HMG-CO A REDUCTIVE INHIBITORS

Abstract: Compounds of either general formulae (I) and (II), wherein R<1> represents C1-8 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl(C1-8)alkyl, C2-8 alkenyl, or C1-6 alkyl substituted phenyl group; R<3> represents a hydrogen atom or a substituent R<4> or M; R<4> represents a C1-5 alkyl group, or a C1-5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino, or acetylamino; R<5> represents a hydrogen atom or C1-3 alkyl group; M represents a cation capable of forming a pharmaceutically acceptable salt; Q represents C=O or CHOH; and each of a and b is independently a single or double bond are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and, therefore, are useful in the treatment or prevention of hypercholesterolaemia, hyperlipoproteinaemia and atherosclerosis.

Description: HMG-CO A REDUCTIVE INHIBITORS This invention relates to pharmaceutically active compounds, which are substituted decalins. The compounds of the present invention are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) , the rate limiting enzyme in the biosynthesis of cholesterol in mammals including man, and as such are useful in the treatment of hypercholesterolaemia and hyperlipidaemia. Clinical evidence shows that reduction of serum cholesterol levels leads to a decreased risk of heart disease. The natural fermentation products compactin (disclosed by A. Endo, et al. in Journal of Antibiotics. 29, 1346-1348 (1976)) and mevinolin (disclosed by A.W. Alberts, et al. in J. Proc. Natl. Acad. Sci. U.S.A.. 77 , 3957 ( 1980 ) ) are very active antihypercholesterolaemic agents which limit cholesterol biosynthesis by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme and natural point of cholesterolgenesis regulation in mammals, including man. Compactin (R = H, a = double bond) and mevinolin (R = α-CH 3 , a = double bond; also known as lovastatin) have the structures shown below:- Also known in the art are the natural products dihydrocompactin (R = H, a = single bond) disclosed by Y.K.T. Lam et al. , Journal of Antibiotics. 34, 614-616 (1981), dihydromevinolin (R = α-CH 3 , a = single bond) disclosed by G. Albers-Schonberg et al. , Journal of Antibiotics. 34, 507-512 (1981), and eptastatin (R = β-OH, a = double bond) disclosed by N. Serizawa et al. , in Journal of Antibiotics. 36, 604-607 (1983) . US-A-4293496 (Willard) discloses a number of semi-synthetic analogues of mevinolin having the structure where the dotted lines represent single or double bonds and R is C 1 _ 8 straight chain alkyl, C 3 _ 10 branched chain alkyl except (S)-2-butyl, C 3 _ 10 cycloalkyl, C 2 -_ι 0 alkenyl, c ι-ιo F 3 substituted alkyl, halophenyl, phenyl C 1 _ 3 alkyl and substituted phenyl C 1 _ 3 alkyl. US-A-4444784 , US-A-4661483 , US-A-4668699 , and US-A-4771071 (Hoffman) disclose compounds of similar structure where the R group contains extra functional groups, for example ether, amide and ester groups. In J. Med. Chem.. 29, 849-852 (1986), .F. Hoffman et al. report the synthesis and testing of a number of the analogues referred to above, the preferred compound (now known as simvastatin) having the structure US-A-4820865 (Terahara) discloses compounds having the structure wherein R represents a Cτ__ 10 alkyl group. In general, the above patents also cover compounds in which the delta lactone has been hydrolysed to a delta hydroxy acid or a salt of that acid. None of the cited patents and articles disclose or suggest the possibility of preparing the compounds of the present invention. The unique pattern of substituents on the decalin ring system differs from the cited art, whilst the compounds exhibit potent HMG-CoA activity. The present invention provides novel decalin based compounds which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and, therefore, are useful in the treatment or prevention of hypercholestero1aemia , hyperlipoproteinaemia and atherosclerosis. According to a first aspect of the invention there is provided a compound of either formulae I and II: wherein: R 1 represents C-^g alkyl, C 3 _ 8 cycloalkyl, C 3 _ 8 cycloalkyl(C^g)alkyl, c 2- 8 or ι- 6 a lfcγl substituted phenyl group; R 3 represents a hydrogen atom or a substituent R 4 or M; R 4 represents a - - ζ alkyl group, or a C 1 _ 5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino, or acetylamino; R 5 represents a hydrogen atom or a C^- j alkyl group; M represents a cation capable of forming a pharmaceutically acceptable salt; Q represents C=0 or CHOH; and each of a and b are independently a single or double bond. The term "C^g alkyl" refers to a straight or branched chain alkyl moiety having one to eight carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl, dimethyl-propyl, hexyl, and octyl, and cognate terms (such as "C-^g alkoxy") are to be construed accordingly. The term "C 3 _ 8 cycloalkyl" refers to a saturated alicyclic moiety having from 3 to 8 carbon atoms arranged in a ring and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. The term H C 2 _ 8 alkenyl" refers to a straight or branched chain alkyl moiety having one to eight carbon atoms and having in addition at least one double bond, of either E or Z stereochemistry where applicable. This term would include, for example, vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl. The term "substituted", as applied to a phenyl or other aromatic ring, means substituted with up to four substituents each of which independently may be C^g alkyl, Cχ- ζ alkoxy, hydroxy, thiol, amino, halo (including fluoro, chloro, bro o, and iodo) , trifluoromethyl or nitro. The phrase "a pharmaceutically acceptable salt" as used herein and in the claims is intended to include non-toxic alkali metal salts such as sodium, potassium, calcium and magnesium, the ammonium salt and salts with non-toxic amines such as trialkylamines, dibenzylamine, pyridine, N-methylmorpholine, N-methylpiperidine and other amines which have been used to form salts of carboxylic acids. There are several chiral centres in the compounds according to the invention because of the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms gives rise to a number of diastereoisomers with the appropriate R or S designated stereochemistry at each asymmetric centre. General Formulae I and II and, where appropriate, all other formulae in this specification are to be understood to include all such stereoisomers and mixtures (for example racemic mixtures) thereof. Disregarding any asymmetric centers that may be present in the groups R 1 , R 3 , and R 5 , the preferred relative and absolute stereochemistry is as shown in formula III. More specifically for the compound III the Cahn, Ingold, Prelog designations for the absolute configurations are 1(S), 2(S), 4a(R) , 6(R) , 8(S), 8a(S), 4'(R), 6'(R). (III) It is preferred that all of the compounds of Formulae I and II should have (wherever possible) the same spacial orientation of groups at each chiral carbon atom and therefore belong to the same stereochemical series. The R-S designation for each center may not be identical to that found for compound III because of the details of the sequence rules for determining that designation. Clearly in compounds of Formula II in which Q is the group C=0 then the carbon atom labelled C-6' is not an asymmetric centre. In compounds of Formula II in which Q is the group CHOH, the preferred stereochemistry is that in which the two carbon atoms bearing the hydroxy groups have the same spatial arrangement as the corresponding carbon atoms in the lactone in compound III. The preferred isomer is referrred to as the syn diol. The preferred compounds include those in which independently or in any combination: R 1 represents C 4 _ 6 branched alkyl; R 3 is R 4 R 4 represents l . 