DE4037693A1 - 13-DEOXO-4'-DEOXY-4'-JODANTHRACYCLINE - Google Patents
13-DEOXO-4'-DEOXY-4'-JODANTHRACYCLINEInfo
- Publication number
- DE4037693A1 DE4037693A1 DE4037693A DE4037693A DE4037693A1 DE 4037693 A1 DE4037693 A1 DE 4037693A1 DE 4037693 A DE4037693 A DE 4037693A DE 4037693 A DE4037693 A DE 4037693A DE 4037693 A1 DE4037693 A1 DE 4037693A1
- Authority
- DE
- Germany
- Prior art keywords
- formula
- deoxy
- derivative
- pharmaceutically acceptable
- acid addition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 17
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 14
- 229930182470 glycoside Natural products 0.000 claims description 14
- 150000002338 glycosides Chemical class 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 150000007857 hydrazones Chemical class 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- -1 Cyanoborohydride Chemical compound 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 5
- VJRITMATACIYAF-UHFFFAOYSA-N benzenesulfonohydrazide Chemical compound NNS(=O)(=O)C1=CC=CC=C1 VJRITMATACIYAF-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 5
- 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 4
- UZSHFUWBHXJQAR-UHFFFAOYSA-N 4-fluorobenzenesulfonohydrazide Chemical compound NNS(=O)(=O)C1=CC=C(F)C=C1 UZSHFUWBHXJQAR-UHFFFAOYSA-N 0.000 claims description 4
- 229960000975 daunorubicin Drugs 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- QSFQGKRLZCXSPE-UHFFFAOYSA-N 4-nitrobenzenesulfonohydrazide Chemical compound NNS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 QSFQGKRLZCXSPE-UHFFFAOYSA-N 0.000 claims description 2
- RIXHOXYAFWQBGU-UHFFFAOYSA-N 7-(4-amino-5-iodo-6-methyloxan-2-yl)oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(=O)CO)CC1OC1CC(N)C(I)C(C)O1 RIXHOXYAFWQBGU-UHFFFAOYSA-N 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000000434 field desorption mass spectrometry Methods 0.000 description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical class 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 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 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 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 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 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- ZWVMLYRJXORSEP-LURJTMIESA-N (2s)-hexane-1,2,6-triol Chemical compound OCCCC[C@H](O)CO ZWVMLYRJXORSEP-LURJTMIESA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Description
Die vorliegende Erfindung betrifft Anthracycline, ein Verfahren zu ihrer Herstellung, pharmazeutische Zusammensetzungen, die diese enthalten und ihre Verwendung bei der Behandlung von menschlicher Malignität.The present invention relates to anthracyclines Process for their preparation, pharmaceutical Compositions containing them and their use in the treatment of human malignancy.
Die vorliegende Erfindung betrifft Anthracyclinglycoside, die die allgemeine Formel I habenThe present invention relates to anthracycline glycosides, which have the general formula I.
wobei R₁ ein Wasserstoffatom oder eine Hydroxygruppe
ist, und ihre pharmazeutisch geeigneten Säurezugabesalze.
Ein geeignetes Salz ist das Hydrochloridsalz. Die
Erfindung stellt somit 13-Deoxodaunorubizin und
Doxorubicin Analoge, die ein Jodatom in der C-4′ Position
des Zuckerrestes haben, zur Verfügung. Insbesondere
betrifft die vorliegende Erfindung die folgenden
Anthracycline:
Ia: 13-Deoxo-4′-deoxy-4′-joddaunorubicin (R₁=H)
Ib: 13-Deoxo-4′-deoxy-4′-joddoxorubicin (R₁=OH).wherein R₁ is a hydrogen atom or a hydroxy group, and their pharmaceutically acceptable acid addition salts. A suitable salt is the hydrochloride salt. The invention thus provides 13-deoxodaunorubicin and doxorubicin analogs which have an iodine atom in the C-4 'position of the sugar residue. In particular, the present invention relates to the following anthracyclines:
Ia: 13-deoxo-4′-deoxy-4′-iododunorubicin (R₁ = H)
Ib: 13-deoxo-4'-deoxy-4'-iododoxorubicin (R₁ = OH).
Die erfindungsgemäßen Verfahren werden mittels eines Verfahrens hergestellt, das umfaßt:The methods according to the invention are carried out using a Process prepared, which comprises:
- (i) das Schützen der 3′-Aminogruppe des 4′-Deoxy-4′-jod-daunorubicin, 4′-deoxy-4′-iod-doxorubicin oder eines Säurezugabesalzes davon, wobei ein geschütztes Aminoderivat der Formel (III′) gebildet wird: wobei X eine aminoschützende Gruppe darstellt;(i) protecting the 3'-amino group of 4'-deoxy-4'-iodo-daunorubicin, 4'-deoxy-4'-iodo-doxorubicin or an acid addition salt thereof, thereby forming a protected amino derivative of the formula (III ') becomes: where X represents an amino protecting group;
- (ii) das Umsetzen des geschützten Aminoderivats der Formel (III′) mit einem Benzolsulfonylhydrazin, das eine elektronenanziehende Gruppe an dem aromatischen Ring hat, wobei ein Hydrazon der Formel (IV′) gebildet wird: (ii) reacting the protected amino derivative of formula (III ') with a benzenesulfonylhydrazine which has an electron attractive group on the aromatic ring to form a hydrazone of formula (IV'):
- (iii) das Reduzieren des Hydrazons der Formel (IV′), wobei das 13-Deoxoderivat der Formel (V′) gebildet wird: (iii) reducing the hydrazone of formula (IV ') to form the 13-deoxo derivative of formula (V'):
- (iv) das Entfernen der aminoschützenden Gruppe aus dem 13-Deoxoderivat der Formel (V′), wobei ein Anthracyclinglycosid der Formel (I) gebildet wird, und(iv) removing the amino protecting group from the 13-Deoxoderivat of formula (V '), where a Anthracycline glycoside of the formula (I) is formed, and
- (v) falls gewünscht, das Umwandeln des Anthracyclinglycosids der Formel (I) in ein pharmazeutisch geeignetes Säurezugabesalz davon.(v) if desired, converting the Anthracycline glycosides of the formula (I) in one pharmaceutically acceptable acid addition salt thereof.
