BG61418B2 - Antihypercholesterolemic compounds and their use - Google Patents

Abstract

1. A compound of formula in which R' is H or CH3, R is 1,1-dimethylpropyl, C3-10 cycloalkyl, C2-C10alkenyl, C1-10 alkyl substituted with CF3, phenyl, halophenyl, phenyl-C1-3 alkyl, substituted phenyl-C 1-3 alkyl wherein the substituent is halogen, C 1-3 alkyl or C 1-3 alkoxy, dotted lines at X, Y and Z denote possible double bonds which, if present, are either a combination of X and Z, or X, Y or Z appears alone, or the corresponding dihydroxy acid of formula or a pharmaceutically acceptable salt of this acid, its C1-4 alkyl ester or C1-4 alkyl ester of the acid substituted with phenyl, dimethylamino or with acetylamino.6. A pharmaceutical antihypercholesterolemic composition, characterized in that it contains a pharmaceutical carrier and an antihypercholesterolemic effective amount of a compound of structural formula I or of the corresponding dihydroxy acid of formula II, or of a pharmaceutically acceptable salt of this acid, of its C1-4 alkyl ester or of C1- 4 alkyl ester of the acid substituted with phenyl, dimethylamino or acetylamino. 11. A method for treating patients with hypercholesterolemia, which comprises administering an antihypercholesterolemic effective amount of a compound of structural formula I or of the corresponding dihydroxy acid of formula II.18 claims

Description

This is a partial sequel to a request sir. No. 175 460 (currently pending review), registered on 05.08.1980 (now abandoned), which in turn is a continuation of application Ser. No. 118 051 (also under examination at the same time as the present one), registered on 04.02.1980 (now abandoned).

The invention relates to a group of 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-ones, to the hydroxy acid forms of these pyranones, to the pharmaceutically acceptable salts of these hydroxy acids and to the lower alkyl esters of these acids, substituted by lower alkyl, phenyl, dimethylamino or acetylamino . These compounds are potent inhibitors of cholesterol biosynthesis.

In particular, the invention relates to a compound of structure I given in Table I, in which the structure dashed lines at X, Y and Z denote possible double bonds which, if shown, are either a combination of X and Z, or X, Y or Z appear independently; R represents C _{1 | 0} straight or branched alkyl chain (with the exception of (S) 2-butyl), _{C>] 0} cycloalkyl, _C2-10 alkenyl, ₍₁₀ alkyl substituted with CF _3, phenyl, halophenyl, fenilC. _H alkyl or substituted phenyl-C. _H alkyl in which the substituent is a halogen atom, an alkyl group or Cj _H alkoxyl group; and the free hydroxy acids of formula II, obtained by opening the lactone ring in the compounds of formula I in table I.

BACKGROUND OF THE INVENTION

Some mevalon derivatives are known to inhibit the cholesterol biosynthesis of F.M.Singer et al. Proc. Soc. Exper. Biol. Med., 102,370 (1959) and F.H.Hulcher, Arch. Biochem. Biophys., 146,422 (1971). However, it has been found that the activity of these known compounds is not always satisfactory in order to find practical application.

Recently, Endo et al. reported (US Patent Nos. 4,049,495; 4,137,332 and 3,983,140) to obtain fermentation products that are too active in inhibiting cholesterol biosynthesis. The most active member of this group of natural products, referred to here as (now) 'compact', Sha 5 (R '= H), has been reported by Brown et al. To have a complex mevalonolactone structure (J. Chem. Soc. Perkin I, 1165, 1976).

Later Monaghan et al. describe in US Patent No. 4,231,938, listed on page 10, an inhibitor designated MK803 with the Illa structure (R '= CH ₃ ) given in Table I, which was isolated in completely different fermentation. In U.S. Patent Application Ser. No. 154 157, registered May 15, 2880, 1980, Albers-Schonberg et al., Describe the dihydro MK-803 given by formula IIIr (R '= CH ₃ ) in Table I, which has the same activity as MK-803 and is isolated by the same fermentation as MK-803 was isolated. 20 In U.S. Patent Application Ser. No. 118 050, registered Feb. 4, 1980, Patchett et al., Describes the dihydro and tetrahydro derivatives of MK-803 with different structures (6b, species (R '= CH ₃ ) in Table I), obtained by catalytic hydrogenation of MK -803. In U.S. Patent Application Ser. No. 118 049, filed Feb. 4, 1980, Willard describes the preparation of 8hydroxy derivatives (IVa-d (R '= CH ₃ ) in Table 1), which are starting materials for the preparation of some of the new Compounds according to the invention.

The tetrahydro analogue of compactin (III, R '= H) is reported in published Japanese patent application (Kokai) 55009-024.

The dihydro analogue of compactin with structure IIr (R = H) was recently isolated from the nutrient media for fermentation of compactin, as reported by Gullo et al., In U.S. Patent Application Serial No. 207 508, 40, filed Nov. 17. 1980.

The preparation of the starting material, Hlr (R '= CH ₃ ), as mentioned above, has been described by Albert-Schonberg et al. in U.S. Patent Application Ser. No. 154 157, registered 45 on 05/25/1980, and is the product of subsequent fermentation with a strain of Aspergillus terreus, ATCC No. 20542, designated MF-4845 in the MERCK and CO cell culture collection.

Preparation of Compound IIIr (R '= CH ₃ ) 50 A. Fermentation

The lyophilized culture vial MF4845 is opened aseptically and the contents are suspended in 250 ml wide

Erlenmeyer flask (sowing flask), holding approximately 10 ml of environment with the following composition: Wednesday Maize extract 5 g Tomato paste 40 g Oatmeal 10 g Glucose y. g Trace element solution 10 g Distilled water 1000 ml pH 6.8, with NaOH Trace element solution FeSO, .7H, 0 4 1 1000 mg MnSO ₄ .4H ₂ 0 1000 mg CuC1 ₂ .2H ₂ 0 25 mg CaCl ₂ .2H ₂ O 100 mg n _{3 in 3} 56 mg / NH _4/6 Mo ₇ 0 ₂₄ .4H ₂ 0 19 mg ZnSO ₄ .7H ₂ 0 200 mg Distilled deionized water 1000 ml

The contaminated flask was incubated for 24 hours at 28 ° C on a shaker at 220 rpm (amplitude 5.08 cm). A wide-necked two-liter Erlenmeyer flask containing 500 ml of medium was infected with 10 ml of the first-stage fermentation culture medium. It was also shaken at 28 ° C for 24 h.

A 756 1 stainless steel fermentation vessel is charged with 485 1 of medium containing:

Crystalline glucose Peptonized milk Autolysed yeast Polyglycol P2000

4.5% w / v

2.5% w / v

0.25% w / v

0.25% vol./vol.

The pH of the medium was adjusted to 7.0, after which it was sterilized for 15 min at 121 ° C. A second fermentation culture from the second step was added above and the mixture was incubated at 85 rpm for 12 h and then at 130 rpm for 84 h, with a temperature of 28 ° C. An air flow of 0.14 m ³ / min for 12 h was then applied and then 0.28 m ³ / min for 84 h.

B. Isolation

1. Extraction

Two doses of 378 l of the entire culture medium were collected, acidified with stirring to pH 4.1 by carefully adding 800 ml of concentrated hydrochloric acid, extracted by adding 284 l of ethyl j-cetate and stirred again for 2 h.I

Then about 11.35 kgΐ of filter aid is added, which is-1 containing silica and the total suspension is aspirated through a 61 cm filter press.

Additionally, 284 1 ethyl acetate * is used to flush the filter press and | extraction is continued by reversing the suction direction through the press 4 times. Thereafter, all the washing liquid (solvent) is expelled from the press and collected with the first filtrate. The filtrate of the two phases was allowed to precipitate and the aqueous layer was separated.

The ethyl acetate layer was washed with 37.8 l of deionized water, the phases were allowed to decompose and the ethyl acetate extracts were concentrated in vacuo to give a residue of |

37,8 1.I

2. LactonizationJ

Additional 1134 I culture media were extracted with ethyl acetate and the extracts were taken added to the above extract, then both- | the mint (of the extracts) is reduced to about

113,4 I with vacuum distillation. About 189 l of toluene was added and the batch was concentrated.

under vacuum to 121 1. This operation is repeated.

The necessary amount of toluene is then added to bring the volume to 284 l.

The vacuum was removed and the batch was refluxed for 2 h, with the temperature exceeding 106 ° C.

This solution was concentrated in vacuo to a small volume, which was then further concentrated to give an oil residue in a large rotary evaporator in vacuo.

3. Silica gel chromatography

The above extract was washed with other solvents by the addition of 7.56 methylene chloride and then concentrated again to an oil.

