DE2735891A1 - NEW NAPHTHACENE QUINONE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

NEW NAPHTHACENE QUINONE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION

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Publication number
DE2735891A1
DE2735891A1 DE19772735891 DE2735891A DE2735891A1 DE 2735891 A1 DE2735891 A1 DE 2735891A1 DE 19772735891 DE19772735891 DE 19772735891 DE 2735891 A DE2735891 A DE 2735891A DE 2735891 A1 DE2735891 A1 DE 2735891A1
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Prior art keywords
general formula
new
formula
trifluoroacetyl
production
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DE19772735891
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German (de)
Inventor
Pietro Giardino
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Pfizer Italia SRL
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Farmaceutici Italia SpA
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    • 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

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Saccharide Compounds (AREA)

Description

PATENTANWÄLTEPATENT LAWYERS

OpUng. P. WIRTH · Dr. V. SCHMIED-KOWARZIK DlpMno. G. DANNENBERG · Dr. P. WEINHOLD · Dr. D. GUDELOpUng. P. WIRTH Dr. V. SCHMIED-KOWARZIK DlpMno. G. DANNENBERG Dr. P. WEINHOLD Dr. D. GUDEL

335024 SIEGFRIEDSTRASSE · 335024 SIEGFRIEDSTRASSE

(080) ' β·***»** m, arm****» *r-m.t λλ± (080) 'β *** »** m, poor ****» * rm.t λλ ±

335025 8000 MÖNCHEN 40 335025 8000 MONKS 40

Case: G 370 Wd/ShCase: G 370 Wd / Sh

SOCIETA FARFiACEUTICI ITALIA 1/2 Largo Guido Donegani 1-20121 Mailand/Italien SOCIETA FARFiACEUTICI ITALIA 1/2 Largo Guido Donegani 1-20121 Milan / Italy

Neue Naphthacenchlnondcrlvate und Verfahren zu deren Herstellung. New Naphthacenchlnondcrlvate and processes for H creation.

809807/0785809807/0785

Die vorliegende Erfindung bezieht sich auf Naphthcfcen- ' chinonderivatc und ein Verfahren zu deren Herstellung. .The present invention relates to naphthenic ' quinone derivatives and a process for their preparation. .

Die Haphtarenchinonderivate der vorliegenden Erfindung besitzen die allgemeine FormelThe haphtharenequinone derivatives of the present invention have the general formula

R2 O OHR 2 O OH

CO-CH9-O-C-RCO-CH 9 -OCR

„ 0 " 0

,(D, (D

NH-COCF.NH-COCF.

worin R1 und R jeweils Wasserstoff, Chlor, Brom, Methyl oder Methoxy bedeuten und R. nied.Alkyl mit 3 bis 5 C-Atomen darstel'.t, mit der Maßgabe, daß zumindest eine der Gruppen R1 und R2 Wasserstoff ist.where R 1 and R each represent hydrogen, chlorine, bromine, methyl or methoxy and R. represents lower alkyl having 3 to 5 carbon atoms, with the proviso that at least one of the groups R 1 and R 2 is hydrogen .

Die Verbindungen der Erfindung besitzen phanaakologische Wirkungen, insbesondere Antitumoreigenschaften.The compounds of the invention have phanaacological effects, particularly anti-tumor properties.

Die Erfindung bezieht sich auch auf ein Verfahren zur Herstellung der Verbindungen der Formel (I), wobeiThe invention also relates to a process for the preparation of the compounds of formula (I), wherein

eine Verbindung der allgemeinen Formel a compound of the general formula

OHOH

COCH,COCH,

,ill), ill)

809807/0765809807/0765

.HCl.HCl

worin R1 und R_ die obige Bedeutung haben, zum entsprechenden 14-Bromderivat der allgemeinen Formel in which R 1 and R_ have the above meaning for the corresponding 14-bromo derivative of the general formula

