IE50972B1 - Benzo-fused bicyclononanes - Google Patents

Description

This invention relates to compounds which can be used as intermediates in the preparation of the benzo-fused carbacyclin analogues described and claimed in GB-A-2121802.

Novel compounds according to the present invention are those of formulae A, B, C and D: wherein either Rg and R4 are independently selected from hydrogen, methyl and fluorine, provided that CRgR4 is not CFMe, and is C2_g alkyl, cis-CH^CH-CH^-CH-j, -(CH2)-CHOR1q-CH3 and R^g is an acid-hydrolysable blocking group, - (CH.,) 3-CH=CH (CHg) 2 or optionally ringsubstituted phenoxy, phenyl, benzyl, phenylethyl or phenylpropyl in which there are no more than 3 ring substituents (no more than 2 of which are alkyl) independently selected from chlorine, fluorine, trifluoromethyl, Cg_3 alkyl and Cg_3 alkoxy, provided that neither R3 nor R4 is fluorine when R? is optionally substituted phenoxy; or CR3R4~R7 is 2-(2-furyl)ethyl, 2-(3-thienyl)ethoxy, 3-thienyloxymethyl, or C4_7 cycloalkyl optionally carrying up to three alkyl substituents; M, is a-OR1n:B-Rc or a-Rc:B-OR._ in which Rc is 6 10 5 5 10 5 hydrogen or methyl and RgQ is as defined above; R^g is H, OH, CH2OH, OR^q M CH2°R10 an^ R10 an acid-hydrolysable blocking group; R20 is H, α-OH, β-OH or =0; R33 is GHO or CHgORg, and R32 is hydrogen or n replaceable blocking group; Z4 is -CH2~ or -(CH2)g-CF2- and f is zero, 1, 2 or 3; and X. is COOR., CH_0H, CH_NL_L, or COL.; 1 2 2 2 3 4 in which R^ is hydrogen, a pharmacologically acceptable cation, C1-12alky)-> C3_io cycloalkyl, C?_12 aralkyl, phenyl optionally substituted up to three times 80972 by chlorine atoms or Cj_4 alky] radicals, or phenyl substituted in the para-position by -NHCOR2g, -COR2g, benzoyloxy, acetamidobenzoyloxy or -CH=N-NH-CONH2 in which R2c; is methyl, phenyl, acetamidophenyl, benzamido5 phenyl or -NH2 and R2g is methyl, methoxy, phenyl or -nh2; L2 and are independently selected from hydrogen and Cj_4 alkyl; and L4 is -NR27R28, -NR2gCOR£7, -NR2gSO2R£7 or cyclo10 amino selected from pyrrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino and 3,4-didehydropiperidinyl optionally substituted by one or two Ci-12 alkyl radicals, in which R27 is hydrogen, C3_32 alkyl, C3_lo cycloalkyl, C7_12 aralkyl, phenyl optionally substituted by up to three substituents selected from chlorine, Cj_3 alkyl, hydroxy, carboxy, (Cj_4 alkoxy)carbonyl and nitro, carboxy(Cj_4 alkyl), carbamoyl(C^_4 alkyl), cyano (C^_4 alkyl)-, acetyl(Cj_4 alkyl), benzo (C3_4 alkyl) optionally substituted by up to three substituents selected from chlorine, C^_3 alkyl, hydroxy, Cj_3 alkoxy, carboxy, (c^_4 alkoxy)carbonyl and nitro, pyridyl optionally substituted by up to three substituents selected from chlorine, 3 alkyl and Cj_3 alkoxy, pyridyl(C^_4 alkyl) optionally substituted by up to three substituents selected from chlorine, C^_3 alkyl and hydroxy, or mono-, di- or tri-hydroxy(C^_4 alkyl), R27 is R27 other than hydrogen, R2g is hydrogen or C4_32aTltyl, and R29 is hydrogen or Cj_4 alkyl.

The nomenclature used for the prostacyclin and carba30 cyclin analogues described herein is the same as in GB-A-2070596, Reference should also be made to that specification for a description of examples of the various groups in the compounds of the invention, andalso for a description of blocking group introduction and removal.

The preparation of compounds of formula D will be described with reference to the accompanying Chart, in which R_o is a silyl protective group, as defined in 2 o GB-A-2070596.

