HRP930775A2 - New antihypercholesterolemic compounds, intermediates and process for the preparation thereof - Google Patents

Description

The invention relates to the group 6(R)-[2-(8'-acyloxy-2'-methyl-6'-methyl (or hydrogen)-polyhydronaphthyl-1')-ethyl]-4(R)-hydroxy- 3 ,4,5,6-tetrahydro-2H-pyran-2-one and on the oxyacid form of said pyranones, on pharmaceutically acceptable salts of said oxyacids and on lower alkyl and phenyl or dimethylamino and acetylamino group substituted lower alkyl esters of said oxyacids.

In more detail, the present invention relates to the compounds of structure 1 in Table I, in which dashed lines X, Y and Z show the probable double bonds, the double bonds being indicated, when either is present, or X and Z together in combination, or X, Y or Z individually; R represents C1-10 straight or branched chain alkyl (except (S)-2-butyl), C3-10 cycloalkyl, C2-10 alkenyl, C1-10SF3- substituted alkyl, phenyl, halophenyl, phenyl-C-1-3 alkyl or substituted phenyl-C1-3 alkyl, wherein the substituent is halogen, C1-3 alkyl or C1-3 alkoxy; and to free oxyacids of formula II formed by opening the lactone ring of formula I in Table I.

The invention also relates to 6(R)-[2-(8'-hydroxy-2'-6'-dimethylpolylhydroxy naphthyl-1')ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro -2H-pyran-2-ones, as intermediates for the 8'-acyloxy compounds described above.

Some mevalonate derivatives are known to inhibit cholesterol biosynthesis; compare with F.M. Singer et al., Proc. Soc. Exper. Biol. Med.. 102. 370 (1959) and F.H. Hulcher, Arch. Biochem. Biophys. 146. 422 (1971). In addition, it was not found that the activity of these known compounds was always satisfactory, i.e. to have a practical application.

Recently Endo et al reported (U.S. Letters Patent 4,049,495, Patent 4,137,322 and Patent 3,983,140) the production of fermentation products that were extremely active in inhibiting cholesterol biosynthesis. Brown et al (J.Chem. Soc. Perkin 1165 (1976)) showed that the most active member of this group of natural compounds, now called compactin, IIIa (R'=H) has a complex mevalone structure.

More recently, Monaghan et al. in the U.S. patent 4,231,938, which is incorporated herein by reference, presented an inhibitor, designated as MK-803, which in Table 1 has the structure IIIa (R'=CH3), of the cation process. Albers-Schonberg et al. (USSN 154,157, filed May 28, 1980) described dihydro MK-803, designated as IIId (R'=CH3) in Table 1, of the same potency as MK-803 isolated from the same fermentation from which was isolated MK-803. Patchett et al. (USSN 118,050, filed February 4, 1980) describe dihydro and tetrahydro derivatives of MK-803 of different structures (IIIb,c,i,e (R'=CH3) in Table I), which were obtained by catalytic hydrogenation of MK- 803.

The tetrahydro analog IIIe (R'=H) of compactin is described in published Japanese application (Kokai) 55009-024.

Recently, a dihydro analog of compactin of structure IIId (R=H) was isolated from fermentation mixtures with compactin, as reported by Gullo et al (U.S. Application Ser. No. 207,508, filed Nov. 17, 1980).

The starting materials, IIIa and IIId, (R'=CH3) are fermentation products with Aspergillus terreus strain. ATCC No. 20542, designated in the culture collection of MERCK & CO., Rahway, New Jersey as MF-4845.

Preparation of compounds IIIa and IIId. (R'=CH3)

A. Fermentation

The test tube with the lyophilized culture MF.4845 was opened septically, and the contents were suspended in a 250 ml Erlenmeyer flask without partitions (seeding flask) in which there is approximately 10 ml of medium with the following composition:

The substrate

Corn steep in liquid 5 g

Tomato paste 40 g

Oatmeal 10g

Glucose 10g

Solution of microelements 10 g

Distilled water 1000 ml

pH 6.8 using NaOH

A solution of microelements

FeSO4.7H2O 1000 mg

MnSO4.4H2O 1000 mg

CuCl2. 2 H2O 25 mg

CaCl2. 2 H2O 100mg

H3BO3 56 mg

(NH4)6Me7O24. 4 H2O 19 mg

ZnSO4. 7 H2O 200 mg

Distilled deionized water 1000 mg

The inoculated flask is incubated for 24 hours at 28°C with stirring at 220 rpm (stroke 50.8 mm). Then, a 2-liter Erlenmeyer flask, without partitions, containing 500 ml of medium, is inoculated with 10 ml of the culture propagated in the first stage of fermentation, obtained from the mentioned seeding mixture. And that mixture is stirred for 24 hours at 28°C. Next, 485 liters of medium is placed in a 200 gallon (757 liter) stainless steel fermentation vessel consisting of:

Cerelose 4.5% wt./vol.

Peptonized milk 2.5% wt./vol.

Autolyzed yeast 0.25% wt./vol.

Polyglycol p2000 0.25% wt./vol.

whose pH is adjusted to 7.0. The substrate is sterilized for 15 minutes at 121°C. One liter of upper second phase is then added, and the mixture is incubated for 12 hours at 85 rpm, then 84 hours at 130 rpm, with an air flow of 5 cfm (2.4 I/s) for 12 hours , and then 10 cfm (4.8 I/s) over a period of 84 hours.

B. Isolation

1. Extraction

Two one hundred gallon (378.5 L) batches of the complete mixture are mixed, acidified with stirring to pH 4.1 with careful addition of 800 ml of concentrated hydrochloric acid, and extracted with 75 gallons (284 L) of ethyl acetate with further stirring for 2 hours.

About 25 Ib (11.3 kg) of silicate filter aid is then added and the total mixture (sludge) is pumped through a 24 inch (610 mm) filter press. An additional 75 gallons (284 I) of ethyl acetate is used to wash the filter cake, and extraction is continued, reversing the direction of pumping through the press, four times. Then all the solvent from the washing is thrown out of the press and mixed with the first filtrate. The two-phase filtrate is left to settle, and the aqueous layer is removed. The ethyl acetate layer is washed with 10 gallons (37.9 L) of deionized water, the phases are separated, and the ethyl acetate extracts are concentrated in vacuo to a residue of about 10 gallons (37.9 L).

2. Lactonization

The extracts in ethyl acetate of an additional 300 gallons (1135.5 L) of the mixture are added to the above extract, and the volume is reduced to about 30 gallons (113.6 L) by vacuum distillation. About 50 gallons (189.3 L) of toluene are added, and the batch is concentrated in vacuo to 32 gallons (121.1 L); this stage of operation is repeated, then sufficient new toluene is added to bring the volume up to 75 gallons (283.9 I). The batch is brought to reflux without a vacuum and maintained in this way for 2 hours, with a temperature higher than 106°C.

This solution is then concentrated under vacuum to a small volume, which is further concentrated to an oily residue in a large rotary evaporator under vacuum.

3. Chromatography on silica gel

The above extract is washed with 2 gallons (7.6 L) of methylene chloride and re-concentrated to an oil until free of other solvents.

The oily residue is dissolved in about 5 gallons (18.9 L) of ethyl acetate / methylene chloride (30/70; vol./vol.), and a slurry is prepared by adding 2.8 kg of silica gel. The resulting mixture (sludge) is loaded as a top layer on top of a 12 in x 50 in (304.8 mm x 1270 mm) silica gel column, which is packed in the same solvent mixture.

Elution is done with a mixture of ethyl acetate / methylene chloride (40/60; vol./vol.) at a speed of 800 ml/min. A first stage of 10 gallons (37.9 L) is collected, followed by four fractions of 4 gallons (15.1 L) each.

