JPH0138116B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 6(R)-[2-(8'-etherified-hydroxy-2',6'-dimethylpolyhydronaphthyl-
1′)-ethyl]-4(R)-hydroxy-3,4,
The present invention relates to the 5,6-tetrahydro-2H-pyran-2-one group and pharmaceutically acceptable salts of the hydroxy acids of the pyranone. More specifically, the invention provides the formula [In the formula, R represents lower alkyl, phenyl lower alkyl (the phenyl nucleus can be substituted with halo), and straight-chain or branched lower alkenyl, and both of the broken lines X and Z or only X is a double bond; , and W is

[Formula] or

##STR1## where M is H or a cation capable of forming a pharmaceutically acceptable salt. ]. It is known that certain mevalonic acid derivatives inhibit cholesterol biosynthesis. for example,
FMSinger et al., Proc.Soc.Exper.Biol.Med. 102 ,
370 (1959) and FHHulcher, Arch.Biochem.
See Biophys. 146 , 422 (1971). Nevertheless, it has been found that the activity of these known compounds is not always satisfactory for practical applications. Recently, Endo et al. have reported the production of fermentation products that completely inhibit cholesterol biosynthesis. (U.S. Letter Patent No. 4049495, Patent No.
4137322 and Patent No. 3983140). This natural product (now called Compactin)
Brown et al. [J.Chem.Soc.Perkin I.1165 (1976)]
It has been reported that mevalolactone has a complex structure. More recently, Monaghan et al. (USSN No. 48946,
(filed on June 15, 1979) reported a more potent inhibitor having structure a in the table below, which was isolated from a completely different fermentation product, and is incorporated as a cited document in the text. . Albers−
Schonberg et al. (USSN No. 154157, May 28, 1980)
(Hide issue) describes an equally potent compound, dihydro-a, isolated from the same fermentation product. Patchett et al. (USSN 118050, filed February 8, 1980) describe dihydro derivatives of a having the structure of compound b prepared by catalytic hydrogenation of a. The starting material b described above is disclosed in U.S. Patent Application No.
No. 118050 (filed February 4, 1980, Patchett et al.), and the following flow sheet and preparation method are consistent with that description. flow sheet Reactions and Reagents (1) Hydrogenation is carried out using tris-(triphenylphosphine)chlorodium in toluene at 1 atmosphere and room temperature. 6a[2-(8a-2(S)-methylbutyryloxy-2β,6α-dimethyl-1,2,3,4,6,
7,8,8a-octahydronaphthyl-1)ethyl]-4β-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, b,
Preparation of 50 mg (0.1236 mmol) of compound a in 10 ml of dry toluene and equimolar amounts of tris-(triphenylphosphine)chlororhodium (114.35
mg, 0.1236 mmol) is hydrogenated at room temperature for 6 days. The amount of hydrogen absorbed is 14.6ml.
The mixture is evaporated to dryness in vacuo. red residue,
It was subjected to preparative thin layer chromatography on silver nitrate-treated silica gel and developed twice in a 10% ethyl acetate-ether system. The yield of compound b is 22.3 mg. Mass spectrum (M/e) 406 (m ⁺ ) 304 (m-102) 286 (m-102-18) nmr (CDCl ₃ , 300MHz) δ4.37 (m, 1H) 4.60 (m, 1H) 5.37 (dt , J = 2.5Hz, 1H) 5.41 (m, 1H) We believe that the 8'-acyloxy group of the polyhydroxynaphthyl moiety in a and b described by the various inventors mentioned above is 8' - etherified hydroxy derivatives, compounds a and b, which were also found to be potent inhibitors of cholesterol synthesis at the level of HMG coenzyme A reductase. More specifically, it has been found that compounds of structures a and Ib are potent antihypercholesterolaemic agents and are less susceptible to hydrolysis than the previous compounds.
Particularly preferred are those in which the group to be etherified is a branched alkyl such as isobutyl, halophenyl-C _1-3 lower alkyl such as fluorobenzyl, or lower alkenyl such as allyl. The absolute structures of these compounds were determined by X-ray analysis. The table is a convenient summary of these structures and their stereochemical relationships. Reference numbers for various compounds, including series having a polyhydroxynaphthyl structure, are kept the same throughout this application document. Each of the ethers a and b forming the present invention has 7 to 8 asymmetric centers. The relative and absolute configurations of these asymmetric centers are shown in the table. More specifically, for the ether a, Cahn, Ingold,
According to the Prelog representation, the absolute configurations are 4(R), 6(R),
1′(S), 2′(S), 6′(R), 8′(S) and 8a′
(S). [RSCahn, C. Ingold and V. Prelog, Ang.
Chem.Int.Ed vol. 5, p. 385 (1966)].