5 alkyl and more preferably methyl or ethyl; R 5 represents methyl; Q represents CHOH; and/or b is a single bond. Each M is preferably free from centres of asymmetry and is more preferably sodium, potassium or ammonium, and most preferably sodium. For simplicity, each formula in which an M appears has been written as if M were monovalent and, preferably, it is. However, M may also be divalent or trivalent and, when it is, it balances the charge of two or three carboxylic acid groups, respectively. Thus Formula II and every other formula containing an M embraces compounds wherein M is divalent or trivalent, e.g. compounds containing two or three mono carboxylate-containing anions per cation M. Particularly preferred compounds are 1) Methyl 7-{l-[(lS, 2S, 4aR, 6R, 8S, 8aS)-6-hydroxy- 8-[(2(S)-methyl-l-oxobutyl)oxy]-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro-2-methylnaphthalenyl] }-3(R) ,5(R)- dihydroxyheptanoate 2) (IS, 2S, 4aR, 6R, 8S, 8aS, 4'R, 6'R, 2"S)-6'-[2- (1 , 2 , 4a, 5 , 6 , 7 , 8 , 8a-octahydro-6-hydroxy- 2-methyl-8- [ (2"-methyl-l"-oxobutyl) oxy] -1-naphtha- lenyl ] ethyl ] tetrahydro-4 ' -hydroxy-2H-pyran-2 ' -one 3) Sodium 7- { l- [ ( lS , 2S , 4aR, 6R, 8S , 8aS) -6- hydroxy-8-[ (2(S)-methyl-l-oxobutyl)oxy]-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro-2-methylnaphthalenyl] }- 3(R) ,5(R)-dihydroxyheptanoate For simplicity the compounds of Formula II may be subdivided according to the exact form of R 3 and Q. Thus the compounds in which Q is the group C=0 and R 3 is a group of formula R 4 are considered to be compounds of the subgroup Ila, whereas if R 3 is M the ketones are in the subgroup lie. Compounds in which Q is the group CHOH and R 3 is a group of form R4 make up the subgroup lib, when R 3 is hydrogen the compounds are of subgroup lie, and when R 3 is a group of formula M the compounds are of the subgroup lid. The present invention also provides novel processes for the preparation of the compounds of general formulae I and II as well as certain intermediates in their preparation, as will now be described by reference to the drawings, in which:- Figure 1 shows reaction scheme I, which shows the interconversion of compounds of general formula I with subgroups Ila, lib, lie and lid; Figure 2 shows reaction scheme II, which shows a preparative route of compounds of subgroups Ila and He from compounds of general formula XIV, which in turn are preparable from compounds of general formula VII; Figure 3 shows reaction scheme III, which shows a different preparative route of compounds of general formula XIV, this time from compounds of general formula XV; and Figure 4 shows reaction scheme IV, which shows a preparative route of compounds of general formulae VII and XV from compounds of general formulae XXII, which in turn may be prepared from compounds of general formula XXIII. The compounds of the various subgroups Ila-IId of general formula II (hereafter referred to as general formulae Ila to lid) , and those of general formula I, may be prepared by the general reaction route shown in Scheme I in which R 1 , R 4 , R 5 and M are as previously defined. Unless the context otherwise requires, substituents in the general formulae in the Schemes I and II have the same values as the corresponding substituents in general formulae I and II. According to a second aspect of the invention, there is provided a process for the preparation of a compound of either of general formulae I and II, the process comprising: (a) deprotecting and optionally reducing a compound of general formula XIV as shown in Scheme II in Figure 2 to form a compound of general formula Ila; and (b) optionally after step (a) converting a compound of general formula I or Ila directly or indirectly into another compound of general formula I or II. A ketone of general formula Ila may be reduced to a dihydroxy ester of general formula lib by reduction of the ketone group with a reducing agent such as those well known in the art e.g. sodium borohydride, sodium cyanoborohydride, zinc borohydride, lithium tri-s_-butylborohydride or other similar reducing agents that will not reduce the ester functionality. Preferably, the reaction is carried out in such a manner as to maximize the production of the preferred syn isomer of the compound of general formula lib. The stereoselective reduction of compounds of general formula Ila is preferably carried out in two stages, in the first stage the ketone ester is reacted with a trialkylborane, preferably tri-n-butyl borane, or an alkoxydialkylborane, preferably methoxydiethylborane or ethoxydiethylborane (Chemistry Letters. 1987, 1923-1926) at a temperature between -78 β C and ambient temperature in an inert organic solvent such as tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane, and optionally in the presence of a protic solvent such as methanol or ethanol, and preferably in a mixture of tetrahydrofuran and methanol. The complex which is thus produced is then reduced with sodium borohydride at a temperature between -78*C and -20 * C. The resulting compound of general formula lib produced from the stereoselective reduction contains two asymmetric carbon atoms bearing hydroxyl groups in a svn configuration. Thus reduction of the ketone radical under the preferred conditions described herein produces mostly the syn isomers of compounds of general formula lib and only a small amount of the less preferred anti isomers. The ratio of isomers produced will vary according to the specific compound utilized and the reaction conditions employed. Normally, this ratio will be approximately 9:1 to 9.8 : 0.2. However, the use of a non-specific reduction method will normally produce a near 1:1 mixture of diastereoisomers. Nevertheless, the mixture of isomers may be separated and purified by conventional techniques and then converted to the compounds of general formula I in a conventional manner well-known to those skilled in the art. The compounds of general formula lib may be cyclised to the corresponding lactones of general formula I for example by heating in an inert organic solvent such as benzene, toluene or xylene and azetropically removing the alcohol which is produced. Preferably, the lactonisation is carried out by heating the compounds of general formula lib with an acid, preferably p_-toluenesulphonic acid, in benzene or toluene, evaporating the solvent and alcohol thus formed, and repeating the process until all of the compound of general formula lib has been consumed. If the relative stereochemical configuration of the two carbon atoms bearing the hydroxy groups are established as syn in general formula lid, then lactonisation will produce the preferred trans lactone of general formula I, otherwise the lactonisation will produce a mixture of trans and cis lactones. A compound of general formula lid may be prepared from a compound of general formula lib or a compound of general formula I by hydrolysis, preferably hydrolysis with a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a mixture of water and an organic solvent such as methanol, ethanol or tetrahydrofuran at a temperature between O'C and 50°C inclusive, preferably at ambient temperature. The cation in compounds of general formula lid is usually determined by the cation of the hydroxide employed; however, the cation may then be exchanged for another cation for example by treatment with an ion-exchange resin. The compounds of general formula He may be obtained from compounds of general formula lid by neutralisation, for example by careful neutralisation with a mineral acid such as hydrochloric, sulphuric or nitric in aqueous solution, followed by extraction with an appropriate organic solvent. Alternatively, the acids of general formula He may be obtained by treating the compounds of general formula lid with an ion exchange resin. If the acids of general formula He are allowed to stand in solution they slowly re-lactonise to the compounds of general formula I. This process may be accelerated by heating a solution of the acid under conditions that remove the water formed, such as in a Dean-Stark apparatus, or by stirring the solution with a drying agent such as anhydrous sodium sulphate, magnesium sulphate or molecular sieves. Lactones of general formula I may, if desired, be hydrolysed in the presence of an alcohol and a catalytic amount of acid, preferably p_-toluenesulphonic acid, to produce compounds of general formula lib. A ketone of general formula Ila may be prepared by the methods outlined in Scheme II, in which R 1 , R 4 , and R 5 are as previously described, and P 1 , P 2 and R 11 are defined below. Compounds of general formula Ila wherein b is a double bond may be prepared by removing the protecting groups P 2 and P 3 from the compounds of general formula XIV. This may be achieved in the preferred cases in which P 2 and P 3 are trialkylsilyl or alkyldiarylsilyl by the use of conditions that generate fluoride anions, and preferably by using tetrabutylammonium fluoride in tetrahydrofuran buffered with acetic acid or hydrofluoric acid in aqueous acetonitrile. Compounds of general formula