Fractions 6 to 10 inclusive are concentrated in vacuo to an oily residue which is dissolved in hot ethyl acetate, treated with decolorizing charcoal, filtered hot and cooled. Crystals of compound IIIa (R'=CH3) are separated by filtration, so the mother solutions are concentrated to oil and further chromatographed. Pure IIIa (R'=CH3) has a m.p. 170-171°C.

4. Re-chromatography on silica gel

Residual stock solutions from similar mixture extractions, corresponding to an additional 600 gallons (22271 I) of fermentation production, were combined with the above in methylene chloride solution. Half of this solution is taken for further chromatography on silica gel. A small aliquot shows a total solids content of 325 g. The solution is treated with 40 g of decolorizing charcoal, filtered, and the cake washed with methylene chloride. The mixture of filtrate and washing liquor is concentrated in vacuo to an oily residue. This is dissolved again in 800 ml of ethyl acetate / methylene chloride mixture (30/70; vol./vol.) and 225 g of silica gel is added to obtain a sludge. which is poured into the same mixture of solvents. The separation is carried out with a mixture of ethyl acetate / methylene chloride (40/60; vol./vol.). The first phase of 3 liters is separated from the side, and then fractions of 800 ml each are collected.

5. Chromatography on reverse-phase filling

Forty ml of fraction 12 from the above chromatography is concentrated to an oil, weighing 500 mg, and the oil is redissolved in 5 ml of acetonitrile. This solution in acetonitrile was added to a 5/8" (15.875 mm) OD stainless steel chromatographic column to which a reverse-phase liquid chromatography packing material "Bondapak C18/PorasilB" (VVaters Associates, Inc.) was added. , Milford, Mass, 01757).The column is eluted with a mixture consisting of (vol./vol.) 55% acetonitrile and 45% 0.05 M ammonium phosphate solution pH3. The eluted volume between 1360 ml and 1700 ml is mixed according to the refractive index. The organic solvent was removed in vacuo, and the remaining aqueous solution was extracted with ethyl acetate. After removal of ethyl acetate in vacuo, 120 mg of the compound remained, which was crystallized from a concentrated solution in acetonitrile, giving crystals of the compound IIId (R'=CH3), mp 129-131 °C.

Preparation of compounds IIIb,c,e

Starting materials IIIb, IIIc and IIIe (R'=CH3) are prepared according to the process scheme and preparative methods given below.

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Reactions and reagents

1. Hydrogenation at about 20-75°C and at a pressure of about atmospheric to about 4 atmospheres, in the presence

tris(triphenylphosphorine)chlororhodium, in an atmospheric solvent such as benzene, toluene or xylene, preferably toluene. The most favorable conditions are around 40°C and around 2-7 atmospheres in toluene.

2. Hydrogenation at around 20-25°C and at around atmospheric pressure, in the presence of 5% palladium on calcium carbonate, in a lower alkanol, eg C1-3 alkanol, and especially ethanol.

3. Hydrogenation at around 20-25°C and atmospheric pressure, in the presence of platinum oxide in ethyl acetate.

4. Hydrogenation at 20-25°C and atmospheric pressure, in the presence of 10% palladium on charcoal in ethyl acetate.

Getting

6 α [2-(8' β-2-(S)-methylbutyryloxy-2' β,6' α-dimethyl-1,2',3',4',6',7',8',8' α-Octahydronaphthyl-1)ethyl]-4 β -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one. IIIb (R'=CH3)

A mixture of 50 mg (0.1236 mmol) of compound IIIa (R'=CH3) and an equal molar amount (114.35 mg, 0.1236 mmol) of tris(triphenylphosphine)chlororhodium in 10 ml of dry toluene was hydrogenated for 6 days at room temperature, where 14.6 ml of hydrogen is bound. The mixture was evaporated in vacuo to dryness. The red residue is preparatively chromatographed in a thin layer on silicon dioxide plates, impregnated with silver nitrate, and developed twice in the 10% ethyl acetate-ester system. The yield of compound IIIb (R'=CH3) was 22.3 mg.

Mass spectrum (M/e) 406 (m+)

304(m-102)

286(m-102-18)

NMR (CDCl3, 300 MHz) δ 4.37 (m, 1H)

4.60 (m, 1H)

5.34 (d of t, J=2.5 Hz, 1H)

5.41 (m, 1H)

Getting

6 α [2-(8' β.-2-(S)-methylbutyryloxy-2' β,6' α-dimethyl-1'.2'.3'.4'.6'.7'.8'. 8'a-octahydronaphthyl-1)ethyl 4 3 -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, IIIc (R'=CH3)

A solution of 80.91 mg (0.2 mmol) of compound IIIa (R'=CH3) in 10 ml of absolute ethanol in the presence of an equal weight of 5% Pd on CaCO3 is hydrogenated at a pressure of 1 atmosphere until the binding of one mole is observed of hydrogen equivalents. The catalyst was then removed by filtration, and the filtrate was evaporated to dryness (81 mg). After purification by preparative thin-layer chromatography, due to the removal of a small amount of tetrahydro compound which was formed as a by-product, 72 mg of the 1.4 reduction product IIIc (R'=CH3) was isolated.

Mass spectrum (M/e) 406 (m+)

304(m-102)

286 (304-H2O)

NMR (CDCl3, 300 MHz) δ 4.38 (m, 1H)

4.64 (m, 1H)

5.28 (d of t,J=3.5Hz,1H)

5.48 (m, 1H)

Getting

6α[2-(8'β-2-(S)-methylbutyryloxy-2'β,6α-dimethyl-1'.2'.3'.4'.4'aα.5'.6'.7'. 8',8'a-decahydronaphthyl-1)ethyl]-4β-hydroxy-3.4.5.6-tetrahydro-2H-pyran-2-one. IIIe(R'=CH3)

A solution of 80.91 mg (0.2 mmol) of compound IIIa (R'=CH3) in 10 ml of ethyl acetate is hydrogenated in the presence of an equal weight of platinum oxide at a pressure of 1 atmosphere. During 1 hour, exactly 2 mole equivalents of hydrogen are consumed. The catalyst is removed by filtration, and the filtrate is concentrated to dryness and an oil is obtained. Cis and trans isomers were separated by preparative thin-layer chromatography on silica gel plates (10% ethylacetate-ester system; bands determined by water jet). The trans isomer IIIe (R'=CH3) appears as a more polar spot compared to the cis isomer, and 60 mg was isolated.

Mass spectrum (M/e) 408 (m+)

323 (m-85)

306(m-102)

NMR (CDCl3, 300 MHz) δ 4.36 (broad singlet, 1H)

4.59 (m, 1H)

5.19 (d of t,J=2.5Hz, 1H)

FERMENTAL PRODUCTION OF COMPOUND IIId (R'=H)

A. Fermentation

Natural isolate of Penicillium citrinum. NRRL 8082 was taken for the preparation of skewed yeast and malt extract (YME), which was incubated for 2 weeks at 28°C.

A portion (1/5) of slanted medium (MF-4870a) was used to inoculate each of 5 septate culture flasks (250 ml) containing 44 ml of KF culture medium with CaCl2. A portion of the grown culture (about 1.5 ml) was taken to inoculate each of 100 production medium flasks (250 ml, without partitions), containing 40 ml of LM production medium without malt extract. Production flasks were incubated for 4 days at 25°C.

The second group of production medium flasks (140), each containing 40 ml of LM production medium without modification, were inoculated and incubated under the same conditions described above. The mixtures of both fermentations are mixed.

