IT8909564A1 - 8-FLUORO-ANTHRACYCLIN, RELATED MANUFACTURING PROCEDURES AND THEIR USE. - Google Patents
8-FLUORO-ANTHRACYCLIN, RELATED MANUFACTURING PROCEDURES AND THEIR USE.Info
- Publication number
- IT8909564A1 IT8909564A1 IT1989A09564A IT0956489A IT8909564A1 IT 8909564 A1 IT8909564 A1 IT 8909564A1 IT 1989A09564 A IT1989A09564 A IT 1989A09564A IT 0956489 A IT0956489 A IT 0956489A IT 8909564 A1 IT8909564 A1 IT 8909564A1
- Authority
- IT
- Italy
- Prior art keywords
- formula
- aglycone
- production
- intermediate product
- compound according
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 238000000034 method Methods 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 25
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 claims description 12
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 claims description 12
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000013067 intermediate product Substances 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- -1 for example formiate Chemical class 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 238000005858 glycosidation reaction Methods 0.000 claims description 3
- DFWWTQSJYNWQPT-UHFFFAOYSA-N 2,3-bis(bromomethyl)-1,4-dimethoxyanthracene-9,10-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C(OC)=C(CBr)C(CBr)=C2OC DFWWTQSJYNWQPT-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- XRGPFNGLRSIPSA-UHFFFAOYSA-N butyn-2-one Chemical compound CC(=O)C#C XRGPFNGLRSIPSA-UHFFFAOYSA-N 0.000 claims description 2
- 230000017858 demethylation Effects 0.000 claims description 2
- 238000010520 demethylation reaction Methods 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 125000000466 oxiranyl group Chemical group 0.000 claims description 2
- 150000004965 peroxy acids Chemical class 0.000 claims description 2
- 230000004224 protection Effects 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 208000028018 Lymphocytic leukaemia Diseases 0.000 claims 2
- 238000010511 deprotection reaction Methods 0.000 claims 2
- 230000007062 hydrolysis Effects 0.000 claims 2
- 238000006460 hydrolysis reaction Methods 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 claims 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 238000006735 epoxidation reaction Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
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- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- RBWNDBNSJFCLBZ-UHFFFAOYSA-N 7-methyl-5,6,7,8-tetrahydro-3h-[1]benzothiolo[2,3-d]pyrimidine-4-thione Chemical compound N1=CNC(=S)C2=C1SC1=C2CCC(C)C1 RBWNDBNSJFCLBZ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
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- 239000004698 Polyethylene Substances 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
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- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
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- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
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- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
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- 231100000259 cardiotoxicity Toxicity 0.000 description 1
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- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
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- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
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Description
Descrizione dell'Invenzione Industriale dal titolo: 8-FLUORO-ANTRACICLINE, RELATIVI PROCEDIMENTI DI FABBRICAZIONE E LORO USO" Description of the Industrial Invention entitled: 8-FLUORO-ANTHRACYCLIN, RELATED MANUFACTURING PROCEDURES AND THEIR USE "
RIASSUNTO SUMMARY
8-fluoro-antracicline di formula generale : 8-fluoro-anthracyclines of general formula:
dove X = H o OH e dove: R1 = H e R2 = OH; oppure R1 = OH e R2 = H; oppure R1 = H e R2 = H; nonch? loro procedimenti di fabbricazione e uso quali nuovi agenti antitumorali where X = H or OH and where: R1 = H and R2 = OH; or R1 = OH and R2 = H; or R1 = H and R2 = H; as well? their manufacturing processes and use as novel anticancer agents
DESCRIZIONE DESCRIPTION
L'invenzione si riferisce a nuovi derivati del 2?-acetil-2?,4?,5 ,12-tetraidrossi-3?-fluoro-1,2,3,4-tetraidro-6 ,11-naftacendione, ai preparati farmaceutici contenenti detti prodotti ed ai metodi per produrre e utilizzare questi derivati. The invention refers to new derivatives of 2? -Acetyl-2?, 4?, 5, 12-tetrahydroxy-3? -Fluoro-1,2,3,4-tetrahydro-6, 11-naphtacendione, to pharmaceutical preparations containing said products and the methods for producing and using these derivatives.
