NO854713L - ALKYLIDENDIOKSY COMPOUNDS. - Google Patents
ALKYLIDENDIOKSY COMPOUNDS.Info
- Publication number
- NO854713L NO854713L NO854713A NO854713A NO854713L NO 854713 L NO854713 L NO 854713L NO 854713 A NO854713 A NO 854713A NO 854713 A NO854713 A NO 854713A NO 854713 L NO854713 L NO 854713L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- lower alkyl
- hydrogen
- compounds
- residues
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- GFSXWQUSLTVUBW-UHFFFAOYSA-N 10bh-benzo[h]chromene Chemical compound C1=CC=C2C3OC=CC=C3C=CC2=C1 GFSXWQUSLTVUBW-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000013543 active substance Substances 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 241000700605 Viruses Species 0.000 description 17
- 239000000725 suspension Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 241001430294 unidentified retrovirus Species 0.000 description 11
- -1 vide n-penty 1 Chemical group 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 239000000825 pharmaceutical preparation Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 102100034343 Integrase Human genes 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 9
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 208000032839 leukemia Diseases 0.000 description 8
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 5
- 208000030507 AIDS Diseases 0.000 description 5
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
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- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 229940100445 wheat starch Drugs 0.000 description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
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- 239000000969 carrier Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 150000004053 quinones Chemical class 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- PWDRXAGBIBJHNE-UHFFFAOYSA-N 2h-pyran-5,6-dione Chemical compound O=C1OCC=CC1=O PWDRXAGBIBJHNE-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 208000000389 T-cell leukemia Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
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- 239000002585 base Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
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- 239000008298 dragée Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
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- 235000011852 gelatine desserts Nutrition 0.000 description 2
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- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
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- 230000000144 pharmacologic effect Effects 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical group CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
Foreliggende oppfinnelse vedrører alkylidendioksy-forbindelser samt fremstillig derav, videre farmasøytiske preparater som inneholder slike forbindelser og anvendelsen av sistnevnte som farmakologisk virksomme stoffer . The present invention relates to alkylidenedioxy compounds as well as preparations thereof, further pharmaceutical preparations containing such compounds and the use of the latter as pharmacologically active substances.
Først og fremst vedrører foreliggende oppfinnelse forbindelser av formelen First and foremost, the present invention relates to compounds of the formula
hvor R-} og I?2 . uavhengig av hverandre, står for hydrogen, lavere alkyl eller aryl, eller sammen står for lavere where R-} and I?2 . independently of each other, stand for hydrogen, lower alkyl or aryl, or together stand for lower
alkylen, R5og R4står, uavhengig av hverandre , f or hydrogen, lavere alkyl eller aryl, eller står sammen for lavere alkylen, og ringen A har ingen ytterligere substituenter eller er i tillegg substituert med lavere alkyl, lavere alkoksy og/eller halogen. alkylene, R5 and R4 stand, independently of each other, for hydrogen, lower alkyl or aryl, or together stand for lower alkylene, and ring A has no further substituents or is additionally substituted with lower alkyl, lower alkoxy and/or halogen.
I ovenstående og det etterfølgende inneholder énverdige organiske rester samt forbindelser som er betegnet med "lavere" t.o.m. 7 , fortrinnsvis t.o.m. 4, og først og fremst 1 eller 2 karbonatomer. To-verdige organiske rester inneholder fortrinnsvis 4- til 6 karbonatomer. In the above and the following contains monovalent organic residues as well as compounds designated by "lower" up to and including 7, preferably up to 4, and primarily 1 or 2 carbon atoms. Divalent organic residues preferably contain 4 to 6 carbon atoms.
Lavere alkyl betyr først og fremst metyl og etyl, men kan også stå for n-propyl, isopropyl, n-butyl, isobutyl eller tert-butyl, vi dere n-penty 1 , n-heksyl og n-heptyl. Lower alkyl primarily means methyl and ethyl, but can also stand for n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, vide n-penty 1 , n-hexyl and n-heptyl.
Aryl er først og fremst monocyklisk, karbocyklisk aryl , f.eks. eventuelt substituert fenyl, hvor substituentene bl.a. kan vær lavere alkyl, lavere alkoksy eller halogen. Aryl is primarily monocyclic, carbocyclic aryl, e.g. optionally substituted phenyl, where the substituents i.a. can be lower alkyl, lower alkoxy or halogen.
Lavere alkylen er f.eks. 1 , 4-butylen, 1 , 5-pentylen eller 1,6-heksylen. Lower alkylene is e.g. 1,4-butylene, 1,5-pentylene or 1,6-hexylene.
Lavere alkoksy er spesielt metoksy eller etoksy, videre n-propoksy, isopropoksy, n-butoksy eller isobutoksy, videre n-pentyloksy. Lower alkoxy is in particular methoxy or ethoxy, further n-propoxy, isopropoxy, n-butoxy or isobutoxy, further n-pentyloxy.
Halogen betyr fortrinnsvis halogen med et atomnummer på høyst 35, dvs. fluor , klor eller brom. Halogen preferably means halogen with an atomic number of no more than 35, i.e. fluorine, chlorine or bromine.
Det antas at forbindelsene ifølge foreliggende oppfinnelse er "prodrugs" som hemmer den reverse transkriptasen av et for retrovira (eller onkonarvira), som RNS-tumor- og leukemi-vira, karakteristisk enzym; retrovira trenger dette enzymet for den naturlige replikasjonscyklusen (Baltimore, Nature, bind 226, side 1209 ( 1 970 ); og Temin ogMizutani, Nature, bind 226, side 121 1 ( 1970 )). It is believed that the compounds according to the present invention are "prodrugs" that inhibit the reverse transcriptase of an enzyme characteristic of retroviruses (or onconarviruses), such as RNS tumor and leukemia viruses; retroviruses require this enzyme for the natural replication cycle (Baltimore, Nature, vol. 226, p. 1209 ( 1970 ); and Temin and Mizutani, Nature, vol. 226, p. 121 1 ( 1970 )).
Den hemmende vi rkningen på vi rus inf eks j oner kan fastslås ved hjelp in vivo forsøksanordninger. Følgelig har forbindelser av formel I ved dyreforsøk ved visse neoplastiske sykdommer som er fremkalt ved RNS-tumorvi ra, eller hvor RNS-tumorvi ra kan påvises, en sterk virkning. De forlenger f.eks. den midlere overlevelsestiden for mus etter infeksjon med Rausch-leukemivirus (RLV, et RNS-tumorvirus). The inhibitory effect on viral infections can be determined using in vivo experimental devices. Accordingly, compounds of formula I in animal experiments in certain neoplastic diseases induced by RNS tumor virus, or in which RNS tumor virus can be detected, have a strong effect. They e.g. extend the mean survival time of mice after infection with Rausch leukemia virus (RLV, an RNS tumor virus).