Various substrates used in the above mentioned fermentations:

Skewed YME

Dextrose 4 g/l

Malt extract 10g/l

Yeast extract 4 g/l

Agar 20 g/l

Distilled water up to 1 liter

pH 7.0

KF culture medium with CaCl

CaCl210g

Corn steep in liquid 5 g Tomato paste 40 g Oat flour 10 g Cellulose 10 g Mixture of microelements 10 ml Distilled water 1000 mlpH 6.8

Mixture of microelements

FeSO4. 7H2O 1 gMnSO4. 4H2O 1 gCuCl2. 2H2O 25 gCaCl2 100gN3BO3 56 g(NH4)6Mo7O24. 4H2O 19gZnSO4. 7H2O 200 g Distilled water 1000 g

LM production base without malt extract

Dextrose 20 gGlycerol 20 mlArdamine pH 10gCoCl2. 6H2O 8 mg Polyglycol p 2000 0.25% Distilled water 1000 mlpH 7.0

LM production base without modification

Dextrose 20 g

Glycerol 20 ml

Ardamine pH 10g

Malt extract 20 g

CoCl2. 6H2O 8 mg

Polyglycol p 2000 0.25%

Distilled water 1000ml

pH 7.0

B Isolation

The fully mixed mixture (10.3 L) is filtered, and the mycelium cake is washed with 2.5 L of deionized water. The mixed filtrate and washing water are adjusted to pH 4 with the help of 1N hydrochloric acid. The aqueous solution is extracted with 7 l of ethyl acetate, and the extract is re-extracted with 3 x 2 l of aqueous sodium hydroxide solution. The mixed extract in sodium hydroxide is adjusted to pH 3.8 with 1N hydrochloric acid and extracted with 2 L, then 1 L of ethyl acetate. The mixed solution in ethyl acetate was dried with anhydrous NaSO 4 , filtered and concentrated to dryness. The oily residue is dissolved in toluene and refluxed for 1 hour. The solution in toluene is concentrated to dryness, and the residue is dissolved in 18 ml of a mixture of n-hexane / toluene / methanol (4/1/1 by volume). This solution is poured onto a Sephadex LH-20 column, 30 ml (inner diameter) x 40 cm, equilibrated in the same solvent system. After elution with 300 ml of solvent, a fraction of 10 ml was obtained, which was concentrated to an oil. 45 mg of dihydrocompactin (compound IIId (R'=H)), mol. wt. 392.2560 determined by mass spectrum (calculated for C23H36O5, 392.2558).

In KBr, the main IR peaks obtained with Fourier Transform-IR (FTIR, Nicolet, Model 7199) are at 1724, 1704, 1258, 1078 and 1070 cm-1. The peak at 3005 cm-1 and the absence of a peak at 3030 cm-1 are important.

Nuclear magnetic resonance (NMR) spectra were obtained in CDCl3, (~1 mg/0.5 ml) on a Varian SC-300 superconducting NMR spectrometer. The following peak positions are given in ppm (5) relative to the internal tetramethylsilane (TMS).

δ Mark

5.62 d,d,d (2.17, 4.5, 10.0) H3, (or 4')

5.43 d (10) H4, (or 3')

5.20 m H8.

4.63 m H6

4.39 m H4

2.75 d,d(17.5, 5.5) 3-CH 2

2.63 d,d,d (17.5, 4.0, 1.5)

2.39 m CH3HCC = O

2.29 m H4a' + H2'

1.14 d CH3CHC=O

0.90 t of CH3CH2

0.84 d 2' - CH3

________________________________________________________

d: doublet; m: multiplet; t: triplet

The finding shows that the structure:

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We found that the a-group in the compound IIIa (R'=CH3) and the hydroderivatives, IIIb-e, can be removed cleanly, so that the group 6(R)-[2-(8-hydroxy-2,6-dimethyl) is obtained -poylhydronaphthyl-1)ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, which are themselves hypocholesterolemic agents, and which are extremely useful as intermediates in obtaining new ester, and are even stronger for this application.

Obtaining new alcohols of this invention is performed by heating the esters IIIa-e (R'=CH3) with an alkali metal hydroxide, eg lithium hydroxide, potassium hydroxide or sodium hydroxide, in a liquid solvent, eg water or alcohols, for a long period of time. The best is lithium hydroxide in water, with reflux for about 50-72 hours or under pressure at higher temperatures of 120-180°C, for a shorter period of about 8-24 hours.

The pyranone ring is easily opened, but the removal of the acyl group from the side chain is not easily performed. Heating must be prolonged and/or pressure must be used. An inert atmosphere is also useful. It is completely unexpected that molecules with so many highly sensitive functional centers can withstand the harsh conditions required to remove the highly damaged α-methylbutyryl ester. It is particularly unexpected, and it was found, that the yields are high.

In the case of compound IIIa-e (R'=H), the saponification of the S'-ester proceeds much more easily in about 20 hours, giving IVa-e (R'=H).

Compound IVa (R'=R) is known as ML-236A as disclosed by Endo et al. in the US. Patent 3,983,140.

The products are isolated by acidification and extraction with organic solvents, resulting in the trioxoacid form of compound IVa-e. These trioxyacids can be re-lactonized by heating a solution of the acid in a suitable organic solvent, eg toluene or benzene, in a device that allows continuous separation of the water formed.

The alcohols that are part of this invention have structures IVa-e (R'=CH3) as well as trioxyacids that are formed by the opening of lactone rings.

An alternative synthetic pathway for compounds IVb,c,e comprises a step of hydrolysis of IIIa to IVa as described herein, followed by hydrogenation of IVa under the conditions previously described for obtaining IIIb,c,e, whereby, depending on these reaction conditions, products IVb, IVc or IVe.

Preparation of compounds IVa-e

Starting materials, such as the 8' α-hydroxy compounds IVa-e (R'=CH3) described by Willard (serial number 118,049) are obtained from various 8'-esters described by Monaghan et al. (IIIa, R'=CH3) , Albers-Schonberg with co-workers (IIId, R'=CH3) and Patchett with co-workers (IIIb,c,e, R'=CH3), so that they are heated for a longer period of time with a lithium hydroxide solution. The pyranone ring is easily opened, but the removal of the acyl group in the side chain is not easily achieved. An inert atmosphere is helpful.

In the case of compound IIIa-e (R'=H), the saponification* of the 8'-ester proceeds much more easily to the end, in about 20 hours.

The 8'-hydroxy products are isolated by acidification and extraction in organic solvents, which gives the oxyacid form in which the pyranone ring is still open. These oxyacids are again lactonized by heating a solution of the acid in a suitable organic solvent, eg benzene or toluene, in a device that enables continuous separation of the resulting water.

Compound IVa (R'=H) is known as ML-236A, as reported by Endo et al. in the US. patent 3,983,140.

In their lactone form, these alcohols are in Table I of the compounds of formula IVa-e, and they are obtained in the manner described in the following preparative examples.

Getting

6(R)-[2-(8'(S)-hydroxy-2'(S).6'(R)-dimethyl-1'.2'.6'.7'.8'.8'a( R)-hexahydro naphthyl-1'(S))-ethyl]-4(R)-hydroxy- 3.4.5. 6-tetrahydro-2H-pyran-2-one. IVa(R=CH3)

A mixture of 8.0 g (19.78 mmol) of MK-803 (IIIa, R'=CH 3 ) and 8.31 g (197.8 mmol) of LiOH. H2O in 600 ml of water is stirred for 56 hours under reflux in a nitrogen atmosphere. The reaction mixture was cooled to 0°C and, with stirring, treated with 20 ml of concentrated hydrochloric acid. The mixture is then extracted with three parts of 250 ml each of ether, and the individual extracts are washed, one after the other, with three parts of 200 ml each of water, and then with 200 ml of saturated salt solution. After drying with MgSO4, this organic solution is filtered, and the solvent is evaporated in a vacuum so that an oily residue is obtained. This residue is dissolved in 200 ml of toluene and heated for 2 hours at reflux in a nitrogen atmosphere, with continuous extraction of water, to achieve re-lactonization. Evaporation of toluene and trituration of the residue with hexane afforded 5.5 g (81%) of the title compound IVa (R'=CH3), as a white solid, which did not require further purification.