E' noto che le antracicline sono importanti agenti antitumorali con efficacia clinica nei confronti di molti tipi di tumore umano. Comunque il loro impiego terapeutico ? limitato dagli effetti collaterali, particolarmente la cardiotossicit? dose-correlata (vedere ad esempio F. Arcamone, DOXORUBICIN, ANTITUMOR ANTIBIOTICS, Pergamon Press, New York, 1981; oppure J.W.Lown (ED.) ANTHRACYCLINE AND ANTHRACENEDIONE-BASED ANTICANCER AGENTS, Elsevier, 1988). Anthracyclines are known to be important antitumor agents with clinical efficacy against many types of human cancer. However their therapeutic use? limited by side effects, particularly cardiotoxicity? dose-related (see for example F. Arcamone, DOXORUBICIN, ANTITUMOR ANTIBIOTICS, Pergamon Press, New York, 1981; or J.W.Lown (ED.) ANTHRACYCLINE AND ANTHRACENEDIONE-BASED ANTICANCER AGENTS, Elsevier, 1988).
E1 stato ora sorprendentemente scoperto che la introduzione di un atomo di fluoro al posto di un atomo di idrogeno in posizione 3p dell'aglicone delle antracicline antitumorali aumenta l'attivit? antitumorale e la selettivit? di azione di tali composti. Ne risultano pertanto dei composti che sorprendentemente - e presumibilmente in connessione con una diversa reattivit? dell'ossidrile in 2? o per motivi pure non prevedibili dagli esperti del ramo - presentano vantaggi nei confronti dei farmaci attualmente in uso nella terapia dei tumori umani. It has now been surprisingly discovered that the introduction of a fluorine atom in place of a hydrogen atom in the 3p position of the aglycone of the anticancer anthracyclines increases the activity. antitumor and selectivity? of action of such compounds. The result is therefore some compounds that surprisingly - and presumably in connection with a different reactivity? of hydroxyl in 2? or for reasons not foreseeable by those skilled in the art - they have advantages over the drugs currently used in the therapy of human tumors.
La presente invenzione si riferisce quindi a nuovi fluoro derivati dell'antraciclina di formula generale The present invention therefore refers to new fluorine derivatives of anthracycline of general formula
dove X = H o OH e where X = H or OH e
L'invenzione rivendica anche un nuovo metodo di sintesi utile per ottenere l'aglicone della formula: The invention also claims a new synthesis method useful for obtaining the aglycone of the formula:
nonch? il detto aglicone. as well? the said aglycone.
La sintesi per ottenere l'aglicone ? riportata nel seguente schema: The synthesis to obtain the aglycone? shown in the following diagram:
L ' invenzione riguarda anche i prodotti intermedi The invention also relates to intermediate products
III a IX suddetti III to IX above
Il composto I ? ottenuto secondo F A.J.Kerdesky, R.D. Ardecky, M. V. Lakshmikantham e M.P. Cava, J. AM. Compound I? obtained according to F A.J. Kerdesky, R.D. Ardecky, M. V. Lakshmikantham and M.P. Quarry, J. AM.
CHEM. SOC. 1981, 103, 1992-1996; o secondo R.J.Ardecky, D.Dominguer e M.P. Cava, J. ORG. CHEM. 1982, 47, 409-412. CHEM. SOC. 1981, 103, 1992-1996; or according to R.J. Ardecky, D. Dominguer and M.P. Quarry, J. ORG. CHEM. 1982, 47, 409-412.
Per ottenere il composto intermedio III si usa una fc variante a quanto riportato da Kerdesky et al. (F.A.J. To obtain the intermediate compound III, a variant fc is used as reported by Kerdesky et al. (F.A.J.
Kerdesky, R.D. Ardecky, M.V. Lakshmikantham e M.P.Cava, J. AM. CHEM. SOC. 1981, 103, 1992-1996): la ciclizzazione avviene per reazione del 3-butin-2-one con l'1,4-dimetossi-2,3-bis (bromometil) antrachinone che nelle condizioni di reazione si comporta formalmente come un diene. Il naftacendione viene poi ossidato sul doppio legame 2,3 (composto intermedio IV) con un perossiacido in opportuno solvente. Kerdesky, R.D. Ardecky, M.V. Lakshmikantham and M.P.Cava, J. AM. CHEM. SOC. 1981, 103, 1992-1996): cyclization occurs by reaction of 3-butin-2-one with 1,4-dimethoxy-2,3-bis (bromomethyl) anthraquinone which in the reaction conditions formally behaves as a diene. The naphthcendione is then oxidized on the double bond 2,3 (intermediate compound IV) with a peroxyacid in a suitable solvent.