The oily residue dissolves in about

19 1 ethyl acetate / methylene chloride (30/70; v / v), mixture, and by adding 2.8 kg of silica gel, a suspension is obtained.

The slurry was applied to a 30.5 x 127 cm (30.5 x 127 cm) top part of the silica gel column in the same solvent mixture.

This was followed by elution with ethyl acetate 3

I methylene chloride (40/60; v / v) at a rate of 800 ml / min. The first fraction of 37.8 l and the subsequent fractions of 15 l each were collected.

Fractions 6 to 10, inclusive, were concentrated in vacuo to an oily residue, 5 which was dissolved in hot ethyl acetate, treated with decolourising charcoal, filtered hot and cooled. The crystals of compound Illa (R '= CH ₃ ) were filtered off and the mother liquor was concentrated to give 10 oil, which was further chromatographed.

4. Repeat chromatography on silica gel

Residues from a mother liquor from a similar 15 extract of the culture medium were treated to obtain an additional 2268 l of fermentation, which was collected with the above dissolved in methylene chloride. Half of this solution was taken for further chromatography on silica gel. A small sample shows a total solids content of 325 g. The solution was treated with 40 g of decolourising carbon, filtered and the filter cake washed with methylene chloride. The washing liquids and the filtrate were collected and concentrated in vacuo to an oily residue. The latter was redissolved in 800 ml of a mixture of ethyl acetate and methylene chloride (30/70; v / v) and suspended with 225 g of silica gel. The slurry was passed 30 from the top of a 14 x 36 cm silica gel column in the same solvent mixture. Appears with a mixture of ethyl acetate-methylene chloride (40/60; v / v). The first fraction of 3 l is separated off and 35 subsequent fractions of 800 ml each are collected.

5. Reverse phase chromatography ml of fraction 12 separated after the above chromatography are concentrated to a mass of. The weight was 500 mg and the oil was dissolved in 5 ml of acetonitrile. The acetonitrile mixture;

is passed through a column of stainless hundred-!

mana measuring 1.6 cm outside diameter and

183 cm length, filled with maternal substance for reverse phase preparative liquid chromatograph-1 - “Bondapak C18 / PorasilB” I (Waters Assoc. Inc., Milford, Mass. 01757).

The column was eluted with a mixture containing 55%;

vol. acetonitrile and 45% vol. 0.05 M ammonium phosphate, pH = 3. Obtained from 1360 to 1700 ml of eluate, which is collected based on the determined refractive index. The organic solvent was removed in vacuo and the remaining aqueous solution was extracted with ethyl acetate. After removal of the ethyl acetate in vacuo, 120 mg of a compound are left, which crystallizes from the concentrated acetonitrile solution to give crystals of compound II (R '= CH ₃ ), m.p. 129-131 ° C. :

Preparation of compounds IIIb, c, e

The starting materials 1116, III and III (R'1 - CH ₃ ), as mentioned above, are described * in US patent application Ser.

050, registered on 04.02.1980, from which the following technological scheme and methods of production were taken and cited.

The unmethylated analogs, IIIb, IIIb and IIId (R '= H) are obtained exactly as described in the cited application, the starting product being Ilia (R' = H) in all three cases.!

In order to obtain Shd, it is better to | is reduced Shm as the desired conversion | The perhidronaphthalene ring which appears in the starting materials remains in the final product and the need for separation of the isomers is avoided.

Technical scheme

Reactions and Reagents

1. Hydrogenation at a temperature of from 20 to 75 ° C and at a pressure of from about atmospheric to about 4 atmospheres above tri / triphenylphosphine / chlorodium in an aromatic solvent, such as benzene, toluene or xylene, preferably in toluene. Preferred conditions are: 40 ° C, pressure from 2 to 7 atmospheres, solvent - toluene.

2. Hydrogenation at about 20 dd 25 ° C and at a pressure around atmospheric pressure over 5% palladium on calcium carbonate in a lower alkanol, such as C, _H alkanol and in particular ethanol.

3. Hydrogenation at a temperature of about 20-45 25 ° C and at atmospheric pressure above platinum oxide in ethyl acetate.

4. Hydrogenation at a temperature of 20 to

25 ° C and at atmospheric pressure above 10% palladium on carbon in ethyl acetate. 50

Preparation of 6a12- (8'y3-2- (5) -methylbutyryloxy-2 '/ 3,6'a-dimethyl, 2', 3 ', 4', 6 ', 7', 8 ', 8'a- octa-hydronaphthyl-1 / ethyl 1/4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2one, III (R '= CH ₃ )

A mixture of 50 mg (0.1236 mmol) of compound IIIa (R '= CH ₃ ) and an equimolar amount (114.35 mg, 0.1236 mmol) of tri / triphenylphosphine / chloride in 10 ml of dry toluene was hydrogenated at room temperature for 6 days, with complete ingestion of 14.6 ml of hydrogen. The mixture was evaporated in vacuo to dryness. The red residue was subjected to preparative thin layer chromatography on silica plates impregnated with silver nitrate and manifested twice in 10% ethyl acetate / ether system. The yield of compound IIIb (R '= CH ₃ ) was 22.3 mg.

Mass spectrum (M) e (406) m ⁺ (304) m 102 (286 m-102-18).

NMR / CDC1 ₃ , 300 MHz (δ 4.37 / t, 1H / 4.60 / t, 1H / 5.34 / d from t, J = 2.5 Hz, 1H / 5.41 / t, 1H) .

Preparation of 6α 12- (8 ') - 2- (5) -methylbutyryloxy-2,3,6'a-dimethyl1', 2 ', 3', 5 ', 6', 7 ', 8', 8'a- octahydronaphthyl-1 / ethyl 1-4 / 3-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2one, P1b (R '= CH ₃ )

A solution of 80.91 mg (0.2 mmol) of compound IIIa (R '= CH ₃ ) in 10 ml absolute ethanol, in the presence of the same weight of 5% Pd on CaCO ₃ , was hydrogenated at 1 atmosphere until established. absorption of one mole equivalent of hydrogen. The catalyst was then removed by filtration and the filtrate evaporated to dryness (81 mg). After purification by preparative thin layer chromatography to remove the small amount of side tetrahydro compound, 72 mg of the 1,4-reducing product IIIb (R '= CH ₃ ) was isolated.

Mass spectrum / M / e / 406 / m 7 304 / m 102/286/304-H ₂ 0 /

NMR / CDCl ₃ , 300 MHz (04.38), 1H (4.64), 1H (5.28) d of t, J = 3.5 Hz, 1H (5.48 (m, 1H)).

Getting 6 a-12- (8 ')? -2 (S) -methyl 5 ', 6', 7 ', 8', 8'a-decahydronaphthyl-1 / ethyl 1-4β hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, Bd (R '= CH ₃ )

A solution of 80.91 mg (0.2 mmol) of compound Illa (R '= CH ₃ ) in 10 ml of ethyl acetate was hydrogenated in the presence of an equivalent amount of platinum oxide at a pressure of 1 atmosphere. Exactly 2 molar equivalents of hydrogen are consumed in 1 hour. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give an oil. The cis and trans isomers were separated by preparative thin layer chromatography on silica gel plates (10% ethyl acetate-ether system, detection of zones by water spray). The trans isomer of 1Pd (R '= CH ₃ ) appears as a more polar spot than the cis isomer, isolating 60 mg.

Mass Spectrum / M / e / 408 / m 7 323 / m-85/306 / m-102 /

NMR (CDCl ₃ ), 300 MHz (β 4.36) (broad singlet, 1 H (4.59) m, 1 H (5.19) d of t, J = 2.5 Hz, 1 H).

Fermentation Preparation of Compound 1Pr / R '= H /

A. Fermentation

The native isolate of Penicillium citrinum, NRRL 8082 was used to prepare yeast maul-malt extract (DME) on inclined agar, which was incubated for 2 weeks at 28 ° C.

Part / 1/5 / of inclined arap / MF4870a / was used to inoculate (infect) each of the five wide-necked culture flasks (250 ml) containing 44 ml of KF seed medium with CaCl ₂ . They were incubated for 3 days at 28 ° C and 220 rpm. A portion of the grown spores (about 1.5 ml) was used to inoculate each of the 100 flasks with production medium (250 ml wide-necked flasks) containing 40 ml of LM production medium, without malt extract. These production flasks were incubated for 4 days at 25 ° C.

Another group of flasks with production (culture) medium (140 pieces), each containing 40 ml of LM production medium without modification, were inoculated and incubated under the same conditions previously described. The nutrient media from both fermentations were collected.

