HRP940724A2 - Novel xantin derivatives having an adenosin-antagonistic activity - Google Patents
Novel xantin derivatives having an adenosin-antagonistic activity Download PDFInfo
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- HRP940724A2 HRP940724A2 HRP-2423/89A HRP940724A HRP940724A2 HR P940724 A2 HRP940724 A2 HR P940724A2 HR P940724 A HRP940724 A HR P940724A HR P940724 A2 HRP940724 A2 HR P940724A2
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- 230000000694 effects Effects 0.000 title description 6
- -1 3,4-methylenedioxyphenyl Chemical group 0.000 claims abstract description 58
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 35
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 claims abstract description 29
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 26
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 23
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 10
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims abstract description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 7
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 7
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 claims abstract description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 5
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- 150000001413 amino acids Chemical class 0.000 claims abstract description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- 125000004432 carbon atom Chemical group C* 0.000 claims description 31
- 239000000126 substance Substances 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 10
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 8
- 239000013543 active substance Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 229940075420 xanthine Drugs 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- 150000001924 cycloalkanes Chemical group 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 claims description 4
- ZURRKVIQUKNLHF-UHFFFAOYSA-N 4,7,7-trimethylbicyclo[2.2.1]heptane-3-carboxylic acid Chemical group C1CC2(C)C(C(O)=O)CC1C2(C)C ZURRKVIQUKNLHF-UHFFFAOYSA-N 0.000 claims description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 4
- 125000000468 ketone group Chemical group 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- 238000003747 Grignard reaction Methods 0.000 claims description 2
- 229930194542 Keto Natural products 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical class OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 125000005336 allyloxy group Chemical group 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims description 2
- UGUUDTWORXNLAK-UHFFFAOYSA-N azidoalcohol Chemical compound ON=[N+]=[N-] UGUUDTWORXNLAK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 150000001925 cycloalkenes Chemical class 0.000 claims description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 2
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 claims description 2
- LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 claims description 2
- 150000004662 dithiols Chemical class 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 125000000627 niacin group Chemical group 0.000 claims description 2
- 229960003512 nicotinic acid Drugs 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 7
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims 2
- WWNNZCOKKKDOPX-UHFFFAOYSA-N N-methylnicotinate Chemical compound C[N+]1=CC=CC(C([O-])=O)=C1 WWNNZCOKKKDOPX-UHFFFAOYSA-N 0.000 claims 1
- 230000003042 antagnostic effect Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 claims 1
- 125000006384 methylpyridyl group Chemical group 0.000 claims 1
- 229940081066 picolinic acid Drugs 0.000 claims 1
- 150000004885 piperazines Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 6
- CJVFIJXEPCVCTK-LWMBYGOMSA-N (2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)C(C)C CJVFIJXEPCVCTK-LWMBYGOMSA-N 0.000 abstract 1
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- 125000002619 bicyclic group Chemical group 0.000 abstract 1
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 125000000392 cycloalkenyl group Chemical group 0.000 abstract 1
- 125000002541 furyl group Chemical group 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 abstract 1
- 125000004430 oxygen atom Chemical group O* 0.000 abstract 1
- 125000004434 sulfur atom Chemical group 0.000 abstract 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 abstract 1
- 125000001544 thienyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 92
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000013078 crystal Substances 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 230000033228 biological regulation Effects 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 150000001299 aldehydes Chemical class 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- RUHGOZFOVBMWOO-UHFFFAOYSA-N 8-(3-oxocyclopentyl)-1,3-dipropyl-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C1CCC(=O)C1 RUHGOZFOVBMWOO-UHFFFAOYSA-N 0.000 description 7
- 229920002261 Corn starch Polymers 0.000 description 7
- 150000001298 alcohols Chemical class 0.000 description 7
- 239000008120 corn starch Substances 0.000 description 7
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- 239000000706 filtrate Substances 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
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- 239000008346 aqueous phase Substances 0.000 description 6
- 150000001735 carboxylic acids Chemical class 0.000 description 6
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- NRECPLZNMXAXRH-UHFFFAOYSA-N 8-(3-hydroxycyclopentyl)-1,3-dipropyl-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C1CCC(O)C1 NRECPLZNMXAXRH-UHFFFAOYSA-N 0.000 description 5
- 229940083747 low-ceiling diuretics xanthine derivative Drugs 0.000 description 5
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- 238000002156 mixing Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- WQADWIOXOXRPLN-UHFFFAOYSA-N 1,3-dithiane Chemical compound C1CSCSC1 WQADWIOXOXRPLN-UHFFFAOYSA-N 0.000 description 4
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- JSAVMACNWUUICZ-UHFFFAOYSA-N 5-(2,6-dioxo-1,3-dipropyl-7h-purin-8-yl)furan-2-carbaldehyde Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C1=CC=C(C=O)O1 JSAVMACNWUUICZ-UHFFFAOYSA-N 0.000 description 3
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- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- QCZZSANNLWPGEA-UHFFFAOYSA-N 1-(4-phenylphenyl)ethanone Chemical compound C1=CC(C(=O)C)=CC=C1C1=CC=CC=C1 QCZZSANNLWPGEA-UHFFFAOYSA-N 0.000 description 2
- CWKXDPPQCVWXAG-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde Chemical compound O1CCOC2=CC(C=O)=CC=C21 CWKXDPPQCVWXAG-UHFFFAOYSA-N 0.000 description 2
- XQQBUAPQHNYYRS-UHFFFAOYSA-N 2-methylthiophene Chemical compound CC1=CC=CS1 XQQBUAPQHNYYRS-UHFFFAOYSA-N 0.000 description 2
- JIZRGGUCOQKGQD-UHFFFAOYSA-N 2-nitrothiophene Chemical compound [O-][N+](=O)C1=CC=CS1 JIZRGGUCOQKGQD-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- 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
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
Izum se odnosi na nove derivate ksantina, na postupke za njihovu pripravu i na njihovu uporabu kao lijeka.
Novi ksantini imaju strukturu s općom formulom I
[image]
u kojoj mogu značiti
R1lkilnu skupinu s 1 do 6 - ponajprije 1 do 4 - ugljikova atoma, alkenilnu skupinu s 3 ili 4 ugljikova atoma; alkinilnu skupinu s 3 ili 4 ugljikova atoma;
R2 alkenilnu skupinu s 3 ili 4 ugljikova atoma, alkilnu skupinu s 1 do 6 - ponajprije 1 do 4 - ugljikova atoma, u danom primjeru supstituiranu benzilnu skupinu, alkinilnu skupinu s 3 ili 4 ugljikova atoma;
R3C-vezan zasićen ili nezasićen pet-, šest- ili sedmeročlani heterociklički prsten, koji sadrži jedan ili više hetero atoma, izabranih iz grupe kisik ili sumpor, i mogu u danom primjeru nositi jedan od slijedećih ostataka
C1 do C6 - ponajprije C1 do C4 - alkil,
=O, -CHO, -CH2OR4, -CH2OR7, COOR4,
CONR5R6, pri čemu može furanski ili tiofenski ostatak nositi i jedan od ostataka
-CH=CH-CONR5R6,
-CH=C(COOR4)2 (R4 jednaka ili različita),
-CH=C(COOR4)(CONR5R6),
-CH=C(COOR4)(CH2OR4) (R4 jednaka ili različita)
-CH=(COOR4)(CH2OR7),
-CH=C(CH2OR4)2,
-CH=C(CH2OR7)2,
-CH=C(CONR5R6)CH2OR4,
-CH=C(CONR5R6)CH2OR7 ili nitro i tetrahidrofuranski ostatak također ostatak
-(CH2)2-CONR5R6;
R3 C4 do C8 - cikloalken, koji može biti supstituiran sa C2 do C4-alkenilom,
R3C4 do C8 - ponajprije C5 i C6 - cikloalkanon ili
C4 do C8 - ponajprije C5 i C6 - cikloalkanol, koji mogu biti u položaju α substituirani sa C2 do C6 - ponajprije C2 do C4- alkenilom, C2 do C6 - ponajprije C2 do C4 - alkinilom, u danom primjeru supstituiranim benzilom, sa CH2OR4, CH2COOR7, (CH2)2CN,
R3 C3 do C8 - ponajprije C5 i C6 - cikloalkan, koji može u danom primjeru biti supstituiran sa C1 do C6 - ponajprije C1 i C4- alkilom, =CH2, =N-NH-arilom, ponajprije =N-NH-fenilom, pri čemu arilni odnosno fenilni ostatak može biti supstituiran,
=N-NH-C1 do C6-alkilom, =NOH,
-OCONH-arilom, ponajprije -OCONH-fenilom, pri čemu arilni odnosno fenilni ostatak može biti supstituiran,
OCONH-C1 - C6-alkilom,
-OR4, -OR7, -(CH2)1-COOR4,
-(CH2)l-NR4R4 (R4 jednaka ili različita),
-(CH2)l-CONR5R6,
-(CH2)l-OR4, -(CH2)l-OR7,
pri čemu l znači jedan od brojeva 0, 1, 2, 3 ili 4, ili ostatak =CAH - pri čemu A može značiti COOR4, CN, CONR5R5, CH=CH-COOR4, CH=CH-CONR4R6, CH2OR4, ili CH2OR7, ili je cikloalkan supstituiran sa C1 do C6, ponajprije C1 do C4 - alkilom, vinilom, alilom, u danom primjeru supstituiranim fenilom, u danom primjeru supstituiranim C1-C4 -alkilfenilom, i nosi kao drugi supstituent hidroksilnu skupinu u geminalnom položaju glede na prvi supstituent;
R3 stvara zajedno s cikloalkanom ketal opće formule
[image]
u kojoj znače
Ra C1-C4-alkil i
Rb C1-C4-alkil ili Ra i Rb zajedno stvaraju C2- ili C3- alkilenski ostatak, koji može u danom primjeru biti jedan puta ili dva puta supstituiran sa C1 do C5-alkilom, C1-C5-alkiloksikarbonilom, hidroksi-C1 do C5-alkilom, ponajprije hidroksimetilom;
R3 u danom primjeru supstituirani ostatak formule
[image]
R3 ostatak formule
[image]
i
R4 vodik, alkilnu skupinu s 1 do 13 - ponajprije 1 do 6 i 11 do 13 - ugljikova atoma, u danom primjeru
supstituiranu cikloalkilnu skupinu s 3 do 6 ugljikova atoma, u danom primjeru supstituiranu benzilnu skupinu, alkenilnu skupinu s 3 do 13 - ponajprije 3 do 6 ugljikova atoma, propargilni ostatak, tritilni ostatak,
R5 vodik, alkilnu skupinu s 1 do 6 - ponajprije 1 do 4 - ugljikova atoma, u danom primjeru supstituiranu cikloalkilnu skupinu s 3 do 6 ugljikova atoma;
R6 vodik, alkilnu skupinu s 1 do 6 - ponajprije 1 do 4 - ugljikova atoma, u danom primjeru supstituiranu benzilnu skupinu, ostatak s općim formulama
-(CH2)n-NR5R5,
-((CH2)n-O-(CH2)m-O)k-(CH2)n-NR5R5
(R5 jednaka ili različita)
s n = 2, 3, 4, 5, 6, 7 ili 8, m = 2, 3, 4, 5 ili 6
i k = 0 ili 1,
[image]
(R5 jednaka ili različita),
pri čemu se piperazinski prsten može supstituirati sa C1-C4 -alkilom - ponajprije metilom,
C-vezan piperidinilni ostatak, koji je u danom primjeru supstituiran sa C1 do C4-alkilom ili N-vezanim benzilnim ostatkom ili
R5 i R6 stvaraju zajedno s dušikovim atomom u danom primjeru s C1-C4-alkilom supstituiran pet- ili šest-ili sedmeročlani prsten, koji može sadržavati daljnji heteroatom iz grupe kisik, sumpor ili dušik, pri čemu se može atom dušika supstituirati s ostatkom R4;
R7 preko karbonilne funkcije vezan aminokiselinski ostatak prirodne amino kiseline, CO-C1-C13-alkil, ponajprije CO-C2-C4-alkil, metoksiacetil, preko karbonilne skupine vezani ostatak kamfanske kiseline, abietinoil, 4-aminobutiroil, u danom primjeru supstituirani benzoil, ponajprije trimetoksibenzoil, ostatak opće formule CO-B, pri čemu je B u danom primjeru supstituiran, C-vezan 5-, 6- ili 7-člani heterocikl,
kao i u danom primjeru njihovi racemati, njihovi optičko aktivni spojevi kao i njihove farmakološki besprijekorne kiselinske adicijske soli.