i in
Ved forsøkene med Rausch-leukemi 4 Q (NIH) infiseres hunnmus av stammen Balb/c (18 til 34 dager gamle) med 0 ,2 ml aven virussuspensjon av mildt materiale f ra mus som er infisert 4-6 uker tidligere fortynnet ti ganger med Hanks-opp løsning. I et forsøk behandles i hvert tilfelle 15 dyr enten med forsøksforbindelsen, eller som en kontroll med Placebo, kontinuerlig per os. Den første tilførselen foregår 30 minutter før infeksjonen, videre tilførsler én gang daglig og fem ganger i uken i løpet av 4 uker. Som kriterium for virkningen tjener forlengelsen av overlevelsestiden. Mens man hos kontrolldyrene fra 30 dager etter infeksjonen kan finne en leukemi med leukemiske blodceller i et antall på over 50 . 000/mm3 og dyrene begynner å dø, forlenges overlevelsestiden for hunnmusene som er behandlet med 1 25 mg/kg p.o. av forsøksforbindelsen signifikant. Den utgjør f.eks. for 6,6-dimetyl-4,5-dihydro-6H-(1,3-dioksolo)[3,4]-nafto-[1 ,2-b]pyran ved 2 0-gangers p.o.-tilførsel til hunnmus av stammen Balb/c i en mengde på 125 mg/kg (10 dyr pr. gruppe) 60,9 dager, sammenlignet med overlevelsestiden for kontrolldyrene på 31,7 dager (p < 0,001 Cox-forsøk). In the experiments with Rausch leukemia 4 Q (NIH), female mice of the strain Balb/c (18 to 34 days old) are infected with 0.2 ml of virus suspension of mild material from mice infected 4-6 weeks previously diluted tenfold with Hanks-up solution. In an experiment, in each case 15 animals are treated either with the test compound, or as a control with Placebo, continuously per os. The first application takes place 30 minutes before the infection, further applications once a day and five times a week during 4 weeks. The criterion for the effect is the extension of the survival time. While in the control animals, from 30 days after the infection, a leukemia with leukemic blood cells in a number of more than 50 can be found. 000/mm3 and the animals begin to die, the survival time is prolonged for the female mice treated with 1 25 mg/kg p.o. of the test compound significantly. It constitutes e.g. for 6,6-dimethyl-4,5-dihydro-6H-(1,3-dioxolo)[3,4]-naphtho-[1 ,2-b]pyran by 20-fold p.o. administration to female mice of the strain Balb/c at a dose of 125 mg/kg (10 animals per group) 60.9 days, compared to the survival time of the control animals of 31.7 days (p < 0.001 Cox test).
Den farmakologiske virkningen av forbindelsene ifølge foreliggende oppfinnelse er ledsaget av en god tålbarhet. Den maksimalt tolererte dosen av den ovenfor nevnte 6 , 6--dimetyl-4,5-dihydro-6H-(1,3-dioksolo)[3,4]nafto[1,2-b]pyran hos mus etter én gangs p.o.- og i.p.-tilførsel med etter-følgende 7 dagers observasjonstid over 2.500 mg/kg, henholdsvis over 1 .250 mg/kg. The pharmacological action of the compounds according to the present invention is accompanied by good tolerability. The maximum tolerated dose of the above-mentioned 6,6-dimethyl-4,5-dihydro-6H-(1,3-dioxolo)[3,4]naphtho[1,2-b]pyran in mice after a single p.o. - and i.p. administration with a subsequent 7-day observation period above 2,500 mg/kg, respectively above 1,250 mg/kg.
Påvisningen av sykdommer som er forårsaket av retrovira baseres f.eks. på følgende funn: Påvisningen av type C-retrovira og dannelsen av disse ved revers transkriptase hos mennesker opptrer først ved en T-celleleukemi; viruset er kalt humant T-celleleukemi-virus (HTLV-I). Ved andre T-celleleukemier og -lymfomer er de samme vira og et liknende retrovirus (HTLV-II) funnet (Gallo, "Cancer Surveys" (Ed. Franks, Wyke og Weiss), bind 3 , side 1 13-160 (Oxford Univ. Press, 1984)). Videre er et slikt virus også isolert i forbindelse med AIDS (Acquired Immune Deficiency Syndrome) (Gottlieb et al., Morbid. Mortal. WeeklyRep., The detection of diseases caused by retroviruses is based, for example, on on the following findings: The detection of type C retroviruses and their formation by reverse transcriptase in humans first occurs in T-cell leukaemia; the virus is called human T-cell leukemia virus (HTLV-I). In other T-cell leukemias and lymphomas, the same viruses and a similar retrovirus (HTLV-II) have been found (Gallo, "Cancer Surveys" (Ed. Franks, Wyke and Weiss), volume 3, page 1 13-160 (Oxford Univ .Press, 1984)). Furthermore, such a virus is also isolated in connection with AIDS (Acquired Immune Deficiency Syndrome) (Gottlieb et al., Morbid. Mortal. WeeklyRep.,
bind 30, side 25, (1981 ); Friedman-Kien et al ., Morbid. Volume 30, Page 25, (1981); Friedman-Kien et al., Morbid.
Mor tal . W4eekly Rep. , bind 30 , side 305 (1 981 ); Gottlieb et al. , New Engl. J . Med. , bind 305 , side 1 425 ( 1 981 ); Masur , New Engl. J . Med. , bind 305 , side 1431 (1981 ); Siegal et al., New Engl. J. Med., bind 305', side 1439 (1981 ); "CDC Task Force on Kaspoi's Sarcoma and Opportunistic Infections", New Engl. J. Med., bind 3 0 6 , si de 248 ( 1 982 ); dette ble betegnet med HTLV-III (Essex et al. , Science, bind 220, side 859 (1983), Gelmann et al., bind 220, side 862 Mother number. W4eekly Rep. , volume 30, page 305 (1981); Gottlieb et al. , New Engl. J. With. , volume 305 , page 1 425 ( 1 981 ); Masur, New Engl. J. With. , volume 305, page 1431 (1981); Siegal et al., New Engl. J. Med., volume 305', page 1439 (1981); "CDC Task Force on Kaspoi's Sarcoma and Opportunistic Infections", New Engl. J. Med., volume 3 0 6 , say de 248 ( 1 982 ); this was designated HTLV-III (Essex et al., Science, vol. 220, page 859 (1983), Gelmann et al., vol. 220, page 862
(1983); Gallo et al. , Scinece , bind 220, side 865 (1 983 ); Gallo, "Cancer Surverys", bind 3, side 113 (1984); Barré-Sinoussi et al . , Science, bind 220, si de 868 ( 1 983 ) ; Hirsch og Levy, "Viruses in Human Malignancy and AIDS", ASCO/AACR Symposium, mai 1984, Toronto). (1983); Gallo et al. , Scinece , volume 220, page 865 ( 1 983 ); Gallo, "Cancer Surverys", Volume 3, page 113 (1984); Barré-Sinoussi et al. , Science, vol 220, say de 868 ( 1 983 ) ; Hirsch and Levy, "Viruses in Human Malignancy and AIDS", ASCO/AACR Symposium, May 1984, Toronto).
Disse retrovira som inneholder HTLV-familien trenger den reverse transkriptasen for dannelse av et dobbeltkjedet-DNA (Provirus) som " intigreres" i cellegenomet og kan føre til malign transformasjon (Strayer og Gillespie, "The Nature and Organization of Retroviral Genes in Animal Cells". Virology Monographs , bind 1 7 ( Springer Ed. , 1 980 ) . These retroviruses that contain the HTLV family need the reverse transcriptase for the formation of a double-stranded DNA (Provirus) that "integrates" into the cell genome and can lead to malignant transformation (Strayer and Gillespie, "The Nature and Organization of Retroviral Genes in Animal Cells" .Virology Monographs, Volume 1 7 (Springer Ed., 1980).
