INDENE ANALOGS OF MEVALONOLACTONE AND DERIVATIVES THEREOF

Abstract: Compounds of formula (I), wherein R is hydrogen or primary or secondary C1-6alkyl, R1 is primary or secondary C1-6alkyl or R and R1 together are (CH2)m or (Z)-CH2-CH=CH-CH2- wherein m is 2, 3, 4, 5 or 6, Ro is C1-6alkyl, C3-7cycloalkyl or ring A (II) each or R2 and R4 is independently hydrogen, C1-4alkyl, C1-4alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, each of R3 and R5 is independently hydrogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R6 is hydrogen, C1-2alkyl, C1-2alkoxy, fluoro or chloro, with the proviso that there may only be one each of trifluoromethyl, phenoxy or benzyloxy on each of the phenyl and indene rings X is -(CH2)n - or - (CH2)qCH=CH(CH2)q- wherein n is 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1, and Z is (III) wherein Q is (IV) wherein each R7 is the same primary or secondary C1-6alkyl or together they represent -(CH2)2-, -(CH2)3-, R10 is hydrogen or C1-3alkyl, with the proviso that Q may be other than (V) only when X is -CH=CH- or -CH2-CH=CH- and/or R10 is C1-3alkyl, in free acid form, or in the form of an ester or -lactone thereof or in salt form as appropriate, which are indicated for use as hypolipoproteinemic and anti-atherosclerotic agents.

Description: INDENE ANALOGS OF MEVALO OLACTONE AND DERIVATIVES THEREOF The invention concerns indene analogs of evalonolactone and derivatives thereof, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals in particular as hypoli- poproteine ic and anti-atherosclerotic agents. The invention is especially concerned with compounds of formula I R, is primary or secondary C, β alkyl or R and R- together are (CH-,).. or (Z)-CH 2 -CH=CH-CH-,- wherein m is 2, 3, 4, 5 or 6, Ro is C or ring A each of R-, and ogen, C, -alkyl, C, .alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, each of R- and R g is independently hydrogen, C, -alkyl, C, -alkoxy, trifluoro methyl, fluoro, chloro, phenoxy or benzyloxy, R β is hydrogen, C-_ 2 alkyl, C,_ 2 alkoxy, fluoro or chloro, with the proviso that there may only be one each of trifluoromethyl, phenoxy or benzyloxy on each of the phenyl and indene rings X is -(CH„) - or -(CH CH«CH(CH 9 ) - 2 n 2 q 2 q wherein n is 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1, wherein Q is - wherein each R 7 is the same primary or secondary C, fi alkyl or togethe they represent -(CH -,-, -( ^ CH "2 > 3 R-J Q is hydrogen or C, gβlkyl, with the proviso that Q may be other than -CH- only when X is -CH=CH- or -CH 2 -CH=CH- and/or 1Q is C-_-.alkyl, OH in free acid form, or in the form of an ester or -lactone thereof or in salt form as appropriate. Suitable esters include physiologically acceptable esters e.g. physiolo¬ gically hydrolysable and -acceptable esters. By the term "physiologically-hydrolysable and -acceptable ester" is meant an ester of a compound in accordance with the invention in which the carboxyl moiety if present is esterified, and which is hydrolysable under physiological conditions to yield an alcohol which is itself physiologically acceptable, e.g. non-toxic at desired dosage levels. For the avoidance of doubt, throughout this application it is the right hand side of the X radical that is attached to the Z group. Preferred such esters as Z can be represente together with the free acid by formula Ila -CH-CH -C-CH.-COOR,, Ila I 2 I z OH OH or formula lie R -Q'-CH 2 -C-CH 2 -C00R- 1 lie OH wherein R^ is hydrogen, C-_ 4 alkyl or benzyl preferably hydrogen, butyl or benzyl, h the further proviso that R,, is other Whe s a cation. When Z is in lactone form it forms a -lactone of formula lib and references to "lactone" hereinafter refer to S-lactones. Salts of the compounds of the invention, e.g. of the compounds of formula I, include in particular their pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include e.g. alkali metal salts such as the sodium and potassium salts and salts with ammonium. References to compounds of formula I, II, Ila, lib and He and sub¬ species thereof are intended to cover all forms unless otherwise stated. Depending on the nature of R, and R the compounds of formula I may be divided into two main groups, namely, those wherein R is hydrogen or primary or secondary C, β alkyl (Group IA) and those wherein R, and R together represent -(CHJ - or (Z)-CH ? -CH=CH-CH_- (Group IB). These groups may be further divided ΓH depending on the nature of Z, namely when Q is . " and the Z is in other than lactone form (sub-group "a"); when Z is a group of formula lib (sub-group "b"); and when Q is -C- or —,Cr- and Z is in other than lactone form (sub- group "c"). 0 2 H 7 Iκ 7 The resulting six groups are designated as IAa, IAb, IAc, IBa, IBb, IBc. As is self-evident to those in the art, each compound of Groups IAa, IAb, IBa and IBb (and every subscope and species thereof) has two centres of asymmetry (the two carbon atoms bearing the hydroxy groups in the group of formula Ila and the carbon atom bearing the hydroxy group and the carbon atom having the free valence in the group of formula lib and, therefore, there are four stereoiso eric forms (enantio ers) of each compound (two race- mates or pairs of diastereoisomers), provided that R and R, are identical or taken together are -(CHJ - or (Z)-CH 2 -CH=CH-CH 2 - and that R- - does not contain any centre of asymmetry. The four stereoisomers may be designated as the R,R, R,S, S,R and S,S enantiomers, all four stereoisomers being within the scope of this invention. When R and R, are different and/or R,^ contains one or more centres of asymmetry, there are eight or more stereoisomers. Since it is preferred that R and R. be identical or taken together -(C m " or (Z)-CH--CH=CH-CH ? - and that R,. does not contain a centre of asymmetry and for reasons of simplicity any additional stereoisomers resulting from the presence of a centre of asymmetry in the 1-position of the indene ring and/or one or more centres of asymmetry in R,, will usually be ignored, it being assumed that R and R, are identical or taken together are -(CH .- or (Z)-CH--CH=CH-CH-- and that R,, is free of centres of asymmetry. As is also self-evident each compound of Groups IAc and IBc (and every subscope and species thereof) has one centre of asymmetry (the carbon atom bearing the hydroxy group in formula He and therefore there are two enantiomers of each compound, provided that R and R, are identical or taken together are -(CH )- or (Z)-CH-,-CH=CH-CH-- and that R,, does not contain any centre of asymmetry. The two stereoisomers may be designated as the 3R and 3S isomers, both being within the scope of this invention. When R and R, are different and/or R,, contains one or more centres of asymmetry, there are four or more stereo¬ isomers. For the reasons set forth above, any additional stereoisomers resulting from the presence of a centre of asymmetry in the 1-position of the indene ring and/or one or more centres of asymmetry in R,, will usually be ignored. Ro preferably does not contain an asymmetric carbon atom and is prefer¬ ably Ro' where Ro' is C, .alkyl not containing an asymmetric carbon atom or Ring A, more preferably Ro", wherein Ro" is ring A wherein R. is R.', R ς is R-.', and R- is R g ' even more preferably Ro"' where Ro"' is ring A wherein R. is R-", R ς is R ς " and R g is R g " and most preferably Ro"" wherein Ro"" is ring A wherein 4 is R 4 "', R ς is R ς "' and R g is Rg"'. In Ro"" R 4 * " is preferably R 4 "". When R is hydrogen or primary or secondary C, g alkyl it is preferably hydrogen or primary or secondary C, g alkyl not containing an asymmetric carbo atom and is preferably R', where R' is hydrogen or primary or secondary C, 4 alkyl not containing an asymmetric carbon atom, more preferably R" where R" is hydrogen or C, -alkyl and most preferably C, -alkyl and R, is preferab primary or secondary C, g a1kyl not containing any asymmetric carbon atom and is preferably R, ', where R, ' is primary or secondary C, 4 alkyl not containing an asymmetric carbon atom, more preferably R-", where R," is C, - alkyl, and most preferably C, -alkyl. Prferably, when R, R 1 , etc. is other than hydrogen, R, R\ etc., as the case may be, is identical to R, , R, ' , etc., as the case may be. When R and R_ taken together are -(CHJ - or (Z)-CH 2 -CH=CH-CH--, they are preferably -(CHJ -, more preferably -(CHJ ,-, even more preferably -(CHJ „- and most preferably -(CH 2 ) „,-, especially -(CH 2 ) 4 -, wherein m is as defined above, and m', m" and m"' are as defined below. R- is preferably