Spojevi opće formule I, a kojima se daje prednost, su oni u kojima znači
R1 ravnu alkilnu skupinu s 3 do 4 ugljikova atoma, alilnu skupinu, propargilnu skupinu;
R2 alilnu skupinu, alkilnu skupinu s 3 do 4 ugljikova atoma, propargilnu skupinu;
R3 ostatak, izabran iz skupine furan, tetrahidrofuran, tetrahidrofuranon, tiofen, ditiol, ditian ili tetrahidropiran, koji može nositi jednoga od sljedećih supstituenata
metil, etil, propil, butil, CHO, CH2OR4, CH2OR7, COOR4, CONR5R6,
R3 s
-CH=CH-CONR5R6, -CH=C(COOR4)2 (R4 jednaka ili različita),
-CH=C(COOR4)6(CONR5R6),
-CH=C(COOR4)(CH2OR4) (R4 jednaka ili različita),
-CH=C(COOR4)(CH2OR7),
-(CH2)n-CONR5R6,
-CH=C(CH2OR4)2,
-CH=C(CH2OR7)2,
-CH=C(CONR5R6)CH2OR4 ili
-CH=C(CONR5R6)CH2OR7 susupstituiran furan;
R3 ciklopentan ili cikloheksan, koji je u danom primjeru supstituiran s metilom, etilom, propilom, izo-propilom, terc-butilom, alilom, vinilom, fenilom ili benzilom, pri čemu je kao geminalni supstituent prisutna hidroksi skupina;
R3 ciklopentan ili cikloheksan, supstituiran s hidroksi, metoksi, etoksi, propiloksi, trimetoksikarbonilom,izo-propiloksi, u danom primjeru supstituirani benziloksi, aliloksi, propargiloksi, -CH2-CH2-OH,
-CH2-COOCH3, =CH-COOCH3, =C-CN,
-(CH2)2NH2,
=CH2,
[image]
=NOH, -CH2OH, OR4 s R4 = metil ili tritil,
OR7, gdje je R7 COCH3, COC2H5, COC3H7,
CO terc-butil, -CO-fenil ili COCH2-fenil, koji je u danom primjeru supstituiran, CO-piridil,
-CO-(N-metil-4H-piridil),
-CO-(metilpiridil), -COCH2-CH=CH2,
-CO-CH2-CΞCH;
R3 ostatak
[image]
s Ra, Rb = CH3, C2H5 ili Ra i
Rb zajedno-CH2-CH2-,
R3 ciklopentanon ili cikloheksanon,
R3 cikloalkan ili cikloalken s 4 do 8 ugljikova atoma, koji se može u danom primjeru supstituirati s ravnom ili razgranatom alkenilnom skupinom s 2 do 4 ugljikova atoma, ciklopentanon ili ciklopentanol ili cikloheksanon ili cikloheksanol, koji mogu u položaju α glede na keto ili hidroksi skupinu biti supstituirani sa C2 do C4-alkenilom, C3 ili C4-alkinilom, benzilom, -CH2CH2CN, (CH2)3NR5R5 (R5 jednaka ili različita), CH2COOR4, CH2OR4, pri čemu može R4 značiti vodik, metil, etil ili propil;
R3 norbonan ili norbonen - u danom primjeru supstituiran,
[image]
R4 vodik, alkilnu skupinu s 1 do 3 ugljikova, ciklopropilnu skupinu, ciklopentilnu skupinu, benzil, alilnu skupinu, propargilnu skupinu, trifenilmetilnu skupinu;
R5 vodik, alkilnu skupinu s 1 do 3 ugljikova atoma;
ciklopropilnu skupinu, benzilnu skupinu;
R6 vodik, metil, etil, propil,
-(CH2)n-NH2 (n=2-8),
-(CH2)nNEt2 (n=2,3) ili
-(CH2)3-O-(CH2)4-O-(CH2)3-NH2,
N-benzil-piperidin-4-il-, ili R5 i R6 zajedno s dušikovim atomima pipiridinski, piperazinski, morfolinski
ostatak, koji u danom primjeru može biti supstituiran s C1-C4-alkilnim ostatkom, ponajprije metilom;
R7 prolinoil, CO-(CH2)0-3-CH3,
(-)-metoksiacetil, preko karbonilne skupine vezan ostatak kamfanske kiseline, abietinoil, benzoil,
4-aminobutiroil, 3,4,5-trihidroksibenzoil,
3,4,5-trimetoksibenzoil, ostatak nikotinske kiseline, ostatak N-metilnikotinske kiseline,
ostatak N-metil-4H-nikotinske kiseline,
kao i u danom primjeru njihove kiselinske adicijske soli.
Spojevi, a kojima se daje prednost, su spojevi opće formule I, u kojima R3 stvara u danom primjeru supstituiran ciklopentanski ostatak, pri čemu se supstituent nalazi u položaju 3 ciklopentanskog prstena. Posebice se daje prednost ostatku R3 za 3-oksociklopentan.
Kao alkilne skupine navodimo za primjer - također kao sastavni dio drugih supstitueata - metil, etil, propil, izo-propil, butil, sec-butil, terc-butil, pentil, izo-pentil, neo-pentil, heksil, izo-heksil i kao primjere za alkilne ostatke s duljim lancem dekanil, undekanil, dodekanil i tridekanil kao i njihove izomere. Kao alkenilne ostatke navodimo za primjer alil ( u koliko ne stvaraju enamine), propenil, izo-propenil, butenil i izo-butenil (Et=etil).
Kao cikloalkilne ostatke označavamo npr. ciklopropil, ciklobutil, ciklopentil ili cikloheksil, koji mogu biti supstituirani alkilom s 1 do 4 ugljikova atoma. Benzilni ostatak kao i fenilna skupina mogu biti jedanput ili više puta supstituirani alkilom s 1 do 4 ugljikova atoma -ponajprije metilom, - alkoksi s 1 do 4 ugljikova atoma - ponajprije metoksi, - hidroksi i/ili halogenom - kao npr. florom, klorom ili bromom.
Pojam aril predstavlja aromatski prstenasti sustav s 6 do 12 ugljikova atoma, koji se može u danom primjeru supstituirati sa C1-C4-alkilom, halogenom, hidroksi, nitro, C1-C4-alkoksi, amino, C1-C4-alkilamino, i/ili C1-C4-dialkilamino; arilni ostatak koji ima prednost je fenil.
Kao primjere navodimo:
2-klorofenil, 2-bromofenil, 3-florofenil,
2,3-diklorofenil, 4-hidroksifenil, 2-metilfenil,
4-metilfenil, 3-etilfenil, 4-propilfenil,
4-izopropilfenil, 4-butilfenil, 4-terc-butilfenil
4-pentilfenil, 2,4-dimetilfenil,
2-trifluorometilfenil, 3-trifluorometilfenil,
2-metoksifenil, 4-metoksifenil, 3-etoksifenil,
2-proproksifenil, 4-butoksifenil, 2,4-dimetoksifenil,
3,4,5-trimetoksifenil, 2,4-dinitrofenil,
4-nitrofenil.
Kao primjere za cikličke ostatke opće formule NR5R6 neka navedemo: pirol, pirolin, pirolidin, 2-metilpirolidin, 3-metilpirolidin, piperidin - u danom primjeru jedan puta ili više puta supstituiran s C1-C4-alkilom - piperazin, N-metilpiperazin, N-etilpiperazin, N-n-propilpiperazin, N-benzilpiperazin, morfolin, tiomorfolin, imidazol, imidazolin, imidazolidin, pirazol, pirazolin, pirazolidin, - pri čemu se navedeni heterocikl može supstituirati alkilom s 1 do 4 ugljikova atoma - ponajprije metilom.