The analytical sample was prepared by recrystallization of part of this material from butyl chloride, which gave white clusters: m.p. 128-133°C (vacuum);

NMR (CDCl3): § 0.87 (d, 3,J=7Hz, CH3), 1.16 (d,3,J=7Hz, CH3), 2.64 (m, 2, pyranic C3 hydrogens), 4 .27 (brm, 1, naphthalene C8H), 4.37 (m, 1, pyranic C4H), 4.71 (m, 1, pyranic C4H), 5.56 (m, 1, naphthalene C5H), 5.79 (dd, 1, J=6.10Hz, naphthalene C3H), 6.03 (d, 1, J=6.10Hz, naphthalene C4H);

IR (CHCl3) 3400 (OH), 1725 (C=0), 1240, 1120, 1080 cm-1.

Analysis:

Calculated for: C19H28O4 . 0.1H9Cl: C, 70.67; H, 8.84

Found: C, 70.77; H, 8.75.

Alternative getting

6(R)-[8'(S)-hydroxy-2'(S).6'(R)-dimethyl-1'.2'.6'.7'.8'.8'a(R)- hexahydro naphthyl-1'(S)-ethyl]-4(R)-hydroxy-3.4.5.6-tetrahydro-2H-pyran-2-one. IVa (R'=CH3)

A suspension of 188 mg (0.463 mmol) of MK-803 (IIIa, R'=CH3) in 5 ml (5 mmol) of aqueous 1N LiOH solution was stirred for 12 hours at 135°C in a 30 ml stainless steel pressure vessel. . The cooled reaction mixture was acidified with 1M H3PO4 and extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4) and filtered, and the solvent was evaporated. The residue is dissolved in 20 ml of toluene, which is heated for 4 hours at reflux temperature in a Dean-Stark apparatus to achieve re-lactonization. Evaporation of toluene gives the title compound.

Preparation of alcohols IVa (R'=H) and IVb, IVc, IVd and IVe (R'=H or CH3)

If in practice the procedure described above is used, but by replacing the above used IIIa (R'-CH3) with an equivalent amount of ester IIIa (R'=H) or IIIb, IIIc, IIId or IIIe (R'=H or CH3), the corresponding alcohols IVa (R'=H), IVb, IVc, IVd or IVe (R'=H or CH3).

We have found that 8'-hydroxy compounds of structure IV can be acylated, thereby obtaining a new class of 8-acyloxy compounds, structures defined by formulas I and II and the definitions given below. These new compounds are inhibitors of cholesterol synthesis in vivo. The absolute configuration of these compounds is known from X-ray diffraction.

Table 1 gives an appropriate overview of these structures and their stereochemical relationship. The numerical designations of various compounds, including those from different series with polyhydronaphthyl structures, remain the same throughout these specifications and are applied as such. Each of the esters Ia-e (R'=CH3) of this invention has eight chiral centers. The relative and absolute configuration of these asymmetric centers is shown in Table I. In more detail, for ester Ia (R'=CH3), the designations of Cahn, Ingold and Prelog for the absolute configurations are 4(R), 6(R), I' (S), 2'(S), 6'(R), 8'(S) and 8a'(R) [R.S. Cahn, C. Ingold and V. Prelog, Angew. Chem. Int Ed.. 5. 385 (1966)].

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As indicated in formulas Ia-e, each of these compounds has the same spatial orientation of the groups on each chiral carbon atom, and therefore belong to the same stereochemical series. The labeling for each center need not be identical to that found for ester Ia (R'=CH3), due to the details of the sequence rules that apply to that labeling. In the two esters, Id and Ie, which have an additional chiral carbon atom not present in ester Ia, the hydrogen atom at 4a' is in a downward (or α) orientation, as shown in Table I, giving a trans ring orientation.

[image]

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The 8'-acyloxy compounds of this invention can be used as antihypercholesterolemic agents for the treatment of atherosclerosis, hyperlipemia and similar diseases in humans. They can be administered orally or parenterally in the form of capsules, tablets, preparations administered by injection and the like. It is usually preferable to use the oral route of administration. Dosages may vary depending on the age, severity, body weight and other conditions of the human patient, but the daily dose for adults is within the range of about 2 mg to 2000 mg (preferably 10 to 100 mg) given in three or four divided doses. If necessary, higher doses can be applied. The compounds of this invention may also have useful antifungal activities. For example, they can be used to control strains of Penicillium sp. Aspergillus niger. Cladosporium sp. Cochilobolus miyabeanus and Helmintosporium cynodotis. If used for this, they are mixed with suitable formulating agents, powders, emulsifying agents or solvents, such as aqueous ethanol solution, or they can be sprayed or dusted on the plants to be protected.

Preparation of the compounds of this invention is described in process scheme A.

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Definitions - X, Y, Z, R and R' as defined in the specification, and strings a-e as defined in Table 1

Reactions 1) Lithium hydroxide, heat, heat and lactonize

2) t-butyldimethylchlorosilane and imidazole in DMF at ambient temperature in an inert atmosphere

3) Treatment with RCOCl' 4-dimethylaminopyridino in a pyridine solution, preferably in an inert atmosphere

4) Treatment with RCOCH and N.N'-dicyclohexylcarbodiimide and 4-pyrrolidinopyridine in dichloromethane, preferably in an inert atmosphere

5). Three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid per equivalent of ester in THF, preferably in an inert atmosphere

6) Aqueous alkali solution, then careful acidification with dilute acid

7) See the chapter Reactions and Reagents and Process Scheme for synthesis IIIb,c,e

In the new process of this invention, the 4-hydroxyl on the pyranone ring of alcohol IVa-e is first protected with a t-butyldimethylsilyl group by reacting with t-butyldimethylchlorosilane in an inert atmosphere at ambient temperature in the presence of an acid acceptor, such as imidazole, thus they get protected alcohols Va-e. The 8-hydroxyl on the polyhydronaphthyl ring is then acylated in one of two ways. The first consists in treating with an acid chloride that has the desired acyl group in pyridine, in the presence of 4-dimethylaminopyridine as a catalyst.

The second consists in treating 8'-polyhydronaphthol with a free acid having the desired acyl group and a carbodiimide, such as N,N'-dicyclohexylcarbodiimide, with 4-pyrrolidinopyridimone in dichloromethane as catalyst. Protected esters VIa-e are obtained by these procedures. Then, the silyl-protecting group is removed from the 4-hydroxyl of the pyranone ring, using three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid per equivalent of ester VIa-e, thus obtaining the desired compounds Ia-e. The ratio of reagents in this last reaction is critical to process yield and product purity.

Acyl groups thus placed on the 8'-hydroxyl are those in which R and Ia are:

1) C1-10 alkyl with a straight or branched chain, except for 2-(S)-butyl,

2) C3-10 cycloalkyl,

3) C2-10 alkenyl,

4) C1-10 alkyl substituted with SF3,

5) phenyl

6) halophenyl, in which the halogen is chlorine, fluorine, bromine or iodine,

7) phenyl-C1-3 alkyl,

8) substituted phenyl-C1-3 alkyl, in which the substituent is a halogen such as fluorine, chlorine, bromine or iodine, C1-3 alkyl or C1-3 alkoxy.

Preferably, R' is CH 3 .

The best definitions for R are:

C2-5 straight chain alkyl,

C3-10 branched chain alkyl, except 2-(S)-butyl,

C3-10 cycloalkyl,

C3-10 alkenyl, wherein the unsaturation is not conjugated to the carbonyl, in particular

C3-10 branched alkyl, except 2-(S)-butyl.

The best are those types in which R represents 1,1-diethylpropyl or 1-ethyl-1-methylpropyl. And best of all, none of X, Y, or Z is a double bond.