【formula】

[Formula] or

As shown in formulas a and b, all these compounds have the same spatial orientation of the substituents on each asymmetric carbon atom and therefore belong to the same stereochemical series. The R,S designation for each center may differ from that of ether a due to the details of the continuity law used to determine the designation.

【table】

[Table] The compounds of the present invention are very useful as antihypercholesterolemic agents for treating atherosclerosis, hyperlipidemia, etc. in humans. They can be administered orally or parenterally in the form of capsules, tablets, injection preparations. Oral administration is usually preferred. Although the dosage will vary depending on the age, severity, weight and other conditions of the human patient, the daily dosage for adults is approximately 2.
mg to 200mg (preferably 10 to 100mg),
Administer in 3 or 4 divided doses. The compounds of this invention have useful antifungal activity.
For example, these compounds include Penicillium sp., Aspergillus niger, Cladosporium sp., Cochliobolus miyabeanus, and Helminthosporium synodotis.
cynodnotis).
For these purposes, the compounds may be combined in suitable formulations,
Mix with a powder, emulsifier, or solvent such as aqueous ethanol and spray or sprinkle on the plants to be protected. The preparation of compounds of the invention is outlined in Flow Sheet A. In summary, this preparation starts with attachment of a t-butyldimethylsilyl protecting group on the 4(R)-hydroxyl group on the pyranone ring. This product is then reduced to convert the keto group on the pyranone ring to an alcohol and then protected with a tetrahydropyranyl group. This reduction and protection is performed in order to prevent the 4-silyloxy protection from being removed in the next step (that is, the removal of the acyl group from the 8-acyloxy on the polyhydronaphthyl ring using lithium aluminum hydride). Crucially important for synthesis. The 8-hydroxy group thus formed is then etherified by reaction with a suitable reagent. The 2-hydroxy group on the pyran ring is then deprotected and reoxidized to the lactone, followed by removal of the silyl group from the 4-hydroxy group on the pyrazone ring. Definition of flowsheet - R, X, Y, Z are as explained. Reaction-(1) Stirring with t-butyldimethylchlorosilane in a DMF solution in the presence of an imidazole catalyst at 0-50°C. (2) Reaction with di-isobutylaluminum hydride in THF at low temperatures (-100 to -60°C). (3) Treatment with dihydropyran and a catalytic amount of p-toluenesulfonic acid pyridine salt in methylene chloride at room temperature under an inert atmosphere. (4) Treatment with lithium aluminum hydride under an inert atmosphere at 0-40°C in refluxing ether. (5) Sodium hydride and R- at 0-90℃
Stirring with X (X is halogen or other removable group). (6) Stirring at 10-30° for 40-50 hours with a catalytic amount of p-toluenesulfonic acid pyridinium salt in a mixture of 3 parts THF, 1 part acetic acid and 1 part water. Time, temperature and proportions are important to prevent removal of the silyl protecting group. (7) Oxidation with carbon silver on Celite in benzene or toluene at 80-120°C. (8) Treatment with 3 equivalents of tetrabutylammonium fluoride and 4 equivalents of acetic acid in THF at room temperature under an inert atmosphere. (9) Hydrolyze with alkali if necessary. The invention can be illustrated by the following examples. Example 1 6(R)-[2-(8'-(S)-methoxy-2'(S)