Die Zwischenverbindungen der Formel (II′), (IV′) und (V′) und ihre Herstellung sind auch ein Teil der vorliegenden Erfindung.The intermediates of formula (II '), (IV') and (V ′) and their manufacture are also part of the present invention.
Die Ausgangsmaterialien für die Herstellung der neuen Anthracyclinglycoside sind 4′-Deoxy-4′-joddaunorbuicin (IIa, R₁=H) und 4′-Deoxy-4′-joddoxorubicin (IIb, R₁=OH). Beide sind in US-A-44 38 105 beschrieben. Diese Verbindungen können in Form ihrer pharmazeutisch geeigneten Säurezugabesalze, beispielsweise als Hydrochlorid verwendet werden.The raw materials for the production of the new Anthracycline glycosides are 4'-deoxy-4'-iododunorbuicin (IIa, R₁ = H) and 4'-deoxy-4'-iododoxorubicin (IIb, R₁ = OH). Both are described in US-A-44 38 105. These Compounds can be in the form of their pharmaceutical suitable acid addition salts, for example as Hydrochloride can be used.
Die 13-Deoxoderivate Ia, b werden hergestellt, indem ein ähnliches Verfahren wie das, das von T. H. Smith et al (siehe: J. Med. Chem., 21, 178 (1978)) für die Herstellung der 13-Deoxodrivate des Daunorubicins und Doxorubicins beschrieben ist, verwendet wird. Wir haben jedoch bei dem vorliegenden Verfahren gefunden, daß bei Verwendung eines Benzolsulfonylhydrazins, das eine elektronenanziehende Gruppe auf dem aromatischen Ring trägt, wie p-Fluor oder p-Nitrobenzolsulfonylhydrazin, die Reduktion des 13-Hydrazonderivats, IVa, b in 30 Minuten anstelle von 6 Stunden, wie von T. H. Smith et al für die Reduktion des 13-Tosylhydrazons des Daunorubicins oder Doxorubicins beschrieben, erfolgt.The 13-deoxo derivatives Ia, b are prepared by a similar procedure to that described by T. H. Smith et al (see: J. Med. Chem., 21, 178 (1978)) for the preparation of the 13 deoxodrivate of daunorubicin and doxorubicin is used. However, we have with that present method found that when using a Benzenesulfonylhydrazine, which is an electron attractive Group on the aromatic ring carries, such as p-fluorine or p-nitrobenzenesulfonylhydrazine, the reduction of 13-hydrazone derivative, IVa, b in 30 minutes instead of 6 Hours as described by T. H. Smith et al for the reduction of 13-tosylhydrazone of daunorubicin or doxorubicin described.
Um 13-Deoxoderivate 1a, b herzustellen, werden die Ausgangs 4′-Jodanthracycline IIa, b zuerst beispielsweise als N-Trifluoracetamido IIIa, b geschützt. Bei der vorliegenden Erfindung ist deshalb X vorzugsweise -COCF₃. Das geschützte Aminoderivat wird dann in das entsprechende Hydrazon wie 13-(p-Fluorbenzolsulfonyl)-hydrazon IVa, b oder 13-(p-Nitrobenzolsulfonyl)hydrazon umgewandelt. Das Benzolsulfonylhydrazin, das eine elektronenanziehende Gruppe an dem Benzolring hat, wird mit dem geschützten Aminoderivat zur Reaktion gebracht. Beispielsweise wird in einer Ausführungsform das geschützte Aminoderivat mit einem Überschuß von p-Fluorbenzolsulfonylhydrazin in Methanol und in Anwesenheit einer katalytischen Menge von p-Toluolsulfonsäure bei Temperatur 6 Tage lang zur Reaktion.In order to produce 13-deoxo derivatives 1a, b, the Starting 4'-iodoanthracyclins IIa, b first, for example protected as N-trifluoroacetamido IIIa, b. In the X is therefore preferred in the present invention -COCF₃. The protected amino derivative is then in the corresponding hydrazone like 13- (p-fluorobenzenesulfonyl) hydrazone IVa, b or 13- (p-Nitrobenzenesulfonyl) hydrazone converted. The Benzenesulfonylhydrazine, which is an electron-withdrawing Group on the benzene ring is protected with the Amino derivative brought to reaction. For example, in one embodiment with the protected amino derivative an excess of p-fluorobenzenesulfonylhydrazine in Methanol and in the presence of a catalytic amount of p-Toluenesulfonic acid at temperature for 6 days Reaction.