hydrogen, C, -alkyl, n-butyl, i-butyl, t-butyl, C, -- alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy and is preferably R-', where R-' is hydrogen, C, -alkyl, methoxy, fluoro, chloro or benzyloxy, more preferably R 2 ", where R-," is hydrogen or C, -alkyl, and most preferably hydrogen. R- is preferably R-', where R-' is hydrogen or C, -alkyl, and more preferably hydrogen. Preferably, not more than one of R-, and R- is a member of the group consisting of t-butyl, trifluoromethyl, phenoxy and benzyloxy. More prefer¬ ably, R- and R_ are not ortho to each other unless at least one of them is a member of the group consisting of hydrogen, C, -,alkyl, C-_-alkoxy, fluoro and chloro. R. is preferably hydrogen, C, -alkyl, n-butyl, i-butyl, t-butyl, C, ,- alkoxy, n-butoxy, i-butόxy, trifluoromethyl, fluoro, chloro, phenoxy or -benzyloxy and is preferably R.', where R is hydrogen, C, -alkyl, trifluoro¬ methyl, fluoro or chloro, more preferably R.", where R 4 " is hydrogen or C, ? - alkyl, and most preferably R ", where R."' is hydrogen or methyl, especially R '"', where R "" is hydrogen or 3-methyl. R ς is preferably R-.', where RJ is hydrogen, C,_-alkyl, fluoro or chloro more preferably R 5 ", where R 5 " is hydrogen or fluoro, and most preferably R-'", where R-."' is hydrogen or 4-fluoro. R g is preferably R g ', where R g ' is hydrogen or C, -,alkyl, more preferabl R g ", where R g " is hydrogen or methyl, and most preferably R g '"» where R g "' is hydrogen or 5-met yl . Preferably, not more than one of R. and R ς is a member of the group consisting of t-butyl, trifluoromethyl, phenoxy and benzyloxy. More preferabl no two of R 4 (R 4 ', R 4 ", etc.), R g (RJ, R 5 ", etc.) and R g (R g ', R g ", etc.) are ortho to each other unless at least one member of each pair of substi- tuents that are ortho to each other is a member of the group consisting of hydrogen, C, 2 alkyl, C, -alkoxy, fluoro and chloro. The preferred R.-bearing phenyl groups are phenyl , 4-fluorophenyl , 3,4- and 3,5-dimethylphenyl, 4-fluoro-3-methylphenyl and 3,5-dimethyl-4-fluoro- phenyl, with 4-fluorophenyl and 3,5-dimethylphenyl being more preferred. Preferably each R 7 is C, -.alkyl or both R 's taken together are (CHJ- or (CH-)-; more preferably each R 7 is C, 2 alkyl or both R 7 's taken together are (CHJ 2 or (CHJ_ and most preferably each R 7 is C, -.alkyl. R, Q is preferably - I '. where R, ' is hydrogen or methyl, and more preferably hydrogen. R,, is preferably R- - 1 - where R,,' is hydrogen, C, -alkyl, n-butyl, i-butyl, t-butyl or benzyl especially R,," where R,," is hydrogen or C, -- alkyl, more preferably R,," ' which is hydrogen or C, -,alkyl. Compounds of formula I wherein Z is of formula II, Ila or He are most preferably in salt form. Preferred salt-forming cations are those free from centres of asymmetry especially e.g. sodium, potassium or ammonium, most preferably sodium. Such cations may also be di- or tri-valent and are balance by 2 or 3 carboxylate containing anions. Any -CH=CH- containing bridge as X is preferably trans i.e. (E). X is preferably X' which is CH-CH- or -(E)-CH=CH-, more preferably -(E)- CH=CH-. Z is preferably a group of formula Ila, lib or He wherein R,- is R, ' (especially hydrogen) more preferably a group of formula Ila, lib or lie, wherein R, Q is hydrogen and R,, is R,, 1 or a cation even more preferably a group of formula IIa or lib whereinR,- is hydrogen, and R_, is R,," or ' a cation;and most preferably a group of formula Ila wherein R-- is hydrogen, and R,, is a cation, especially sodium. m is preferably m', where m' is 2, 3, 4 or 5, more preferably ", where m" is 2, 3 or 4, and most preferably m"', where m 1 " is 2 or 4, especially-4. n is preferably 2. As between otherwise identical compounds of formula I, those wherein Z is other than lactone form are generally preferred over those wherein Z is a group of formula lib, with those wherein Q is CH being generally preferred over those wherein Q has another meaning. 1 -" "1 Insofar as the compounds of Groups IAa and IBa and each of the subgroups thereof are concerned, the erythro isomers are preferred over the threo isomers, erythro and threo referring to the relative positions of the hydroxy groups in the 3- and 5-positions of the group of formula Ila. Insofar as the compounds of Groups IAb and IBb and each of the subgroups thereof are concerned, the trans lactones are generally preferred over the cis lactones, cijj. and trans referring to the relative positions of R.- and the hydrogen atom in the 6-position of the group of formula lib. The preferred stereoisomers of the compounds of formula I having only two centres of asymmetry wherein X is -CH=CH- or -CH 2 -CH=CH- and Z is a grou of formula Ila are the 3R,5S and 3R,5R isomers and the racemate of which each is a constituent, i.e. the 3R,5S-3S,5R (erythro) and 3R,5R-3S,5S (threo) raeemates, with the 3R,5S isomer and the racemate of which it is a constitue being more preferred and the 3R,5S isomer being most preferred. The preferred stereoisomers of the compounds of formula I having only two centres of asymmetry wherein X is -(CHJ - or -CH=CH-CH 2 - and Z is a group of formula Ila are the 3R,5R and 3R,5S isomers and the racemate of which each is a constituent, i.e. the 3R,5R-3S,5S (erythro) and 3R,5S-3S,5R (threo) raeemates, with the 3R,5R isomer and the racemate of which it is a constituent being more preferred and the 3R,5R isomer being most preferred. The preferred stereoisomers of the compounds of formula I having only two centres of asymmetry wherein X is -CH=CH- or -CH-CH=CH- and Z is a group of formula lib are the 4R,6S and 4R,6R isomers and the racemate of which each is a constituent, i.e. the 4R,6S-4S,6R (trans lactone) and 4R,6R-4S,6S (cis lactone) raeemates, with the 4R,6S isomer and the racemate of which it is a constituent being more preferred and the 4R,6S isomer being most preferred. The preferred stereoisomers of the compounds of formula I having only two centres of asymmetry wherein X is -(CHJ - or -CH=CH-CH 2 , and Z is a group of formula lib are the 4R,6R and 4R,6S isomers and the racemate of which each is a constituent, i.e. the 4R,6R-4S,6S (trans lactone) and 4R,6S- 4S,6R (cis lactone) raeemates, with the 4R.6R isomer and the racemate of which it is a constituent being more preferred and the 4R,6R isomer being most preferred. The preferences set forth in the preceding four paragraphs also apply to the compounds of Groups IAa, IAb, IBa, IBb having more than two centres of asymmetry and represent the preferred configurations of the indicated positions. The preferred stereoisomers of the compounds of formula I having just -CH- one centre of asymmetry wherein Q is other than ■ are the 3R isomers and OH the racemate of which they are constituents i.e. the 3R-3S racemate with the 3R isomer being more preferred. These preferences also apply to the compounds of Groups IAc and IBc having more than one centre of asymmetry and represent the preferred configuration of the indicated position. Each of the preferences set forth above applies, not only to the compounds of formula I, but also to the compounds of Groups IAa, IAb, IAc, IBa, IBb and IBc as well as to every subgroup thereof set forth in the speci fication, e.g. Groups (i) et seq., unless otherwise indicated. When any preference contains a variable, the preferred significances of that variable apply to the preference in question, unless otherwise indicated. Preferred groups of compounds of formula I include the compounds (i) of Group IAa wherein Ro is Ro', R is R\ R, is R, ', R 2 is R ' , R- is R ', R 1Q is R- 0 ', R- - is R^' and X is X', (ii) of (i) wherein Ro is Ro", R,- is hydrogen, R,, is R ι - ι " > and X is (E)-CH=CH-, (iii) of (ii) wherein Ro is Ro"', R is R", R ] is R- " , R-, is R 2 ", R 3 is hydrogen, and R-, is R,,"*, or especially a cation, (iv) of (iii) wherein Ro is Ro"' wherein R 4 "' is R 4 "\ R is C-^alkyl, R, is C, 2 alkyl and 2 is hydrogen (v) of (iv) wherein R,, is a cation especially sodium, potassium or ammonium, especially sodium, (vi) of Group IAb wherein Ro is Ro', R is R', R, is R, ', R 2 is R , R 3 is R 3 ', R 10 is R 10 ', and X is X', (vii) and (vi) wherein Ro is Ro", R- Q is hydrogen, and X is (E)-CH=CH-, (viii) of (vii) wherein Ro is Ro"', R is R", R- is R^', R 2 is R 2 " and R 3 is hydrogen, (ix) of (viii) wherein Ro is Ro"" wherein R 4 "' is R 4 "", R is C,_ 2 alkyl, R l is C i-2 a1ky ^ ancl R 2 is h y dro en» (x) of Group IBa wherein Ro is Ro', R and R, taken together are -(CHJ - R 2 is R 2 ', R 3 is R 3 ', R, Q is R- ' R- - is R,-\ and X is X', (xi) of (x) wherein Ro is Ro", R, Q is hydrogen, R,, is R,,", and X is (E)-CH=CH-, (xii) of (xi) wherein Ro is Ro"', R 2 is R 2 ", R 3 is hydrogen, R,, is R-."', particularly a cation, and m is m', (xiii) of (xii) wherein Ro is Ro"" wherein R '" is R 4 "", R 2 is hydrogen, and m is m", (xiv) of (xiii) wherein R,, is a cation in particular sodium, potassium or ammonium, especially sodium, (xv) of Group IBb wherein Ro is Ro', R and R, taken together are -(CHJ R 2 is R , R 3 is R 3 ', R,- is R,-', and X is X', (xvi) of (xv) wherein Ro is Ro", R, Q is hydrogen, and X is (E)-CH=CH-, (xvii) of (xvi) wherein Ro is Ro'", R 2 is R-,", R-. is hydrogen, and m is m', (xviii) of (xvii) wherein Ro is Ro"" wherein R '" is R 4 "", R- is hydroge and m is m", (xix)-(xxviii) of (i)-(v) and (x)-(xiv) wherein the hydroxy groups in the 3- and 5-positions of the group of formula Ila have the erythro configura tion, (xxix)-(xxxvi) of (vi)-(ix) and (xv)-(xviii) wherein R,- and the hydroge atom in the 6-position of the group of formula lib are trans to each other, i.e. the trans lactones, (xxxvii) of Group IAc wherein Ro is Ro', R is R', R. is R, ', R- is R ' , R 3 is R-' each R 7 is C, -.alkyl or the two R s taken together are (CHJ 2 or (CHJ-, R-- is ι0 ' > R-- is R,,' and X is X* with the proviso that X may be -CH 2 CH 2 - only when R,- is methyl, (xxxviii) of (xxxvii) wherein Ro is Ro" each R 7 is C, 2 alkyl or the two R s taken together are (CHJ 2 or (CHJ 3> R,- is hydrogen, R- - is R,," and X is (E)-CH=CH-, (xxxix) of (xxxviii) wherein Ro is Ro", R is R", R, is R- ", R 2 is R 2 ", R- is hydrogen, each R 7 is C, 2 alkyl and R., is hydrogen or C,_ 2 alkyl, most preferably a cation, (xl) of (xxxix) wherein Ro is Ro"" wherein R 4 "' is R 4 "", R is C- -alkyl, R. is C,_ 2 alkyl, and R 2 is hydrogen, (xii) of (xl) wherein R., is a cation, especially sodium, potassium or ammonium, particularly sodium, (xiii) of Group IBc wherein Ro is Ro', R and R, taken together are -(CH 's taken together th the provisos CH-,CH 2 - only when R- I is met y , (xliii) of (xiii) wherein Ro is Ro", each R ? is C^alk l or both R 's taken together are -(CHJ 2 -.-, R. Q is hydrogen, R- - is R- j ,", and X is (E)-CH=CH- (xliv) of (xliii) wherein Ro is Ro"', R-, is R 2 ", R 3 is hydrogen, each R 7 is C- ] . 2 alkyl, R__ is R,,"' (especially a cation), and m is m', (xlv) of (xliv) wherein Ro is Ro"" wherein R *" is R 4 "", R 2 is hydrogen, and m is m", (xlvi) of (xlv) wherein R,, is a cation, particularly sodium, potassium or ammonium especially sodium and (xlvii)-(lvi) of (xxxvii)-(xlvi) wherein Q is -CO-. Groups (i)-(xviii) and (xxxvii)-(lvi) embrace each of the possible stereoisomers, raeemates and mixtures of diastereoisomers. Groups (xix)- (xxviii) embrace the 3R,5S and 3S.5R isomers and the 3R,5S-3S,5R racemate of the compounds wherein X is (E)-CH=CH- having just two centres o asymmetry and the corresponding compounds having more than two centres of asymmetry, and Groups (xix) and(xxiv) also embrace the 3R.5R and 3S.5S isomers and the 3R,5R-3S,5S racemate of the compounds wherein X is -CH-,CH 2 - having just two centres of asymmetry and the corresponding compounds having more than two centres of asymmetry. Groups (xxix)-(xxxvi) embrace the 4R,6S and 4S,6R isomers and the 4R,6S-4S,6R racemate of the compounds wherein X is (E)-CH=CH- having just two centres of asymmetry and the corresponding compounds having more than two centres of asymmetry and Groups (xxix) and (xxxiii) also embrac the 4R,6R and 4S,6S isomers and the 4R,6R-4S,6S racemate of the compounds wherein X is -CH 2 CH-,- having just two centres of asymmetry and the corres¬ ponding compounds having more than two centres of asymmetry. A particular compound group covers those compounds of formula I wherein Ro represents ring A R is hydrogen or primary or secondary C, g alkyl not containing an asymmetric carbon atom, and R, is primary or secondary C, g alkyl not containing an asymmetric carbon atom or R and R, taken together are -(CHJ - or (Z)-CH--CH=CH-CH--, I 2 m 2 2 wherein m is 2, 3, 4, 5 or 6, R-, is hydrogen, C, -alkyl, n-butyl, i_-butyl , t butyl , C, 3 alkoxy, ni-butoxy, i_-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R, is hydrogen, C, -alkyl, C, -alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the proviso that not more than one of R ? and R- is trifluoromethyl, not more than one of R- and R- is phenoxy, and not more than one of R 2 and R-, is benzyloxy, R 4 is hydrogen, C, -alkyl, n_-butyl , v-butyl, t_-butyl , C,_-alkoxy, n_-butoxy, i_-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R- is hydrogen, C, -alkyl, C, -alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R fi is hydrogen, C, -alkyl, C- -alkoxy, fluoro or chloro, with the provisos that not more than one of R 4 and R ς is trifluoromethyl, not more than one of R 4 and R ς is phenoxy, and not more than one of R 4 and R- is benzyloxy, is -(CH.), - or (E)-CH=CH-, wherein n is 1, 2 or 3, and ■ ]ιo is -CH-CH 2 -C-CH 2 -C00R n (a) or OH dH wherein R, Q is hydrogen or C, -alkyl, and R-. is hydrogen, R- 2 or M, wherein R, 2 is a physiologically acceptable and hydrolyzable ester group, and M is a pharmaceutically acceptable cation. The compounds of formula I may be prepared by the following reactions wherein Ind stands for and substituents are as defined above. a) when X is (CHJ or (E)-CH=CH- and R,- is hydrogen reducing a compound of formula IV Ind-X,-CH-CH--C-CH--COOR,- IV ' .H H 2 ,3 wherein R.- is a radical forming an ester, and X, is (CHJ or (E)-CH=CH-, b) when X is (CHJ or (E)-CH=CH- and R, Q is C, -alkyl hydrolysing a compound of formula XII XII c=o R 14 wherein R, Q is C, -alkyl, R- . is part of an ester forming group and X, and R,, are as defined above, c) when X is -CH=CH- or -CH 2 -CH=CH- and lib is in 4R.6S configuration or X is -CH-CH- or CH-CH-CH-, and lib is in 4R,6R configuration deprotecting a compound of formula XXXIX ro Ind- OX" υ XXXIX wherein X" represents -CH 2 CH 2 , -CH 2 CH 2 CH 2> -CH=CH- or -CH-,CH=CH- and Pro is a protecting group, d) when X is -(CH^-, -(CHJ 3 -, -(CHJ CH=CH(CHJ - deprotecting a compound of formula XXXII Ind-X"'-CH-CH--C-CH-C00R,- XXXII I Z ι 2 13 OPro OPro wherein X" 1 is -(CH,),-, -(CHJ,- or -(CHJ -CH=CH-(CHJ -, . i . q 2 q and q, R,-, ^- and Pro are as defined above, oxidising the corresponding compound of formula I wherein Q and II is in ester form ketalising the corresponding R _ c _ compound of formula I wherein Q is g) hydrolysing a compound of formula I in the form of an ester or a lactone o h) esterifying or lactonising a compound of formula I in free acid form, and when a free carboxyl group is present, recovering the compound obtained in free acid form or in the form of a salt. R,- is preferably C, -alkyl, n-butyl, i-butyl, t-butyl or benzyl, more preferably C, -alkyl and especially C, 2 alkyl and R- . is preferably C | _ 3 alky more preferably n-C, -alkyl, especially C, 2 alkyl. Process a) is particularly suited for compounds wherein X is -(CHJ - or (E)-CH=CH and in ester form. Process b) is particularly suited for compounds wherein X is -(CHJ - or (E)-CH=CH in salt form. Process c) is particularly suited for compounds wherein X is -(E)-CH=CH and the lactone is in 4R,6S configuration and those wherein X is-CH 2 CH-- and the lactone is in 4R,6R configuration. Process d) is particularly suited for compounds in ester form. It will readily be appreciated that the various forms of the compounds of formula I may be interconverted as indicated in g) and h) above, whereby lactonisation may only take place when Q is -CH- and ketals cannot be isolat in free acid form or esterified. OH In the same way compounds obtained according to a) to f) may be as appro priate hydrolysed to free acid forms and free acid forms may be esterified or lactonised to produce a desired end-product. The invention thus also provides a process for preparing a compound of formula I which comprises hydrolysing a compound of formula I in ester or lactone form or esterifying or lactonising a compound of formula I in free acid form and when a free carboxyl group is present recovering the compound obtained in free acid form or in the form of a salt. Unless otherwise stated reactions are performed in a manner conventional for the type of reaction involved. Molar ratios and reaction times are as a rule conventional and non-critical and are chosen according to principles well established in the art on the basis of reactions and conditions employed Solvents, alone or as mixtures, are generally chosen which