BE901445A - Anticancer 4':de-oxo 4':halo doxorubicin 14:ester(s) - prepd. by treating de-oxo halo:doxorubicin with bromine and an acid salt - Google Patents
Anticancer 4':de-oxo 4':halo doxorubicin 14:ester(s) - prepd. by treating de-oxo halo:doxorubicin with bromine and an acid salt Download PDFInfo
- Publication number
- BE901445A BE901445A BE0/214291A BE214291A BE901445A BE 901445 A BE901445 A BE 901445A BE 0/214291 A BE0/214291 A BE 0/214291A BE 214291 A BE214291 A BE 214291A BE 901445 A BE901445 A BE 901445A
- Authority
- BE
- Belgium
- Prior art keywords
- deoxy
- doxorubicin
- alkyl
- acid
- group
- Prior art date
Links
- 239000002253 acid Chemical class 0.000 title claims abstract description 13
- 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 title claims abstract description 10
- 150000003839 salts Chemical class 0.000 title claims abstract description 10
- 229910052794 bromium Inorganic materials 0.000 title claims abstract description 9
- 229960004679 doxorubicin Drugs 0.000 title claims abstract description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 title claims abstract description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 150000002148 esters Chemical class 0.000 title claims description 8
- 125000001475 halogen functional group Chemical group 0.000 title abstract 3
- 230000001093 anti-cancer Effects 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 150000007513 acids Chemical class 0.000 claims abstract description 4
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims abstract description 3
- PDQGEKGUTOTUNV-TZSSRYMLSA-N 4'-deoxy-4'-iododoxorubicin 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](I)[C@H](C)O1 PDQGEKGUTOTUNV-TZSSRYMLSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 125000000627 niacin group Chemical group 0.000 claims description 2
- 235000001968 nicotinic acid Nutrition 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 150000002739 metals Chemical class 0.000 claims 1
- 229960000975 daunorubicin Drugs 0.000 abstract description 10
- -1 aryl carbonic acid Chemical compound 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 abstract description 3
- 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 abstract 1
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 229910052783 alkali metal Inorganic materials 0.000 abstract 1
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 125000003282 alkyl amino group Chemical group 0.000 abstract 1
- 125000005210 alkyl ammonium group Chemical group 0.000 abstract 1
- 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 abstract 1
- 239000012442 inert solvent Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 125000001453 quaternary ammonium group Chemical group 0.000 abstract 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- IBTWUVRCFHJPKN-UHFFFAOYSA-N hydron;pyridine-3-carboxylic acid;chloride Chemical group Cl.OC(=O)C1=CC=CN=C1 IBTWUVRCFHJPKN-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000005474 octanoate group Chemical group 0.000 description 1
- IPMSGDXIFAMMSO-UHFFFAOYSA-N octanoic acid;hydrochloride Chemical group Cl.CCCCCCCC(O)=O IPMSGDXIFAMMSO-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000000075 primary alcohol group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 description 1
- KFLRWGSAMLBHBV-UHFFFAOYSA-M sodium;pyridine-3-carboxylate Chemical compound [Na+].[O-]C(=O)C1=CC=CN=C1 KFLRWGSAMLBHBV-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
4'-Deoxy-4'-halo doxorubicin 14-esters of formula (I) are new. R = acyl group derived from one of the following acids: mono- or di-carboxylic aliphatic, aromatic, cycloaliphatic, araliphatic, or heterocyclic, which may contain up to 20C atoms and may be substituted by any of the following: halogen, OH, alkyl, alkoxy, amino, mono or di alkylamino, nitro, alkyl or aryl carbonic acid, carbamic acid, alkyl carbamic acid, or sulphonic acid. - Prepn. has a 4'-deoxy-4'-halo daunorubicin dissolved in an anhydrous solvent and treated with bromine at ambient temp., to give the corresp. 14-bromo deriv. This is then treated with a salt ROM, where M is an alkali metal alkaline earth metal, quaternary ammonium, or quaternary alkyl ammonium, in an inert solvent.
Description
"Esters des 4'-haloanthracyclines"
ESTERS DES 4'-HALOANTHRACYCLINES
La présente invention concerne une nouvelle classe d'anthracyclines anticancéreuses.