Das sich ergebende Hydrazon, wie beispielsweise die p-Fluorbenzolsulfonylhydrazone IVa, b können mittels Kristallisation wiedergewonnen werden. Üblicherweise wird es anschließend mit einem Cyanborhydrid behandelt. Das Hydrazon kann deshalb mit einer equimolaren Menge von alkalischem Cyanborhydridsalz wie Natriumcyanborhydrid und von 10-Camphorsulfonsäure behandelt werden. Dieses wird bewirkt, indem Methanol 40 Minuten lang unter Rückfluß gekocht wird, wobei 13-Deoxo-4′-deoxy-jod-N-trifluoracetylderivate Va, b erhalten werden, aus denen nach wäßriger alkalischer Behandlung die Verbindungen Ia und Ib erhalten werden. Diese Verbindungen können dann in Form ihrer pharmazeutisch geeigneten Salze isoliert werden. Ein Hydrochloridsalz kann durch Behandlung mit methanolischem Chlorwasserstoff erhalten werden.The resulting hydrazone, such as that p-fluorobenzenesulfonyl hydrazones IVa, b can be obtained using Crystallization can be recovered. Usually then treated it with a cyanoborohydride. The Hydrazone can therefore be used with an equimolar amount of alkaline cyanoborohydride salt such as sodium cyanoborohydride and be treated by 10-camphorsulfonic acid. This will effected by refluxing methanol for 40 minutes is cooked, with 13-deoxo-4'-deoxy-iodine-N-trifluoroacetyl derivatives Va, b are obtained from which after aqueous alkaline treatment the compounds Ia and Ib can be obtained. These connections can then be in the form their pharmaceutically acceptable salts are isolated. A Hydrochloride salt can be treated with methanolic Hydrogen chloride can be obtained.
In einer bevorzugten Ausführungsform des gegenwärtigen Verfahrens wird 4′-Deoxy-4′-joddaunorubicin oder 4′-Deoxy-4′-joddoxorubicinhydrochlorid, gelöst in nicht wäßrigem Methylenchlorid, bei einer Temperatur von 0°C, eine Stunde lang mit Trifluoressigsäureanhydrid zur Reaktion gebracht, wobei das N-Trifluoracetylderivat erhalten wird, das in methanolischer Lösung bei Raumtemperatur 3 Tage lang mit einem Überschuß von p-Fluorbenzolsulfonylhydrazin unter Verwendung von p-Toluolsulfonsäure als Katalysator zur Reaktion gebracht wird; das so erhaltene 13-p-Fluorbenzolsulfonylhydrazin wird mit Natriumcyanborhydrid und 10-Camphorsulfonsäure 30 Minuten lang in Methanol bei Rückflußtemperatur behandelt, wobei das relevante 13-Deoxoderivat erhalten wird, das nach milder alkalischer Hydrolyse mit 0,1 N- Natriumhydroxyd bei 0°C, um die N-Trifluoracetyl schützende Gruppe zu entfernen, das gewünschte Glycosid der Formel I ergibt, das durch Behandlung mit methanolischem Chlorid als Hydrochlorid isoliert wird.In a preferred embodiment of the current Process is 4'-deoxy-4'-iodine or or 4'-deoxy-4'-iododoxorubicin hydrochloride, dissolved in not aqueous methylene chloride, at a temperature of 0 ° C, for one hour with trifluoroacetic anhydride Reaction brought, the N-trifluoroacetyl derivative is obtained in methanolic solution Room temperature for 3 days with an excess of p-fluorobenzenesulfonyl hydrazine using p-Toluenesulfonic acid reacted as a catalyst becomes; the 13-p-fluorobenzenesulfonylhydrazine thus obtained is 30 with sodium cyanoborohydride and 10-camphorsulfonic acid Treated in methanol at reflux for minutes to obtain the relevant 13-deoxo derivative, the after mild alkaline hydrolysis with 0.1 N Sodium hydroxide at 0 ° C to the N-trifluoroacetyl protective group to remove the desired glycoside of formula I results from treatment with methanolic chloride is isolated as the hydrochloride.
Das folgende Reaktionsschema verdeutlicht das vorliegende Verfahren: The following reaction scheme illustrates the present Method:
Die Erfindung stellt pharmazeutische Zusammensetzungen, die ein Anthracyclinglycosid der Formel I oder ein pharmazeutisch geeignetes Salz davon zusammen mit einem pharmazeutisch geeigneten Verdünnungsmittel oder Träger umfassen, zur Verfügung.The invention provides pharmaceutical compositions which is an anthracycline glycoside of the formula I or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluents or carriers include, available.
Es können übliche Träger und Verdünnungsmittel verwendet werden. Die Zusammensetzung kann in herkömmlicher Art formuliert und verabreicht werden.Usual carriers and diluents can be used will. The composition can be in a conventional manner be formulated and administered.