Per ottenere il composto intermedio V si opera l'apertura dell'anello ossiranico con un fluoro nucleofilo, come per esempio il reagente di Olah. To obtain the intermediate compound V, the oxirane ring is opened with a nucleophilic fluorine, such as for example Olah's reagent.
La demetilazione degli ossidrili fenolici, per ottenere il composto intermedio VI, viene effettuata, in resa pressoch? quantitativa, con un adatto acido di Lewis, come per esempio boro tricloruro. The demethylation of the phenolic hydroxyls, in order to obtain the intermediate compound VI, is carried out, in yield almost? quantitative, with a suitable Lewis acid, such as boron trichloride.
Prima di bromurare la posizione 4 ? preferibile proteggere la catena acetilica, ad esempio con glicole etilenico (composto intermedio VII). La successiva bromurazione in posizione 4 viene effettuata con un adatto agente bromurante, come per esempio bromo o N-bromosuccinimmide, in opportuno solvente, in presenza o meno di iniziatori radicalici quali luce o azo-bis-isobutirronitrile. Il bromo derivato ottenuto subisce facilmente la sostituzione con un ossidrile per dare l'intermedio Vili. Quest'ultimo viene deprotetto in ambiente acido, ottenendo cos? il 20-acetil-2?,4?,5,12-tetraidrossi-3?-fluoro-1,2,3,4-tetraidro--6,11-naftacendione (intermedio IX). Before brominating position 4? it is preferable to protect the acetyl chain, for example with ethylene glycol (intermediate compound VII). The subsequent bromination in position 4 is carried out with a suitable brominating agent, such as for example bromine or N-bromosuccinimide, in a suitable solvent, in the presence or not of radical initiators such as light or azo-bis-isobutyronitrile. The bromine derivative obtained easily undergoes substitution with a hydroxyl to give the intermediate VIII. The latter is deprotected in an acidic environment, thus obtaining? 20-acetyl-2?, 4?, 5,12-tetrahydroxy-3? -fluoro-1,2,3,4-tetrahydro - 6,11-naphthycendione (intermediate IX).
La sintesi procede come segue - per raggiungere il prodotto finale XIII - con una glicosidazione ad esempio con: The synthesis proceeds as follows - to reach the final product XIII - with a glycosidation for example with:
per proseguire con la rimozione delle protezioni ed ottenere: to continue with the removal of the protections and obtain:
XIII XIII
La glicosidazione del composto IX per dare 1 composti di formula generale oggetto della presente invenzione con X = H avviene attraverso reazione del composto IX con un derivato glucidico opportunamente protetto e presentante, in posizione 1, una funzione chimica capace di originare,nelle condizioni adatte, un carbocatione sufficientemente stabilizzato e capace di dar luogo ad una condensazione con l'ossidrile benzilico del composto IX e formazione di un legame glucosidico. Esempi tipici di reattivi glucidici sono la 3-N-trifluoroacetil-l,4-bis(0-p-nitrobenzoil)-daunosammina(X), la 3-N-trifluoroacetil-l,4-bis(O-p-nitrobenzoil)-acosamina (XI), la 3-N-trifluoroacetil-l-O-p--nitrobenzoil-4-desossi-daunosammina (XII), oppure 3,4-di-triflaoroacetil-l-clorodaunosammina, la 3,4-di trifluoroacetil-l-cloroacosammina, o il corrispondente 4-desossi derivato. The glycosidation of compound IX to give the compounds of general formula object of the present invention with X = H takes place through the reaction of compound IX with a glucidic derivative suitably protected and having, in position 1, a chemical function capable of originating, under suitable conditions, a sufficiently stabilized carbocation capable of giving rise to a condensation with the benzyl hydroxyl of compound IX and the formation of a glucosidic bond. Typical examples of glucose reagents are 3-N-trifluoroacetyl-1,4-bis (0-p-nitrobenzoyl) -daunosamine (X), 3-N-trifluoroacetyl-1,4-bis (O-p-nitrobenzoyl) -acosamine (XI), 3-N-trifluoroacetyl-1-O-p - nitrobenzoyl-4-deoxy-daunosamine (XII), or 3,4-di-triflaoroacetyl-1-chlorodaunosamine, 3,4-di-trifluoroacetyl-1-chloroacosamine, or the corresponding 4-deoxy derivative.