For the fermentations mentioned above, the media used are:

Yeast-malt extract on inclined agar

Dextrose 4.0 g / l Malt extract 10.0 g / l Yeast extract 4.0 g / l Agar 20.0 g / l Distilled water to 1 1 pH 7.0 KF seed medium with CaCl ₂ CaCl ₂ 10,0 g Maize extract 5.0 g Tomato paste 40,0 g Oatmeal 10,0 g Crystalline glucose 10,0 g Mixture of trace elements 10,0 ml Distilled water 1000,0 ml pH 6,8 Mixture of trace elements FeSO, .7H, 0 1.0 g MnSO _d .4H, 0 1.0 g CuC1 ₂ .2H ₂ 0 25,0 mg CaCl ₂ 100,0 mg n _{3 in 3} 56,0 mg / NH _4/6 Mo ₇ 0 ₂₄ .4H ₂ 0 19.0 mg ZnSO .7H, 0 4 2 200 mg Distilled water 1000 ml

LM production medium without malt extract

Dextrose20 g

Glycerin 20 ml

Ardamin pH10 g

CoCl ₂ .6H ₂ 08 g

Polyglycol p 20000,25%

Distilled water 1000 ml pH7,0

LM production environment without modification

Dextrose20 g

Glycerin 20 ml

Ardamin pH10 g

Malt extract20 g

CoCl ₂ .6H ₂ 08 mg

Polyglycol p 20000,25%

Distilled water 1000ml pH7,0

B. Isolation

Total nutrient collected (10.3

1) Filter and wash the micelles with

2.5 1 deionized water. The pH of the collected filtrate and the washing liquids was adjusted to 4.0 with 1N hydrochloric acid. The aqueous solution was extracted with 7 l of ethyl acetate and the extract was re-extracted with 3 x 2 l aqueous sodium hydroxide solution. The combined sodium hydroxide extract extract was treated with 1N hydrochloric acid to reach pH 3.8, then extracted with 2 L, once and twice with 1 L of ethyl acetate. The combined ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The oily residue was dissolved in toluene and refluxed for 1 h. The toluene solution was concentrated to dryness and the residue was dissolved in 18 ml of a mixture of n-hexane (toluene / methanol (4 (1/1 by volume)).

The solution was passed through a Sephadex LH-20 column of dimensions 30 mm (inner diameter) x 40 cm, calibrated with the same solvent system. Elution with 300 ml of solvent gave a 10 ml fraction which was concentrated to an oil. HPLC on an ES Industries Chromega R column, sized (9 mm x 50 cm) using a mixture of acetonitrile / water (60/40 volume ratio) as eluant, yields 45 mg of dihydrocompactin (Compound III, R '= H) m.p. 392.2560 by mass spectroscopy (calculated for

H, ₆ O ₅ - 392.2558).

In potassium bromide, the major infrared peaks obtained on Fourier Transform - IR (FTIR, Nicolet, model 7199) are 5 at 1724, 1704, 1258, 1078 and 1070 cm @ -1. What matters is the maximum at 3005 cm ¹ and the maximum at 3030 cm ¹ .

Nuclear magnetic resonance spectrum was obtained in CDC1 ₃ (- 1 mg / 0.5 ml) on a Varian 10 SC-300 superconducting NMR spectrometer.

The following is the distribution of peaks (maxima) given in ppm! Β / with respect to an internal indicator - tetramethylsilane (TMS).

ό Relate

5.62 d, d, d / 2.17, 4.5, 10.0 /

5.43 d / 10 /

5.20 m

4,63 m

4.39 m

2.75 d, d / 17.5, 5.5 /

2.63 d, d, d / 17.5, 4.0, 1.5 /

2.39 m

2.29 m

1.14 d

0,90 t

0.84 d

H ₃ '/ d / n; / s / n ₈ 'n ₆ n _{4 s} -ss,

CHjHCC ^ ^H 4a ' ^{+ H} ; ₍

CH ₃ CHN ₃ CH ₂ CH ₂

CHCH 'd - doublet; m is a multiplet; t is a triplet

The data suggest the following structure:

Preparation of Compounds IVa-e

The starting materials, the 8 ' -hydroxy compounds IVa-d (R ' = CH ₃ ), are described in U.S. Patent Application No. 118 049 and are prepared from various 8'-esters described by Monaghan et al. (1 Pa, R '= CH ₃ ), Albert Schonberg et al. (Nr, R '= CH ₃ ) and Patchett et al. (Br, c, e, R '= CH ₃ ) by heating with a solution of lithium hydroxide for a long time. Piran7

the new ring is easily opened, but the remainder of the side acyl group is not easily affected. Heat must be extended and / or pressure applied. Applying an inert atmosphere would also be beneficial. 5

When Shad compounds (R '= H) are obtained, saponification of the 8′-esters is much easier and complete completely in about 20 h.

The 8'-hydroxy products are isolated by acidification and extraction with organic 10 solvents to give the trihydroxy acid form in which the pyranone ring is still open. These trihydroxy acids are reactonized by heating an acid solution in a suitable organic solvent, such as benzene or toluene, in an apparatus allowing continuous separation of the formed water.

The compound IVa (R-H) is known as ML-236A and is described by Endo et al. in U.S. Patent No. 3,983,140. In their lactone form, these alcohols are compounds of formulas IVa-e in Table I and are prepared as described below.

Preparation of 6 (R) -12- / 8 '/ S / -x ^ pok- 25 ch-2' / S /, 6 '/ RZ-dimethyl D, 2', 6 ', 7', 8 ', 8 'a (R) -hexahydronaphthyl-N (S) -ethyl 1-4 (E) -hydroxy3,4,5,6-tetrahydro-2H-pyran-2-ones, IVa (R' = CH ₃ )

A mixture of 8.0 g (19.78 mmol) of MK-803 (IIIa, 30 R '= CH ₃ ) and 8.31 g (197.8 mmol) of LiOH.H ₂ O in 600 ml of water was stirred by heating with refluxed under nitrogen for 56 h. The reaction mixture was cooled to 0 ° and treated with stirring with 20 ml of concentrated hydrochloric acid. The mixture was extracted with three portions of 250 ml of ether and the combined extracts washed sequentially with three portions of 200 ml of water and then with 200 ml of saturated brine. After drying on magnesium 40 sulfate, this organic solution was filtered and the solvent was evaporated in vacuo to give an oily residue. This residue was dissolved in 200 ml of toluene and refluxed under nitrogen for 45 hours for 2 hours, followed by continuous separation of water to give relactonization. Evaporation of the toluene and treatment of the residue with hexane afforded 5.15 g (81%) of the desired compound of 50 formula IVa (R '= CH ₃ ) as a white solid that did not require further purification.

An analytical sample was prepared by recrystallization of a portion of the above substance from butyl chloride to give white clusters: m.p. 128-131 ° (vacuum); NMR / CDC1 ₃ / ό 0.87 / d, 3, J = 7 Hz, CH ₃ /, 1.16 / d, 3, J = Ί Hz, CH ₃ /, 2.64 / m, 2, pyran C ₃ H'S /, 4.27 (brm, 1, naphthalene C _g H), 4.37 (m, 1, pyran C ₄ H), 4.71 (m, 1, pyran C ₆ H), 5.56 / m, 1, naphthalene C ₅ H /, 5.79 (dd, 1, J = 6.10 Hz, naphthalene C ₃ H), 6.03 / d, 1, J = 10 Hz, naphthalene C ₄ H /; IR (CHCl ₃ (3400) OH), 1725 (C = O), 1240, 1120, 1080 cm ¹ .

Elemental analysis:

Calculated for C ₁₉ H _J8 0 ₄ .0.1C ₄ H _g Cl C 70.67; H, 8.84

Found: C, 70.77; H, 8.75.

Alternative preparation of 6 (R) -1218 '(8) -hydroxy-2' (8), 6 '(E) -dimethyl, 2', 6 ', 7', 8 ', 8'a (R) -hexahydronaphthyl -N (S) ethyl-4- (E) -hydroxy-3,4,5,6-tetrahydro-2Hpyran-2-one, IVa (R '= CH ₃ )

A suspension of 188 mg (0.463 mmol) of MK803 (Illa, R '= CH ₃ ) in 5 ml (5 mmol) of 1N aqueous LiOH was shaken for 12 h at 135 ° C in a stainless steel autoclave with a volume of 30 ml. The cooled reaction mixture was acidified with 1M H ₃ PO ₄ and extracted with ethyl acetate. The ethyl acetate solution was dried (magnesium sulfate), filtered and the solvent was evaporated. The residue was dissolved in 20 ml of toluene and heated to reflux for 4 hours in a Dean Stark apparatus to obtain reactonization. Evaporation of the toluene afforded the desired compound.

