JPS58210043A - 6(r)-(2-(8(s)(2,2-dimethylbutyryloxy)- 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 - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Compounds with sodium, potassium.

Pharmaceutically usable salts such as calcium, magnesium, ammonium salts etc. or methyl, ethyl or alpha
- Alkyl esters such as monoglycerides, antihypercholesterolemic agents and processes for their production.

2, which has a similar structure and biological activity to Compound I;
Three compounds have been reported in the literature. U.S. Patent No. 3,
9 8 3, 1 4 0 ends with ML-236
describes the fermentative production of a compound that has become known as B. and combactin. U.S. Patent No. 4,23
1,938 and Albers-Schomberg et al. in U.S. Pat. No. 4,294,846, mevinolin and 4a,5-
The fermentative production of each dihydromevinolin is described.

Furthermore, Published Japanese Application No. 55009-024 describes tetrahydrocombactin in which the polyhydronaphthyl moiety is decalin.

Therefore, in the present invention, instead of the hexahydronaphthyl group, a trans-decalin moiety and a natural 8 (S)-[
2 (S) monomethylbutyryl] group instead of 8(S)
Novel compounds of formula I derived from mevinolin having a -(2,2-dimethylbutyryloxy) group are provided.

Also provided are methods for producing the novel compounds of the present invention.

The novel compounds of the present invention are compounds having the structural formula I or ■a: or sodium, potassium.

Pharmaceutically usable salts such as magnesium, ammonium salts, etc. or alkyl esters such as methyl, ethyl or α-monoglycerides.

The method of the present invention is illustrated by the following composite diagrams ■ and H.

Synthesis Diagram ■ Synthesis Diagram II "3 H■ Synthesis Diagram I and ■ show three different routes from the same starting material to reach the intermediate compound V and then two steps to the novel compound of the invention ■. These The step method consists of the following:

Step 1: Compound MK-803 (mevinolin) or its 4a,5 dihydro derivative is treated with excess lithium hydroxide in aqueous solution for 2 to about 4 days at 50-1 o-oo (reflux temperature), cooled, acidified, Lactonization is carried out by extraction with a solvent and heating in a toluene solution.

Step 2: Diol nI or ■ in an aprotic solvent such as DMF at or near ambient temperature from 12 to
Mono-silylation produces the 4-silyl ether by treatment with tert-butyldimethylsilyl chloride and imidazole for about 24 hours.

Stage 3. The double bonds of the polyhydronaphthyl moiety are reduced with hydrogen and a noble metal catalyst, such as platinum oxide, in an organic solvent such as ethyl acetate at ambient temperature of 1 to 100 ml at atmospheric pressure for about 10 to 20 hours.

After separation of the produced decalin, the product is preferably chromatographed on silica gel to separate only the trans-decalin V.

Step 4 The 8-hydroxyl group of (1) is reacted with an acylation catalyst such as 4-pyrrolidinopyridine, 4-dimethylaminopyridine, or 4-hydroxybenztriazole in pyridine at about 4 to about 100° to about 140°. 1
Esterification is achieved by treatment with 2,2-dimethylbutyryl chloride for 0 hours.

Step 5: 4-0-silyl group with THF, ether, ■
Compound ■ with about 4 equivalents of glacial acetic acid and about 3 equivalents of tetrabutylammonium fluoride trihydrate for 1 to 3 days under an inert atmosphere for about 15 to 30 minutes in an ethereal solvent such as , 2-dimethoxyethane, etc. be processed and removed.

Compounds of the invention are used to treat atherosclerosis.

It is useful as an antihypercholesterolemic agent for the treatment of hyperlipidemia and similar diseases.

It can be administered orally or parenterally in the form of capsules, tablets, injection preparations and the like. It is usually preferable to use the oral route.

The daily dose for adult humans is approximately 2-2007n9 administered in 3 or 4 divided doses, although the dosage can vary depending on the patient's age, weight, and other conditions.
is within the range of

Higher doses can be advantageously applied as required.

Compounds of the invention can also be used for their useful antifungal activity. It is mixed with formulations, powders, emulsifiers, or solvents suitable for these uses, such as aqueous ethanol, and sprayed or applied to the plants to be protected.

Example 1 Step 1: 6(R)-1m2-(8(S)-hydroxy-2(S), 6(R)-dimethyl-1,2,6,
7゜8,8a (R)-hexahydronaphthyl-1(S
) ethyl) -4(R)-hydroxy-3゜4,5.6
Preparation of -tetrahydro-2H-pyran-2-one (2)Mevinolin (50,2, 0.124 mol) and Li0H-N20 (52,OfJ, 1) in water (3 t)
．． The mixture of 24 mol) was magnetically stirred at reflux under N2 atmosphere for 72 hours. The stirred mixture 'fI: cooled to 0°C in an ice/acetone bath) was added to 12 NHC7' (120d) at such a rate that the temperature did not exceed 3°C.