Ila wherein b is a single bond may be obtained from compounds of general formula Ila wherein b is a double bond by reduction of the carbon-carbon double bond of the enone system, using reagents and conditions that do not affect the other functional groups present. Examples of such reagents are sodium hydrogen telluride, triphenyltin hydride, or tri-n-butyl tin hydride with a palladium or platinum catalyst. Compounds of general formula Ila wherein b is a single bond may also be prepared from enones of general formula XIV by reduction of the double bond followed by deprotection. For example it is possible to reduce the double bond by treatment of the enone with a trialkylsilane, preferably triethylsilane, and a catalyst such as tris(triphenylphosphine) rhodium chloride [Wilkinson's catalyst] either neat, using an excess of the silane, or in an inert hydrocarbon solvent such as benzene or toluene at a temperature between ambient and reflux, preferably 50-70 β C. The crude silyl enol ether thus produced is treated with hydrofluoric acid in aqueous acetonitrile to give the compound of general formula Ila in which b is a single bond. However, the preferred method of transformation of the compound XIV is to treat firstly with a reducing agent such as sodium hydrogen telluride, or such mixtures as tri-n-butyltin hydride with a palladium or platinum catalyst and then deprotect in a second and separate reaction, in a manner similar to the deprotection of the compound of general formula XIV. Compounds of general formula He may be prepared from compounds of general formula Ha by hydrolysis with a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a mixture of water and an organic solvent such as methanol, ethanol or tetrahydrofuran at a temperature between O'C and 50 ° C, preferably ambient temperature. The cation in compounds of general formula He is usually determined by the cation of the hydroxide employed; however, the cation may then be exchanged for another cation by treatment with, for example, ion-exchange resins. Compounds of general formula Ila may be used as intermediates in the production of compounds of general formulae Ilb-e and of general formula I as detailed in Scheme I, or they may be used as HMG-CoA reductase inhibitors in their own right. An enone of general formula XIV may be prepared from an aldehyde of general formula XII by reaction with a phosphonate of general formula XIII in which R 11 is a lower alkyl group (e.g. C l . Q or, preferably, C^^ alkyl group such as methyl or ethyl) , and the group P 2 is any group suitable for the protection of hydroxyl groups, but preferably trialkylsilyl or alkyldiarylsilyl. The reaction between the aldehyde of general formula XII and the phosphonate of general formula XIII is preferably carried out in either of the following two ways. In a first method the aldehyde of general formula XII and phosphonate of general formula XIII are reacted together in the presence of a chelating metal halide such as lithium chloride or magnesium bromide and a mild organic base such as triethylamine or l,8-diazabicyclo[4.5.0]undec-7-ene (DBU) in an inert solvent such as acetonitrile or dimethylsulphoxide at ambient temperature. In a second method the phosphonate of general formula XIII is first treated with a strong organic base such as lithium diisopropylamide or lithium or sodium bis(trimethylsilyl)amide in an inert organic solvent such as diethyl ether or tetrahydrofuran at a temperature between -78 # C and O'C, the aldehyde of general formula XII added at the same temperature, and the mixture allowed to warm to ambient temperature, all under an inert atmosphere. An aldehyde of general formula XII may be prepared from an alcohol of general formula X by conventional oxidation reagents such as pyridinium chlorochromate or pyridinium dichromate, or by using a catalytic quantity of tetra-n.-propylammonium per-ruthenate and N-methylmorpholine N-oxide, in an inert organic solvent such as dichloromethane or tetrahydrofuran, but preferably the oxidation is carried out using Swern , s protocol. An intermediate alcohol of general formula X may be prepared for example in either of two ways from a diol of general formula VII. In the first method the diol of general formula VII is di-acylated for example by treatment with an excess of an acid anhydride ((R 1 C0) 2 0)or acid halide (R^-CO.Hal) in the presence of a catalyst such as 4-(N,N-dimethylamino)pyridine, and a base such as triethylamine or pyridine until both hydroxyl groups in the compound of general formula VII have reacted. The diacylated compound of general formula XI is then hydrolysed for example by treatment with an alkali metal hydroxide such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a solvent such as water or an alcohol, or a mixture of such solvents, at a temperature between 0 β C and ambient for a time suitable to maximise the production of the alcohol of general formula X. In the second and preferred of the two exemplary methods the diol of general formula VII is treated under conditions that will selectively protect the primary alcohol, either as an ester or an ether. Such conditions are well known to one skilled in the art, but the preferred conditions are to treat with one equivalent of a trialkylsilylchloride in the presence of imidazole and optionally, a mild organic base such as triethylamine or pyridine, and preferably using dichloromethane or chloroform as a solvent. The product of such a reaction will be a compound of general formula VIII wherein P 1 is a trialkylsilyl moiety or other protective group. The compound of general formula VIII is then acylated, for example using the conditions described above, that is treatment with the appropriate acid halide (R 1 CO.Hal) or preferably the anhydride ((R 1 CO) 2 0) using a mild organic base such as triethylamine or pyridine and optionally using a catalyst such as 4-(N,N-dimethylamino)pyridine. The resulting intermediate compound of general formula IX, may then be deprotected to give the alcohol of general formula X using such conditions as are appropriate for the removal of the group P , without affecting the rest of the molecule. For the removal of the preferred trialkylsilyl group, the preferred method is to treat the protected alcohol of general formula IX with a very mild acid or acid salt, for example pyridinium p-toluenesulphonic acid, in a solvent such as methanol or ethanol. However, it will be appreciated by one skilled in the art that other methods are available for the removal of the preferred group, or that other protecting groups may be used in the transformation of the diol of general formula VII to the alcohol of general formula X. Intermediate compounds of general formula XIV may also be synthesised from the protected alcohols of general formula XV using the sequence of reactions shown in Scheme HI, in which R 4 , R 5 , R 11 , P 2 and P 3 are as previously defined, and P is defined below. An intermediate of general formula XIV may be prepared from an enone of general formula XVIII by acylation for example using conventional means. Thus a compound of general formula XIV may be prepared by treating an alcohol of general formula XVIII with an acid halide such as a chloride or bromide (R 1 CO.Hal), or, preferably, an anhydride ((R 1 C0 2 0) in the presence of a mild organic base such as pyridine or triethylamine, and preferably using a catalyst such as 4-(N,N-dimethylamino)pyridine, either neat or in an inert solvent, preferably dichloromethane or chloroform at a temperature between 0°C and reflux. Alternatively the transformation may be carried out using the acid (R 1 C0 2 H) and a coupling reagent such as a carbodiimide and a catalyst such as N,N-dimethylaminopyridine, in an inert solvent and preferably at ambient temperature. An enone of general formula XVIII may be prepared from an aldehyde of general formula XVII and a phosphonate of general formula XIII as defined above, for example by using a chelating metal halide such as lithium chloride or magnesium bromide and a mild organic base such as triethylamine or DBU in an inert organic solvent preferably acetonitrile or dimethylsulphoxide, at a temperature from 0°C to ambient and preferably under an inert atmosphere. To prepare an aldehyde of general formula XVII an alcohol of general formula XV, in which the group P 4 is any group suitable for the protection of alcohols, may be oxidised to