 1
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- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
FREMGANGSMÅTE VED FREMSTILLING AV TERAPEUTISK AKTIVE 1-FTALAZON-DERIVATER. PROCEDURE FOR THE PRODUCTION OF THERAPEUTICALLY ACTIVE 1-PHTHALAZONE DERIVATIVES.
Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av nye, farmasoytisk verdifulle 1-ftalazonderivater. Mer spesielt tilveiebringer oppfinnelsen en fremgangsmåte for fremstilling av et 1-ftalazon-derivat med den generelle formel I The present invention relates to a method for the production of new, pharmaceutical valuable 1-phthalazone derivatives. More particularly, the invention provides a method for the preparation of a 1-phthalazone derivative of the general formula I
Fremgangsmåten for fremstilling av 1-ftalazon-derivatet med formelen (I) karakteriseres ved at The method for producing the 1-phthalazone derivative with the formula (I) is characterized by
(a) en forbindelse med den generelle formel II(a) a compound of the general formula II
hvori R betyr en acylgruppe, fortrinnsvis en acetyl-, propyl- eller benzoyl-gruppe, får reagere med isobutylen i nærvær av en katalysator, og deretter hydrolyseres det erholdte produkt med den generelle formel III in which R means an acyl group, preferably an acetyl, propyl or benzoyl group, is allowed to react with isobutylene in the presence of a catalyst, and then the product obtained is hydrolysed with the general formula III
hvori R har den foran angitte betydning, . in which R has the above meaning, .
til forbindelsen med formel (I), ellerto the compound of formula (I), or
(b) en forbindelse med den generelle formel (II) omdannes til en forbindelse med den generelle formel II<1>(b) a compound of the general formula (II) is converted into a compound of the general formula II<1>
hvori R har den foran angitte betydning og X betyr et halogenatom, wherein R has the above meaning and X means a halogen atom,
og reagerer med tert.-butanol i nærvær av en katalysator, og deretter hydrolyseres det erholdte produkt med formel (II) til forbindelsen med formel (I). and reacts with tert.-butanol in the presence of a catalyst, and then the obtained product of formula (II) is hydrolysed to the compound of formula (I).
Ifolge belgisk patent nr. 787.139 har det blitt funnet at alkoksykarbonyl-4-hydr.oksymetyl-l-ftalazonene har verdifulle virkninger ved behandlingen av blodninger, trombose og åreforkalkning. Senere undersokninger av det metaboliske forlop hos dyr og kliniske forsok med 7-etoksykarbonyl-4-hydroksymetyl-l-ftalazon åpenbarte at forbindelsen, når den ble According to Belgian Patent No. 787,139, it has been found that the alkoxycarbonyl-4-hydroxymethyl-1-phthalazones have valuable effects in the treatment of bleeding, thrombosis and arteriosclerosis. Later investigations of the metabolic course in animals and clinical trials with 7-ethoxycarbonyl-4-hydroxymethyl-l-phthalazone revealed that the compound, when
administrert til dyr eller mennesker, metaboliserte til den tilsvarende 7-karboksyl-forbindelsen, med det resultat at administered to animals or humans, metabolized to the corresponding 7-carboxyl compound, with the result that
Hl varigheten av den biologiske virkningen til forbindelsen er Hl is the duration of the biological action of the compound
relativt kort. Videre har det blitt funnet at tert.-butoksy- relatively short. Furthermore, it has been found that tert.-butoxy-
j karbonyl-4-hydroksymetyl-l-ftalazon er motstandsdyktig overfor den metaboliske degradasjon og har forlengede biologiske virkninger, sammenlignet med de tilsvarende rett-kjedete alkoksy-karbonyl-forbindelser. j carbonyl-4-hydroxymethyl-1-phthalazone is resistant to the metabolic degradation and has prolonged biological effects, compared to the corresponding straight-chain alkoxy-carbonyl compounds.