remain inert and liquid during the reaction in question. Examples of inert atmospheres are usually nitrogen or a nobel gas, nitrogen being preferred. Most reactions, including those wherein use of an inert atmosphere is not mentioned, are carried out under such for convenience. EP 114027 and 117228 including the examples thereof disclose analogous processes and further suitable reaction conditions. Reduction according to a) is preferably carried out using a mild reducin agent such as sodium borohydride or, a complex of t-butylamine and borane in an inert organic solvent such as a lower alkanol, preferably ethanol, conveniently at a temperature of -10° to 30°C, under an inert atmosphere. Use of an optically pure starting material will lead to only two optical isomers (diastereoisomers) of the resulting end product. However, if stereo- specificity is desired it is preferred to utilize a stereo-selective reductio in order to maximize production of a mixture of the erythro stereoisomers (racemate) of which the preferred stereoisomer (as set forth above) is a constituent. Stereoselective reduction is preferably carried out in three steps. For example in the first step, the ketoester of formula IV is treated with a tri(primary or secondary C-, .alkyl)borane, preferably triethylborane or tri-n-butylborane, and optionally air to form a complex. The reaction temperature is suitably 0° to 50°C, preferably 0° to 25°C. The first step is carried out in an anhydrous inert organic solvent, preferably an ether solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or 1,2-diethoxyethane, with tetrahydrofuran, being the most preferred solvent especially in a 3-4:1 mixture with methanol when pure erythro product is desired. In the second step, the complex is reduced with sodium borohydride, preferably in the same solvent as utilized for the first step, at -100° to -40°C, preferably -100° to -70°C. In the third step, the product of the second step is, for example, treated with, preferably, anhydrous methanol at 20° to 40°C, preferably 20° to 25°C. The amount of methanol is not criti¬ cal. However, a large excess, e.g. 50-500 moles per mole of ketoester of formula IV is typically utilized. Alternatively a mixture of methanol, e.g. 30% aqueous H-0-, and a pH 7-7.2 aq. phosphate buffer is used. Hydrolysis according to b) or g) is carried out in a manner conventional for such reactions e.g. employing an inorganic hydroxide such as NaOH or KOH with, if desired subsequent acidification to give the free acid form. Suitable solvents are mixtures of water and water miscible solvents such as lower alkanols e.g. methanol or ethanol and reaction conveniently takes place at temperatures from 0°C to reflux preferably 0° to 75°C e.g. 20° to 70°C. If it is desired to recover the compound in a salt form corresponding to the cation of the hydroxide employed then slightly less than equivalent amounts of the latter may be employed. In b) R-. will conveniently be the same as R,- e.g. C, -alkyl more preferably n-C, -.alkyl, especially C, -. Oxidation according to e) can be carried out when X is -CH=CH- or -CH 2 CH=CH- using activated n0 2 at 20° to 80°C, preferably 40° to 80°C in an anhydrous inert organic solvent such as an ether solvent e.g. (C-HJ-0, 1,2-diethoxyethane, 1,2-dimethoxyethane, tetrahydrofuran and mixtures thereof or when X is (CHJ or -CH=CH-CH 2 using Swerns reagent (oxalyl chloride + dimethylsulfoxide) with triethylamine in e.g. -CH-C1- at -60° to -40°C prefer ably -50°C. Ketalisation according to f) can be carried out in the case of open chain ketals using H-C(0RJ, in the presence of catalytic amounts of pyridinium p-toluene sulfonate and a hydrocarbon solvent, for example benzene toluene, xylene and mixtures thereof, halogenated lower alkane solvent, for example carbon tetrachloride, chloroform, 1,1-dichloroethane, 1,2-dichloro- ethane, ethylene chloride and 1,1 ,2-trichloroethane, usually preferably methylene chloride or benzene at 20-25°C or for cyclic ketals using H0-(CHJ__ 3 -0H under the same conditions. Lactonisation according to h) is carried out in conventional manner e.g. by heating the corresponding acid in anhydrous inert organic solvent e.g. a hydrocarbon such as benzene, toluene or a xylene or mixtures thereof, preferably at temperatures of 75°C to reflux although more preferably not above 150°C. Preferably, however, a lactoni¬ sation agent, e.g. a carbodiimide, preferably a water-soluble carbodiimide such as N-cyclohexyl-N'-[2'-(methylmorpholinium)ethyl]carbodiimide p-toluenesulfonate, in an anhydrous inert organic solvent, e.g. a halogenated lower alkane, preferably methylene chloride is employed. Reaction temperatures then lie typically between 10° and 35°C, especially 20° to 25°. As is evident to those in the art, a racemic threo 3,5-di-hydroxy- carboxylic acid yields a racemic cis lactone (two stereoisomers) and a racemic erythro 3,5-dihydroxycarboxylic acid yields a racemic trans lactone (two stereoisomers). Likewise if a single enantiomer of the 3,5-dihydroxycarboxylic acid is utilized, a single enantiomer of the lactone is obtained. For example, lactonisation of a 3R,5S erythro dihydroxycarboxylic acid yields a 4R,6S lactone. Esterification according to h) is conventional, employing e.g. a large excess of a compound R 13 0H, wherein R,- is as defined above at e.g. 20°C to 40°C in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid. Direct esterification is parti¬ cularly suited when Q is -C-. II 0 Preferably, however, esterification takes place by first forming the corresponding lactone and reacting this with M ? OR,- (M ? =Na or K ) at 0° to 70°C preferably 20° to 25°C in an inert organic solvent e.g. an ether such as tetrahydrofuran or an alcohol of formula R 13 0H if a liquid. Examples of protecting groups in reaction c) and d) are diphenyl- t-butylsilyl, tri-isopropylsilyl or dimethyl-t-butylsilyl, benzyl, triphenylmethyl, tetrahydrofuran-2-yl, tetrahydrop ran-2-yl, 4-methoxytetrahydrofuran-4-yl, C-,_ g n-alkanoyl. Especially preferred are trisubstituted silyl radicals in particular diphenyl-t-butylsilyl (-Pro'). Deprotection is carried out in conventional manner e.g. by cleavage under mild conditions such as employing e.g. for removal of a diphenyl-t- butylsilyl a fluoride reagent e.g. tetra-n-butylammonium fluoride in an anhydrous inert organic medium preferably tetrahydrofuran containing glacial acetic acid at temperatures of 20° to 60°C, especially 20° to 25°C. Preferably 1-4 moles of fluoride per mole protecting group are used with 1-2 moles, preferably 1.2 to 1.5 mmoles of glacial acetic acid to each mole of fluoride. The required starting materials may be prepared for example as illustrated in the following reaction schemes or in the examples herein¬ after. Further suitable reaction conditions are disclosed e.g. in EP 114027 and 117228 including the examples thereof. Abreviations: AIO - anhydrous inert organic solvent ES - ether solvent e.g. diethylether, 1,2-diethoxyethane, 1,2-di¬ methoxyethane, THF or mixtures thereof HC - hydrocarbon solvent e.g. benzene, toluene, xylene or mixtures thereof HLA - halogenated lower alkane solvent e.g. CCK, CHC1-, 1,1-dichloro- ethane, 1,2-dichloroethane, methylene chloride, 1,1,2,-tri- chloroethane, preferably CH-,C1 2 10 - inert organic solvent THF - tetrahydrofuran LDA - lithiumdiisopropylamide nBuLi - n-butyllithium DMF - dimethylformamide DIBAH - diisobutylaluminium hydride Variables not previously defined R_ 5 is C, -alkyl, preferably methyl s CH 2 or (CH 2 ) 2 s a direct bond or CH- s -CH=CH-, -CH=CH-CH 2 - or -CHg-CH^CH- preferably (E)-CH=CH-, (E)-CH=CH-CH 2 - or (E)-CH 2 -CH=CH- especi al ly (E)-CH=CH-, s (CH 2 ) 2 - or -(CH 2 ) 3 - especi al ly -(CH 2 ) 2 > s -CH=CH- or -CH 2 -CH=CH-, preferably CH=CH and especi al ly E)-CH=CH- Y s Cl , Br or I Y ' i s Cl or Br C 4 H 9 Lac-, = as Lac, but in 4R,6R Laci = configuration ^5 Pro' Si - t 4 H g R_ 3 ' is C, 3 alkyl, n-butyl, i-butyl, t-butyl or benzyl each R, g is independently CH 3 or C -L and they are preferably the same CH 2 -Y' The conditions given hereinabove are largely conventional for such reactions and can be varied in conventional manner according to the particular intermediates/end products. This applies e.g. to molar ratios, temperature, reaction times and the like which are chosen according to principles well established in the art on the basis of reactants and conditions employed. Intermediates, the production of which is not described above, are either known or may be prepared according to or analogously to