Kao heterocikličke ostatke, koji mogu biti vezani preko ugljikovog atoma, navodimo za primjer tiofen, 2-metiltiofen, 2-nitrotiofen, furan, 2-nitrofuran, tetrahidrofuran, 2-metiltetrahidrofuran,2-hidroksimetilfuran, tetrahidrofuranon, γ-butirolakton, α-piran, γ-piran, 1,3-dioksolan, 1,2-oksatiolan, 1,2-oksatiepan, tetrahidropiran, tiolan, 1,3-ditian, 1,3-ditiolan, 1,3-ditiolen, furfural, pri čemu se heterocikl može supstituirati kao što je navedeno u definicijama.
Kao heterocikličke ostatke, koji se mogu vezati preko C-atoma i koji sadrže najmanje jedan atom dušika, navodimo za primjer piridin, pirol, pirolin, pirolidin, piperidin, piperazin, morfolin, tiomorfolin, imidazol, imidazolin, imidazolidin, pirazolin, pirazolidin - pri čemu su navedeni heterocikli supstituirani sa C1-C4-alkilom.
Kao primjeri za prirodne amino kiseline vrijede alanin, valin, leucin, izoleucin, prolin, fenilalanin, triptofan, metionin, serin, treonin, cistein, tirozin, asparagin, glutamin, arginin, lizin.
Spojevi u smislu izuma su atagonisti adenozina; naročito imaju veliki afinitet (do 1,6 nM) do A1-receptora i veliku selektivnost za ovu vrstu receptora.
Tvari antagoniziraju u režnjevima hipokampusa s lenozinom inducirano gušenje akcijskog potencijala više stanica poslije električne stimulacije. In vivo možemo ustanoviti povečani sadržaj acetilholina u mozgu štakora.
Ovi rezultati ukazuju na to, da opisani derivati ksantina pojačavaju prirodnu staničnu aktivnost holinergnih neurona u mozgu i istiću se dakle kao funkcionalni holinomimetici sa centralnim djelovanjem.
EEG-ispitivanja kod mačaka pokazuju jasno povečanje vigilancije.
Tvari ove vrste su jako interesantne za simptomatično liječenje degenerativnih staračkih oboljenja, kao staračke slaboumnosti i Alzheimerove bolesti.
Veliki afinitet za receptore omogućava liječenje u malim dozama, tako da skoro nema sporednih učinaka a za koje nije kriva blokada receptora adenozina. Jednako bi zbog velike A1-selektivnosti spojeva izostali sporedni učinci ovisni o A1. Pored njihove uporabe, kao gerontopsihofarmatika I nootropika, mogli bi biti opisani antagonisti adenozina korisni za liječenje bolesti srca I krvotoka. Daljnje moguće indikacije su degenerativna oboljenja, kao što su npr. Organski moždani sindrom, Parkinson, traumatska oštećenja centralnog živčanog sustava, post stroke neurogical deficit, respiratory depression, (intoxication, post op), moždana trauma iz ranog djetinjstva. Farmakološki rezultati su prikazani u tablici Ia. Metode ispitivanja odgovaraju onima koje su navedene u sljedećim literaturnim navodima:
Lohse, M.J., V. Lenschow and U. Schwabe (1984) Mol. Pharmacol. 26, 1-9; citanina
Virus. M.R., T. Baglajewski and M. Rachelovacki (1984) Neurotiology of Agenig 5, 61-62;
Daly, J.W. W. Padgett, M.T. Shamin, P. Butts-Lamb and J. Waters (1985) J. Med. Chem. 28, 487-492;
Bruns. R.F., G.H. Lu and T.A. Pugsley (1986) Mol.Pharmacol. 29, 331-346.
Tablica Ia
Primjeri prema Ki [nMol]
tablici I (A1)
22 8 ⋅ 10-9
24 3 ⋅ 10-9
28 6 ⋅ 10-9
33 3 ⋅ 10-9
39 4 ⋅ 10-9
40 2 ⋅ 10-9
45 2 ⋅ 10-9
49 2 ⋅ 10-9
50 2 ⋅ 10-9
Spojeve u smislu izuma možemo prirediti prema samo po sebi poznatim analognim postupcima.
Općenito dobivamo 8-supstituirane 1,3-dialkil-ksantine kemijskom pretvorbom 1,3-dialkildiaminouracila s aldehidima, karboksilnim kiselinama ili kloridima karboksilnih kiselina ili kemijskom pretvorbom 1,3-dialkil-6-amino-5-nitrozouracila s aldehidima.
5,6-diamino-1,3-dimetiluracil se dobije; derivate, supstituirane s drugim ostacima, pripravljamo reakcijom odgovarajuće dialkiluree sa cijanooctenom kiselinom, tomu slijedi nitroziranje i u datom primjeru hidriranje ili redukcija s ditionitom u diamin. (J. Org. Chem. 16,1879 (1951)i Can. J. Chem. 45, 3413 (1968).
[image]
*dietilazodikarboksilat
(Rimski brojevi se odnose na radne propise, navedeni u eksperimentalnom dijelu).
Ksantine s jednim benzilnim ostatkom u položaju 3 i jednim, od njega različitim ostatkom, u položaju 1 dobijemo s 1-alkiliranjem odgovarajućih prethodnih molekula, koje su u položaju 3 supstituirane s benzilnom skupinom i u položaju 8 odgovarajuće supstituirane.
Ove možemo dobiti preko kemijske pretvorbe monobenziluree i cijanooctene kiseline u 6-amino-1-benziluracil (L.-F. Tietze und Th. Eicher, Reaktionen und Synthesen, Georg Thieme Verlag, Stuttgart 1981, str. 322), alkiliranje s željenim ostatkom u položaju 3 (XIV), nitroziranje položaja 5 (XV) i hidriranje u 3-supstituiran 1-benzil-5,6-diaminouracil (XVI). Aldehide, karboksilne kiseline i kiselinske kloride, koje upotrijebljavamo u kemijskoj pretvorbi s 5,6-diaminouracilima, možemo pripraviti prema postupcima poznatim iz literature.
U odgovarajućim primjerima možemo pripraviti opisane ksantine kemijskom pretvorbom 1,3-dialkil-6-klorobarbiturnih kiselina s H2N-CH2-R3, nitroziranjem zatvaranjem prstena ( vidi J. Med. Chem. 32, 1231 (1989)).
[image]
Prema ovako opisanim postupcima možemo pripraviti derivate ksantina, u kojima R3 ima npr. ovo značenje:
Tiofen, 2-metiltiofen, 2-nitrotiofen, furan, cikloheksan, cikloheksanon, tetrahidrofuranon, 1,3-ditian, piran, ciklobutan, cikloheksan, norbonen i drugi, u koliko možemo kemijski pretvoriti s odgovarajućim diaminouracilom već funkcionalizirane odgovarajuće aldehide R3CHO, karboksilne kiseline R3COOH ili njihove reaktivne derivate. Na tako dobivenim "ksantinskim osnovnim tvarima" možemo nato izvesti daljnje sintetske varijacije. Reaktivne funkcionalne skupine potrebno je kod toga u danom primjeru zaštiti na uobičajen način.
Ako polazimo od odgovarajućih 8-cikloalkanona, možemo redukcijom pripraviti odgovarajuće alkohole, koje možemo opet esterificirati s karboksilnim kiselinama ili kiselinskim kloridima ili kemijski pretvoriti s izocijanatima u karbamate. Kemijskom pretvorbom odgovarajućih ketona s hidroksilaminima možemo dobiti odgovarajuće oksime - sa supstituiranim hidrazinima odgovarajuće hidrazone. Keto funkciju možemo i na uobičajen način ketalizirati s alkoholima. Redukcija ketala - npr. s LiAlH4/AlCl3 - daje odgovarajuće etere. (U svim slijedećim formulama potrebno je zato shvatiti položaj ostataka samo kao primjere, ne da bi spojevi u smislu izuma bili ograničeni na navedene položaje).
[image]
n = 1 - 5; X = "ksantin"
Wittig-Hornerove kemijske pretvorbe na keto funkcijama s esterima fosfonskih kiselina dovode do supstituiranih olefina. Supstituirani spojevi dolje navedenih vrsta dostupni su s esterifikacijom karboksilnih kiselina, tvorbi amida kao i redukciji u alkohol i tomu slijedećoj esterifikaciji ili eterifikaciji, koje zatim možemo hidrirati.
[image]
8-furilne ili 8-tiofenilne derivate možemo formulirati po Vilsmeieru (IV). Tako dobivene aldehide uporabimo kod polaznog stupnja Wittig-Hornerove reakcije (X) s fosfonatima; produkte možemo dalje odgovarajuće derivatizirati prema gore navedenom postupku.
[image]
A = O, S; Z = privučen ostatak, X = ksantin
Aldehidi su prijemljivi za Knoevenagelovu reakciju (XI) s esterima malonske kiseline. Esterske skupine možemo reducirati u alkohole i ove esterificiramo ili eterificiramo.
Saponifikaciji jedne od esterskih skupina dajemo monokarboksilnu kiselinu. Ova se upotrebljava kao polazni stupanj za sintezu "miješanih funkcionalnih " derivata. Tako možemo dobiti kombinaciju ester/amid, alkohol (također esterificiran ili eterificiran)/karboksilna kiselina, alkohol (također esterificiran ili eterificiran)/amid, alkohol (također esterificiran ili eterificiran)/ester, miješani esteri.
[image]
[image]
X = ksantin
A = O, S;
Redukcijom odgovarajućih dostupnih aldehida dobijemo alkohole, koje možemo esterificirati ili eterificirati. Oksidacijske reakcije daju karboksilne kiseline, koje se s njihove strane mogu pretvoriti u estere ili amide.
