GB2162179A - Naphthyl analogs of mevalonolactone and derivatives thereof, processes for their production and their use - Google Patents

Naphthyl analogs of mevalonolactone and derivatives thereof, processes for their production and their use Download PDF

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GB2162179A
GB2162179A GB08518490A GB8518490A GB2162179A GB 2162179 A GB2162179 A GB 2162179A GB 08518490 A GB08518490 A GB 08518490A GB 8518490 A GB8518490 A GB 8518490A GB 2162179 A GB2162179 A GB 2162179A
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Paul Leroy Anderson
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Abstract

Compounds of formula I <IMAGE> wherein R1 is C1-3alkyl, and <IMAGE> wherein R7 is hydrogen, R8 or M, wherein R8 is a physiologically acceptable and hydrolyzable ester forming group, and M is a cation, which are indicated for use in the treatment of hyperlipoproteinemia and atherosclerosis.

Description

SPECIFICATION Naphthyl analogs of mevalonolactone and derivatives thereof, processes for their production and their use This invention relates to compounds of the formula
wherein R1 is C,-3alkyl, and Z is
wherein R, is hydrogen, R8 or M, wherein R8 is a physiologically acceptable and hydrolyzable ester forming group, and M is a cation, processes for and intermediates in the synthesis thereof, pharmaceutical compositions comprising a compound of Formula I and the use of the compounds of formula I for inhibiting cholesterol biosynthesis and lowering the blood cholesterol level and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis.
EP Published Application No. 0117228awl (hereinafter EP 117228) describes a wide range of naphthyl analogs of mevalonolactone as hypolipoproteinemic and anti-atherosclerotic agents but makes no mention of the compound type of the present invention.
By the term "physiologically acceptable and hydrolyzable ester forming group" is meant a group which, together with the -COO- radical to which it is attached, forms an ester group which is physiologically acceptable and hydrolyzable under physiological conditions to yield a compound of formula I wherein R7 is hydrogen and an alcohol which itself is physiologically acceptable, i.e., non-toxic at the desired dosage level.
As is self-evident to those in the art, each compound of formula I (and every subscope and species thereof) has two centers of asymmetry (the two carbon atoms bearing the hydroxy groups in the group of formula a and the carbon atom bearing the hydroxy group and the carbon atom having the free valence in the group of formula b)and, therefore, there are two stereoisomeric forms (enantiomers) of each compound (a racemate). The two stereoisomers of the compounds wherein Z is a group of formula a are the 3R,5S and 3S,5R isomers and the two stereoisomers of the compounds wherein Z is a group of formula b are the 4R,6S and 4S,6R isomers, both the individual stereoisomers and the racemates being within the scope of this invention. Should R7 contain one or more centers of asymmetry, there are four or more stereoisomers.Since it is preferred that R7 does not contain a center of asymmetry and, for reasons of simplicity, any additional stereoisomers resulting from the presence of one or more centers of asymmetry in R7 will be ignored, it being assumed that R7 is free of centers of asymmetry.
The preferred stereoisomer of each compound wherein Z is a group of formula a is the 3R,5S, isomer and the preferred stereoisomer of each compound wherein Z is a group of formula b is the 4R,6S isomer.
These preferences also apply to the compounds of formula I having more than two centers of asymmetry and represent the preferred configurations of the indicated positions.
R, is preferably methyl or isopropyl.
R7 is preferably F7,, where R7, is hydrogen, C,-3-alkyl or M, more preferably R7", where R7" is hydrogen, C,-2-alkyl or M, and most preferably M, especially sodium. M is preferably M' and most preferably sodium.
R8 is preferably free of certers or asymmetry, especially as F8,, where P8, is C,-3alkyl, n-butyl, i- butyl, tbutyl or benzyl, more preferably C1-3alkyl and most preferably CI-2alkyl.
M is preferably a pharmaceutically acceptable cation and further free from centers of asymmetry and is more preferably M', i.e,, sodium, potassium or ammonium, and most preferably sodium. For simplicity, each of the formulae in which M appears (in the specification and the claims) has been written as if M were monovalent and, preferably, it is. However, it may also be divalent or trivalent and, when it is, it balances the charge of two or three carboxy groups, respectively.