Plus particulièrement, la présente invention concerne les esters en position 14 de la 4'-déoxy-4'-halodoxorubicine ayant pour formule :
<EMI ID=1.1>
où R est un radical acyle d'un acide choisi dans le groupe comprenant un acide substitué ou non substitué, aliphatique mono- ou dicarboxylique, aromatique, cycloaliphatique, arylaliphatique, hétérocyclique, et possédant de 1 à 20 atomes de carbone, l'élément de substitution étant choisi dans le groupe comprenant les halogènes^ les radicaux hydroxyles, alkyles, alkyoxyles, les groupes amino libres, les groupes mono- ou dialkyles substitués et les groupes nitro et d'un acide alkyle ou aryle carbonique, d'un acide carbamique ou alkylcarbamique et de l'acide sulfonique, tandis que X est .choisi dans le groupe comprenant F ,CI, Br et I.
Le brevet belge 892,943 appartenant au demandeur a déjà décrit et revendiqué la 4-déoxy-4'-iodo-daunorubicine et la 4'-déoxy-4'-iodo-doxorubicine présentant ,une efficacité anticancéreuse remarquable.
Au cours des travaux expérimentaux du demandeur, on a constaté, avec surprise, que certains dérivés de
<EMI ID=2.1> la 4'-déoxy-4'-iodo-doxorubicine, conformes à la formule 1, présentent une efficacité anticancéreuse supérieure à celle des composés de base , dans lesquels le groupe alcool primaire est libre, tandis que la cardiotoxicité correspondante est diminuée.
On a constaté également qu'on peut mettre en position 4', outre l'iode, d'autres atomes d'halogènes tels que fluor, brome et chlore. Toutefois, les dérivés iodés en position 4' se sont avérés particulièrement intéressants d'un point de vue pharmacologique.
Un autre objet de la présente invention est un procédé de préparation des esters en position 14 de la 4'déoxy-4'-halo-doxorubicine présentant la formule 1 cidessus, au départ de la 4'-déoxy-4'-halo-daunorubicine.
Les produits de départ-du procédé propre à la présente invention sont des produits connus, qui ont fait l'objet d'une invention du demandeur. Plus particulièrement, la 4'-déoxy-4'-iodo-daunorubicine a été décrite et revendiquée dans le brevet belge 892,943, tandis que les composés correspondants 4-brom 4'-fluor et 4' chlor ont été décrits et revendiqués dans la demande de brevet britannique n[deg.] 8321676 du demandeur.
<EMI ID=3.1>
un sel, et de préférence d'un chlorure, dissoute dans un solvant organique anhydre approprié ou dans un mélange de ceux-ci tels que le méthanol et le chloroforme, est mise en réaction avec le brome à température ambiante, de manière à obtenir le dérivé bromé en position 14 correspondant de la 4'-déoxy-4'-halo-daunoru-bicine, qui est isolé sous forme de sel tel qu'un chlorure, en appliquant des techniques connues en soi.
L'ester de la 4'-déoxy-4'-halo-doxorubicine propre à la présente invention et répondant à la formule
1 ci-dessus, est préparé en faisant réagir le dérivé bromé en position 14 de la 4'-déoxy-4'-halo-daunorubi-
<EMI ID=4.1>
cine ou l'un de ses sels, et de préférence un chlorure, avec un sel de l'acide désiré. Plus particulièrement, le procédé propre à la présente invention comprend la mise en réaction du chlorure du dérivé bromé en position 14 de la 4'-déoxy-4'-halo-daunorubicine avec un sel répondant à la formule ROM, où R a la signification mentionnée ci-dessus, tandis que M est un métal alcalin ou alcalino-terreux, ou encore un radical ammonium quaternaire substitué éventuellement par un groupe alkyle. La réaction s 'effectue en présence d'un solvant polaire inerte tel que l'acétone, et à température d'ébullition, pendant une courte période;. ou encore à froid avec un temps de réaction prolongé.