Preparation of alcohols IVa (R '= H) and 1V6, IVb, IVr and 1Ud (R' = H or CH ₃ )

Following essentially any of the procedures described above, but instead of 111a (R '= CH ₃ ), an equivalent amount of the esters IIIa (R' ^ - H) or III, III, III, II and 1R (R ') is used. = H or CH ₃ ), the corresponding alcohols IVa (R '= H), 1V6, IVb, 1Ud and IVr (R' = H or CH ₃ ) are obtained.

Description of the invention

It has now been found that 8'-hydroxy compounds of structure IV can be acylated to give a new class of 8-acyloxy compounds of structure defined by formulas I and II and the definitions given below. These new compounds are not formed in the fermentation processes described by Endo,

Monaghan, Alberts-Schonberg or Gullo. They are inhibitors of cholesterol synthesis in vivo.

The absolute configuration of these compounds is determined by X-ray diffraction. These structures and their stereochemical relationship are presented in Table I. The numerical designations in the various compounds, including the different rows of polyhydronaphthyl structures, remain the same until the end of the description. Each of the esters of the invention Ia-d (R '= CH ₃ ) contains seven or eight chiral centers. The relative and absolute configuration of these asymmetric centers is shown in Table I. In particular, for ester la (R '= CH ₃ ) the absolute configuration instructions are 4 / R /, 6 / R /, D / S /, 2 / S /, 67R /, 87S / and 8a '/ R / (see RS Cahn, C. Ingold and V. Prelog, Angew. Chem. Int. Ed., 5, 385 (1966)).

o L, o

And

la (R '= CH ₃ )

As shown in formulas Ia-e, all these compounds have the same spatial orientation of groups or each chiral carbon atom and therefore belong to the same stereochemical series. The RS designation for each center may not be identical to that found for the ester la (R '= CH ₃ ) due to the details in the ordering (sequence) rules used to determine this designation. In the two esters 1d and 1g having an additional chiral carbon atom that does not appear in ester 1a, the hydrogen atom at 4a 'is in the α orientation, as shown in Table I, giving a trans ring compound.

Table 1

The compounds of the invention and their stereo-relations

Stereochemistry of Hydronaphthyl Rows (Groups)

Rows Available Double Structure | (groups) connections

The compounds of the invention are useful as antihypercholesterolemic agents for the treatment of atherosclerosis, hyperlipemia and other similar diseases in humans. They may be administered orally or parenterally in the form of capsules, tablets, injections or the like. Oral administration is generally preferred. Doses may vary depending on age, disease severity, body weight and other 10 conditions, but the daily adult dose is in the range of about 2 mg to 2000 mg (preferably 10 to 100 mg) and is divided into three or four single doses. Higher 15 doses are preferred if necessary.

The compounds of the invention also have fungicidal activity. For example, they can be used to control strains of the Penicillium species, such as 20 Aspergillus niger, Cla dosporium, Cochliobolus miyabeanus and Helminthosporium cynodnotis. For this application, they are mixed with suitable formulating agents, powders, emulsifiers or solvents such as ethanol 25 and sprayed or sprayed on the plants to be protected.

The preparation of the compounds according to the invention is shown in Scheme A. 30

Flow diagram A

X, Y, Z, R, and R 'are as defined in the specification, and the designations a-e, respectively!

These are given in Table I. '

Reactions: / 1 / Lithium hydroxide, heating, acidification and lactonization.

(2) Tert-butyldimethylchlorosilane and imidazole in dimethylformamide at ambient temperature and in an inert atmosphere.I / 3 / Treatment with RCOC1 and 4-dimethylaminopyridine in a pyridine solution for preference under an inert atmosphere.

/ 4 / Treatment with RCOOH and Ν, Ν′-dicyclohexylcarbodiimide and 4-pyrrolidinopyridine in dichloromethane, preferably under an inert atmosphere.

(5) Three equivalents of tetrabutylammonium-;

eV fluoride and four equivalent acetic acid selenium equivalent of tetrahydrofuran ester, preferably in an inert atmosphere., / 6 / Aqueous solution of the base, followed by careful acidification with dilute acid.

/ 7 / See Reactions and Reagents, and Technological Scheme for the Synthesis of 1116, c, e.

In the new process according to the invention, the 4-hydroxy group in the pyranone ring of alcohols IVa-e is initially protected by.

tert-butyldimethylsilyl group by reaction with tert-butyldimethylchlorosilane in inert- | in an atmosphere, at ambient temperature, in the presence of an acid acceptor, such as imidazole, to obtain protected Va-e alcohols. The hydroxy group at the 8th position in the polyhydronaphthyl ring is then acylated in one of two ways.

The first method involves treating the acid chloride of the desired acyl group in 1 pyridine and in the presence of n _and 4-dimethylamino- | pyridine as catalyst. The second method involves treating the 8'-polyhydronaptol with the free acid of the desired acylo-;

and a carbodiimide, such as Ν, Νcyclohexylcarbodiimide, with 4-pyrrolidinopyridine as a catalyst in dichloromethane. This mode of operation gives protected esters VIa-e.

The silyl protecting group is then removed from the hydroxy group in the 4th place in the pyranone ring using three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid for the equivalent compounds Ia-e. The ratio of reagents in the last reaction is critical for the yield of the process and the purity of the products.

The acyl groups thus attached to the 8'-hydroxy group are those wherein R in Ia-e is:

/ C ₍₁₀ straight or branched alkyl chain, with the exception of / SZ-2-butyl;

2 / C ₃₁₀ cycloalkyl,

3 / C ₂₁₀ alkenyl,

4 / C, ₁₀ alkyl substituted with CF ₃ ,

5 / phenyl,

6 / halophenyl, as halo means chlorine, bromine, fluorine or iodine,

7 / phenyl-C _1-3 alkyl,

8) substituted phenyl-C _1-3 alkyl, in which the substituent is halo, such as fluorine, chlorine, bromine or iodine, C 1 -C 6 alkyl or C ₃ alkoxy.

Preferably R 'is CH ₃ .

Preferred values for R are: C _2-5 straight chain alkyl, C ₃₁₀ branched alkyl chain, except for / SZ-2-butyl, C _3-10 cycloalkyl, C _{3- O} alkenyl, in which the unsaturated bond is not fused with the carbonyl group, and in particular a C _3-10 branched alkyl chain, with the exception of S 2 -butyl.

Preferred compounds are those wherein R is 1,1-diethylpropyl or 1-ethyl-1methylpropyl. Particularly preferred are those compounds in which none of X, Y or Z represents a double bond.

The compounds Ia-d can be hydrolyzed with bases such as the sodium base to give salts, such as the sodium salt of the compounds Pa-e. The use of bases with other pharmaceutically acceptable cations gives salts of these cations. Careful acidification of the salts yields the hydroxy acids Pa-e, which are converted to compounds la-e at acidic pH. Treatment of compounds Ia-e in the presence of an alkali or acid catalyst with methanol, ethanol, propanol or with butanol or phenyl-, dimethylamino- or acetylamino-alkanols results in the corresponding esters of compounds Pa-e, which also are part of this invention.

The pharmaceutically acceptable salts of the invention include those salts formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine arginine, ornithine, choline, N, N '-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-N-yl-methylbenzimidazole, diethylamine, piperazine and tri / hydroxymethylmethyl-hydroxymethyl.

Example 1. 6 / R / -12- / 87S / -2 '', 2 '-flHMeτilπpoπanoilokci-27S /, 67R / -dimeτill', ² ', 6', ^7, 8 ', 8'a / R / -hexcaxidrophenyl-17S // ethyl 1-4 (N) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one

Step A: Preparation of 6 (R) -12- (87S) -XHflpokcH-27S (-67R) -flHMeTHa-r, 2 ', 6', 7 ', 8', 8'a (R) -hexahydronaphthyl-17 S // ethyl 1-4 (R) - (dimethyl-tert-butylsilyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-one Va (R '= CH ₃ )

A mixture of alcohol IVa (R '= CH ₃ ) (18.3 g, 57.1 mmol), 21.5 g (142.8 mmol) tert-butyldimethylchlorosilane and 19.4 g (285.6 mmol) imidazole in 200 ml of N, N-dimethylformamide was stirred at 20 ° C under a nitrogen atmosphere for 18 h. The reaction mixture was then diluted with 1500 ml of ether and washed sequentially with water, 2% aqueous hydrochloric acid, water and saturated sodium bicarbonate. The ether solution was dried over magnesium sulfate, filtered and its volume reduced to 1 I. After 600 ml of hexane was added, the volume was reduced again to 600 ml in a steam bath. The product crystallizes at room temperature; After isolation and air drying, 13.7 g of a white soft substance are obtained. The mother liquors were reduced to 250 ml and a second portion of crystals was isolated after the solution was left at 0 ° C overnight. The total yield was 17.13 g (69%) of the above compound which was obtained as a white soft substance: m.p. 142-144 ° C (vacuum); NMR / CDC1 ₃ / <5 0,10 / S, 6, / CH _3/2 Si /, 0,90 / S, 9 / CH _3/3 C Si /, 1,19 / d, 3, J = 7 Hz, CH ₃ /, 2.58 / d, 2, J = 4 Hz, pyran C ₃ H'S /, 4.3 / m, 2, pyran C ₄ H and naphthalene C ₈ H / 4.70 / m, 1, pyran C ₆ H /, 5.57 / t, 1, naphthalene C ₅ H /, 5.58 / dd, 1, J = 6.10 Hz, naphthalene C ₃ H /, 6.03 / d, 1 , J = 10 Hz naphthalene C ₄ N /.