,(IH), (IH)

worin R1 und R- die obige Bedeutung haben, bromiert, das 14-Bromderivat mit Trifluoressig.säureanhydrid unter Bildung des entsprechenden N-Trifluorace.:ylderivats der allgemeinen Formel T wherein R 1 and R- have the above meaning, brominated, the 14-bromo derivative with Trifluoressig.säureanhydrid to form the corresponding N-Trifluorace.:ylderivats of the general formula T

CH2-Br *0HCH 2 -Br * 0H

,(IV), (IV)

HOHO

NH -COCF,NH -COCF,

worin R1 und R_ die obige Bedeutung haben, behandelt und das Trifluoracetylderivat mit einem Natrium- oder Kaliumsalz einer Carbonsäure mit 4 bis 6 C-Atomen zu einer Verbindung der Formel (1) umgesetzt wird. wherein R 1 and R_ have the above meaning, treated and the trifluoroacetyl derivative is reacted with a sodium or potassium salt of a carboxylic acid having 4 to 6 carbon atoms to give a compound of the formula (1).

809807/0765809807/0765

Die Bromierung kann entsprechend dem in der GB-PS 1 217 133 beschriebenen Verfahren erfolgen.The bromination can be carried out as described in GB-PS 1 217 133 are carried out.

Die folgenden Beispiele sollen die vorliegende Erfindung näher erläutern, ohne daß diese jedoch hierauf beschränkt sein soll.The following examples are intended to explain the present invention in more detail without, however, being restricted thereto target.

Beispiel 1: N-Trifluoracetyl-4-demethoxydoxorubicinvaleriat (I; R1=R2=H, R3= n-Butyl)Example 1: N-trifluoroacetyl-4-demethoxydoxorubicin valeriate (I; R 1 = R 2 = H, R 3 = n-butyl)

1 ml Äthylorthoformiat wurde zu 1 g 4-Demethoxydaunorubicinhydrochlorid (II; R1=R =H), gelöst in 14 ml Methanol und 38 ml Dioxan, zugesetzt. Die Lösung wurde bei 1O°C gehalten und 1,96 mMol Brom in 3 ml Chloroform und 1,71 milol 2,5N Chlorwasserstoff in Methanol wurden auf einmal zugesetzt. Nach einer Stunde wurde die Lösung in eine Mischung aus 100 ml Petroläther und 200 ml Diäthylather gegossen. Der Niederschlag wurde in 150 ml Dioxan und 150 ml O,25N Bromwasserstoff gelöst. Die Lösung wurde über Nacht bei 25 C gehalten und anschließend zuerst mit Chloroform und dann mit n-Butanol extrahiert. Die Chloroformextrakte wurden verworfen und die n-Butanoloxtrakte im Vakuum eingeengt. Bei Verdünnen mit Diäthylather wurden 1,1 g 14-Brom-4-demethoxydaunorubicinhydrobromid (III; R1=R2=H) gesammelt und in 80 ml Dichlormethan suspendiert. Zu der gerührten Suspension, die auf -2°C gekühlt wurde, wurden 27,5 ml Trifluoracetanhydrid zugesetzt und die erhaltene Lösung eine halbe Stunde bei 0 C gehalten. Dann wurde die Lösung mit eirfer 3 %igen Natriumbicarbonatlösung und anschließend mit Wasser zur Neutralität gewaschen. Die organische Schicht wurde im Vakuum zur Trockene eingedampft, der Rückstand in 80 ml Aceton gelöst und 1,3 g trockene« Kaliumvaleriat zugegeben. Nach Rühren während 2 Stunden bei 50 C wurde die Lösung im Vakuum eingeengt, der Rückstand in 22 ml Chloroform gelöst und mit einer wässerigen Natriumbicarbonatlösung und dann mit Wasser zur Neutralität gewaschen. Das organische Lösungsmittel wurde im Vakuum abgedampft und der rohe Rückstand auf einer Silikagelsäule unter Verwendung von zuerst Chloroform und dann einer Mischung aus Chloroform und Aceton (90:10, bezogen auf1 ml of ethyl orthoformate was added to 1 g of 4-demethoxydaunorubicin hydrochloride (II; R 1 = R = H) dissolved in 14 ml of methanol and 38 ml of dioxane. The solution was kept at 10 ° C and 1.96 mmoles of bromine in 3 ml of chloroform and 1.71 mmoles of 2.5N hydrogen chloride in methanol were added all at once. After one hour, the solution was poured into a mixture of 100 ml of petroleum ether and 200 ml of diethyl ether. The precipitate was dissolved in 150 ml of dioxane and 150 ml of 0.25N hydrogen bromide. The solution was kept at 25 ° C. overnight and then extracted first with chloroform and then with n-butanol. The chloroform extracts were discarded and the n-butanol ox extracts concentrated in vacuo. Upon dilution with diethyl ether, 1.1 g of 14-bromo-4-demethoxydaunorubicin hydrobromide (III; R 1 = R 2 = H) were collected and suspended in 80 ml of dichloromethane. 27.5 ml of trifluoroacetic anhydride were added to the stirred suspension, which was cooled to -2 ° C., and the resulting solution was kept at 0 ° C. for half an hour. The solution was then washed with a 3% sodium bicarbonate solution and then with water to neutrality. The organic layer was evaporated to dryness in vacuo, the residue was dissolved in 80 ml of acetone and 1.3 g of dry potassium valerate were added. After stirring for 2 hours at 50 ° C., the solution was concentrated in vacuo, the residue was dissolved in 22 ml of chloroform and washed with an aqueous sodium bicarbonate solution and then with water to neutrality. The organic solvent was evaporated in vacuo and the crude residue on a silica gel column using first chloroform and then a mixture of chloroform and acetone (90:10 based on