Les esters en position 14 de la 4'-déoxy-4'-halodoxorubicine ainsi obtenus sont isolés tels quels ou transformés en un sel d'un acide organique ou inorganique, puis sont purifiés par extraction et purification.
Les exemples suivants illustrent l'invention,sans en limiter la portée.
EXEMPLE 1
Acétate en position 14 de la 4'-déoxy-4'-iodo-doxorubicine.
On dissout 2,0 g de chlorure de 4'-déoxy-4'-iododaunorubicine dans 150 ml de chloroforme que l'on traite avec 9,25 ml d'une solution de brome à 2% dans le chloroforme.
Le mélange de réaction est mis à reposer à température ambiante pendant une nuit : le produit cristallin ainsi formé est séparé par filtration et on obtient, par recristallisation dans l'acétate d'éthyle, 1:,7 g de chlorure de dérivé bromé en position 14 de la 4'-déoxy-
<EMI ID=5.1>
On met en suspension 1,0 g de dérivé bromé en position 14 de 4'-déoxy-4'-iodo-daunorubicine dans 650ml d'acétone anhydre, que l'on traite avec 2,7 g d'acéta-
<EMI ID=6.1> te de potassium finement divisé.
La solution est mise à bouillir avec agitation pendant 50 minutes, et le solvant est éliminé par filtration sous vide. Le résidu est repris avec une solution 01N d'acide chlorhydrique et cette solution est extraite 3 fois avec 40 ml de chloroforme, puis avec
du butanol. Après concentration, on obtient 0,65 g de chlorure d'acétate en position 14 de la 4'-déoxy-4'iodo-doxorubicine.
EXEMPLE 2
Octanoate en position 14 de la 4'-déoxy-4'-doxorubicine.
On met en suspension 2,8 g de dérivé bromé en position 14 de la 4'-déoxy-4'-iodo-daunorubicine préparé suivant la méthode décrite à l'exemple 1, dans 500 ml d'acétone anhydre auxquels on ajoute 4g d'octanoate de sodium séché. Le mélange de réaction est mis à bouillir pendant une heure 40 minutes, puis est filtré, et le solvant est évaporé sous vide. Le résidu est repris avec 150 ml de chloroforme et 50 ml de méthanol et acidifié avec une solution méthaholique d'acide chlorhydrique. La solution est concentrée et le précipité ainsi obtenu est recristallisé dans le méthanol-chloroforme, de manière à obtenir 1,8 g de chlorure d'octanoate en position 14 de 4'-déoxy-4'-iôdo-doxorubicine.
EXEMPLE 3
Benzoate en position 14 de la 4'-déoxy-4'iododoxorubicine
On traite une suspension de 1,5 g de dérivé bromé en position 14 de la 4'-déoxy-4'-iodo-daunorubicine
dns 800 ml d'acétone anhydre avec 3,5 g de benzoate de sodium. La solution est mise à bouillir avec agitation pendant 3 heures, et le solvant est éliminé par filtra-tion sous vide. On ajoute au résidu une solution de 3,0 g de bicarbonate de sodium dans 100 ml d'eau,puis
200 ml de chloroforme et, après agitation, la phase aqueuse est séparée et extraite à nouveau avec du chloroforme. Les extraits organiques combinés sont évaporés, pour les réduire à un faible volume, puis sont acidifiés avec de l'acide chlorhydrique 1N dans le méthanol. Le précipité ainsi obtenu donne, par recristallisation dans le méthanol-chloroforme, 1,2 g de chloru-
<EMI ID=7.1>
doxorubicine.
EXEMPLE 4
Nicotinate en position 14 de la 4'-déoxy-4'-iododoxorubicine
On traite 1,4 g de dérivé bromé en position 14 de la 4'-déoxy-4'-iodo-daunorubicine en suspension dans
700 ml d'acétone anhydre avec 3,5 g de nicotinate de sodium, et le mélange est mis à bouillir pendant 3 heures avec agitation, puis est refroidi, filtré et évaporé à sec sous vide.