known methods e.g. as described in EP 114027 and 117228 including the examples thereof. Process CA to CD are for example described in EP 114027. Reaction products, both intermediates and final, can be isolated (e.g. from compound mixtures or reaction mixtures) and purified in conventional manner whereby intermediates can, where appropriate, be employed directly in a subsequent reaction. Mixtures of stereoisomers (cis, trans and optical) can be separated by conventional means at whatever stage of synthesis is appropriate. Such methods include re-crystallisation, chromatography, formation of esters with optically pure acids and alcohols or of amides and salts with subsequent reconversion under retention of optical purity. - For example diastereoisomeric (-)- -naphthylphenylmethylsilyl derivatives of a lactone type end product of formula I may be separated by conven¬ tional means. Salts may be prepared in conventional manner from free acids, lactones and esters and vice-versa. In some cases e.g. for groups IAc, IBc in ketal form ion-exchange may be required for salt formation. Whilst all salts are covered by the invention pharmaceutically acceptable salts especially sodium, potassium and ammonium par. * cularly sodium salts are preferred. The various forms of the compounds of formula I are by virtue of their interconvertability useful as intermediates in addition to the use set out below. Also within the scope of this invention are the intermediates of formulae IV, XII, XXXII, XXXIV, XXXVII, XXXIX, XLVI, XLVIII, L-LII, LV, LVII-LIX, LX, LXI, LXIV and products of reactions CB and CC. The preferences for each variable are the same as set out for formula I and preferred groups of compounds correspond to those listed for formula I as appropriate to and consistent therewith. The compounds of formula I possess pharmacological activity in particular as competitive inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and as a consequence are inhibitors of cholesterol biosynthesis as demonstrated in the following tests. Test A: In Vitro Microsomal Assay of HMG-CoA Reductase Inhibition: As described in EP 114027 or 117228 (dosage range 0.0001-2000 mol). Test B: In Vivo Cholesterol Biosynthesis Inhibition As described in EP 114027 or 117228 (dosage range 0.01-200 mg/kg). The compounds are thus indicated for use as hypolipoproteinemic and an ' ti-atherosclerotic agents. An indicated suitable daily dosage for use in the treatment of hyperlipoproteinemia and atherosclerosis is from about 1 to 2000 mg preferably 1 to 150 g suitably administered one to four times daily or in controlled release form. A typical dosage unit for oral administration may contain 0.25 to 500 mg. The compounds of formula I may be administered in similar manner as known compounds suggested for use in such indications e.g. Compactin or Mevinolin. * The suitable daily dosage for a particular compound will depend a number of factors such as its relative potency of activity. It has, for example been determined that the preferred compound (compound of example no. 2) obtained an ED--, of 0.07 mg/kg in Test B compared with 3.5 mg/kg for Compactin and 0.41 mg/kg for Mevinolin. It is therefore indicated that the compounds may be administered at similar or signifi¬ cantly lower dosages (e.g. 1 - 30 mg/d) than conventionally proposed e.g. for Compactin. The invention therefore also concerns a method of treating hyperli¬ poproteinemia or atherosclerosis by administration of a compound of formula I in free acid form or in the form of a physiologically- acceptable ester or a lactone thereof or in pharmaceutically acceptable salt form as well as such compounds for use as pharmaceuticals e.g. as hypolipoproteinemic and anti-atherosclerotic agents. The compounds may be administered alone, or in admixture with a pharmaceutically acceptable diluent or carrier, and, optionally other excipients, and administered orally in such forms as tablets, elixirs, capsules or suspensions or parenterally in such forms as injectable solutions or suspensions. The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Such compositions also form part of the invention. The following examples, in which all temperatures are in °C illustrate the invention. EXAMPLE 1 Ethyl erythro-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-spiro[cyclo- pentane-l,T-(lH)-inden]-2'-yl]hept-6-enoate (Cmpd. No. 1) Step 1 (Reaction AA) 3-(4'-Fluorophenyl)-lH-indene (Compound XLIIIa) A solution of 5.1 g (39 mmoles) of 1-indanone in 15 ml of anhydrous diethyl ether is added over a 30 minute period to a solution of 4- fluorophenylmagnesium bromide (prepared from 7.97 g (45.5 mmoles) of l-bromo-4-fluorobenzene, 1.33 g (54.7 mmoles) of magnesium turnings and a trace of iodine in 25 ml of anhydrous diethyl ether) stirred at 20°-25°C under nitrogen. The reaction mixture is stirred at 20°-25°C under nitrogen for 16 hours and quenched with saturated ammonium chloride solution. The organic phase is separated, dried over anhydrous sodium sulfate and evaporated at reduced pressure, and the residual oil is dissolved in 16 ml of glacial acetic acid. The obtained solution is refluxed for 15 minutes, and the acetic acid is evaporated at reduced pressure. The residue is flash chromato- graphed on a silica gel column utilizing 10% ethyl acetate/petroleum ether as the eluant, and the eluant is evaporated at reduced pressure to obtain a solid which is recrystallized from 95% ethanol to obtain the product, m.p. 38-40°C. Step 2 (Reaction AD) 3-(4'-Fluorophenyl)-!H-indene-2-carboxa1dehyde (Cmpd. XLVIa) 5 ml of acetonitrile is added to a mixture of 0.973 ml (10 mmoles) of phosphorus oxychloride and 1.3 ml (10 mmoles) of N-methylformanilide stirred at 20°-25°C, the reaction mixture is stirred at 20°-25°C for 30 minutes and cooled to 5°C, a solution of 2 g (9.5 mmoles) of XLIIIa in 5 ml of acetonitrile is added dropwise with stirring, and the reaction mixture is stirred at 20°-25°C for 6.5 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is poured onto ice and extracted several times with 4:1 diethyl ether/ petroleum ether. The extracts are combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, passed through a short silica gel column and evaporated at reduced pressure to obtain the crude product as an oil. The oil is dissolved in chloroform and flash chromatographed on a silica gel column, the eluant is evaporated at reduced pressure, and the residue is crystallized from petroleum ether to obtain the product, m.p. 70°-71°C. Step 3 (Reaction AI) Methyl (E)-3-[3'-(4"-f1uorophenyl )-1H-inden-2'-ylIpropenoate Compound XLVIIIa) A solution of 573 mg (2.42 mmoles) of Compound XLVIa and 1.01 g (2.91 mmoles) of (carbo ethoxymethylene)triphenylphosphorane in 6 ml of dry toluene is refluxed under nitrogen for 7 hours. The reaction mixture is cooled to 20°-25°C, diethyl ether is added, and the mixture is filtered through a short silica gel column. The eluate is evaporated at reduced pressure to obtain a yellow oil which is crystallized from 95% ethanol to obtain the product, m.p. 121°-122°C. Step 4 (Reaction AJ) Methyl (E)-3-[3'-(4"-f1uoropheny1 )spiro[cyclopentane-l ,T (lH)-inden]-2'- ylIpropenoate (Compound La) 112 mg (2.3 mmoles) of sodium hydride (as a 50% by weight dispersion in mineral oil) is added to a solution of 340 mg (1.16 mmoles) of compound XLVIIIa in 5 ml of dry dimethylforma ide stirred at 0°C, the reaction mixture is stirred at 0°C for 10 minutes, 0.143 ml (1.16 mmoles) of 1,4-dibromobutane is added dropwise with stirring over a 5 minute period, and the reaction mixture is allowed to gradually warm to 20°-25°C with stirring and stirred at 20°-25°C for 16 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is diluted with diethyl ether, dilute hydrochloric acid is added, and the mixture is extracted three times with diethyl ether. The diethyl ether extracts are combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness at reduced pressure. The residue is chromatographed on a silica gel column utilizing 4:1 petroleum ether/acetone as the eluant to obtain the product, m.p. 143°-145°C. Step 5 (Reaction AL) (E) -3-[3 ' -(4"-fluorophenyl ) spi ro[cyc1 opentane-l , T ( 1H) -i nden]-2 ' -y1 ]- prop-2-en-l -ol (Compound Lla) 2 ml of 1.5M diisobutylaluminium hydride/toluene (3 mmoles) is added dropwise to a solution of 220 mg (0.632 mmole) of Compound La in 4 ml of dry methylene chloride stirred at -78°C under nitrogen, and the reaction mixture is stirred under the same conditions for 20 minutes, quenched with dilute hydrochloric acid and