I09807/07ISI09807 / 07IS

das Volumen) als Eluierungsmittel chromatographiert. Es wurden 0,6 g Produkt erhalten. Rf = 0,3 bei Dünnschichtchromatographie auf Kieselerde unter Verwendung einer Mischung von Chloroform, Methanol und Wasser (240:20:1, bezogen auf das Volumen).the volume) chromatographed as the eluent. There were 0.6 g of product obtained. Rf = 0.3 on thin layer chromatography on silica using a mixture of chloroform, Methanol and water (240: 20: 1 by volume).

Beispiele 2 bis 12:Examples 2 to 12:

Beispiel 1 wurde wiederholt, wobei jedoch.das Ausgangsmaterial und/oder das Alkalimetallcarboxylat, wie in der nachstehenden Tabelle angegeben, andere waren. In der Tabelle sind die Ausgangsmaterialien mit A, B, C und D bezeichnet und die Alkalimetallcarboxylate mit E, F und G. Deren Bedeutung ist wie folgt:Example 1 was repeated except that the starting material and / or the alkali metal carboxylate, as indicated in the table below, were different. In the table, the starting materials are labeled A, B, C and D and the alkali metal carboxylates are labeled E, F and G. Their meaning is as follows:

A: 4-Demethoxydaunorubicinhydro^hlorid (II; R1=R2=H) B: 2,3-Dimethyl-4-demethoxydaunorubicinhydrochlorid (II;A: 4-demethoxydaunorubicin hydrochloride (II; R 1 = R 2 = H) B: 2,3-dimethyl-4-demethoxydaunorubicin hydrochloride (II;

R1-CH3, R2=H)
C: 2,3-Dichlor-4-demethoxydaunorubicinhydrochlorid (II;R 1 -CH 3 , R 2 = H)
C: 2,3-dichloro-4-demethoxydaunorubicin hydrochloride (II;

R1-Cl, R2=H)
D: 1,4-Dimethyl-4-demethoxydaunorubicinhydrochlorid (II; R 1 -Cl, R 2 = H)
D: 1,4-dimethyl-4-demethoxydaunorubicin hydrochloride (II;

R1=H, R2=CH3)
E: Kaliumvaleriat
P: Natriumbutyrat
G: NatriumhexanoatR 1 = H, R 2 = CH 3 )
E: potassium valerate
P: sodium butyrate
G: sodium hexanoate