Le résidu est repris avec 100 ml de chloroforme et
100 ml d'une solution à 2% de bicarbonate de sodium. Après 'agitation, la phase aqueuse est séparée et ex-:
traite à nouveau avec du chloroforme et les extraits chloroformiques combinés sont lavés et évaporés pour les réduire à un faible volume. Une solution méthanolique d'acide chlorhydrique 1N est alors ajoutée et le précipité cristallisé dans le méthanol-chloroforme donne 1,0 g de chlorure de nicotinate en position 14 de
la 4'-déoxy-4'-iodo-doxorubicine.
Si l'on opère suivant la méthode décrite dans les exemples précédents, mais en utilisant des sels appropriés d'autres acides, on obtient les esters suivants de la 4'-épidoxorubicine : 14-formate, 14-propionate,
14-glycinate,14-emysuccinate et 14-cyclopentylpropionate.
<EMI ID=8.1>
"4'-haloanthracycline esters"
ESTERS OF 4'-HALOANTHRACYCLINES
The present invention relates to a new class of anticancer anthracyclines.
More particularly, the present invention relates to the esters in position 14 of 4'-deoxy-4'-halodoxorubicin having the formula:
<EMI ID = 1.1>
where R is an acyl radical of an acid chosen from the group comprising a substituted or unsubstituted, aliphatic mono- or dicarboxylic, aromatic, cycloaliphatic, arylaliphatic, heterocyclic acid and having from 1 to 20 carbon atoms, the element of substitution being chosen from the group comprising halogens, hydroxyl, alkyl or alkyloxy radicals, free amino groups, substituted mono- or dialkyl groups and nitro groups and an alkyl or aryl carbonic acid, a carbamic acid or alkylcarbamic acid and sulfonic acid, while X is selected from the group consisting of F, CI, Br and I.
Belgian patent 892,943 belonging to the applicant has already described and claimed 4-deoxy-4'-iodo-daunorubicin and 4'-deoxy-4'-iodo-doxorubicin exhibiting remarkable anticancer efficacy.
During the applicant's experimental work, it was surprisingly found that certain derivatives of
<EMI ID = 2.1> 4'-deoxy-4'-iodo-doxorubicin, in accordance with formula 1, have an anticancer efficacy greater than that of the base compounds, in which the primary alcohol group is free, while cardiotoxicity corresponding is decreased.
It has also been found that other halogen atoms such as fluorine, bromine and chlorine can be placed in the 4 'position, in addition to iodine. However, the iodinated derivatives in the 4 ′ position have proved to be particularly advantageous from a pharmacological point of view.
Another object of the present invention is a process for the preparation of the esters in position 14 of 4'-deoxy-4'-halo-doxorubicin having the formula 1 above, starting from 4'-deoxy-4'-halo-daunorubicin .
The starting materials of the process specific to the present invention are known products, which have been the subject of an invention of the applicant. More particularly, 4'-deoxy-4'-iodo-daunorubicin has been described and claimed in Belgian patent 892,943, while the corresponding compounds 4-brom 4'-fluorine and 4 'chlor have been described and claimed in the application. Applicant's British Patent No. [deg.] 8321676.
<EMI ID = 3.1>
a salt, and preferably a chloride, dissolved in a suitable anhydrous organic solvent or in a mixture of these such as methanol and chloroform, is reacted with bromine at room temperature, so as to obtain the corresponding brominated derivative in position 14 of 4'-deoxy-4'-halo-daunoru-bicine, which is isolated in the form of a salt such as a chloride, by applying techniques known per se.
The 4'-deoxy-4'-halo-doxorubicin ester specific to the present invention and corresponding to the formula
1 above, is prepared by reacting the brominated derivative in position 14 of 4'-deoxy-4'-halo-daunorubi-
<EMI ID = 4.1>
cine or one of its salts, and preferably a chloride, with a salt of the desired acid. More particularly, the process specific to the present invention comprises reacting the chloride of the brominated derivative in position 14 of 4'-deoxy-4'-halo-daunorubicin with a salt corresponding to the formula ROM, where R has the meaning mentioned above, while M is an alkali or alkaline earth metal, or alternatively a quaternary ammonium radical optionally substituted by an alkyl group. The reaction is carried out in the presence of an inert polar solvent such as acetone, and at boiling temperature, for a short period. or even cold with an extended reaction time.