Quale gruppo protettivo della funzione alcolica dello zucchero pu? anche essere usato il trimetilsilile derivato, mentre la posizione 1 dello stesso pu? essere attivata anche come 1-bromo, 1-fluoro, 1-trimetilsililossi, 1-acetossi, o come 1,2-glicole. Which protective group of the alcoholic function of sugar can? also be used the derivative trimethylsilyl, while the position 1 of the same can? also be activated as 1-bromo, 1-fluoro, 1-trimethylsilyloxy, 1-acetoxy, or as 1,2-glycol.
Agenti condensanti nella reazione tra reattivo glucidico e intermedio IX possono essere sali come argento .triflato o argento perclorato, miscele di ossido e bromuro mercurico, trimetilsililtriflato, oppure acidi come acido p-toluensolfonico, oppure acidi di Lewis come un boro trialogenuro, stagno tetracloruro o composti chimici con propriet? equivalenti. I solventi usati sono generalmente solventi clorurati come cloruro di metilene, idrocarburi, come benzene o toluene, eteri, come tetraidrofurano, oppure miscele di questi fra loro e/o con altri solventi quali la dimetilformammide, in presenza o in assenza di basi organiche quali piridina, collidina o equivalenti. Condensing agents in the reaction between glucose reactive and intermediate IX can be salts such as silver triflate or silver perchlorate, mixtures of mercuric oxide and bromide, trimethylsilyl triflate, or acids such as p-toluenesulfonic acid, or Lewis acids such as a boron trihalide, tin tetrachloride or chemical compounds with properties equivalents. The solvents used are generally chlorinated solvents such as methylene chloride, hydrocarbons, such as benzene or toluene, ethers, such as tetrahydrofuran, or mixtures of these with each other and / or with other solvents such as dimethylformamide, in the presence or absence of organic bases such as pyridine , collidina or equivalent.
I gruppi protettivi sul residuo glucidico vengono rimossi con opportuni reagenti basici, secondo procedure note in letteratura. The protective groups on the glucose residue are removed with suitable basic reagents, according to procedures known in the literature.
L'ottenimento di composti con X = OH viene effettuato partendo dai cloridrati o altri opportuni sali dei corrispondenti composti con X = H per trattamento con bromo in una miscela di solventi, preferibilmente alcool metilico e diossano, anche se la natura dei solventi, una volta che fossero compatibili con le condizioni di reazione, non pu? limitare il significato della presente invenzione. Il 14-bromo derivato ottenuto viene quindi sostituito con l'ossidrile attraverso una reazione con soluzioni acquose di una base inorganica, come un idrato alcalino, od organico, come un'ammina, oppure di un sale come un sale alcalino di un acido minerale debole o di un acido organico, ad esempio il sodiobicarbonato od il sodio formiato. Compounds with X = OH are obtained starting from the hydrochlorides or other suitable salts of the corresponding compounds with X = H by treatment with bromine in a mixture of solvents, preferably methyl alcohol and dioxane, even if the nature of the solvents once that they were compatible with the reaction conditions, can not? limit the meaning of the present invention. The 14-bromine derivative obtained is then substituted with hydroxyl through a reaction with aqueous solutions of an inorganic base, such as an alkaline hydrate, or organic, such as an amine, or of a salt such as an alkaline salt of a weak mineral acid. or an organic acid, for example sodium bicarbonate or sodium formate.
Si de'scrive ora una possibile reazione di sintesi a partire dai prodotti I e II. A possible synthesis reaction starting from products I and II is now described.
