NZ214101A - Naphthacene derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £14101 ' ■/ _ 1410 Priority Date(s): I?.. .1.. &?.'/ .??.

Complete Specification Filed: all.

Class: CPnC>as/.0A/.Q6j <&7?.83$3)Q6./.0% Publication Date: a.o.raM?..

P.O. Journal, No: ..iZffif?.

NO DRAWINGS NEW ZEALAND PATENTS ACT, J 953 Divided from No. 205669 No.: UM%r the provisions of ftiflN btion 23 H) the 1 „ j IptcWcatlon has been ante-date The anthracycline derivatives provided by the present invention are compounds of the general formula 0 OH OH wherein Ra represents a hydrogen atom, a trichloroacety1, lower alkyl, aryl or aryl-(lower alkyl) group, a 5-membered or 6-meitLbered hetercaromatic group in which the hetero atom is oxygen or sulphur, or a group of formula -(CH2)n-C0Rf (a) / .

■. • S.T 214101 20435& wherein R' represents a hydroxy, lower alkoxy, amino/ lower alkylamino, di(lower alkyl)-amino or arvlamino group, n stands for an integer of 1 to 4, n' stands for an integer of 2 to 10, and X represents a group of the formula CH. or -ch2-, (i) '3 I -CH- (ii) -CH2-CH2-, (iii) with the proviso that any carboxy, hydroxy or amino group present on-an aryl substituent is in protected form and a carboxy group present on group (a) is in protected form.

The term "lower alkyl" used in this Specification, alone or in combinations such as in aryl-(lower alkyl), lower alkylamino and di(lower alkyl)amino, means a straight--chain or branched-chain alkyl group containing from 1 to 5 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, n-pentyl and the like. The term "aryl", alone or in combinations such as in aryl-(lower alkyl) and arylamino, means the phenyl group or a substi-tuted-phenyl group, i.e. a phenyl group carrying one or more substituents selected from, for example, lower alkyl, lower alkoxy, halogen, nitra, amino, carboxy, hydroxy, cyano and O o trirluoromethyl. Examples of substituted-phenyl groups are thus p-tolyl, p-methoxyphenyl, m-hydroxyphenyl, o-nitro-phenyl, p-nitrophenyl, p-chlorophenyl, 2,4-dichlorophenvl and the like. Benzyl, p-chlorobenzyl and 2-phenylethyl can be named as examples of aryl-(lower alkyl) groups and anilino can be named as an example of an arylamino grouts. • Examples of 5-membered and 6-membered heteroaromatic groups denoted by Ra are thienyl and the like. The term "lower alkoxy" means a lower alkyl ether group in which the lower alkyl moiety is as defined earlier, examples of such lower alkoxy groups being methoxy, ethoxy, n--propoxy," isopropoxy etc. Examples of lower alkylamino groups are methylamino, ethylamino, n-propylamino and the like and examples of di(lower alkyl)amino groups are di-methylamino, diethylamino and the like.

An interesting class of compounds of formula I comprises those in which Ra represents a lower alkyl, aryl or aryl-(lower alkyl) group, a 5-membered or 6-membered heter-aromatic group in which the hetero atom is oxygen or sulphur or a group of formula (a).

A preferred class of compounds of formula I comprises those in which Ra represents an aryl group, especially ^'phenyl. Compounds of formula I in which X represents a group of formula (i) or (ii) hereinbefore are also preferred.

A carboxy or hydroxy group present in R in a compound of formula I can be protected in the form of any con- iona'l readily hydrolyzable ester. Preferably, for the rotection of a hydroxy group an ester is derived from a 2 14101 lower alkanecarboxylic acid such as acetic acid etc. An si amino group present in R can be protected in a conventional manner; for example by means of a suitable acvl group.

The compounds of formula T can be prepared/ for example, by reacting a compound of the general formula 0 OK wherein X has the significance given earlier and Ar represents an aryl: group, with an isocyanate of the general formula t 0= C =«N—Ra' .-'III a p I £ ■ wherein R has any of the values of R hereinbefore except a hydrogen atom, or with a diisocyanate of the general formula 0=C =N— SNH—R IV a I wherein R , X and Ar have the significance given earlier, to an ester exchange with a 1,3-aiol and, if desired, cleaving ofr a trichicroacetyl grouo denoted bv Rs from the product.

The reaction of a compound of formula II with an isocyanate of formula Ilia or a diisocyanate of formula Illb is conveniently carried out in a tertiary organic amine (e.g. pyridine or the like). When an isocyanate of formula Ilia is used, the reaction can conveniently be carried out at an elevated temperature, for example a temperature from substantially 60°C to substantially 80°C. The isocyanate of formula Ilia can be formed in situ by Pi * using a corresponding azide of the formula R -CO-N^ and carrying out the reaction at a temperature at which the azide liberates nitrogen and rearranges to form the isocyanate. When a diisocyanate of formula Illb is used, it can be convenient to carry out the reaction at about room temperature, suitably over an extended period of time. 2 14101 The reaction product of formula IV is then subjected to an estsr exchange with a 1,3-diol. This is suitably-effected by reacting a compound of formula IV with an excess of a 1,3-ciol in the presence of an acid. An especially preferred 1,3-diol is 2-methyl-2,4-pentaneciol. Preferred among the acids which, can be used are the Icwer alkane-carboxylic acids such as acetic acid and the like. This reaction is conveniently carried out in the presence of an inert organic solvent such as a halogenated hydrocarbon (e.g. dichloromethane etc) and at about room temperature.

The optional, cleavage of the trichloroacstyl group denoted by R from a compound of formula I, can be carried out by treatment with aqueous alkali such as aqueous sodium droxide.