extracted several times with methylene chloride. The methylene chloride extracts are combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain the product which solidifies upon standing, m.p. 102°-104°C. Step 6 (Reaction AM) (E)-3-[3'-(4"-fluorophenyl)spiro[cyclopentane-l,T(lH)-inden]-2'-yl]- prop-2-enal (Compound Llla) 300 mg (3.45 mmoles) of activated manganese dioxide is added to a solution of 170 mg (0.531 mmole)) of Compound Lla in 4 ml of dry toluene stirred at 20°-25°C, and the reaction mixture is stirred at 20°-25°C under nitrogen for 24 hours, filtered to remove the manganese dioxide and evaporated at reduced pressure to obtain the yellow product which solidifies upon standing, m.p. 123-125°, following recrystallisation from diethylether/petroleum ether, 129°-130°C. Step 7 (Reaction CA) Ethyl (E)-7-C3'-(4"-fluorophenyl)spiro[cyclopentane-l,1 '(lH)-inden]-2'- yl]-5-hydroxy-3-oxohept-6-enoate (Compound IVa) (a) A stock solution of the dianion of ethyl acetoacetate is prepared as follows: 7.5 ml of 1.6M n_-butyllithium/hexane (12.0 mmoles) is added over a period of 5 minutes to a solution of 1.23 g (12.2 mmoles) of diisopropylamine in 25 ml of dry tetrahydrofuran stirred at -5°-0°C under nitrogen, the rate of addition being such that the temperature does not exceed 5°C. The reaction mixture is stirred at -30°C for 15 minutes under nitrogen, 780.8 mg (6 mmoles) of ethyl acetoacetate (dried over molecular sieves) is slowly added, and the reaction mixture is stirred at -30° to -20°C under nitrogen for 45 minutes. (b) 3.3 ml of the stock solution of the dianion of ethyl acetoacetate of Part (a) (0.6 mmoles) is added to a solution of 126 mg (0.396 mmole) of Compound LIla in 3 ml of dry tetrahydrofuran stirred at -60°C under nitrogen, and the reaction mixture is stirred under the same conditions for 1 hour, quenched with water, acidified with dilute hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate extracts are combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness at reduced pressure. The residue is purified by preparative thin layer chromatography on silica gel plates utilizing 4:1 petroleum ether/acetone as the solvent to obtain the product as a pale yellow oil . The product is a racemate that may be resolved by conventional means to obtain the 5R and 5S enantiomers. Step 8 (Reaction a)) Ethyl erythro-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl )spiro[cyclopen- tane-1,1 '(lH)-inden]-2'-yl]hept-5-enoate (Compound No. 1) (a) 0.8 ml of 1M. triethylborane/tetrahydrofuran (0.8 mmole) is added to a solution of 300 mg (0.67 mmole) of Compound IVa in 10 ml of dry tetrahydrofuran stirred at 20°-25°C, 0.2 ml of air is added * via syringe, the reaction mixture is stirred at 20°-25°C for 2 hours and cooled to -78°C, 0.06 g (1.59 mmoles) of sodium borohydride is added in one portion, and the reaction mixture is stirred at -78°C for 48 hours, the reaction mixture being maintained under nitrogen throughout. The cooling bath is removed, and IN. hydrochloric acid is slowly added dropwise until the evolution of hydrogen ceases and the mixture is acidic (pH^5), the internal temperature of the mixture being maintained below -20°C throughout. 10 ml of water is added, the mixture is extracted three times with diethyl ether, and the diethyl ether extracts are combined, washed twice with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a crude oil. (b) A solution of the product of Part (a) in 5 ml of methanol is stirred at 20°-25°C for 66 hours under nirogen and evaporated to dryness at reduced pressure. The residue is chromatographed on a silica gel column utilizing 1:1 diethyl ether/petroleum ether as the eluant to obtain the crude product which solidifies on standing. Repeated recrystallisation from diethyl ether/hexane give the product as a white solid, m.p. 90°-93°C. N.M.R. (CDC1 3 ) : 1.3 (t, 3H), 1.6-1.9 ( , 4H), 2.2 (m, 6H), 2.5 (m, 2H), 3.2 (bs, 1H), 3.7 (bs, 1H), 4.15 (q, 2H), 4.25 (m, 1H), 4.45 (m, 1H), 5.8 (dd (J-=8 Hz., J 2 =20 Hz.] 1H), 6.5 (d (J=20 Hz.), 1H), 7.0-7.5 (m, 8H) EXAMPLE 2 Sodium erythro-(E)-3,5-dihydroxy-7-[3'-(4"-f1uorophenyl )-spiro[cyclo- pentane-1,1 '(!H)-inden]-2'-yl]hept-6-enoate (Compound no. 2) 0.11 ml of IN. sodium hydroxide solution (0.11 mmole) is added to a solution of 50 mg (0.111 mmole) of Compound No. 1 in 3 ml of absolute ethanol stirred at 0°C, and the reaction mixture is stirred at 0°C under nitrogen for 1.5 hours and evaporated to dryness at reduced pressure. The residue is washed three times with diethyl ether to obtain the product, m.p. > 170°C (dec). N.M.R. (CDC1 3 +CD 3 0D) : 1.5-2.5 (m, 12H), 4.1 ( , 1H), 4.3 (m, 1H), 5.8 (dd (J-=8 Hz., J-,=20 Hz.), 1H), 6.4 (d (J=20 Hz.), 1H), 7.0-7.5 ( , 8H) Compounds 1 and 2 are about 24:1 mixtures of the erythro and threo raeemates which may be separated by conventional means. The principal product, the erythro racemate, may be resolved into two optically pure enantiomers, the 3R.5S and 3S,5R isomers, of which the former is preferred. The minor product, the threo racemate, may be resolved into the 3R.5R and 3S,5S isomers, of which the former is preferred. The use of a starting material synthesized by utilizing a non-stereoselective reduction would afford a mixture of all four stereoisomers wherein the ratio of the erythro isomers to the threo isomers ranges from 3:2 to 2:3. EXAMPLE 3 (E)-3,5-dihydroxy-7-[3'-(3",5"-dimethylpheny1)spiro[cyc1opentane-1,l '- (lH)-inden]-2'-yl]hept-6-enoic acid, its sodium salt and its ethyl ester (Compounds Nos. 3, 4 and 5) (a) 31 ml of 1M. triethylborane/tetrahydrofuran (31 mmoles) is added to a solution of 12.0 g (<26.2 mmoles) of ethyl (E)-7-[3 * -(3",5"- dimethylphenyl )spiro[cyclopentane-l,l ' (lH)-inden]-2'-yl]-5-hydroxy-3-oxo- hept-6-enoate (Compound IVb) (preparable analogously to Example 1 steps 1 to 7) in 500 ml of dry tetrahydrofuran stirred at 20°-25°C, 50 ml of air (at 25°C and 760 mm Hg.) is added via a syringe, the reaction mixture is stirred at 20°-25°C for 2 hours and cooled to -78°C, 1.14 g (30.2 mmoles) of sodium borohydride is added in one portion, and the reaction mixture is stirred for 16 hours at -78°C and allowed to warm to 20°-25°C, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is evaporated to dryness at reduced pressure, the residue is vacuum dried, diethyl ether is added, the insoluble material is removed by filtration, and the filtrate is evaporated at reduced pressure. 50 ml of water is added to the oily residue, and the mixture is extracted twice with diethyl ether. The diethyl ether extracts are combined and cooled to 0°C, 10 ml of methnol, 5 ml of 30% aqueous hydrogen peroxide and 10 ml of an aqueous phosphate buffer having a pH of 7 (0.054M. sodium, 0.024M. potassium and 0.047M. phosphate) are added, and the reaction mixture is stirred at 0°C under nitrogen for 45 minutes. Most of the diethyl ether and methanol is evaporated at reduced pressure, the residual aqueous solution is extracted with diethyl ether three times, and the diethyl ether extracts are combined and evaporated at reduced pressure to obtain the crude product as a yellow oil (Compound No.5). N.M.R. (CDC1 3 ) : 1.25 (t, 3H), 1.6-2.3 (m, 10H), 2.4 (s, 6H), 2,5 (m, 2H), 3.5 (s, 1H), 3.7 (d, 1H), 4.15 (q, 2H), 4.25 ( , 1H), 4.4 (m, 1H), 5.7 (dd, 1H), 6.5 (d (J=20 Hz.), 1H), 6.95-7.4 (m, 7H) (b) The aqueous layer from the initial diethyl ether extraction (prior to the addition of methanol, hydrogen peroxide and buffer) is acidified with dilute hydrochloric acid, and the mixture is extracted twice with ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate, filtered and evaporated at * reduced pressure to obtain the crude compound as a foam (Compound No. 3). (c) 6.5 ml of IN. sodium hydroxide solution (6.5 mmoles) is added to a solution of 3 g ("-=6.5 mmoles) of the crude compound (from Part (a)) in 25 ml of ethanol stirred at 0°, and the reaction mixture is stirred at 0°C under nitrogen for 30 minutes, washed with diethyl ether, acidified with dilute hydrochloric acid and extracted with diethyl ether twice. The diethyl ether extracts are combined, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain Compound No. 3 as an oil. The reaction mixture, prior to the acidification, contains the sodium salt of Compound No. 3 (Compound No. 4). It may be isolated and purified conventionally. m.p.