III (2-acetil-5 ,12-dimetossi-l,4-diidro-6,11-naftscendione) III (2-acetyl-5, 12-dimethoxy-1,4-dihydro-6,11-naftscendione)
In una miscela costituita da mi 50 di dimetllacetammlde e mi 10 di diossano vengono disciolti sotto azoto g 29 (193 mmoli) di Nal. La dissoluzione ? esotermica: quando la temperatura ? scesa a 40?C si aggiungono in una sola porzione g 6,6 (97 mmoli) di butinone II. Si porta la temperatura della miscela a 65?C e vi si gocciola, in un'ora, una soluzione composta da g 5 (11 mmoli) di I e mi 100 di dimetilacetammide , mantenendo la temperatura vicina al valore iniziale. Al termine dell'aggiunta si lascia sotto agitazione a 65-70?C ancora per un'ora, quindi si raffredda e si versa in mi 600 di acqua. Il solido che si ottiene viene filtrato, lavato bene con acqua e seccato sotto vuoto su P O a dare 83.85 di III. P.f.: In a mixture consisting of 50 ml of dimethylacetamide and 10 ml of dioxane, 29 g (193 mmoles) of Nal are dissolved under nitrogen. The dissolution? exothermic: when the temperature? dropped to 40 ° C, 6.6 g (97 mmoles) of butinone II are added in a single portion. The temperature of the mixture is brought to 65 ° C and a solution composed of 5 g (11 mmoles) of I and 100 ml of dimethylacetamide is dropped into it in one hour, keeping the temperature close to the initial value. At the end of the addition it is left under stirring at 65-70 ° C for a further hour, then it is cooled and poured into 600 ml of water. The solid obtained is filtered, washed well with water and dried under vacuum over PO to give 83.85 of III. P.f .:
IV (2-acetil-2,3-epossi-5,12-dimetossi-I,2,3,4-tetra!-dro-6,11-naftacendione) IV (2-acetyl-2,3-epoxy-5,12-dimethoxy-I, 2,3,4-tetra! -Dro-6,11-naphtacendione)
In mi 400 di cloroformio si rifluiscono per 7 ore, sotto azoto, g 3.0 (8.3 mmoli) di III e g 18 di mCPBA 55% (57 mmoli). La miscela di reazione, raffreddata a temperatura ambiente, viene trattata con soluzione di bisolfito sodico al 10% (2x100 mi), quindi con bicarbonato sodico al 5% (3x100 mi), infine con acqua. La fase organica viene seccata su solfato di sodio ed il solvente evaporato. Si purifica il grezzo di reazione sospendendolo in carbonio tetracloruro bollente, si raffredda, si filtra e si lava bene il solido con lo stesso solvente a dare mg 850 di IV al 90% di purezza (resa: 30%). P.f.: 241-245?C (dee.) In 400 ml of chloroform, 3.0 g (8.3 mmoles) of III and 18 g of 55% mCPBA (57 mmoles) are refluxed for 7 hours under nitrogen. The reaction mixture, cooled to room temperature, is treated with 10% sodium bisulfite solution (2x100 ml), then with 5% sodium bicarbonate (3x100 ml), finally with water. The organic phase is dried over sodium sulphate and the solvent evaporated. The raw reaction product is purified by suspending it in boiling carbon tetrachloride, it is cooled, filtered and the solid washed well with the same solvent to give 850 mg of IV at 90% purity (yield: 30%). P.f .: 241-245? C (dee.)
V (2?-acetil-20i-idrossl-3?-fluoro-5,12-dimetossi--1,2,3,4-tetraidro-6,11-naftacendione) V (2? -Acetyl-20i-hydroxl-3? -Fluoro-5,12-dimethoxy - 1,2,3,4-tetrahydro-6,11-naphtacendione)
In una beuta di polietilene si fanno reagire per 24 ore a temperatura ambiente, in atmosfera di azoto, g 1.4 (3.7 mmoli) di IV e ml 50 di HF/piridlna 70%. Si versa la miscela di reazione in g 600 di ghiaccio agitando bene, quindi si filtra il solido che si ottiene e lo si lava ripetutamente con acqua. Si secca questo grezzo sotto vuoto su P O e lo si sospende in mi 100 di acetone bollente; si lascia raffreddare e si filtra lavando il solido con poco acetone a dare mg 880 di V. P.f. 241-245?C dee. (resa: 60%). In a polyethylene flask, 1.4 g (3.7 mmoles) of IV and 50 ml of 70% HF / pyridine are reacted for 24 hours at room temperature, in a nitrogen atmosphere. The reaction mixture is poured into 600 g of ice, stirring well, then the solid obtained is filtered and washed repeatedly with water. This crude is dried under vacuum over PO and suspended in 100 ml of boiling acetone; it is allowed to cool and filtered, washing the solid with a little acetone to give 880 mg of V. M.p. 241-245? C dee. (yield: 60%).
