1 This invention relates to organic compounds including

^• 2 anthracycl ines and anthracycli nones. In a specific aspect

3 this invention relates to carminomycinone and analogues and

4 derivatives thereof i ncludi ng daunomycinone and analogues

5 and derivatives thereof, to novel o ganic compounds which

6 are useful in the synthesis of carminomycinone and its

7 analogues and derivatives, to methods of production of

8 organic compounds which are valuable precursors in the

9 production of carminomycinone and its derivati ves and 0 analogues and to methods of production of analogues of 1 anthracycl i nes . 2 Reference wil l be made to the accompanyi ng drawi ngs 3 which are structural drawings of various chemical compounds 4 and reaction schemes. 5 The compounds of formula I are named, according to the 6 substituents borne, as set out below. The three glycosides 7 are i so la te d a nd adm i n i s te re d as s al ts , us ua l l y 8 hydrochlorides. All ami no compounds referred to throughout 9 this specification and cl a ms are considered to ncl ude 0 salts as well as free bases, 1 R' R" R"' 2 Daunomycin CH ₃ H alpha-L-d unosaminyl 3 Adriamycin CH ₃ OH alpha-L-daunos minyl 4 .Ca mino ycin H H alpha-L-daunosaminyl 5 Daunomycinone CH ₃ H H 6 Adriamycinone CH ₃ OH H 7 Carminomycinone H H H 8 Modified compounds with different glycosidic residues 9 including oligosaccharides, and with di fferent aglycones 30 are known, in particular those where the glycosidic sugar is 31 4'-deoxy-, 4'-epi-, or JN-tri f 1 uoroacetyl-daunosa i ne and/or 32 where the aglycone l acks the oxy substituent at position 4 33 or 11.

34 At least the compounds daunomyci n and adriamycin are

35 ther apeu ti ca 11 y useful. The. other compounds at least have

36 ut i l ity as i ntermedi ates i n the product io n of

37 phar aceuti cal s.

38 The present invention provides compounds of formula III

and tautomeric forms thereof wherein:-

R- _j - R ₄ are H, al kyl, aryl, alkaryl, halogen, hydroxy, alkoxy, aryloxy, aralkoxy, acyloxy, a ino or alkylamino;

Ra is H, halogen, alkoxy, aryloxy or acyloxy; and

R _j . is H, halogen, alkoxy, aryloxy or acyloxy.

Provided that if R-j R, and R, are all, H, R _h is not H or ch lo ro. and provided that if R-| - R 4 are al l H and R _a is chloro or bro o R-., is not chloro.

Preferred compounds of formula III are those wherein:-

(a) not all of R-j - R4 are H;

(b) R4 is hydroxy, alkoxy, aralkoxy or acyloxy;

(c) R _a i s H, Br, Cl; and

(d) R tø is H, Br, Cl, methoxy, acyloxy.

The present i nvention also provides compounds of formula IV and tautomeric forms thereof wherein: R-j is H, alkyl, aralkyl or acyl;

R2 is H, halogen, alkoxy, aryloxy or acyloxy; or R is H, halogen, alkoxy, aryloxy or acyloxy.

Preferred compounds of formula IV are those where in:-

(a) Raj is H or methyl;

(b) R ₂ is H, Br or Cl; or

(c) R ₃ is H, Br, Cl.

The present invention al so provides compounds of formula II and tautomeric forms thereof wherein:- R-j - R4 have the meaning given above;

Rg has the same meaning as given to R-j - R4 or may be gl cosyloxy;

Rg and R have the same meaning as given to R-] - R4 and alternatively may be al ko xy ca rbon l , ar yl oxyc ar bo ny 1 or carboxy; one of R _χ or R ^ i s hydroxy and -the other is H, hal, al koxy, aryloxy or acyloxy;

R-] Q and R ] -| taken together are oxo or ethylenedioxy (provided that if R-J Q and R - ^* • ^* taken together are ethylenedioxy then i f R is hydrogen or methoxy, R^ is not hydrogen or acetoxy); or R-JQ is hydroxy; and

_p ^f PI

1 R1 - _j is hydroxyalkyl or di hydroxyal ky1 or —CO—R- _j 5 where

2 R-J5 is H, alkyl, aryl, aralkyl, hydroxyalkyl. .

3 Preferred compounds of formula II are those wherein:-

4 (a) not al 1 of R- _] - R ₄ i s H;