an aldehyde of general formula XVI for example by conventional means such as pyridinium chlorochromate or pyridinium dichromate, or by using a catalytic quantity of tetra-n_-propylammonium per-ruthenate (TPAP) in the presence of N-methylmorpholine N-oxide in an inert solvent, preferably dichloromethane , but most preferably by using S ern's protocol. The protecting group P 4 may then be removed by any appropriate method known in the art to give a hydroxy aldehyde of general formula XVII. The intermediate alcohols VII and XV required for the syntheses outlined in reaction schemes II and HI may be prepared as shown in general reaction scheme IV, in which R 5 , P 3 and P 4 are as previously defined and R 10 is lower alkyl, preferably methyl or ethyl. The intermediate alcohols of general formula VII may be prepared by reduction of the ester group in the compounds of general formula XXII using conventional reagents such as lithium aluminium hydride, di - is obuty 1 alumin ium hydride or lithium triethylborohydride in an inert organic solvent such as diethyl ether or tetrahydrofuran, at ambient temperature to reflux, under an inert atmosphere. The alcohols of general formula VII may be then be used as outlined in scheme II. An intermediate of general formula XV may be obtained from an ester of general formula XXII by first protection and then reduction. The protective group P 4 may be any ether group known in the art for the protection of alcohols, for example trialkylsilyl, alkoxymethyl, benzyl, or substituted benzyl ethers, and may be introduced using the conventional methods for such groups. The reduction of the ester group may then be carried out using the conventional methods described above, to yield the alcohol of general formula XV which may then be used as outlined in scheme III. The intermediate of general formula XXII may be prepared in two steps from the ester of general formula XXVII. In the first step the acetate group is removed, for example by ester exchange using either acidic or basic conditions, but preferably by treatment with a solution of sodium ethoxide in ethanol at ambient temperature. In the second step the hydroxyl group released in the first step is protected with the group P 3 , where P 3 is as previously defined. This transformation may be carried out in any suitable manner known in the art, but in the preferred case in which P 3 is an alkyldiarylsilyl group, the reaction is preferably performed by treating the alcohol with an alkyldiarylsilylchloride in the presence of a mild base such as imidazole, in a solvent such as dimethyl- formamide, chloroform or dichloromethane. The intermediate acetate of general formula XXVII may be obtained from the methyl ketone of general formula XXV by means of, for example, the Baeyer-Villiger reaction. The application of this reaction to the synthesis of novel compounds constitutes an important aspect of this invention. For example, the ketone of general formula XXV may be treated with a per-acid such as peracetic acid, trifluoroperacetic acid or trimethylsilyl peroxide in an inert solvent such as dichloromethane or chloroform. Optionally the double bond (if present) in the compound of general formula XXV may be protected prior to the oxidation reaction, for example by reacting with bromine to give the dibromo-derivative; after oxidation of the methyl ketone group in a manner similar to that described above the double bond may be restored by treatment of the product of oxidation with zinc in acetic acid to yield the acetate of general formula XXVII. The methyl ketone of general formula XXV may be obtained from the lactone of general formula XXIII for example by either of the two following methods. In a first method the keto-sulphone of general formula XXIV may be produced from the lactone of general formula XXIII by reaction with an anion or dianion of methyl sulphone in an inert organic solvent, preferably tetrahydrofuran, at -78 β C to ambient temperature under an inert atmosphere. The methyl ketone may then be obtained by treating the keto-sulphone with a reagent that can selectively remove the sulphone group, such as Raney nickel, sodium amalgam or aluminium amalgam in a solvent such as an alcohol, or by treatment with tributyltin hydride. In a second and preferred method the lactone of general formula XXIII is reacted with the anion of tert-butyl acetate (generated by conventional means) in a solvent such as tetrahydrofuran or diethyl ether under an inert atmosphere at a temperature from -70*C to ambient. The ketone of general formula XXVI thus obtained may then be treated with a strong acid such as trifluoroacetic acid in a solvent such as dichloromethane or tetrahydrofuran optionally containing a little water, at room temperature, to give the methyl ketone of general formula XXV. The ketone of general formula XXV may be used as obtained from either of the two methods outlined above, or if desired the stereochemistry of the carbon atom to which the methyl ketone group is attached may be altered by treatment with a mild base such as a sodium alkoxide in an alcoholic solvent. This treatment may give a product of general formula XXV in which the methyl ketone group is mainly in the equatorial position and only small amount in the axial position. Intermediates of general formula XXIII in which R 5 is methyl, R 1 is ethyl, and a is a double bond, are known in the literature (J. Chem. Soc.. Chem. Commun. f 1987, 1986) . Those intermediates in which R 5 and R 10 are other groups within the appropriate definitions may be prepared using routes analogous to the known route, but using the appropriately different starting materials. Such a change is within the scope of one skilled in the art. Methods for the reduction to give as a single bond in compounds with structures similar to the compounds of general formulae I, II, VTI - XII, and XIV - XXVII are known in the art (for examples, see Tetrahedron 1986, 42, 4909-4951 or US-A-4826999) . Some of these methods may use reagents that deleteriously affect the compounds of general formulae I, II, VII - XII, and XIV - XXVII; however, other methods may be suitable for the required transformations in some or all of the compounds of general formulae I, II, VII - XII, and XIV - XXVII. Thus it is within the capabilities of one skilled in the art to select appropriate methodology for the interconversion of compounds wherein a may be a single or double bond in order to obtain the compounds of general formula I or II with the required single or double bond at a.. A phosphonate of general formula XIII in which R 4 and R 11 are methyl and P 2 is a t-butyldimethylsilyl group is known in the art (J. Orσ. Chem.. 1988, 53, 2374-2378) . In general, reagents are used in sufficient quantities to completely convert starting materials to products but to be themselves substantially consumed during the course of the reaction. However the amounts may often be varied as is evident to one of ordinary skill in the art. For example, in a reaction of two compounds one of which is not readily available and one of which is, an excess of the readily available compound may be used to drive the reaction further towards completion (unless the use of an excess would increase the synthesis of an undesired compound) . Likewise, most of the temperature ranges given in the preceding descriptions are merely exemplary, and it is within the ability of one of ordinary skill in the art to vary those that are not critical. The reaction times set forth in the preceding description are also merely exemplary and may be varied. As is well-known, the reaction time is often inversely related to the reaction temperature. Generally, each reaction is monitored by, for example, thin layer chromatography and is terminated when at least one starting material is no longer present, or when it appears that no more of the desired product is being formed. Conventional work-up procedures have generally been omitted from the preceding descriptions. As utilised in the preceding descriptions, the term "solvent" embraces mixtures of solvents and implies that the reaction medium is a liquid at the desired reaction temperature. It should, therefore, be understood that not all of the solvents listed for a particular reaction may be utilised for the entire cited temperature range. It should also be understood that the solvent must be at least substantially inert to the reactants