Die erfindungsgemäßen Verbindungen sind bei Verfahren zur Behandlung des menschlichen oder tierischen Körpers mittels Therapie geeignet. Sie sind als Antitumormittel geeignet. Eine therapeutisch wirksame Menge wird dem Patienten verabreicht. Es kann eine Menge verabreicht werden, die ausreicht, um das Wachsen des Tumors zu inhibieren. Der Tumor kann ein Colon Adenocarzinom oder Gross Leukämietumor sein.The compounds according to the invention are used in processes for Treatment of the human or animal body suitable with therapy. They are used as an anti-tumor agent suitable. A therapeutically effective amount will be given Administered to patients. It can be administered a lot enough to stop the tumor from growing inhibit. The tumor can be a colon or adenocarcinoma Gross leukemia tumor.
Die folgenden Beispiele verdeutlichen die Erfindung.The following examples illustrate the invention.
4′-Deoxy-4′-joddaunorubicin (IIa, 0,67 g, 1 mmol), wurde in Form seines Hydrochloridsalzes durch 1stündige Behandlung mit Trifluorautanhydrid (2 ml) in nicht wäßrigem Methylenchlorid (100 ml) bei 0°C unter Verwendung von Standardverfahren (siehe: F. Arcamone et al., Chim. Ind. (Milan) 51, 834, (1969)) quantitativ in das entsprechende N-Trifluoracetylderivat IIIa umgewandelt. TLC auf Kieselgelplatte F₂₅₄ (Merck) Lösungsmittelsystem Methylenchlorid/Aceton (95 : 5 bezogen auf das Volumen) Rf = 0,68; FDMS m/z 732 (M)⁺. 4'-Deoxy-4'-iododunorubicin (IIa, 0.67 g, 1 mmol), was in the form of its hydrochloride salt by treatment for 1 hour with trifluoroautanhydride (2 ml) in non-aqueous methylene chloride (100 ml) at 0 ° C using Standard procedures (see: F. Arcamone et al., Chim. Ind. (Milan) 51, 834, (1969)) were quantitatively converted into the corresponding N-trifluoroacetyl derivative IIIa. TLC on silica gel plate F₂₅₄ (Merck) solvent system methylene chloride / acetone (95: 5 by volume) R f = 0.68; FDMS m / z 732 (M) ⁺.
Die Verbindung IIIa (0,7 g, 0,1 mmol) wurde in Methanol (200 ml) gelöst, p-Fluorbenzolsulfonylhydrazin (0,7 g, 3,6 mmol) und eine katalytische Menge von p-Toluolsulfonsäure wurden hinzugefügt und die Reaktionsmischung wurde 3 Tage lang im Dunkeln bei Raumtemperatur stehengelassen. Anschließend wurde das Lösungsmittel unter reduziertem Druck entfernt und nach Kristallisation aus Ether/Hexan 1/1 wurde 13-(p-Fluorbenzolsulfonyl)hydrazon-4′-deoxy-4′- jod-N-trifluoracetyldaunorubicin (IVa, 0,82 g, Ausbeute: 90%) wiedergewonnen. TLC auf Kieselgelplatte F254 (Merck), Lösungsmittelsystem Methylenchlorid/Aceton (95 : 5 bezogen auf Volumen) Rf=0,35; FDMS m/z 920 (M)⁺.Compound IIIa (0.7 g, 0.1 mmol) was dissolved in methanol (200 ml), p-fluorobenzenesulfonylhydrazine (0.7 g, 3.6 mmol) and a catalytic amount of p-toluenesulfonic acid were added and the reaction mixture was left in the dark at room temperature for 3 days. The solvent was then removed under reduced pressure and after crystallization from ether / hexane 1/1, 13- (p-fluorobenzenesulfonyl) hydrazone-4'-deoxy-4'-iodo-N-trifluoroacetyldaunorubicin (IVa, 0.82 g, yield : 90%). TLC on silica gel plate F 254 (Merck), solvent system methylene chloride / acetone (95: 5 by volume) R f = 0.35; FDMS m / z 920 (M) ⁺.
Die Verbindung IVa wurde in Methanol (60 ml) unter einem Stickstoffstrom gelöst, Natriumcyanborhydrid (0,7 g) und 10-Camphorsulfonsäure (0,7 g) wurden hinzugefügt und die Reaktionsmischung wurde 30 Minuten lang unter Rückfluß gekocht. Dann wurde die Reaktionsmischung in Wasser-Eis, das Natriumbicarbonat enthält, gegeben, es wurde einige Minuten lang gerührt und mit Methylenchlorid extrahiert. Die organische Phase wurde abgetrennt, mit Wasser gewaschen, über wasserfreiem Natriumsulfat getrocknet und abfiltriert.Compound IVa was dissolved in methanol (60 ml) under a Dissolved nitrogen stream, sodium cyanoborohydride (0.7 g) and 10-camphorsulfonic acid (0.7 g) was added and the The reaction mixture was refluxed for 30 minutes cooked. Then the reaction mixture was poured into water-ice, that contains sodium bicarbonate, there have been some Stirred for minutes and extracted with methylene chloride. The organic phase was separated off with water washed, dried over anhydrous sodium sulfate and filtered off.