With respect to the Chart, the formula CLXXI compound is known in the art, or prepared by methods known in the art; see US-A-4181789. This compound is conveniently transformed to the corresponding formula CLXXII methylene and formula CLXXIII hydroxymethyl compounds by methods known in the art. Such procedures are described in US-A-4012467 and US-A-4060534. iO The formula CLXXIII compound thus prepared is converted to the formula CLXXIV mesylate by methods known lii the art, e.g. reaction with methanesulfonyl chloride in a tertiary amine base such as triethylamine. Alternatively, other sulfonated derivatives corresponding to the formula CLXXIV compound are prepared, preferably from readily-available sulfonating reagents such as the corresponding sulfonyl chlondeo. For example, the corresponding tolulenesulfonate may be prepared.

Thereafter, the formula CLXXIV mesylate (or other sulfonate) is selectively hydrolysed to yield the formula CI.XXV phenol derivatives. Selective hydrolysis of R2g silyl ether groups in the presence of protected R^g or hydroxyl groups is accomplished by methods described in GB-A-2070596, i.e. the use of tetra-n-butylammonium flucnde. The formula CLXXV phenol derivative is then cyclised to yield the formula D compound. Cyclisation proceeds most conveniently by treatment with base at elevated temperatures. for example, n-butyllithium, sodium hydride or potassium hydride, is conveniently employed, at the reflux temperature, in an organic solvent sue), as tetrahydrofuran or glyme.

Compounds of formulae A, B and C in which R^g is CH2ORg2 and Rg2 is a replaceable blocking group are prepared by conversion of a compound of formula CCl, first by ω-carboxyalkylation. Methods known in the art are employed, e.g. methods for preparing 3,7-interphenylene-PGFu compounds and corresponding phenolic intermediates. For example, the preparation proceeds by 'reaction of the formula CCl compound with sodium hydride and the alkyl bromoalkanoate corresponding to the —Z^-COORj group to be introduced into the molecule. Thereafter, the corresponding compound in which R^-j is CH2OH by deprotection, e.g. hydrolysis under mild acidic conditions of the protective group, followed by transformation to various otiier C-1 derivatives by methods described in GB-A-2079596.

Compounds of formula A, B and C in which is CHO may be prepared by ozonolysis, by methods otherwise known in the art, of a corresponding compound as claimed in any of claims 1 to 3 of GB-A-2121802 in which Yg is transCH=CH.

The following Examples illustrate the invention. EXAMPLE 1 Refer to the Chart.

A. A solution of methyl phenyl-N-methylsulfoxinune (3.39 g) in dry tetrahydrofuran (60 nil) is alternately degassed and flushed with nitrogen, cooled to -78°C and treated dropwise over 7 min wi-h 2.8 M methylmagnesium chloride (7.16 ml). The resulting solution is stirred at -78°C for 30 min, then at 0JC for 15 min. The reaction is cooled to -78’C and treated with a solution of 3-oxa-1,2,4,5,6, -pentanor--3,7-inter-i.. phenylene-PGEg, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether) (6.05 g), a iormula Cl,XXI compound, in dry tetrahydrofuran i35 ml). The resulting mixture is stirred for 1.75 hr while the temperature is permitted to rise from -78 to 0°C, and is then stirred for 1 hr at 0’C. The reaction mixture is then diluted with brine (170 ml) and extracted with diethyl ether. The ethereal extracts are then washed successively with brine (170 ml), 0.5 M aqueous potassium bisulfate (170 ml), saturated aqueous sodium bicarbonate (170 ml) and brine (170 ml), dried over magnesium sulfate, filtered and concentrated to a yellow oil (8.0 g), 9-(N-methylphenylsu1fox imi nomethyl)-3-oxa-l,2,4,5,6-pentanor-3,7-inter-m6 phenylene-PGFlt 3-(t-butyldimethylsilyl ether), ll,15-bis(tetrahydropyranyl ether). A degassed solution of 9-[(N-methyl)phenylsulfoximinomethyl]-3-oxa-l,2,4,5,6-pentanor-3,7-inter-m-phenyiene-PGF1, 3-(t-butyldimethylsi1yl ether), ll,15-bis(ti.vrahydropyranyl ether) (8.0 g) in tetrahydrofuran (150 ml) is cooled to O’C, treated with 50% acetic acid/water (45 ml) then immediately with aluminum amalgam unccf nitrogen. (The aluminum amalgam is prepared by washing 20 mesh alumina, 8.00 g, with diethyl ether, 170 ml, methanol, 340 ml, mercuric chloride, 8.03 g, in water, 275 ml, methanol, 170 ml, and diethyl ether, 170 ml).