Tert.-butoksykarbonyl-4-hydroksymetyl-l-ftalazon-derivåtetThe tert.-butoxycarbonyl-4-hydroxymethyl-1-phthalazone deriv
kan fremstilles ved reaksjonen som er beskrevet i den forannevnte beskrivelse, hvilken skjematisk kan angis som folger: can be produced by the reaction described in the aforementioned description, which can be schematically stated as follows:
I henhold til denne fremstillingsmåte forestres karboksyl-gruppen i 4-stillingen, som skal omdannes til hydroksymetyl-gruppen til en tert.-butoksykarbonylgruppe, som deretter According to this production method, the carboxyl group in the 4-position is esterified, which is to be converted to the hydroxymethyl group to a tert.-butoxycarbonyl group, which then
splittes av. Under hensyntagen til det faktum at den kommersi-elle fremstillingen av tert.-butyl-esterne er komplisert og split off. Taking into account the fact that the commercial production of the tert-butyl esters is complicated and
kostbar, så er fremgangsmåten, beskrevet i forannevnte belgiske patent, kommersielt ufordelaktig med hensyn til fremstillingen i overensstemmelse med det foran angitte skjema (I). expensive, then the method, described in the aforementioned Belgian patent, is commercially disadvantageous with regard to the production in accordance with the above-mentioned scheme (I).
Vi har funnet at forbindelsen med formel (I) kan fremstilles kommersielt mer fordelaktig enn tidligere kjent, ved at man forst fremstiller etoksykarbonyl-4-hydroksymetyl-l-ftalazon ved prosessen som er beskrevet i forannevnte belgiske patent, deretter hydrolyserer og acetylerer den for å danne en forbindelse med formel (II) eller (II<1>), og så omdanner den til sin tertiære butylester ved fremgangsmåten ifolge nærværende oppfinnelse. We have found that the compound of formula (I) can be prepared commercially more advantageously than previously known, by first preparing ethoxycarbonyl-4-hydroxymethyl-l-phthalazone by the process described in the aforementioned Belgian patent, then hydrolyzing and acetylating it to form a compound of formula (II) or (II<1>), and then convert it to its tertiary butyl ester by the method according to the present invention.
Forbindelsene ifolge nærværende oppfinnelse ble funnet å The compounds according to the present invention were found to
være hoy-aktive ved forhindring av åreforkalkning og ved inhibering av kolesterol-avleiring i arterie-veggene ved forsok med åreforkalkning, indusert ved kolesterol-matning. Deres aktivitet er ca. tre ganger hoyere enn for det tilsvarende etoksykarbonyl-derivat.Nærværende forbindelser forhindrer også okningen av koaguleringsevnen og trombosefaren hos blod som er indusert med kolesterol eller adrenalin. Aktiviteten er i dette tilfelle ca. fem ganger storre enn hos det tilsvarende etoksykarbonylderivat. Det vil si at nærværende forbindelser mer effektivt forhindrer en nedsettelse av tiden for klumpedannelse i blodet, såvel som den forsterkende effekt .av.adenosin-difosfat-indusert blodplate-aggregering hos mennesker. be highly active in the prevention of atherosclerosis and in the inhibition of cholesterol deposition in the artery walls in trials with atherosclerosis, induced by cholesterol feeding. Their activity is approx. three times higher than for the corresponding ethoxycarbonyl derivative. The compounds present also prevent the increase in the coagulation ability and the risk of thrombosis in blood induced with cholesterol or adrenaline. In this case, the activity is approx. five times greater than in the corresponding ethoxycarbonyl derivative. That is, the present compounds more effectively prevent a reduction in blood clotting time as well as the enhancing effect of adenosine diphosphate-induced platelet aggregation in humans.
Videre ble nærværende forbindelser funnet . å være virksomme til å senke og normalisere for hoyt blodtrykk i forsok med hypertensjon hos spontant hypertensive rotter, mens det tilsvarende etoksykarbonylderivatet ikke har noen betydningsfull virkning på det forhoyede blod-trykk hos rotter. Denne ! aktivitet til nærværende forbindelser kan være forbundet med Furthermore, the present compounds were found. to be effective in lowering and normalizing excessively high blood pressure in experiments with hypertension in spontaneously hypertensive rats, while the corresponding ethoxycarbonyl derivative has no significant effect on the elevated blood pressure in rats. This ! activity to the present compounds may be associated with
I deres inhibitoriske effekt på cyklisk AMP-fosfodiesterase, hvilket er eksemplifisert ved "Biologiske forsok". In their inhibitory effect on cyclic AMP phosphodiesterase, which is exemplified by "Biological experiments".