Das Lösungsmittel wurde unter reduziertem Druck entfernt und der Rest wurde unter Verwendung einer Mischung aus Methylenchlorid/Aceton (95 : 5 bezogen auf das Volumen) als Eluierungssystem auf Silikagel chromatographiert, wobei 13-Deoxo-4′-deoxy-4′-jod-N-trifluoracetyldaunorubicin (Va, 0,4 g, Ausbeute 55%) erhalten wurde. TLC auf Kieselgelplatte F₂₅₄ (Merck) Lösungsmittelsystem Methylenchlorid/Aceton (95 : 5 bezogen auf das Volumen) Rf = 0,82 FDMS m/z 718 (M)⁺. The solvent was removed under reduced pressure and the remainder was chromatographed on silica gel using a methylene chloride / acetone mixture (95: 5 by volume) as the elution system, with 13-deoxo-4'-deoxy-4'-iodine-N -trifluoroacetyldaunorubicin (Va, 0.4 g, yield 55%) was obtained. TLC on silica gel plate F₂₅₄ (Merck) solvent system methylene chloride / acetone (95: 5 by volume) R f = 0.82 FDMS m / z 718 (M) ⁺.
Milde alkalische Behandlung des N-Trifluoracetylderivats
Va mit wäßrigem 0,1 N-Natriumhydroxid bei 0°C ergab nach
Standardaufarbeitung bei pH 7,5 und
Methylenchloridextraktion,
13-Deoxo-4′-deoxy-4′-joddaunorubicin (Ia 0,35 g), das durch
Behandlung mit methanolischem Chlorwasserstoff in sein
Hydrochloridsalz umgewandelt wurde. TLC auf
Kieselgelplatte F₂₅₄ (Merck) Lösungsmittelsystem
Methylenchlorid/Methanol/Essigsäure/Wasser (30 : 4 : 1 : 0,5
bezogen auf das Volumen):
Rf = 0.56; FDMS m/z 622 [M]⁺.
¹HNMR (400 MHz, CDCl₃) δ:
13.99 (s, 1H, 6-OH); 13.39 (s, 1H, 11-OH); 8.05 (d, J=7.6 Hz,
1H, 1-H); 7.79 (dd, J=7.6, 8.5 Hz, 1H, 2-H); 7.40 (d, J=8.5 Hz,
1H, 3-H); 5.47 (d, J=3.8 Hz, 1H, 1′-H); 5.26 (m, 1H, 7-H);
4.49 (m, 1H, 4′-H); 4.10 (s, 3H, OCH₃); 3.51 (q, J=6.OHz,
1H, 5′-H); 3.26 (d, J=18.8 Hz, 1H, 10-Heq); 2.58 (d,
J=18.8 Hz, 1H, 10-Hax); 2.37 (m, 1H, 8-Heq); 2.17 (m, 1H,
3′-H); 1.9-1.6 (m, 5H, CH₂CH₃, 2′-CH₂, 8-Hax); 1.34 (d,
J=6.0Hz, 3H, CH₃CH); 1.08 (t, J=7.3 Hz, 3H, CH₃CH₂).Mildly alkaline treatment of the N-trifluoroacetyl derivative Va with aqueous 0.1 N sodium hydroxide at 0 ° C. gave, after standard work-up at pH 7.5 and methylene chloride extraction, 13-deoxo-4'-deoxy-4'-iodine dunorubicin (Ia 0.35 g ), which was converted into its hydrochloride salt by treatment with methanolic hydrogen chloride. TLC on silica gel plate F₂₅₄ (Merck) solvent system methylene chloride / methanol / acetic acid / water (30: 4: 1: 0.5 by volume):
R f = 0.56; FDMS m / z 622 [M] ⁺.
¹HNMR (400 MHz, CDCl₃) δ:
13.99 (s, 1H, 6- OH ); 13.39 (s, 1H, 11- OH ); 8.05 (d, J = 7.6 Hz, 1H, 1- H ); 7.79 (dd, J = 7.6, 8.5 Hz, 1H, 2-H); 7:40 (d, J = 8.5 Hz, 1H, 3- H); 5.47 (d, J = 3.8 Hz, 1H, 1'- H ); 5.26 (m, 1H, 7- H ); 4.49 (m, 1H, 4'- H ); 4.10 (s, 3H, O CH ₃); 3.51 (q, J = 6.OHz, 1H, 5'- H ); 3.26 (d, J = 18.8 Hz, 1H, 10- H eq); 2.58 (d, J = 18.8 Hz, 1H, 10- H ax); 2.37 (m, 1H, 8- H eq); 2.17 (m, 1H, 3'- H ); 1.9-1.6 (m, 5H, CH ₂CH₃, 2'- CH ₂, 8- H ax); 1.34 (d, J = 6.0Hz, 3H, CH ₃CH); 1.08 (t, J = 7.3 Hz, 3H, CH ₃CH₂).