The preferred compounds of Formula I wherein Z is a group of Formula a are those (i) wherein R7 is P7, (ii) of (i) wherein R7 is R7", (iii) of (ii) wherein R7 is M, (iv) of (iii) wherein R7 is M', (v) of (iv) wherein R7 is sodium, and (vi)-(x) of (i)-(v) wherein R, is methyl or isopropyl.
Groups (i)-(x) embrace the 3R,5S-3S,5R racemates and the 3R,5S and 3S,5R enantiomers, of which the racemates and the 3R,5S enantiomers are preferred.
The preferred compounds of Formula I wherein Z is a group of Formula b are those wherein P1 is methyl or isopropyl. This group embraces the 4R,6S-4S,6R racemates and the 4R,6S and 4S,6R enantiomers, of which the racemates and the 4R,6S enantiomers are preferred.
The compounds of formula I may be prepared for example by a) stereoselectively reducing a compound of formula I wherein Z is Z' where Z' is
wherein P8 is a radical forming a physiologically hydrolysable and -acceptable ester, b) hydrolysing a compound of formula I in the form of a physiologically-hydrolysable ester or a lactone or c) 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. In process a) P8 is preferably C1.3aIkyl, n-butyl, i-butyl, t-butyl or benzyi more preferably C 3alkyl and most preferably C,,alkyl.
It will readily be appreciated that the various forms of the compounds of formula I may be interconverted as indicated in b) and c) above.
In the same way compounds obtained according to a) may be 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.
The processes can be carried out in conventional manner.
The end products are obtained as racemates which may be separated in conventional manner.
Insofar as the preparation of starting materials is not described, they are either known or may be obtained analogously to procedures described herein or to known procedures.
Reaction products both intermediate and final may be isolated and purified in conventional manner.
As stated above the processes for preparing end products and intermediates; for separation of isomers; for isolation and purification as well as for the formation of salts, are carried out in conventional manner e.g. described in, or analogously to the examples hereinafter, or the description of e.g. EP 117228 or 114027. EP 117228 and 114027 also describe further processes suitable for preparing intermediates and end products.
Also within the scope of the invention are the intermediates of Example 1 steps 1 to 6 (compounds i) to vi) and those corresponding to Example 1 steps 2 to 6 with the 3'-methyl group replaced by a 3'-(C2.
7)alkyl group, e.g. compounds vii) and viii).
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 Test B: In Vitro Cell Culture Cholesterol Biosynthesis Screen: As described in EP 114027 or 117228.
Test C: In Vivo Cholesterol Biosynthesis Inhibition: As described in EP 114027 or 117228.
The compounds are thus indicated for use as hypolipoproteinemic and anti-atherosclerotic agents.
An indicated suitable daily dosage for use in the treatment of hyperlipoproteinemia and atherosclerosis is from about 1 to 1000 mg, suitably 1 to 150 mg, suitably administered in divided dosages one to four times daily or in sustained release form. A typical dosage unit for oral administration may contain 0.5 to 500 mg.
They may be administered 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.
The invention therefore also concerns a method of treating hyperlipoproteinemia or atherosclerosis by administration of a compound of formula I 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 and 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-[1 '-(3",5"-dimethylphenyl)- 3'-methylnaphth-2'-yl]hept-6-enoate (cmpd.
no. 1, R, = CH3r, Z = a), R7 = C2H5) Step 1 4,4-Dimethyl-2-[1 '-(3",5"-dimethylphenyl)naphth-2'-yI]-2- oxazoline (Compound (i)) (a) Preparation of Grignard reagent: 80 g. (0.432 mole) of 1-bromo-3,5-dimethylbenzene is added over a 1 hour period to 10.8 g. (0.44 mole) of magnesium turnings and a trace of iodine in 545 ml. of dry tetrahydrofuran (distilled over sodium) stirred under nitrogen, the addition being at a rate such that the reaction mixture gently refluxes, the reaction mixture being heated at 40 -45 C. to initiate the reaction. After the reaction, the reaction mixture is refluxed for 2 hours under nitrogen and cooled to 20"-25"C.