5 (b) R is hydroxy, alkoxy, aralkoxy or acyloxy;

6 .(c)(1) R _χ is hydroxy; R ^ is H, Br,Cl, methoxy;

7 (i) Rg, Rg and R -j are H and R-JQ and R -j -j taken together

8 are oxo;

9 or (i i) R3 is hydroxy or glycosyloxy; and Rg and R-j ₂ 10 are H; and R -J Q i s hydroxy; and R -j -j i s hydroxyal kyl, 11 di hydr oxya 1 kyl or R- _j -j i s - CO -R -j 5 where R-j 5 is- H, alkyl, 12 a r y ^* l , aralkyl, hydroxyalkyl; or 13 (c)( I I) R _χ i s H; R _b i s hydroxy; Rg i s H, hydroxy, 14 glycosyloxy; Rg and R 2 ^are H ^ar| d R Q i ^s hydroxy; and R-j-j is 15 —CO— R-j 5 where R -j 5 is H, alkyl, aryl, aralkyl, hydroxyalkyl; 16 or R-j-j is hydroxyalkyl, di hydroxyal kyl. 17 The -present invention al so provi des compounds .of 18 formula II and tautomeric forms thereof wherein:- 19 (i) R-]-R are H; 20 R4 and Rχ taken together are -OSO O-; 21 Rtø is hydroxy, alkoxy, aralkoxy or acyloxy; 22 ^R 8 ^"R 15 are as defined above. 23 or 24 (ii) R- _j and RL taken together are -OSO2O- 26 R _χ is hydroxy, alkoxy, aralkoxy or acyloxy; 27 Rg-R-|5 are as defined above. 28 The present invention also provides the novel compounds 29 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 19, 20, 21, 22, 30 23, 24 and 25 of the Reaction Schemes I, I I, I II or V 31 substituted, if desired and where possible, with any one or 32 more of R-j - R -j 5, R _χ , R _a or Rj-, as defined above. 33 The present invention provides a method of obtaining a

34 precursor of carmi nomyci none or of daunomyci none or thei r,

35 analogues or deri atives comprising reacting a compound of

36 formul a III with a substituted butadiene under conditions ^' 37 forming the A ring of a compound of formula II and

38 converti ng the group Rj. at position 10 in formula III to a

1 hydroxy group which taken with the hydroxy group at position

2 9 in formula III leads to a system tautomeric ith the

3 anthracycl i none chromophore.

4 The present invention provides a method of obtaining a

5 precursor of carminomycinone or its analogues or derivatives

6 comprising reacting a compound of formula IV ith a

7 substituted butadiene under conditions forming the A ring of

8 a compound of formula II and converting the group R-i in

9 formula IV to H and hydrolysing the bridging sulfate. 10 If necessary, a compound so obtained is further reacted 11 to obtain a desired compound of formula II. 12 The present invention also provides a method of .13 obtaining precursors of 4-deoxy car inomycinone, that is of 14 4-demethoxy daunomyci none, or its analogues or derivatives 15 comp ising reacting a compound of formula III, where R4 is H 16 and R- _| -R ₃ and Rtø are as defined above, th 17 substituted butadiene under conditions forming the A ng of 18 a compound of fo mula II and converting the group ^' R _j . at 19 posit on 10 in fo mula I II to a hydroxy group which taken 20 ith the hydroxy group at position 9 in formula III leads to 21 a system tautomeric with the anthracycl i none chromophore. 22 The present invention also provides a method of 23 obtaining precursors of 12-deoxy carminomycinone or of 12- 24 deoxy da.u nomyci none or their analogues or derivatives 25 comprising reacting a compound of formula III with a 26 substituted butadiene under conditions forming the A ring of 27 a compound of formula II and, where R^ is not already H, 28 converting it to H. . - 29 The reaction with the substituted butadiene can be 30 improved if there is a halogen atom, preferably bromine or ^" 31 chlorine atom, at- the 2-position of the compounds of formula 32 III or IV. 33 Butadienes of particular interest as reagents are those

34 bea ing one or more of a l-R^-substi tuent, a 2 - 35 tri al kyl si lyloxy- or 2-al koxy- or 2 - hy d ro xy al ky 1 - or 2-

36 oxoalkyl-, or 2-hydroxyo xo a 1 y 1 - or 2 -d i hy ro xy a 1 ky 1 -

37 substituent, a 3-Rg-substi tuent, and a 4-Rg-substi tuent.