1.44 mol). This mixture was converted into solid Naα
and extracted with ether (4 x 500rn!). The combined extracts were washed with brine (2 x 250 ml), dried over MgSO4 and evaporated to give an orange oil (
31.7 r). Add this oil to toluene (250mg)
Relactonization was carried out by dissolving the solution in a Dean-Stark apparatus under N2 atmosphere for 4 hours at reflux with continuous separation of water. The toluene was evaporated leaving an oily residue which was dissolved in ether (1.5t). This solution was dissolved in saturated NaHCO
3 (250d), washed with N20 (250ml) and brine (250rILe), dried and evaporated to yield a solid residue. This solid 'wohexane (200
mJ) to give a cream colored solid (29,
7r, 75%) and requires no further purification for synthetic purposes. An analytical sample was prepared by recrystallizing a portion of the above from n-butyl chloride, producing a colorless mass. mp128-131°C.

Step 2.6 (R) -C2-(8(S)-hydroxy-2(S),6(R)-dimethyl-1,2,6,7°8
, 8a (R)-hexahydronaphthyl-1(S))
ethyl] 4 (R) -tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-
Preparation of pyran-2-one (3) Alcohol FIT (in DMF (200 ml))
18,3f.

A solution of tert-butyldimethylsilyl chloride (10,3?, 0.068 mol) was magnetically stirred at ambient temperature for 18 hours. The reaction mixture was diluted with ether (1500 mA) and water (200 d), 2%
Aqueous HO (20(7), water (200ml), saturated Na
Washed successively with HCO3 (200 ml) and water (2 x 200 ml) and dried over M9s04. The filtered ether solution was concentrated to 1 t, diluted to 600, d with bovine sun, and the resulting solution was washed to 600 ml.

The mixture was concentrated to form a white solid (13,7y) ff:. A second collection of crystals (3,4y) was added to the mother liquor for 250 m
e I/C was reduced and obtained by storage at 0°C overnight. The combined yield was 17.17 (69 inches) and the solid melted at 142-4°C.

Step 3.6)-4:2-(8(S)-hydroxy-2
(S), 6 (S)-dimethyl-1,2,3,4,
4a(S), 5.6.7.8.8a(S) decahydronaphthyl-1(S)ethyl) -4(R) -t
ert-butyldimethylsilyloxy-3゜4,5.6-tetrahydro-2H-pyran-2-one (
Preparation of 4) A mixture of silyl ether (5,0,0.011'5 mol) and Pt02 (1,09) in ethyl acetate (200 mJ) was hydrogenated overnight in a Parr low pressure hydrogenator. The catalyst was removed by filtration, and the r liquid was concentrated to dryness, leaving a white solid. This solid was mixed with silica gel 7″ (230 ~
Chromatography was performed on an 80m column containing 400 mesh). Methylene chloride/acetone (9
8:2. v:v.

1, s t ) to generate a pre-fraction, which was discarded. Continuation of elution with the same eluent (2t) yielded the title compound (a, 4y, 67%) m, p, 146-7 as a white solid.
℃ was obtained.

Step 4: 6(R)-[2-48(S)-(2,2-
dimethylbutyryloxy)-2(S).

6(S)-dimethyl-1,2,3,4,4a (S)
, 5゜6,. 7.8.8a (s)-zolohydronaphthyl-1(S)]ethyl]-4(R)-tert
-butyldimethylsilyloxy-3,4゜5.6-tetrahydro-2H-pyran 2,2-dimethylbutyryl chloride (0,067f, 0.0005 mol) in pyridine (2g) alcohol V (0,11fit) ,0.0002
5 mol) and 4-pyrrolidinopyridine (0,0074
f, 0.00005 mol) in a magnetically stirred solution. After heating the solution to 100° C. for 3 hours under N2, add 0.0335 ml of 2,2-dimethylbutyryl chloride.
ft' and 4-pyrrolidinopyricine 0. 39 g of OO was added and heating continued for an additional 3 hours.