,
6′(R)-dimethyl-1′,2′,6′,7′,8′,
8a'(R)-hexahydronaphthyl-1'(S))-ethyl]-4(R)-hydroxy-3,4,5,6
-Tetrahydro-2H-pyran-2-one (compound a, R=methyl) A Preparation of compound a A solution of t-butyldimethylsilyl chloride (180 mg, 1.2 mmol) in DMF (2.4 ml) was
Add to a stirred mixture of compound a (300 mg, 0.741 mmol) and imidazole (204 mg, 3 mmol) in DMF (3 ml) while maintaining the temperature at 0°C. The resulting mixture at room temperature
Stir for 16 hours. Pour this into cold water and extract with ether. The ether extract is washed with hydrochloric acid (0.05N) and 5% aqueous sodium bicarbonate, dried over MgSO ₄ and filtered. The liquid was evaporated in vacuo, and compound a was removed as a pale yellow oily residue (0.441
g) remains. This is used directly in the next reaction without purification. nmr( _CDCl3 )δ0.08(6H,
s), 0.89 (9H, s), 1.08 (3H, s), 1.10 (3H,
d), 2.57 (2H, d), 4.3 (H, m), 4.6 (H,
m), 5.4 (m, H), 5.54 (H, m), 5.8 (H,
dd), 6.03(H, d). Rf = 0.81 (silica gel, methylene chloride: acetone = 9:1) B Preparation of compound a A solution of di-isobutylaluminum hydride (1 M in hexane, 0.9 ml) was added under a nitrogen atmosphere.
Compound a above (0.441 g) in THF (15 ml)
Add via syringe to the stirred solution of The temperature is maintained at -78°C during the addition period. The resulting mixture is stirred at −78° C. for 0.5 h. Methanol (0.15ml) is added and the mixture is stirred for 10 minutes. Remove the cooling bath and add water (0.6 ml), Celite (0.6 g) and Na ₂ SO ₄ (3 g). The resulting mixture is stirred at room temperature for 0.5 h and filtered.
Wash the collected solid with ether. The liquid and washings were combined and concentrated under reduced pressure to yield compound a as a colorless oil (0.45 g), which was used in the next reaction without further purification. nmr
(CDCl ₃ ) 1.07 (3H, d), 1.10 (3H, d), 3.5~
4.2 (2H, m), 4.3 (H, m), 5.1 (H, m), 5.4
(H, m), 5.55 (H, m), 5.8 (H, dd), 6.05
(H, d). Rf = 0.48 (silica gel, methylene chloride: acetone = 25:1). C Preparation of Compound a Compound a (0.45 ml) in methylene chloride (2 ml)
To a stirred mixture of g) and p-toluenesulfonic acid pyridinium salt (20 mg, 0.08 mmol) is added dihydropyran (0.6 ml, 6.74 mmol) dropwise. The resulting mixture is stirred at room temperature under nitrogen atmosphere for 16 hours. Pour this into cold water and extract with ether. The ethereal extracts are washed with aqueous sodium bicarbonate, dried over MgSO ₄ and filtered. The liquid is dried in vacuo to give an oily residue, which is applied to a silica gel column. Elution with methylene chloride:acetone, 50:1 (V/V) gives compound a (0.281 g, 0.46 mmol, 62% overall yield of steps A-C) as a colorless thick oil. nmr (CDCl ₃ ) δ0.07 (6H, S),
0.92 (9H, s), 1.07 (2H, d), 1.10 (2H, d),
3.4-4.1 (4H, m), 4.9-5.3 (2H, m), 5.4
(H, m), 5.55 (H, m), 5.8 (H, dd), 6.02
(H, d). Rf = 0.69 (silica gel, methylene chloride: acetone = 25:1). D Preparation of Compound a To a stirred suspension of lithium aluminum hydride (35 mg, 0.92 mmol) in ether (3 ml) was added compound a (96 mg, 0.92 mmol) in ether (2.5 ml).