>160°C (dec). N.M.R. (CDC1 3 +CD 3 0D) : 1.5-2.35 (m, 12H), 2.3 (s, 6H), 4.1 (m, 1H), 4.3 (m, 1H), 5.75 (dd, 1H), 6.45 (d (H=20 Hz.), 1H), 6.95-7.4 (m, 7H) Compounds 3, 4 and 5 are approximately 3-9:1 mixtures of the erythro and threo raeemates which may be separated by conventional means, e.g. lactonization of the free acid, separation of the ci_s and trans lactones, hydrolysis of the lactones, etc. The principal product, the erythro racemate in each case, may be resolved into two optically pure enantiomers, the 3R,5S and 3S,5R enantiomers, of which the former is preferred. The minor product, the threo racemate in each case, may be resolved to obtain the 3R,5R and 3S,5S enantiomers, of which the former is preferred. The use of a non-stereoselective reduction would afford a mixture of all four stereoisomers wherein the ratio of the erythro stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3. -33- EXAMPLE 4 (E)-Trans-6-(2 , -[3"-(3" t ,5"'-dimethylphenyl)spiro[cyclopentane-l,T- (1H)-inden]-2"-yl]ethenyl )-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (Compound No. 6) and the corresponding ci_s_ lactone (Compound No. 7) (a) 8.7 g (20.5 mmoles) of N-cyclohexyl-N , C2'-(N"-methylmorpholinium) ethyl]carbodiimide p_-toluenesulphonate is added to a solution of 8.7g O 0.1 mmoles) of Compound No. 3 in 250 ml of methylene chloride (freshly filtered through basic alumina), and the reaction mixture is stirred at 20°-25°C under nitrogen for about 3 hours (until no Compound No. 3 is detectable by thin layer chromatography) and evaporated to dryness at reduced pressure. Water is added, and the mixture is extracted three times with diethyl ether. The diethyl ether extracts are combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness at reduced pressure to obtain an about 3-4:1 mixture of Compounds No. 6 and No. 7 as a yellow foam. (b) The product of Part (a) is separated on a Waters Prep-500 high pressure liquid chromatography apparatus utilizing a silica gel column and 15:4.5:10.5 n_-hexane/acetonitrile/methyl t-butyl ether to elute the trans lactone (Compound No. 6), a solid foam. N.M.R. (CDC1 3 ) : 1.7-2.3 (m, 10H), 2.35 (s, 6H), 2.7 ( , 2H), 4.4 (m, 1H), 5.25 ( , 1H), 5.75 (dd (J-=10 Hz., J-.=20 Hz.), 1H), 6.55 (d (J=20 Hz.), 1H), 6.9-7.5 (m,7H) Also eluted from the column is the cis lactone (Compound No. 7), also a solid foam. N.M.R. (CDC1 3 ) : 1.7-2.5 (m, 10H), 2.35 (s, 6H), 2.8 (m, 2H), 4.3 (m, 1H), 4.7 (m, 1H), 5.75 (dd (J^IO Hz., J 2 =20 Hz.), 1H), 6.5 (d (J=20 Hz) Hz.), 1H), 6.95-7.4 (m,7H) Compounds No. 6 and No. 7 are both raeemates that may be resolved by conventional means to obtain, in the case of the former, the 4R,6S and 4S,6R enantiomers, of which the former is preferred, and, in the case of the latter, the 4R,6R and 4S,6S enantiomers, of which the former is preferred. EXAMPLE 5 Sodium erythro-(E)-3,5-dihydroxy-7-[3'-(3",5"-dimethylphenyl )-spiro[cyclo- pentane-1,1 '(lH)-inden]-2'-yl]hept-6-enoate (Compound No. 8) and Sodium threo-(E)-3,5-dihydroxy-7-[3'-(3",5"-dimethylphenyl)-spiroCcyclo- pentane-1,1 * (lH)-inden]-2'-yl]hept-6-enoate (Compound No. 9) 0.16 of IN. sodium hydroxide solution (0.16 mmole) is added to a solution of 70 mg (0.169 mmole) of Compound No. 6 in 3 ml of absolute ethanol stirred at 0°C, and the reaction mixture is stirred at 0°C under nitrogen for 30 minutes and evaporated to dryness at reduced pressure. The residue is washed with anhydrous diethyl ether and vacuum dried to obtain the product as a pale yellow solid m.p.> 170°C (dec.) N.M.R. (CDC1 +CD-.0D) : 1.5-2.35 ( , 12H), 2.3 (s, 6H), 4.1 (bs, 1H), e 3 4.3 (bs, 1H), 5.75 (dd (J-.=10 Hz., J-,=20 Hz.), 1H), 6.45 (d (J=20 Hz.), 1H), 6.95-7.4 (m,7H) Compound No. 9 is prepared analogously from Compound No. 7. m.p. 160°C (dec) N.M.R. (CDC1-.+CD-.0D) : Essentially the same as that of Compound No.8 Compounds Nos. 8 and 9 are raeemates that may be resolved by conventional means to obtain the 3R,5S and 3S,5R enantiomers (no. 8) and 3R,5R and 3S,5S (No. 9), of which the former in each case are preferred. EXAMPLE 6 Ethyl (+)-(E)-7-[3 * -(4"-fluorophenyl)-spiro[cyclopentane-l ,1 ' (IH)-inden]- -2'-yl]-3-hydroxy-5-oxohept-6-enoate (Compound No.10) A mixture of 310 mg of Compound No. 1, 600 mg of activated manganese dioxide and 5 ml of toluene is stirred under nitrogen at 20°-25°C for 24 hours, at 60°C for 8 hours, at 20°-25°C for 16 hours and at 80°C for 8 hours and allowed to cool to 20°-25°C. Diethyl ether is added, the mixture is filtered and the filtrate is evaporated at reduced pressure to obtain an oil. The oil is purified by preparative thin layer chromatography on silica gel plate utilizing 80% diethyl ether/ petroleum ether as the solvent. The band containing the product is scraped and eluted with ethyl acetate and the solution is filtered and evaporated at reduced pressure to obtain the product as a yellow solid, m.p. 107°-109°C. The product is a racemate that may be resolved by conventional means to obtain the 3R and 3S enantiomers. EXAMPLE 7 Ethyl (+_)-(E)-5,5-dimethoxy-7-[3'-(4"-f1uorophenyl )spiroCcyclopentane- 1,1 '(lH)-inden]-2'-yl]-3-hydroxyhept-6-enoate (Compound No.11) A mixture of 90 mg ofCompound No. 10, 0.1 ml of trimethyl ortho- formate, 2 mg of pyridinium p-toluenesulfonate and 3 ml of methylene chloride is stirred under nitrogen for 45 hours at 20°-25°C and evaporated at reduced pressure, and the residual oil is purified by preparative thin layer chromatography on a silica gel plate utilizing 60% diethyl ether/petroleum ether as the solvent. The band containing the product is scraped and eluted with ethyl acetate and the solution is filtered and evaporated at reduced pressure to obtain the product as a yellow oil . The product is a racemate that may be resolved by conventional means to obtain the 3R and 3S enantiomers. The following compounds may be prepared analogously or as otherwise described hereinbefore. T A B L E I Compounds of Group IAa ( wherein Ro is. ring A) T A B L E II (Compounds of Group IAb; Ro = ring A) T A B L E III (Compounds of Group IBa; Ro = ring A) T A B L E IV (Compounds of Group IBb; Ro = ring A) T A B E V (Compounds of Group IBa) T A B L E VI (Compounds of Group IBc; Ro = ring A) In Tables I - VI DI = approximately 1:1 mixture of diastereoisomers with respect to the 1-position of the indene ring E = erythro racemate T = threo racemate cis = cis lactone trans - trans lactone Thus, for example, "DI; E:T =Λ85:15" means that the compound is a mixture of eight stereoisomers wherein the ratio of the four erythro stereoisomers to the four threo stereoisomers is about 85:15 and the ratio of the four stereoisomers wherein R, has one configuration to the four stereoisomers wherein R, has the opposite configuration is about 1:1. N.M.R. Data Cmpd. o. 12 (CDC1 3 ): 0.3 (d (J-10 Hz.), 3H), 1.2 (t, 3H) , 1.35 (d (J-10 Hz.), 3H), 1.7 (in, 2H) , 2.5 (m, 2H) , 3.3 (s, 1H), 3.7 (m, 1H) , 4.2 (q, 2H) , 4.3 (m, 1H), 4.5 (m, 1H), 5.8 (dd (J -10 Hz., J 2 -20 Hz.), 1H), 6.5 (d (J-20 Hz.), 1H) , 7.0-7.5 (m, 8H) 13 (CDCI3+CD3OD): 0.35 (d (J-10 Hz.), 3H) , 1.4 (d (J-10 Hz.), 3H), 1.65 (m, 2H), 2.2-2.6 (m, 3H), 3.75 (bs, 1H), 4.15 (m, 1H), 4.4 (m, 1H), 5.9 (dd (J -10 Hz., J 2 » 20 Hz.), 1H), 6.55 (d (J-20 Hz.), 1H), 7.0-7.5 (m, 8H) 14 (CDCI3): 1.3 (t, 3H), 1.5 (d, 6H) , 1.6-1.9 (πt, 2H), 2.5 (d, 2H), 4.2 (q, 2H), 4.3 (m, 1H), 4.5 (m, 1H), 6.0 (dd (J -10 Hz., J 2 -20 Hz.), 1H), 6.55 (d (J-20 Hz.), 1H), 7.1-7.4 (in, 8H) 15 (CDCI3+CD3OD): 1.4 (d, 6H), 1.5 (ID, 2H) , 2.2 (m, 2H) , 4.15 (m, 1H), 4.3 (m, 1H) , 5.9 (dd Jτ-10 Hz., J 2 -20 Hz.), 1H), 6.4 (d (J-20 Hz.), 1H), 7.0-7.4 (m, 8H) 16 (COCI3): 0.35 (m, 6H), 1.3 (t (J-10 Hz.), 3H) , 1.7 (m, 4H), 2.0 (n, 4H), 2.5 (d (J-10 Hz.), 2H) , 4.2 (q (J-10 Hz.), 2H) , 4.3 (m, 1H) , 4.45 (m, 1H), 5.9 (dd (Jj-IO Hz., J 2 -20 Hz.), 1H), 6.5 (d (J-20 Hz.), 1H), 7.1-7.4 (m, 8H) 17 (CDCI3+CD3OD): 0.35 (n, 6H), 1.7 (in, 2HJ , 2.0 (m, 4H) , 2.3 (m, 2H), 4.1 (m, 1H), 4.35 ( , 1H), 5.9 (d (J j -10 Hz., J 2 -20 Hz.), 1H), 6.5 (d (J-20 Hz.), 1H), 7.0-7.5 (m, 8H) C pd.No. 18 (CDC1 3 ): 1.25 (t, 3H), 1.5 (d (J-8 Hz.), 6H), 1.55-1.9 (m, 2H), 2.35 (s, 6H), 2.5 (d, 2H), 4.15 (q, 2H), 4.3 (m, 1H), 4.45 (m, 1H), 5.9 (dd (Jl-10 Hz., J2-20 Hz.), 1H), 6.55 (d (J-20 Hz.), 1H), 7.0-7.4 (tn, 7H) 19 (CDCI3+CD3OD): 1.4 (d, 6H), 1.5-1.9 (m, 2H), 2.2-2.5 (m, 8H), 4.1 (m, 1H), 4.45 ( , 1H), 5.9 (dd (Jτ-10 Hz., J2-20 Hz.), 1H), 6.5 (d (J-20 Hz.), 1H), 7.0-7.4 (m, 7H) 20 (CDCI3): 0.35 (d (J-10 Hz.), 3H), 1.4 (d (J-10 Hz.), 3H), 1.8-2.2 (m, 3H), 2.4-2.9 (m, 3H), 3.8 (bs, 1H), 4.45 (ba, 1H), 5.3 (m, 1H), 5.9 (dq, 1H), 6.6 (d (J-20 Hz.), 1H), 7.0-7.6 (m, 8H) 21 (CDCI3): 0.35 (d (J-10 Hz.), 3H), 1.4 (d (J-10 Hz.), 3H), 1.8-2.2 (m, 2H), 2.25-3.05 (m, 4H), 3.8 (bs, 1H), 4.3 (m, 1H), 4.8 (m, 1H), 5.9 (m, 1H), 6.6 (d (J-20 Hz.), 1H), 7.0-7.6 (m, 8H) 22 (CDCI3): 1.5 (d (J-8 Hz.), 6H), 1.8-2.1 (m, 2H), 2.5-2.8 (m, 2H), 4.4 (m, 1H), 5.2 ( , 1H), 5.9 (dd (J1-10 Hz., 2 -20 Hz.), 1H), 6.55 (d (J-20 Hz.), 1H), 7.1-7.5 (ra, 8H) 23 (COCI3): 1.5 (d, 6H), 1.8-2.1 (m, 2H), 2.4 (s, 6H), 2.5-3.0 (m, 2H), 4.4 (m, 1H), 5.2 (m, 1H), 5.9 (dd, 1H), 6.6 (d, 1H), 6.95-7.45 (m, 7H) Cmpd.No. 24 (CDC1 3 ): 1.3 (t, 3H), 1.5-2.0 (m, 6H), 2.5 (d, 2H), 3.2 (s, IH), 3.8 (S, 1H), 4.2 (q, 2H), 4.2-4.45 ( , 2H), 5.5 (dd (J1-IO Hz., J 2 -20 Hz.), 1H) # 6.5 (d (J-20 Hz.), IH), 7.0-7.45 (m, 8H) 25 (CDCI3+CD3OD): 1.5-2.4 (m, 8H), 4.1 (m, 1H), 4.3 (m, 1H), 5.5 (dd (J -10 Hz.