employed, intermediates generated and end products under the reaction conditions utilised. The term "inert atmosphere", as utilised in the preceding descriptions, means an atmosphere that does not react with any of the reactants, intermediates or end products or otherwise interfere with the reaction. While a carbon dioxide atmosphere is suitable for certain reactions, the inert atmosphere is usually nitrogen, helium, neon, or argon, or a mixture thereof, and most often dry argon to maintain anhydrous conditions. Most reactions, including those where the use of an inert atmosphere is not specified, are carried out under an inert atmosphere, usually dry argon, for convenience. The product of each reaction may, if desired, be purified by conventional techniques such as recrystalisation (if a solid) , column chromatgraphy, preparative thin layer chromatography, gas chromatography (if sufficiently volatile) , fractional distillation under high vacuum (if sufficiently volatile) or high pressure (performance) liquid chromatography (HPLC) . Often, however, the crude product of one reaction may be employed in the following reaction without purification or even isolation. Some reactions, particularly those utilizing strong bases or reducing agents, require anhydrous solvents. Where this is the case solvents may be dried before use using conventional techniques and an inert atmosphere used. Some of the reactions described above may yield mixtures of two or more products, only one of which leads to the desired compound of general formula I or II. Any mixture so obtained may be separated by conventional techniques such as those set forth in the preceding paragraphs. Certain of the intermediate componds described above are believed to be novel, in particular compounds of general formulae VII-XII, XIV-XXH, and XXV-XXVII. All other intermediate compounds in which R 5 is not methyl are also believed to be novel. Novel intermediates and processes for preparing them form further aspects of this invention. Compounds of this invention are useful as antihypercholesterolaemic agents for the treatment of arteriosclerosis, hyperlipidaemia , familial hypercholesterolaemia and the like diseases in humans. According to a third aspect of the invention, there is therefore provided a compound of general formula I or II for use in medicine, particularly as antihypercholesterolaemic agents. According to a fourth aspect of the invention, there is provided the use of a compound of general formula I or II in the preparation of an antihypercholesterolaemic agent. Compounds of the invention can therefore be used in a method for the treatment or prophylaxis of hypercholesterolaemia in general and arteriosclerosis, familial hypercholesterolaemia or hyperlipidaemia in particular comprising administering to a patient an effective dose of a compound of general formula I or II or a mixture thereof. According to a fifth aspect of the invention, there is provided a pharmaceutical composition comprising a compound of general formulae I or II, or a mixture thereof, and a pharmaceutically acceptable carrier. Such a composition may simply be prepared by the admixture of the ingredients. Compounds of general formulae I and II may be administered orally or rectally or parenterally in the form of a capsule, a tablet, an injectable preparation or the like. It is usually desirable to use the oral route. Doses may be varied, depending on the age, severity, body weight and other conditions of human patients but daily dosage for adults is within a range of from about 2 mg to 2000 mg (preferably 5 to 100 mg) which may be given in one to four divided doses. Higher doses may be favourably employed as required. The compounds of this invention may also be co-administered with pharmaceutically acceptable nontoxic cationic polymers capable of binding bile acids in a non-reabsorbable form in the gastrointestinal tract. Examples of such polymers include cholestyramine, colestipol and poly[methyl-(3- trimethylamino-propyl)iminotrimethylene dihalide] . The relative amounts of the compounds of this invention and these polymers is between 1:100 and 1:15000. The intrinsic HMG-CoA reductase inhibition activity of the claimed compounds may be measured in in vitro protocols described in detail in the Examples below. Included within the scope of this invention is the method of treating arteriosclerosis, familial hypercholesterolaemia or hyperlipidaemia which comprises administering to a subject in need of such treatment a nontoxic therapeutically effective amount of the compounds of general formulae I or II or pharmaceutical compositions thereof. The following examples show representative compounds encompassed by this invention and their syntheses. However, it should be understood that they are for the purposes of illustration only. Organic solutions were dried over sodium sulphate or magnesium sulphate, and evaporated under reduced pressure. NMR spectra were recorded at ambient temperature in deuteriochlorofor at 250 MHz for proton and 62.5 MHz for carbon unless noted otherwise. All chemical shifts are given in parts per million relative to tetramethylsilane. Infra red spectra were recorded at ambient temperature in solution in chloroform, or in the solid state in a potassium bromide disc as noted, and are are expressed in reciprocal centimeters. Chromatography was carried out using Woelm 32-60 μm silica. Example 1 Methyl 7-(l-f(lS, 2S. 4aR. 6R. 8S. 8aS)-6-hvdroxy-8- r (2(S)-methyl-l-oxobutyl)oxy1-l. 2. 4a. 5. 6. 7. 8. 8a-octahydro-2-methylnaphthalenyl1 )-3 (R) .5(R) -di- hydroxyheptanoate Step 1 t-Butyl 3-[(lS, 2S, 4aR, 6S, 8S, 8aS)-6-(l-ethoxy- carbonyl-1, 2, 4a, 5, 6, 7, 8, 8a-octahydro-8-hydroxy- 2-methylnaphthalenyl) ]-3-oxopropionate (XXVI) A solution of freshly distilled tert-butyl acetate (4.4 g, 38 mmole) in dry tetrahydrofuran (5 mL) was added dropwise to a well stirred solution of lithium hexamethyldisilazide in THF (1.0 M; 38 mmole) at -78 β C under an argon atmosphere. After 3.5 hours, a solution of (+)-Ethyl (IS, 2S, 4aR, 6S, 8S, 8aS)-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro-2-methyl-6,8-naphthalenecarbo- lactone-1-carboxylate (XXIII; R 5 represents methyl, R 10 represents ethyl) (2.0 g, 7.58 mmole) in dry THF (5 L) was added dropwise, the solution stirred for 90 minutes at -70 β C then quenched with a saturated solution of ammonium chloride (15 mL) . The mixture was warmed to room temperature, then separated and the aqueous phase extracted with dichloromethane (2 x 40 mL) . The combined organic phases were washed with brine (20 mL) then dried and evaporated to leave a gum (3.34 g) which was purified by column chromatography eluting with 4:1 hexane:ethyl acetate to 1:1 ethyl acetate:hexane, to give the title compound (1.6 g, 56%). delta H 5.50 (IH, ddd, J 9.8, 4.5 and 2.5 Hz, 3-H) , 5.31 (IH, d, J 9.8 Hz, 4-H) , 4.16 (IH, m, 8-H) , 4.07 (2H, m, OCH 2 ), 3.69 (IH, m, OH), 3.44 (2H, d, J 1.8 Hz, COCH 2 CO) , 2.95 (IH, t, J 6.3 Hz, 6-H) , 2.76 (IH, dd, J 11.6 and 6.0 Hz, 1-H) , 2.52 (IH, m, 2-H) , 2.18 (IH, br d, J 16.3 Hz, 7-Hax) , 2.13 - 2.0 (2H, m, 4a-H and 5-Hax) , 1.78 (IH, ddd, J 15.2, 6.4 and 3.5 Hz, 7-Heq) , 1.45 - 1.28 (11H, m, t-Bu, 8a-H, and 5-Hax) , 1.18 (3H, t, J 7 Hz, CH 2 CH 3 ) and 0.82 (3H, d, J 7 Hz, CHCH 3 ) . delta C 210.0, 173.3, 166.3, 131.4, 129.6, 81.9, 64.7, 59.8, 48.1, 46.0, 44.4, 40.1, 32.5, 32.2, 32.0, 29.4, 27.8, 17.4 and 14.1. Step 2 Ethyl (IS, 2S, 4aR, 6R, 8S, 8aS) (1, 2, 4a, 5, 6, 7, 8, 8a)-Octahydro-8-hydroxy-2-methyl-6-(1-oxoethyl)naphtha- lenyl-l-carboxylate (XXV) Trifluoroacetic acid (3.75 mL, 48.7 mmole) was added to a stirred solution of the keto-ester (XXVI) prepared in step 1 (1.5 g, 3.9 mmole) in dichloromethane (4 mL) , followed by water (0.3 mL) . The solution was stirred for 75 minutes, then brine (10 mL) and dichloromethane (10 mL) added, the aqueous phase separated and extracted with dichloromethane (3 x 10 mL) . The combined organics were washed with a saturated sodium bicarbonate solution (20 mL) and brine (10 mL) , dried and evaporated to give a solid. The solid (1.1 g) was dissolved in sodium ethoxide solution (prepared by dissolving sodium (70 mg, 3.04 mmole) in absolute ethanol (20 mL) ) and after 1 hour the solvent was evaporated to give a gum, which was partitioned between brine (20 mL) and dichloromethane (50 L) . The aqueous phase was separated, extracted with dichloromethane (50 mL) and the combined organic