(b) The Grignard reagent solution from Part (a) of this step is slowly added over a 45 minute period to 84.0 g. (0.329 mole) of 4,4-dimethyl-2-(1'-methoxynaphth-2'-yl)-2- oxazoline stirred at 45"C. in 500 ml of dry tetrahydrofuran under nitrogen with cooling (the reaction being exothermic). The reaction mixture is stirred at 20 -25 C under nitrogen for 16 hours and is quenched by addition of saturated ammonium chloride solution. The mixture is extracted with ethyl acetate, and the ethyl acetate extract is dried over anhydrous sodium sulfate and evaporated at reduced pressure to a small volume. While cooling and agitating the mixture, diethyl ether and then petroleum ether are added.The resulting solids are collected by filtration and vacuum dried at 40"C. to obtained the white crystalline product m.p. 97 -100 C.
Step 2 4,4-Dimethyl-2-[1'-(3",5"-dimethylphenyl)-3'-methylnaphth- 2-yl]-2-oxazoline (Compound ii) Over a 30 minute period, 236.1 ml. of 1.6M. n-butyllithium/n-hexane (0.377 mole) is added to 108 g.
(0.33 mole) of Compound i) in 1.8 1. of anhydrous diethyl ether stirred at -5 C., the reaction mixture is stirred at -5 C, for 1 hour, 85.8 g. (0.60 mole) of methyl iodide is added dropwise over a 15 minute period with stirring at -5 C., and the reaction mixture is allowed to warm to 20"-25"C, and stirred at 20"- 25"C. for 16 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is carefully poured into a mixture of saturated sodium chloride solution and ice and filtered to remove some insoluble material.The diethyl ether phase is separated, the aqueous phase is extracted with diethyl ether, and the diethyl ether phases are combined, dried over anhydrous sodium sulfate and evaporated at reduced pressure to a small volume. Petroleum ether is added, and the crystalline product is collected and vacuum dried m.p. 153"-156"C.
Step 3 2-[1 '-(3",5"-Dimethylphenyl)-3'-methylnapth-2'-yl]-3,4,4- trimethyl-2-oxazolinium iodide (Compound iii).
220 ml. (3.53 moles) of methyl iodide is added to 129 g. (0.376 mole) of Compound ii) in 600 ml. of nitromethane, and the reaction mixture is heated to 60"C. under nitrogen, stirred at 60"C. under nitrogen for 1 hour and cooled to 30"C. during which the product begins to crystallize. 1 I. of diethyl ether is added at 30"C., the mixture is stirred for 15-20 minutes, and the solids are collected by filtration, washed with diethyl ether and vacuum dried at 45"C, to obtain the crystalline product,m.p. > 290"C (dec.).
Step 4 1-(3',5'-Dimethylphenyl)-3-methyl-2-naphthaldehyde (Compound iv) (a) 37 g. (1.7 moles) of lithium borohydride is added portionwise over a 3 hour period to 150 g. (0.3 mole) of Compound iii) in 1.8 1. of dry tetrahydrofuran (dried over molecular sieves) and 720 ml. of absolute ethanol (dried over molecular sieves) stirred at -15 --5 C. under nitrogen. The reaction mixture is stirred for 2 hours at -100C. under nitrogen, and a mixture of ice and saturated sodium chloride solution is added. The mixture is extracted with ethyl acetate, the ethyl acetate extract is dried over an hydros sodium sulfate and evaporated at reduced pressure to a small volume, and the crystalline oxazolidine is obtained by the addition of diethyl ether followed by petroleum ether m.p. 151"-156"C.
(b) 1.5 1. of 2N. hydrochloric acid (3 moles) is added dropwise over a 15 minute period to 99 g. (0.275 mole) of the product of Part (a) of this step in 1.8 1. of ethanol and 600 ml. of tetrahydrofuran stirred at 15"C., and the reaction mixture is stirred at 20 -25 C, for 4 hours.Water is added, and the mixture is extracted with diethyl ether. The diethyl ether extract is dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure, and the residue is triturated with petroleum ether to obtain the product which is dried at 20 -25 C. under high vacuum m.p. 105"-107"C.
Step 5 (E)-3-[1'-(3",5"-Dimethylphenyl)-3'-methylnaphth-2'-yljprop-2- enal (Compound v) (a) Preparation of cis-1-ethoxy-2-tri-n-butyl- stannylethylene: 7.0 g. (0.1 mole) of ethoxyacetylene is added over a period of 1 hour to 29.1 g. (0.1 mole) of tri-n-butyltin hydride stirred under nitrogen at 50"C., and the reaction mixture is heated under nitrogen at 50"-55"C. for 3 hours and at 60"-70"C. for 1 hour.