Forbindelsene ifolge nærværende oppfinnelse er således anvendbare for behandling av hypertensive sykdommer, åreforkalkning-og trombose-sykdommer. De er også potensielt anvendbare for behandling av sykdommer som skyldes misd~av cyklisk AMP, såsom, cancer j mentale og nevrologiske uregelmessigheter, hormonelle forstyrrelser og hjertefeil. The compounds according to the present invention are thus applicable for the treatment of hypertensive diseases, atherosclerosis and thrombosis diseases. They are also potentially useful for the treatment of diseases caused by the malfunction of cyclic AMP, such as cancer, mental and neurological abnormalities, hormonal disorders and heart defects.
Utgangsforbindelsene ifolge nærværende oppfinnelse kan fremstilles fra forbindelsene som er beskrevet i The starting compounds according to the present invention can be prepared from the compounds described in
belgisk patent nr. 787.139. F.eks. gir hydrolyse av 7-etoksykarbonyl-4-hydroksymetyl-l-ftalazon, som er beskrevet i forannevnte beskrivelse, og etterfølgende acylering med et acylanhydrid eller acylklorid ved en kjent metode, et 4-acyloksymetyl-7-karboksyl-l-ftalazon som tilsvarer forbindelsen med formel (II). En fordelaktig acylgruppe med formel (II) er en acetylgruppe. Belgian Patent No. 787,139. E.g. hydrolysis of 7-ethoxycarbonyl-4-hydroxymethyl-1-phthalazone, which is described in the above description, and subsequent acylation with an acyl anhydride or acyl chloride by a known method, gives a 4-acyloxymethyl-7-carboxyl-1-phthalazone corresponding to the compound with formula (II). An advantageous acyl group of formula (II) is an acetyl group.
I en utforelsesform av fremgangsmåte (a) ifolge oppfinnelsen kan reaksjonen mellom forbindelsen med formel (II) og isobutylen utfores i nærvær av et opplosningsmiddel, som f.eks. dioksan eller tetrahydrofuran. Isobutylen anvendes fortrinnsvis i en overekvimolekylær mengde, og konsentrert svovelsyre anvendes fordelaktig som katalysator for reaksjonen. Reaksjonsblandingen, som fortrinnsvis er plassert i et hoy-trykks-kar eller bomberor, omrores ved en temperatur på 0 - 60°C. In an embodiment of method (a) according to the invention, the reaction between the compound of formula (II) and isobutylene can be carried out in the presence of a solvent, such as e.g. dioxane or tetrahydrofuran. Isobutylene is preferably used in an over-equimolecular amount, and concentrated sulfuric acid is advantageously used as a catalyst for the reaction. The reaction mixture, which is preferably placed in a high-pressure vessel or bomb tube, is stirred at a temperature of 0 - 60°C.
I en utforelsesform av fremgangsmåte (b) ifolge oppfinnelsen, kan reaksjonen mellom forbindelsen med den generelle formel (II') og tert.-butanol utfores i fravær av et opplosningsmiddel, under anvendelse av et overskudd av abs. tert.-butanol. En katalysator eller et dehydrokloreringsmiddel, f.eks. dimetylanilin, dietylanilin, pyridin, kollidin eller magnesium kan med fordel tilsettes til reaksjonsblandingen. Reaksjonen utfores fortrinnsvis ved en temperatur på fra 0 - |150°C, spesielt omkring kokepunktet til tert.-butanol. i In an embodiment of method (b) according to the invention, the reaction between the compound of the general formula (II') and tert.-butanol can be carried out in the absence of a solvent, using an excess of abs. tert.-butanol. A catalyst or a dehydrochlorinating agent, e.g. dimethylaniline, diethylaniline, pyridine, collidine or magnesium can advantageously be added to the reaction mixture. The reaction is preferably carried out at a temperature of from 0 - |150°C, especially around the boiling point of tert-butanol. in
I Acylgruppen til forbindelsen med formel (III), som således erholdes ved fremgangsmåte (a) eller (b), fjernes ved partiell hydrolyse med et lite overskudd av base, såsom kaliumhydroksyd I The acyl group of the compound of formula (III), which is thus obtained by method (a) or (b), is removed by partial hydrolysis with a small excess of base, such as potassium hydroxide
eller kaliumkarbonat ved en kjent metode, for å gi forbindelse or potassium carbonate by a known method, to give compound
(I). (IN).