The compounds of formula TI hereinbefore can be prepared, for example, as described in the Examples hereinafter or in analogy thereto.

The comoounds of formula I hereinbefore are useful as intermediates in the preparation of anthracycline glycosides into which they can be converted as is described in mere detail in our New Zealand Patent Specification No. 205669.

The following Examples illustrate the present invention: ,/ 14101 c o Sxamole 1 (i) 0.8 g of (IS ) -cis-1, 2,3,4,6, 11-hexahydro--5 ,12-dihvdroxy- 3-hydraxvmethyl-5 ,11-dioxo-l, 3-naphthacene-diyl benzeneboronats was dissolved in ICO ml of pyridine and 0.9 g of phenyl isocyanate v/as added. The mixture was heated at 60°C for 45 minutes, cooled and the solvent was removed by evaporation. The residue was taken up in 100 ml of di ch lor one thane, some colourless insoluble material was removed by filtration, the filtrate was washed with 50 ml of 5M hydrochloric acid and twice with 50 ml of water each time, dried over anhydrous sodium sulphate and evaporated to give crude (IS ) -cis-1,2,3,4,5, ll-hexahycrc-5 ,12-di-hvdraxy-5, ll-dioxo-3- (phenylcarbamcyloxy) me thy 1-1, 3--naphthaceneciy 1 benzsr.sborar.a~s in the form of a red solid which was used without further purification. (ii) The benzeneboronats obtained according tc paragraph (i) was dissolved in a mixture of 30 ml of dichlorcmethane, 30 ml of 2-methyl-2/4-centaneciol and 3 ml of acetic acid and the solution was left to stand (^) at room temperature overnight. The solution was diluted with 100 ml of dichloromethane, washed with three 100 ml portions of water, dried over anhydrous sodium sulphate and evaporated. Trituration of the residue with ethyl aceta-e/ diethyl ether gave 0.82 g of (IS) -cis-1, 2,3,4,6, ll-he:cahydrc--1,3,5,12-tstrahycroxy-5 , li-dioxc-3- (phenylcarbamcvloxy) -methylnaphthacene in the form of red crystals of melting point 225 °-226 °C; [al^0 = +136.0° (c = 0.05% in dicxan). 2 1410' a _ The (IS)-cis-1,2,3,4,6,ll-hexahvdro-5,12-dihydroxy--3-hycroxymethyl-6 , 11-cLioxo-l, 3-naphthacenediyl benzer.e-boronate used as the starting material in paragraph (1) was prepared according to procedure (A) or (3) described hereinafter: (A) 2.0 g of (IS)-cis-3-acetoxymethy1-1,2,3,4, 6,11--hexahydro-1,3,5,12-tetrahydroxy-6,11-dioxonaphthacene were dissolved in a mixture of 2SO ml of dichlorcmethane and 250 ml of methanol- The mixture was stirred at rocm temperature and sufficient 0.1M aqueous sodium hydroxide solution was added to maintain a deep purple colcur. The mixture was stirred for 5 hours. The reaction was quenched by the addition of acetic acid to restore the orange colour and most of the solvent was removed by evaporation. 100 nl of water were added to the residue and the orance-rad precipitate produced was collected by filtration and dried in vacuo. There were obtained 1.7 g of (iS)-cis--1,2,3,4,6, ll-hexahydro-1,3, 5 ,12-tetrahydro:c/-3-hydroxy-methyl-S, 11-dioxcnaphthacene in the form, of crange-rec crystals of melting point 212°-214°C; Ccr] = +131.3° (c = 0.1% in dioxan). 4.0 g of the compound obtained according to the preceding paragraph were suspended in 1000 ml of tatra-hydrofuran and treated with 2.5 g of benzenehoronic acid and 0.1 g of acetic acid. The mixture was heated under .>3SR*r- \~" i 2. 1410 - 9. - reflux for 30 nu.nut.as, ccolec. and the solvent was removed by evaporation to give a red residue. After trituration with methanol, there were obtained 4.65 g of (lS)-cis--1,2,3,4,6, ll-hexahvdro-5 ,12-dihydroxv-3-hydroxyiuethy 1 --6 ,11-dioxo-l, 3-naphthacenediyl benzeneboronate in the form of orange-red crystals of melting point 253°-259°C; [el"° = +355.0° (c = 0.1% in dioxan). (3) 1.0 g of (IS)-cis-3-acetoxymethvl-l, 2, 3 , 4, 6 ,11 -hexahycro-5 ,12-dihycroxy-a , 11-dicxo-l, 3-naphthacenediyl benzeneboronate was dissolved in a mixture of 100 ml of dichlorcmethane arc 100 ml of methanol. The mixture was stirred at room temperature and sufficient 0.1M aqueous sodium hydroxide was added to produce a deep purple colour The mix-ure was stirred for 4 hours and then quenched by the addiricn of acetic acid to restore the orange colour. The solvent was removed by evaporation and the residue was tritura-ed with methanol to give 0.7 g of (IS) -cis-1,2,3,4 6 ,11-hexahycro-5 ,12-dihydroxy-3-hydroxymethy 1-6 ,11-dioxo--1,3-naphthaceneciyl benzsnebcronata in the form of orange -rec crystals which were identical with the compound prepared according to procedure (A).