Compounds IIa-e can be hydrolyzed with bases, such as NaOH, to give salts, such as the sodium salt of compounds IIa-e. By using bases with other pharmaceutically acceptable cations, salts with these cations are obtained. By carefully acidifying the salt, oxyacids IIa-e are obtained, which are returned at acidic pH, and compounds IIa-e. By treating compounds Ia-e, with acid or base catalysis, with methanol, ethanol, propanol or butanol or phenyl-, dimethylamino-, or adethylamino-alkanols, the corresponding esters of compounds IIa-e are obtained, which also form part of this invention.

Pharmaceutically acceptable salts of this invention include those formed from cations, such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, tetramethylammonium, as well as those formed from amines, such as ammonia, ethylenediamine, N -methylglucamine, arginine, ornithine, choline, N.N'-dibenzoethylenediamine, chlorprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1'-yl-methylbenzimidazole, diethylamine, piperazine and tris( hydroxymethyl)-aminomethane.

Example 1

6(R)-[2-(8'(S)-2",2"dimethylpropanoyloxy-2'(S).6'(R)-dimethyl-1'.2'.6'.7'.8' .8'a (R)-hexahydronaphthyl-1'(S))-ethyl]-4(R)-hydroxy-3.4.5.6-tetrahydro-2H-pyran-2-one

Phase A:

Preparation of 6(R)-[2-(8'(S)-hydroxy-2'(S).6'(R)-dimethyl-1'.2'.6'.7'.8'.8'a (R)-Hexahydro naphthyl-1'(S)-ethyl]-(R)-(dimethyl-butylsilyloxy)-3.4.5.6-tetrahydro-2H-pyran-2-one. Va (R'=CH3)

A mixture of alcohol IVa (R'=CH3) (18.3 g, 57.1 mmol), 21.5 g (142.8 mmol) of tert-butyldimethylchlorosilane and 19.4 g (285.6 mmol) of imidazole in 200 ml of N ,N-dimethylformamide is stirred for 18 hours at 20°C in a nitrogen atmosphere. The reaction mixture is then diluted with 1500 ml of ether and washed, one after the other, with water, 2% aqueous hydrochloric acid solution, water and saturated sodium bicarbonate. The ethereal solution is dried with MgSO4 and filtered, reducing the volume to 1 liter. After adding 600 ml of hexane, the volume on the steam bath was reduced to 600 ml. The product crystallizes at room temperature. After isolation and drying at room temperature, 13.7 g of a white fluffy solid is obtained. The volume of the mother solutions was reduced to 250 ml, and after standing this solution overnight at 0°C, the second yield of crystals was isolated. The total yield was 17.13 g (69%) of the title compound as a white fluffy solid: m.p. 142-144°C (vacuum); NMR (CDCl3) δ 0.10 (s,6(CH3)2Si), 0.90 (s,9,(CH3)3CSi), 1.19 (d,3,J=7Hz, CH3), 2.58 (d,2,J=4Hz, pyranic C3 hydrogens), 4.3 (m,2, pyranic C4H and naphthalene C8H), 4.70 (m,1, pyranic C6H), 5.57 (m,1, naphthalene C5H), 5.58 (dd, 1, J=6.10Hz, naphthalene C3H), 6.03 (d, 1, J=10Hz, naphthalene C4H).

Analysis:

Calcd for: C25H42O4Si: C, 69.08; H, 9.74

Found: C, 69.46; H, 9.83.

Phase B:

Preparation of 6(R)-[2-(8'(S)-2",2"dimethylpropanoyloxy-2'(S),6'(R)-dimethyl-1'.2'.6'.7'.8 '.8'a (R)-Hexahydronaphthyl-1'(S)-ethy]-4(R)-(dimethyl-tert-butylsilyloxy)-3.4.5.6-tetrahydro-2H-pyran-2-one. Vla (R'=CH3)

A solution of 6.0 g (13.8 mmol) of alcohol Va (R'=CH3) from phase A and 200 mg of 4-dimethylaminopyridine in 50 ml of pyridine was cooled to 0°C under a nitrogen atmosphere. 6.8 ml (6.65 g, 55.2 mmol) of pivaloyl chloride was added to this solution with stirring for 15 minutes. The reaction mixture was stirred for 1 hour at 0°C and then for 4 days at 20°C. The reaction mixture is diluted with 750 ml of ether and washed with a 2% aqueous solution of hydrochloric acid, until the washing water becomes acidic, and then with a NaHCO3 solution. After drying with MgSO4, the solution was filtered and evaporated to give 7.81 g of the title compound as a light orange oil: NMR (CDCl3) δ 0.09 (s,6(CH3)2Si), 0.88 (s,9, (CH3)3CSi), 1.28 (s,9,(CH3)3CCO2-), 2.57 (d,2,J=4Hz, pyranic C3 hydrogens), 4.32 (m,1,pyranic C4H), 4.63 (m,1,pyranic C4H), 5.34 (m,1,naphthalene C6H), 5.54 (m,1,naphthalene C8H), 5.78 (dd,1,J=6.10Hz, naphthalene C3H), 6.03 (d,1,J=10Hz, naphthalene C4H).

Applying the procedure essentially as described in Example 1, phase B, but replacing the pivaloyl chloride, which is used therein, with an equimolar amount of acid chloride of the structure R-COCI described in Table II, esters of the structure Vla (R'=CH3) are obtained, which are also described in Table II.

[image]

[image]

[image]

Phase C:

Preparation of 6(R)-[2-(S'(S)-2",2"dimethylpropanoyloxy-2'(S),6'(R)-dimethyl-1',2',6',7',8 (R)-Hexahydronaphthyl-1' (S)-ethyl]-4(R)-hydroxy-3.4.5.6-tetrahydro-2H-pyran-2-one. Ia (R'=CH3)

Solutions 10.0 g (31.7 mmol) Bu4N+F-. 3H20 and 2.4 ml (2.5 g, 42.3 mmol) of acetic acid in 50 ml of tetrahydrofuran, add 7.81 g (13.8 mmol) of silyl ether IVa (R'=CH3) from phase B in 50 ml tetrahydrofuran. This mixture is stirred for 18 hours at 20°C in a nitrogen atmosphere. The reaction mixture is diluted with 700 ml of ether and washed, one after the other, with 2% hydrochloric acid solution, water and saturated aqueous NaHCO3 solution. The organic solution was dried (MgSO4) and filtered. After evaporation of the solvent, 6.45 g of a whitish solid remains. This material was crystallized from 100 ml of butyl chloride, and the isolated crystals were dried for 4 hours at 35°/0.01 mm to give 4.0 g (72%) of the title compound as whitish needles: m.p. 167.5-170.5° (vacuum); NMR (CDCl3) § 0.88 (d,3,J=7Hz, CH3), 1.08 (d,3,J=7Hz, CH3), 1.19 (s,9,(CH3)3C), 2 .67 (d,2,J=4Hz, pyranic C3H), 4.39 (m,1,pyranic C4H), 4.65 (m,1,pyranic C6H), 5.36 (m,1,naphthalene C8H) , 5.55 (m,1,naphthalene C5H), 5.80 (dd,1,J=6.1Hz, naphthalene CH3), 6.04 (d,1,J=10Hz, naphthalene C4H); HPLC (4.6 mm x 25 cm Partisil 10 PAC, 10% isopropanol/hexane, 4 ml/min) retention time 4.4 min.

Analysis:

Calcd for: C24H36O5: C, 71.25; H, 8.97

Found: C, 71.40; H, 8.93

Applying the procedure from Example 1, phase C, but replacing the 2,2-dimethylpropanoloxysilyl ether, compound Vla (R'=CH3), which was used there, with an equimolar amount of other esters of structure Vla (R'=CH3), described in Table II , esters of structure Ia (R'=CH3) are obtained, described in Table III.