Cool the reaction, dilute with ether (50 ml) and
NHCt (2X 5rrd and saline (2x10
me). The ether solution was dried over Mg504, filtered and evaporated to yield a yellow oil (0.1367). This oil was chromatographed on a 30 mm column containing silica gel 6" (230-400 mesh). The column was chromatographed under atmospheric pressure with CH2α2 (3001 nl) followed by cH2α2/acetone (98:2, V:V
, 100 m7, and a pre-fraction was generated and discarded.

CH2C/, /acet:/(98:2.V:V, 50m
Continue elution with 1) to obtain the desired product (1) as a pale yellow oil.
0,0811,60%) was obtained.

Stage 5: 6(R) C2(8(S) −(2,
2-dimethylbutyryloxy)-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,
Preparation of 5,6-tetrahydro-2H-pyran-2-one Silyl ether Vl' (0.5 g, 0.00093 mol) Ice HOAc (0.224 f, 0.00372
Mo/L) and tetrabutylammonium fluoride trihydrate (0.88f, 0100279 mol) were added to the containing sulfTHF (30me). The solution was stirred magnetically under N2 atmosphere for 48 hours.

The reaction solution was diluted with ether (150 ml) and diluted with H2O (
The ether solution was dried with MgSO4, filtered once and evaporated to give a viscous oil (0.451).

This oil was chromatographed on a 40 column containing silica gel 6'' (230-400 mesh).
．． The 20-fraction was collected by elution with V:V). Fractions 21-37 were combined and concentrated to dryness to yield the title compound (0.37f, 94%) as a solid. Analytical samples were prepared by recrystallizing the solid from ether/hexane to give colorless plates, mp 159-160<0>C.

Example 2 Ethyl 3(R),5(R)-dihydroxy-7-C8(
s) -(2,2-dimethylbutyryloxy)-2(s
) , , 6 (s)-dimethyl-1,2,3,4,
4a (S).

5, 6.7.8.8a(S)-decahydronaphthyl-1
(S)] Sodium heptanoate methoxide (30 mg) is added to a stirred suspension of compound I (3, Of) in ethanol (50 ml) under a nitrogen atmosphere. The resulting solution is stirred at ambient temperature for 1/2 hour and then diluted with ether (300 rM). Etheral solution 'f: Washed with H20 (3X 50 m/ml, dried with M2SO4 and filtered. R liquid is evaporated in vacuo leaving an oil, containing silica gel 6" (230-400 mesh). Chromatography was carried out on a 60 ml column using methylene chloride/ethanol (96:4) at atmospheric pressure.
．． Elution with V:V, 250 m/) gave the title compound as a solid.

Example 3 2.3-dihydroxypropyl 3), 5(R)-dihydroxy-7-[8(s)-(2,2-dimethylbutyryloxy)-2(S), 6(s)-dimethyl −
1, 2, 3, 4, 4a (S), 5.6.7.8.8a
DM the sodium salt of (S)-decahyde compound Ia
I in a solution of compound I, 0.229 in F (2me)
Prepared by adding NNaOH (0.55 ml). After stirring the solution for 15 minutes, 1-iodo-2,3-dihydroxypropane (0,; 1M') is added and the stirred solution is heated at 80<0>C (oil bath) for 6 hours. After cooling to ambient temperature, the reaction solution is poured into ether (100-). Add this ethereal solution to saline solution (2 x 25 ml)
Wash with water, dry with Mg5O6 and filter thoroughly. The P solution was evaporated in vacuo, the oil remained, and the silica gel 6″ (230–4
00 mesh)'f: Chromatography is performed on a 20-column containing column. Acetone-methylene chloride (atmospheric pressure)
60:40. v:v) to yield the title compound as an oil that solidifies upon storage in the freezer overnight.

Continued from page 1 0 Inventor Lopert L. Smith 1355 Picklich Lane, Lansor, Pennsylvania, United States of America 19446

Claims (1)

[Claims] 1. Treating a compound having the structural formula: with 2,2-dimethylbutyl chloride to produce a compound having the structural formula: Tetrabutylammonium fluoride trihydrate in an ethereal solvent. and acetic acid to produce a compound of structural formula (I), which is then optionally converted to a pharmaceutically acceptable salt of Compound Ia or a methyl, ethyl or α-monoglyceride ester of Compound Ia. Method for producing a compound having structural formula I or Ia: [Ia. 2. Compounds having structural formula I or ■a: IIa or a pharmaceutically usable salt of Ia or a methyl, ethyl or α-monoglyceride ester of Ia. 3. A pharmaceutical composition comprising a pharmaceutical carrier and an effective amount of a compound having structural formula (1) or Ia, or a pharmaceutically usable salt of Ia, or a methyl, ethyl salt, or α-monoglyceride ester of Ia. thing.