4′-Deoxy-4′-joddoxorubicin (IIb, 0,5 g, 0,72 mmol) wurde in Form seines Hydrochloridsalzes zuerst in das entsprechende N-Trifluoracetylderivat IIIb (TLC auf Kieselgelplatte F₂₅₄ (Merck), Lösungsmittelsystem: Methylenchlorid/Aceton (8 : 2 bezogen auf das Volumen) Rf = 0.30; FDMS m/z 748 (M)⁺ umgewandelt und anschließend in 13-(p-fluorbenzolsulfonyl)-hydrazon-4′-deoxy-4′-jod-N- trifluoracetyldoxorubicin (IVb, 0,54 g, Ausbeute 80%), wobei das Verfahren, das in Beispiel 1 beschrieben wird, angewandt wurde. TLC auf Kieselgelplatte F₂₅₄ (Merck) Lösungsmittelsystem: Methylenchlorid/Aceton (8 : 2 bezogen auf das Volumen) Rf = 0,12, FDMS m/z 936 (M)⁺.4'-Deoxy-4'-iododoxorubicin (IIb, 0.5 g, 0.72 mmol) was first in the form of its hydrochloride salt in the corresponding N-trifluoroacetyl derivative IIIb (TLC on silica gel plate F₂₅₄ (Merck), solvent system: methylene chloride / acetone ( 8: 2 based on volume) R f = 0.30; FDMS m / z 748 (M) ⁺ and then converted to 13- (p-fluorobenzenesulfonyl) hydrazone-4'-deoxy-4'-iodine-N-trifluoroacetyldoxorubicin ( IVb, 0.54 g, yield 80%), using the procedure described in Example 1. TLC on silica gel plate F₂₅₄ (Merck) solvent system: methylene chloride / acetone (8: 2 by volume) R f = 0.12, FDMS m / z 936 (M) ⁺.
Das Hydrazonderivat IVb (0,54 g, 0,57 mmol) wurde nach
Behandlung mit Natriumcyanborhydrid (0,5 g) und
10-Camphorsulfonsäure (0,5 g) in Methanol (100 ml) wie in
Beispiel 1 beschrieben, in das entsprechende
13-Deoxo-4′-deoxy-4′-iodo-N-trifluoroacetylderivat (Vb,
0,21 g, Ausbeute 50%) reduziert. TLC auf Kieselgelplatte
F₂₅₄ (Merck), Lösungsmittelsystem:
Methylenchlorid/Aceton (8 : 2 bezogen auf das Volumen)
Rf=0.36; FDMS m/z 734 [M]⁺ ¹HNMR (400 MHz, CDCl₃) δ:
14.01 (s, 1H, 6-OH); 13.36 (s, 1H, 11-OH); 8.07 (d, J=7.7 Hz,
1H, 1-H); 7,81 (d, J=7.7, 8.4 Hz, 1H, 2-H); 7.41 (d, J=8.4 Hz,
1H, 3-H); 6.29 (d, J=8.4 Hz, 1H, NHCOCF₃); 5.52 (d, J=3.8 Hz,
1H, 1′-H); 5.26 (m, 1H, 7-H); 4.62 (m, 1H, 4′-H); 4.10 (s,
3H, OCH₃); 4.1-3.9 (m, 2H, CH₂OH); 3.7-3.5 (m, 1H, 3′-H);
3.53 (q, J=18.9 Hz, 1 H, 10-Heq); 3.09 (m, 1H, CH₂OH); 2.62
(m, 1H, 8-Heq); 2.35 [m, 1H, 14-CH(H)]; 2.04 [M, 2H,
14-CH(H) and 2′-CH(H)]; 1.9-1.8 [m, 2H, 8-Hax and 2′-CH(H)];
1,34 (d, J=6.OHz, 3H, 5′-CH₃CH).The hydrazone derivative IVb (0.54 g, 0.57 mmol) was, after treatment with sodium cyanoborohydride (0.5 g) and 10-camphorsulfonic acid (0.5 g) in methanol (100 ml) as described in Example 1, in the corresponding 13-Deoxo-4'-deoxy-4'-iodo-N-trifluoroacetyl derivative (Vb, 0.21 g, yield 50%) reduced. TLC on silica gel plate F₂₅₄ (Merck), solvent system:
Methylene chloride / acetone (8: 2 by volume)
R f = 0.36; FDMS m / z 734 [M] ⁺¹HNMR (400 MHz, CDCl₃) δ: 14.01 (s, 1H, 6- OH ); 13.36 (s, 1H, 11- OH ); 8:07 (d, J = 7.7 Hz, 1H, 1H); 7.81 (d, J = 7.7, 8.4 Hz, 1H, 2-H); 7:41 (d, J = 8.4 Hz, 1H, 3- H); 6.29 (d, J = 8.4 Hz, 1H, NH COCF₃); 5.52 (d, J = 3.8 Hz, 1H, 1'- H ); 5.26 (m, 1H, 7- H ); 4.62 (m, 1H, 4'- H ); 4.10 (s, 3H, O CH ₃); 4.1-3.9 (m, 2H, CH ₂OH); 3.7-3.5 (m, 1H, 3'- H ); 3.53 (q, J = 18.9 Hz, 1H, 10- H eq); 3:09 (m, 1H, CH₂O H); 2.62 (m, 1H, 8- H eq); 2.35 [m, 1H, 14- CH (H)]; 2.04 [M, 2H, 14- CH (H) and 2'- CH (H)]; 1.9-1.8 [m, 2H, 8- H ax and 2'- CH (H)]; 1.34 (d, J = 6.OHz, 3H, 5'- CH ₃CH).