The resulting black suspension is stirred for 1.75 hr during which the reaction temperature is permitted to go from 0° to 15°C (slowly) then cooled to 0°, treated with ethyl acetate (210 ml) and stirred for an additional 30 min at O’C. The suspension is filtered through diatomaeous earth and the filter cake washed with ethyl acetate. The combined filtrate is then washed with brine (300 ml), 0.5 M aqueous potassium bisulfate (300 ml), saturated aqueous sodium bicarbonate (300 ml) and brine (300 ml), dried, filtered, and concentrated to a yellow oil, crude formula CLXXII compound (6.03 g), 9-deoxy-9-methylene-3~oxa-l,2,3,4,5,6-pentanor-3,7-inter-m-phenylene-P GFj, 3-{t-butyldimethylsilyl ether), ll,15-bis(tetrahydropyranyl ether). The crude product is combined with that from a repeat preparation to yield 10.1 g of formula CLXXII product which is chromatographed on silica gel eluting with 5% ethyl acetate in Skellysolve 8 (SSB, isomeric hexanes) to yield 6.93 g of 9-deoxy9-methylene-3-oxa-l,2,4,5,6-pentanor-3,7-inter-m-'phenyl ene-PGFj, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether). NMR absorptions are observed at 4.52-5.12 and 6.53-7.306. Infrared absorptions are observed at 1600 and 1655 cm1. Silica gel TlC is 0.39 in 10% ethyl acetate in hexane.

B. A degassed solution of 9-deoxy-9-methylene-3-oxa-l,2,4,5,6pentanor-3,7-i nter-m-phenylene-PGF j, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether), the reaction product of Part A, (1.33 g) in dry tetrahydrofuran (70 ml) is cooled to O’C and treated under nitrogen with 0.5 M 9-borabicyclo[3.3.ijnonane (14 ml), dropwise over 5 min. The colorless solution is stirred for 4.5 hr at 0° and treated with 301 hydrogen peroxide (6 ml) followed by 3 N potassium hydroxide (6 ml). The resulting suspension is stirred for an addi7 tional 30 min at 0°C and for 75 min while warming to room temperature. The reaction mixture is transferred to a separatory funnel, diluted with brine (300 ml) and ethyl acetate (300 ml). The layers are separated, and the aqueous layer extracted with ethyl acetate (600 ml). The organic extracts are washed with brine (6 ml), dried, filtered, and contrated to formula CLXXIII product, a colorless oil (3.3 g), 9-deoxy-9a-(hydroxymethyl)-3-oxa-l,2,4,5,6-pentanor-3,7i.iter-m-phenylene-PGFj, 3-(t-butyldimethyl silyl ether), 11,15-bis(tetrahydropyranyl ether). The crude formula CLXXIII product is chromatographed on silica gel (300 g) in 35% ethyl acetate in hexane to yield 1.26 g of 9-deoxy-9a-(hydroxymethyl)-3-oxa-l,2,4,5,6pentanor-3,7-inter-m-phenylene-PGFx, 3-(t-butyl dimethylsilyl ether), ll,15-bis(tetrahydropyranyl ether) as a colorless oil. NMR absorptions are observed at 4.73, 5.12-5.70, 6.52-7.236. Infrared absor15 ptions are observed at 3480 and 1670 cm 1. Silica gel TLC Rf is 0.21 in 35% ethyl acetate in hexane.