Example 2 (i) 1.0 g of (IS)-cis-1,2,3,4,6,ll-hexahydro-5,12--dihydroxy- 3-hvdroxyme thy 1-6 ,11-dicxo-l, 3-naphthacenediyl j benzeneboronate was reacted with 0.5 g of 4-chlorophenvl 2 14101 isocyanate in 100 mi of pyridine according to the method described in Example l(i). Analogous working-up gave (15)--cis-3-(4-chlaropher.ylcarbamoylcxy) methyl-1,2,3,4, 6,11--hexahycro-5 ,12-dihydroxv-S,11-dioxo-l, 3-r.aphthacenediyl benzeneboronate in the form of a red solid which was used without further purification. (ii) The benzeneboronate obtained according to paragraph (i) was treated according to the procedure described in Example l(ii) to give (lS)-cis-3-(4-chlcro-phenylcarb amoyloxy)-erhvl-l,2,3,4,6,ll-hexahvdro-1,3,5,12--tetrahydroxy-6,11-cioxonaphthacene which was obtained in the form of orange-red crysrals of melting point 264 °-265 °C; [c]D = +125.1° (c = 0.05% in cioxan) .

Example 3 (i) A solution of 1.0 g of (IS)-cis-1, 2,3,4,6,ll-hexahvdro-5, 12-dihvdrcxy- 3-hydroxymethy!-€ , 11-dioxc-l, 3-r.aphthacenediyl benzeneboronate and 1.0 g of 4-nitrobenzoyl aside in 100 ml of pyridine was heated at 75°C for 1.25 hours, cooled and the pyridine was then removed by evaporation. The red residue was taken up in 200 ml of cichloromethane, insoluble material was removed by filtration and the solution was washed with 50 ml of 5M hydrochloric acid and with two 100 ml portions of water. After drying over anhydrous sodium sulphate, the solvent was removed by evaporation to give crude (IS)-cis-1,2,3,4,6,ll-hexahydro-5,12-dihydraxy--3-(4-nitrophenvlcarbamoyloxy)methy1-3,11-dioxo-l,3-naphiha-cenediyl benzeneboronate in the form of a red gusi which was used without further purification.

» / ' * - / - J 2 14101 (ii) The benzeneboronate obtained according to paragraph (i) was treated according to the procedura described in Example i(ii). 950 mg of (IS) -cis-1, 2,3 ,4 , 5 , LI--hexahycro-1 ,3,5,12-tstrahycroxy- 3- (4-ni trophanylcarbamcyl-oxy) methyl-6, 11-dioxonaphthacene were obtained in the form of orange-red crystals cf melting point 237°-239°C; [cJq° = +117.4° (c = 0.05% in dioxan).

Example 4 '(i) 0.7 g of (IS)-cis-1,2,3 ,4 ,6,ll-haxahvdro-5,12--dihydroxy-3-hydroxymethyl-6 ,11-dioxo-l,3-naphthacenediyl benzeneboronate was traared with 2 .0 g of 4-sethoxybenzoyl azide in pyridine according to the procedure described in Example 3 (i) to give (IS) -cis-1, 2 , 3, 4,6 , ll-hexahydro-5,12--dihydrcxv-3- (4-merhcxyphenylcarbamcyloxy)nieth.yl-5,11-dioxo--1,3-naphthacenediyl benzeneboronate in the form of a red gum which was used without further purification. (ii) The bencsnehcrcnate obtained according to . paragraph (i) was sarsc. according to the procedure described in Example l(ii). 675 mg of (IS)-cis-1,2,3,4,6,11--hexah.ydro-1,3,5 , II- tatrahvcroxy-3- (4-methoxyphenylcarbam-ovloxy)methvl—5 , ll-dicxcnachthacene were obtained in the form of orange-rad crys-als of melting point 196°-197°C; [a]^ = +156.6° (c = 0.25% in dioxan).

Examcle 5 / >•' / 2 1 4 (i) A mixture of 0.6 g cf (IS) -cis-1, 2,3,4,6,11-hexa-hvdro-5 ,12-dihydroxy-3-hydrcxyir.ethyi-6 ,11-dioxo-l/3-naphthacenediyl benzeneboronate and 0.5 g of 3-acetoxvbenzoyl azide in pyridine was heated at 80°C for 35 minutes and then a further 0.7 g of 3-acetoxybenzoyl azice was added. Heating was continued for a further 45 minutes, the solvent was removed by evaporation, the residue was taken up in 2C0 ml of dichlorcmethane and insoluble material was removed by-filtration. The filtrate was washed with 50 ml of 5M hydrochloric acid and with two 50 ml portions of water, dried over anhydrous sodium sulphate and evaporated to give cruce (IS) -cis-3- (3-ace toxvpneny Icarbamovlcxy) raethvl-1,2,3,4,6,11--hexahydro-5 ,12-dihydroxv-6 ,11-dioxo-l, 3-naphthacenediyl benzeneboronate in the form of an orange—red gum which was used without further purification. (ii) The benzeneboronate obtained according to paragraph (i) was treated according to the procedure described in Example l(ii). 0.71 g of (IS) -cis-3-(3--acetoxypher.y lcarbamoyloxy) methvl-1,2,3,4,6 ,11-hexahydro--1, 3 ,5,12-tetrahydroxy-6 ,11-dioxonaphthacene was obtained in the form of a red gum, Example 6 " 2141 (i) A mixture of 1.0 g of (IS)-cis-1,2,3,4,6,11-hexa-hydrc-5 ,12-dihy dr o : Examole 7 (i) A solution of 1.0 g of (IS)-cis-1,2,3,4,6,11--hexahydrc-5 ,12-dihydroxy-3- hydroxymethyl—S , 11-dioxo-l, 3--naphthacenediyl benzeneboronate and 3.0 g of thicphene-2--carboxylic acid azide in 100 ml of pyridine was heated at 21410 o 75°C for 1.5 hours, cooled and left to stand at room tampers tura for a further 15 hours. The pyridine was removed by evaporation and the red residue was taken up in 200 ml of dichlorcnethane. Insoluble material was removed by filtration and the solution was washed with 50 ml of 5M hydrochloric acid and the two 100 ml portions of water. After drying ever anhydrous sodium sulphate, the solvent was removed by evaporation and the residue was purified by chromatography on silica gel using ethyl acetate/n-hexane for the elution, there being obtained 1.035 g of (IS)-cis-1,2,3,4,6, ll-hexahycrc-5 ,12-cih.ydro.xy-3- (2-thienylcarhamoylojcy) -methyl-5,11—cioxo-1,3-naphthaceneciyl benzsneboronate in the fora of orange red crystals of melting point 243°-245°C (from ethyl acetate) ; [a] ^ = -r271.5° (c = 0.05% in dioxan) . (ii) The benzeneboronate obtained according to paragraph (i) was treated according to the procedure described in Example 1(ii) to give (IS)-cis-1,2,3/4/6,11-hexahydro--1,3,5,12- te trahydroxy-3- (2-thienylcarhamoyloxy) -ethyl-6,11-^ -dioxcnapnthacene in the form of an amorphous orange powder w of melting point 144°-146°C.