I de angitte prosesser (a) og (b) kan produktene lett separeres og renses ved konvensjonelle metoder, hvilket er vist i de folgende eksempler. In the specified processes (a) and (b), the products can be easily separated and purified by conventional methods, which is shown in the following examples.
Forbindelsene ifolge nærværende oppfinnelse kan administreres alene eller inkorporeres i farmasøytiske sammensetninger, såsom pulvere, tabletter, granula, kapsler, pastiller, suspensjoner og andre doseformer for parenteral administrasjon. Den effektive mengden av forbindelsen med formel (I) kan fritt forandres ifolge en spesielt tilsiktet dose, men vanligvis The compounds according to the present invention can be administered alone or incorporated into pharmaceutical compositions, such as powders, tablets, granules, capsules, lozenges, suspensions and other dosage forms for parenteral administration. The effective amount of the compound of formula (I) may be freely varied according to a particularly intended dose, but usually
brukes fra 0,1 til 80%, basert på den totale mengde bærer-eller fortynningsmiddel og forbindelsen av formel (I): Kort is used from 0.1 to 80%, based on the total amount of carrier or diluent and the compound of formula (I): Brief
sagt kan det kreves enhver onsket konsentrasjon for adminis-trasjonen i doser som ligger i området fra 1 - 100 mg/kg kroppsvekt pr. dag. that said, any desired concentration can be required for the administration in doses that lie in the range from 1 - 100 mg/kg body weight per day.
Bæreren eller fortynningsmidlet kan være en farmasøytisk aksepterbar væske eller et fast stoff, og uttrykket "bærer" anvendes i nærværende oppfinnelse også om hjelpestoffer. Eksempler på væske-bærerer er destillert vann for injeksjons-f ormål, isotonisk natriumkloridopplosning , Ringer<e>s opplosning, Locke's opplosning, polyetylenglykol, etylalkohol, propylen-glykol, glycerol og vegetabilsk olje. Faststoff-bæreren omfatter f.eks. natriumklorid, glukose, laktose, stivelse, sakkarose,,cetylalkohol, kakaosmor og spermacet. The carrier or diluent can be a pharmaceutically acceptable liquid or a solid, and the term "carrier" is used in the present invention also for excipients. Examples of liquid carriers are distilled water for injection purposes, isotonic sodium chloride solution, Ringer's solution, Locke's solution, polyethylene glycol, ethyl alcohol, propylene glycol, glycerol and vegetable oil. The solid carrier includes e.g. sodium chloride, glucose, lactose, starch, sucrose, cetyl alcohol, cocoa butter and spermacetate.
De folcfende eksempler illustrerer oppfinnelsen, men begrenser ikke oppfinneIsesomfanget. The following examples illustrate the invention, but do not limit the scope of the invention.