(b) Preparation of cis-1-lithium-2-ethoxyethylene: 50.14 ml, of 1.6M. n-butyllithium/n-hexane (0.082 mole) is added dropwise over a 15 minute period to 28.9 g. (0.08 mole) of cis-1-ethoxy-2-tri-n-butylstan- nylethylene in 700 ml. of dry tetrahydrofuran stirred at -60 C. under nitrogen, and the reaction mixture is stirred at -60 C. under nitrogen for 1 hour to obtain a solution of cis-1-lithium-2-ethoxyethylene.
(c) 20.0 g. (0.073 mole) of Compound iv) in 80 ml. of dry tetrahydrofuran is added to the product of Part (b) of this step, and the reaction mixture is stirred at -60 C. under nitrogen for 2 hours and carefully quenched with saturated ammonium chloride solution. (The temperature rises to 20 -25 C, during the addition.) The mixture is extracted with ethyl acetate, and the ethyl acetate extract is dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure. The residue is partitioned between acetonitrile and n-hexane, and the acetonitrile layer is reextracted with n-hexane and evaporated to dryness at reduced pressure to obtain the crude enol ether intermediate.
(d) 400 ml. of tetrahydrofuran, 100 ml. of water and 1 g. of p-toluenesulfonic acid H2O are added to 10 g. of the enol ether product of Part (c) of this step, and the reaction mixture is stirred at 20"-25"C. for 16 hours. 1.5 1. of water is added, and the mixture is extracted three times with ethyl acetate. The ethyl acetate extracts are combined, washed with saturated sodium chloride solution, washed with 50-60 ml. of 10% sodium bicarbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated at reduced pressure. The residue is dried at 40"C. under high vacuum for 5 hours to obtain the crude product as a yellow oil.
Step 6 Ethyl (E)-7-[1 '-(3",5"-di methyl phenyl)-3'-methylnaphth-2'- yl]-5-hydroxy-3-oxohept-6-enoate (Compound vi) (a) 82.9 ml. of 1.6M. n-butyllithium/n-hexane (0.133 mole) is added dropwise to 13.4 g. (0.133 mole) of diisopropylamine in 360 ml. of dry tetrahydrofuran stirred at -5 C. under nitrogen, and the reaction mixture is stirred under the same conditions for 15 minutes to obtain a solution of lithium diisopropylamide.
(b) 8.6 g. (0.066 mole) of ethyl acetoacetate is added dropwise to the product of Part (a) of this step stirred at -5 -0 C., the reaction mixture is stirred at -5 -0 C. for 1 hour and cooled to -60 C., a solution of 12 g. of crude Compound v) in 100 ml. of dry tetrahydrofuran is slowly added, and the reaction mixture is stirred at -600C. for 2 hours, the reaction mixture being maintained under nitrogen throughout.
The reaction mixture is slowly added to saturated ammonium chloride solution, and the mixture is extracted with ethyl acetate. The ethyl acetate extract is dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure to obtain the crude product as an oil.
The product is a racemate that may be resolved to obtain the 5R and 5S enantiomers.
Step 7 Ethyl erythro-(E)-3,5-dihydroxy-7-[1 '-(3",5"-d imethylphenyl)- 3'-methyl na phth-2'-yl ] hept-6-enoate (Compound no. 1) (a) 42 ml. of 1M. triethylborane/tetrahydrofuran (42 mmoles) is added dropwise to 11.6 g. (27 mmoles) of crude Compound vi) in 500 ml. of dry tetrahydrofuran (distilled over sodium) stirred at 20"-25"C. under nitrogen, 200 ml. of air (at 760 mm. Hg. and 25"C.) is bubbled in, and the reaction mixture is stirred at 20"-25"C. for 1 hour and cooled to -78-- 69"C. 1.9 g. (50 mmoles) of sodium borohydride is added, and the reaction mixture is stirred at -78" --69 C. for 16 hours under nitrogen.The reaction mixture is warmed to -20 C., and 150 ml. of 2N. hydrochloric acid is added dropwise with rapid agitation over a 15 minute period. Water is added, and the mixture is extracted with diethyl ether.The diethyl ether extract is dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure, and 50 ml. of isopropanol (reagent grade) is added. The mixture is heated in an oil bath for about 1 minute (100"C. bath temperature), allowed to cool and seeded with one crystal of the product (from a previous batch) and cooled in a refrigerator for 16 hours. The precipitate is collected by filtration, washed with cold isopropanol and dried under high vacuum to obtain the cyclic ethyl boron ester, m.p. 80"-81"C.