# J2-20 Hz.), 1H), 6.4 (d (J-20 Hz.), IH), 7.0-7.5 (m, 8H) 26 ( C 6 D 6 > °' 9 (t ' J=1 ° Hz ' 3H >' 1.1-2.4 ( m, 14H) , 3.8 (q,J=10 Hz, 2H) , 3.9-4.4 (m, 2H) , 6.0 (dd, J=20 and lOHz, IH) , 6.7 (m, IH) 6.8-7.8 (m, 8H) . 27 (CgDg) 0.9 (m, 2H) , 1.2-2.5 (m, 12H) , 3.8 (m, 2H) , 4.0 (m, IH) , 4.1-4.3 (m, IH) , 5.9 (dd,J=20 and 10 Hz IH), 6.8 (dd,J=20 and 10 Hz, IH) , 6.9-7.5 (m, 9H) . 11 (CgDg) 0.9 (t,J=10 Hz, 3H), 1.2-3.1 (m, 12H) , 3.2 (ds, 6H) , 3.9 (q,J=10 Hz, 2H) , 4.8 (m, IH) , 6.5 (d,J=20 Hz, IH) , 6.8-7.4 (m, 8H) , 7.7 (d,J=20 Hz, IH) . 28 (CDC1 3 ) 1.3 (t, 3H), 1.4-2.5 (m, 16H) , 3.7 (m, 2H) , 4.2 (q, J=10 Hz, 2H) , 6.8-7.3 (m, 8H) . Cmpd.No. 30 (CDC1 3 ) 1.8-3.0 (m, 12H) , 4.4 (m, IH) , 5.2 (m, IH) , 5.7 (dd, J-10 and 20 Hz, IH) , 6.5 (d, J=20 Hz, IH) , 7.1-7.5 ( , 8H) . The following additional smaller peaks : 4.3 (m) , 4.7 ( ) , 5.8 (dd) , 6.45 (d) , due to the corresponding cis lactone. 29 { e D 6 ) °- 9 < fc ' J=1 ° Hz ' 3H > ' 1 - 4 (dd ' J=1 ° and 20 Hz ' 6H) , 1.5-2.4 (m, 12H) , 3.4 (m, IH) , 3.8 (q, J=10 Hz, 2H), 4.15 (m, IH) , 4.4 (m, IH) , 5.8 (dd, J=20 and 10 Hz, IH) , 6.9 (dd, J=20 and 1 Hz, IH) , 7.0-7.6 (m, 4H) . The following small peaks at 4.55 (m), 5.9 (dd) , 6.8 (d) , due to the threo isomer. All nuclear magnetic resonance spectra were taken at ambient temperature on a 200 MHz. spectrometer. All chemical shifts are given in p.p.m. (£ ) relative to tetra ethylsilane, and where a single S value is given for anything other than a sharp singlet, it is its center point. In the N.M.R. data: bs = broad singlet d = doublet dd = doublet of a doublet dq = doublet of a quartet m = multiplet q - quartet s = singlet t = triplet ds = double singlet

Claims: WE CLAIM: 1. A compound of formula I wherein R is hydrog secondary C, g alkyl, R, is primary or secondary C, g alkyl or R and R- together are (CH 2 ) m or (Z)-CH 2 >CH=CH-CH 2 - wherein m is 2, 3, 4, 5 or 6, Ro is C, g alky1, or ring A each of R, and R. is inde d l h d ogen, C, .alkyl, C, 4 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzylox each of R 3 and R ς is independently hydrogen, C, -alkyl, C, -.alkoxy, triflu methyl, fluoro, chloro, phenoxy or benzyloxy, Rg is hydrogen, C, -alkyl, C, -alkoxy, fluoro or chloro, with the proviso that there may only be one each of trifluoromethyl, pheno or benzyloxy on each of the phenyl and indene rings X is -(CHJ - or -(CH-) CH=CH(CH 9 ) - 2 n 2 q 2 q wherein n is 1, 2 or 3 and both q's are 0 or one is 0 and the othe is 1, wherein Q is - • CC--,, - - .Cc_ -- or -C ( H- β 1 1 OH R 7 R- wherein each R- is the same primary or secondary C, .alkyl or togeth they represent -(CH^-, -(CH 2 ) 3 -, R. Q is hydrogen or C, -alkyl, with the proviso that Q may be other than -CH- only when X is -CH=CH- or -CH 2 -CH=CH- and/or R- Q is C^alkyl, OH in free acid form, or in the form of an ester or -1actone thereof or in salt form as appropriate. 2. A compound according to Claim 1 wherein Ro represents ring A R is hydrogen or primary or secondary C, g alky1 not containing an asymmetri carbon atom, and R. is primary or secondary C, g alkyl not containing an asymmetric carbon atom or R and R- taken together are -(CH^- or (Z)-CH 2 -CH=CH-CH 2 -, wherein m is 2, 3, 4, 5 or 6, R- is hydrogen, C, -alkyl, n_-butyl, i_-butyl, t-butyl, C, 3 alkoxy, -butoxy, i_-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R- is hydrogen, C, -alkyl, C, -alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the proviso that not more than one of R- and R 3 is trifluoromethyl, not more than one of R- and R 3 is phenoxy, and not more than one of R 2 and R 3 is benzyloxy, R. is hydrogen, C, 3 alkyl, in-butyl, i_-butyl, ^-butyl, C, 3 alkoxy, ii-butoxy, i_-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R 5 is hydrogen, C, -.alkyl, C, -.alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R g is hydrogen, C. -alkyl, C, 2 alkoxy, fluoro or chloro, with the provisos that not more than one of R 4 and R- is trifluoromethyl not more than one of R 4 and Rς is phenoxy, and not more than one of R 4 and R- is benzyloxy, X i s "(CH 2 ) n - or (E)-CH-CH-, wherein n i s 1 , 2 or 3, and R 10 Z i s wherein R, Q is hydrogen or C, 3 alkyl, and R... is hydrogen, R. 2 or M, wherein R- 2 is a physiologically acceptable and hydrolyzable ester group, and M is a pharmaceutically acceptable cation. 3. A compound according to Claim 1, wherein R, R,, Ro, 2 to R g , X and Z have meanings selected from those hereinbefore defined in groups (i) to (lvi). 4. A compound selected from erythro-(E)-3,5-dihydroxy-7-[3'-(4"-f1uoro- phenyl)-spiro[cyclopentane-l,l' (lH)-inden]-2'-y|j-hept-6-enoic acid and erythro-(E)-3,5-dihydroxy-7-[3'-(3",5"-dimethylpheny1)-spiro[cyclopentane- 1,1' (lH)-inden]-2'-yl]hept-6-enoic acid in free acid or salt form. 5. A compound according to Claim 4 in sodium salt form. 6. A pharmaceutical composition comprising a compound according to Claim 1 as appropriate in free acid form or in the form of a physiologi¬ cally hydrolysable and -acceptable ester or a lactone thereof or in pharma¬ ceutically acceptable salt form, together with a pharmaceutically acceptable diluent or carrier. 7. A compound according to Claim 1 as appropriate in free acid form or in the form of a physiologically-hydrolysable and -acceptable ester or a lactone thereof or in pharmaceutically acceptable salt form for use as a pharmaceutical. 8. A compound according to Claim 1 as appropriate in free acid form or in the form of a physiologically-hydrolysable and -acceptable ester or a lactone thereof or in pharmaceutically acceptable salt form for use in inhibiting cholesterol biosynthesis or treating atherosclerosis. 9. A process for preparing a compound according to Claim 1 which comprises hydrolysing a compound of formula I in ester or lactone form or esterifying or lactonising a compound of formula I in free acid form and when a free carboxyl group is present recovering the compound obtained in free acid form or in the form of a salt. 10. A process for preparing a compound according to Claim 1 which comprises a) when X is (CH or (E)-CH=CH- and R. Q is hydrogen reducing a compound of formula IV IV wherein R_ 3 is a radical forming an ester, and X- is (CH 2 ) n or (E)-CH=CH-, b) when X is (CH or (E)-CH=CH- and R. Q is C^alkyl hydrolysing a compound of formula XII Ind-X XII R 14 wherein R, Q is ^ -alkyl, R- . is part of an ester forming group and X. and R, 3 are as defined above, c) when X is -CH=CH- or -CH 2 >CH=CH- and lib is in 4R.6S configuration or X configuration deprotecting a XXXIX wherein X" represents -CH 2 CH 2 , -CH 2 CH 2 CH 2 , -CH=CH- or -CH 2 CH=CH- and Pro is a protecting group, d) when X is -(CH^-, -(CH 2 ) 3 -, -(CH 2 ) CH=CH(CH 2 ) - deprotecting a compound of formula XXXII Ind-X"'-CH-CH--C-CH-C00R.- XXXII I 2 , 2 13 OPro OPro wherein X"' is -(CH^-, -(CH 2 ) 3 - or -(CH 2 ) -CH=CH-(CH 2 ) -, and q, R,-, R, 3 and Pro are as defined above, e) when Q is -C- oxidising the corresponding compound of formula I wherein f) when Q is -' ** *- and II is in ester form ketalising the corresponding I I R, R 7 co pound of formul 'a I wherein Q is -£C- g) hydrolysing a compound of formula I in the form of an ester or a lactone o h) esterifying or lactonising a compound of formula I in free acid form, and when a free carboxyl group is present, recovering the compound obtained in free acid form or in the form of a salt. 11. A compound of formulae IV, XII, XXXII, XXXIV, XXXVII, XXXIX, XLVI, XLVIII, L-LII, LV, LVII-LIX, LX, XI, LXIV. 12. A compound according to Claim 1 or a process according to Claim 10 substantially as hereinbefore described with reference to Examples 1 to 7 and/or compounds 1 to 30.

Inventors: KATHAWALA FAIZULLA G, WATTANASIN SOMPONG, KATHAWALA, FAIZULLA, G., WATTANASIN, SOMPONG
Applicants: SANDOZ AG
Application year: 1985
Main classification: C07C69
IPC codes: C07C17, C07C27, C07C33, C07C41, C07C43, C07C45, C07C47, C07C51, C07C57, C07C59, C07C67, C07C69, C07D309, C07F7