EKSEMPEL 1EXAMPLE 1
Fremstilling av 4- acetoksymetyl- 7- tert.- butoksykarbonyl- 1-ftalazon Preparation of 4-acetoxymethyl-7-tert.-butoxycarbonyl-1-phthalazone
1) I et tykkvegget glassror ble det plasert 4-acetoksymetyl-7-karboksy-l-ftalazon (1,2 g, dekomponeringspunkt 252 - 253°C) og dioksan (50 ml), og deretter ble roret avkjolt med torr is-aceton. Isobutylen (12 ml) ble innfort i roret og deretter ble konsentrert svovelsyre (4 ml) tilsatt under omroring med en magnetisk omrorer. Etter lukking av roret ble innholdet omrort i 10 timer ved romtemperatur. Innholdet ble helt i en 10%'ig, vandig opplosning av natriumkarbonat, og blandingen ble ekstrahert med etylacetat. Ekstraktet ble torket over magnesiumsulfat og inndampet. Resten ble omkrystallisert fra etanol for å gi 4-acetoksymetyl-7-tert.-butoksykarbonyl-l-ftalazon (760 mg) som smelter ved 202 - 203°C. IR-spektrum: (KBr, cm<-1>) 1740, 1720, 1660, 1360, 1295, 1240, 1160, 1120, 1035. 1) 4-acetoxymethyl-7-carboxy-l-phthalazone (1.2 g, decomposition point 252 - 253°C) and dioxane (50 ml) were placed in a thick-walled glass beaker, and then the beaker was cooled with dry ice-acetone . Isobutylene (12 mL) was introduced into the stirrer and then concentrated sulfuric acid (4 mL) was added while stirring with a magnetic stirrer. After closing the stirrer, the contents were stirred for 10 hours at room temperature. The contents were poured into a 10% aqueous solution of sodium carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated. The residue was recrystallized from ethanol to give 4-acetoxymethyl-7-tert-butoxycarbonyl-1-phthalazone (760 mg) melting at 202-203°C. IR spectrum: (KBr, cm<-1>) 1740, 1720, 1660, 1360, 1295, 1240, 1160, 1120, 1035.
2) En blanding av 4-acetoksymetyl-7-karboksy-l-ftalazon (2 g) og destillert tionylklorid (20 ml) ble forsiktig tilbakelops-behandlet ved 70 - 80°C i 3 timer. Overskytende tionylklorid ble fjernet under redusert trykk og deretter ble absolutt benzen (IO ml) tilsatt til resten. Benzenet ble 2) A mixture of 4-acetoxymethyl-7-carboxy-1-phthalazone (2 g) and distilled thionyl chloride (20 ml) was gently refluxed at 70-80°C for 3 hours. Excess thionyl chloride was removed under reduced pressure and then absolute benzene (10 mL) was added to the residue. The benzene remained
igjen fjernet under redusert trykk, og resten ble opplost i absolutt tert.-butanol (30 ml). Dimetylanilin (2,2 ml) ble tilsatt til oppløsningen under omroring og blandingen ble tilbakelbpsbehandlet i 30 timer under fuktighets-frie betingelser. Losningsmidlet ble fjernet under redusert trykk og den resulterende resten ble gjort basisk med en vandig natriumkarbonat-losning. Blandingen ble ekstrahert med etylacetat og ekstraktet ble torket og losningsmidlet fjernet. Resten ble omkrystallisert fra etanol for å gi 4-acetoksymetyl-7-tert.-butoksykarbonyl-l-ftalazon (1,2 g) som smelter ved 202 - 203°C. Det infrarode spektrum dekket det til proven som ble erholdt il). again removed under reduced pressure, and the residue was dissolved in absolute tert.-butanol (30 mL). Dimethylaniline (2.2 ml) was added to the solution with stirring and the mixture was refluxed for 30 hours under moisture-free conditions. The solvent was removed under reduced pressure and the resulting residue was basified with an aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate and the extract was dried and the solvent removed. The residue was recrystallized from ethanol to give 4-acetoxymethyl-7-tert-butoxycarbonyl-1-phthalazone (1.2 g) melting at 202-203°C. The infrared spectrum covered that of the sample obtained il).