Mens det etter induksjonen av maligne leukemi, lymfatiske eller tumorøse nydannelser ved retrovira kan påvises en reduksjon av den reverse transskriptasen og viraene HTLV-I og -II og sekundære, ved disse vira-induserteonkogener styrer replikasjonen av de maligne cellene, kan viruset HTLV-III og den reverse transkriptasen ved AIDS ikke bare påvises på et tidlig stadium, men derimot gjennom hele sykdomsforløpet. Den løpende infeksjonen og funksjons-forstyrrelsen av immunkompetente T-hj elperceller f ører til slutt til sammenbrudd av immunsystemet med dødelig utgang. While after the induction of malignant leukaemia, lymphatic or tumorous new formations by retroviruses a reduction of the reverse transcriptase and the viruses HTLV-I and -II and secondary, in these virus-induced oncogenes control the replication of the malignant cells, can be demonstrated, the virus HTLV-III and the reverse transcriptase in AIDS is not only detected at an early stage, but throughout the course of the disease. The ongoing infection and the functional disturbance of immunocompetent T-helper cells eventually leads to a breakdown of the immune system with a fatal outcome.
Det er å annta at en hemning av den reverse transkriptasen og virusreplikasj onen ved positiv enzym- og virusantigen--påvisning (Beardsley, Nature, bind 311, side 195 ( 1984)) It is assumed that an inhibition of the reverse transcriptase and virus replication upon positive enzyme and virus antigen detection (Beardsley, Nature, vol. 311, page 195 (1984))
hos risikopasienter , f.eks. homoseksuelle, påvirker sykdoms- in risk patients, e.g. homosexuals, affects disease-
prosessen. Ved induksjonen av leukemi og lymfomer forårsaket av retrovira (HTLV-I og HTVL-II) , samt muligens også ved sarkomer og mammakarsinomer som er indusert av retrovira, skulle der imot en profylaktisk anvendelse være mulig, så fremt en enkel og bredt anvendelig diagnostisk behandling av slike risikopasienter kan forutsettes. the process. In the induction of leukemia and lymphomas caused by retroviruses (HTLV-I and HTVL-II), as well as possibly also in the case of sarcomas and mammary carcinomas which are induced by retroviruses, a prophylactic application should, on the other hand, be possible, as well as a simple and widely applicable diagnostic treatment of such risk patients can be assumed.
Også i forbindelse med ikke-A og ikke-B-hepatitt er den reverse transkriptasen som spesifikt enzym funnet i forbindelse med viruspartikler (Seto et al., Lancet, side 941 Also in connection with non-A and non-B hepatitis, the reverse transcriptase as a specific enzyme has been found in connection with virus particles (Seto et al., Lancet, page 941
(1984)). (1984)).
Forbindelsen ifølge foreliggende oppfinnelse kan følgelig anvendes til profylakse og terapi ved sykdommer hvor den reverse transkriptasen er av betydning, fremfor alt ved maligne sykdommer som er forårsaket av type-C-retrovi ra eller hvor disse er en medvirkende årsak, men også ved visse immunsykdommer og auto-immunsykdommer. Som tumorsykdommer kommer først og fremst av retrovira forårsakede leukemier, lymfomer og lymfosarkomer, samt osteosarkomer og mammakarsinomer i betraktning. Forbindelsene ifølge foreliggende oppfinnelse egner seg spesielt også til residivprofylakse etter kirurgisk terapi, stråleterapi eller sytostatisk eller antimetabolisk kjemoterapi. Som immunsykdom kan nevnes AIDS, som auto-immunsykdom systemisk Lupuserythematosus, hvor ifølge nyere resultater RNS-tumorvira også synes å spille en viktig rolle (Dennman, Med., Biol., bind 53, side 61 ( 1 975 ); Panem et al. , New England J . Med. , bind 295 , 470 The compound according to the present invention can therefore be used for prophylaxis and therapy in diseases where the reverse transcriptase is important, above all in malignant diseases which are caused by type C retroviruses or where these are a contributing cause, but also in certain immune diseases and auto-immune diseases. As tumor diseases, leukaemias, lymphomas and lymphosarcomas, as well as osteosarcomas and mammary carcinomas, caused primarily by retroviruses come into consideration. The compounds according to the present invention are also particularly suitable for relapse prophylaxis after surgical therapy, radiation therapy or cytostatic or antimetabolic chemotherapy. AIDS can be mentioned as an immune disease, and systemic Lupuserythematosus as an auto-immune disease, where, according to recent results, RNS tumor viruses also seem to play an important role (Dennman, Med., Biol., volume 53, page 61 ( 1975 ); Panem et al. , New England J. Med., vol 295 , 470
(1976)). (1976)).
Oppfinnelsen vedrører spesielt forbindelser av formel I hvor R-]står for hydrogen eller lavere alkyl og R2f or hydrogen, lavere alkyl eller fenyl, R3og R4står, uavhengig av hverandre, for hydrogen eller lavere alkyl, og ringen A inneholder ingen ytterligere substituenter eller er i tillegg substituert med lavere alkyl, lavere alkoksy og/eller halogen, hvor rester som betegnes med "lavere" fortrinnsvis inneholder 1 eller 2karbonatomer og halogener har et atomnummer på høyst 35. The invention relates in particular to compounds of formula I where R-] stands for hydrogen or lower alkyl and R 2 for hydrogen, lower alkyl or phenyl, R 3 and R 4 stand, independently of each other, for hydrogen or lower alkyl, and the ring A contains no further substituents or is in additionally substituted with lower alkyl, lower alkoxy and/or halogen, where residues denoted by "lower" preferably contain 1 or 2 carbon atoms and halogens have an atomic number of at most 35.
Oppfinnelsen vedrører først og fremst forbindelser av formel I hvor R-| står for hydrogen eller lavere alkyl og R2for lavere alkyl eller fenyl, og begge restene R3og R4er hydrogen eller uavhengig av hverandre står for hydrogen eller lavere alkyl, hvor rester som betegnes med "lavere" fortinnsvis inneholder 1 eller 2 karbonatomer. The invention primarily relates to compounds of formula I where R-| stands for hydrogen or lower alkyl and R2 for lower alkyl or phenyl, and both residues R3 and R4 are hydrogen or independently of each other stand for hydrogen or lower alkyl, where residues denoted by "lower" preferably contain 1 or 2 carbon atoms.
Forbindelsene av formel I kan fremstilles på i og for seg kjent måte, f. eks. ved at man omsetter en forbindelse av formelen The compounds of formula I can be prepared in a manner known per se, e.g. by converting a compound of the formula
eller et reaktivt derivat derav meden reagens som innfører resten av formelen or a reactive derivative thereof with reagent introducing the rest of the formula
Reaktive derivater av forbindelser av formel II er f.eks. salter, som alkalimetall-, f.eks. natrium- eller kalium-salter. Reactive derivatives of compounds of formula II are e.g. salts, such as alkali metal, e.g. sodium or potassium salts.