O Exam-ole 8 A solution of 1.0 g of (IS)-cis-1,2,3,4,6,ll-hexahydro-5 , 12-cihydroxy-3-hydroxymethy 1-5,11-dioxo-l, 3-naphthacenediyl benzeneboronate and 0.88 g of methyl 3-isocyanato- / J 2 1410 1 propionate in 12 ml of dry pyridine vas stirred a- rocm temperature for 4 days. The pyridine was removed by evaporation under reduced pressure and the rac residue was dissolved in 60 ml of dichloromethane, 1.33 ml of 2-methyl--2,4-pentanediol and 0.56 ml of glacial acetic acid. The mixture was then stirred at room temperature for 40 hours. The solution was diluted with 500 ml of dichloronethane and washed with four 150 ml portions of water. After drying over anhydrous sodium sulphate, the solvent was removed by evaporation cc give a red crystalline product. Trituration with diethyl ether gave 0.34 g of (IS)-cis-1,2,3,4,5,11--hexahvdro-1, 3,5,12-tetrahydroxy-3-[ [2- (methoxycarbonvl) -ethyl] carbamcyloxy] methy1-5,11-dioxonaphthacene in the form of orange-red crystals of melting point 145°-1493C; [cj = +113.9° (c = 0.05% in cicxan). (i) 0.2 g of (IS)-cis-1,2,3,4,6, 11-hexahydrc-l,3,5, 12-1etrany dr cxy-3- [ [ 2- (methoxvcarbonyl) ethyl] carbamcvlcxy] -methyl-6,11-dioxcnaphthacene was heated at 30°G for 2 hours with 0.05 g cf benzeneboronic acid in 60 ml of tsrrahydro— furan containing 4 drops of glacial acetic acid. The solvent was removed by evaporation to give a residual volume of 8 ml and 3 2 ml of 0.1M aqueous sodium hydroxide were added. The mixture was stirred at room temperature for 2.5 hours and then acidified to pH 2 by the dropwise addition of concentrated hydrochloric acid. The mixture was diluted with Example 9 2 14101 200 ml of water and the product was extracted with 100 ml of n-butanol and then with 50 ml cf r.-hutanol. The n-butanol extracts were combined and evaporated. The red crystalline residue was triturated with diethyl ether and filtered to give 0.2 g of (IS) -cis-3-[ ( 2-carboxyethyl) carbamoyloxy] -me thy 1-1, 2, 3,4,6, ll-hexahydro-5 ,12-dihycroxy-5 ,11, dioxo-1, 3-O -naphthacenediyl benzeneboronate in the form of an orange powder which was used in the next step without further purification. (ii) 0.2 g of the compound obtained according to paragraph (i) was suspended in 44 ml of dichloromethane and 0.2 g of oxalyl chloride and 2 drops of disethylformamide were added. The mixture was stirred at rccm temperature for 2 hours with the exclusion of moisture , there being obtained a red solution. This solution was cooled to 0°C and 0.4 g of n-propvlanine was added. After 2.5 hours, the solution was diluted with 100 ml of dichloromethane and the resulting solution was washed with 50 mi of 10% hydrochloric acid and then with 50 ml of water. After drying over anhydrous sodium sulphate, the solution was concentrated to 20 ml and 2 ml of 2-methyl-2,4-pentanediol and 5 drops of glacial acetic acid were added. The solution was left to stand at rccm temperature for 52 hours and was then diluted with 100 ml of dichlorome thane, washed with four 50 ml portions of water, dried over anhydrous sodium sulphate and evaporated to give a red crystalline solid. Trituration with diethyl ether gave 0.14 g of (IS)-cis-1,2,3,4,6,11--hexahydro-1,3,5,12-tstrahvdroxv-6 , ll-dioxo-3- [ [ 2- (propyl-carbamoyl ) ethyl] carbamoyloxy] methylnaphthacene in the form o o ! 2 14101 - 17 Urr of orange-red crystals of melting point 120°-125 °C; [a]^ = +8 6.9° (c = 0.05% in dioxan) .