(b) 4.49 g. (9.5 mmoles) of the cyclic ethylboron ester product of Part (a) of this step is stirred in 250 ml. of methanol (reagent grade) at 20"-25"C. for 5 hours.The reaction mixture is evaporated to dryness at reduced pressure, the residue is dissolved in diethyl ether, and the diethyl ether solution is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated at reduced pressure to obtain the product (compound No. 1) as a light yellow oil.
N.M.R. (CDCI3): 1.30 (t, 3H (J = 1.5 Hz.)), 1.45 (m, 2H), 2.35 (s, 6H), 2.42 (m, 2H), 2.50 (s, 3H), 3.65 (bm, 1H), 4.10 (bm, 1H), 4.15 (m, 1H), 4.20 (q, 2H (J = 1.5 Hz.)), 4.35 (m, 1H), 5.45 (dd, 1H(J = 1.5 Hz. and 2 Hz.)), 6.50 (d, 1H (J = 3.5 Hz.)), 6.85 (d, 2H), 7.0 (bs, 1H), 7.35 (m, 3H), 7.75 (m, 2H) This compound may also be prepared e.g. by reaction of compound no. 4 with Na-or K-ethoxide in e.g.
ethanol.
Example 2 Sodium erythro-(E)-3,5-dihydroxy-7-[1 '(3",5"-dimethylphenyl)- 3'-methylnaphth-2'-yl]hept-6-enoate (Compound no. 2, RI = CH3, Z = a), R7 = sodium).
9.0 ml. of 1N. sodium hydroxide solution (9 mmoles) is added dropwise over a 15 minute period to 4.01 g. (9.3 mmoles) of Compound no. 1 in 250 ml. of absolute ethanol stirred at 0 -5 C.The reaction mixture is stirred for 2 hours during the course of which the reaction mixture is allowed to warm to 20 - 25"C. The reaction mixture is evaporated to dryness at reduced pressure, and the residue is dried under high vacuum for 2 hours and dissolved in chloroform (spectral grade). The chloroform solution is dried over anhydrous sodium sulfate, concentrated at reduced pressure to a volume of 50 ml. and, with cooling and stirring, anhydrous diethyl ether is added.The precipitate is collected by filtration, dried under nitrogen, washed with anhydrous diethyl ether and vacuum dried to obtain the product, m.p. > 230 C.
(dec.) N.M.R. (CDCI3 + CD3OD): 1.3 (m, 2H), 2.25 (m, 2H), 2.35 (s, 6H), 2.52 (s, 3H), 4.01 (m, 1H), 4.28 (m, 1H), 5.45 (dd, 1H) (J = 1.25 Hz. and 2.0 Hz.)), 6.45 (d, 1H(J = 3.5 Hz.)), 6.85 (d, 2H), 7.0 (s, 1H), 7.34 (m, 3H), 7.70 (m, 2H) This compound may also be prepared by reaction of compound no. 4 with IN NaOH.
Example 3 Erythro-(E)-3,5-dihydroxy-7-[1 '-(3",5"-dimethylphenyl )-3'- methylnaphth-2'-yl]hept-6-enoic acid (Compound no. 3, Ri = CH3, Z = a), R7 = H) prepared e.g. from Compound no. 1 by reaction with NaOH followed by HCI.
Example 4 (E)-Trans-6-(2'-[1"-(3"',5"7-dimethylphenyl)-3"-methylnaphth- 2"-yl]ethenyl )-4-hydroxy-3,4,5,6-tetrahy- dro-2H-pyran-2-one (Compound no. 4, F1 = CH3, Z = b) prepared e.g. by lactonisation of compound no. 3, m.p. 53"-56"C. (trans/cis mixture 5.7 1).
N.M.R. (CDCl3): 1.65 (m, 2H.), 1.73 (m, 1H), 2.39 (s, 6H), 2.52 (s, 3H), 2.65 (m, 2H), 4.02 (m, 1H), 5.12 (m, 1H), 5.45 (dd, 1H (J = 1.25 Hz. and 2 Hz.)), 6.55 (d, 1H (J = 3.25 Hz.)), 6.85 (m, 2H), 7.05 (s, 1H), 7.37 (m, 3H), 7.75 (m, 2H) The starting material for compounds of formula I wherein R, = i-C3H7 can be prepared analogously to steps 7 and 8 of Example 10 of EP 117228.