C. A degassed solution of 9-deoxy-9a-hydroxymethyl-3-oxaI, 2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFx, 3-(t-butyldimethylsilyl ether), ll,15-bis(tetrahydropyranyl ether) (2.01 g), reaction product of Part B, in dry methylene chloride (45 ml) is cooled to -5°C under nitrogen and treated with triethylamine (0.72 ml), then with methanesulfonyl chloride (0.76 ml). The resulting solution is stirred at -5°C for 5 min then for 75 min while warming to ambient temperature. The reaction solution is poured over ice, and the resulting mixture swirled for a few minutes then transferred to a separatory funnel and partitioned between diethyl ether and brine. The layers are separated, and the aqueous layer extracted with ether (400 ml). The organic layer is washed with brine (200 ml) and saturated aqueous sodium bicarbonate (400 ml), dried, filtered, and conctrated to a formula CLXXIV product, a colorless oil (2.69 g), 9-deoxy-9a-mesyloxymethyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m- phenyl ene-PGFj, 3-{t-butyldimethylsilyl ether), ll,15-bis(tetrahydropyranyl ether). This product (2.69 g) is chromatographed on silica gel (185 g) eluting with 25% ethyl acetate in Skellysolve B to yield 1.99 g of 9-deoxy-9az -mesyloxymethyl-3-oxa-l,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFj), II, 15-bis(tetrahydropyranyl ether). NMR absorptions are observed at 2.95, 4.70, 5.20-5.70, ana 6.52-7.22a. Silica gel TLC Rf is 0.30 in 35% ethyl acetate in hexane. 0. A degassed solution of 9-deoxy-9a-mesyloxymethyl-3-oxa1.2.4.5.6- pentanor-3,7-inter-m-phenylene-PGFi, 3-(t-butyldimethylsilyl ether), ll,15-bis(tetrahydropyranyl ether) (0.971 g), the reaction product of Part C, in dry tetrahydrofuran (35 ml) is cooled to 0°C and treated under nitrogen with 0.75 M tetrabutyl ammonium fluoride (2.6 ml). The resulting amber solutoin ’S stirred for 2.5 hr at 0-5 eC and is partitioned between ethyl acetate (150 ml) and brine (150 ml). The layers are separated, and the aqueous layer extracted with ethyl acetate (300 ml). The organic layer is then washed with 0.5 M aqueous aitmonium chloride (150 ml), saturated aqueous sodium bicarbonate (300 ml) and brine (150 ml), dried, filtered and concentrated to give 0.82 g of fonnula CLXXV product, 9-deoxy-9a-mexyloxymethyl-3-oxa-l,2,4,5,6pentanor-3,7-i nter-m-phenylene-PGF j, 11,15-bis(tetrahydropyranyl ether. Infrared absorptions, are observed at 3330 cm*1. Silica gel TLC Rf is 0.37 in 50% ethyl acetate in hexane.

E. A degassed solution of 9-deoxy-9a-mesyl oxymethyl-3-oxa1.2.4.5.6- pentanor-3,7-inter-m-phenylene-PGF[, 11,15-bi s(tetrahydropyranyl ether) (0.82 g), reaction product of Part D, is cooled to -40“C under argon and treated with 57% sodium hydride (0.67 g). The resulting suspension is then stirred for 40 min at -40°C then 15 min at 0°C. The suspension is stirred for an ’dditional 20 min while warming to room temperature and then stirred for 2.5 hr at reflux. The reaction is then cooled to 10°C, diluted with ice cold brine (200 ml) and extracted witn ethyl acetate (450 ml). The ethyl acetate extracts are then washed with brine (300 ml), dried, filtered and concentrated to give 0.72 g of the formula CLXXVI crude product. The crude product is chromatographed in silica gel (175 g) in 25% ethyl acetate in Skellysolve B to yield 0.49 g of 9-deoxy-2',9a-methano-3oxa-1,2,4,5,6-pentanor-3,7-(1',3'-inter-phenylene)-PGF,, 11,15-bis(tetrahydropyranyl ether). NMR absorptions are observed at 4.77, 5.32-6.03, and 6.52-7.226. Infrared absorptions are observed at 3340 and 1670 cm*1. Silica gel TLC Rg is 0.56 in 35% ethyl acetate in hexane. 50S7g EXAMPLE 2 9-Deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7(1',3'-inter-phenylene)-16,16-difluoro-PGF^ Refer to the Chart.