VI (2?-acetil-2?,5,12-triidrossi-3?-fluoro-1,2,3,4-tetraidro-6,11-naftacendione) VI (2? -Acetyl-2?, 5,12-trihydroxy-3? -Fluoro-1,2,3,4-tetrahydro-6,11-naphtacendione)
In mi 15 di metilene cloruro anidro si sospendono, sotto azoto, mg 82 (0.21 mmoli) di V e, dopo aver portato a -65?C la temperatura con un bagno di acetone e ghiaccio secco, si aggiungono in 5' mi 3 di una soluzione 1M di Boro tricloruro (3 mmoli) in metilene cloruro. Si lascia sotto agitazione per 30' a -65?C prima di aggiungere lentamente mi 4 di metanolo e lasciare tornare la miscela di reazione a temperatura ambiente. Per evaporazione del solvente si ottengono infine mg 79 (100%) di VI. P.f.: 247-253?C. In 15 ml of anhydrous methylene chloride, 82 mg (0.21 mmoles) of V are suspended under nitrogen and, after having brought the temperature to -65 ° C with an acetone and dry ice bath, add in 5 'ml 3 of a 1M solution of Boron trichloride (3 mmoles) in methylene chloride. The mixture is left under stirring for 30 'at -65 ° C before slowly adding 4 ml of methanol and allowing the reaction mixture to return to room temperature. Finally, by evaporation of the solvent 79 mg (100%) of VI are obtained. P.f .: 247-253? C.
VII (20-[2-metil-1,3-diossolanil-2-il]2? 5,12-triidrossi-3?-fluoro-1 ,2,3,4-tetraidro-6,11-naftacendione) In una beuta da ml 250 dotata di apparecchio di Dean Stark, si fanno reagire, in atmosfera di azoto, mg 320 (0.86 mmoli) di VII e .? 7.77 (mi 7, 124 mmoli) di glicol etilenico a riflusso in mi 100 di benzene, in presenza di mg 70 (0.4 mmoli) di acido p-toluensolfonico, eliminando dall'ambiente di reazione l'azeotropo che via via distilla. Al termine si concentra il solvente a piccolo volume e si filtra il solido ottenuto lavandolo successivamente con poco benzene, etanolo, acqua, soluzione acquosa di bicarbonato sodico al 5% ed ancora con acqua. Si secca infine sotto vuoto a 80?C a dare mg 283 (0.68 mmoli) di VII: Pf. VII (20- [2-methyl-1,3-dioxolanyl-2-yl] 2? 5,12-trihydroxy-3? -Fluoro-1, 2,3,4-tetrahydro-6,11-naphtacendione) In a 250 ml flask equipped with a Dean Stark device, 320 mg (0.86 mmol) of VII e are reacted in a nitrogen atmosphere. 7.77 (ml 7, 124 mmoles) of ethylene glycol at reflux in 100 ml of benzene, in the presence of 70 mg (0.4 mmoles) of p-toluenesulfonic acid, eliminating from the reaction environment the azeotrope which gradually distills. At the end the solvent is concentrated to a small volume and the solid obtained is filtered by washing it subsequently with a little benzene, ethanol, water, aqueous solution of sodium bicarbonate at 5% and again with water. Finally, it is dried under vacuum at 80 ° C to give 283 mg (0.68 mmoles) of VII: Pf.
237-240?C. (Resa 79.1%). P.f. 239-241?C (toluene). 237-240? C. (Yield 79.1%). P.f. 239-241? C (toluene).