Step 1 4,4-Dimethyl-2-[1 '-(3",5"-dimethylphenyl)-3'-methoxynaphth-2'- yl]-2-oxazoline (Compound no. vii).
Step 2 4,4-Dimethyl-2-[1'-(3",5"-dimethylphenyl)-3'-(1"-methylethyl)- naphth-2'-yl]-2-oxazoline (Compound no.
viii).
The compounds obtained in Examples 1 to 4 may contain a small amount of the corresponding threo (Z = a)) or cis (Z=b) racemate. This-can vary according to process usedlconditions employed e.g. from 5 to 15%. The two racemates may be separated from each other by conventional means, and each may be resolved by conventional means.The erythro racemate yields the 3R, 5S and 3S,5R enantiomers, and the threo racemate yields the 3R,5R and 3S,5S enantiomers.
Throughout the examples, the term "reduced pressure" denotes aspirator pressure. Where no solvent is specified in connection with a solution, the solvent is water, and all solvent mixtures are by volume.
When a reaction is carried out under nitrogen, dry nitrogen is used to maintain anhydrous conditions.
All nuclear magnetic resonance spectra were taken at ambient temperature on a 200 MHz. spectrometer. All chemical shifts are given in p.p.m. (8) relative to tetramethylsilane, and where a single 8 value is given for anything other than a sharp singlet, it is its center point. In the N.M.R. data: bm = broad multiplet bs = broad singlet d = doublet dd = doublet of a doublet m = multiplet q = quartet s = singlet t = triplet Starting materials may be obtained e.g. as described in EP 117228, in particular Examples 14 and 10 thereof.

Claims (10)

1. A compound of the formula I
wherein R, is C.-3alkyl, and Z is
wherein R, is hydrogen, R8 or M, wherein R8 is a physiologically acceptable and hydrolyzable ester form- ing group, and M is a cation.
2. A compound according to Claim 1 wherein when R7 is M, M is a pharmaceutically acceptable c a- tion.
3. Erythro (E)-3,5-dihydroxy-7-(1'-(3",5"-dimethylphenyl)- dimethylphenyI)-3'-methylnaphth-2'-yl]lept- 6-enoate.
4. A compound according to Claim 1, 2 or 3 in free form or in the form of its ethyl ester or sodium salt.
5. A pharmaceutical composition comprising a compound according to Claim 2 together with a (,har- maceutically acceptable diluent or carrier.
6. A compound according to Claim 2 for use as a pharmaceutical.
7. A compound according to Claim 2 for use in inhibiting cholesterol biosynthesis or treating atherosclerosis.
8. A process for preparing a compound according to Claim 1 which comprises hydrolysing a compound of formula I in ester or lactone from 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.
9. A process for preparing a compound according to Claim 1 which comprises a) stereoselectively reducing a compound of formula I wherein Z is Z' where Z' is
wherein R5 is a radical forming a physiologically hydrolysable and -acceptable ester, b) hydrolysing a compound of formula I in the form of a physiologically-hydrolysable ester or a lactone or c) 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. The compounds designated(i) to (viii) as hereinbefore identified.