A. Diethyl ether (55 ml), tri-n-butylphosphine (2.28 5 g) and cuprous iodide (2.13 g) are combined with stirring. The resulting mixture is alternately degassed and flushed with nitrogen at 25°C for 1 hr. The resulting solution is then cooled to -78°C and is hereafter referred to as solution 32-1. Separately, 60 ml of anhydrous diethyl ether and 6.47 g of m-bromophenol, t-butyldimethylsilyl ether are combined; the resulting solution is alternately degassed and flushed with nitrogen and cooled to -78°C. ;After ί cooling, the resulting mixture is treated with 44.16 ml of a 1.02 M solution of t-butyllithium in n-pentane.

This reaction mixture is then stirred at -78°C for 1 hr and hereafter referred to as solution 32-11. Solution 3?-II is then transferred with stirring over 15 min to solution 32-1 under a nitrogen atmosphere. The resulting solution changed in colour from clear to yellow to an orange-brown to tan. The resulting mixture is then stirred at -78°C fcr 30 min and labelled solution 32-111. Thereafter 4a-hydroxy-3B-(4‘,4'-difluoro-3‘ahydroxy-trans-l'-octenyl)-2-methylene-cyclopentanone, 4,3'-bis(tetrahydropyran-2-yl ether), 4 g, Example 25 of United States Patent 4,181,798, and 38 ml of anhydrous dry ethyl ether are combined with stirring and the resulting mixture alternately degassed and flushed with nitrogen and thereafter cooled to -78“C. The resulting solution is referred to herein as solution·32-1V. Solution 32-IV is then added to solution 32-111 with vigorous stirring over 25 min at -78°C under a nitrogen atmosphere. The reaction mixture is then stirred at -78°C for 30 min and thereafter transferred to 100 ml of 8% glacial acetic acid in diethyl ether (-40°C) with vigorous stirring under a nitrogen atmosphere. The resulting mixture is then diluted with brine and extracted with diethyl ether· The ethereal extracts are then washed with aqueous sodium bicarbonate in brine, dried over sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel eluting with 20% ethyl acetate in Skellysolve 8 to yield 5.56 g of pure formula CLXXI compound: 16,16-difluoro-3-oxa-l,2,4,5,6-pentanor3,7-inter-m-phenylene-PGEi, 3-(t-butyldimethylsilyl ether), 11,15bis(tetrahydropyran-2-yl ether). NMR absorptions (CDCl3) are observed at 0.18, 3.1-5.0, 5.67, 6.52-6.88, and 6.88-7.2 6. Infrared absorptions are observed at 1745, 1600, 1585, 1490, 1275, 1260, 1200, 1155, 1125, 1075, 1035, 1025, 975, 840, and 780 cm’i. Silica gel TLC Rf is 0.36 and 0.41 in 25% ethyl acetate in Skellysolve B. Silica gel TLC Rf is 0.5 in 5% acetone in methylene chloride B. Following the procedure of Example 31, Part A, 3.47 g of the reaction product of Part A of this example is converted to 2.98 g of formula CLXXI! product as a colorless oil, 9-deoxy-9-methylene-3-oxal,2,4,5,6-pentanor-3,7-inter-m-pheny1ene-16,16-difluoro-PGFi, 3-(tbutylsilyl ether), ll,15-bis(tetrahydropyranyl ether). NMR absorptions are observed at 0.17, 0.97, 1.0-3.2, 3.2-4.4, 4.4-5.0, 5.3-6.0, and 6.4-7.36. Infrared absorptions are observed at 1655, 1605, 1585, 1485, 1275, 1260, 1200, 1144, 1125, 1080, 1025, 970, 870, and 780 cm’1. Silica gel TLC Rf is 0.31 and at 0.36 in 10% ethyl acetate in hexane.