[image]
Dvostruku vezu u 8-norbornenilnim derivatima možemo kemijskom pretvorbom s KMnO4 pretvoriti u cis-diol. Reakcija s m-kloroperbenzojevom kiselinom daje epoksid, kojeg se može otvoriti u trans-diol, kemijskom pretvorbom s natrijevim azidom u azido alkohol ili reducirati s litijevim tetrahidridoalanatom u odgovarajući alkohol. α-amino alkohol možemo dobiti s hidriranjem.
Ako polazimo od derivata ksantina, u kojima je R3 znači cikloalkanon, s Grignardovom reakcijom ili kemijskom pretvorbom s Li-organskim reagensima dobivamo derivate opće formule
[image]
u kojoj znači R8 metil, etil, butil, terc-butil, vinil, fenil i benzil.
Gore navedene cikloalkanone možemo prevesti tako zvanim Nozaki-Lombardovim reagensom u odgovarajuće metilenske derivate, koje možemo zatim reducirati u metilne spojeve (J. Org. Chem. 50,(8),1212(1985) ili koji daju poslije hidroboriranja s BH3-CH3SCH3/H2O2, OH- hidroksimetilne derivate.
Redukcija karbonilne skupine u - u danom primjeru supstituiranih - cikloalkanonima, npr. s natrijevim tetrahidridoboranatom, dovodi do odgovarajućih alkohola, koje možemo u slijedećim stupnjevima reakcije esterificirati ili eterificirati. Priprava enantiomerno čistih derivata ksantina, koji kao supstituent R3 mogu imati ciklopentanski ostatak, može se izvesti prema slijedećoj shemi sinteze:
[image]
Opći propisi XVIII i XIX sadrže daljnje pojedinosti o stereospecifičnim sintezama.
Opći propis I: Zatvaranje prstena s aldehidom
PRIMJER 1
1,3-dipropil-8-(1,4-benzodioksan-6-il)ksantin
2,18 g (0,013 mola) 1,4-benzodioksan-6-aldehida, 80 ml etanola i 2,4 ml ledene octene kiseline pomiješamo i dodamo 2,8 g (0,012 mola) 5,6-diamino-1,3-dipropiluracila. Bistru otopinu kuhamo 2 1/4 sata uz refluks i zatim ohladimo na 60oC. Pri toj temperaturi dokapavamo 2,1 ml (0,013 mola) dietil estera azodikarboksilne kiseline i nastaloj gustoj suspenziji dodamo 80 ml etanola i kuhamo 2 sata uz refluks. Nakon daljnjih 20 sati pri sobnoj temperaturi, ohladimo smjesu na 5oC, čvrstu tvar odsišemo i isperemo etanolom i eterom. Dobijemo 4,1 g sive čvrste tvari naslovnog spoja (= 92 % teor.), tal. 280-282oC.
Opći radni propis Ia: Zatvaranje prstena s aldehidima.
Primjer 1a
1-propil-3-benzil-8-(1,4-benzodioksan-6-il)ksantin
K 2,9 g (0,01 mola) 1-benzil-3-propil-5-nitrozo-6-aminouracila i 2,3 g (0,014 mola) 1,4-benzodioksan-6-aldehida u 60 ml dimetilformamida dodamo 0,5 g (0,014 mola) 1,1-dimetilhidrazina i smjesu zagrijavamo uz refluks 8 sati. Poslije uobičajene prerade etanolom očistimo kristaliničan ostatak te ga odsišemo. Dobijemo 1,0 g žutih kristala naslovnog spoja s tal. 290oC.
Opći propis II: Zatvaranje prstena s karboksilnom kiselinom.
Primjer 2
1,3-dipropil-8-(tetrahidropiran-4-il)ksantin
3,2 g (0,025 mola) tetrahidropiran-4-karboksilne kiseline, 4,0 g (0,025 mola) karbonildiimidazola i 85 ml apsolutnog metilen-klorida miješamo 30 minuta pri sobnoj temperaturi. Nakon dodatka 5,7 g (0,025 mola) 5,6-diamino-1,3-dipropiluracila miješamo smjesu pri sobnoj temperaturi 4 sata i nato uparimo u vakuumu. Ostatku dodamo 130 ml vode i 11,6 g kalcijeva kidroksida, miješamo pri 80oC 30 minuta i poslije hlađenja s ledom zakiselimo s konc. HCl. Smjesu ekstrahiramo s etilacetatom i organsku fazu posušimo i uparimo. Kromatografija kristaliničnog ostatka na silikagelu (CH2Cl2/CH3OH 99 :1) daje 1,7 g bijelih kristala naslovnog spoja (15 % teor.), tal. 171-172oC.
Primjer 2a
1,3-dipropil-8-(3-oksociklopentil)-ksantin
2,4 g (0,014 mola) 1,4-dioksaspiro|4,4|nonan-7-karboksilne kiseline otopimo u 56 ml metilen-klorida i nakon dodatka 2,2 g (0,014 mola) karbonildiimidazola miješamo pri sobnoj temperaturi 1 sat. Nato dodamo 3,2 g (0,014 mola) 5,6-diamino-1,3-dipropiluracila i još miješamo 4 sata pri sobnoj temperaturi. Otopinu uparimo u vakuumu, uljastom ostatku dodamo 70 ml vode i 4,5 g Ca(OH)2 i miješamo 1 sat pri 70oC. Dodamo 100 ml 50 %-nog NaOH, miješamo još jedan sat pri 70oC i 16 sati pri sobnoj temperaturi. Tijekom hlađenja s ledom podesimo otopinu na pH 6 s HCl i ekstrahiramo s metilen-kloridom. Sjedinjene organske faze daju poslije sušenja i uparavanja u vakuumu kristaliničan ostatak, kojeg prekristaliziramo iz etanola s aktivnim ugljenom. Dobijemo 0,8 g (16 %) bijelih kristala s tal. 147-148oC.
Dioksolansku zaštitnu skupinu nato hidroliziramo s kiselinom na način poznat iz literature i dobijemo naslovni spoj.
Primjer 2b
1,3-dipropil-8-(3-oksociklopentil)-ksantin
a)Priređivanje 3-okso-ciklopentankarboksilne kiseline
K 100,0 g metil estera 3-oksopentankarboksilne kiseline (0,7 mola) dodamo 1000 ml 2-molarne kloridne kiseline i miješamo 10 sati pri temperaturi vrenja. Otopinu ohladimo i u vakuumu potpuno uparimo. Preostalu vodu uklonimo s 3-puta po 50 ml toluena (toluen dodati preostatku i oddestilirati na Rotavaporu sa punim vakuumom vodenog mlaza i temperature vodene kupelji od 60 do 70oC). Sirovi dobitak destiliramo frakcionom destilacijom u visokom vakuumu.
1. frakcija: vrel.0,0220o -110oC (daje: 1,2 g ulja)
2. frakcija: vrel.0,02110o -116oC
daje: 4,7 g djelomično kristaliničnog ulja
3. frakcija: vrel.0,02116o -121oC
daje; 74,0 g bezbojnoga ulja, koje je kasnije iskristaliziralo.
Dobitak 74,0 g (82,1 % teor.).
K 8,8 g 3-oksociklopentankarboksilne kiseline (0,072 mola) u 240 ml apsolutnoga metilen-klorida dodamo uz miješanje pri 20oC do 25oC 11,6 g karbonildiimidazola i miješamo 2 sata pri sobnoj temperaturi. Nato pri 20-25oC dodamo 16,0 g 1,6-diamino-1,3-di-n-propil-uracila (0,072 mola) i još miješamo 3 sata pri sobnoj temperaturi. Reakcijsku smjesu uparimo u vakuumu do suhoga. Uljnatom ostatku dodamo 3200 ml destilirane vode i 35 g kalcijeva hidroksida i miješamo 0,5 sata pri 80oC. Nato ohladimo na 5oC i s konc. kloridnom kiselinom podesimo na pH 1 do 2 i 3-puta ekstrahiramo s po 100 ml CH2Cl2. Sjedinjene organske faze isperemo jedanput s 100 ml vode, posušimo s magnezijevim sulfatom, odfiltriramo i do suhoga uparimo. Sirovi dobitak očistimo preko 350 g Kieselgela S160 s oko 4 l eluenta CH2Cl2:CH3OH 99:1. ^iste frakcije do suhoga uparimo. Kristaliničan ostatak očistimo s 100 ml etera i odsišemo.
Dobitak: 11,5 g sivih kristala(50,2 % teor.).
Tal.: 164-168oC.
Opći propis III: Zatvaranje prstena s kiselinskim kloridom.
Primjer 3
1,3-dipropil-8-(4,7,7-trimetil-2-oksa-biciklo[2.2.1]heptan-3-on-1-il)ksantin
1,2 g (5,4 mmola) 5,6-diamino-1,3-dipropiluracila i 1,0 g trietilamina (10 mmola) otopimo u 50 ml apsolutnog metilen-klorida. Nakon dokapavanja 1,2 g (5,5 mmola) klorida kamfanske kiseline miješamo 20 sati pri sobnoj temperaturi i uparimo u vakuumu. Ostatku dodamo 28 ml vode i 1,7 g kalcijeva hidroksida i miješamo 3 sata pri 80oC. Suspenziju ohladimo s ledom, te ju prilikom hlađenja zakiselimo i ekstrahiramo s metilen-kloridom. Sjedinjene organske faze posušimo i uparimo, ostatak očistimo kromatografijom na silikagelu (CH2Cl2/CH3OH 99:1).
Dobijemo 200 mg bijelih kristala naslovnog spoja (10 % teor.), tal. 200-201oC.
Opći propis IV: Vilsmeierova reakcija.
Primjer 4
1,3-dipropil-8-(2-formilfuran-5-il)ksantin
K 400 ml apsolutnog dimetilformamida dokapavamo kod 0-10oC 16,4 g (0,11 mola) fosforoksiklorida. Kod 5-15oC dodamo otopinu 15,0 g (0,05 mola) 1,3-dipropil-8-furanilksantina u 330 ml dimetilformamida. Nastavljamo s miješanjem 1 sat pri sobnoj temperaturi i 7 sati pri 85oC. Smjesu stavimo na 500 ml leda i ekstrahiramo s metilen-kloridom. Sjedinjene organske ekstrakte posušimo i uparimo u vakuumu, ostatak kristaliziramo iz etera.