0.159 mmol) solution. The resulting mixture is heated to reflux under a nitrogen atmosphere for 15 minutes, then cooled to room temperature and stirred for 16 hours. The reaction mixture was mixed with water (30μ), 20% sodium hydroxide (35μ),
and water (105 μ). The resulting mixture is stirred at room temperature for 1 hour and filtered.
The liquid is concentrated to give an oily residue, which is applied to a column of silica gel. Elution of the column with methylene chloride:acetone, 50:1 (V/V) affords compound a (58 mg, 0.111 mmol, 70%) as a colorless glassy oil. nmr
(CDCl ₃ ) δ0.065 (6H, s), 0.90 (9H, s),
1.20 (3H, d), 3.3~4.4 (5H, m), 4.9~5.3
(2H, m), 5.57 (H, m), 5.8 (H, dd), 6.08
(H, d). Rf=0.33 (silica gel, methylene chloride:acetone, 50:1). E Preparation of compound a (R=methyl) Sodium hydride (50%
Oil dispersion, 38 mg, 0.75 mmol, washed with petroleum ether before use) was added to a stirred suspension of DMF (1
A solution of compound a (44 mg, 0.084 mmol) in ml) is added at room temperature under nitrogen atmosphere. The resulting mixture is heated on a steam bath for 10 minutes and cooled to room temperature. Methyl iodide (0.1ml, 1.6
mmol) and heat the resulting reaction mixture on a steam bath for 10 min. The mixture is cooled to room temperature, poured into cold water and extracted with ether. Wash the ether extract with dilute hydrochloric acid and sodium bicarbonate solution,
Dry with _MgSO4 and filter. When the liquid is evaporated, an oily residue remains, which is applied to a silica gel column. Methylene chloride:acetone, 50:1
Elution at (V/V) gives compound a (R=methyl), (29 mg, 0.054 mmol, 65%) as a colorless glassy oil. nmr ( _CDCl3 )
δ0.070 (6H, s), 0.90 (9H, s), 1.15 (3H,
d), 3.34 (3H, s), 3.4-4.1 (4H, m), 4.26
(H, m), 4.9-5.3 (2H, m), 5.5 (H, m),
5.75 (H, dd), 6.0 (H, d). Rf=0.37, 0.40
(Silica gel, methylene chloride:acetone, 50:
1). F Preparation of compound a (R=methyl) THF (2 ml), acetic acid (0.8 ml) and water (0.6 ml)
Compound a (prepared in E. 82 mg,
powdered p-toluenesulfonic acid pyridine salt (20 mg,
0.008 mmol) at once. The resulting mixture is stirred at room temperature under nitrogen atmosphere for 36 hours. The reaction mixture is poured into cold water and extracted with ether. The ether extract is washed with water and aqueous sodium bicarbonate, dried over MgSO ₄ and filtered. Concentrate the liquid in vacuo to an oily residue that is applied to a column of silica gel. The column was eluted with methylene chloride:acetone, 50:1 (V/V), initially containing the starting tetrahydropyranyl ether (26 mg,
0.049 mmol) is obtained. Continuing elution with the same solvent yields compound a (R=methyl) (23
mg, 0.051 mmol, 49% based on consumed starting material) is obtained as a colorless glassy oil. nmr (CDCl ₃ ) δ1.14 (3H, d), 3.34 (3H,
s), 3.6-4.4 (3H, m), 5.0-5.3 (H, m),
5.55 (H, m), 5.80 (H, dd), 6.00 (H, d).
Rf = 0.23 (silica gel, methylene chloride:acetone, 50:1) G Preparation of compound a (R = methyl) Compound a (prepared in F. 23 mg, 0.051 mmol) in benzene (7.5 ml) and freshly prepared A mixture of carbon silver/celite (1.6 g) is heated to reflux for 0.5 h under nitrogen atmosphere. Cool the reaction mixture to room temperature. Collect undissolved solids and wash with ether. When the liquid and washing liquid are combined and evaporated using a rotary evaporator, compound a (R=