Reagenser som egner seg for innføring av resten av formel Ia er f.eks. forbindelser av formelen hvor X-]og X2, uavhengig av hverandre, står for foretret eller forestret hydroksy, men først og fremst sammen står for diazogruppen. Foretret hydroksy er f.eks. lavere alkoksy, som metoksy eller etoksy, mens forestret hydroksy spesielt står for halogen, spesielt brom eller jod, eller for lavere alkanoyloksy, f.eks. azetoksy. Foretrukne forbindelser av formel III er de tilsvarende diazofor-bindelsene, spesielt diazolaverealkaner og først og fremst diazometan. Reagents which are suitable for introducing the remainder of formula Ia are e.g. compounds of the formula where X-] and X2, independently of each other, stand for etherified or esterified hydroxy, but primarily together stand for the diazo group. Etherated hydroxy is e.g. lower alkoxy, such as methoxy or ethoxy, while esterified hydroxy in particular stands for halogen, especially bromine or iodine, or for lower alkanoyloxy, e.g. acetoxy. Preferred compounds of formula III are the corresponding diazophor compounds, especially diazolaveralkanes and primarily diazomethane.
Reaksjonen gjennomføres på i og for seg kjent måte, vanlig-vis i nærvær av et egnet fortynnings- eller oppløsnings-middel, diazoreagensen fortrinnsvis i nærvær av et vannf ritt eteroppløsningsmiddel, som dietyleterog/ellertetrahydro-furan, om nødvendig under avkjøling eller oppvarming, f.eks. i et temperaturområde fra ca. -10°C til ca. 1 0 0 ° C, i en lukket beholder og/eller under en atmosfære av inertgass. The reaction is carried out in a manner known per se, usually in the presence of a suitable diluent or solvent, the diazo reagent preferably in the presence of an anhydrous ether solvent, such as diethyl ether and/or tetrahydrofuran, if necessary under cooling or heating, f .ex. in a temperature range from approx. -10°C to approx. 1 0 0 ° C, in a closed container and/or under an atmosphere of inert gas.
Utgangsf orbindelsene av formel II kan f .eks. fremstilles ved reduksjon av tilsvarende kjente kinonforbindelser av formelen som f.eks. ved kataly ttisk hydrering. Fortrinnsvis fremstilles utgangsstof f ene (II) in situ, siden de ellers meget lett tilbakeoksyderes til de tilsvarende kinonene av formel IV. Siden diazoforbindelsen av formel III reduserer kinonforbindelsene (IV) ti 1 utgangsstoffene av formel Ia og samtidig kan innføre den ønskede resten av formel Ila, utgjør den fremgangsmåtevarianten hvor en forbindelse av formelen IV omsettes med en forbindelse av formel III hvor X-j og X2sammen står for diazogruppen, spesielt med en diazolavere alkan og først og fremst med diazometan, hvorved man arbeider med et overskudd av diazof orbindelsen (III) , den foretrukne fremgangsmåten til fremstilling av forbindelser av formel I. The starting compounds of formula II can e.g. are produced by reduction of corresponding known quinone compounds of the formula such as e.g. by catalytic hydrogenation. Preferably, the starting substances f ene (II) are prepared in situ, since they are otherwise very easily reoxidized to the corresponding quinones of formula IV. Since the diazo compound of formula III reduces the quinone compounds (IV) to 1 starting materials of formula Ia and at the same time can introduce the desired residue of formula Ila, it constitutes the process variant where a compound of formula IV is reacted with a compound of formula III where X-j and X2 together stand for the diazo group , especially with a diazole lower alkane and primarily with diazomethane, whereby one works with an excess of the diazoph or compound (III), the preferred method for the preparation of compounds of formula I.
Foreliggende oppfinnelse vedrører videre farmasøytiske preparater som, som virksomt stoff, inneholder en av forbindelsene av formel I ifølge oppfinnelsen. Ved farma-søytiske preparater ifølge oppfinnelsen dreier det seg om preparater til enteral, som oral eller rektal, eller parenteral tilførsel, f.eks. i.v., i.m., eller topisk. Preparatene inneholder enten utelukkende det virksomme stoffet eller fortrinnsvis det virksomme stoffet blandet med et farmasøytisk anvendelig bærermateriale. Doseringen av det virksomme stoffet avhenger av behandl ingsobj ekte , dets alder og individuelle tilstand, samt tilførselsmåten. The present invention further relates to pharmaceutical preparations which, as active substance, contain one of the compounds of formula I according to the invention. Pharmaceutical preparations according to the invention are preparations for enteral, such as oral or rectal, or parenteral administration, e.g. i.v., i.m., or topically. The preparations contain either exclusively the active substance or preferably the active substance mixed with a pharmaceutically usable carrier material. The dosage of the active substance depends on the object of treatment, its age and individual condition, as well as the method of administration.
De farmasøytiske preparatene inneholder fra ca. 5% til ca. 95% av det virksomme stoffet, hvor enkeltdosepreparater fortrinnsvis inneholder fra ca. 20% til ca. 90% og ikke--enkeltdoserte preparater fortinnsvis inneholder ca. 5% til ca. 20% virksomt stoff. Farmasøytiske preparater ifølge oppfinnelsen i enhetsdoseform, som dragéer, tabletter, kapsler, suppositoriereller ampuller, inneholder ca. 0,05g til ca. 1 ,5 g, fortrinnsvis ca. 0,1 g til ca. 1,0 g av det virksomme stoffet. The pharmaceutical preparations contain from approx. 5% to approx. 95% of the active substance, where single-dose preparations preferably contain from approx. 20% to approx. 90% and non-single-dose preparations preferably contain approx. 5% to approx. 20% active ingredient. Pharmaceutical preparations according to the invention in unit dose form, such as dragées, tablets, capsules, suppositories or ampoules, contain approx. 0.05g to approx. 1.5 g, preferably approx. 0.1 g to approx. 1.0 g of the active substance.
De farmasøytiske preparatene ifølge foreliggende oppfinnelse fremstilles på i og for seg kjent måte, f . eks . ved konvensjonelle blande-, granulerings-, dragérings-, opp-løsnings- eller lyofiliseringsfremgangsmåter. Man kan fremstille farmasøytiske preparater for oral anvendelse ved at man blander det virksomme stoffet med ett eller flere faste bærerstoffer, eventuelt granulerer den fremstilte blandingen, og bearbeider blandingen, henholdsvis granulatet, om ønsket, eventuelt etter tilsats av ytterligere hjelpestoffer, til tabletter eller dragékjerner. The pharmaceutical preparations according to the present invention are produced in a manner known per se, e.g. e.g. by conventional mixing, granulating, coating, dissolving or lyophilizing methods. Pharmaceutical preparations for oral use can be prepared by mixing the active substance with one or more solid carriers, optionally granulating the prepared mixture, and processing the mixture, respectively the granulate, if desired, possibly after the addition of additional excipients, into tablets or dragee cores.