Dobijemo 12,1 g smeđih kristala naslovnog spoja (73 % teor.), tal. 215-217oC.
Opći propis V: Oksidacija aldehida u kiselinu.
Primjer 5
1,3-dipropil-8-(2-karboksifuran-5-il)ksantin
Otopinu 0,26 g (1,5 mmola) srebro nitrata u 2 ml vode potresamo 5 minuta s otopinom 0,4 g natrijeva hidroksida u 1 ml vode. Sivo crni talog srebro oksida pustimo da se slegne i isperemo s vodom i zatim preuzmemo u 5 ml vode i dodamo 1,3-dipropil-8-[5-formil-(2-furanil)]ksantina. Smjesu zagrijemo na 50oC i polako dokapavamo otopinu 0,1 g natrijeva hidroksida u 2 ml vode. Nastavimo miješati 15 minuta pri 50oC i 1 sat pri sobnoj temperaturi i filtriramo. Filtrat zakiselimo i dodamo mu metilen-klorida, izlučeni talog odsišemo i isperemo s metilen-kloridom i eterom.
Dobijemo 0,4 g svijetlo žutih kristala naslovnog spoja (77 % teor.).
Opći propis VI: Knoevenagelova reakcija.
Primjer 6
1,3-dipropil-8-[2-(2,2-bis(etoksikarbonil)vinil)-furan-5-il]ksantin
Zajedno stavimo 2,5 g (7,6 mmola) 1,3-dipropil-8-[5-formil-(2-furanil)]ksantina, 1,2 g (7,6 mmola) dietilestera malonske kiseline, 0,03 g (0,3 mmola) piperidina, 0,09 g (1,5 mmola) ledene octene kiseline i 5 ml benzena p.a. i kuhamo 6 sati u separatoru vode. Nakon hlađenja razrijedimo ostatak s 10 ml toluena, čvrstu tvar odsišemo i otopimo u 100 ml toplog metilen-klorida. Otopinu filtriramo, filtrat uparimo u vakuumu i ostatak prekristaliziramo iz 2-propanola.
Dobijemo 1,0 g žutih kristala naslovnog spoja (28 % teor.), tal. 220-222oC.
Opći propis VII: Općenita priprava amida.
Primjer 7
1,3-dipropil-8-[2-(N,N-dietilaminokarbonil)furan-5-il]-ksantin
1,0 g (2,9 mmola) 1,3-dipropil-8-[2-karboksifuran-5-il]ksantina otopimo u apsolutnom dimetilformamidu i kod 0-5oC dodamo 0,38 g trietilamina i 0,45 g (3,3 mmola) izobutilkloro-formijata. Nastavimo s miješanjem 2 sata pri 0-5oC, a zatim dodamo 0,34 g (2,9 mmola) N,N-dietilamino-etilamina i smjesu još miješamo oko 12 sati u otapajućoj ledenoj kupelji. Nastavimo uparavanje u visokom vakuumu, dodamo metilen-klorid i vodu, zalužimo i ekstrahiramo s metilen-kloridom. Organske faze svaki puta odbacimo, vodenu fazu zakiselimo i ponovno ekstrahiramo. Sjedinjene organske ekstrakte posušimo, filtriramo i uparimo, a ostatak kristaliziramo iz etilacetata.
Dobijemo 0,25 g žućkastih kristala naslovnog spoja, tal. 247-250oC.
Opći propis VIII: Redukcija ketona ili aldehida u alkohol.
Primjer 8
1,3-dipropil-8-(1-hidroksiciklopent-3-il_ksantin
0,5 g (1,6 mmola) 1,3-dipropil-8-(1-okso-3-ciklopentil)ksantina, 10 ml etanola i 0,1 g (2,6 mmola) natrijeva tetrahidroboranata miješamo 2 1/2 sata pri sobnoj temperaturi. Nastavimo uparavanje u vakuumu te dodamo vodu i metilen-klorid, vodenu fazu zakiselimo i ekstrahiramo. Sjedinjene organske ekstrakte posušimo i uparimo u vakuumu. Ostatak rastavimo u izomere kromatografijom na silikagelu
CH2Cl2/CH3OH 95:5). Iz 1. frakcije dobijemo 0,4 g bijelih kristala naslovnog spoja (39 % teor.), tal. 174-176oC, i iz 2. frakcije 0,4 g bijelih kristala naslovnog spoja (39 % teor.), tal. 191-193oC.
Opći propis IX: Aciliranje alkohola.
Primjer 9
1,3-dipropil-8-[1-((4,7,7-trimetil-2-oksa-biciklo[2.2.1]heptan-3-on-1-il)karboniloksi)ciklopentan-3-il]ksantin
0,2 g (0,6 mmola) 1,3-dipropil-8-(1-hidroksi-3-ciklopentil)ksantina i 0,24 g (3 mmola) piridina umiješamo u 10 ml apsolutnog metilen-klorida i nakon dodatka 0,2 g (0,9 mmola) klorida kamfanske kiseline miješamo 4 sata pri sobnoj temperaturi. Nastavimo dodavanje vode i vodenu fazu odvojimo. Organsku fazu posušimo i uparimo u vakuumu, ostatak zatim očistimo kromatografijom na silikagelu (CH2Cl2/CH3OH 95:5).
Dobijemo 50 mg žućkastog ulja naslovnog spoja.
Opći propis X: Wittig-Hornerova reakcija.
Primjer 10
1,3-dipropil-8-(1-cijanometilenciklopent-3-il)ksantin
0,28 g (1,6 mmola) dietilestera cijanmetanfosfonske kiseline otopimo u 20 ml apsolutnoga benzena i kuhamo s 0,13 g (3,2 mmola) 60 %-nog dispergiranog natrijeva hidrida uz refluks 5 sati. Nastavimo s uparavanjem u vakuumu i preuzmemo u metilen-kloridu i vodi i zatim zakiselimo. Vodenu fazu ekstrahiramo i sjedinjene organske ekstrakte posušimo i uparimo. Ovome sljedeća kromatografija na silikagelu (CH2Cl2/CH3OH 97:3) daje 0,1 g bezbojnog ulja naslovnog spoja (18 % teor.).
Opći propis XI: Hidriranje dvostruke veze.
Primjer 11
1,3-dipropil-8-(norbornan-2-il)ksantin
1,0 g (3,1 mmola) 1,3-dipropil-8-(5-norbornen-2-il)ksantina hidriramo pod tlakom u 30 ml etanola uz dodatak paladija na ugljenu, dok se više ne primjećuje preuzimanje vodika. Katalizator odfiltriramo, filtrat uparimo i ostatak kromatografiramo na silikagelu (CH2Cl2/CH3OH 99:1).
Dobijemo 0,4 g bijelih kristala naslovnog spoja (39 % teor.), tal. 136-138oC.
Opći propis XII: Saponifikacija estera.
Primjer 12
1,3-dipropil-8-(2-(2'-etoksikarbonil-2'-karboksivinil)-furan-5-il)ksantin
K otopini 0,8 g (1,4 mmola) kalijeva hidroksida u 20 ml etanola dodamo 3,2 g (6,8 mmola) 1,3-dipropil-8-[2-(2',2'-bis(etoksikarbonil)vinil)-furan-5-il]ksantina i smjesu kuhamo 4 sata uz refluks. Nakon hlađenja razrijedimo s 50 ml vode i ekstrahiramo s metilen-kloridom. Vodenu fazu uz hlađenje u ledu zakiselimo, a nastali talog odfiltriramo i isperemo s vodom.
Dobijemo 2,2 g žućkastih kristala naslovnog spoja ( 73 % teor.), tal. 252-253oC.
Opći propis XIII: Redukcija estera u alkohol.
1,7 mmola estera otopimo u 5 ml tetrahidrofurana i dokapavamo k suspenziji litijeva alumianata (0,04 g, 1,1 mmola) u 5 ml tetrahidrofurana. Smjesu miješamo 36 sati pri sobnoj temperaturi i dodamo joj zasićenu otopinu diamonijeva tartarata. Vodenu fazu ekstrahiramo s etilacetatom, sjedinjene organske ekstrakte posušimo i uparimo u vakuumu.
Produkt očistimo kristalizacijom ili kromatografijom na silikagelu.
Opći propis XIV: N-alkiliranje.
Primjer 13
1-benzil-3-propil-6-aminouracil
3,0 g (0,04 mola) 1-benzil-6-aminouracila pomiješamo s 2,2 g (0,018 mola) n-propilbromida, 4,2 ml 15 %-ne natrijeve lužine i 7 ml etanola 3 sata pri 70oC. Smjesu izlijemo na led i ekstrahiramo s metilen-kloridom. Organske faze posušimo i uparimo. Preostalo ulje kristaliziramo iz smjese metilen-klorida i metanola.
Dobijemo 1,62 g bijelih kristala naslovnog spoja (47 % teor.), tal. 189-192oC.
Opći propis XV: Nitroziranje.
Primjer 14
1-benzil-3-propil-5-nitrozo-6-aminouracil
2,0 g (7,7 mmola) 6-amino-1-benzil-3-propiluracila zagrijemo sa 15 ml vode na 80oC i dodamo 0,55 g natrijeva nitrita u 3 ml vode. Nakon dodatka 1 ml ledene octene kiseline izluči se crvena čvrsta tvar. pH podesimo na 4 i suspenziju miješamo pri 80oC još 30 minuta. Nakon hlađenja kristale odsišemo i isperemo s vodom.
Dobijemo 1,9 g crvenoljubičastih kristala naslovnog spoja (86 % teor.), tal. 208-212oC/raspad.
Opći propis XVI: Hidriranje nitrozo spoja.
3-supstituirani 6-amino-1-benzil-5-nitrozouracil preuzmemo u metanolu i nakon dodatka Raneyevog nikla hidriramo pod tlakom.