38 The present invent on also provides a method of

obtaining 5-deoxy daunomycin or 5-deoxy adriamycin or their analogues or deri vati ves comprising either reduction of "a compound of formula I or tautomeric forms thereof, where R-, is not H, or reduction of a compound of formula I I or tautomeric forms thereof, where R4 is not OH, in either case to give a compound of formula II where R _χ is H. REACTION SCHEME I .

The compound 1 in scheme I which is used as a starting material is 1, 8-di ydroxy-9, 1 O-anthraqui none (chrysazin) and is avail able as a rel ativel y cheap dyestuff intermediate. The step, compound 1 to compound ^' 2 w as performed i n accordance with the method described in BIOS Report 1484, P.22. O itting the hydrolytic work-up from this procedure led to compound 24, ethylation of which gave compound 25.

The conversion compound 2 to compound 3 was effected in the presence of thionyl chlori de and achieved, in the particular instance, three important requi ements (a) - (c).

(a) The 9, 10-anthraquinone compound 2 which is unsuitable for further reaction i n its own ri ght, i s converted into a reacti ve 1,4-anthraqui none. Suitabl e reacti vity of the latter compound results from exposure of the uns.ubsti tuted 2,3-double bond of the quinonoid system.

(b) The 1 , 4-anthraqui none compound 3 has the possibility of reacti ng regiosel ectively, that i s with predictabl e di scrimi nation between positions 2 and 3. This i s because the carbonyl groups 1 and 4 which control such processes are themselves clearly differentiated, being respectively adjacent t ^' o a hydroxy and to a chloro subs.ti tuent.

(c) The conversion of compound 2 into compound 3 is itself regio specific. The potentially competitive process leading to the unwanted iso eric compound was ^' not observed . at all.

The operation compound 2 to compound 3 thus resolves a fundamental problem towards formul ating a regi os pe ci f i c synthesi s of anthracyclines, namely of being able to use a substituent on one side of the molecule (the hydroxy group of ring D) to discriminate between reactive centres remotely located on the other side of the molecule (positions 2 and 3 of compound 3).

In the conversion compound 3 to compound 4 the more exposed of the two hydroxy groups of (3) read ly unde go e"s selective protection to g ve the monoacetate (4). None of the unwanted isomeric monoacetate at the 9-posit on was observed. Retention of a free hydroxy group at position 9, as in compound 4 was necessary for di recti e purposes i n the subsequent step, conversion to the 2-bromo derivative compound 5. None of the unwanted isomeric 3-bromo derivative was observed i n thi s step. (The 2-chloro deri vati ve analogous to (5) has also been obtained and it shows si ilar chemical behaviour). The bro o derivati ve compound 5 is activated towards regiospecific cycloaddition of 2-trimethylsilyloxybutadiene, a readi ly accessi bl e reagent which i s commercial ly avai labl e. On being heated smooth conversion occurs to the cycloadduct compound 6. Treatment of the cycloadduct compound 6 then effected deacetyl ation and 1,2-el imination of hydrogen bromide to give the 1,4-quinone compound 7. The latter product on being treated with acid affords the tetracycl ic 5,12-quinone compound 8, the desired compound in the synthesis. The conversion compound 7 to compound 8 is an important step in the sequence, permitting hydrolytic removal of the chloro group under conditions sufficiently mild so as not to cause aromatization of ring A. This step provides the necessary complement to the step of compound 2 to compound 3 described above. Having introduced controlled discrimination into the system in the form of the chloro substituent specifical ly placed at position 10 of compound 3, the synthesis requires its replacement by an oxygen substituent once its function has been achieved, i.e., once an A-ring having the correct orientation has been formed. This requirement is accomplished in the conv-ersion of ^* compound 7 to compound 8. In considering the sequence (5) to (6) to (7) to (8), whil st it was possible to isolate the two intermediates compounds 6 and 7 if required, it is more efficient to carry

OJ.'P

1 out the entire process (5) to (8) as a one-pot operation.

2 The yield was calculated accordingly.

3 The tetracyclic ketone compound 8 as obtained herein

4 was identical with an authentic sample derived by chemical

5 degradation of natural daunomycin.