TLC: CCl4/AcOEt 2:1 R =0.54 TLC: CCl4 / AcOEt 2: 1 R = 0.54
VIII (2?-[2-metil-l,3-dioasolanil-2-il]-2?,4?,5,12-tetraidrossi-3?-fluoro-l ,2,3,4-tetraidro-6,11-naftacendione) VIII (2? - [2-methyl-1,3-dioasolanyl-2-yl] -2?, 4?, 5,12-tetrahydroxy-3? -Fluoro-1,3,4-tetrahydro-6, 11-naphtacendione)
Si sospendono mg 880 di VII in ml 200 di carbonio tetracloruro, sotto azoto, insieme a mg 880 di potassio carbonato. Si aggiunge una soluzione di mg 500 di bromo in mi 20 di carbonio tetracloruro. Si irraggia con una lampada da 500W portando la miscela a leggero riflusso. Dopo circa 5' si ha solubilizzazione del prodotto. La reazione viene fermata dopo 1 ora. Si diluisce con ml 200 di cloroformio e si lava con bicarbonato e poi con acqua. Si anidrifica su sodio solfato e si evapora il solvente. Si cromatografa il residuo su silice, eluendo prima con carbonio tetracloruro/etile acetato 3:1 per eliminare il prodotto di partenza residuo e i prodotti secondari. Si eluisce poi con etile acetato fino a ottenere mg 300 di VIII. 880 mg of VII are suspended in 200 ml of carbon tetrachloride, under nitrogen, together with 880 mg of potassium carbonate. A solution of 500 mg of bromine in 20 ml of carbon tetrachloride is added. It is irradiated with a 500W lamp bringing the mixture to a slight ebb. After about 5 'the product is dissolved. The reaction is stopped after 1 hour. It is diluted with 200 ml of chloroform and washed with bicarbonate and then with water. It is dried on sodium sulphate and the solvent is evaporated. The residue is chromatographed on silica, first eluting with carbon tetrachloride / ethyl acetate 3: 1 to eliminate the residual starting product and by-products. It is then eluted with ethyl acetate until 300 mg of VIII is obtained.
IX (20-acetil-2?,4?,5,12-tetraidrossi-3?-fluoro--1,2,3,4-tetraidro-6 ,11-naftacendione) IX (20-acetyl-2?, 4?, 5,12-tetrahydroxy-3? -Fluoro - 1,2,3,4-tetrahydro-6, 11-naphthycendione)
In mi 5 di CH2C12 anidro si solubilizzano, sotto azoto, mg 82 (0.19 mmoli) di VIII e la soluzione ottenuta si raffredda a 0?C. Si aggiungono quindi mi 5 (5 mmoli) di una soluzione 1M di BC1 in CH CI e si toglie il bagno di ghiaccio. Si lascia sotto agitazione a temperatura ambiente per 2 giorni, quindi si aggiungono con cautela mi 15 di acqua e s? lava, dopo aver diluito con mi 20 di CH Cl2 con acqua (3x20 mi). Si secca la fase organica su sodio solfato, s? evapora il solvente e si purifica il grezzo per cromatografia su colonna di silice (eluente: CHC1 /acetone 4:1). Si ottengono mg 40 di IX. (Resa 50?). In 5 ml of anhydrous CH2C12, 82 mg (0.19 mmoles) of VIII are solubilized under nitrogen and the solution obtained is cooled to 0 ° C. Then 5 ml (5 mmoles) of a 1M solution of BC1 in CH Cl are added and the ice bath is removed. It is left under stirring at room temperature for 2 days, then 15 ml of water and s? Are carefully added. wash, after having diluted with 20 ml of CH Cl2 with water (3x20 ml). The organic phase is dried on sodium sulfate, yes? the solvent is evaporated and the crude is purified by chromatography on a silica column (eluent: CHCl / acetone 4: 1). 40 mg of IX are obtained. (Yield 50?).