phases washed with brine (20 L) , dried and evaporated to leave a gum, which was purified by column chromatography eluting with 1:2 ethyl acetate:hexane to give the title ketone (XXV) (0.945 g, 87%) . nu max. (KBr disc) 3700 - 3100, 1730, 1705. delta H 5.57 (IH, ddd, J 9.8, 4.4 and 2.7 Hz, 3-H) , 5.42 (IH, d, J 9.8 Hz, 4-H) , 4.43 (IH, br S, 8-H) , 4.23 - 4.07 (2H, m, 0CH2), 2.9 (IH, tt, J 12.6 and 3.7 Hz, 6-H) , 2.84 (IH, dd, J 11.6 and 5.9, 1-H) , 2.64 (IH, m, 2-H) , 2.40 (IH, m, 4a-H) , 2.16 (3H, s, CH 3 CO) , 2.15 - 1.9 (2H, m, 5-Heq and 7-Heq) , 1.68 - 1.32 (3H, m) , 1.27 (3H, t, J 7 HZ, CH 2 CH 3 ), 1.25 (IH, m) and 0.93 (3H, d, j; 7 HZ, CHCH 3 ) . delta C 210.0, 173.5, 131.0, 130.0, 65.9, 60.0, 45.4, 44.9, 39.4, 35.4, 34.3, 33.2, 32.4, 28.0, 17.3 and 14.2. Step 3 Ethyl (IR, 2R, 3S , 4S , 4aS , 6R, 8S , 8aR) 3 , 4-dibromo- decahydro - 8 -hydroxy- 2 -methy l - 6 - ( l - oxoethy l ) - naphthalenyl-1-carboxylate A solution of bromine (0.54 g, 3.4 mmole) in carbon tetrachloride (25 mL) was added dropwise to a cold (-20 β C), stirred, solution of the compound of step 2 (XXV) (0.94 g, 3.37 mmole) in a mixture of the same solvent (25 mL) and absolute ethanol (1.5 mL) , under an argon atmosphere. The pale orange solution was stirred for 10 minutes then washed with an aqueous solution of NaHS0 3 , followed by a saturated solution of sodium hydrogen carbonate (30 mL) . The organic solution was dried and evaporated to leave the dibromide (1.61 g) as a solid, which was used directly in the next step. delta H 4.87 (IH, m, CHBr) , 4.53 (IH, m, CHBr) , 4.35 (IH, m, 8-H) , 4.22 - 4.09 (2H, m, 0CH 2 ) , 3.40 (IH, dd, J 11.6 and 5.1 Hz, 1-H) , 2.99 (IH, tt, J 12.3 and 3.6 Hz, 6-H) , 2.77 (IH, , 2-H) , 2.49 (IH, tt, J 11.3 and 3.6 HZ, 4a-H) , 2.16 (3H, s, CH 3 C0) , 2.15 - 1.54 (5H, m) , 1.32 (3H, d, J 7 Hz, CHCH 3 ) , and 1.26 (3H, t, J 7.2 Hz, CH 2 CH 3 ). delta C 211.5, 173.1, 65.5, 60.3, 57.5, 57.4, 43.9, 42.0, 39.2, 35.2, 35.0, 33.7, 32.1, 27.9, 19.5 and 14.1. Step 4 Ethyl (IR, 2R, 3S, 4S, 4aS, 6R, 8S, 8aR) 6-acetoxy-3 , 4- dibromodecahydro-8-hydroxy-2-methylnaphthalenyl-l- carboxylate Trifluoroacetic anhydride (7.75 mL, 55.5 mmole) was added to a well -stirred mixture of hydrogen peroxide solution (60% w/v, 1.2 mL, 20.8 mmole) in dichloromethane (5 mL) at O'C. After 15 minutes, the clear solution was added rapidly to a stirred ice-cold solution of the crude dibromide from the previous step (1.52 g) in dichloromethane (6 mL) , then the cooling bath was removed. After 30 minutes, more dichloromethane (25 mL) was added, the solution re-cooled to O'C and saturated sodium bicarbonate solution added slowly until the mixture reached pH 8. The aqueous phase was separated, extracted with dichloromethane (2 x 25 mL) and the combined organic extracts dried and evaporated to leave the acetate, (1.37 g) as a white foam. delta H (key peaks) 5.17 (IH, tt, J 11.5 and 4.4 Hz, 6-H) and 2.02 (3H, s, CH 3 C0 2 ) . Step 5 Ethyl (IS, 2S, 4aR, 6R, 8S, 8aS) 6-acetoxy-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro-8-hydroxy-2-methylnaphthalenyl-l- carboxylate (XXVII) Freshly prepared active zinc (1.91 g, 29.2 mmole) was added in several portions to a stirred solution of the crude acetate from the previous step (1.33 g) and acetic acid (0.5 mL) in dry ether (15 mL) . After the refluxing had subsided, the mixture was stirred for 15 minutes, then filtered and the solid washed with ether. The filtrate was washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was purified by column chromatography eluting with 1:4 ethyl acetate:hexane, to give the title compound (645 mg, 65% from XXV) . delta H (key peaks) 5.55 (IH, ddd, J 9.8, 4.1 and 2.7 Hz, 3-H) , 5.39 (IH, d, J 9.8 Hz, 4-H) and 5.12 (IH, tt, J 11.5, 4.5, 6-H) . delta C 173.5, 170.5, 131.0, 129.7, 69.3, 67.0, 60.0, 44.6, 39.2, 37.8, 32.4, 32.2, 21.2, 17.4 and 14.2. Step 6 Ethyl (IS, 2S, 4aR, 6R, 8S, 8aS) 1, 2, 4a, 5, 6, 1 , 8, 8a-octahydro-6,8-dihydroxy-2-methylnaphthalenyl-l- carboxylate The acetate (XXVII) prepared in step 5 (615 mg, 2.08 mmole) was dissolved in a solution of sodium ethoxide (8 mL) , prepared using sodium metal (50.2 mg, 2.18 mmole) . After 30 minutes, the solvent was evaporated and the residue partitioned between brine (25 mL) and dichloromethane (25 mL) . The brine was extracted with more dichloromethane (2 x 25 mL) and the combined organic extracts dried and evaporated to leave the alcohol as a solid (0.476 g, 90%). delta H (key peaks) 4.05 (IH, tt, J 11.3 and 4.5 Hz, 6-H) . delta C 173.6, 130.9, 130.1, 67.4, 66.3, 60.0, 44.8, 42.9, 41.8, 39.2, 32.5, 17.4, 14.2. Step 7 Ethyl (IS, 2S, 4aR, 6R, 8S, 8aS) 6-t-butyldiphenyl- silyloxy-1, 2, 4a, 5, 6, 7, 8, 8a-octahydro-2methyl- naphthalenyl-1-carboxylate (XXII) Tert-butyldiphenylsilylchloride (0.44 mL, 1.71 mmole) was added dropwise to a stirred solution of the diol prepared in the previous step (416 mg, 1.64 mmole) and imidazole (223 mg, 3.27 mmole) in dry DMF (3 mL) , under an argon atmosphere. After 16 hours, brine (10 mL) was added, and the mixture extracted with ether (2 x 20 mL) , which was then washed sequentially with 2M hydrochloric acid (10 mL) , water (2 x 10 L) and saturated sodium bicarbonate solution (10 mL) . The organic solution was dried and evaporated to leave the crude title compound (XXII) (740 mg) . delta H (key peaks) 7.74 - 7.32 (10H, m, Ph) and 1.06 (9H, s, t-butyl) . Step 8 (IS, 2S, 4aR, 6R, 8S, 8aS) 6-t-Butyldiphenylsilyloxy-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro-l-hydroxymethyl-2- methylnaphthalene (VII) A solution of the ester (XXII) prepared in the previous step (0.74 g) in dry ether (6 mL) was added dropwise to a solution of lithium aluminium hydride (0.19 g, 4.92 mmole) in dry ether (5 mL) , cooled in a cold water bath. After 1 hour water (0.2 mL) was added slowly to the stirred, cooled mixture, followed by aqueous sodium hydroxide (15 %; 0.2 mL) then more water (0.6 mL) . The mixture was filtered and the filtrate evaporated to leave a gum (0.74 g) , which was purified by column chromatography eluting with 1:2 ethyl acetate:hexane to give the title diol (VII) (0.67 g, 91%). nu max. (KBr) 3660 - 3100, 3100 - 3000. delta H (key peaks) 3.67 - 3.52 (2H, m, CH 2 OH) . delta C 135.7, 134.7, 134.6, 131.9, 131.0, 129.4, 127.4, 68.0, 67.8, 64.9, 42.4, 42.2, 42.0, 40.9, 34.5, 33.7, 27.0, 19.1 and 15.5. Step 9 (IS, 2S, 4aR, 6R, 8S, 8aS)-l-(t-Butyldimethylsilyloxy- methyl)-6-(t-butyldiphenylsilyloxy)-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro-8-hydroxy-2-methylnaphthalene (VIII) t-Butyldimethylsilylchloride (0.228g, 1.51 mmol) was added in portions to a stirred solution of the diol (VII) prepared in step 8 (0.622g, 1.38 mmol) in dichloromethane (10 mL) under an atmosphere of argon. The mixture was stirred for 18 hours then more dichloromethane (20 mL) added and the organic phase washed successively with IM H 3 P0 4 (10 mL) , sodium hydrogen carbonate solution (10 mL) and brine (10 mL) . The dichloromethane was dried and evaporated to leave a gum, which was purified by column chromatography eluting with 19:1 hexane:ethyl acetate to give the title compound as a gum (0.668g, 86%). delta H (key peaks) 0.89 (9H, s, SiC(CH 3 ) 3 ), 0.076 (3H, s, SiCH 3 ) and 0.073 (3H, s, SiCH 3 ) . Step 10 8-[(lS, 2S, 4aR, 6R, 8S, 8aS)-l-(t-Butyldimethylsilyl- oxymethyl)-6-(t-butyldiphenylsilyloxy)-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro-2-methylnaphthalenyl] 2(S)-methyl- butyrate (IX) A solution of the alcohol (VIII) prepared in step 9 (0.668g, 1.18 mmol), 2-S methylbutyric anhydride (1.32 g, 7.1 mmol), 4-(dimethylamino)pyridine (22 mg) and dry pyridine (2.00 mL, 24.9 mmol) in dichloromethane (2.0 mL) was stirred for 26 hours under argon. Methanol (10 mL) was added and after stirring for 2 hours, diethyl ether (100 mL) added and the solution washed with IM H 3 P0 4 (30 mL) , water (2 x 25 mL) and saturated sodium hydrogen carbonate solution (25 L) . The organic solution was dried and evaporated, to leave the ester (IX) as a gum (0.734g) which was used in the next step without further purification. delta H (key peaks) 5.03 (IH, m, 8-H) , 2.15 (IH, obscured sextet, J 6.9 Hz, CO.CH) , 1.6 - 1.2 (2H, obscured ultiplet, CH 2 CH 3 ), 0.97 (3H, d, J 6.8 Hz, C0.CHCH 3 ) and 0.80 (3H, t, J 7.4 Hz, CH 2 CH 3 ) . Step 11 8-[(lS, 2S, 4aR, 6R, 8S, 8aS)-6-(t-Butyldiphenylsilyl- oxy)-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro-l-hydroxy- methyl-2-methylnaphthalenyl] 