Durch milde alkalische Behandlung des
N-Trifluoracetylderivats Vb mit wäßrigem 0,1 N-
Natriumhydroxid bei 0°C und anschließender
Standardaufarbeitung mit Methylenchloridextraktion bei pH
7.5 wurde 13-Deoxo-4′-deoxy-4′-joddoxorubicin (IIb, 0,15 g)
erhalten, das durch Behandlung mit methanolischem
Chlorwasserstoff in sein Hydrochloridsalz umgewandelt
wurde, TLC auf Kieselgelplatte F₂₅₄ (Merck),
Lösungsmittelsystem;
Methylenchlorid/Methanol/Essigsäure/Wasser (30 : 4 : 1 : 0,5
bezogen auf das Volumen) Rf = 0,44; FDMS m/z 638 (M)⁺.By mildly alkaline treatment of the N-trifluoroacetyl derivative Vb with aqueous 0.1 N sodium hydroxide at 0 ° C. and subsequent standard work-up with methylene chloride extraction at pH 7.5, 13-deoxo-4′-deoxy-4′-iododoxorubicin (IIb, 0.15 g ) obtained, which was converted into its hydrochloride salt by treatment with methanolic hydrogen chloride, TLC on silica gel plate F₂₅₄ (Merck), solvent system;
Methylene chloride / methanol / acetic acid / water (30: 4: 1: 0.5 by volume) R f = 0.44; FDMS m / z 638 (M) ⁺.
Claims (12)
- (i) das Schützen der 3′-Aminogruppe des 4′-Deoxy-4′-jod-daunorubicin, des 4′-deoxy-4′-iod-doxorubicin oder eines Säurezugabesalzes davon, wobei ein geschütztes Aminoderivat der Formel (III′) gebildet wird: wobei X eine aminoschützende Gruppe darstellt;
- (ii) das Umsetzen des geschützten Aminoderivats der Formel (III′) mit einem Benzolsulfonylhydrazin, das eine elektronenanziehende Gruppe an dem aromatischen Ring hat, wobei ein Hydrazon der Formel (IV′) gebildet wird:
- (iii) das Reduzieren des Hydrazons der Formel (IV′), wobei das 13-Deoxoderivat der Formel (V′) gebildet wird:
- (iv) das Entfernen der aminoschützenden Gruppe aus dem 13-Deoxyderivat der Formel (V′), wobei ein Anthracyclinglycosid der Formel (I) gebildet wird, und
- (v) falls gewünscht, das Umwandeln des Anthracyclinglycosids der Formel (I) in ein pharmazeutisch geeignetes Säurezugabesalz davon.
- (i) protecting the 3'-amino group of the 4'-deoxy-4'-iodo-daunorubicin, the 4'-deoxy-4'-iodo-doxorubicin or an acid addition salt thereof, a protected amino derivative of the formula (III ') is formed: where X represents an amino protecting group;
- (ii) reacting the protected amino derivative of formula (III ') with a benzenesulfonylhydrazine which has an electron attractive group on the aromatic ring to form a hydrazone of formula (IV'):
- (iii) reducing the hydrazone of formula (IV ') to form the 13-deoxo derivative of formula (V'):
- (iv) removing the amino protecting group from the 13-deoxy derivative of formula (V ') to form an anthracycline glycoside of formula (I), and
- (v) if desired, converting the anthracycline glycoside of formula (I) into a pharmaceutically acceptable acid addition salt thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8927000A GB2238540B (en) | 1989-11-29 | 1989-11-29 | 13-deoxy-4'-deoxy-4'-iodoanthracyclines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE4037693A1 true DE4037693A1 (en) | 1991-06-06 |
Family
ID=10667130
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE4037693A Ceased DE4037693A1 (en) | 1989-11-29 | 1990-11-27 | 13-DEOXO-4'-DEOXY-4'-JODANTHRACYCLINE |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPH03190892A (en) |
| DE (1) | DE4037693A1 (en) |
| GB (1) | GB2238540B (en) |
| IT (1) | IT1245851B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996007665A1 (en) * | 1994-09-09 | 1996-03-14 | Pharmacia S.P.A. | Anthracycline derivatives |
| RU2155589C2 (en) * | 1993-08-06 | 2000-09-10 | Поликлинико Сан Маттео, Иституто ди риковеро э Кура а Караттере Шиентифико ди Диритто Публико | Use of 4'-iodo-4'-deoxydoxorubicine for treatment of patients with amyloidosis, method of treatment of patients with amyloidosis |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9416007D0 (en) * | 1994-08-08 | 1994-09-28 | Erba Carlo Spa | Anthracyclinone derivatives |
| US5948896A (en) * | 1997-08-13 | 1999-09-07 | Gem Pharmaceuticals | Processes for preparing 13-deoxy anthracycline derivatives |
| US5942605A (en) * | 1998-03-03 | 1999-08-24 | Gem Pharmaceuticals, Inc. | 5-imino-13-deoxy anthracycline derivatives, their uses, and processes for preparing them |