C. Following the procedure of Example 31, Part B, 2.83 g of the reaction product of Part B of this example is converted to 2.5 g of formula CLXXIII product as a colorless oil, 9-deoxy-9a-(hydroxymethyl }-3-oxa-l, 2, 4,5,6- pentanor-3, 7- inter-m- pheny I ene-16,16-di fluoro11 PGFj, 3-(t-butyldimethyl silyl ether), ll,15-bis(tetrahydropyranyl ether). NMR absorptions (CDC13) are observed at 0.18, 0.98, 1.15-3.0, 3.0-4,5, 4.5-5.0, 5.3-5.9, and 6.4-7.36. Infrared absorptions are observed at 3460, 1670, 1500. 1585, 1485, 1275, 1260, 1160, 1135, · 1125, 1075, 1025, 975, 840, and 780 cm1· Silica gel TLC Rf is 0.28 in 35X ethyl acetate in hexane. * D. Following the procedure of Example 31, Part C, the reaction product of Part C of this example (2.29 g) is converted to 1.83 g of formula CLXXIV product as a colorless oil, 9-deoxy-9a-mesyloxymethyl10 S-oxa-l.Z^.S.S-pentanor-S.T-inter-m-phenylene-lS.lS-difluoro-PGFg, 3-(t-butyldimethylsilyl ether), 11,15-bis(te^, ahydropyranyl ether). NMR absorptions are observed at 0.18, 0.98, 1.15-2.85, 2.95, 311-4.5, 4.5-5.0, 5.2-5.9, and 6.5-7.46. Infrared absorptions are observed at 2930, 2860, 1605, 1590, 1490, 1465, 1440, 1360, 1275, 1200, 1175, 1120, 1025, 975, and 840 cm1. Silica gel TLC Rf is 0.28 in 30% ethyl acetate and hexane.

E. Following the procedure of Example 31, Part D, 1.7 g of the reaction product of Pari D of this example is converted to 1.6 g of formula CLXXV product as a yellow oil, 9-deoxy-9a-mesyloxymethyl-320 oxa-l^.d.S.fj-pentanor-S^-inter-m-phenylene-lS.lS-.iifluoro-PGFg, ll,15-bis(tetrahydropyranyl ether). Silica gel TLC R£ is 0.34 in ethyl acetate and hexane (1:1).

F. Following the procedure of Example 31, Part E, 1.52 g of the reaction product of Part D of this example is converted to 0.83 g of formula CLXXVI product as a white foam, 9-deoxy-2',9a-methano-3-oxaI, 2,4,5,6-pent a nor-3,7-(11,3' - inter-phenyl eneLie.ie-difluoro-PGFg, II, 15-bis(tetrahydropyranyl ether). NMR absorptions are observed at 0.95, 1.05-2.9.5, 3.5-5.0, 5.3-6.0, and 6.5-7.26. Infrared absorptions are observed at 3350, 2930, 1670, 1615, 1590, 1465, 1280, 1200, 1120, 1070, and 975 cm*1. The mass spectrum exhibits - peaks at 534, 451, 446, 402, and 348. Silica gel TLC R£ is 0.26 in ethyl acetate and hexane (1:3) and 0,40 in acetone and methylene chloride (1:19).

EXAMPLE 3 As described in GB-A-2121802, the reaction product of Example 1 may be converted to 9-deoxy-9',9a-methano-3oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF^ methyl ester, 11,15-bis(tetrahydropyranyl ether). Ozone is bubbled through a solution of 0.72 g of that reaction product in 50 ml of absolute methanol at -78°C for 5 min. Thereafter, oxygen is bubbled through the resulting solution for 5 min and the solution is treated with 16 ml of dimethyl sulfide. After standing for 16 hrs at 0eC under a nitrogen atmosphere and for 2¾ hrs at ambient temperature, the solution is diluted with 200 ml of ethyl acetate, washed successively with 100 ml of brine, 100 ml ί of saturated aqueovs sodium bicarbonate and 100 ml of brine, dried ever anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on 175 q of silica gel eluting with 35% ethyl acetate in hexane to yield 367 mg of a colourless oil, 9-deoxy-2’,9a-methano3-oxa-4,5,6,13,14,15,16,17,18,19,20-undecanor-3,7-(1',3'20 inter-phenylv.ie)-12-formyl-PGF|, methyl ester. NMR absorptions (CLCl^) are observed at 1.0-3.0, 3,1-4.5, 3.63, 6.45-7.34 and 9.776, The mass spectrum exhibits peaks at 388 ar.d 304. Silica gel TLC R^ is 0.19 and 0.22 in 25% and 30% ethyl acetate in hexane.