2(S)-methylbutyrate (X) The protected alcohol (IX) prepared in step 10, was dissolved in a solution of tosic acid monohydrate (200 mg, 1.07 mmol) in methanol (250 mL) . After 2 hours, saturated sodium hydrogen carbonate solution (100 mL) was added, the mixture stirred for 5 minutes then concentrated to about 30 mL volume. The residue was extracted with dichloromethane (3 x 100 mL) ; the dichloromethane dried and evaporated to leave a gum (0.728g) which was purified by column chromatography eluting with 9:1 hexane: ethyl acetate to 4:1 hexane:ethyl acetate to give the title compound (418 mg) plus unreacted started material (IX) (137 mg) . The unreacted material (IX) (137 mg) was recycled using the same ratio of reagents and purified by column chromatography as above to give a further 68 mg of the title compound, a combined total yield of 486 mg (85%) . delta H (key peaks) absence of signals at 0.87, 0.053 and 0.023 for t-butyldimethylsilyl group. delta C 175.7, 135.6, 134.4, 134.1, 132.6, 129.7, 129.5, 127.4, 69.8, 68.2, 61.8, 41.9, 41.3, 40.0, 39.3, 39.2, 34.8, 31.5, 26.9, 26.2, 19.0, 16.3, 15.4 and 11.4. Step 12 8-[(lS, 2S, 4aR, 6R, 8S, 8aS)-6-(t-Butyldiphenylsilyl- oxy)-l-formyl-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro- 2-methylnaphthalenyl) ] 2(S)-methylbutyrate (XII) A solution of dry DMSO (178 mg, 2.28 mmol) in dry dichloromethane (0.7 mL) was added to a stirred solution of oxalylchloride (145 mg, 1.14 mmol) in dry dichloromethane (1.8 mL) under argon, at -70*C. After 5 minutes, a solution of the alcohol (X) prepared in step 11 (486 mg, 0.91 mmol) in dry dichloromethane (1.8 mL) was added rapidly. After a further 10 minutes a second batch of "activated DMSO" (prepared as above) was added to the stirred mixture, then after an additional 10 minutes dry triethylamine (1.14 L, 8.2 mmol) was added rapidly. After 5 minutes more at -70 * C, the solution was allowed to warm to room temperature, diethyl ether (50 mL) was added and the organic phase washed successively with IM H 3 P0 4 (20 mL) , water (2 x 20 mL) , saturated sodium hydrogen carbonate solution (20 mL) and dried. Evaporation gave the crude aldehyde (XII) (513 mg) which was purified by column chromatography eluting with 1:15 ethyl acetate:hexane) to give the title compound (398 mg, 82%) . delta H (key peaks) 9.69 (IH, d, J 2.5 Hz, CHO) , 2.52 (IH, ddd, J 11.3, 5.7 and 2.5 Hz, 1-H) . delta C (key peak) 203.2. Step 13 Methyl 7-{l-[(lR, 2R, 4aR, 6R, 8S, 8aS)-6-(t-butyldi- phenylsilyloxy)-8-[ (2(S)-methyl-1-oxobutyl)oxy]-l, 2, 4a, 5, 6, 7, 8, 8a octahydro-2-methylnaphthylenyl] } -3 (R) -(t-butyldimethylsilyloxy) -5-oxohepten-6-oate (XIV) Lithium bis(trimethylsilyl)amide in THF (1.0 M; 1.42 mmol) was added slowly to a stirred solution of methyl 3(R)-(t-butyldimethylsilyloxy)-6-(dimethoxyphosphonyl)- -5-oxohexanoate (XIII; R 4 and R 11 both represent methyl, P 2 represents the t-butyldimethylsilyl group) (0.68 g, 1.78 mmol) in THF (5 mL) at -70 β C, under an atmosphere of argon. After 1 hour, a solution of the aldehyde (XII) prepared in the previous step (378 mg, 0.71 mmol) in THF (5 mL) was added dropwise, the solution warmed to room temperature, and stirred for 66 hours. Saturated ammonium chloride solution (5 mL) was added and the mixture extracted with dichloromethane (3 x 25 mL) . The combined dichloromethane extracts were dried, evaporated and the residue purified by column chromatography eluting with 19:1 hexane: ethyl acetate to give the title compound (380 mg, 68%) . delta H (key peaks) 6.74 (IH, dd, J 15.75 and 10.2 Hz, 7 , -H), 5.92 (IH, d, J 15.75 Hz, 6'-H), 4.89 (IH, m, 8-H) , 4.60 (IH, pentet, J 6.3 Hz, 3'-H), 3.65 (3H, s, C0 2 Me) , 2.74 and 2.49 (m, 2 x 2H, H-2' and H-4') and 1.02 (9H, s, SiC(CH 3 ) 3 ). delta C 197.1, 174.6, 171.4, 147.9, 135.6, 134.3, 133.9, 131.9, 131.8, 129.9, 129.5, 127.4, 70.2, 68.1, 65.9, 51.3, 47.5, 42.7, 42.4, 41.7, 41.1, 40.4, 39.7, 35.7, 34.0, 26.8, 26.1, 25.6, 19.0, 17.8, 16.5, 16.3, 11.7, -4.8 and -5.1. Step 14 Methyl 7-{l-[(lS, 2S, 4aR, 6R, 8S, 8aS)-6-hydroxy- 8-[ (2(S)-methyl-l-oxobutyl)oxy]-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro-2-methylnaphthalenyl]}-3(R)-hydroxy-5-oxo- heptanoate (Ha) A mixture of tellurium (0.137g, 1.075 mmol) and sodium borohydride (93 mg, 2.47 mmol) in deoxygenated ethanol (5 mL) was heated to reflux, under argon, for 1 hour. The purple solution was cooled and finely ground ammonium chloride (0.58 g, 10.8 mmol) added, followed by a solution of the enone (XIV) prepared in step 13 (340 mg, 0.43 mmol) in deoxygenated ethanol (5 L) . After stirring for 2 hours, a second batch of sodium hydrogen telluride was prepared (on one fifth the scale above) and added to the reaction, together with more ammonium chloride (116 mg, 2.16 mmol). The mixture was stirred for a further 2 hours then saturated ammonium chloride solution (2 mL) added. The mixture was concentrated to a small volume, extracted with dichloromethane (3 x 20 mL) , and the dichloromethane dried and evaporated to leave a gum (355 mg) . A solution of the gum (315 mg) in 1:19 40% aq HF:acetonitrile (20 mL) was stirred for 6 hours at room temperature. Saturated sodium hydrogen carbonate solution (50 mL) was added carefully and the mixture concentrated under reduced pressure, then extracted with ethyl acetate (3 x 100 mL) . The combined organic extracts were dried and evaporated to leave a crude gum (220 mg) , which was purified by column chromatography eluting with 1:1 ethyl acetate:hexane to give the title compound (Ha) (125 mg, 71%) . delta H 5.61 (IH, ddd, J 9.8, 4.8 and 2.7 Hz, 3-H) , 5.40 (IH, br d, J 9.8 Hz, 4-H) , 5.28 (IH, m, 8-H) , 4.43 (IH, m, 3'-H), 3.89 (IH, tt, J 11.2 and 4.5 Hz, 6-H) , 3.70 (3H, S, C0 2 Me) , 2.62 - 2.59 (2H, m) and 2.51 - 2.48 (2H, d, J 6.6 Hz, 2'-H and 4'-H), 2.46 - 1.02 (17H, complex multiplets) , 1.13 (3H, d, J 7.1 Hz, C0.CHCH 3 ), 0.89 (3H, t, J 7.4 Hz, CH 2 CH 3 ) and 0.82 (3H, d, J 7.0 HZ, CHCH 3 ) . delta C 209.7, 175.7, 172.1, 132.4, 129.8, 69.4, 66.5, 64.3, 51.7, 48.0, 41.6, 41.5, 41.0, 40.5, 40.4, 39.5, 36.5, 35.1, 31.3, 26.5, 21.6, 16.6, 14.7 and 11.5. Step 15 Methyl 7-{l-[(lS, 2S, 4aR, 6R, 8S, 8aS)-6-hydroxy- 8-[ (2(S)-methyl-l-oxobutyl)oxy]-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro-2-methylnaphthalenyl] }-3 (R) ,5 (R) -di- hydroxyheptanoate (Hb) Triethylborane in THF (1.0 M; 0.66 mmol) was added to a stirred mixture of methanol/THF (1:4, 6.6 mL) under argon, at room temperature. After 1 hour, the solution was cooled to -70"C and a solution of the ketone (Ha) prepared in step 14 (125 mg, 0.285 mmol) in methanol/THF (1:4, 6.6 mL) added dropwise. The solution was stirred for 90 minutes then sodium borohydride (13 mg, 0.342 mmol) added in one portion and the. solution left at -70 β C for 18 hours. Saturated ammonium chloride solution (10 mL) was added, the mixture allowed to warm to room temperature then water added until the solids just dissolved. The aqueous solution was extracted with ethyl acetate (3 x 50 mL) and the combined organics washed with brine (50 mL) and dried. The solvents were evaporated and the residue dissolved in methanol (25 mL) , which was warmed, then evaporated again. This process was repeated four times, to leave the title triol of this example (lib) as a gum (125 mg) . delta H (key peaks) 4.23 (IH, m, 3'-H), 3.89 - 3.67 (2H, m, 6-H and 5'-H) . Example 2 ( IS . 2S . 4aR . 6R . 8S . 8aS . 4 'R . 6 'R . 2 "S) -6 ' - r 2- ( 1 . 2 . 4a. 5. 6. 7. 8. 8a-octahvdro-6-hydroxy-2-methyl-8-r (2"- methyl-l"-oxobutyl)oxyl-1-naphthalenyl1ethyl1 tetra- hydro-4 '-hydroxy-2H-pyran-2 '-one (I) A mixture of the triol of Example 1 (125 mg) and tosic acid monohydrate (20 mg) in dry benzene (15 mL) was stirred for 30 minutes, then the solvent was evaporated under reduced pressure and replaced with fresh dry benzene (15 mL) . After stirring for 3.5 hours, the solvent was evaporated and the residue partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was separated, dried and evaporated. The crude product was recrystallised from ethyl acetate/hexane to give the pure title compound (49.6 mg) . The mother liquor was evaporated and the residue crystallised as above, to give a second crop of the title compound (14.6 mg) . The two crops were combined, dissolved in ethyl acetate then the solvent allowed to evaporate slowly, giving a total yield of 64.2 mg of lactone. m.pt. 158 - 159"C. Found: C, 67.3; H, 8.78%, C 23 H 36 0g requires C, 67.6; H 8.88%. delta H 5.64 (IH, m, 3-H) , 5.41 (IH, br d, J 9.9 Hz, 4-H) , 5.30 (IH, m, 8-H) , 4.60 (IH, m, 5'-H) , 4.36 (IH, m, 3'-H) , 3.91 (IH, m, 6-H) , 2.74 (IH, dd, J 17.6 and 5.1 HZ, 2'-Hax), 2.61 (IH, m, 2'-Heq), 2.44 - 1.04 (19H, complex m) , 1.14 (3H, d, J 6.9 Hz, CO.CHCH 3 ) , 0.91 (3H, t, J 7.4 Hz , CH 2 CH 3 ) and 0.86 (3H, d, J 7.0 Hz, CHCH 3 ). delta C 176.0, 170.3, 132.7, 129.6, 76.0, 69.6, 66.7, 62.5, 41.7, 41.6, 41.0, 39.7, 38.5, 37.2, 35.9, 35.1, 32.8, 31.4, 26.6, 23.4, 16.7, 14.7 and 11.6. Example 3 Sodium 7-(l-r(lS. 2S. 4aR, 6R. 8S. 8aS) -6-hvdroxy- 8-r f2(S)-methyl-l-oxobutyl)oxy1-l. 2. 