6 It i s to be noted that the four steps (2) to (3), (3)

7 to (4), (4) to (5), and (5) to (8), where re gi oc hem i ca 1

8 considerations are cri ical, all proceeded regiospecifically

9 within the li its of detection. 0 Compound 8 can be converted into (-±)-d au nomyci no ne by -1 Kende's method and can also be converted into ( ± ) - 2 carminomycinone (U.S. Patent Nos. 4,021,457 and 4,070,382). 3 Daunomycinone can be converted i nto adri mycinone (U.S. 4 Patent No. 4,012,448). G 1 y co sy 1 a t i on of these racemic 5 a n t h r ac y c 1 i n o n e s with appropri ate derivatives of L- 6 daunosamine (itself chemically synthes i sab 1 e in enantiomeric

17 form and commerically available) affords the natural

18 enantiomeric anthracycl ines.

19 In summary the conversion (1) to ^" (8) involves five

20 operations and proceeds in a yield of 24% overall.

21 REACTION SCHEME II .

22 A modified synthesis of compound 8 is shown in Reaction

23 Scheme II.

24 It differs from the synthesis in Scheme I in effecting

25 cycl oadd i ti on to the 1 , 4-anthraqu i none compound 3 directly,

26 so as to give the new cycloadduct compound 9. This avoi ded

27 the acetylation and bromination steps used in Example I but 28- it suffers from the disadvantage that cycloaddition to 29 compound 3 requires more severe conditions than to the bromo ^* 30 acetate compound 5. Cycloaddition to compound 3. might

31 conceivably have ^' proceeded less regiospecifically than to

32 compound 5, since the bromo substitutent in such systems

33 generally provides a powerful directive influence; however

34 none of the unwanted orientation was observed.

35 ^' The cycloadduct compound 9 is at the oxidation level of

36 a dihydro quinone. Oxidation to the corresponding quinone

37 system is achieved by fi s ^' t protecting- the isolated keto

38 group in compound 9 as its acetal compound 10, so as to

* ^'

O-v'PI

prevent arom at i zat i on of the A-ring during oxidation. Base- catalysed aerial oxidation of compound 10 then gives t Ire protected quinone compound 11, treatment of which with trif luoroacetic acid as in the last stage of Scheme I again gives the tetracyclic ketone compound 8. REACTION SCHEME III A modified synthesis is shown in Reaction Scheme II I and involves methylation of compound 3 under the defi ned conditions wh ch occurred regiospecifical ly to give the monomethyl ether compound 12, substantially exclusively. In the fol lowi ng stages of the sequence via compound 13 to compound 14 to compound 15 to compound 16 the monomethyl ^' ether compound 12 wen t ^• through an analogous procedure to that applied to the monoacetate compound 4 in Scheme I. The tetracyclic methoxy ketone compound 16 resulting from this sequence can ^' be converted to (±)-daunomyci none (U.S. Patent Nos. 4,021 ,457 and 4,070,382). There are two advantages of this path ay relati ve to those of Schemes I and II. First the methoxy group at position 4, present i n the natural anthracycl i nes i s incorporated efficiently early in the synthesis rather than at a later poorer-yieldi ng stage. Second the overal l synthesis can be ac ieved in one less step and with much higher effi ciency. Thus the overal l yield of ( ± ) - daunomyci none from 1 ,8-di hydroxyanthraqu i none by the pathway of Scheme III i s 4.2% i n eight operations. This compares with a yield of 1.8% in nine operations by Scheme I. REACTION SCHEME IV. Suitable starting material s analogous to compound 2 were made as shown in Reaction Scheme IV. REACTION SCHEME V. Selective - reduction of daunomycin 17 under mildly acidic conditions leads to the 5-deoxy compound 20 in yield of 57% and to the 5-deoxy-13-di hydro compound 21 in yield of 25%. Minor modification of this reaction leads to compound 21 in yield of 71% as the sole glycosidic product. Simi lar reduction of adriamycin 26 gives the 5-deoxy compound 22 in yield of 38% and the 5-deoxy-l 3-dihydro compound 23 in yield