[image]

[image]

[image]

Example 2

6(R)-[2-8'(S)-phenylacetoxy-2'(S),6'(R)-dimethyl-1'.2'.6'.7'.8'.8'a (R )-hexahydronaphthyl-1'(S))-ethyl]-4(R)-hydroxy- 3.4.5.6- tetrahydro-2H-pyran-2-one

Phase A:

Obtaining: 6(R)-[2-(8'(S)-phenylacetoxy-2'(S),6'(R)-dimethyl-1',2',6',7',8',8' and (R)-hexahydronaphthyl-1(S)-ethyl]-4(R)-dimethyl-tert-butylsilyloxy)-3.4.5.6-tetrahydro-2H-pyran-2-one. Vla (R'=CH3)

A solution of 434 mg (81.0 mmol) of alcohol Va (R'=CH3) from Example 1, phase A, 204 mg (1.5 mmol) of phenylacetic acid and 309 mg (1.5 mmol) of N,N'-dicyclohexylcarbodiimide in 10 ml of dichloromethane is treated with 22 mg (0.15 mmol) of 4-pyrrolidinopyridine and stirred at 20°C in a nitrogen atmosphere. After 3 days, the solvent is removed in vacuo, and the residue is suspended in 25 ml of ether and filtered. By evaporating the filtrate, a viscous oil is obtained, which is chromatographed on a silica gel column (230-400 mash = 62μ, - 37μ). Elution (under air pressure) with ether hexane (1:1, vol./vol.) gives 460 mg (83%) of the title compound in the form of a viscous oil: NMR (CDCl3) δ 0.10 (s,6,-(CH3 )2Si), 0.90, (s,9,(CH3)3CSi), 3.58 (s,2,PhCH2-), 5.34 (m,1,naphthalene C8H), 7.30 (s,5 ,Ph).

By applying the procedure from Example 2, phase A, but replacing the phenylacetic acid used there, with an equimolar amount of organic acids of the structure R-COOH, described in Table IV, esters of the structure Vla (R'=CH3) are obtained, which are also described in the Table IV.

[image]

[image]

[image]

Phase B:

Obtaining: 6(R)-[2'(8'(S))-phenylacetoxy-2'(S),6'(R)-dimethyl-1'.2'.6'.7'.8'.8 (R)-Hexahydronaphthyl-1'(S)-ethyl]-4(R)-hydroxy)-3.4.5.6-tetrahydro-2H-pyran-2-one. Ia (R'=CH3)

Applying the procedure described in Example 1, phase C, but replacing the propanoyloxy compound used there with an equimolar amount of the phenylacetoxy compound from Example 2, phase A, gives the title compound, m.p. 109-112°C.

Using other esters, Vla (R'=CH3), described in Example 2, phase A (Table IV), and working according to the procedure from Example 2, phase B, ethers of structure Ia (R'=CH3), described in Table V.

[image]

[image]

[image]

Example 3

6(R)-[2-(8'(S)-2"-ethyl-2"-methylbutyryloxy-2'(S),6'(R)-dimethyl-1'.2'.6'.7' .8'.8'a(R)-hexahydronaphthyl-1'(S))-ethyl]-4(R)-hydroxy-3.4.5.6-tetrahydro-2H-pyran-2-one

Phase A;

Obtaining: 6(R)-[2-(8'(S)-2"-ethyl-2"-methylbutyryloxy-2'(S).6'(R)-dimethyl-1'.2'.6'. 7',8',8'a (R)-hexahydronaphthyl-1'(S)-ethyl](R)-dimethyl-tert-butylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one. Vla (R'=CH3)

3.0 g of 2-ethyl-2-methylbutyryl chloride was added to a solution of 2.17 g (5 mmol) of alcohol Va (R'=CH3) and 74 mg of 4-pyrrolidinopyridine in 20 ml of pyridine, while stirring with a magnetic stirrer. This reaction mixture was stirred for 9 hours at 100°C in an N2 atmosphere. The reaction mixture was diluted with 500 ml of ether and washed with 1N HCl solution until the washing liquid became acidic, then with brine (3 x 50 ml). After drying with MgSO4, the solution was filtered and evaporated to give 4.2 of a dark oil. The oil is chromatographed on a 6 x 15 cm silica gel column (230-400 mash = 62μ - 37μ). Elution (under air pressure) using a mixture of ether and hexane (1:1, vol./vol.) gives 2.6 g (95%) of the title compound in the form of a thick yellow oil: NMR (CDCl3) § 0.08 ( s,6,(CH3)2Si), 0.9 (s,9,(CH3)3CSi), 2.57 (d,2J=4Hz, pyranic C3 hydrogens), 4.30 (m,1,pyranic C4H) , 4.63 (n,1,pyranic C4H), 5.42 (m,1,naphthalene C6H), 5.53 (m,1,naphthalene C3H), 5.78 (dd,1,J=6Hz, 10Hz , naphthalene C3H), 6.03 (d,1,J=10Hz, naphthalene C4H).

Applying the procedure described in Example 3, phase A, but replacing the 2-ethyl-2-methylbutyryl chloride, which is used there, with an equimolar amount of acid chloride of structure R-COCI, described in Table VI, esters of structure Vla (R'=CH3) are obtained , which are also described in Table VI.

[image]

[image]

Phase B:

Obtaining: 6(R)-[2-(8'(S)-2"-ethyl-2"-methylbutyryloxy-2'(S),6'(R)-dimethyl-1',2',6'). 7',8',8'a (R)-hexahydronaphthyl-1'(S)-ethyl]-4(R)-hydroxy-3.4.5.6-tetrahydro-2H-pyran-2-one

Applying the procedure described in Example 1, phase C, or Example 2, phase B, but using as starting material the silyl ether compound from Example 3, phase A, gives the title compound, m.p. 111-113°C (C26H40O5).

The esters of structure la described in Table VII are obtained in a similar way, using other esters VIa (R'=CH3) described in Table VI as starting materials.

[image]

Applying the procedure of Example 1, Phase A, and then working according to Example 1, Phases B and C, or Example 2 or 3, Phases A and B, but replacing the diol of structure IVa (R'=CH3) in Example 1, Phase A with with the corresponding parts of structure IVa (R'=H) or IVb,c,d or e (R'=H, or CH3), silyl ethers of structure Va (R'=H) or Vb,c,d and e ( R'=H, or CH3), esters of structure VIa (R'=H) or VIb.c.d and e (R'=H, or CH3) and new esters of structure Ia (R'=H) or Ib.c.d and e (R '=H, or CH3), according to Process Scheme A,

[image]

[image]

Example 4

6(R)-[2-[8(S)-(2"-ethyl-2"-methylbutyryloxy-2'(S),6'(R)-dimethyl-1'.2'.3'.4' .4'a(S).5'.6'.7'.8'.8'a (S)-decahydronaphthyl- 1'(S)]-ethyl](R)-hydroxy-3.4.5.6-tetrahydro- 2H-pyran-2-one Ia (R'=CH3)

Phase A:

Obtaining: 6(R)-[2-)8'(S)hydroxy-2'(S),6'(S)-dimethyl-1'2',3'4'a(S),5',6 ',7',8',8'a (S)-decahydronaphthyl-1'(S-ethyl]-4(R)-hydroxy-3.4.5.6-tetrahydro-2H-pyran-2-one. IVe (R' =CH3)

A solution of 2.0 g (6.2 mmol) of alcohol IVa (R'=CH3) in 100 ml of ethyl acetate is hydrogenated in the presence of platinum oxide (61 g) at a pressure of 2.8 at, until the absorption of two molar equivalents of hydrogen is observed . The catalyst is removed by filtration, and the filtrate is evaporated to dryness, which gives a white solid (1.9 g), which is chromatographed on a 6 x 20 cm silica gel column (230-400 mash = 62-37 μ,). Elution (under air pressure) with a mixture of acetone and methylene chloride (3:7, vol./vol.) gives 1.0 g (50%) of the title compound in the form of a colorless liquid.