Egnede bærerstoffer er spesielt fyllstoffer som er inerte vedrørende den farmakologiske virkningen, som sukker, f.eks. laktose, sakkarose, manitt eller sorbitt, cellulosepreparater og/eller kalsiumfosfat, f.eks. trikaslsiumfosfat eller kalsiumhydrogenfosfat, videre bindemidler, som stivelser, f.eks. mais-, hvete-, ris- eller potetstivelse, metylcellulose, hydroksypropylmetylcellulose, natrium-karboksymetylcellulose og/eller polyvinylpyrrolidon, og/eller, om ønsket, sprengmidler, som de ovenfor angitte stivelsene, videre karboksymetylstivele, kryssbundet polyvinylpyrrolidon, alginsyre eller et salt derav, som natr iumalginat. Ytterligere hjelpemidler er først og fremst flytregulatorer og smøremidler, f.eks. kiselsyre, talk, stearinsyre eller salter derav, som magnesium- eller kalsiumstearat, og/eller polyetylenglykol. Suitable carriers are especially fillers which are inert with regard to the pharmacological effect, such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphate, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starches, e.g. corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, explosives, such as the above-mentioned starches, further carboxymethylstarch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Further aids are primarily flow regulators and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
Dragékjerner utsetyres med egnede, eventuelt magesaft-resistente, overtrekk, hvorman bl.a. anvender konsentrerte sukkeroppløsninger , som eventuelt inneholder gummi arabicum, talk, polyvinylpyrrolidon, polyetylenglykol og/eller titandioksyd, lakkoppløsninger i egnede organiske opp-løsningsmidlerelleroppløsningsmiddelblandinger, eller, til fremstilling av magesaftresistenteovertrekk, oppløsninger av egnede cellulosepreparater, som acetylcelluloseftalat eller hydroksypropylmetylcelluloseftalat. Tablettene eller dragé-overtrekkene kan tilsettes fargestoffer eller pig-menter, f.eks. til identifisering eller til å angi forskjellige doser av virksomt stoff. Dragon cores are equipped with suitable, possibly gastric juice-resistant, coverings, which, among other things, use concentrated sugar solutions, which possibly contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, varnish solutions in suitable organic solvents or solvent mixtures, or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragé coatings can have dyes or pigments added, e.g. for identification or to indicate different doses of active substance.
Andre, oralt anvendelige farmasøytiske preparater er stikkapsler av gelatin samt myke , lukkede kapsler av gelatin og en mykner, som glyserin eller sorbitol. Stikkapslene kan inneholde det virksomme stoffet i form av et granulat, f.eks. i blanding med fyllstoffer, som maisstivelse, bindemidler og/eller glidemidler, som talk eller magnesium-stearat, og eventuelt stabilisatorer. I myke kapsler er det virksomme stoffet fortrinnsvis oppløst eller suspendert i egnede væsker, som fettholdige oljer, parafinoljer eller flytende polyetylenglykol, hvor eventuelt stabilisatorer kan være tilsatt. Other orally usable pharmaceutical preparations are gelatin capsules as well as soft, closed capsules made of gelatin and a plasticiser, such as glycerin or sorbitol. The capsules can contain the active substance in the form of a granule, e.g. in a mixture with fillers, such as corn starch, binders and/or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oils or liquid polyethylene glycol, where stabilizers may be added.
Andre orale tilførselsformer er f.eks. siruper fremstilt på vanlig måte, som inneholder det virksomme stoffet f .eks. i suspendert form i en konsentrasjon på ca. 5% til 20%, fortrinnsvis ca. 10% el ler en 1 iknende konsent ras j on , som f.eks. ved utmåling av 5 eller 10 ml gir en egnet enkelt-dose. Videre kommer også f.eks. pulverformige eller flytende konsentrater til fremstilling av risteblandinger , f.eks. milk shake, i betraktning. Slike konsentrater kan også være forpakket i enkeltdosemengder. Other oral administration forms are e.g. syrups prepared in the usual way, which contain the active substance, e.g. in suspended form in a concentration of approx. 5% to 20%, preferably approx. 10% or a known concentration ratio, such as measuring out 5 or 10 ml gives a suitable single dose. Furthermore, e.g. powdered or liquid concentrates for the production of shake mixes, e.g. milk shake, considering. Such concentrates can also be packaged in single-dose quantities.
Som rektalt anvendelige farmasøytiske preparater kommer f.eks. suppositorier i betraktning, disse består aven kombinasjon av det virksomme stoffet med en suppositoriegrunnmasse. Som suppositoriegrunnmasse egner seg f.eks. naturlige eller syntetiske triglyserider, parafiner, polyetylenglykoler eller høyere alkanoler. Vider kan også gelatin-rektalkapsler benyttes » som består av en blanding av det virksomme stoffet med en grunnmasse; som grunnmasse-stoffer kommer f.eks. flytende triglyserider, polyetylenglykoler eller parafiner på tale. As rectally applicable pharmaceutical preparations, e.g. suppositories in consideration, these consist of a combination of the active substance with a suppository base. As a suppository base material, e.g. natural or synthetic triglycerides, paraffins, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used » which consist of a mixture of the active substance with a base mass; as base materials come e.g. liquid triglycerides, polyethylene glycols or paraffins in question.
Til parenteral tilførsel kommer f.eks. suspensjoner av forbindelsene ifølge foreliggende oppfinnelse i betraktning, som tilsvarende oljeformigeinjeksjonsuspensjoner, hvor man anvender egnede lipofile oppløsningsmidler eller bærere, som fettholdige oljer, f.eks. sesamolje, eller syntetiske fettsyreestere, f.eks. etyloleat eller triglyserid, eller man kan også anvende vandige injeksjonssuspensjoner som inneholder viskositetsforhøyende stoffer, f.eks. natrium-karboksymetylcellulose, sorbitt og/eller dekstran, og eventuelt også stabilisatorer. For parenteral administration, e.g. suspensions of the compounds according to the present invention in consideration, as corresponding oily injection suspensions, where suitable lipophilic solvents or carriers are used, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglyceride, or you can also use aqueous injection suspensions containing viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran, and optionally also stabilizers.
Til parenteral tilførsel egner seg spesielt liposomdisper-sjoner med forbindelse av formel I. Liposomdispersjonene fremstilles av minst to 1ipidkomponenter, f.eks. fosfatidylserin og fosfatidyletanolamin eller fosfatidylserin og f osf atidylkolin , som innkapsler forbindelsene (I). Liposome dispersions with compounds of formula I are particularly suitable for parenteral administration. The liposome dispersions are prepared from at least two lipid components, e.g. phosphatidylserine and phosphatidylethanolamine or phosphatidylserine and phosphatedylcholine, which encapsulate the compounds (I).