Katalizator odfiltriramo, filtrat uparimo i ostatak očistimo kristalizacijom ili s kromatografijom.
Opći propis XVII: Eterifikacija.
Eterifikacija alkohola se izvodi deprotonizacijom hidroksi funkcije s jakom bazom (npr. natrijevim hidridom u tetrahidrofuranu ili dimetilformamidu, natrijevim hidroksidom) i kemijski pretvora s elektrofilom vrste L-X, pri čemu X može biti halogen, tozil, mezil ili slično.
Opći propis XVIII:
Primjer 15
(+) 1,3-dipropil-8(3-hidroksiciklopentil)ksantin
a) 2,0 g (6,2 mmola) racemičnog 1,3-dipropil-8-(3-hidroksiciklopentil)ksantina suspendiramo u 2 l apsolutnoga toluena i uz snažno miješanje dodamo 640 mg acetanhidrida i 2,0 g lipaze iz Candida cylindracea. Poslije 6 sati pri sobnoj temperaturi enzim odfiltriramo i isperemo s metanolom. Sjedinjene filtrate uparimo do suhog u vakuumu i ostatak kromatografiramo s CH2Cl2/CH3OH 95:5 na silikagelu.
b) Dobijemo 0,6 g acetiliranog produkta, kojeg otopimo u 22 ml apsolutnoga THF i nakon dodatka 70 mg litijeva aluminijeva hidrida miješamo 2 sata pri sobnoj temperaturi. Dok hladimo s ledom hidroliziramo s 5 ml vode, koju dokapavamo, zakiselimo i ekstrahiramo s metilen-kloridom. Organsku fazu posušimo i uparimo i ostatak kromatografiramo s CH2Cl2/CH3OH 95:5 na silikagelu. Dobijemo 450 mg alkohola, koji ima zakretanje |α|20D = +12O (c = 0,4, metanol).
c) Optičko obogaćeni alkohol otopimo u 490 ml apsolutnog metilen-klorida i dodamo 490 ml acetanhidrida i 1,5 g lipaze "Amano P". Smjesu 24 sata miješamo pri sobnoj temperaturi, enzim odfiltriramo i filtrat uparimo do suhog u vakuumu. Kromatografija na silikagelu s CH2Cl2/CH3OH 95:5 daje 480 mg alkohola naslovnog spoja sa zakretanjem |α|20D = +18,2O (c = 0,5, metanol); optički čisti prema HPLC > 99 %.
Opći propis XIX:
Primjer 16
(-) 1,3-dipropil-8-(3-hidroksiciklopentil)ksantin
a) 1,0 g racemičnog 1,3-dipropil-8-(3-hidroksiciklopentil)ksantina suspendiramo u 1 l apsolutnog toluena i miješamo 8 sati pri sobnoj temperaturi s 320 g acetanhidrida i 1,0 g lipaze Candida cylindracea. Enzim odfiltriramo, isperemo s metanolom i filtrate uparimo do suhog u vakuumu. Ostatak kromatografiramo s CH2Cl2/CH3OH 95:5 na silikagelu. Dobijemo 0,45 g kristaliničnog ostatka, kojeg očistimo s eterom i odsišemo. Dobijemo 350 mg kristala sa zakretanjem |α|20D = -13,7O (c = 0,4,metanol).
b) Optičko obogaćeni alkohol ponovno miješamo 16 sati pri sobnoj temperaturi s toluenom s 110 mg acetanhidrida i 350 mg lipaze iz Candida cylindracea. Nastavljamo s preradom kao što je gore opisano. Dobijemo 200 mg bezbojnih kristala sa zakretanjem |α|20D = -20,2o (c = 0,5, CH3OH), čistoća enantiomera prema HPLC > 99,5 %.
Opći propis XIX:
Primjer 16
(+) i (-) 1,3-dipropil-8-(3-oksociklopentil)ksantin
1,0 g optičko čistog alkohola otopimo u 30 ml apsolutnog metilen-klorida i nakon dodatka 1,1 g piridinijeva klorokromata miješamo 2,5 h pri sobnoj temperaturi. Smjesu operemo dvaputa vodom, vodenu fazu ekstrahiramo s metilen-kloridom, sjedinjene organske faze posušimo i uparimo u vakuumu. ^išćenje se izvodi kromatografijom na silikagelu s CH2Cl2/CH3OH 99:1, 98:2 i 97:3.
U ovisnosti od uporabljenog optičko čistog alkohola dobijemo ove spojeve:
(+) alkoholi daju
(-) 1,3-dipropil-8-(3-oksociklopentil)ksantin
|α|20D = -8,3O (c = 0,5, metanol);
(-) alkohol daje
(+)1,3-dipropil-8-(3-oksociklopentil)ksantin
|α|20D = -8,3O (c = 0,5, metanol)
Službena nomenklatura ovih spojeva prema Chemical abstractu je: 8-(3-oksociklopentil)-1,3-dipropil-7H-purin-2,6-dion.
Spojeve navedene u tablici I možemo pripraviti analogno, kao što su opisani u radnim propisima ili prema poznatim analognim postupcima.
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Spojeve opće formule I možemo uporabiti same ili u kombinaciji s drugim aktivnim tvarima u smislu izuma, u danom
primjeru također u kombinaciji s daljnjim aktivnim farmakološko aktivnim tvarima. Pogodni uporabni oblici su npr. tablete, kapsule, čepići, otopine, sokovi, emulzije ili disperzivni prašci. Odgovarajuće tablete možemo npr. dobiti miješanjem aktivne tvari ili aktivnih tvari s poznatim pomoćnim tvarima, npr. inertnim otapalima, kao kalcijevim karbonatom, kalcijevim fosfatom ili mliječnim šećerom, dezintegracijskim sredstvima, kao kukuruznim škrobom ili alginskom kiselinom, vezivima, kao škrobom ili želatinom, lubrikantima, kao magnezijevim stearatom ili talkom, i/ili sredstvima za postizavanje depojnog učinka, kao karboksimetilcelulozom, celuloznim acetatftalatom ili polivinilacetatom. Tablete se mogu sastojati i iz više slojeva.
Na sličan način možemo prirediti dražeje s presvućenim jezgrama, pripravljene analogno tabletama, sa sredstvima koja se obično upotrebljavaju u prevlakama za dražeje, npr. kolidonom ili šelakom, gumi arabikom, talkom, titanovim dioksidom ili šećerom. Za postignuće depojnog učinka ili da zaobiđemo inkompatibilnost, može se jezgra sastojati iz više slojeva. Jednako se tako za postignuće depojnog učinka može i presvlaka dražeje sastojati iz više slojeva, pri čemu možemo uporabiti pomoćne tvari, spomenute gore kod tableta.
Sokovi učinkovina u smislu izuma, odnosno kombinacije učinkovina mogu još dopunsko sadržavati sladila, kao saharin, ciklamat, glicerin ili šećer, kao i sredstvo za poboljšanje okusa, npr. tvari za aromu, kao vanilin ili narančin ekstrakt.
Osim toga mogu sadržavati suspendirane pomoćne tvari ili gustila, kao natrijevu karboksimetilcelulozu, sredstva za vlaženje, npr. kondenzacijske produkte masnih alkohola s etilenoksidom, ili zaštitne tvari, kao p-hidroksibenzoate.
Injekcijske otopine pripravimo na uobičajen način, npr. sa dodatkom sredstava za konzerviranje, kao p-hidroksibenzoata ili stabilizatora, kao alkalijske soli etilendiaminotetraoctene kiseline i punimo ih u injekcijske boce ili ampule.
Kapsule, koje sadrže jednu ili više aktivnih tvari odnosno kombinaciju aktivnih tvari, možemo pripraviti npr. tako da pomiješamo učinkovine s inertnimi nosačima, kao mliječnim šećerom ili sorbitom, i onda ih stavimo u želatinozne kapsule.
Prikladne čepiće možemo pripraviti npr. miješanjem za ovo predviđene nosače sredstava, kao neutralnih masti ili polietilenglikola odnosno njihovih derivata.
Slijedeći primjeri zorno prikazuju ovaj izum, ne da bi njegov obim ograničavali.
Primjeri farmaceutskih formulacija
A) Tablete na tabletu
učinkovina 100 mg
mliječni šećer 140 mg
kukuruzni škrob 240 mg
polivinilpirolidon 15 mg
magnezijev stearat 5 mg
500 mg
Fino mljevenu učinkovinu, mliječni šećer i dio kukuruznog škroba međusobno pomiješamo. Mješavinu prosijemo, našto je ovlažimo otopinom polivinilpirolidona u vodi, gnječimo, vlažnu granuliramo i posušimo. Granulat, ostatak kukuruznog škroba i magnezijev stearat prosijemo i međusobno pomiješamo. Mješavinu prešamo u tablete prikladnog oblika i veličine
B) Tablete na tabletu
učinkovina 80 mg
kukuruzni škrob 190 mg
mliječni šećer 55 mg
mikrokristalinična celuloza 35 mg
polivinilpirolidon 15 mg
natrijev karboksimetil-škrob 23 mg
magnezijev stearat 2 mg
400 mg
Fino mljevenu učinkovinu, dio kukuruznog škroba, mliječni šećer, mikrokristaliničnu celulozu i polivinilpirolidon međusobno pomiješamo, mješavinu prosijemo i s preostatkom kukuruznog škroba i vode preradimo u granulat, kojeg posušimo i prosijemo. Tome dodamo natrijev karboksi-metil škrob i magnezijev stearat, pomiješamo i mješavinu prešamo u tablete prikladnih veličina.