methyl) is obtained as a glassy oil, which is used as is in the next reaction without further purification.
nmr (CDCl ₃ ) δ0.080 (6H, s), 0.90 (9H, s),
1.12 (3H, d), 2.58 (2H, d), 3.33 (3H, s),
3.7 (H, m), 4.3 (H, m), 4.7 (H, m), 5.5
(H, m), 5.74 (H, dd), 5.97 (H, d). Rf＝
0.41 (silica gel, methylene chloride:acetone,
50:1). H Preparation of compound a (R = methyl) Compound a (prepared in G. 24 mg) in THF (3 ml) and acetic acid (25 μ, 0.44 mmol)
Tetrabutylammonium fluoride trihydrate (0.32 mmol in TMF, 0.75 ml,
0.24 mmol) solution. The resulting mixture is stirred at room temperature under nitrogen atmosphere for 44 hours. The reaction mixture is poured into cold water and extracted with ether.
The ethereal extracts are washed with aqueous sodium bicarbonate, dried over MgSO ₄ and filtered. The liquid is evaporated in vacuo to give an oily residue, which is applied to a silica gel column. Methylene chloride:acetone, 9:1
Elution at (V/V) gives compound a (R=methyl) (17 mg, 0.051 mmol, 100% yield in the last two steps) as a colorless glassy oil. This oil solidifies on standing at room temperature and reconstitutes from ether-hexane to give the pure title compound, mp 110-111°C. Rf=0.19 (silica gel, methylene chloride:acetone, 9:1.
nmr (CDCl ₃ ) δ0.87 (3H, d), 1.08 (3H, d),
2.66 (2H, m), 3.34 (3H, s), 3.7 (H, m),
4.37 (H, m), 4.7 (H, m), 5.5 (H, m),
5.74 (H, dd), 5.97 (H, d). Analysis Calculated value for C ₂₀ H ₃₀ O ₄ , C 71.82; H 9.04 Actual value: C 72.03; H 9.05 Example 2 6(R)-[2-(8′-(S)-4″-fluorobenzyloxy- 2′(S),6′(R)-dimethyl-1′,2′
，
6′,7′,8′,8a′(R)-hexahydronaphthyl-
1′(S)ethyl]-4(R)-hydroxy-3,
4,5,6-tetrahydro-2H-pyran-2
Preparation of -one (compound a, R = p-fluorobenzyl) Following the same procedure as described in steps E-H of Example 1 (but instead of methyl iodide, an equivalent amount of 4-
using fluorobenzyl), the following compound is obtained. E Compound a (R = p-fluorobenzyl) Rf = 0.51, 0.57 (silica gel, methylene chloride: acetone, 50:1), nmr (CDCl ₃ ) δ1.15 (3H, d), 4.27 (H, d,
J = 12Hz), 4.70 (H, d, J = 12Hz), 5.5 (H,
m), 5.73 (H, dd), 6.0 (H, d), 6.98 (2H,
m), 7.28 (2H, m). F Compound a (F = p-fluorobenzyl) Rf = 0.18 (silica gel, methylene chloride: acetone, 100:1) nmr (CDCl ₃ ) δ1.15 (3H, d), 4.30 (H, d,
J = 12Hz), 4.75 (H, d, J = 12Hz), 5.5 (H,
m), 5.8 (H, dd), 6.0 (H, d), 7.0 (2H,
m), 7.32 (2H, m). G Preparation of compound a (R = p-fluorobenzyl) Rf = 0.28 (silica gel, methylene chloride: acetone, 100:1) nmr (CDCl ₃ ) δ1.16 (3H, d), 2.52 (2H,
d), 3.97 (H, m), 4.30 (H, d, J = 12Hz),
4.72 (H, d, J = 12Hz), 5.52 (H, m), 5.75
(H, dd), 6.0 (H, d), 7.0 (2H, d), 7.3
(2H, m). H Preparation of compound a (R = p-fluorobenzyl) Rf = 0.30 (silica gel, methylene chloride: acetone, 10:1) mnr (CDCl ₃ ) δ0.86 (3H, d), 1.17 (3H,
d), 2.59 (2H, m), 3.90 (H, m), 4.30 (H,
d=J=12Hz), 4.71(H, d, J=12Hz),
5.53 (H, m), 5.76 (H, dd), 6.01 (H, d),
7.03 (2H, t), 7.33 (2H, m). Example 3A The procedure of Example 1A is repeated using compound b in place of compound a. Then the product is
Treatment of B, C, D, E, F, G and H in the order of procedure gives b in which R is methyl. B By similar treatment using other halides in place of methyl iodide in Step E, the compounds shown in the table were obtained.