1 of 17%. 2 Extended reduction of 17 gi ves the 5, 7-bi sdeo ~y 3 compound 19 in yield of 88%. Compound 19 is also obtained by 4 reduction of the known 7-deoxy daunomyci none 18. 5 The present invention will be further illustrated with 6 the aid of the following examples. 7 EXAMPLE I 8 Preparation of 1 ,4, 5-T ihydroxy-9, 10-anthracenedione 9 (compound 2) and of the C_y_c_l__i£ Sul fate (compound 25). 0 1 , 8-Di hydroxy-9, 10-a nt hracenedione (chrysazi n) 1 (compound 1) (6.85g) was added slowly to a stirred solution 2 of 80% oleum (137g) containing boric acid (3.56g) maintained 3 at 27° i n an oil bath. The resulting purple mixture was 4 stirred for 14 days, then carefully diluted to 83% sulfuric 5 acid by addi tion to ice (56g) contai ned in a very wel l 6 cooled flask. The resulting blue mixture was then heated at 7 140° for 80 mi n under an air condenser. The mixture was 8 cooled to room temperature then diluted into ice-cold water 9 (600ml) with stirring. The suspension was heated to 90° on a 0 steam bath, cooled and filtered through pulped filter paper 1 on a Buchner funnel. The cake was washed with di stil led 2 water (200ml) then dried under reduced pressure, prior to 23 exhaustive extraction with hot ethyl acetate (1000ml). The 24 extracts were fi ltered and evaporated to give a dark red 25 solid which was recrystallized from acetic acid to give the 26 product (compound 2) as red needles, (5.76g, 79%). 27 Alternatively, the purple mi xture from the foregoing 28. reaction was added t-o sufficient ice to cause precipitation. 29 Extr ac ti on w i th di ch lo ro eth an e an d prep arat iv e 30 chromatography of the extract on si l ica gel 60 w ith 31 chloroform as eluant gave the product (compound 24). A 32 sample of thi s compound (10 mg) was stirred with an excess 33 of methyl iodide in chloroform (3 ml) in the presence of 34 si lver oxide (36 mg) for 72 h. at room temperature. The 35 mixture was then filtered and the filtrate evaporated. The 36 residue was chromatographed on silica gel G with chloroform 37 as eluant to give the product (compound 25) (10 mg, 9i 38

EXAMPLE 2 Preparation of 10-Chl oro-8, 9-di hydroxy-1 , 4-anthracenedione (compound 3). 1, 4, 5-Tri hydroxy-9, 1 O-anthracenedione (compound 2) (670 mg) was refluxed in freshly distilled thionyl chloride (7ml) for 40 h while bei ng protected from moi sture. The excess thionyl chloride was evaporated and the residue was taken up in di ch 1 o rome th an e and al lowed to stand overnight. The crystals which separated were fi ltered off and dried. The mother liquor. was applied to a column of silica gel type 60 and eluted with chloroform then chloroform/acetone/acetic acid (95: 5:1). The separated purple band was added to the crystals obtained above to give a combined yield of purple- black product (compound 3) (586 mg, 81%). EXAMPLE 3 Preparation of 8-Acetoxy-10-ch 1 oro-9-hydroxy-1 , 4- anthracenedione (compound 4) . 10-C hi or o-8, 9-di hydroxy- 1 , 4-anthracened ione (compound 3) (180mg) wa s d is so lv ed wi th st ir i ng i n dry te tr ahyd ro f u r an ( 15 ml ) at room temperature. Acetic anhydride (20 drops) and pyridine (15 drops) were added to the sol ution which was then sti rred for 48 h. Acidified water was added and the suspension was extracted with dichloromethane. The combined organic layers were dried and evaporated, and the residue was column ch roma togr ap hed on silica gel 60 (100 g) with chloroform /acetone mixture as the eluant. The major red band gave the product ^* (compound 4) as a red soli d (17.7 g,. 85%). EXAMPLE 4 Preparation of 8-Acetoxy-2-bromo-10-ch 1 oro-9-hydroxy-1 , 4- anthracenedione (compound 5) . 8-Acetoxy-10-chloro-9-hydroxy-1,4-anthracenedione (compound 4) (52 mg). was warmed in acetic acid (2 ml) in a round bottom flas.k. The mixture was cooled and to thi s was added a solution of bromine (-28 mg) in acetic acid (0.1 ml) with stirring. After 1.5h the yellow solution was evaporated