| US7244829B2 (en) * | 2004-11-08 | 2007-07-17 | Gem Pharmaceuticals, Llc | Compositions and processes for preparing 13-deoxy-anthracyclines |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4345070A (en) * | 1980-09-29 | 1982-08-17 | Farmitalia Carlo Erba S.P.A. | Process for the preparation of 4'-deoxy-daunorubicin and 4'-deoxy-doxorubicin |
| US4438105A (en) * | 1982-04-19 | 1984-03-20 | Farmaitalia Carlo Erba S.P.A | 4'-Iododerivatives of anthracycline glycosides |
-
1989
- 1989-11-29 GB GB8927000A patent/GB2238540B/en not_active Expired - Fee Related
-
1990
- 1990-11-14 IT IT02204790A patent/IT1245851B/en active IP Right Grant
- 1990-11-26 JP JP2322250A patent/JPH03190892A/en active Pending
- 1990-11-27 DE DE4037693A patent/DE4037693A1/en not_active Ceased
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2155589C2 (en) * | 1993-08-06 | 2000-09-10 | Поликлинико Сан Маттео, Иституто ди риковеро э Кура а Караттере Шиентифико ди Диритто Публико | Use of 4'-iodo-4'-deoxydoxorubicine for treatment of patients with amyloidosis, method of treatment of patients with amyloidosis |
| WO1996007665A1 (en) * | 1994-09-09 | 1996-03-14 | Pharmacia S.P.A. | Anthracycline derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH03190892A (en) | 1991-08-20 |
| IT1245851B (en) | 1994-10-25 |
| IT9022047A0 (en) | 1990-11-14 |
| GB2238540B (en) | 1993-09-29 |
| IT9022047A1 (en) | 1992-05-14 |
| GB8927000D0 (en) | 1990-01-17 |
| GB2238540A (en) | 1991-06-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE68906045T2 (en) | 3'-DEAMINO-4'-DEOXY-4'-AMINOANTHRACYCLINE. | |
| DE3876482T2 (en) | 4-DEMETHOXY-4-AMINOANTHRACYCLINE. | |
| DE2346535B2 (en) | Process for the preparation of 7-dimethylamino-e-desmethyl-e-deoxytetracycline via 9-tert-butyl-6-desmethyl-6-deoxytetracycline | |
| DE3214559C2 (en) | 4'-Deoxy-4'-iodo-daunorubicin and -doxorubicin and medicaments containing these compounds | |
| DE3219380C2 (en) | Desmethoxy-anthracycline glycosides, processes for their production and pharmaceutical agents containing them | |
| EP0048967A1 (en) | Process for the production of 4'-deoxydaunorubicin and 4'-deoxydoxorubicin, and 4'-epi-4'-trifluoromethyl-sulphonyloxy-N-trifluoroacetyl daunorubicin | |
| AT392793B (en) | METHOD FOR PRODUCING NEW ANTHRACYCLINGLYCOSIDES | |
| DE2515629B2 (en) | 2'-N-substituted paromomycins, processes for their preparation and pharmaceuticals containing these compounds | |
| DE4037693A1 (en) | 13-DEOXO-4'-DEOXY-4'-JODANTHRACYCLINE | |
| DE3734476A1 (en) | ANTHRACYCLINGLYCOSIDES, METHOD FOR THE PRODUCTION THEREOF, INTERMEDIATE PRODUCTS THEREFOR AND MEDICINAL PRODUCTS CONTAINING THE ANTHRACYCLINGLYCOSIDES | |
| EP0022515B1 (en) | Anthracycline glycosides, process for their preparation and therapeutical composition containing them | |
| DE2621507C2 (en) | ||
| DE4117507A1 (en) | METHOD FOR PRODUCING N (ARROW HIGH) 6 (ARROW HIGH) SUBSTITUTED LYSINE DERIVATIVES | |
| DE2819216A1 (en) | NEW ANTHRACYCLINALOGA | |
| DE2731306C3 (en) | 9-deacetyl- and 9-deacetyl-9-epi-daunorubicin, process for their preparation and their use | |
| DE2918291A1 (en) | NEW SUBSTITUTED ANTITUMORANTHRACYCLINE AND METHOD FOR THE PRODUCTION THEREOF | |
| DE2942818C2 (en) | 4'-C-methyl-4'-O-methyl-daunorubicin and -doxorubicin and their 4'-epimers and pharmaceutical compositions containing these compounds | |
| DE69106459T2 (en) | 2-acyloxy-4-morpholinyl anthracycline. | |
| DE3200809C2 (en) | 4'-Deoxy-3'-epi-daunorubicin and -doxorubicin, processes for their preparation and pharmaceuticals containing these compounds | |
| DE4126475B4 (en) | 13-Dihydro-3 '- (2-alkoxy-4-morpholinyl) anthracyclines, process for their preparation, their use and compositions containing them | |
| DE69107431T2 (en) | Deacetylcolchicine derivatives. | |
| DE3905431A1 (en) | 4-Demethyl-4-O-(p-fluorobenzenesulphonyl)anthracycline glycosides | |
| DE3886101T2 (en) | 14-chlorodaunomycin and process for producing 14-chlorodaunomycin and process for producing (2 "R) -4'-O-tetrahydropyramyladriamycin. | |
| DE3638386A1 (en) | NITROANTHRACYCLINE, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THEM | |
| DE3837755A1 (en) | 4-DEMETHOXY-ANTHRACYCLINE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8110 | Request for examination paragraph 44 | ||
| 8131 | Rejection |