Til fremstilling av liposomdispersjonen egner som den ene lipidkomponenten f osf atidylserin av naturlig herkomst med forskjellige eller identiske C"i o-C20-alkan°ylres"ber » f • eks . n-dodekanoyl, n-tetradekanoyl, n-heksadekanoyl eller n-oktadekanoyl, eller C-| o-C20-alkenovlres'ter » f.eks. 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis-heksadecenoyl, 6-cis-, 6-trans-, 9-cis-, 9-trans- eller 11-cis-okta-decenoyol eller 9-cis-icosenoyl, f.eks. fosfatidylserin f ra oksehjerne, eller syntetisk fosfatidylserin med identiske c10-C20-alkenoylrester, f.eks. natrium-1,2-di-(9-cis--oktadecenoyl)-3-sn-fosfatidyl-(S)-serin, og som den andre lipidkomponenten forfatidylkolin av naturlig herkomst med forskjellige eler identiske C1Q-<C>20- alkanoylrester, f.eks. f osf atidylkolin fra hønseegg eller fra soyaolje, syntetisk f osf atidylkolin med identiske C-j Q-C2o-alkan°ylres'ter » f.eks. dimyristoyl-, distearoyl- eller dipalmitoylfos-fatidylkolin, eller syntetisk fosfatidylkolin med en c1 o-C20-alkan°y1~°<S en C -| q-C2 0-alkenoyl res t, f.eks. Phosphatidylserine of natural origin with different or identical C"i o-C20-alkan°yl residues is suitable as the one lipid component for the preparation of the liposome dispersion, e.g. n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl, or C-| o-C20-alkenyl residues » e.g. 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis-hexadecenoyl, 6-cis-, 6-trans-, 9-cis-, 9-trans- or 11-cis-octa-decenoyl or 9-cis- icosenoyl, e.g. phosphatidylserine from ox brain, or synthetic phosphatidylserine with identical C10-C20-alkenoyl residues, e.g. sodium-1,2-di-(9-cis--octadecenoyl)-3-sn-phosphatidyl-(S)-serine, and as the second lipid component forfatidylcholine of natural origin with different or identical C1Q-<C>20- alkanoyl residues , e.g. f phosphatidylcholine from chicken eggs or from soybean oil, synthetic f phosphatidylcholine with identical C-j Q-C2o-alkan°yl residues » e.g. dimyristoyl, distearoyl, or dipalmitoylphos-fatidylcholine, or synthetic phosphatidylcholine with a c1 o-C20 alkane°y1~°<S a C -| q-C2 O-alkenoyl residue, e.g.
1-n-heksadekanoyl-2-(9-cis-oktadecenoyl)-3-sn-fosfatidiyl-kolin. 1-n-hexadecanoyl-2-(9-cis-octadecenoyl)-3-sn-phosphatidiyl-choline.
Liposomdispersjonenlar seg fremstille ved at man eksempelvis fremstiller et lyofilisat av lipidkomponentene og forbindelsen (I) ved fremgangsmåten beskrevet i det tyske utlegningsskrift nr . 2818655, fortrinnsvis etter oppløsning av lipidkomponenten og det virksomme stoffet i tert-butanol, og fjernelse av oppløsningsmiddelet ved temperaturer under -20°, og dispergerer dette lyofilisatet i en isotonisk buf f eroppløsning. Dispersjonen foregår ved risting (Vortex--blander), eller omrøring i vandig fase. Liposomdispersjonen kan deretter anrikes ved sentrifugering og/eller ved gelf il trering eller fraskilles ved ekstruder ing gj ennom et rettporet filter. The liposome dispersion can be prepared by, for example, preparing a lyophilisate of the lipid components and the compound (I) by the method described in the German specification no. 2818655, preferably after dissolving the lipid component and the active substance in tert-butanol, and removing the solvent at temperatures below -20°, and dispersing this lyophilisate in an isotonic buffer solution. The dispersion takes place by shaking (Vortex mixer), or stirring in the aqueous phase. The liposome dispersion can then be enriched by centrifugation and/or by gel filtration or separated by extrusion through a straight-pore filter.
Denne fremgangsmåten egner seg når det anvendes 1 ipofi le, henholdsvis i organiske oppløsningsmidler, f.eks. tert--butanol, oppløselige forbindelseer (I). Ved vannopp-løselige forbindelser (I) fremstiller man et liofilisatbare av lipidkomponenten og dispergerer dette i vandig fase som inneholder den oppløste forbindelsen (I). This method is suitable when 1 ipophile is used, respectively in organic solvents, e.g. tert--butanol, soluble compounds (I). In the case of water-soluble compounds (I), a lyophilizable form of the lipid component is prepared and dispersed in an aqueous phase containing the dissolved compound (I).
Oppfinnelsen vedrører videre en fremgangsmåte til behnadling av sykdommer hvor, som nevnt ovenfor, den reverse transkriptasen er av betydning, kjennetegnet ved atman tilfører en profylaktisk eller terapeutisk virksom mengde av en forbindelse av formel I ifølge oppfinnelsen. I denne sammen-heng anvender man først og fremst det ovenfor nevnte farmasøytiske preparatet ved behandling av en varmblodig organisme med en vekt på ca. 70 kg ved at det tilføres en daglig mengde på ca. 0 , 1 g til ca. 5 g, fortrinnsvis fra ca. 0,5 g til ca. 1,5 g, av en forbindelse ifølge foreliggende oppfinnelse. The invention further relates to a method for treating diseases where, as mentioned above, the reverse transcriptase is important, characterized by adding a prophylactically or therapeutically effective amount of a compound of formula I according to the invention. In this context, one primarily uses the above-mentioned pharmaceutical preparation when treating a warm-blooded organism with a weight of approx. 70 kg by adding a daily amount of approx. 0.1 g to approx. 5 g, preferably from approx. 0.5 g to approx. 1.5 g, of a compound according to the present invention.
De følgende eksemplene illustrerer foreliggende oppfinnelse; temperaturene angis i grader Celsius. The following examples illustrate the present invention; temperatures are given in degrees Celsius.
Eksempel 1 Example 1
6 , 6- dimet, yl- 4 , 5- dihydro- 6H-( 1 , 3- dioksolo) [ 3 , 4] - naf to [ 1 , 2- b]-pyran 6,6-dimeth,yl-4,5-dihydro-6H-(1,3-dioxolo)[3,4]-naphtho[1,2-b]-pyran
En oppløsning av diazometan i dietyleter (fremstilt fra 40 g nitrosometylurinstoff og 40 0 ml dietyleter) blandesdråpe-vis, ved en temperatur på 2-3° med en oppløsning av 22,4 g 2,2-dimetyl-3,4-dihydro-2H-nafto[1,2-b]pyran-5,6-dion (e-lapakon) i 20 0 ml tetrahydrofuran. Reaksjonsblandingen får stå i 16 timer ved romtemperatur. Oppløsningsmiddel-blandingen avdampes under redusert trykk, resten oppløses i 400 ml metylenklorid og filtreres raskt gjennom 400 g silikagel (Merck; 0 , 063-0 , 2 mm) . Fra den første f ilter-fraksjonen oppnås begefarget, krystallinsk materiale (tynnsjiktkromatogram på silikagel "60 F254." Merck; Rf 0,73 (koroform)), som gir tittelf orbindelsen omkrystallisert f ra isopropanol, kokepunkt 84-85 0 . A solution of diazomethane in diethyl ether (prepared from 40 g of nitrosomethylurea and 400 ml of diethyl ether) is mixed dropwise, at a temperature of 2-3°, with a solution of 22.4 g of 2,2-dimethyl-3,4-dihydro- 2H-naphtho[1,2-b]pyran-5,6-dione (ε-lapacon) in 200 ml of tetrahydrofuran. The reaction mixture is allowed to stand for 16 hours at room temperature. The solvent mixture is evaporated under reduced pressure, the residue is dissolved in 400 ml of methylene chloride and quickly filtered through 400 g of silica gel (Merck; 0.063-0.2 mm). From the first filter fraction, beige-colored, crystalline material is obtained (thin-layer chromatogram on silica gel "60 F254." Merck; Rf 0.73 (coroform)), which gives the title compound recrystallized from isopropanol, boiling point 84-85 0 .