809807/0765809807/0765

TabelleTabel

Beispiel
Nr.example
No. Ausgangs
materialStarting
material Alkali-
metall-
carboxy
latAlkali-
metal-
carboxy
lat erhaltenes Produktreceived product NameSurname Formel IFormula I. 22 AA. FF. N-Trifluoracety1-4-de-
methoxy-doxorubicin-
butyratN-trifluoroacety1-4-de-
methoxy-doxorubicin-
butyrate R1=R2=H
R_= n-PropylR 1 = R 2 = H
R_ = n-propyl 33 AA. GG N-Trifluoracety1-4-de-
methoxy-doxorubicin-
hexanoatN-trifluoroacety1-4-de-
methoxy-doxorubicin-
hexanoate R1=R2=H
R_ = n-PentylR 1 = R 2 = H
R_ = n-pentyl 44th BB. EE. N-Trifluoracetyl-2,3-
dimethyl-4-demethoxy-
doxorubicinvaleriatN-trifluoroacetyl-2,3-
dimethyl-4-demethoxy-
doxorubicinvaleriat R1=CH3, R2=H,
R^ = n-ButylR 1 = CH 3 , R 2 = H,
R ^ = n-butyl 55 BB. FF. N-Trifluoracetyl-2,3-
dimethy.i.-4-demethoxy-
doxo*:ubicinburyratN-trifluoroacetyl-2,3-
dimethy.i.-4-demethoxy-
doxo *: ubicinburyrate R1=CH-, R2=H,
R_ = n-PropylR 1 = CH-, R 2 = H,
R_ = n-propyl 66th BB. GG N-Trifluoracetyl-2,3-
dimü*-hyl-4-demethoxydoxo-
rubicinhexanoatN-trifluoroacetyl-2,3-
dimü * -hyl-4-demethoxydoxo-
rubicine hexanoate R1=CH3, R2^H,
R_ = n-PentylR 1 = CH 3 , R 2 ^ H,
R_ = n-pentyl 77th CC. EE. N-Trifluoracetyl-2,3-
dichior-4-demethoxy-
doxorubicinvaleriatN-trifluoroacetyl-2,3-
dichior-4-demethoxy-
doxorubicinvaleriat R1=Cl, R2=H,
R- - n-ButylR 1 = Cl, R 2 = H,
R- - n-butyl 88th CC. FF. N-Trifluoracetyl-2,3-
dichlor-4-demethoxy-
doxorubicinbutyratN-trifluoroacetyl-2,3-
dichloro-4-demethoxy
doxorubicin butyrate R1=Ci, R2-H,
R3 a n-PropylR 1 = Ci, R 2 -H,
R 3 a n-propyl 99 CC. GG N-Trifluoracetyl-2,3-
dichlor-4-demethoxy-
doxorubicinhexanoatN-trifluoroacetyl-2,3-
dichloro-4-demethoxy
doxorubicin hexanoate R1 = Cl, R2=H,R 1 = Cl, R 2 = H,
R3 β n-PentylR 3 β n-pentyl 1010 DD. EE. N-Trifluoracetyl-1,4-
dimethyl-4-demethoxy-
doxorubicinvaleriatN-trifluoroacetyl-1,4-
dimethyl-4-demethoxy-
doxorubicinvaleriat R1=H, R2=CH3,
R3 = n-ButylR 1 = H, R 2 = CH 3 ,
R 3 = n-butyl 1111 DD. FF. N-Trifluoracety 1-1,A-
dinethyl-4-demetho}^-
doxorubicinbui^ratN-trifluoroacety 1-1, A-
dinethyl-4-demetho} ^ -
doxorubicinbui ^ rat R1=H, R2=CH3,
R3 β n-Propyl R 1 = H, R 2 = CH 3 ,
R 3 β n-propyl 1212th DD. GG N-Trifluoracety1-1,4-
dlmeJiyl-4-demethoxy-
doxorubicinhexanoatN-trifluoroacety1-1,4-
dlmeJiyl-4-demethoxy-
doxorubicin hexanoate R1=H, R2=CH3,
R- = n-PentylR 1 = H, R 2 = CH 3 ,
R- = n-pentyl

809807/0765809807/0765

Claims (2)