Elemental analysis: Calculated for CJ1.0: C = 69.08 H = 9.74

42 4 ^{7 7}

Found: C = 69.46 H = 9.83

Step B: Preparation of 6 (R) -12- (87S) 2 '', 2 '' - dimethylpropanoyloxy-27 $ /, b7P / -di11 methyl-D, 2 ', 6', 7 ', 8', 8 '(N) -hexahydronaphthyl-N (8) ethyl 1-4 (N) - (dimethyl-tert-butylsilyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-one, Via (R '= CH ₃ )

A solution of 6.0 g (13.8 mmol) of alcohol 5 Va (R '= CH ₃ ) from step 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 were added to this solution with stirring for 10 to 15 minutes. The reaction mixture was stirred at 0 ° C for 1 h and then at 20 ° C for 4 days. The reaction mixture was diluted with 750 ml of ether and washed with 2% aqueous hydrochloric acid, until the washing liquid 15 was acidic, then washed with saturated sodium bicarbonate solution. After drying over magnesium sulphate the solution was filtered and evaporated, yielding 7,81 g of the title compound as a svetlooran- 20 To live oil: NMR / CDCi ₃ / δ 0,09 / S, 6 / CH _3/2 Si /, 0,88 / S, 9 / CH _3/3 CSi /, 1,28 / S, 9 / CH _3/3 CCO ₂ - /, 2,57 / d, 2, J = 4 Hz, pyran C ₃ H'S /, 4.32 (m, 1, pyran C ₄ H), 4.63 (m, 1, pyran C ₆ H), 5.34 (m, 1, naphthalene C ₈ H), 5.54 / t, 1, naphthalene C ₅ H /, 5,78 / dd, 1, J = 6, 10 Hz, naphthalene C ₃ H /, 6,03 / d, 1, J = 10 Hz, naphthalene ₄ n /.

Following the procedure described in Example 1, step B, but replacing the pivaloyl chloride 30 used therein with an equimolecular amount of acid chloride of the formula R-COC1 given in Table II, esters of the structure Via (R '= CH ₃ ) are obtained. also given in Table II. 35

Table II

Oh

II

RC-0 NMR / CDCl ₃ , d / 40

7.10 / t, 2, J = 8 Hz, p-FPh8.03 / dd, 2, J = 5.8 H, p-FPh- /

2.02 / s, 3, CH ₃ CO ₂ - / 45

1.19 (d, J = 7 Hz, -CH ₃ ester /

1,21 / d, J = 7 Hz, CH ₃ ester / total H / CH, / ₂ CHCH ₂ CO ₂ - 0,83 / d, 6, J = 6 Hz, / 50 CH _3/2 CH- / / CH _3/2 CHCO ₂ - 1,13 / d, 6, J = 6 Hz / CH _3/2 CH /

CH ₃ / CH _2/3 CO ₂ Οχ. », 0,95 / t, 3, J = 7 Hz, CH ₃ - / CH _2/3 from 1.60 to 2.08 / W, 15, adamantyl / CH ₃ / cH ₂ /.so s.n "omega" cH = cH-CO ₂ cf ₃ / ch _2/2 co ₂ ^C 6 ^H 5 ^CO 24-C1c ₆ H ₄ CO ₂ -

2.4- F ₂ C ₆ H ₃ CO _{2 6} H ₅ / CH _2/3 co ₂ 4-FC ₆ H ₄ CH ₂ CO ₂ -

2.4- ESDSN, CO, 4-Cl ₆ H ₄ CH ₂ CO ₂ 4-FC N / CH / CO -

4 2 3 2

CFj

CH3CH-CH ₂ CO ₂ CH ₃ COJ— n

CHj CH ₃ / CH _2/8 sp ₂ CHj '

SI) μ 'CHj

Step B: Preparation of 6 (R) -12- (87S) -2 '', 2 '' - dimethylpropanoyloxy-2 '(8), b7E) -dimethyl-D, 2', 6 ', 7', 8 ' , 8'a N -hexahydronaphthyl N (S) ethyl 1 -4 (E) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, la (R '= CH ₃ )

To a solution of 10.0 g (31.7 mmol) of Bu ₄ N ⁺ F'.3H ₂ O and 2.4 ml (2.5 g, 42.3 mmol) of acetic acid in 50 ml of tetrahydrofuran were added 7.81 g (13.8 mmol) silyl ether Via (R '= CH ₃ ) from step B in 50 ml of tetrahydrofuran. This mixture was stirred at 20 ° C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with 700 ml of ether and washed successively with 2% aqueous hydrochloric acid, water and saturated aqueous sodium bicarbonate. The organic solution was dried over magnesium sulfate and filtered. After evaporating the solvent, 6.45 g of a dirty white solid are left. This substance was crystallized from 100 ml of butyl chloride and the isolated crystals were dried at 35 ° C (0.01 mm, for 1 h to give 4.0 g (72%)) of the above compound, in the form of almost white needles crystals: m.p. 167.5 ° -170.5 ° C (vacuum); NMR / CDC1R ό 0.88 / d, 3, J = 7 Hz, CH ₃ /, 1.08 / d, 3, J = 7 Hz, CH ₃ /, 1.19 / s, 9, / CH ₃ / ₃ C /, 2.67 / d, 2, J = 4 H, pyran C ₃ H, S /, 4.39 / m, l, pyran C ₄ H /, 4.65 / m, 1, pyran C ₆ H, 5.36 (m, 1, naphthalene C, H), 5.55 (m, 1, naphthalene C ₅ H), 5.8 (dd, 1, J = 6.10 Hz, naphthalene C ₃ H) /, 6.04 (d, 1, J = 10 Hz, naphthalene C, H); HPLC / 4.6 mmx 25 cm Partisil 10PAC, 10% isopropanol / hexane, 4 ml / min / retention time 4.4 min.

Elemental analysis: Calculated for C, H, .O · C-71.25; H, 8.97

Found: C, 71.40; H, 8.93

Working analogously to Example 1, Step B, but replacing the 2,2dimethylpropanoyloxy-silyl ester used, Compound Via (R '= CH ₃ ), with an equimolecular amount of other esters of the structure Via (R' = CH ₃ ), given in Table II, esters of the structure la (R '= CH ₃ ) shown in Table III are obtained.

Table III

rco ₂ - formula mp (° C) C, ₄ H „0, 139-148 CHj _ ^ co ₂ - XT 119,5-120,5 F (vacuum) / CH _3/2 CHCH ₂ sr 2 ** with ₂₄ n ₃ d 126-128 / CH _3/2 CHCO ₂ - ^C 23 ^H 34 ⁰ 5 144-147 CH ₃ / CH _{2/3 of} the CO ₂ - c ₂₄ h ₃₆ o ₅ ch ₃ co ₂ - C ₂₁ H _{3 O} 0, .0. 1G, H _O 153-156 4 9

(vacuum)

C ₃₀ H ₄₂ D ₅ .0.05C ₆ H _{| 2}

155-158

4-Cl ₆ H ₄ CO ₂ -

2,4-F ₂ C ₆ H ₃ CO _{2 6} H ₅ / CH _2/3 co ₂ 4-FC ₆ H ₄ CH ₂ CO ₂ -

2,4-F ₂ C ₆ H ₃ CH ₂ CO ₂ 4-C1c ₆ H ₄ CH ₂ CO ₂ 4-FC ₆ H ₄ / CH _2/3 CO ₂ I

CHjCH — CHjCOj—

CHj

RCO ₂ -

CHj

Example 2. 6 (R) -12- (8 '/ 5' -phenylacetone CH-27S), 67R / HMeTrai-r, 2 ', 6', 7 ', 8', 8'a (R) -xek25 sahydronaphthyl -N (5) ethyl 1-4 (R) -hydroxy-

3.4.5.6- tetrahydro-2H-pyran-2-one

Step A: Preparation of 6 (R) -12- (8 '(S) -phenylacetoxy-2' (5), b7k (-dimethyl), 2 ', 6', 7 ', 8', 8'a (E) -hexahydronaphthyl-N (8) // 30 ethyl 1-4 (R) -dimethyl-tert-butylsilyloxy / -