Eksempel 2 : 6, 6- dimetyl- 4, 5- dihydro- 6H-( 1, 5- dioksolo)[ 3, 4] nafto[ 1, 2- b]-pyran Example 2: 6,6-dimethyl-4,5-dihydro-6H-(1,5-dioxolo)[3,4]naphtho[1,2-b]-pyran
En oppløsning av 12,1 g2,2-dimetyl-3,4-dihydro-2H-nafto- A solution of 12.1 g of 2,2-dimethyl-3,4-dihydro-2H-naphtho-
[1 ,2-b]pyran-5,6-dion (3-lapakon) i 1 20 ml dimetylformamid blandes med 11 g trietylamin og 1 g av en platina-på-kull--katalysator (5%) og hydreres ved romtemperartur under normalt trykk. Under utelukkelse av oksygen tilsettes 10,5 ml metyleniodid og blandingen oppvarmes i 5 timer til 10 0°. Det avkjøles, filtreres og f i 1 tratet inndampes under redusert trykk til et volum på ca. 40 ml. Det fortynnes med [1,2-b]pyran-5,6-dione (3-lapacon) in 1 20 ml of dimethylformamide is mixed with 11 g of triethylamine and 1 g of a platinum-on-charcoal catalyst (5%) and hydrated at room temperature under normal pressure. Under exclusion of oxygen, 10.5 ml of methylene iodide are added and the mixture is heated for 5 hours to 100°. It is cooled, filtered and f in 1 funnel evaporated under reduced pressure to a volume of approx. 40 ml. It is diluted with
20 0 ml vann; bunnfallet som oppstår frafi 1treres og utrøres i dietyleter. Den øverststående oppløsningen avdekanteres , vaskes med vann, tørkes over natriumsulfat og inndampes under redusert trykk. Resten opptas i metylenklorid og kromatograferes på 20 0 g silikagel under anvendelse av metylenklorid. Den ønskede tittelforbindelsen oppnås fra den første fraksjonen; og er ifølgetynnskjiktkromatografi identisk med ti ttelf orbindelsen fra eksempel 1 . 20 0 ml of water; the precipitate that occurs is filtered off and stirred in diethyl ether. The upper solution is decanted, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is taken up in methylene chloride and chromatographed on 200 g of silica gel using methylene chloride. The desired title compound is obtained from the first fraction; and is, according to thin-layer chromatography, identical to the 11th compound from example 1.
Eksempel 5 : 9- klor- 6, 6- dimetyl- 4, 5- dihydro- 6H-( 1, 5- dioksolo)[ 5 , 4] nafto-[ 1, 2- b] pyran Example 5: 9-chloro-6,6-dimethyl-4,5-dihydro-6H-(1,5-dioxolo)[5,4]naphtho-[1,2-b]pyran
En til +5° avkj ølt oppløsning av 50 0 mg 9-klor-2 , 2-dimetyl--3,4-dihydro-2H-naftol,2-b]pyran-5,6-dion (9-klor-3-lapakon) fremstilt ifølge J. Med. Chem. 1984, 27, 990-994, i 5 ml THF blandes med 20 ml av en oppløsning av diazometan i eter og får stå i 16 timer ved romtemperatur. Oppløsningsmiddel-blandingen fjernes ved redusert trykk og resten krystal-liseres fra 4 ml isopropanol. Det oppnås gulbege krystaller av tittelforbindelsen med smeltepunkt 116-118°. Fra moderluten oppnås mer av ti ttelf orbindelsen ved kromatograf i på 50 g silikagel og eluering med eddikester-cykloheksan (3:1): Eksempel 4 : 6- metyl- 6- fenyl- 4, 5- dihydro- 6H-( 1, 5- dioksolo)[ 3, 4] nafto-[ 1, 2- b] pyran A cooled to +5° solution of 500 mg of 9-chloro-2,2-dimethyl--3,4-dihydro-2H-naphthol,2-b]pyran-5,6-dione (9-chloro-3 -lapakone) prepared according to J. Med. Chem. 1984, 27, 990-994, in 5 ml of THF is mixed with 20 ml of a solution of diazomethane in ether and allowed to stand for 16 hours at room temperature. The solvent mixture is removed under reduced pressure and the residue is crystallized from 4 ml of isopropanol. Yellow-beige crystals of the title compound with a melting point of 116-118° are obtained. From the mother liquor, more of the tenth compound is obtained by chromatography on 50 g of silica gel and elution with ethyl acetate-cyclohexane (3:1): Example 4: 6-methyl-6-phenyl-4,5-dihydro-6H-(1,5 - dioxolo)[ 3, 4] naphtho-[ 1, 2-b] pyran
En til +5° avkjølt oppløsning av 500 mg 2-metyl-2-fenyl--3,4-dihydro-2H-nafto[l,2-b]pyran (2-desmetyl-2-fenyl--3-lapakon), fremstilt ifølge J. Med. Chem. 1984, 27, 994 i 5 ml THF blandes med 20 ml av en oppløsning av diazometan i eter og får stå i 16 timer ved romtemperatur. Oppløsnings-middelblandingen fjernes ved redusert trykk og resten kromatograferes på 50 g silikagel og elueres med etylen-klorid-metanol (98:2). Fra isopropanol oppnås tittelforbindelsen av gulbege farge. A cooled to +5° solution of 500 mg of 2-methyl-2-phenyl--3,4-dihydro-2H-naphtho[1,2-b]pyran (2-desmethyl-2-phenyl--3-lapacon) , prepared according to J. Med. Chem. 1984, 27, 994 in 5 ml of THF is mixed with 20 ml of a solution of diazomethane in ether and allowed to stand for 16 hours at room temperature. The solvent mixture is removed under reduced pressure and the residue is chromatographed on 50 g of silica gel and eluted with ethylene chloride-methanol (98:2). From isopropanol, the title compound of yellowish-beige color is obtained.
Eksempel 5: Example 5:
Tabletter som inneholder 500 mg 6,6-dimetyl-4,5-dihydfo-2H--(1,3-dioksolo)[3,4]nafto[1,2-b]pyran kan fremstilles på Tablets containing 500 mg of 6,6-dimethyl-4,5-dihydro-2H-(1,3-dioxolo)[3,4]naphtho[1,2-b]pyran can be prepared on
følgende måte: the following way:
Sammensetning (til 10.000 tabletter): Composition (for 10,000 tablets):
Det virksomme stoffet fuktes uniformt med klister av hvetestivelse som er fremstilt ved utrøring av 500 g hvetestivelse med ca. 1 . 30 0 ml avmineralisert vann, og med ytteligere 600 ml avmineralisert vann, det knas til en svak plastisk masse og drives gjennom en sikt med en maskevidde på ca. 3 mm. Granulatet tørkes deretter og drives på nytt gjennom sikten. Det tørkede granulatet som er brakt til en enhetlig kornstørrelse blandes med magnesiumstearatet, stearinsyren, talken og resten av hvetestivelsen og den oppnådde blandingen presses til tabletter . The active ingredient is moistened uniformly with paste of wheat starch which is produced by stirring 500 g of wheat starch with approx. 1. 30 0 ml of demineralized water, and with a further 600 ml of demineralized water, it is crushed to a weak plastic mass and run through a sieve with a mesh size of approx. 3 mm. The granulate is then dried and driven through the screen again. The dried granules brought to a uniform grain size are mixed with the magnesium stearate, stearic acid, talc and the rest of the wheat starch and the resulting mixture is pressed into tablets.