Fremstilling av 7- tert.- butoksykarbonyl- 4- hydroksymetyl- l-ftalazon Preparation of 7-tert.-butoxycarbonyl-4-hydroxymethyl-1-phthalazone
Til en opplosning av kaliumhydroksyd (1,8 g) i etanol (150 ml)To a solution of potassium hydroxide (1.8 g) in ethanol (150 ml)
j ble 4-acetoksymetyl-7-tert.-bu^oksykarbonyl-l-ftalazon (3,4 g) tilsatt- Reaksjonsblandingen ble omrort ved romtemperatur i 3 timer og deretter mettet med karbondioksyd. Blandingen ble konsentrert under redusert trykk og innholdet i flasken ble" 4-acetoxymethyl-7-tert.-bu^oxycarbonyl-1-phthalazone (3.4 g) was added. The reaction mixture was stirred at room temperature for 3 hours and then saturated with carbon dioxide. The mixture was concentrated under reduced pressure and the contents of the flask were
helt i vann og ekstrahert med etylacetat. Ekstraktet ble torket og opplbsningsmidlet ble fjernet. Resten ble omkrystat li sert fra etanol-n-heksan for å gi 7-tert.-butoksykarbonyl-4-hydroksymetyl-l-ftalazon (2,8 g). Dets fysikalske egenskaper var som folger: smp. 2 70 - 2 72°C^ IR-spektrum, (KBr, cm~^) 3500 (bredt), 1730, 1660, 1370, 1310, 1270, 1162, 1130, 1030; poured into water and extracted with ethyl acetate. The extract was dried and the solvent was removed. The residue was recrystallized from ethanol-n-hexane to give 7-tert-butoxycarbonyl-4-hydroxymethyl-1-phthalazone (2.8 g). Its physical properties were as follows: m.p. 2 70 - 2 72°C^ IR spectrum, (KBr, cm~^ ) 3500 (broad), 1730, 1660, 1370, 1310, 1270, 1162, 1130, 1030;
masse-spektrum, m/e 276 (M<+>), 220, 203, 191.mass spectrum, m/e 276 (M<+>), 220, 203, 191.
Biologiske forsokBiological experiments
1) Nærværende forbindelsers effekt ved forhindring av menneske-blodplate- aqqregasjon in vitro 1) The effect of the present compounds in preventing human platelet aggregation in vitro
Forbindelsene ifolge nærværende oppfinnelse viste en frem-ragende effekt når det gjelder å forhindre menneske-blodplateaggregasjon, indusert av ADP (Adenosin-difosfat) eller adrenalin in vitro. The compounds according to the present invention showed an outstanding effect in preventing human platelet aggregation, induced by ADP (Adenosine diphosphate) or adrenaline in vitro.
Prover på menneske CPRP (Citrert blodplate-rik plasma) ble inkubert ved 37°C i 200 sek. med 1/10 volum saltopplosning som inneholder forskjellige mengder av forbindelsen som skal undersokes. Til denne blandingen ble det så tilsatt ADP (3^.. mol) eller adrenalin (1 yug/ml) . Intensiteten av primær og sekundær aggregasjon ble målt med et blodplate-aggregasjons-meter (Chrono-Log, Model 300). Samples of human CPRP (Citrated platelet-rich plasma) were incubated at 37°C for 200 sec. with 1/10 volume of saline containing different amounts of the compound to be investigated. ADP (3..mol) or adrenaline (1 µg/ml) was then added to this mixture. The intensity of primary and secondary aggregation was measured with a platelet aggregation meter (Chrono-Log, Model 300).
Intensiteten til ADP- eller adrenalin-indusert aggregasjonThe intensity of ADP- or epinephrine-induced aggregation
av hver prove som var inkubert med forbindelsen ble sammenlignet med intensiteten til den samme proven som ble inkubert med saltopplosning. Forholdet ble uttrykt som en prosent av aggregasjons-intensiteten hos forbindelsen overfor den samme hos saltopplosningen. Resultatene vises i folgende tabell I. of each sample incubated with the compound was compared to the intensity of the same sample incubated with saline. The ratio was expressed as a percentage of the aggregation intensity of the compound relative to that of the salt solution. The results are shown in the following table I.
Intensiteten til primær og sekundær blodplateaggregasjon ble The intensity of primary and secondary platelet aggregation was
målt ved fremgangsmåten som er beskrevet i H. Yamazaki, T.measured by the method described in H. Yamazaki, T.
!'! Sano, et al, tittel [Platelet Functions in Thromboembolic Dis-!'! Sano, et al, title [Platelet Functions in Thromboembolic Dis-
I orders] Thrombosis et Diatheses Haemorrhagica "in press" og In orders] Thrombosis et Diatheses Haemorrhagica "in press" and
I de heri angitte referanser.In the references given herein.