to gi ve a dark yellow sol id which was boi led wi th ethanol (5 ml) for 3 min on a water bath. The red mi xture was cool ed", di luted with water and extracted into d i c hi or omet ha ne. Ev aporat io n gave a red s ol i d whi ch was col umn chromatographed on silica gel 60 with chloroform as eluant. The mobile red band was recovered to give the product (compound 5) as a red crystalline solid (64 mg, 98%). ^' EXAMPLE 5 Preparation of 7, 10-Di hydro-4, 6, 11 -tri hydroxy-5, 9, 12 (8H)- naphthacenetrione (compound 8) . 8-Acetoxy-2-bromo-10-chloro-9-hydro ^" xy-l,4- anthracenedione (compound 5) (20 mg) was treated wi th 2 - trimethyl si 1 yl oxy-1, 3-butadi ene (72 mg) in refluxing benzene (2.5 ml) under nitrogen for 6 h. The benzene was evaporated under reduced pressure and the residue (compound 6) was dissolved in tr i f 1 uorom ethanesul f on i c acid (0.5 ml) at room temperature with stirring for 10 min. The blue solution was th en qu en ch ed w i th i ce water a nd ext racted it h dichloromethane. The combined organic extract was dried and evaporated to a purple solid (compound 7). This was taken up in trifluoroacetic acid (5 ml) and heated at reflux under a nitrogen atmosphere for 60 min. The orange solution was then diluted with water and extracted with dichloromethane. The dried organic layers were chromatographed on si lica gel layers containing 2% oxalic acid in toluene/ethyl acetate (90:10). The orange band Rf=0.46 was recovered to give the product (compound 8) as a red soli d (7.5 mg, 45%). EXAMPLE 6 Preparation of 3,4,4a, 12a-Tetrahydro-11 -chlororδ, 7- di hydroxy-2 , 5 , 12( 1 H )-naphthacenetri one (compound 9) . 10-C hi or o-8, 9-di hy dr oxy-1 , 4-anthracenedione (compound 3) (100 mg), 2-met ho xy-1 , 3-but ad ie ne (564 mg) and dry benzene (10 ml) were heated in a sealed tube for 4 h at 130°. After cool ing the crude solution was pr epar at i v el y chromatographed on silica gel layers containing oxalic acid (2%) with chloroform as el uant. The major yellow band was recovered to gi ve the product (compound 9) as a yel low crystalline solid (85 mg, 6i

OMPI

EXAMPLE 7

Preparation of Ethylene Acetal of 3, 4, 4a, 12a-Tetrahydro-11 - -- chloro-6, 7-dihydroxy-2, 5, 12(1H)-naphthacenetrione (compound 10).

A sol ution of 3, 4, 4 a, 12 a- te tr ah yd ro -11 -ch 1 o ro -6, 7- dihydroxy-2,5, 12(1H)-naphthacenetrione (compound 9) (17 mg), £ -to! uenesul fonic acid (4 mg) and ethylene glycol (140 mg) i n dry benzene (5 ml) was boi led under refl ux for 4h with azeotropic removal of water. Recovery of the product by partitioning with chloroform and aqueous sodium bicarbonate (5%), drying of the organic phase and evaporation under reduced pressure gave the product (compound 10) which was recrystal 1 i zed from dichloro ethane and light petroleum as yellow needles (18 mg, 95%).

EXAMPLE 8 Preparation of Ethylene Acetal of 3 , 4-Di hydro-11 -chl oro- 6,7-dihydroxy-2,5,12(1H)-naphthacenetrione (compound 11).

Oxygen was bubbled through a solution of ethylene acetal of 3, 4, a , 12 a- te tr ahyd ro -11 -ch 1 o ro -6 , 7 -d i h yd ro xy- 2, 5, 12( 1 H)-naphthacenetrione (compound 10) (15 mg in 5 ml 1M aqueous sodium hydroxide) and dim ethyl sul foxi de (20 ml) for 30 min. The purple solution was then acidified with aqueous acetic acid and extracted with chloroform. The combi ned extracts were washed with water, dried and evaporated under reduced pressure to give a residue which was chro atographed on a sil ica gel layer contai ni ng oxalic aci d ,(2%) with toluene/ethyl acetate (ratio 7:3) as el uant. The major pur-ple band was recovered to give the product (compound 11) as black needles from dichloromethane /.light petrol eum (11 m g, 73%).

EXAMPLE 9 ^" Preparation of 7, 1 O-Dihydro-4, 6, 11 -tri hydroxy-5, 9, 12(8H) -naphthacenetrione- (compound 8).

A solution of ethylene acetal of 3, 4-di hydro-11-chloro- 6, 7-di hydr oxy-2, 5, 12( 1 H)-n ap hthacenetrione (compound 11) (4 mg) in t ri f 1 uo roacet ic acid (2 ml) was heated at 80° under reflux for ^" I h. The solution was cooled, di luted with distil led water (10 ml) and extracted with ethyl acetate.