XIII (4-demetossi-8-fluoro-daunomicina) XIII (4-demethoxy-8-fluoro-daunomycin)
Si sospendono mg 142 di (?)-3-N-trifluoroacetil--1,4-bis(O-p-nitrobenzoil )-1-daunosammina in una soluzione di mg 45 di IX in mi 8,3 di metilene cloruro anidro e ml 7 di etere anidro, sotto azoto, in presenza di mg 600 di setacci molecolari 4A in grani. Si fredda a 0?C e si aggiungono mi 0,08 di trimetilsililtriflato. Dopo tre ore si tratta la miscela di reazione con mi 50 di etile acetato e mi 100 di soluzione satura di sodio bicarbonato, . lavando poi la fase organica con soluzione di sodio cloruro. Si anidrifica, si evapora il solvente e si purifica il residuo per cromatografia su silice, eluendo con cloroformio/acetone 4:1. Si ottengono mg 80 di prodotto, che vengono solubilizzati in mi 0,6 di metilene cloruro e mi 37 di metanolo. Si fredda a 0?C e in atmosfera di azoto si aggiungono mi 1,2 di sodio idrossido 0,1 M. Si agita la soluzione per 30 minuti, quindi si aggiunge acido acetico glaciale fino a portare il colore della soluzione ad arancio chiaro. Si tratta quindi con mi 60 di etile acetato e mi 60 di soluzione di sodio cloruro. La fase organica si lava ancora due volte con soluzione di sodio cloruro, quindi si anidrifica e si evapora. Il residuo si solubilizza in mi 15 di sodio idrossido 0,1 M a 0?C e si agita per 20 minuti, in atmosfera di azoto. Si porta il pH della soluzione a 8 con HC1 5 M, quindi si estrae ripetutamente con cloroformio. La fase organica si lava con acqua, si anidrifica e si concentra sotto vuoto. Il residuo si solubilizza in poco cloroformio e metanolo (9:1), si aggiunge HC1 in metanolo 0,25 M fino a pH 3,5, quindi si aggiunge etere fino a precipitazione del cloridrato di XIII. 142 mg of (?) - 3-N-trifluoroacetyl - 1,4-bis (O-p-nitrobenzoyl) -1-daunosamine are suspended in a solution of 45 mg of IX in 8.3 ml of anhydrous methylene chloride and 7 ml of anhydrous ether, under nitrogen, in the presence of 600 mg of 4A molecular sieves in grains. It is cooled to 0 ° C and 0.08 ml of trimethylsilyl triflate are added. After three hours the reaction mixture is treated with 50 ml of ethyl acetate and 100 ml of saturated sodium bicarbonate solution. then washing the organic phase with sodium chloride solution. It is dried, the solvent is evaporated and the residue is purified by chromatography on silica, eluting with 4: 1 chloroform / acetone. 80 mg of product are obtained, which are solubilized in 0.6 ml of methylene chloride and 37 ml of methanol. It is cold at 0 ° C and in a nitrogen atmosphere, 1.2 ml of 0.1 M sodium hydroxide are added. The solution is stirred for 30 minutes, then glacial acetic acid is added until the color of the solution is light orange. It is then treated with 60 ml of ethyl acetate and 60 ml of sodium chloride solution. The organic phase is washed twice more with sodium chloride solution, then anhydrified and evaporated. The residue is solubilized in 15 ml of 0.1 M sodium hydroxide at 0 ° C and is stirred for 20 minutes, in a nitrogen atmosphere. The pH of the solution is brought to 8 with 5 M HCl, then it is extracted repeatedly with chloroform. The organic phase is washed with water, dried and concentrated under vacuum. The residue is solubilized in a little chloroform and methanol (9: 1), HCl is added in 0.25 M methanol up to pH 3.5, then ether is added until the XIII hydrochloride precipitates.
TLC: (base libera) r =0,52 (CHC1 /MeOH/H O 13:6:1). TLC: (free base) r = 0.52 (CHC1 / MeOH / H O 13: 6: 1).
ATTIVIT?' BIOLOGICA ACTIVITIES? ' BIOLOGICAL
I composti oggetto della presente invenzione sono stati valutati in colture di cellule tumorali umane "in vitro" ed "in vivo" contro tumori trapiantabili del topo secondo i metodi descritti in CANCER CHEMIOTHERAPY REPORTS, Part.3, Voi.3, pp.9 (1972). The compounds object of the present invention were evaluated in cultures of human tumor cells "in vitro" and "in vivo" against transplantable mouse tumors according to the methods described in CANCER CHEMIOTHERAPY REPORTS, Part.3, Vol.3, pp.9 ( 1972).
I composti hanno mostrato un'attivit? superiore a quella della daunorubicina e della doxorubicina impiegati come prodotti di confronto. Did the compounds show activity? higher than that of daunorubicin and doxorubicin used as comparator products.
Claims (20)
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