3.4.5.6- tetrahydro-2H-pyran-2-one, Via (R '= CH ₃ )

A solution of 434 mg (1.0 mmol) of alcohol Va (R '= CH ₃ ) of Example 1, step A, 204 mg of 35 (1.5 mmol) phenylacetic acid and 309 mg (1.5 mmol) of Ν, Ν The '-cyclohexylcarbodiimide in 10 ml of dichloromethane was treated with 22 mg (0.15 mmol) of 4-pyrrolidinpyridine and stirred at 20 ° C under a nitrogen atmosphere. After 3 days, the solvent was removed in vacuo and the residue was suspended in 25 ml of ether and then filtered. After evaporation of the filtrate, a viscous oil is obtained which is chromatographed on a 45 3 x 15 cm column of silica gel, the pores of the silica gel being in the range of 230-400 mesh. The elution was (atmospheric pressure) with ether / hexane (1: 1, v / v) to give 460 mg (83%) of the above compound as a viscous 50 oil: NMR / CDCl ₃ / ≤ 5 0, 10 / S, 6, / CH _3/2 Si /, 0,90 / S, 9, / CH _3/3 CSi /, 3,58 / S, 2, PhCH ₂ - /, 5.34 / m, 1 , naphthalene C _g H /, 7.30 / S, 5, Ph /.

Working as described in Example 2, Step A, but replacing the phenylacetic acid used there with an equimolecular amount of organic acids of formula ROOH given in Table IV, ethers of structure Via (R '= CH) are obtained. ₃ ), also presented in Table IV.

Table IV

R-C-O- NMR / CDCL, <5)

II

[> -so, - 0.78-1.02 / t, 4, cyclopropane / co 1.04 / d, 3, J = 7 Hz, 1 CHjCH-CHjCOj- CH ₃ CHCF ₃ / CHj COj- and CHj 1.88 / S, 3, CH ₃ C = C / 2.17 / d, 3, J = 2 Hz, CH ₃ s = c / SN ₂ CO 3 - NH 3 5.68 / wide singlet, 1, C = CH- / 1.80 / S, 3, CH ₃ C = C / 4.86, 4.92 / S, 2, CH = C /

CO ₂ - CH ₃ / CH _2/6 co ₂ with ₆ N _and CO ₂ CH ₂ = CH-CO ₂ cf ₃ / ch _2/2 coS.N.SO 4-C1c ₆ H ₄ CO ₂ -

2,4-F ₂ C ₆ H ₃ CO ₂ nsa / CH _2/3-CD4 C1c ₆ H ₄ CH ₂ CO ₂ 4-FC ₆ H ₄ / CH _2/3 CO ₂ -

Step B: Preparation of 6 (R) -12- (87S) -phenylacetoxy-278), 6 '(R) -dimethyl1', 2 ', 6', 7 ', 8', 8'a (R) -hexahydronaphthyl -175 // ethyl 1-4 (R) -hydroxy-3,4,5,6-tetrahydro-2Hpyran-2-one, la (R '= CH ₃ )

Following the procedure described in Example 1, Step B, but instead of the propanoyloxy compound using an equimolar amount of the phenylacetoxy compound obtained in Example 2, Step A, the above compound is obtained, m.p. 109-112 ° C.

Using the other esters Via (R '= CH ₃ ) described in Example 2, step A, (Table IV) and working as in Example 2, Step B, esters of structure 1a are obtained (R' = CH ₃ ) given in Table V.

Table V SN, co, about 40 cm-'V'OCHj

RCO ₂ formula m.p. (° C)

ο

II

RC-O45 / CH _3/2 CHCH ₂ CO ₂ / CH _3/2 CHCO ₂ CH ₃ / CH _2/3 SOCF,

CH3CH — CHjCOj—

C ₂₃ H ₃₂ 0 ₅ 1 16-1 19

F0 110-113

35 3 J

C ₂₄ H ₃₄ 0 ₅ 1 13-1 18

С ₂₄ Н ₃₄ 0 ₅ 1 16-1 19 сн ₃ / сн, / ₈ со ₂ CHj

C _2Q H ₄₆ O ₅ (wax)

CH 1226-129

36 5

dream ₃ with _{2 about}

CHj rco ₂ / CH _3/2 CHCH ₂ CO ₂ / CH _3/2 CHCO ₂ CH ₃ / CH _2/3 co ₂ "I

-c-co ₂ -

C-CO 2 CH ₃ / CH _2/6 CO ₂ H _{6 and} CO ₂ CH = CH-CO ₂ cf ₃ / ch _2/2 co ₂ with ₆ n ₅ pm ₂ 4-C1c ₆ H ₄ CO ₂ -

2.4- F ₂ C ₆ H ₃ CO ₂ S.N, / CH _2/3 CO ₂ 4-FC ₆ H ₄ CH ₂ CO ₂ -

2.4- F, CHCHCO, -

4-C1c ₆ H ₄ CH ₂ CO ₂ 4-FC ₆ H ₄ / CH _2/3 CO ₂ (R '= CH ₃₎

3.0 g of 2-ethyl-2-methylbutyryl chloride (20 mmol) were added with magnetic stirring to a solution of 2.17 g (5 mmol) 5 of alcohol Va (R '= CH ₃ ) and 74 mg 4 -pyrrolidinopyridine in 20 ml of pyridine. This reaction mixture was stirred at 100 ° C under a nitrogen atmosphere for 9 h. The reaction mixture was diluted with 500 ml of ether and washed with 1 N 10 hydrochloric acid until the washing solutions became acidic, then washed with brine (3 x 50 ml). The solution was dried over magnesium sulfate, filtered and evaporated to give 4.2 g of a brown oil. This oil was chromatographed on a silica gel column (230-400 mesh) measuring 6 x 15 cm. The elution (at atmospheric pressure) was carried out with ether / hexane (1: 1, v / v) to give 2.6 g (95%) of the above compound in 20 forms of a yellow viscous oil: NMR / CDCl ₃ /. 6 0,08 / S, 6, / CH _3/2 Si /, 0,9 / S, 9, / CH _3/3 CSi /, 2,57 / d, 2, J = 4 Hz pyran C ₃ H'S / , 4,30 / t, 1, pyran C ₄ H /, 4,63 / t, 1, pyran C ₆ H /, 5,42 / t, 1, naphthalene C ₈ N /, 5,53 / t, 1 , naphthalene C ₅ H / 25, 5.78 / dd, 1, J = 6 Hz, 10 Hz, naphthalene C ₃ H /, 6.03 / d, l, J = 10 Hz, naphthalene C ₄ H /.

Acting analogously to the procedure described in Example 3, Step A, but replacing 2-ethyl-2-methylbutyryl chloride with eq 30 the required amount of acid chloride of the formula R-COC1 given in Table VI, esters of the structure Via are obtained (R '= CH ₃ ), also given therein.

Table VI 35

RCO ₂ NMR / CDC1 ₃ , 6 /

^ c-sag- 0.87 / t, 9, CH ₃ CH ₂ CH ₂ / CH ₃ CH _2/2 CCO ₂ / 40 -

EXAMPLE 3 6 / R / -12- / 87S / -2 -eTHa- 2metilbutiriloksi-2 '/ 8/6' / R / -dimetilG, 2 ', 6', ^7, 8 ', 8'a / N -hexahydronaphthyl-N / 8 // ethyl 1-4 (R) -hydroxy-3,4,5,6-tetrahydro-2Hpyran-2-one

Step A: Preparation of 6 (R) -12- (8 ') S (-2-ethyl-2-methylbutyryloxy-27 $) - 6 H-dimethyl-1, 2', 6 ', 7', 8 ', 8'a (E) -hexahydronaphthyl-N (S) (ethyl 1 - 4) (R) - / dimethyl 1-tert. -butylsilyl oxy / -3,4,5,6-tetrahydro-2H-pyran-2-one Via

C — C £> 2—

—With — COJ—

0,78 / t, 9, J = Hz, / CH ₃ CH _2/3 CCO ₂ /

1,48 / q, 6, J = 7 Hz, / CH ₃ CH _2/3 CCO ₂ /

1,28 / S, 6, / CH _3/2 CCO ₂ /

2.20 / S, 3, CH ₃ -C = CH ₂ /

3.86 / t, 2, CH = C /

1,12 / S, 6 / _CH3 / ₂ CCO ₂ /

0,83 / t, 3 / CH ₃ CH ₂ CCO ₂ /

Step B. Preparation of 6 (R) -12 / 87S / 2 "-ethyl-2" -methylbutyryloxy-275 / -67R / -3Hmethyl-D, 2 ', 6', 7 ', 8', 8'a- (R) -hexahydronaphthyl-N / S // ethyl 1-4 (R) hydroxy-3,4,5,6-tetrahydro2H-pyran-2-one

This is done analogously to the procedure described in Example 1, Step B or Example 2, Step B, but a starting material is used as a starting material.