The analytical sample was prepared by recrystallization of part of the material from chloroform, resulting in a white fluffy solid: m.p. 166-8°C.

Phase B:

Obtaining: 6(R)-[2-(8'(S)-hydroxy-2'(S),6'(S)-dimethyl-1'.2'.3'.4'.4'a(S ).5'.6'.7'.8'.8'a (S)-decahydronaphthyl-1'(S)-ethyl]-4(R)-dimethyl-tert.-butylsilyloxy-3.4.5.6-tetrahydro- 2H-pyran-2-one.Ve(R'=CH3)

A solution of alcohol IVa (R'=CH3) (1.0 g, 3.1 mmol), imidazole (1.05 g, 15.4 mmol) and tert-butyldimethylchlorosilane (1.16 g, 7.7 mmol) in 20 ml

of N,N-dimethylformamide, is stirred for 18 hours at 20°C in a nitrogen atmosphere. The reaction solution is diluted with 200 ml of ether and washed, one after the other, with water, a 2% aqueous solution of hydrochloric acid and a salt solution. The ethereal solution was dried over MgSO4 and evaporated to give a white solid (1.8 g), which was chromatographed on a 6 x 20 silica gel column (230-400 mash = 62-37μ). Elution under air pressure with a mixture of acetoinethylene chloride (1:19; vol./vol.) gives 1.0 g (74%) of the title compound in the form of a white solid: m.p. 136-138°C.

Phase C:

Obtaining: 6(R)-[2-[8'(S)-(2"-ethyl-2"-methylbutyryloxy-2'(S),6'(S)-dimethyl-1',2',3' .4'.4'a(S).5'.6'.7'.8'.8'a (S)-decahydronaphthyl-1'(S)]-ethyl]-4(R)-(dimethyl- tert.-butylsilyloxy)-3.4.5.6-tetrahydro-2H-pyran-2-one Vle (R'=CH3)

By replacing alcohol Va (R'=CH3) in phase A from Example 3, with an equimolar amount of alcohol Ve (R'=CH3) and using the procedure from phase A, the corresponding amount of the title compound VIe (R'=CH3) is obtained in the form of a yellow oil . NMR (CDCl3) § 0.08 (s, 6, (CH3)2-Si), 0.90 (s, 9, (CH3)3CSi), 1.13 (s, 6, (CH3)2CO2), 2 .63 (m, 2, pyranic C3 hydrogens), 4.33 (m, 1, pyranic C4H), 4.60 (m, 1, pyranic C6H), 5.23 (m, 1, naphthalene C8H).

Phase D:

Obtaining: 6(R)-[2-[8'(S)-(2"-ethyl-2"-methylbutyryl-2'(S),6(S)-dimethyl-1',2',3', 4',4a(S),5',6',7',8',8a'(S)-decahydronaphthyl-1'(S)]-ethyl]-4(R)-hydroxy-3.4.5.6-tetrahydro -2H-pyran-2-one Ie (R'=CH3)

Replacing the silyl ether in Step C of Example 1 with an equimolar amount of the silyl ether Vle (R'=CH 3 ) from Example 4, Step C, and using the procedure from Step C of Example 1, afforded the desired amount of the title compound as a solid.

The analytical sample was prepared by recrystallization of the material from hexane, which gave white needles: m.p. 146-147°C.

Applying the procedure described in Example 4, phases from A to D, but replacing the diol of structure IVa (R'=CH3) in phase A, with an equivalent amount of diol of structure IVa (R'=H), the following compounds were obtained: IVe ( R'=H) in phase A; Ve (R'=H) in phase E; Vle (R'=H) in phase C; and Ie (R'=H) in phase D.

Example 5

Getting

6(R)-[2-[8'(S)-(2'"-ethyl-2"-methylbutyryloxy-2'(S),6'(R)-dimethyl-1',2',3'). 4',6',7',8'a (S)-octahydronaphthyl-1'(S)]-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one. (R'=CH3)

Phase A

Obtaining: 6(R)-[2-(8'(S)-hydroxy-2'(S).6'(R)-dimethyl-1'.2'.3'.4'.6'.7' .8'a (S)-octahydronaphthyl-1'(S)-ethyl]-4(R)-hydroxy-3.4.5.6-tetrahydro-2H-pyran-2-one IVb (R'=CH3)

Using the procedure described for obtaining starting material IVa (R'=CH3), hydrolysis of MK-803 with reflux of an aqueous solution of LiOH. N20 for 56 hours, but replacing MK-803 with an equimolar amount of compound IIIb (R'=CH3), gives approximately the same yield of the title compound IVb (R'=CH3), m.p. 136-139°C.

Working according to the procedure described in Example 4, phases B, C and D, but replacing compound IVe (R'=CH3), which is used in phase B, with an equimolar amount of compound IVb (R'=CH3) from phase A of that example, obtain approximately the same yields, as in Example 4, of the following compounds:

Phase B:

6(R)-[2-(8'(S)-hydroxy-2'(S),6(R)-dimethyl-1',2',3',4',6',7',8' a (S)-octahydro naphthyl-1'(S)-ethyl]-4(R)-(dimethyl-tert-butylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one, Vb (R'=CH3), mp 140-142°C

Phase C:

6(R)-[2-[(8'(S)-(2"-ethyl-2"methylbutyryloxy)-2'(S),6'(R)-dimethyl-1',2',3', 4',6',7',8'a (S)-octahydronaphthyl-1'(S)]-ethyl]- 4(R)-(dimethyl-tert.-butylsilyloxy)-3,4,5,6- tetrahydro-2H-pyran-2-one, VIb (R'=CH3),

where

[image]

Phase D:

6(R)-[2-[(8'(S)-(2"-ethyl-2"methylbutyryloxy)-2'(S),6'(R)-dimethyl-1,2',3',4 ',6',T,8'a (S)-Octahydronaphthyl-1'(S)]-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one , Ib (R'=CH3), mp 129-131°C

where

[image]

Using the procedure described in Example 5, but using IIIb (R'=H) or IIIc, IIId, or IIIa (R'=H or CH3) as starting material instead of IIIb (R'=CH3), compounds IVb were obtained (R'=H) or IVc.d.e (R'=H or CH3), Vb (R'=H) or Vc.d.e (R'=H or CH3), VIb (R'=H) or VIc.d.e (R'=H or CH3), and Ib (R'=H) or Ic,d,e (R'=H or CH3),

[image]

Example 6

Typical formulations for filling size O hard gelatin capsules contain 3.125, 6.25, 12.5, 25 or 50 mg of one of the novel compounds of the present invention, such as the products of Example 3, Phase B, Example 1, Phase C or Example 2, phase B and finely divided lactose, so that the total content of the capsule is about 580-590 mg.