Example 10 (i) 0.70 g of (IS)-cis-1,2,3,4,o,ll-hexahydro-5,12--cihydroxy-3-[ 1 (R) -(hydroxy)ethyl]-6,11-dioxo-l,3-naphtha-cenediyl benzeneboronate were dissolved in 80 nil of pyridine and 510 mg of phenyl isocyanate were added- The mixture was heated at 50°C for 3 hours, cooled and the solvent was removed by evaporation. The residue was taJcen up in 16 ml of dichlorcmethane, seine colourless insoluble material was removed by filtration and the filtrate was diluted with a further 144 ml of dichloromethane. The resulting solution was washed with 80 ml of 2M hydrochloric acid and 80 ml of water, dried over anhydrous sodium sulphate and evaporated to give 900 mg of (IS)-cis-1,2,3,4,S,ll-hexahvdrc-5,12-ci- —-r-_ / nydroxy-6 , ll-dioxo-3- [1 (R) - (phenylcarbamoylcxy) ethyl] -1,3--naphthacenediy 1 benzeneboronate in the form of a red solid which was- used without further purification. (ii) The benzeneboronate obtained according to paragraph (i) was dissolved in a mixture af 70 ml of dichloro-me thane, 13 ml of 2-methyl-2,4-pentanediol and 3.5 ml of glacial acetic acid and the solution, was heated under reflux for 2.5 hours. The solution was then cooled and washed with four 170 ml portions of water, dried over anhydrous sodium sulphate and evaporated. The residue was triturated with 20 ml of diethyl ether and filtered, there being obtained 610 mg of (IS)-cis-1,2,3,4,6,11-hexahydro-l,3,5,12-tatra-hvdroxy-6 , ll-cioxo-3-[l (R)-(phenyicarhamoyloxy) athyi] naphtha- cene in the form of red crystals of melting point 229.5°- 9n * -234°C; = "*"205° (c = 0.1% in dioxan) .

The (IS)-cis-1,2,3,4,6 ,ll-hexahydro-5,12-dihyaroxy-3-- [ 1 (R) - (hydroxy) ethyl] -6 ,11-dioxo-l,3-naphthacenediyl benzeneboronate used as the starting material in paragraph (i) was prepared as follows: A solution of 10.0 g of (S)-3'-acetyl-11,21,31,4'--tetrahvdro-3 '-hycroxy-5 ' ,8 ' -dircethoxyspiro f 1, 3-dithiolane--2,1'-naphthalene] in 250 ml of dry tetrahydrcfuran was cooled to -73 °C and a solution of 1.12 g of lithium alumin- v":.j V.--V 2 14101 ium hydride in 75 .nil of diethyl ether was added ever a period of a few minutes. The mixture was stirred at -73°C under nitrogen for 30 minutes and then a further 1.12 g of lithium aluminium hydride in 75 ml of diethyl ether were added. After a total reaction time of 45 minutes, 250 ml of 2M hydrochloric acid were added cautiously to the mixture and then 750 ml of water were added. The mixture was extracted with three 600 ml portions of dichlorcmethane and the combined extracts were washed with 300 ml of water, dried over magnesium sulphate and evaporated to give (3'S)--1' ,2' ,3' , 4'-tetrahydro-31-hydroxy-3'- [1-(hydroxy)ethyl] -5 1 , 8'-dimethoxyspiro[1,3-cithiolane-2,11-naphthalene] as a mixture of isomers in the form of a colourless gun which was used without further ourification.

The product obtained according to the preceding paragraph was dissolved in 100 ml of pyridine and 15 ml of acetic anhydride were added to the solution. The mixture was left to stand at room temperature overnight. 200 q of ice and then 2CO ml of 6M hydrochloric acid were added to the mixture. The resulting mixture was then extracted with three 200 ml portions of dichloromethane. The combined extracts were washed with 200 ml of 2M hydrochloric acid anc 200 ml of water, dried over magnesium sulphate and evaporated to give 11.6 g of (31S)- 3'-[1- (acstoxy)ethyl]-1,2,3,4-tetrahydro-3'-hydroxy-5',81-dimethoxyspiro[1,3-dithiolane- / 2 1410 - • 20- -2,l'-naphthal.ene] as a mixture of isomers in the form of a colourless gum which was used without further purification.

The product obtained according to the preceding paragraph was dissolved in 115 ml of tetrahydrofuran and the solution was added over a period of 10 minutes to a stirred suspension of 36.7 g of mercuric oxide and 36.7 g of mercuric chloride in a mixture of 1.15 1 of methanol and ICO ml i of water. The mixture was stirred at room temperature for 1.75 hours and then concentrated in vacuo to about half of its volume. The resulting mixture was diluted with 1.57 1 of dichloromethane and then filtered. The filtrate was washed with three 1 1 portions of water, dried over magnesium sulphate and evaporated to give 8.2 g of (3S)-3-[1-- (acetoxy) ethyl] —1, 2,3, 4 -1 a t r ahy dr o- 3 - hydroxy - 5 ,8-cimethoxy--1-oxo-naphthalene as a mixture of isomers in the form of a colourless oil which was used without further purification.