Som vist i tabell I, så inhiberer nærværende forbindelse den primære aggregasjonen som er indusert av ADP eller adrenalin med ca. sammenlignbar aktivitet overfor 4-hydroksymetyl-l-ftalazon (forbindelsen ifolge belgisk patent nr. 787.138) og 7-etoksykarbonyl-4-hydroksymetyl-l-ftalazon (forbindelsen ifolge belgisk patent nr. 787.139). Imidlertid inhiberer forbindelsen ifolge nærværende oppfinnelse meget mer effektivt den sekundære aggregasjonen, sammenlignet med tidligere forbindelser. Det vil si at nærværende forbindelser inhiberer den sekundære aggregasjonen som er indusert av ADP eller adrenalin i en konsentrasjon på 1 - 2,5^ig/ml med en statistisk betydning, mens 7-etoksykarbonyl-4-hydroksymetyl-l-ftalazon inhiberer den sekundære aggregasjonen i en konsentrasjon på 5-10 ^g/ml. As shown in Table I, the present compound inhibits the primary aggregation induced by ADP or epinephrine by approx. comparable activity towards 4-hydroxymethyl-1-phthalazone (the compound according to Belgian patent no. 787,138) and 7-ethoxycarbonyl-4-hydroxymethyl-1-phthalazone (the compound according to Belgian patent no. 787,139). However, the compound according to the present invention inhibits the secondary aggregation much more effectively, compared to previous compounds. That is, the present compounds inhibit the secondary aggregation induced by ADP or adrenaline at a concentration of 1 - 2.5 µg/ml with a statistical significance, while 7-ethoxycarbonyl-4-hydroxymethyl-1-phthalazone inhibits the secondary the aggregation in a concentration of 5-10 µg/ml.
<1>!2) Nærværende forbindelsers virkning ved inhiberinq av cyklisk AMP- fosfodiesterase hos kaniners arterieveqqer og menneske-blodplater <1>!2) The effect of the present compounds on the inhibition of cyclic AMP phosphodiesterase in rabbit arterial tissues and human platelets
Forbindelsene ifolge nærværende oppfinnelse viste en bestemt inhiberende virkning overfor cyklisk AMP-fosfodiesterase hos kaniners arterievegger og menneske-blodplater. The compounds according to the present invention showed a specific inhibitory action against cyclic AMP phosphodiesterase in rabbit arterial walls and human platelets.
En overliggende væske av homogenisert indre arterievegg, media fra arterieveggen hos kaniner eller menneske-blodplate-rik plasma ble inkubert med en. reaksj onsblanding, bestående av triterium-merket cyklisk AMP (adenosin-3',5'-cyklisk monofos-fat) og forskjellige mengder av forbindelsen. A supernatant of homogenized inner arterial wall, rabbit arterial wall media, or human platelet-rich plasma was incubated with a. reaction mixture, consisting of tritium-labeled cyclic AMP (adenosine-3',5'-cyclic monophosphate) and various amounts of the compound.
Den inkuberte blandingen ble renset ved kolonnekromatografi,The incubated mixture was purified by column chromatography,
og fraksjonen som inneholdt nukleotid ble kvantitativt ana-lysert av en væske-sintilasjonsteller. and the fraction containing nucleotide was quantitatively analyzed by a liquid scintillation counter.
Tabell II viser den inhiberende virkningen til disse forbindelsene mot cyklisk AMP-fosfodiesterase. Figurene i tabellen viser mengden av forbindelsen som kreves for å gi 50% inhibering av cyklisk AMP-fosfodiesterase. Table II shows the inhibitory action of these compounds against cyclic AMP phosphodiesterase. The figures in the table show the amount of compound required to produce 50% inhibition of cyclic AMP phosphodiesterase.