Claims (7)
1. Novi ksantini opće formule I,
[image]
naznačeni time, da.predstavlja
R1 alkilnu skupinu s 1 do 6 - ponajprije 1 do 4 - ugljikova atoma, alkenilnu skupinu s 3 ili 4 ugljikova atoma;
alkinilnu skupinu s 3 ili 4 ugljikova atoma;
R2 alkenilnu skupinu s 3 ili 4 ugljikova atoma, alkilnu skupinu s 1 do 6 - ponajprije 1 do 4 - ugljikova atoma, u datom primjeru supstituiranu benzilnu skupinu, alkinilnu skupinu s 3 ili 4 ugljikova atoma;
R3 C-vezan zasićen ili nezasićen pet-, šest- ili sedmeročlani heterociklički prsten, koji sadrži jedan ili više heteroatoma, izabranih iz grupe kisik ili sumpor, i mogu u datom primjeru nositi jednog od sljedećih ostataka
C1 do C6 - ponajprije C1 do C4 - alkil,
=0, -CHO, -CH2OR4 –CH2OR7, COOR4,
CONR5R6, pri čemu može furanski ili tiofenski ostatak nositi i jedan od ostataka
-CH=CH-CONR5R6
-CH=C (COOR4)2 (R4 jednaka ili različita),
-CH=C (COOR4) (CONR5R6) ,
-CH=C(COOR4) (CH2OR4) (R4 jednaka ili različita)
-CH=(COOR4) (CH2OR7),
-CH=C(CH2OR4)2,
-CH=CH2OR7)2,
-CH=C (CONR5R6) CH2OR4,
-CH=C (CONR5R6) CH2OR7 ili nitro i tetrahidrofuranski ostatak i ostatak
-(CH2)2-CONR5R6;
R3 C4 do C8 - cikloalken, koji može biti supstituiran sa C2 do C4-alkenilom,
R3 C4 do C8 - ponajprije C5 i C6 - cikloalkanon ili
C4 do C8 - ponajprije C5 i C6 - cikloalkanol, koji može biti u položaju α substituirani sa C2 do C6 - ponajprije C2 do C4 - alkenilom, C2 do C6 - ponajprije C2 i C4 -alkinilom, u datom primjeru supstituiranim benzilom, sa CH2OR4, CH2COOR7, (CH2)2CN,
R3 C3 do C8 - ponajprije C5 i C6 - cikloalkan, koji može u datom primjeru biti supstituiran sa C1 do C6 - ponajprij C1 i C4 - alkilom, =CH2, =N-NH-arilom, ponajprije =N-NH-fenilom, pri čemu može arilni odnosno fenilni ostatak biti supstituiran, =N-NH-C1 do C6-alkilom, =NOH,
-OCONH-arilom, ponajprije -OCONH-fenilom, pri čemu može arilni odnosno fenilni ostatak biti supstituiran, OCONH-C1 - C6-alkilom,
-OR4, -OR7, -(CH2)1-COOR4,
- (CH2)1-NR4R4 (R4 jednaka ili različita) ,
-(CH2)1-CONR5R6,
-(CH2)1-OR4, -(CH2)1-OR7,
pri čemu 1 znači jedan od brojeva 0, 1, 2, 3 ili 4, ili ostatak =CAH - pri čemu može A značiti COOR4, CN, CONR5R5 CH=CH-COOR4, CH=CH-CONR4R6, CH2OR4, ili CH2OR7 ili je cikloalkan supstituiran sa C1 do C6 - ponajprije
C1 do C4 - alkilom, vinilom, alilom, u datoni primjeru supstituiranim fenilom, u datom primjeru supstituiranim C1 - C4 -alkilfenilom, i nosi kao drugi supstituent hidroksilnu skupinu u geminalnom položaju glede na prvi supstituent;
R3 stvara zajedno s cikloalkanom ketal opće formule
[image]
u kojoj znače
Ra C1-C4-alkil i
Rb C1-C4-alkil ili Ra i Rb zajedno stvaraju C2- ili C3-alkilenski ostatak, koji može u datom primjeru biti jedanputa ili dva puta supstituiran sa C1 do C5-alkilom, C1-C5-alkiloksikarbonilom, hidroksi-C1 do C5-alkilom,
ponajprije hidroksimetilom;
R3 u datom primjeru supstituirani ostatak formule
[image]
R3 ostatak formule
[image]
i
R4 vodik, alkilnu skupinu s 1 do 13 - ponajprije 1 do 6 i 11 do 13 - ugljikova atoma, u datom primjeru supstituiranu cikloalkilnu skupinu s 3 do 6 ugljikova atoma, u datom primjeru supstituiranu benzilnu skupinu, alkenilnu skupinu s 3 do 13 - ponajprije 3 do 6 -ugljikova atoma, propargilni ostatak, tritilni ostatak,
R5 vodik, alkilnu skupinu s 1 do 6 - ponajprije 1 do 4 -ugljikova atoma, u datom primjeru supstituiranu cikloalkilnu skupinu s 3 do 6 ugljikova atoma;
R6 vodik, alkilnu skupinu s 1 do 6 - ponajprije 1 do 4 -ugljikova atoma, u datom primjeru supstituiranu benzilnu skupinu, ostatak s općim formulama
-(CH2)n-NR5R5,
- ( (CH2)n -O- (CH2)m-O)k (CH2)n-NR5R5
(R5 jednaka ili različita)
s n = 2, 3, 4, 5, 6, 7 ili 8, m = 2, 3, 4, 5 ili 6
i k = 0 ili l,
[image]
(R5 jednaka ili različita),
pri čemu može biti piperazinski prsten supstituiran sa C1-C4 -alkilom -ponajprije metilom, C-vezan piperidinilni ostatak, koji je u datom primjeru supstituiran sa C1 do C4-alkilom ili N-vezanim benzilnim ostatkom ili
R5 i R6 tvore zajedno s dušikovim atomom u datom primjeru sa C1-C4-alkilom supstituiran pet- ili šest-ili sedmeročlani prsten, koji može sadržati daljnji heteroatom iz grupe kisik, sumpor ili dušik, pri čemu može biti atom dušika supstituiran s ostatkom R4;
R7 preko karbonilne funkcije vezan aminokiselinski ostatak prirodne amino kiseline, CO-C1-C13-alkil, ponajprije CO-C2-C4-alkil, metoksiacetil, preko karbonilne skupine vezani ostatak kamfanske kiseline, abietinoil, 4-aminobutiroil, u datom primjeru supstituirani benzoil, ponajprije trimetoksibenzoil, ostatak opće formule CO-B, pri čemu je B u datom primjeru supstituiran, C-vezan 5-, 6- ili 7-člani heterocikl,
kao i u datom primjeru njihovi racemati, njihovi optičko aktivni spojevi kao i njihove farmakuloški besprijekorne kiselinske adicijske soli.
2. Ksantini opće formule I, naznačeni time, da
predstavlja
R1 ravnu alkilnu skupinu s 3 do 4 ugljikova atoma, alilnu skupinu, propargilnu skupinu;
R2 alilnu skupinu, alkilnu skupinu s 3 do 4 ugljikova atoma, propargilnu skupinu;
R3 ostatak, izabran iz skupine furan, tetrahidrofuran, tetrahidrofuranon, tiofen, ditiol, ditian ili tetrahidropiran, koji može nositi jednoga od slijedećih supstituenata
metil, etil, propil, butil, CHO, CH2OR4, CH2OR7, COOR4, CONR5R6,
R3 s
-CH=CH-CONR5R6, -CH=C(COOR4)2 (R4 jednaka ili različita),
-CH=C(COOR4)6(CONR5R6),
-CH=C(COOR4)(CH2OR4) (R4 jednaka ili različita),
-CH=C(COOR4)(CH2OR7),
-(CH2)n-CONR5R6,
-CH=C(CH2OR4)2,
-CH=C(CH2OR7)2,
-CH=C(CONR5R6)CH2OR4 ili
-CH=C(CONR5R6)CH2OR7 susupstituiran furan;
R3 ciklopentan ili cikloheksan, koji je u datom primjeru supstituiran s metilom, etilom, propilom, izo-propilom, t-butilom, alilom, vinilom, fenilom ili benzilom, pri čemu može kao geminalni supstituent biti prisutna hidroksi skupina;
R3 ciklopentan ili cikloheksan, supstituiran s hidroksi, metoksi, etoksi, propiloksi, trimetoksikarbonilom,izo-propiloksi, u datom primjeru supstituiran benziloksi, aliloksi, propargiloksi,
-CH2-CH2-OH,
-CH2-COOCH3, =CH-COOCH3, =C-CN,
-(CH2)2NH2, =CH2,
[image]
=NOH, -CH2OH, OR4 s R4 = metil ili tritil,
OR7, gdje je R7 COCH3, COC2H5, COC3H7,
CO t-butil, -CO-fenil ili COCH2-fenil, koji je u datom primjeru supstituiran, CO-piridil,
-(N-metil-4H-piridil),
- (metilpiridil) , -COCH2-CH=CH2,
-CO-CH2-CCH;
R3 ostatak
[image]
s Ra, Rb = CH3, C2H5 ili Ra i Rb zajedno -CH2-CH2-,
R3 ciklopentanon ili cikloheksanon,
R3 cikloalkan ili cikloalken s 4 do 8 ugljikova atoma, koji može u datom primjeru biti supstituiran s ravnom ili razgranatom alkenilnom skupinom s 2 do 4 ugljikova atoma, ciklopentanon ili ciklopentanol ili cikloheksanon ili cikloheksanol, koji mogu u položaju glede na keto ili hidroksi skupinu biti supstituirani sa C2 do C4-alkenilom,C3 ili C4-alkinilom, benzilom, -CH2CH2CN, (CH2)3NR5R5 (R5 jednaka ili različita), CH2COOR4, CH2OR4, pri čemu R4 može značiti vodik, metil, etil ili propil;
R3 norbonan ili norbonen - u datom primjeru supstituiran,
[image]
R4 vodik, alkilnu skupinu s 1 do 3 ugljikova, ciklopropilnu skupinu, ciklopentilnu skupinu, benzil, alilnu skupinu, propargilnu skupinu, trifenilmetilnu skupinu;
R5 vodik, alkilnu skupinu s 1 do 3 ugljikova atoma; ciklopropilnu skupinu, benzilnu skupinu;
R6 vodik, metil, etil, propil,
-(CH2)n-NH2 (n=2-8),
-(CH2)nNEt2 (n=2,3) ili
-(CH2)3-O-(CH2)4-O-(CH2)3-NH2,
N-benzil-piperidin-4-, ili R5 i R6 zajedno s dušikovim atomima piperidinski, piperazinski, morfolinski ostatak, koji u datom primjeru može biti supstituiran sa C1-C4-alkilnim ostatkom, ponajprije metilom;
R7 prolinoil, (CH2)0-3-CH3,
(-) - metoksiacetil, preko karbonilne skupine vezan ostatak kamfanske kiseline, abietinoil, benzoil,
4-aminobutiroil, 3,4,5-trihidroksibenzoil, 3,4,5-trimetoksibenzoil, ostatak nikotinske kiseline,
izonikotinske kiseline ili pikolinske kiseline,
ostatak N-metilnikotinske kiseline,
ostatak N-metil-4H-nikotinske kiseline,
kao i u datom primjeru njihove kiselinske adicijske soli.