The product obtained according to the preceding paragraph was dissolved in 425 ml of tstrahydrcfuran and 1.9 g of sodium borchydrice were added to the solution. The mixture was stirred at room temperature under nitrogen for 2 hours. A further 1.9 g of sodium borohydrice were added to '« the mixture and stirring was continued for a further 1 hour. 160 ml of 2M hydrochloric acid were added gradually to the mixture, which was then extracted with three 160 ml portions of dichloromethane. The combined extracts were washed with 50 ml of water, dried over magnesium sulphate and evaporated. The residue was dissolved in 500 ml of toluene and 4.56 c of benzeneboronic acid, 0.16 g of p-toluenesulphonic acid and 0.5 mi of glacial acetic acid were added. The mixture was stirred at room temperature under nitrogen overnight and then washed with two 100 ml portions of 10% potassium hydrogen carbonate solution, dried over magnesium sulphate and evaporated to give a colourless oil weighing 9.5 g- The crude product obtained was dissolved in 100 ml of diethyl ether and the mixture was stirred at room temperature for 1 hour. After filtration, there were obtained 4.07 g of (IS) --cis-3- [ 1 (R) - (acetoxy) ethyl] -1,2, 3,4-tetrahycro-5 , 3-di-methoxy-1,3-naphthalenediyl benzeneboronate in the form of white crystals of melting point 176-179°C; [c] ^ = +65.5" (c =0.1% in chloroform) . The mother liquor was concentrated to 20 ml and filtered to give a second crop'weighing 2.10 g. Evaporation of the second mother liquor gave 3.4 g of residue which, after partial separation by column chromatography and subsequent fractional crystallization gave (IS) -cis-3- [ (1S)~ (acatoxy) ethyl] -1, 2,3 ,4-tetrahvdro-5 , 8-di-methoxy-1,3-naphthalenedivl benzeneboronate in the form of white crystals of melting point 143-149°C; = +22.8° (c = 0.1% in chloroform)'.

A solution of 11.94 g of ammonium eerie nitrate in 200 ml of water was added over a period of 5 minutes to a stirred solution of 4.32 g of the foregoing (IS)-cis-3- 214101 - [ (1R) - (acetoxy) ethyl ] -1,2,3, -i-tetrahydro-5 , 3-dinethoxy-l, 3--naphthalenediyl benzeneboronate in 200 ml of acetonitrils. The mixture was stirred at rccm temperature for a further 5 minutes and then poured into 1 1 of water- The resulting mixture was extracted with four 270 ml portions of dichloro-methane and the ccmbinec extracts were washed with 270 ml of water, dried over magnesium sulphate and evaporated to give (IS) -cis-3- [ (13.) - (acetoxy) ethyl] -1,2,3,4, 5,8-hexa-j hydro-5,8-dioxo-l,3-naphthalenediyl benzeneboronate in the form of a yellow oil which was used without further purification. 2.40 g of trans-1, 2-ciacetoxy-l, 2-dihvdroben2ocyclc-butene were added to a solution of the benzeneboronate prepared according to the preceding paragraph in 214 ml of xylene and the mixture was heated at 140°C under a nitrogen atmosphere for 3 hours. The solution was cooled and the solvent was removed by evaporation to give a yellow crystalline product which was washed with diethyl ether and filtered, there being obtained 3.5 g of (IS) -cis-3-[ (13.) - - (acetoxy) ethyl] -1,2,3,4,5,12-hexahydro-5,12-dioxc-l, 3--naphthacsnediyl benzeneboronate in the form of yellow crystals of melting point 175°-184°C; = +147.5° (c = 0.1% in chloroform). 3.6 g of the compound obtained according to the preceding paragraph were dissolved in a mixture of 175 ml • I ! .1 1 I i I ! / 2 14101 of dry pyridine and 90 ml of aceric anhydride. 175 nig of 10% palladium-on-carbcn were added and the mixture was hydrogenated at room temperature ana atnaspheric pressure for 1 hour. The catalyst was removed by filtration and the filter cake was washed with dichloroxaethane. The combined filtrates were evaporated and the residue was triturated with 50 ml of diethyl ether and filtered to give 3.71 g of (IS) -cis-5 ,12-diacetoxv-3- [ (13.) - (acetoxy) ethyl] -1,2,3,4--tetrahydro-1,3-naphthacenediyl benzeneboronate in the form of a pale brown solid of melting point 256°-2590C.

The compound prepared according to the preceding paragraph was dissolved in a mixture of 216 nil of glacial acetic acid and 68 ml of acetic anhydride. 2.88 g of finely ground chromium trioxide were added and the mixture was stirred ar. room temperature for 18 hours. The mixture was poured into 620 ml of water and the resulting suspension was extracted with fcur 320 ml portions of dichlorcmethane- The combined extracts were washed with four 450 ml portions of water, dried over magnesium sulphate and evaporated. The residue was trituracac with 50 ml of diethyl ether and filtered, there being obtained 1.77 g of (IS) -cis-5,12-diacetoxy-3-- [ (1R) - (acetoxy) ethyl] -1,2,3,4,5, ll-hexahydro-6,ll-dioxc--1,3-napnthacenediyl benzenebcronate in the form of a pale yellow solid of melting point 221°-223.5°C. 1 / I J 2 14101 J A solution cf the compound obtained according to the preceding paragraph in 340 nil of dichloromethane was cooled to -78°C. A solution of 7 g of boron trichloride in 28 ml of dichloromethane was added and the mixture was stirred and allowed to warm to 0°C over a period of 2.5 hours. The mixture was poured into 340 ml of ice-cold 2M hydrochloric acid and the layers were separated. The aqueous layer was extracted with two 280 ml portions of dichloromethane and the combined organic solutions were washed with two 250 ml portions of water, dried over magnesium sulphate and evaporated to give 1.7 g of crude (IS)-cis-3-[(1R)-(acetoxy)-ethyl] -1,2,3,4,6, ll-hexahydro-5,12-dihydroxy-o , 11-dioxo-l, 3--naphthacsnediyl benzeneboronate in the form of a red solid which was used without further purification. i 1.2 g of th- compound prepared according to the preceding paragraph were dissolved in a mixture of 120 ml of dichloromethane and 120 ml of methanol. 48 ml of 0.1M aqueous sodium hydroxide were added and the resulting deep purple solution was heated under reflux for 3 hours. The mixture was allowed to cool and glacial acetic acid was added until the solution became bright red. The solution was poured into 430 ml of water and the resulting mixture was extracted with two 240 ml portions of dichloromethane. The combined extracts were washed with 360 ml of water, dried over anhydrous sodium sulphate and evaporated to give - 25. - 2 14101 o 0.70 g of (IS)-cis-1,2,3,4,5,ll-hexahydro-5 ,12-diiydroxy-3-- [1 (R) -(hydroxy)ethyl]-5,11-dioxo-l,3-naphthacenediyl benzeneboronate in the fon of a red gum which was used without further purification.