The combined organic l ayers were washed with di stil led water, dried and evaporated to give the crude produ-srt (compound 8) which was recrystal 1 i zed from ethyl acetate as brown m i crocrystal s (2.5mg 74%). EXAMPLE 10 Preparation of 10-Chloro-9-hydroxy-8-methoxy-l , 4- anthracenedione (compound 12). 1 O-Chloro-8, 9-di hydroxy-1 , 4-a nt hr ac en ed io ne (compound 3) (100 mg) was di ssolved with sti rring in dry di ethyl sulfoxide (25 ml) under a nitrogen atmosphere. Sodium hydride (80% dispersion, 28.5 mg) was added to the solution in one aliquot. The resulting dark blue solution as sti red for 5 min then methyl iodi de (156 mg, 0.1 ml) was added i n one lot. Stirri ng was conti nued for 10 min then another aliquot of methyl iodide (0.1 ml) was added to the mixture. After a further 5 m.in the dark bl ue solution was quenched w ith i ce-cold phosphate buffer (pH7) to give a red suspension which was extracted with chloroform. The combined organic extracts were dried and evaporated to a crude solid which was chromatographed on a column of silica gel 60 with chloroform as el uant. The mobile red band gave the product (compound 12) as a red sol id (84 mg, 88%). This yield was calculated after allowing for recovered starting material (10 mg). EXAMPLE 11 Preparation of 2-Bromo-1Q-chl oro-9-hydroxy-8-methoxy-1 , 4- anthracenedione (compound 13). 10-Chloro-9-hydroxy-5-methoxy-l ,4-anthracenedione (compound 12) (50 mg) was dissolved in acetic acid (5 ml) to saturation by warming. T e mixture was cooled to room temperature before addition of bromine (27 mg) in acetic acid (0.15 ml). The mixture was stirred for 120 min. then excess acetic acid was evaporated under reduced pressure. The crude soli d dibromide was di ssolved in ethanol (5 ml) containing boron trifluoride etherate (5 drops) and heated at reflux for 20 min. The resulting red-purple sol ution which deposited some crystals was cooled and diluted with distil led water (20 ml). After standi ng overnight, the

precipitated red-black sol id was fil tered off to gi ve the product (compound 13) (58 mg, 91%). EXAMPLE 12 Preparation of 7, 10-Di hydro-6, 11 -di hydroxy-4-methoxy-5, 9, 12 (8H)-naphthacenetrione (compound 16) . 2-Bromo-10-chloro-9-hydroxy-8-methoxy-1 , 4- anthracenedione (compound 13) (55 mg) was dissolved i n dry benzene under nitrogen at reflux. 2-Trimethyl si lyl oxy-1 , 3- butadiene (212 mg) in benzene (0.5 ml) was added and the mi xture was refl uxed for 12.5 h altogether. Excess benzene was evaporated under reduced pressure to give a dark red s o l i d ( com po u n d 14) w h i c h w a s d i s so l ved i n tr i f 1 uoromet ha ne su 1 f on i c acid at room temperature with stirring under a nitrogen atmosphere. After 20 min.. the dark bl ue sol ution was quenched with ice and extracted with dichloromethane. The combined organic extracts were dried and evaporated to dryness under reduced pressure. The residue (compound 15) was dissolved in trifluoroace ic acid (5 ml) and refl uxed under nitrogen for 90 min. The d k red solution was dil uted with cold disti lled water and then extracted ith dichloromethane. The combined organ c layers were dried, evaporated and the crude residue was preparati vely chromatographed on si l ica gel layers containing 2% oxalic acid in toluene/ethyl acetate (80:20). The red-orange band Rf = 0.23-0.35 was recovered to give the product (compound 16) as a red solid (23 mg, 45%). Al ternatively the dark red solid from the foregoing reaction was dissolved in- acetic acid (11 ml) containing sodi um acetate (440 mg). The mi xture was stirred under nitrogen for 10 min at room temperature and was then heated at ref lu x for a fu rthe r 5 m in. Extra ct ion w ith dichloromethane gave compound 15 as a red solid. Thi s was converted to compound 16 (14 mg, 30%) as above. EXAMPLE 13 Preparation of (9R)-9-Acetyl-9, 12-di hydroxy-4-methoxy- 7, 8, 9, 10-tetrahydro-6, 11 - naphthacenedione (compound 19). Daunomycin hydroc hi o i d e (compound 17) (20 mg) in dry methanol (20 ml) was catalyti cal 1y reduced with hydrogen gas