The esters in position 14 of 4'-deoxy-4'-halodoxorubicin thus obtained are isolated as such or transformed into a salt of an organic or inorganic acid, then are purified by extraction and purification.
The following examples illustrate the invention without limiting its scope.
EXAMPLE 1
Acetate in position 14 of 4'-deoxy-4'-iodo-doxorubicin.
2.0 g of 4'-deoxy-4'-iododaunorubicin chloride are dissolved in 150 ml of chloroform which is treated with 9.25 ml of a 2% bromine solution in chloroform.
The reaction mixture is left to stand at ambient temperature overnight: the crystalline product thus formed is separated by filtration and, by recrystallization from ethyl acetate, 1.7 g of brominated derivative chloride are obtained in position 14 of 4'-deoxy-
<EMI ID = 5.1>
1.0 g of brominated derivative in position 14 of 4'-deoxy-4'-iodo-daunorubicin is suspended in 650 ml of anhydrous acetone, which is treated with 2.7 g of acetate.
<EMI ID = 6.1> finely divided potassium te.
The solution is boiled with stirring for 50 minutes, and the solvent is removed by vacuum filtration. The residue is taken up with a 01N hydrochloric acid solution and this solution is extracted 3 times with 40 ml of chloroform, then with
butanol. After concentration, 0.65 g of acetate chloride is obtained in position 14 of 4'-deoxy-4'iodo-doxorubicin.
EXAMPLE 2
Octanoate in position 14 of 4'-deoxy-4'-doxorubicin.
2.8 g of brominated derivative in position 14 of 4'-deoxy-4'-iodo-daunorubicin prepared according to the method described in Example 1 are suspended in 500 ml of anhydrous acetone to which 4g of d are added. 'dried sodium octanoate. The reaction mixture is boiled for one hour 40 minutes, then is filtered, and the solvent is evaporated in vacuo. The residue is taken up in 150 ml of chloroform and 50 ml of methanol and acidified with a methaholic solution of hydrochloric acid. The solution is concentrated and the precipitate thus obtained is recrystallized from methanol-chloroform, so as to obtain 1.8 g of octanoate chloride in position 14 of 4'-deoxy-4'-iodo-doxorubicin.
EXAMPLE 3
Benzoate in position 14 of 4'-deoxy-4'iododoxorubicin
A suspension of 1.5 g of brominated derivative in position 14 of 4'-deoxy-4'-iodo-daunorubicin is treated
In 800 ml of anhydrous acetone with 3.5 g of sodium benzoate. The solution is boiled with stirring for 3 hours, and the solvent is removed by vacuum filtration. A solution of 3.0 g of sodium bicarbonate in 100 ml of water is added to the residue, then
200 ml of chloroform and, after stirring, the aqueous phase is separated and extracted again with chloroform. The combined organic extracts are evaporated, to reduce them to a small volume, then are acidified with 1N hydrochloric acid in methanol. The precipitate thus obtained gives, by recrystallization from methanol-chloroform, 1.2 g of chloro-
<EMI ID = 7.1>
doxorubicin.
EXAMPLE 4
Nicotinate in position 14 of 4'-deoxy-4'-iododoxorubicin
1.4 g of brominated derivative in position 14 of 4'-deoxy-4'-iodo-daunorubicin in suspension in
700 ml of anhydrous acetone with 3.5 g of sodium nicotinate, and the mixture is boiled for 3 hours with stirring, then is cooled, filtered and evaporated to dryness under vacuum.
The residue is taken up with 100 ml of chloroform and
100 ml of a 2% solution of sodium bicarbonate. After stirring, the aqueous phase is separated and ex:
treated again with chloroform and the combined chloroform extracts are washed and evaporated to reduce them to a small volume. A 1N methanolic hydrochloric acid solution is then added and the precipitate crystallized from methanol-chloroform gives 1.0 g of nicotinate chloride in position 14 of
4'-deoxy-4'-iodo-doxorubicin.
If one operates according to the method described in the preceding examples, but using appropriate salts of other acids, the following esters of 4'-epidoxorubicin are obtained: 14-formate, 14-propionate,
14-glycinate, 14-emysuccinate and 14-cyclopentylpropionate.