Examnla 11 (i) 1.1 g of (IS)-cis-1,2,3,4,6,ll-hexahydro-5,12--dihydroxy-3-hydroxymethyl-S, 11-dioxo-l, 3-naphthacenediyl benzeneboronate were dissolved in 100 ml of dry pyridine containing 1.8 g of p-tolvl isocyanate. The mixture was heated at 80°C for 110 minutes and worked-up according to the procedure described in Example l(i) to give (IS)-cis--1,2,3,4,6,ll-hexahydro-5,12-dihvdroxy-6,ll-cioxo-3-(p--tolylcarbamovloxy)methy1-1,3-naphthacenediyl benzeneboronate in the form of a red gum. (ii) The compound obtained according to the procedure described in paracraon (i) was treated according to the (O procedure described in Example 1 (ii) to give 0.83 g of (15)--cis-1,2,3,4,6,11-hexahydrc-i,3,5,12-tetrahydroxy-5,11- -dioxc-3-(p-tolylcarbamoyloxy) methyInaphthacer.e in the fcm of red crystals of melting point 215-218°C; = + 132-9C (c = 0.05% in dioxan). - ■1; SMB.' 2 14101 Example 12 (i) 1.0 g of (lS)-cis-l,2,3,4,6,ll-hexahydre-5,12--dihydroxy-3-hydroxymethyl-5, ll-dioxo-l,3-naphthacenediyl benzeneboronate was dissolved in 100 ml of dry pyridine containing 1.5 g of o-nitrobenzyl isocyanate and the mixture was heated at 80°C for 1.5 hours. After working-up according to the procedure described in Example l(i), there was obtained (IS) -cis-1, 2 ,3,4,6, ll-hexahydro-5,12-dihvdroxy-3- - C (o-nitrobenzylcarbamoyloxy)methyl]-6, ll-cioxo-l, 3-naphthacenediyl benzeneboronate in the form of an orange gum. (ii) The compound obtained according to the procedure described in paragraph (i) was treated according to the procedure described in Example 1 (ii) to give 1-2 g of (IS) --cis-1, 2,3,4,6,11-hexahvdro-l, 3,5,12-tetrahydroxy-3- [ (o--nitrobenzyicarbamoyloxy) methyl] -6 ,11-dioxcnaphthacene in * the form of red crystals of melting point 123-125°C; [cjj^ = +91.1° (c = 0.05% in dioxan).

Exanrale 13 (i) 2.5 g of thiophene-3-carhcxylic acid azide in 80 ml of dry pyridine was heated at 75°C for 45 minutes. 1.65 g of (IS)-cis-1, 2 , 3, 4 , 6 , ll-hexahydro-5,12-dihydroxy-3--hvdroxymethyl-6 ,11-dioxo-l, 3-naphthacenediyl benzeneboronate were added and the mixture was heated at 70°C for 80 minutes. After working-up according to the procedure described in Example l(i), there was obtained (IS)-cis-1,2,3, 214101 4,6, ll-hexahvdro-5 ,12— dihvdroxy—3— (3—thienylcarbamovloxv) — methy 1-6,11-dioxo-l, 3-naphthaceneciyl benzeneboronate in the form of a red gum. (ii) The compound obtained according to the procedure described in paragraph (i) was treated according to the procedure described in Example l(ii) to give 1.56 g of (1S)--cis-1, 2,3,4,6,11-hexahydro-l, 3, 5 r12-tetrahydroxy-3- (3--thienylcarbamoyloxv) methy 1-6 ,11-dioxonaphthacene in the form of orange-red crystals of melting point 138-141°C; [cc]q0 = +118.8° (c = 0.049% in dioxan).

Exams le 14- (i) 1.0 g of (IS) -cis-1,2,3,4, 6, ll-hexahycro-5,12--dihydrcxy-3-hydroxymethyl-6,11-dioxo-l, 3-naphthaceneciyl benzeneboronate was suspended in 200 ml of dichloromethane and 0.5 g of trichloroacetvl isocyanate was added- After stirring at room temperature for 1 hour, a clear red solution was obtained. The solvent was removed by evaporation and the residue was dissolved in a mixture of 15 ml of dichloromethane, 15 ml of 2-methy 1-2,4-pentar.ediol and 3 ml of acetic acid. The resulting mixture was left to stand at room temperature overnight. The solution was then diluted with 100 ml of dichloromethane and washed with four 75 ml portions of water. After drying over anhydrous sodium sulphate, the solvent was removed by evaporation and the residue was triturated with a'mixture of ethyl acetate and 2 1410 diethyl ether, there being obtained 1.1 g of (LS)-cis-3-- (trichloroacetylcarbamovloxv) methvl-1,2,3,4,6,11-hexahydro--1, 3 , 5 ,12-tetrahycroxy-6 ,11-aioxonachthacene in the fom of a red powder of melting point 125—128°C; [cc]^ = +51.9° (c = 0.05% in dioxan).