[Table] Example 4 Preparation of the sodium salt of the hydroxy acid corresponding to lactone a of Example 1 a obtained in Example 1 in 2 ml of ethanol
Add 1 ml of NaOH water ( ^{10 -4 mol} ,
1 equivalent). After standing at room temperature for 1 hour, the mixture was dried in vacuo and the W of compound a was

A sodium salt of formula is obtained. The IC ₅₀ (nM) test results for the sodium salt of the compound of the invention obtained in Example 3 are shown in the table.

【table】

【table】

[Table] For free carboxylic acid, add 2 ml of sodium salt.
Re-dissolve in ethanol-water (1:1) and add 10 ml of
Add to 0.1N hydrochloric acid and extract the liberated hydroxy acid with ethyl acetate. The latter solvent is washed once with water, dried and the bath medium is removed in vacuo, ensuring that the bath temperature does not exceed 30°. Hydroxy acids gradually revert to lactones when left untreated.

Claims (1)

[Claims] 1 formula [In the formula, R represents lower alkyl, phenyl lower alkyl (the phenyl nucleus can be substituted with halo), and straight-chain or branched lower alkenyl, and both of the broken lines X and Z or only X is a double bond; , and W is [Formula] or [Formula] (M is H or a cationic group capable of forming a pharmaceutically acceptable salt). ] A compound represented by 2. The compound according to claim 1, wherein W is [Formula]. 3. The compound according to claim 1, wherein W is [Formula]. 4. The compound according to claim 1, wherein both X and Z are double bonds. 5. The compound according to claim 1, wherein R is methyl. 6. The compound according to claim 1, wherein R is p-fluorobenzyl. 7 formula [In the formula, R represents lower alkyl, phenyl lower alkyl (the phenyl nucleus can be substituted with halo), and straight-chain or branched lower alkenyl, and both of the broken lines X and Z or only X is a double bond; , and W is [Formula] or [Formula] (or H or a cation capable of forming a pharmaceutically acceptable salt). (b) reducing the product with di-isobutylaluminum hydride; (c) reacting the product of step (b) with dihydropyran and a catalytic amount of p-toluenesulfonate pyridine; (d) treating the product of step (c) with lithium aluminum hydride; (e) treating the alcohol from step (d) with sodium hydride and the reagent RA, where R is as previously described;
(f) the product of step (e) is treated with 3 parts of THF in the presence of a catalytic amount of p-toluenesulfonic acid pyridine salt;
(g) oxidize the product of step (f) with carbon silver on Celite; (h) oxidize the product of step (g) at room temperature. , treated with a mixture of 3 equivalents of tetrabutylammonium fluoride and 4 equivalents of acetic acid in tetrahydrofuran,
Obtain the target product when W is [formula], and if necessary, (i) by hydrolyzing the product of step (h),
A method characterized by obtaining an object where W is [Formula].