3. Postupak za pripravu ksantina opće formule 1
[image]
u kojoj su R1, R2 i R3 definirani kao u zahtjevu 1 i 2,
naznačeni time, da
a) spoj opće formule
[image]
u kojoj su R1 i, kemijski pretvorimo sa spojem opće formule R3CHO, u kojoj je R3
definiran kao prije, pri čemu je potrebno funkcionalnu skupinu R3 u datom primjeru zaštiti, i zatim cikliziramo s
N,N-dimetilhidrazinom; ili
b) spoj opće formule
[image]
kemijski prtvorimo sa spojem opće formule R3CHO, R3COOH ili njihovim reaktivnim derivatima - pri čemu je potrebno funkcionalnu skupinu R3 u datom primjeru zaštititi, i zatim cikliziramo u ksantin s općom formulom I; ili
c) spoj opće formule
[image]
u kojoj su R1 , R2 i R3 definirani kao prije,
cikliziramo u spoj opće formule I,
i nato spoj, prireden prema a, b ili c, u datom primjeru prema samo po sebi poznatim postupcima obradimo ovako:
d) spoj opće formule 1
[image]
u kojoj X znači ksantinski ostatak, prevedemo
1) u spoj formule
[image]
ili 3) u spoj
[image]
[image]
koje možemo u datom primjeru hidrirati,
ili
6) u spoj
[image]
ili
7) s Grignardovom reakcijom ili s kemijskom pretvorbom s Li-organskim reagensima u spoj opće formule
[image]
ili
8) s kemijskom pretvorbom s Nozaki-Lombardovim reagensom
u spoj
[image]
kojeg možemo reducirati u metilni derivat ili s BH3/CH3SCH3/H2O2/OH- prevedemo u odgovarajući hidroksimetilni spoj;
ili
e) spoj opće formule
[image]
u kojoj znače X ksantinski ostatak i A kisik ili sumpor, formuliramo i u datom primjeru nato kemijski pretvorimo s esterima malonske kiseline u spojeve sa strukturom
[image]
te onda možemo, prema samo po sebi poznatim analognim postupcima, prevesti u spoj sa strukturom
[image]
ili
f) aldehid s formulom
[image]
prevedemo u kiselinu odnosno ester formule
[image]
ili u primjeru A = 0 u amid formule,
[image]
ili
g) 8-norbornenilne derivate opće formule 1 s kemijskom pretvorbom s KMnO4 pretvorimo u cis-diol ili prevedemo s m-klorperbenzojevom kiselinom u epoksid, koji se dade otvoriti u trans-diol kemijski pretvoriti s natrijevim azidom u azido alkohol ili reducirati s litijevim tetrahidridoalanatom u odgovarajući alkohol;
pri čemu su pri gore navedenim kemijskim pretvorbama ostatki R4 i R5, R6 i R7 definirani kao u zahtjevu 1 ili 2;
h) odgovarajuće spojeve opće formule 1 možemo prema samo po sebi poznatim postupcima prevesti u njihove kiselinske adicijske soli.
4. Uporaba spoja opće formule 1 prema zahtjevu 1 ili 2 kao lijeka.
5. Uporaba spoja opće formule 1 prema zahtjevu 1 ili 2 kao lijeka s antagonističnim djelovanjem prema andenozinu.
6. Farmaceutski pripravci, naznačeni time, da sadrže kao aktivnu tvar jedan ili više spojeva opće formule 1 ili njihove fiziološki podnošljive kiselinske adicijske soli u kombinaciji s uobičajenim pomoćnim i/ili tvarima nosača.
7. Postupak za pripravu farmaceutskih pripravaka prema zahtjevu 6, naznačen time, da spojeve opće formule 1 preradimo s uobičajenim galenskim pomoćnim i/ili tvarima nosača u uobičajne farmaceutske uporabne oblike.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3843117A DE3843117A1 (de) | 1988-12-22 | 1988-12-22 | Neue xanthinderivate mit adenosin-antagonistischer wirkung |
| YU242389A YU47934B (sh) | 1988-12-22 | 1989-12-20 | Novi derivati ksantina sa antagonističnim dejstvom prema adenziju |
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|---|---|
| HRP940724A2 true HRP940724A2 (en) | 1997-06-30 |
Family
ID=6369764
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP-2423/89A HRP940724A2 (en) | 1988-12-22 | 1994-10-21 | Novel xantin derivatives having an adenosin-antagonistic activity |
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| BG (1) | BG61669B2 (hr) |
| BR (1) | BR1100527A (hr) |
| CA (1) | CA2006387C (hr) |
| CZ (1) | CZ286230B6 (hr) |
| DD (1) | DD290421A5 (hr) |
| DE (3) | DE8817122U1 (hr) |
| DK (1) | DK652689A (hr) |
| ES (1) | ES2086313T3 (hr) |
| FI (1) | FI96513C (hr) |
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| HU (1) | HU218674B (hr) |
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Families Citing this family (69)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE8817122U1 (de) * | 1988-12-22 | 1993-02-04 | Boehringer Ingelheim Kg, 55218 Ingelheim | Neue Xanthinderivate mit Adenosinantogenistischer Wirkung |
| JPH06102662B2 (ja) * | 1989-09-01 | 1994-12-14 | 協和醗酵工業株式会社 | キサンチン誘導体 |
| US5290782A (en) * | 1989-09-01 | 1994-03-01 | Kyowa Hakko Kogyo Co., Ltd. | Xanthine derivatives |
| US5047534A (en) * | 1990-03-26 | 1991-09-10 | Merrell Dow Pharmaceuticals Inc. | Selective adenosine receptor agents |
| DE4019892A1 (de) * | 1990-06-22 | 1992-01-02 | Boehringer Ingelheim Kg | Neue xanthinderivate |
| CA2061544A1 (en) * | 1991-02-25 | 1992-08-26 | Fumio Suzuki | Xanthine compounds |
| GB9111130D0 (en) * | 1991-05-23 | 1991-07-17 | Ici Plc | Azole derivatives |
| GB9111131D0 (en) * | 1991-05-23 | 1991-07-17 | Ici Plc | Heterocyclic compounds |
| EP0541120B1 (en) * | 1991-11-08 | 1999-05-26 | Kyowa Hakko Kogyo Co., Ltd. | Xanthine derivatives for the treatment of dementia |
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-
1988
- 1988-12-22 DE DE8817122U patent/DE8817122U1/de not_active Expired - Lifetime
- 1988-12-22 DE DE3843117A patent/DE3843117A1/de not_active Ceased
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1989
- 1989-12-19 DE DE58909657T patent/DE58909657D1/de not_active Expired - Fee Related
- 1989-12-19 EP EP89123412A patent/EP0374808B1/de not_active Expired - Lifetime
- 1989-12-19 CZ CS19897197A patent/CZ286230B6/cs not_active IP Right Cessation
- 1989-12-19 ES ES89123412T patent/ES2086313T3/es not_active Expired - Lifetime
- 1989-12-19 AT AT89123412T patent/ATE136897T1/de not_active IP Right Cessation
- 1989-12-19 SG SG1996003965A patent/SG46380A1/en unknown
- 1989-12-19 SK SK7197-89A patent/SK279525B6/sk unknown
- 1989-12-20 PL PL28287889A patent/PL162877B1/pl unknown
- 1989-12-20 FI FI896117A patent/FI96513C/fi not_active IP Right Cessation
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- 1989-12-20 DD DD89335983A patent/DD290421A5/de not_active IP Right Cessation
- 1989-12-20 SI SI8912423A patent/SI8912423B/sl unknown
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- 1989-12-21 DK DK652689A patent/DK652689A/da not_active Application Discontinuation
- 1989-12-21 IE IE414789A patent/IE74205B1/en not_active IP Right Cessation
- 1989-12-21 CA CA002006387A patent/CA2006387C/en not_active Expired - Fee Related
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- 1989-12-21 HU HU736/89A patent/HU218674B/hu not_active IP Right Cessation
- 1989-12-21 PT PT92658A patent/PT92658B/pt not_active IP Right Cessation
- 1989-12-21 KR KR1019890019085A patent/KR0165666B1/ko not_active IP Right Cessation
- 1989-12-22 JP JP1334668A patent/JP2565576B2/ja not_active Expired - Lifetime
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1991
- 1991-04-25 US US07/691,193 patent/US5175291A/en not_active Expired - Fee Related
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1992
- 1992-05-07 RU SU925011448A patent/RU2057752C1/ru active
- 1992-06-26 MX MX9203618A patent/MX9203618A/es unknown
- 1992-07-10 PH PH44630A patent/PH31111A/en unknown
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1993
- 1993-07-27 US US08/097,478 patent/US5532368A/en not_active Expired - Fee Related
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1994
- 1994-02-08 BG BG098441A patent/BG61669B2/bg unknown
- 1994-10-21 HR HRP-2423/89A patent/HRP940724A2/hr not_active Application Discontinuation
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1995
- 1995-05-30 US US08/454,452 patent/US5696124A/en not_active Expired - Fee Related
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1996
- 1996-04-23 GR GR960401119T patent/GR3019733T3/el unknown
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