Example 15 (i) 1.0 g of (IS) -cis-1, 2, 3 ,4 , 6 , ll-hexahydro-5 ,12--dihydroxy-3- [1 (S)- (hydroxy) ethyl] -6,11-dioxo-l, 3-naphrha- 0 cenediyl benzeneboronate was treated with 1.5 g of phenyl O isocyanate according to the procedure described in Example ; 1(3(1)"" to give crude (IS) -cis-1, 2,3,4,6, ll-hexahydro-5 ,12--dihydrcxy-6 , ll-dioxo-3- [1 (S) - (phenylcarbamoylcxv) ethyl] --1,3-naphthacenediyl benzeneboronate in the form of a red gum which was used without further purification. (ii) The benzeneboronate obtained according to paragraph (i) was treated according to the procedure described ^ in Example 10'(ii) to give 0.925 g of (IS)-cis-1,2,3,4,6,11- -hexahydro-1, 3,5,12-tstrahydroxy-6 , ll-dioxo-3-Cl(S) - (phenyl carbamoyloxy) ethyl] naphthacene in the form of a red powder of melting point 155-160°C; [c]^ = +61-9° (c = 0.05% in dioxan).

O 214101 The (IS ) -cis-1, 2,3,4,6, ll-hexahydro-5,12-dihydroxy--3- [1 (S) - (hydroxy) ethyl] - 6 ,11-dioxo-l, 3-naahthacenedivl benzeneboronate used as the starting material in paragraph (i) was prepared as follows: The (IS) -cis-3- [1(S) - (acetoxy) ethyl]-1,2,3,4-tetra-hydro-5,8-dimethoxv-l,3-naphthal:enediyl benzeneboronate obtained as described in Example 10 was treated according to an analogous sequence of reactions as described for the corresponding (IS)-cis-3-[1 (R) - (acetoxy) ethyl]-isomer to give the following compounds: (IS) -cis-3- [1 (S) - (acetoxy) ethyl]-1, 2,3,4,5,12-hexa-hvdro-5 ,12-dioxo-l, 3-naphthacer.ediyi benzeneboronate as yellow crystals of melting point 172-174°C; = +98.7° (c = 0.05% in chloroform); (IS) -cis-5 ,12-di ace toxy-3- [1 (S) - (acetoxy) ethyl] -1,2, 3,4-tetrahvdro-l,3-naphthacenediyl benzeneboronate as pale yellow crystals of melting point 238-240°C; Ec]D = +208.2° (c = 0.05s in chloroform); (IS) -cis-5 ,12-di ace toxy-3- [1 (S) - (acetoxy) ethyl] -1,2,3, 4,6, ll-hexahydro-5 ,11-dioxo-l, 3-naphthacenediyl benzeneboronate as pale yellow crystals of melting point 178-180°C; [c]p^ = +146.6° (c = 0.05% in chloroform); and (IS) -cis-1,2, 3,4,6, ll-hexahydrc-5,12-diir/droxy-3-- [1 (S) - (hydroxy) ethyl] -6 ,11-dioxo-l, 3-naphthacenediyl benzeneboronate as red crystals of melting point 224-226°C; [a]^°= +269 .9° (c = 0.05% in dioxan). • •• / > - ■ I ' ■... v ; - 214101 4fH SIP — JQ — ^R^SwZBE.

Claims (10)

WHAT WE CLAIM IS:

1. Coiacounds of the general formula or X—o — Ra 10 15 wherein R represents a hydrogen a torn, a trichloroacetyl, lower alkyl, aryl or aryl-(lower alkyl) group, a 5-memJbered or 6-mesiberad hetercarcmstic group in which the hetero atom is oxygen or sulphur, or a grouo of foraula -(CH_) -COR1 / n (a) /C-NH—(CH2)n,- Cb) - 31 - 214101 'lu wherein R' represents a hydroxy, lower alkoxy, amino, lower alkylamino, di (lower alkyl) r-amino or arylamino group, n stands for an integer of 1 to 4, n' stands for an integer of 2 to 10, and x represents a group of the formula CH 3 -ch2-, -ch- or -CH2"CH2-, (i) (ii) (iii) / with the proviso that any carboxy, hydroxy or amino group present on'-an aryl substituent is in .protected form and a carboxy group present on group (a) is in protected form. O o 214101 - 32 -

2. Compounds according to claim 1, wherein Ra represents a lower alkyl, aryl or aryl-(lower alkyl) group, a 5-membered or 6-membered heteroaromatic group in which the hetero atom is oxygen or sulphur or a group of formula (a).

3. Compounds according to claim 2, wherein Ra represents an aryl group.

4. Compounds according to claim 3, wherein Ra represents phenyl.

5. Compounds according to any one of claims 2 to 4, wherein X represents a group of formula (i) or (ii) given in claim 1.

6. Compounds according to any one of claims 1 to 5, wherein X is -CI^-.

7. Compounds according to claim 6, wherein Ra is phenyl, 4-chlorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-acetoxy-phenyl, methyl, 2-thienyl, 3-thienyl,2-(methoxycarbonyl)-ethyl, 2-(propylcarbamoyl)-ethyl, p-tolyl, o-nitrobenzyl or trichloroacetyl.

8. Compounds according to any one of claims 1 to 5, wherein X is -chj-chj-. 214101 'diii - 33 -

9. Compounds according to claim 8, wherein Ra is phenyl.

10. The 1,2,3,4,6,11-hexahydro-l,3,5,12-tetrahydroxy 6,11-dioxo naphthacene derivatives of formula I given in claim 1 as described in Examples 1 to 15. dated this ^ day of ^ A. J. PARK & SON per agents for the applicants