GB08518490A 1984-07-24 1985-07-22 Naphthyl analogs of mevalonolactone and derivatives thereof, processes for their production and their use Withdrawn GB2162179A (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4792614A (en) * 1987-08-05 1988-12-20 American Home Products Corporation Substituted furans as inhibitors of 3-hydroxy-3-methylglutaryl-coa reductase
US4812583A (en) * 1987-09-11 1989-03-14 American Home Products Corporation Substituted acyloxyalkylphenylethylene inhibitors of 3-hydroxy-3-methylglutaryl-coa reductase
EP0306649A1 (en) * 1987-07-10 1989-03-15 Hoechst Aktiengesellschaft 3,5-Dihydroxycarboxylic acids and their derivatives, processes for their preparation, their use as medicaments, pharmaceutic preparations and intermediate products
US4904646A (en) * 1987-05-22 1990-02-27 E. R. Squibb & Sons, Inc. Phosphorus-containing HMG-COA reductase inhibitors
US5091378A (en) * 1987-05-22 1992-02-25 E. R. Squibb & Sons, Inc. Phosphorus-containing HMG-CoA reductase inhibitors, new intermediates and method
US5686433A (en) * 1988-08-29 1997-11-11 E.R. Squibb & Sons, Inc. Quinoline and pyridine anchors for HMG-CoA reductase inhibitors
EP1284264A1 (en) * 1996-09-19 2003-02-19 Brantford Chemicals Inc. Process for producing simvastatin
EP1743630A2 (en) 1997-07-31 2007-01-17 Kos Pharmaceuticals, Inc. Pharmaceutical combination
EP2033630A1 (en) 2007-09-07 2009-03-11 Seoul Pharm. Co. Ltd. A novel controlled release-niacin formulation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3818570A1 (en) * 1988-06-01 1989-12-21 Boehringer Mannheim Gmbh NEW 6-SUBSTITUTED-4-HYDROXY-TETRAHYDRO-PYRANE-2-ON-DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0017228A1 (en) * 1979-04-04 1980-10-15 Nec Corporation Memory device

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0017228A1 (en) * 1979-04-04 1980-10-15 Nec Corporation Memory device

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4904646A (en) * 1987-05-22 1990-02-27 E. R. Squibb & Sons, Inc. Phosphorus-containing HMG-COA reductase inhibitors
US5091378A (en) * 1987-05-22 1992-02-25 E. R. Squibb & Sons, Inc. Phosphorus-containing HMG-CoA reductase inhibitors, new intermediates and method
EP0306649A1 (en) * 1987-07-10 1989-03-15 Hoechst Aktiengesellschaft 3,5-Dihydroxycarboxylic acids and their derivatives, processes for their preparation, their use as medicaments, pharmaceutic preparations and intermediate products
US4792614A (en) * 1987-08-05 1988-12-20 American Home Products Corporation Substituted furans as inhibitors of 3-hydroxy-3-methylglutaryl-coa reductase
US4812583A (en) * 1987-09-11 1989-03-14 American Home Products Corporation Substituted acyloxyalkylphenylethylene inhibitors of 3-hydroxy-3-methylglutaryl-coa reductase
US5686433A (en) * 1988-08-29 1997-11-11 E.R. Squibb & Sons, Inc. Quinoline and pyridine anchors for HMG-CoA reductase inhibitors
US5691322A (en) * 1988-08-29 1997-11-25 E.R. Squibb & Sons, Inc. Quinoline and pyridine anchors for HMG-CoA reductase inhibitors
EP1284264A1 (en) * 1996-09-19 2003-02-19 Brantford Chemicals Inc. Process for producing simvastatin
EP1743630A2 (en) 1997-07-31 2007-01-17 Kos Pharmaceuticals, Inc. Pharmaceutical combination
EP1743644A1 (en) 1997-07-31 2007-01-17 Kos Pharmaceuticals, Inc. Combinations of hmg-coa reductase inhibitors and nicotinic acid and methods for treating hyperlipidemia
EP2033630A1 (en) 2007-09-07 2009-03-11 Seoul Pharm. Co. Ltd. A novel controlled release-niacin formulation

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KR860001045A (en) 1986-02-22
SE8503556L (en) 1986-01-25
GR851805B (en) 1985-11-26
LU86012A1 (en) 1986-02-12
SE8503556D0 (en) 1985-07-22
FI852851A0 (en) 1985-07-22
JPS6137754A (en) 1986-02-22
FI852851L (en) 1986-01-25
ES8705356A1 (en) 1987-05-01
AU4522685A (en) 1986-01-30
DK333785A (en) 1986-01-25
NL8502010A (en) 1986-02-17
IT8548385A0 (en) 1985-07-23
DK333785D0 (en) 1985-07-22
HUT39142A (en) 1986-08-28
DE3525256A1 (en) 1986-01-30
FR2568248A1 (en) 1986-01-31
BE902914A (en) 1986-01-17
PT80845B (en) 1987-03-24
PH21444A (en) 1987-10-20
ES545454A0 (en) 1987-05-01
IT1200095B (en) 1989-01-05
GB8518490D0 (en) 1985-08-29
PT80845A (en) 1985-08-01
ZA855594B (en) 1987-02-25
IL75874A0 (en) 1985-11-29
PL254654A1 (en) 1986-08-26

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