4a. 5. 6. 7. 8. 8a-octahvdro-2-methylnaphthalenvπ 1-3 (R) .5 (R) -di- hvdroxyheptanoate (lid) A solution of the lactone of example 2 (4.0 mg; 9.8 umole) in a mixture of water (50 uL) and sodium hydroxide in methanol (0.1 M; 10.8 umole) was stirred at room temperature for 18 hours, and the solvent evaporated to leave the sodium salt as a gum. Example 4 - Pharmacology IN VITRO DETERMINATION OF INHIBITORY POTENTIAL OF HMG-CoA REDUCTASE INHIBITORS HMG-CoA reductase was induced in rats by feeding a normal diet supplemented with 3% cholestyramine resin for one week prior to sacrifice. The livers were excised from the sacrificed rats and microsomal pellets prepared by the method of Kleinsek et a2., Proc. Natl. Acad. Sci. USA. 74 (4), pp 1431-1435, 1977. Briefly, the livers were immediately placed in ice-cold buffer I and homogenised in a Potter-Elvehjem type glass/teflon homogeniser (10 passes at 1000 rpm) . The homogenate was centrifuged twice at 20,000 x g to remove debris. The supernatant was centrifuged at 100,000 x g for 75 minutes, the microsomal pellet resuspended in buffer II and centrifuged at 100,000 x g for 75 minutes. The resultant pellet was stored at -70 β C until required for assay purposes. Buffer I Buffer II 50 mM KP0 4 pH 7.0 50 mM KP0 4 pH 7.0 0.2 M sucrose 0.2 M sucrose 2 mM DTT 2 mM DTT 50 mM EDTA Assay of HMG-CoA Reductase Activity and Determination of Activity of Inhibitors Membrane bound enzyme isolated as above is used for determining the activity of inhibitors. The assay is performed in a total volume of 300 μL in 100 mM KP0 4 pH 7.2 buffer, containing 3 mM MgCl 2 , 5 mM glucose-6-phosphate, 10 mM reduced glutathione, 1 mM NADP, 1 unit glucose-6-phosphate dehydrogenase, and 1 mg/mL BSA, with resuspended enzyme. Putative inhibitors are dissolved in dimethylsulphoxide and 10 μL aliquots added to the incubation. The assay is pre-incubated at 37*C for 10 minutes and initiated by the addition of 0.1 μCi 3-hydroxy- 3-methyl-[3- 14 C]glutaryl coenzyme A (52 Ci/Mole) followed by incubating the complete reaction at 37°C for 10 minutes. At the end of this period the reaction is stopped by adding 300 μL of a 10 mM mevalonolactone solution in 0.1 M hydrochloric acid and the mevalonic acid product allowed to lactonise for a further period of 30 minutes. The product is then isolated by chromatography using BIO-REX 5 resin and the enzyme activity quantified by liquid scintillation spectrophotometry. (The expression "BIO-REX" is a trade mark.) Appropriate controls are included in the assay and IC 50 values obtained by graphical means. The compound of Example 3 exhibited an IC 50 of 14 nM by this method, which compared favourably with the corresponding value for the known compound dihydromevinolin (30 nM) . Examples of unit dosage compositions are as follows: Example 5 Capsules: Per 10,000 Ingredients Per Capsule Capsules 1. Active ingredient (Cpd of Formula I) 40.0 mg 400 g 2. Lactose 150.0 mg 1500 g 3. Magnesium stearate 4.0 πi 40 σ 194.0 mg 1940 g Procedure for capsules: Step 1. Blend ingredients No. 1 and No. 2 in a suitable blender. Step 2. Pass blend from Step 1 through a No. 30 mesh (0.59 mm) screen. Step 3. Place screened blend from Step 2 in a suitable blender with ingredient No. 3 and blend until the mixture is lubricated. Step 4. Fill into No. 1 hard gelatin capsule shells on a capsule machine. Example 6 Tablets: 1. 2. 3. 4. 5. 101.3 mg 1013 g Procedure for tablets: Step 1. Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender. Step 2. Add sufficient water portionwise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules. Step 3. The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38mm) screen. Step 4. The wet granules are then dried in an oven at 140°F (60°C) until dry. Step 5. The dry granules are lubricated with ingredient No. 5. Step 6. The lubricated granules are compressed on a suitable tablet press. Example 7 Intramuscular Injection: Ingredient Per ml. Per litre 1. Formula I compound Active ingredient 10.0 mg 10 g 2. Istonic buffer solution pH 4.0. q.s. q.s. Procedure: Step 1. Dissolve the active ingredient in the buffer solution. Step 2. Aseptically filter the solution from Step 1. Step 3. The sterile solution is now aseptically filled into sterile ampoules. Step 4. The ampoules are sealed under aspetic conditions. Example 8 Suppositories: Ingredients l. Formula I compound Active ingredient 2. Polyethylene Glycol 1000 3. Polyethylene Glycol 4000 1840.0 mg 1,840 g Procedure: Step 1. Melt ingredient No. 2 and No. 3 together and stir until uniform. Step 2. Dissolve ingredient No. 1 in the molten mass from Step 1 and stir until uniform. Step 3. Pour the molten mass from Step 2 into suppository moulds and chill. Step 4. Remove the suppositories from moulds and wrap.

Claims: CLAIMS 1. A compound of either general formulae I and II: wherein I II R represents C 1-8 alkyl, C 3 _ 8 cycloalkyl, C 3 _ 8 cycloalkyl alkyl, C 2 _ 8 alkenyl, or C 1-6 alkyl substituted phenyl group; R 3 represents a hydrogen atom or a substituent R 4 or M; R 4 represents a C1-5 alkyl group, or a C 1 _ 5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino, or acetylamino; R 5 represents a hydrogen atom or C 1 _ 3 alkyl group; M represents a cation capable of forming a pharmaceutically acceptable salt; Q represents C=0 or CHOH; and each of a and b is independently a single or double bond. 2. A compound claimed in claim 1, which has one or more of the following substituents independently or in any combination: R 1 represents C 4 _ 6 branched alkyl; R 3 is R 4 ; R 4 represents C 1-5 alkyl and more preferably methyl of ethyl; Q represents CHOH ; and/or b is a single bond. 3. A compound according to claim 2, wherein R 1 represents a branched C alkyl group and R5 represents methyl. 4. (IS, 2S, 4aR, 6R, 8S, 8aS, 4'R, 6'R, 2"S)-6'-[2-(l, 2, 4a, 5, 6, 7, 8, 8a-octahydro- 6-hydroxy-2-methyl-8-[ (2"- methyl-l"-oxobutyl)oxy]-l- naphthalenyl]ethyl] tetra- hydro-4'-hydroxy-2H-pyran- 2'-one 5. A compound according to claim 2, wherein R 1 represents a branched C 4 alkyl group, R 3 represents methyl or ethyl, R 5 represents methyl, and Q represents the group CHOH. 6. Methyl 7-{l-[(lS, 2S, 4aR, 6R, 8S, 8aS)-6- hydroxy-8-[(2(S)-methyl-l-oxobutyl)oxy]-l, 2, 4a, 5, 6, 7, 8, 8a-octahydro-2-methylnaphthalenyl] }-3 (R) , 5(R)-dihydroxyheptanoate 7. A compound as defined in any one of the claims 1 to 6 for use in medicine. 8. The use of a compound as defined in claims 1 to 6 in the preparation of an antihypercholesterolaemic agent. 9. A pharmaceutical composition comprising a compound as defined in any of claims 1 to 6, or a mixture of such compounds, and a pharmaceutically acceptable carrier therefor. 10. A composition as claimed in claim 9 comprising a pharmaceutically acceptable non-toxic cationic polymer capable of binding bile acids in a non-reabsorbable form in the gastrointestinal tract. 11. A process for the preparation of a compound of either general formulae I or II as defined in claim 1, the process comprising: (a) deprotecting and optionally reducing a compound of general formula XIV to form a compound of general formula Ha; and (b) optionally converting a compound of general formula I or Ha directly or indirectly into another co pond of general formula I or II. 12. A compound of any of general formulae VII to XII, XIV to XXII and XXV to XXVII. 13. A process for the preparation of a compound of general formula XXVII, the process comprising oxidising under Baeyer-Villiger conditions a compound of general formula XXV.

Inventors: DAVIDSON ALAN HORNSBY, LEWIS CHRISTOPHER NORMAN, TODD RICHARD SIMON, DAVIDSON, ALAN, HORNSBY, LEWIS, CHRISTOPHER, NORMAN, TODD, RICHARD, SIMON
Applicants: BRITISH BIO TECHNOLOGY, BRITISH BIO-TECHNOLOGY LIMITED
Application year: 1991
Main classification: C07D309
IPC codes: A61K31, A61P3, A61P9, C07C69, C07C219, C07D309