\Z 1 ii 34 : «6 R18 CHART CLXXI CLXXII CLXXIII 50973 CLXXIV Ψ He Φ CLXXV ι t ! )

Claims (4)

1. CLAIMS wherein R^g is H, OH, CHjOH, OR 10 or CHjORjq and Rjq is an acid-hydrolysable blocking group; R 20 is Η, α-ΟΗ, β-ΟΗ or =0; R 33 is CHO or CH 2 OR 32 and R 32 is hydrogen or a replaceable blocking group; Z 4 is -CH 2 - or -(CH 2 ) £ -CF 2 - and f is zero, one, 2 or 3; and Xj is COORj, CH 2 OH, CH 2 NL 2 L 3 or COL 4 ; in which Rj is hydrogen, a pharmacologically acceptable cation, c 1_ 12 alkyl, C 3_3q cycloalkyl, C 7_i2 aralkyl, phenyl optionally substituted up to 3 times by chlorine atoms or Cj_4 alkyl radicals, or phenyl substituted in the para-position by -NHCOR 2 g,-COR 2 g, benzoyloxy, acetamidobenzoyloxy or -CH=N-NH-CONH 2 in which R 2g is methyl,phenyl, acetamidophenyl, benzamidophenyl or -NH 2 and R 26 is methyl, methoxy, phenyl or -ϊ'Η 2 ; L 2 and L 3 are independently selected from hydrogen and Cj_ 4 alkyl; and L 4 is -NR^R^, -NR^COR^, -NR2gSO 2 R 27 or cycloamino selected from pyrrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino and 3,4-didehydropiperidinyl optionally substituted by one or 2 Cj_ 12 alkyl radicals, in which R 27 is hydrogen, c 1-12 alkyl, c 3_ 1 q cycloalkyl, aralkyl, phenyl optionally substituted by up to 3 substituents selected from chlorine, Cy_ 3 alkyl, hydroxy, carboxy, (C 3 _ 4 alkoxy)carbonyl and nitro, carboxy(C 3 _ 4 alkyl), carbamoyl(C 3 _ 4 alkyl), cyano (C^ 5 alkyl), acetyl(C 1 _ 4 alkyl), benzo(C 1 _ 4 alkyl) optionally substituted by up to 3 substituents selected from chlorine, c 3_ 3 alkyl, hydroxy, Cj_ 3 alkoxy, carboxy, (0^_ 4 alkoxy)carbonyl and nitro, pyridyl optionally substituted by up to 3 substituents selected from 1° chlorine, C 3 _ 3 alkyl and C 3 _ 3 alkoxy, pyridyl(C 3 _ 4 alkyl) optionally substituted by up to 3 substituents selected from chlorine, C 1-3 alkyl and hydroxy, or mono-, di- or tri-hydroxy(C 3 _ 4 alkyl), R 27 is R 27 other than hydrogen, R 28 is hydrogen or C 3 _ 12 alkyl, and R 2g is hydrogen or 15 C 3 _ 4 alkyl.

2. A compound of the formula wherein R^g, R 33/ Z 4 and are as defined in claim 1.

3. A compound of the formula either Rg and R^ are independently selected from hydrogen, methyl and fluorine, provided that CR,R 4 is not CFMe, and R? is C 2 _ g alkyl, cis-CH=CH-CH 2 ~CH 3 , 10 -(CH 2 )-CHORgg-CHg and R 1Q is an acid-hydrolysable blocking group, -(CH 2 )g-CH=CH(CHg) 2 or optionally ring-substituted phenoxy, phenyl, benzyl, phenylethyl or phenylpropyl in which there are no more than 3 ring substituents (no more than 2 of which are alkyl) independently selected from 15 chlorine, fluorine, trifluoromethyl, C 1 _ 3 alkyl and C 1-3 alkoxy, provided that neither R 3 nor R 4 is fluorine when R? is optionally substituted phenoxy; or CR^R^-R? is 2-(2-furyl)ethyl, 2-(3-thienyl)eth oxy, 3-thienyloxymethyl, or cycloalkyl optionally carrying up to 3 alkyl substituents; M, is α-OR, . : f3-R_ or a-R_ : β-OR, . in which R, is 6 1U b b 1U b

4. 5 hydrogen or methyl and is as defined above.