_ ^ co ₂ - _F xr 4-Cl ₆ H ₄ CO ₂ - 5 CH ₃ CO ₂ - 2,4-F ₂ C ₆ H ₃ CO ₂ Fr. CH3 ₆ H ₅ / CH _2/3 sp ₂

hunting ether prepared according to Example 3, steps A and 10 to give the above compound, m.p. 111from ° s. / s ₂₆ n _4O at ₅ /

Similarly, the esters of structure 1a described in Table VII are obtained using the other esters starting from 15, Via (R '= CH ₃ ) given in Table VI.

Table VII / CH _3/2 CHCH ₂ CO ₂ / CH _3/2 CHCO ₂ -

4-FC ₆ H ₄ CH ₂ CO ₂ 2,4-F ₂ C ₆ H ₃ CH ₂ CO ₂ 4-Cl. H CH, CO 6 4 2 2

ROC, m.p. (° C) CH ₃ / CH _2/6 omega ₂ -

81-83

129-132

75-78 with ₆ N "sp ₂ CH = CH-CO ₂ cf ₃ / ch _2/2 co ₂ C SO1-

C _and H ₃₈ 0 ₅ 135-138

Following the procedure of Example 35, Step A, and then Steps B and B, also of Example 1 or Example 2 or 3, Steps A and B, but instead of a diol of structure IVa (R '= CH ₃ ) in example 1, step A, the corresponding diols of structure IVa (R '= H) or IV6, B, r or e 40 (R' = H or CH ₃ ) are used, silyl esters of structures Va (( R '= H) or V6, B, r and e (R-H or CH ₃ ), esters of the structure Via (R' = H) or Y1b, c, d and e (R '= H, or CH ₃ ) and new esters of structures la (R '= H) 45 or 1b, c, d and e (R' = H or CH ₃ ) according to scheme A, in which

R - <10> of the 8'-alkanoyl group is:

C ₆ H ₅ CO ₂ CF 3

CHjCH— CH2OO2—

CH ₃ / CH _2/8 CO ₂ CH ₃

CH3

Example 4 Preparation of 6 (R) - {2-18 / 5 // 2-ethyl-2 '' - methyl butyry.toxy (-275), b75) - di-methyl-1, 2 ', 3', 4 ', 4'a / 8 /, 5', 6 ', 7', 8 ', 8'a (S) -acetichydronaphthyl-1 / S / IeTHa} -4 (R) hydroxy-

3,4,5,6-tetrahydro-2H-pyran-2-one, 1d (R '= CH ₃ )

Step A: Preparation of 6 (R) -12- (87S) hydroxy-275), b78 (dimethyl-D, 2 ', 3', 4 ', 4'a) (8) ethyl 1-4 (R) hydroxy- C, 4,5,6-tetrahydro-2Hpyran-2-one, 1 Ud (R '= CH ₃ )

A solution of 2 g (6.2 mmol) of alcohol IVa (R '= CH ₃ ) in 100 ml of ethyl acetate was hydrogenated in the presence of platinum oxide (1 g) at a pressure of 40 liters until absorption of two molar equivalents of hydrogen was established. . The catalyst was removed by filtration and the filtrate was evaporated to dryness to give a white solid (1.9 g) which was chromatographed on a 6 x 20 cm silica gel column (230-400 mesh). The elution (at atmospheric pressure) was carried out with acetone / methylene chloride (3: 7, v / v) to give 1.0 g (50%) of the above compound as a colorless solid.

The analytical sample was prepared by recrystallizing a portion of the chloroform substance to give a white soft substance: m.p. 166-8 ° C.

Step B: Preparation Ha6 / R / -12- / 8 '/ S / xHapokM-2 / S /, 6 / S / -amnH, T-r23,4,4'a / S / 5', 6 ', 7 ', 8', 8'a (5) -decahydronaphthyl-N (5) -ethyl 1-4 (k) - dimethyl-tert-butylsilyloxy) 3,4,5,6-tetrahydro2H-pyran-2-one, Beats (R '= CH ₃ )

Alcohol solution IVa (R '= CH ₃ ) (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 was stirred at 20 ° C under a nitrogen atmosphere for 18 h. The reaction solution was diluted with 200 ml of ether and washed successively with water, 2% aqueous hydrochloric acid and brine. The ether solution was dried over magnesium sulfate and evaporated to give a white solid (1.8 g) which was chromatographed on a 6 x 20 cm silica column (230-400 mesh). Elution was carried out at atmospheric pressure with acetone / methylene chloride (1:19, v / v) to give 1.0 g (74%) of the above compound as a white solid: m.p. 136-138 ° C.

Step B: Preparation of 6 (R) - {218 '/ S // 2''- ethyl-2 "-methylbutyryloxy (-275), b75 (dimethyl-D, 2', 3 ', 4', 4 ' a) (5), 5 ', 6', 7 ', 8', 8'a (5) -decahydronaphthyl-N (5) ethyl} -4 (1 H) dimethyl-tert-butyl silyloxy (-3,4) 5,6-tetrahydro-2H-pyran2-one, IId (R '= CH ₃ ) 50

In Example 3, step A replaces the alcohol Va (R '= CH ₃ ) with a squimolar amount of alcohol Ud (R' = CH ₃ ), followed by the procedure of Step A in this example to obtain the corresponding amount of the above compound , Yl (R '= CH ₃ ), as a yellow 5 oil. NMR / CDC1 ₃ / δ 0,08 / S, 6, / CH _3/2 Si /, 0,90 / S, 9, / CH _3/3 / CSi /, 1,13 / S, 6, / CH ₃ ( ₂ CO ₂ ), 2.63 (m, 2, pyran C ₃ H'S), 4.33 (m, l, pyran C ₄ H), 4.60 (m, l, pyran C ₆ H), 5, 23 (m, 1, naphthalene C ₈ N).

Step D: Preparation of 6 / R / - {2-I87S //

2 '' - ethyl-2 "-methylbutyryloxy (-2 ') S, b (S) -dimethyl-D, 2', 3 ', 4', 4'a (8), 5 ', 6', 7 ', 8', 8'a (8) -decahydronaphthyl-N (5) ethyl} -4 (E) -hydroxy-3,4,5,6tetrahydro-2H-pyran-2-one, 1e (R '= CH ₃ )

With an equimolar amount of silyl ether,

Y1d (R '= CH ₃ ) obtained according to Example 4, step B, is substituted for silyl ether in step B of example 1 and the procedure of step B of example 1 is followed to give the corresponding amount of the above compound as of a solid.

An analytical sample was prepared by recrystallizing the substance from hexane to give white needle crystals: m.p.

146-147 ° C.

Working analogously to the procedures described in Example 4 and going through all steps A to D, but replacing the diol of structure IVa (R '= CH ₃ ) in step A with an equimolecular amount of diol of structure IVa (R' = H), the compounds were obtained in the sequence: 1mg (R '= H) in step A; B (R '= H) in step B; Y1e (R '= H) in step B; and 1e (R '= H) in step D.

Example 5. 6 (R) - {2-I87S / 72 '' - cth.t-2 'methyl butyry.toxy (-278), 6' - (R) - dimethyl, 2 ', 3', 4 ', 6 ', 7', 8'a (S) -octahydronaphthyl-N (S) ethyl} -4 (R) -hydroxy-3,4,5,6-tetrahydro-2Hpyran-2-one, Io (R '= CH ₃ )

Step A: Preparation of 6 (R) -I2- (87S (hydroxy-278), 6-7 (dimethyl) -1 ', 2', 3 ', 4', 6 ', 7', 8'a (S) -octahydronaphthyl- N / S / ethyl 1-4 (N) hydroxy-3,4,5,6-tetrahydro-2Hpyran-2-one, (IV b), (R '= CH ₃ )

Following is essentially the procedure described for the preparation of starting material IVa (R '= CH ₃ ) by hydrolysis of MK-803 under reflux, together with an aqueous solution of LiOH.H ₂ O for 56 h, here replacing MK-803 with an equimolecular amount of compound IIIb (R '= CH ₃ ) to give the above compound in a comparable yield,

IV6 (R '= CH ₃ ); Mp 136-139 ° C.