Claims (27)

1. Procedure for obtaining compounds of the structural formula [image] characterized in that: R' represents H or CH3; R is 1) C1-10 alkyl with a straight or branched chain, except for 2-(S)-butyl, 2) C3-10 cycloalkyl, 3) C2-10 alkenyl, 4) C1-10 alkyl substituted with CF3, 5) phenyl 6) halophenyl 7) phenyl-C1-3 alkyl, 8) substituted phenyl-C1-3 alkyl, in which the substituent is halogen, C1-3 alkyl or C1-3 alkoxy; dashed lines at X, Y and Z show possible double bonds, where said double bonds, if present, can be X and Z in combination, or X, Y or Z alone; and corresponding dioxyacids of the formula: [image] or pharmaceutically acceptable salts of the mentioned acids, and C1-4 alkyl esters of the mentioned acids or C1-4 alkyl esters of the mentioned acids substituted with a phenyldimethylamino- or acetylamino group, characterized in that: 1) the compound of the formula: [image] heated with an alkali metal hydroxide in a liquid solvent, then acidified and lactonized to give compound Ia-e: 2) structure connection: [image] reacts with t-butyldimethylchlorosilane in an inert atmosphere, at room temperature in the presence of an acid acceptor; 3) the resulting 4-t-butyldimethylsilyloxy compound is acylated so that: a) mixed in a solution with acid chloride, RCOCl, in pyridine, in an inert atmosphere, in the presence of an acylation catalyst, or b) mixed in solution at ambient temperature with acid, RCOOH, and N.N-dicyclohexylcarbodiimide, in the presence of an acylation catalyst, and what 4) the silyl group is removed by stirring at room temperature in tetrahydrofuran in the presence of 3 equivalents of tetrabutylammonium chloride and 4 equivalents of acetic acid per equivalent of the silyl compound. 2. Process according to claim 1, characterized in that R' represents CH3. 3. The process according to claim 1, characterized in that R represents branched C3-10 alkyl, except for 2-(S)-butyl. alkyl, 4. The method according to claim 1, characterized in that [image] 5. The method according to claims 1, 2, 3 or 4, characterized in that none of X, Y and Z is a double bond. 6. The method according to claim 2, characterized in that it is for obtaining compounds of the formula [image] 7. Process according to claim 1, for obtaining a compound of the structural formula: [image] characterized by R showing: 1) C1-10 alkyl with a straight or branched chain, except for 2-(S)-butyl, 2) C3-10 cycloalkyl, 3) C2-10 alkenyl, 4) C1-10 alkyl substituted with CF3, 5) phenyl 6) halophenyl 7) phenyl-C1-3 alkyl, 8) substituted phenyl-C1-3 alkyl, in which the substituent is halogen, C1-3 alkyl or C1-3 alkoxy; dashed lines at X, Y and Z show possible double bonds, where said double bonds, if present, can be X and Z in combination, or X, Y or Z alone; and corresponding dioxyacids of the formula: [image] or pharmaceutically acceptable salts of the mentioned acids, and C1-4 alkyl esters of the mentioned acids or C1-4 alkyl esters of the mentioned acids substituted with a phenyldimethylamino- or acetylamino group, characterized in that: 1) joint structure; [image] reacts with t-butyldimethylchlorosilane in an inert atmosphere, at room temperature in the presence of an acid acceptor; 2) the resulting 4-t-butyldimethylsilyloxy compound is acylated so that: a) mixed in a solution with acid chloride, RCOCl, in pyridine, in an inert atmosphere, in the presence of an acylation catalyst, or b) mixed in solution at ambient temperature with acid, RCOOH, and N,N-dicyclohexylcarbodiimide, in the presence of an acylation catalyst, and what 3) the silyl group is removed by stirring at room temperature in tetrahydrofuran in the presence of 3 equivalents of tetrabutylammonium chloride and 4 equivalents of acetic acid per equivalent of the silyl compound. 8. The process according to claim 7, characterized in that R' represents CH3. 9. The process according to claim 7, characterized in that R represents a branched C3-10 alkyl, except for 2-(S)-butyl. 10. The method according to claim 7, characterized in that R represents 1-ethyl-t-methylpropyl or 1,1-diethylpropyl 11. The method according to claim 7, 8, 9 or 10, characterized in that none of X, Y or Z is a double bond. 12. Compound formula: [image] characterized in that: R' represents H or CH3; R is 1) C1-10 alkyl with a straight or branched chain, except for 2-(S)-butyl, 2) C3-10 cycloalkyl, 3) C2-10 alkenyl, 4) C1-10 alkyl substituted with CF3, 5) phenyl 6) halophenyl 7) phenyl-C1-3 alkyl, 8) substituted phenyl-C1-3 alkyl, in which the substituent is halogen, C1-3 alkyl or C1-3 alkoxy; dashed lines at X, Y and Z show possible double bonds, where said double bonds, if present, can be X and Z in combination, or X, Y or Z alone; and corresponding dioxyacids of the formula: [image] or pharmaceutically acceptable salts of the mentioned acids, and C1-4 alkylesters of the mentioned acids or C1-4 alkylesters of the mentioned acids substituted with a phenyldimethylamino- or acetylamino group. 13. The compound of claim 12, characterized in that R' represents CH3. 14. The compound of claim 12, characterized in that R represents branched C3-10 alkyl, except 2-(S)-butyl. 15. The compound of claim 12, characterized in that R represents 1-ethyl-1-methylpropyl or 1,1-diethylpropyl 16. The compound of claim 12, 13, 14 or 15, characterized in that none of X, Y or Z is a double bond. 17. Compound formula: [image] wherein the dashed lines represent possible double bonds, wherein said double bonds, if present, may be X and Z in combination, or X, Y or Z alone. 18. A pharmaceutical antihypercholesterolemic compound characterized by the fact that it includes a pharmaceutical base and an antihypercholesterolemic effective amount of a compound of the structural formula: [image] characterized by: R' represents H or CH3; R is 1) C1-10 alkyl with a straight or branched chain, except for 2-(S)-butyl, 2) C3-10 cycloalkyl, 3) C2-10 alkenyl, 4) C1-10 alkyl substituted with CF3, 5) phenyl 6) halophenyl 7) phenyl-C1-3 alkyl, 8) substituted phenyl-C1-3 alkyl, in which the substituent is halogen, C1-3 alkyl or C1-3 alkoxy; dashed lines at X, Y and Z show possible double bonds, where said double bonds, if present, can be X and Z in combination, or X, Y or Z alone; and corresponding dioxyacids of the formula: [image] or pharmaceutically acceptable salts of the mentioned acids, and C1-4 alkylesters of the mentioned acids or C1-4 alkylesters of the mentioned acids substituted with a phenyldimethylamino- or acetylamino group. 19. The compound of claim 18, characterized in that R' represents CH3. 20. The compound of claim 18, characterized in that R represents branched C3-10 alkyl, except 2-(S)-butyl. 21. The compound of claim 18, characterized in that R represents 1-ethyl-methylpropyl or 1,1-diethylpropyl 22. The compound of claim 18, 19, 20 or 21, characterized in that none of X, Y or Z is a double bond. 23. The method of treating hypercholesterolemia, in patients who need such treatment, indicated by the fact that it includes the administration of an active dose of an antihypercholesterolemic compound of the structural formula: [image] indicated by that what is R 1) C1-10 alkyl with a straight or branched chain, except for 2-(S)-butyl, 2) C3-10 cycloalkyl, 3) C2-10 alkenyl, 4) C1-10 alkyl substituted with CF3, 5) phenyl 6) halophenyl 7) phenyl-C1-3 alkyl, 8) substituted phenyl-C1-3 alkyl, in which the substituent is halogen, C1-3 alkyl or C1-3 alkoxy; dashed lines at X, Y and Z show possible double bonds, where said double bonds, if present, can be X and Z in combination, or X, Y or Z alone; and corresponding dioxyacids of the formula: [image] or pharmaceutically acceptable salts of the mentioned acids, and C1-4 alkylesters of the mentioned acids or C1-4 alkylesters of the mentioned acids substituted with a phenyldimethylamino- or acetylamino group. 24. The process of claim 23, characterized in that R' represents CH3. 25. The process of claim 23, characterized in that R represents branched C3-10 alkyl, except 2-(S)-butyl. 26. The method of claim 23, characterized in that R represents 1-ethyl-methylpropyl or 1,1-diethylpropyl 27. The method of claim 23, 24, 25 or 26, characterized in that none of X, Y or Z is a double bond.