and 5% pal ladi um on bari um sulfate (20 mg) 5.5 h at room temperature. Exposure of the mixture to the atmosphere gave a red sol ution which was fi ltered, evaporated and prepar at iv el y chromatographed on sil ica gel layers using chloroform/methanol (98:2) as eluant. The red band Rf 0.28- 0.43 gave the product (compound 19) as a red solid (12 mg, 88%). EXAMPLE 14 Preparation of 5-Deoxy Daunomycin (compound 20) and of 5- Deoxy-13-di hydro Daunomycin (compound 21 ) A solution of daunomycin hydrochloride (compound 17) (50 mg) in dry methanol (20 ml) containing chloroacetic acid (200 mg) was shaken with hydrogen and Adams catalyst (10 mg) for 50 min at room temperature. The mixture was then filtered, the filtrate diluted with water (50 ml) and washed with dichloromethane to remove non-gl ycosi di c materials, the aqueous residue was then br-ought to pH 8.5 with aqueous sodium bicarbonate. Extraction with dichloromethane and chromatography on a column of si l ica gel 60 ith chl oroform /methanol /w ater (100:20:1) as eluant gave 5-deoxy daunomycin (compound 20) (26 mg, 57%) as a dark red sol id. Further elution with ch lo ro fo rm /met ha no 1 /wa te r (80:20:1) gave 5-deoxy- 13-d i hyd ro daunomycin (compound 21) (12 mg, 25%) as a dark red sol id. EXAMPLE ^' 15 Preparation of 5-Deoxy-13-di hydro Daunomycin (compound 21) A solution of daunomycin hydrochoride (compound 17) (10.4 mg) in dry methanol (6 ml) was shaken with hydrogen and Adams catalyst (8.7 mg) for 70 min at room temperature. The mixture was then fi ltered, the fi ltrate diluted with water (10 ml) and washed with dichloromethane to remove non- glycosidic materials, the aqueous residue was brought to pH 8.5 with aqueous sodium bicarbonate. Extraction with dichloromethane gave 5-deoxy-13-di hydro daunomycin (compound 21) (6.7 mg, 71%) as a dark red sol id. EXAMPLE 16 Preparation of 5-Deoxy Adriamycin (compound 22) and of 5- Deoxy-13-dihydro Adriamycin (compound 23) .

A solution of adriamycin hydrochloride (compound 26) (20 mg) in dry methanol (8 ml) containing chloroacetic acid (80 mg) was shaken with hydrogen and Ad am s _. ca ta ly st (5 mg) for 40 min at room temperature. The mixture was fi ltered, the fi ltrate diluted with water (20 ml) and brought to pH 8.5 with aqueous so ium bicarbonate. Extraction with chloroform and chromatography on a column of silica gel 60 with chl oroform /methanol /water (80:20:1) as eluant gave 5- deoxy adriamycin (compound 22) (7 mg, 38%) as a dark red solid. Further elution gave 5-d eo xy-13-di hydro adriamycin (compound 23) (3 mg, 17%) as a dark r ed sol id. Compounds in accordance ith this invention which have al kyl groups as such or as part of another radical such as al karyl, al koxy, aral koxy, al karyl , aralyl, acyloxy, al kylamino, al ko xy ca rbon yl , mono- or po 1 y-h yd ro xy al ky 1 include those wherein the al kyl groups are saturated or unsaturated, have from 1-20 carbon atoms, preferably 1-6 carbon atoms, and may bear such substituents as are common in the art incl uding halogen, hydroxy, a i no, im ino, nitroso, carbonyl , carboxy together with such other -substituents as may .be desired and as are listed as radicals in IUPAC nomenclature rules. Compounds in accordance with this invention which have aryl groups as such or as part of another radical such as al karyl, aral kyl, aryloxy, aryloxycarbonyl include those wherein the aryl moiety is a single or multi-ring aromatic system which may bear similar substituents as discussed above in respect of alkyl groups and which may contain he ero ^' atoms such as nitrogen, oxygen or sulfur. The claims form part of the disclosure of this specification. Modifications and adaptations may be made to the above described without departing from the spirit and scope of this invention which includes every novel feature and combination of features disclosed herein.

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