Using the method of operation given in Example 4, steps B, C, and D, but replacing compound 1Du (R '= CH ₃ ) in step B with an equimolecular amount of compound IV6 (R' = CH ₃ ), 5 obtained in step A of this example, the following compounds were obtained in comparable yields to those given in example 4:

Step B: 6 (R) -I2- (87S) -XHflpokn-27S), b7E) -dimethyl-D, 2 ', 3', 4 ', 6', 7 ', 8'a (5) -octahydro- 10 naphthyl-N (S) -ethyl 1-4 (R) - (dimethyl-tert-butylsilyloxy) -3,4,5,6-tetrahydro-2H-pyran-2one, V6 (R '= - CH ₃ ), mp 140-142 ° C.

Step B: 6 (R) - {2-I / 87S) - (2 "-e ^ -2 '' - Methyl butyryloxy (-27 $), b7 AND (dimethyl-15 D, 2 ', 3', 4 ', 6', 7 ', 8'a (5) -octahydronaphthyl-N (3) ethyl} -4 (R) - (dimethyl-tert-butylsilyloxy) -

3,4,5,6-tetrahydro-2H-pyran-2-one VI6

(R '= CH) in which R-C-0 e Λ 20 II -CO1- 0

Step D: 6 (R) - {2-I87S // 2 ”-etroi-2-Methylbutyryloxy (-273), b7Iadimethyl-25 r, 2 ', 3', 4 ', 6', 7 ', 8'a (S) -octahydronaphthyl-N (S) ethyl} -4 (E) hydroxy-3,4,5,6-tetrahydro-2Hpyran-2-one, 16 (R '= CH ₃ ), m.p. 129-131 ° C, at which

R-C-0

II

Working essentially as described in Example 5, but using compounds starting from IIIb (R '= H) or IIIb, IIIr 35 or IId (R' = H or CH ₃ ), instead of compound 1116 ( R '= CH ₃ ) are obtained in the order of the compounds: 1V6 (R' = H) or 1Bc, d, e (R '= H or CH ₃ ), V6 (R' = H) or Bc, d, e (R '= H or CH ₃ ), V16 (R' = H) or Y1c, d, d (R '= H or CH ₃ ), 40 and 1b (R' = H) or 1c, d, d (R '= H or CH ₃ ) where

R-C-0 is “Λ

-CO1 ⁰ J

EXAMPLE 6 Conventional, null-sized hard gelatin capsule 45 formulations include 3.125, 6.25, 12.5 or 50 mg of one of the new compounds of the invention, such as the products obtained according to Example 3, Step B, Example 1, Step B, or 50 Example 2, Step B, together with the required amount of finely ground lactose to obtain a total capsule content of about 580-590 mg.

Claims (18)

Patent claims 1. Antihypercholesterolemic compounds with the general formula in which R' is H or CH ₃ ; R is 1,1-dimethylpropyl, C _3-10 cycloalkyl, C _2- C ₁₀ alkenyl, C _3- alkyl substituted with CF ₃ , phenyl, halophenyl, phenyl-C ₃ alkyl, substituted phenyl-C ₃ alkyl, in which the substituent is halo, C 3 alkyl or (φ ₃ alkoxy; the dotted lines at X, Y and Z indicate possible double bonds, which if present, are either a combination of X and Z, or X, Y or Z present alone; or the corresponding dihydroxy acid of formula or a pharmaceutically acceptable salt of said acid, its _C1-4 alkyl ester or a _C1-4 alkyl ester of said acid substituted with phenyl, dimethylamino or acetylamino. 2. An antihypercholesterolemic compound according to claim I, wherein R' is CH ₃ . 3. An antihypercholesterolemic compound according to claim 1, wherein R is 1,1-dimethylpropyl. 4. An antihypercholesterolemic compound according to claim 2, wherein Re is 1,1-dimethylpropyl. I 5. An antihypercholesterolemic compound according to claim 1, wherein X, Y and Z are saturated bonds. 6. A pharmaceutical antihypercholesterolemic composition, characterized in that it contains a pharmaceutical carrier and an antihypercholesterolemic effective amount of a compound with the structural formula in which R' is H or CH ₃ ; R is 1,1-dimethylpropyl, C _3-10 cycloalkyl, C _2-10 alkenyl, C, ₁₀ alkyl substituted with CF ₃ , phenyl, halophenyl, phenyl-C, ₃ alkyl, substituted phenyl _- C ₁₃ alkyl, in which the substituent is halo, C ₁₃ alkyl or C ₁₃ alkoxy; the dotted lines at X, Y and Z indicate possible double bonds, which if present, are either a combination of X and Z, or X, Y or Z appear alone; or from the corresponding dihydroxy acid of formula or from a pharmaceutically acceptable salt of this acid, from a C1-4 alkyl ester thereof or from a _C4-4 alkyl ester of the acid substituted with phenyl, dimethylamino or acetylamino. 7. A pharmaceutical composition according to claim 6, characterized in that R' is Cn ₃ . 8. A pharmaceutical composition according to claim 6, wherein R is 1,1-dimethylpropyl. 9. A pharmaceutical composition according to claim 7, wherein R is 1,1-dimethylpropyl. 10. Pharmaceutical composition according to the invention 5. The compound of claim 6, wherein X, Y and Z are saturated bonds. 11. A method for treating patients with hypercholesterolemia, which includes administering an effective antihypercholesterolemic agent 10 amount of compound with structural formula in which R' is H or CH ₃ ; R is 1,1-dimethylpropyl, C _3-10 cycloalkyl _{, C 2-10 alkenyl} , C _t-10 alkyl substituted with CF ₃ , phenyl, halophenyl, phenyl-C , ,alkyl, substituted phenyl-C , alkyl, in which the substituent is halo, C _1-3 alkyl or C _1-3 alkoxy; the dotted lines at X, Y and Z indicate possible double bonds, which if present, are either a combination of X and Ζ, or X, Υ and Ζ appear alone; or from the corresponding dihydroxy acid of formula or a pharmaceutically acceptable salt of this acid, of its C ₍₄₎ alkyl ester or of its phenyl, dimethylamino or acetylamino substituted C ₍₄₎ alkyl ester. 12. A method according to claim 11, wherein R' is CH ₃ . 13. A method according to claim 11, wherein R is 1,1-dimethylpropyl. 14. A method according to claim 12, wherein R is 1,1-dimethylpropyl. 15. A method according to claim 11, characterized in that X, Y and Z are saturated bonds. 16. Antihypercholesterolemic compound of formula wherein R' is H or CH ₃ ; R is C _{3 10} cycloalkyl, C ₂₁₀ alkenyl, (% ₁₀ alkyl substituted with CF ₃ , phenyl, halophenyl, phenyl-C 25 ₃ alkyl, substituted phenyl-C ₃ alkyl, in which the substituent is halo, C ₃ alkyl or C ₃ alkoxy; the dotted lines at X, Y and Z indicate possible double bonds, which if present, are either a combination of X and Z, or X, Y and Z occur alone; or the corresponding dihydroxy acid of formula or a pharmaceutically acceptable salt of said acid, its _C1-4 alkyl ester or its phenyl, dimethylamino or acetylamino substituted _C1-4 alkyl ester. 17. A pharmaceutical antihypercholesterolemic composition, characterized in that it contains a pharmaceutical carrier and an antihypercholesterolemic effective amount of a compound with the structural formula in which R' is H or CH ₃ ; R is C _3-10 cycloalkyl, C _2-10 alkenyl, C _{] 10} alkyl substituted with CF ₃ , phenyl, halophenyl, phenyl-C ^ ₃ alkyl, substituted phenyl-C ₁₃ alkyl, in which the substituent is halogeno, (% ₃ alkyl or (% ₃ alkoxy; the dotted lines at X, Y and Z denote possible double bonds, which if present, are either a combination of X and Z, or X, Y and Z appear alone; or of its dihydroxy acid with the formula or a pharmaceutically acceptable salt of this acid, a _C1-4 alkyl ester thereof or a phenyl, dimethylamino or acetylamino substituted _C1-4 alkyl ester thereof. 18. A method for treating patients with hypercholesterolemia, which comprises administering an antihypercholesterolemic effective amount of a compound with the structural formula wherein R' is H or CH ₃ ; R is C _{3 10} cycloalkyl, C _{2 10} alkenyl, C ₁₀ alkyl substituted with CF ₃ , phenyl, halophenyl, phenyl-C 1 ₃ alkyl, substituted phenyl-C _{1 3} alkyl, in which the substituent is halo, C _{1 3} alkyl or C ₃ alkoxy; the dotted lines at X, Y and Z indicate possible double bonds, which if present, are either a combination of X and Z, or X, Y or Z present alone; or of a dihydroxy acid thereof of the formula or a pharmaceutically acceptable salt of this acid, a C _1-4 alkyl ester thereof or a phenyl, dimethylamino or acetylamino substituted C _2-4 alkyl ester thereof.