<EMI ID = 8.1>
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BE0/214291A BE901445A (en) | 1985-01-04 | 1985-01-04 | Anticancer 4':de-oxo 4':halo doxorubicin 14:ester(s) - prepd. by treating de-oxo halo:doxorubicin with bromine and an acid salt |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BE0/214291A BE901445A (en) | 1985-01-04 | 1985-01-04 | Anticancer 4':de-oxo 4':halo doxorubicin 14:ester(s) - prepd. by treating de-oxo halo:doxorubicin with bromine and an acid salt |
| BE901445 | 1985-01-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BE901445A true BE901445A (en) | 1985-05-02 |
Family
ID=25654401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BE0/214291A BE901445A (en) | 1985-01-04 | 1985-01-04 | Anticancer 4':de-oxo 4':halo doxorubicin 14:ester(s) - prepd. by treating de-oxo halo:doxorubicin with bromine and an acid salt |
Country Status (1)
| Country | Link |
|---|---|
| BE (1) | BE901445A (en) |
-
1985
- 1985-01-04 BE BE0/214291A patent/BE901445A/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CH375017A (en) | Process for the preparation of novel imidazole derivatives | |
| JPH08134055A (en) | Production of 3-o-substituted-ascorbic acid | |
| EP0325537B1 (en) | Process for the synthesis of 3'-azido-3'-deoxythymidine and the like | |
| JPH0129191B2 (en) | ||
| BE901445A (en) | Anticancer 4':de-oxo 4':halo doxorubicin 14:ester(s) - prepd. by treating de-oxo halo:doxorubicin with bromine and an acid salt | |
| EP0433267B1 (en) | Process for preparing eicosatetraynoic acid | |
| BE901444A (en) | New anticancer 4:deoxy-doxorubicin 14:ester(s) - prepd. by treating 4:deoxy daunorubicin with bromine and then with an acid salt | |
| US4264500A (en) | Process of making 6-chloro-α-methyl-carbazole-2-acetic acid | |
| US4463195A (en) | Process for producing o-nitrobenzaldehyde | |
| BE901443A (en) | New anticancer 4:epi:doxorubicin 14:ester(s) - prepd. by brominating 4:epi:daunorubicin and treating the 14:bromo compound with an acid salt | |
| EP0223647A2 (en) | Alkyl carboxamides of pyridyl alkyl amines, their preparation and their use as medicaments | |
| CH438347A (en) | Process for preparing new colchicium derivatives | |
| JP3058399B2 (en) | [[4-Substituted acetyl-O-phenylene] dioxy] diacetate derivative and method for producing the same | |
| FR2513638A1 (en) | PROCESS FOR THE PREPARATION OF VINCAMINE ACID ESTERS | |
| BE892370A (en) | Alpha 2,3-di:oxo-piperazino-carbonyl-amino phenyl-acetamido-penicillin - and corresp. 3-1-methyl-tetrazolyl-thiomethyl cephalosporin(s) prepn. using tri:methyl-chloro-silane activated di:oxo piperazine | |
| US4308383A (en) | N-(3-(1'-3"-Oxapentamethyleneamino-ethylideneamino)-2,4,6-triiodobenzoyl)-β-amino-α-methylpropionitrile | |
| BE818471A (en) | PROCESS FOR PREPARING 1-ARALKYL-4-AMINO-METHYLPIPERIDINE-4-OLS | |
| BE876979A (en) | PROCESS FOR THE PREPARATION OF PENICILLANIC ACID PHTHALIDYL ESTER | |
| BE513130A (en) | ||
| BE498859A (en) | ||
| CH540248A (en) | Process for the preparation of substituted chromone-2-carboxylic acids | |
| BE858897A (en) | PHTHALIDYL ESTERS OF THERAPEUTICALLY ACTIVE ARYL-ALKANOIC ACIDS AND PROCESS FOR THEIR PREPARATION | |
| CH426858A (en) | Process for preparing new colchicium derivatives | |
| BE506999A (en) | ||
| BE633627A (en) |