Eksempel 6 : Example 6:
En 1 0% suspensj on som inneholder 6,6-dimetyl-4,5-dihydro-2H--(1,3-dioksolo)[3,4]nafto[1,2-b]pyran, kan fremstilles på følgende måte : A 10% suspension containing 6,6-dimethyl-4,5-dihydro-2H-(1,3-dioxolo)[3,4]naphtho[1,2-b]pyran can be prepared as follows :
Sammensetning (til 500 ml): Composition (for 500 ml):
En suspensjon av det virksomme stoffet i 250 g propylenglykol og 1.250 ml avmineralisert vann males med en kolloid-mølle. Den fine suspensjonen, med en gjennomsnittlig partikkelstørrelse under 10 pm, dispergeres i en oppløsning av hydroksypropylmetylcellulose, sitronsyre og sakkarin--natrium i 250 ml avmineralisert vann og i sorbittopp-løsningen. Under omrøring tilsettes det til denne suspensjonen en oppløsning av 4-hydroksy-benzosyremetylesteren og 4-hydroksybenzosyrepropylesteren i 250 g propylenglykol og bringebæraroma. Etter tilsats av avmineralisert vann til et volum på 5 . 000 ml får man en suspensjon som inneholder 50 0 mg virksomt stoff i 5 ml. A suspension of the active substance in 250 g of propylene glycol and 1,250 ml of demineralized water is ground with a colloid mill. The fine suspension, with an average particle size below 10 µm, is dispersed in a solution of hydroxypropylmethylcellulose, citric acid and saccharin sodium in 250 ml of demineralized water and in the sorbitol top solution. While stirring, a solution of the 4-hydroxybenzoic acid methyl ester and the 4-hydroxybenzoic acid propyl ester in 250 g of propylene glycol and raspberry aroma is added to this suspension. After adding demineralized water to a volume of 5 . 000 ml gives a suspension containing 500 mg of active substance in 5 ml.
Eksempel 7: Example 7:
Kapsler som hver inneholder 300 mg 6,6-dimetyl-4,5-dihydro--2H-(1 ,3-dioksolo)[3,4]nafto[1 ,2-b]pyran kan fremstilles på følgende måte : Capsules each containing 300 mg of 6,6-dimethyl-4,5-dihydro-2H-(1,3-dioxolo)[3,4]naphtho[1,2-b]pyran can be prepared as follows:
Sammensetning (til 10.000 kapsler): Composition (for 10,000 capsules):
Det virksomme stoffet blandes med magnesiumstearatet og porsjoner på 0,31 g av blandingen fylles ved hjelp aven innkapslingsmaskin i hårdgelatinkapsler. The active substance is mixed with the magnesium stearate and portions of 0.31 g of the mixture are filled using an encapsulation machine into hard gelatin capsules.
Eksempel 8: Example 8:
En vandig injeksjonssuspensjon (for intramuskulærtilførsel) som inneholder 1,0g 6,6-dimetyl-4,5-dihydro-2H-(1,3--dioksolo)[3,4]nafto[1 ,2-b]pyran, pr . 5 ml, kan fremstilles på følgende måte: Suspens. j onsmedium: An aqueous injection suspension (for intramuscular administration) containing 1.0g of 6,6-dimethyl-4,5-dihydro-2H-(1,3--dioxolo)[3,4]naphtho[1,2-b]pyran, per . 5 ml, can be prepared in the following way: Suspension. j ons medium:
Det sterile virksomme stoffet bearbeides under antimikro-bielle betingelser med suspensjonsmediet på en slik måte at man får en steril suspensjon som inneholder 1 ,0 g av det virksomme stoffet i 5 ml. The sterile active substance is processed under antimicrobial conditions with the suspension medium in such a way that a sterile suspension containing 1.0 g of the active substance in 5 ml is obtained.
Eksempel 9 : Example 9 :
En vandig injeksjonssuspensjon (for intramuskulærtilførsel) som inneholder 0,75g 6,6-dimetyl-4,5-dihydro-2H-(1,3--dioksolo ) [3 , 4]naf to [ 1 , 2-b]pyran pr . 5 ml kan fremstilles på følgende måte: An aqueous suspension for injection (for intramuscular administration) containing 0.75 g of 6,6-dimethyl-4,5-dihydro-2H-(1,3--dioxolo) [3, 4]naphtho [1, 2-b]pyran per . 5 ml can be prepared as follows:
Suspens. j onsmedium: Suspension. j ons medium:
Det sterile virksomme stoffet bearbeides under antimikro-bielle betingelser med suspensj onsmediet på en slik måte at man får en steril suspensjon som inneholder 0,75 g virksomt stoff i 5 ml. The sterile active substance is processed under antimicrobial conditions with the suspension medium in such a way that a sterile suspension containing 0.75 g of active substance in 5 ml is obtained.
Claims (4)
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EP (1) | EP0184990A1 (en) |
JP (1) | JPS61130291A (en) |
KR (1) | KR860004063A (en) |
AU (1) | AU5034985A (en) |
DD (1) | DD239205A5 (en) |
DK (1) | DK544585A (en) |
FI (1) | FI854633A (en) |
GR (1) | GR852816B (en) |
IL (1) | IL77137A0 (en) |
MA (1) | MA20579A1 (en) |
MC (1) | MC1711A1 (en) |
MT (1) | MTP975B (en) |
MW (1) | MW3885A1 (en) |
NO (1) | NO854713L (en) |
OA (1) | OA08175A (en) |
PL (1) | PL256441A1 (en) |
PT (1) | PT81555B (en) |
ZA (1) | ZA858989B (en) |
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US7074824B2 (en) | 2001-07-31 | 2006-07-11 | Arqule, Inc. | Pharmaceutical compositions containing beta-lapachone, or derivatives or analogs thereof, and methods of using same |
US6962944B2 (en) | 2001-07-31 | 2005-11-08 | Arqule, Inc. | Pharmaceutical compositions containing beta-lapachone, or derivatives or analogs thereof, and methods of using same |
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- 1985-11-21 EP EP85810556A patent/EP0184990A1/en not_active Withdrawn
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- 1985-11-25 ZM ZM88/85A patent/ZM8885A1/en unknown
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DK544585D0 (en) | 1985-11-25 |
FI854633A0 (en) | 1985-11-22 |
MTP975B (en) | 1990-03-30 |
DD239205A5 (en) | 1986-09-17 |
PT81555A (en) | 1985-12-01 |
OA08175A (en) | 1987-03-31 |
ZW21085A1 (en) | 1986-06-25 |
DK544585A (en) | 1986-05-27 |
MA20579A1 (en) | 1986-07-01 |
AU5034985A (en) | 1986-06-05 |
PL256441A1 (en) | 1986-10-21 |
EP0184990A1 (en) | 1986-06-18 |
MW3885A1 (en) | 1986-12-10 |
MC1711A1 (en) | 1986-09-22 |
FI854633A (en) | 1986-05-27 |
IL77137A0 (en) | 1986-04-29 |
GR852816B (en) | 1986-03-21 |
ZA858989B (en) | 1986-07-30 |
JPS61130291A (en) | 1986-06-18 |
KR860004063A (en) | 1986-06-16 |
ZM8885A1 (en) | 1986-06-27 |
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