Som vist i tabell II så er nærværende forbindelse mer hoy-aktiv for å inhibere difosfoesterase enn teofyllin, koffein eller forbindelsen som tidligere er kjent. Det betyr at nærværende forbindelser er effektive for å oke konsentrasjonen av cyklisk AMP i blodplater og arterievegger. As shown in Table II, the present compound is more highly active in inhibiting diphosphoesterase than theophylline, caffeine or the compound previously known. This means that the present compounds are effective in increasing the concentration of cyclic AMP in blood platelets and artery walls.
!Fremgangsmåten ifolge eksperimentet ble utfort ifolge metoden som er beskrevet i H. Hidaka og M. Shibuya: tittel "A new assay of cyklic nucleotide phosphodiesterase and its application to human", Biochemical Medicine, (in press). !The procedure according to the experiment was carried out according to the method described in H. Hidaka and M. Shibuya: title "A new assay of cyclic nucleotide phosphodiesterase and its application to human", Biochemical Medicine, (in press).
3) Nærværende forbindelsers hypotensive effekt hos spontant hypertensive rotter 3) Hypotensive effect of the present compounds in spontaneously hypertensive rats
Nærværende forbindelser har en unik hypotensiv effekt på spontant hypertensive rotter. De spontant hypertensive rottene, for-kortet til SH-rotter, fremstilles ved selektiv oppaling av spontant hypertensive rotter og kontinuerlig innavling av hypertensive hanrotter, og de kan være anerkjent som genetisk hypertensive. Det er antatt at SH-rotter har en slående likhet The present compounds have a unique hypotensive effect on spontaneously hypertensive rats. The spontaneously hypertensive rats, short for SH rats, are produced by selective breeding of spontaneously hypertensive rats and continuous inbreeding of hypertensive male rats, and they can be recognized as genetically hypertensive. It is believed that SH rats have a striking resemblance
med menneskenes typiske hypertensjon og de har blitt påfort denne sykelige tilstand. with people's typical hypertension and they have been forced into this morbid condition.
4-hydroksymetyl-l-ftalazon og 7-etoksykarbonyl-4-hydroksymetyl-1-ftalazon, beskrevet i teknikkens stand, viste ingen betydelig hypotensiv effekt ved intraperitoneal eller oral dose opptil 50 mg/kg. På den annen side viser nærværende forbindelser en slående effekt i doser på 0,78 til 50 mg/kg, inngitt intraperitonealt eller oralt som vist i tabell III-b. 4-Hydroxymethyl-1-phthalazone and 7-ethoxycarbonyl-4-hydroxymethyl-1-phthalazone, described in the prior art, showed no significant hypotensive effect at intraperitoneal or oral doses up to 50 mg/kg. On the other hand, the present compounds show a striking effect in doses of 0.78 to 50 mg/kg, administered intraperitoneally or orally as shown in Table III-b.
I blodtrykks-testen ble det anvendt SH-rotter som veier 210 - 250 g og som er 13 - 15 uker gamle, og de undersokte forbindelsene ble administrert intraperitonealt. Hver verdi i tabell III viser en gjennomsnittlig figur for tre rotter. In the blood pressure test, SH rats weighing 210 - 250 g and which are 13 - 15 weeks old were used, and the investigated compounds were administered intraperitoneally. Each value in Table III shows an average figure for three rats.
4) Toksisitets- test 4) Toxicity test
Resultatene av toksisitets-testen (LD^Q) til forbindelsene ifolge nærværende oppfinnelse med de tidligere kjente forbindelser er vist i den folgende tabell. Proven ble utfort ved oral administrasjon og ved anvendelse av mus. Toksisitets-testen viste at disse forbindelser er forholdsmessig ikke-toksiske. The results of the toxicity test (LD^Q) of the compounds according to the present invention with the previously known compounds are shown in the following table. The test was carried out by oral administration and using mice. The toxicity test showed that these compounds are relatively non-toxic.
Claims (1)
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JP12126073A JPS5732065B2 (en) | 1973-10-30 | 1973-10-30 | |
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JP12175773A JPS5724786B2 (en) | 1973-10-31 | 1973-10-31 | |
JP12175873A JPS5724787B2 (en) | 1973-10-31 | 1973-10-31 |
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NO751157A NO751157L (en) | 1973-10-30 | 1974-10-29 |
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