Patentansprüche :Patent claims: 1.J Neue Naphthacenchinonderivate der allgemeinen Formel 1. J New naphthacenquinone derivatives of the general formula R2 P R 2 P CO-CII0-O-C-R0 1V^ >v^ ^r^ "^V XT 2 Il 3 CO-CII 0 -OCR 0 1V ^> v ^ ^ r ^ "^ V XT 2 Il 3 (D(D worin R1 und R_ jeweils Wasserstoff, Chlor, Brom, Methyl oder Methcxy bedeuten und R_ Alkyl mit 3 bis 5 C-Atomen ist, mit der Maßgabe, daß zumindest eine der Gruppen R1 und R? Wasserstoff darstellt. where R 1 and R_ are each hydrogen, chlorine, bromine, methyl or methoxy and R_ is alkyl having 3 to 5 carbon atoms, with the proviso that at least one of the groups R 1 and R ? Represents hydrogen. 2. Verfahren zur Herstellung von Naphthacenchinonderivateii der Formel (I), dadurch gekennzeichnet, daß man eine Verbindung der allgemeinen Formel2. Process for the preparation of naphthacenchinonderivateii of the formula (I), characterized in that a compound is used the general formula COCHCOCH , (II), (II) HOHO 809807/0765809807/0765 NHNH .HCl.HCl ORIGINAL INSPECTEDORIGINAL INSPECTED worin R1 und R^ die in Anspruch 1 angegebene Bedeutung haben, mit Brom zum entsprechenden 14-Bromderivat der allgemeinen Formel —wherein R 1 and R ^ have the meaning given in claim 1, with bromine to the corresponding 14-bromo derivative of the general formula - CO-CH2BrCO-CH 2 Br (III)(III) HOHO NH.NH. .HBr.HBr umsetzt, welches mit Trifluoracetanhydrid zum N-Trifluoracety!derivat der allgemeinen Formelconverts which with trifluoroacetic anhydride to the N-trifluoroacetyl derivative the general formula (IV)(IV) NH-COCFNH-COCF umgesetzt wird, v/elches schließlich mit dem Natrium- oder Kaliumsalz einer Carbonsäure mit höchstens 5 C-Atomen rar Verbindung der Formel (I) umgesetzt wird.is implemented, v / elches finally with the sodium or Potassium salt of a carboxylic acid with a maximum of 5 carbon atoms is rare Compound of formula (I) is implemented. 809807/0765809807/0765
DE19772735891 1976-08-12 1977-08-09 NEW NAPHTHACENE QUINONE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION Withdrawn DE2735891A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB33523/76A GB1535080A (en) 1976-08-12 1976-08-12 Naphthacenequinone derivatives

Publications (1)

Publication Number Publication Date
DE2735891A1 true DE2735891A1 (en) 1978-02-16

Family

ID=10354073

Family Applications (1)

Application Number Title Priority Date Filing Date
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Country Status (4)

Country Link
JP (1) JPS5377052A (en)
DE (1) DE2735891A1 (en)
FR (1) FR2361417A1 (en)
GB (1) GB1535080A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4526960A (en) * 1982-09-28 1985-07-02 Hoffmann-La Roche Inc. Anthracycline glycosides

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2135221A1 (en) * 1971-05-04 1972-12-15 Farmaceutici Italia Doxorubicin 14-esters prepn - by treating 14-bromodaunomycin with a salt of the corresp acid
US4035566A (en) * 1975-09-25 1977-07-12 Sidney Farber Cancer Institute, Inc. N-trifluoroacetyladriamycin-14-alkanoates and therapeutic compositions containing same
GB1511680A (en) * 1975-11-18 1978-05-24 Farmaceutici Italia Daunosaminyl anthracyclinones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NICHTS-ERMITTELT *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4526960A (en) * 1982-09-28 1985-07-02 Hoffmann-La Roche Inc. Anthracycline glycosides

Also Published As

Publication number Publication date
FR2361417B1 (en) 1982-10-22
GB1535080A (en) 1978-12-06
JPS5377052A (en) 1978-07-08
FR2361417A1 (en) 1978-03-10

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