JPS6344159B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula [In the formula, R ₁ is (C _1-22 ) alkyl, R is the formula (a) is an aralkyl group, and Ra is hydrogen, fluorine, chlorine, bromine or iodine,
(C _1-4 ) alkyl or alkoxy or trifluoromethyl, Rc is hydrogen, (C _1-4 ) alkyl or

[Formula], Y′ is hydrogen, fluorine, chlorine, bromine or iodine,
or (C _1-4 )alkyl, or R is the formula (b) is an indolyl group, and R ₄ is (C _1-8 )alkyl. Preferred compounds of formula a [In the formula, R ₁ ' is C _1-22 alkyl which may be branched at a point other than the α-carbon atom, Ra is as defined above, and Rc ₁ is

[In the formula, R has the same meaning as above]

The compound with the formula There is also provided a process for the preparation of a compound of the formula, characterized in that it is acylated with a compound of the formula: [wherein R ₁ has the same meaning as defined above] or a reactive derivative thereof. Reaction conditions for this type of acylation reaction are known. Suitable compound derivatives include acid chlorides, active esters, carbodiimide adducts or mixed acid anhydrides. The acylating agent preferably has the formula [wherein R ₆ is (C _1-4 )alkyl, R ₁ is as defined above, and R ₂ and R ₃ are both methyl]. The process of the invention can be carried out neat or in the presence of an inert organic solvent such as an ether, a halogenated hydrocarbon such as methylene chloride, chloroform, or an excess of a compound of formula. Methylene chloride is suitable as solvent. The reaction temperature is not critical, but is preferably about -50°C to +30°C, especially about -10°C to +20°C. The reaction is suitably about 1~
This is carried out over a period of 72 hours, preferably about 4 to 16 hours. The resulting compounds can be isolated and purified using conventional techniques. Compounds of formula can be prepared according to the following reaction scheme: In the above formula, R ₁ , R ₂ , R ₃ and R ₆ have the same meanings as above, B is boron, and R ₈ and R ₉ are each independent of each other.

[Formula] Represents hydrogen or (C _1-8 ) alkyl, or R ₈
and R ₉ together

[Formula] or

[Formula], n is 1-3, and (R ₇ ) ₃ -n is [(C _1-8 )alkyl] ₃ -n, or when n is 1,

[Formula] or

[Formula]. In reaction step (d), suitable acid binders include pyridine, triethylamine and diisopropylamine, preferably triethylamine. Suitable solvents are aprotic solvents such as halogenated hydrocarbons such as methylene chloride, chloroform or aromatic hydrocarbons such as benzene, toluene and acetonitrile. A preferred solvent is methylene chloride. The reaction temperature is, for example, about -50°C to +30°C, in particular -20°C to +20°C. The reaction is carried out, for example, for about 10 minutes to 18 hours, preferably for about 30 minutes to 3 hours. The product can be recovered using conventional techniques. However, the compound of the formula is used as is in the preparation of the final compound without proper isolation. In step (c), a compound of formula is treated with an oxidizing agent,
For example, it is reacted with potassium permanganate or preferably with chromium trioxide, preferably under acidic conditions. Suitable acids include mineral acids such as phosphoric acid, acetic acid or especially sulfuric acid. A suitable solvent is acetone, especially acetone in combination with a small amount of water, but combinations of water with other inert solvents such as diethyl ether can also be used. The reaction temperature is preferably about -
40° to +30°C, especially -10°C to +5°C. The reaction is carried out, for example, for about 10 minutes to 6 hours, preferably 2 to 3 hours. In step (b), a compound of formula is mixed with water and a first
in one step with an organic or inorganic base and in a second step with a hydroperoxide in an inert organic solvent, e.g.
Reaction with tert-lower alkyl hydroperoxide or hydrogen peroxide, preferably t-butyl hydroperoxide. Suitable bases include organic bases such as methyldiisopropylamine, pyridine,
or preferably triethylamine. Less preferred are inorganic bases, such as alkali metal hydroxides. Suitable solvents include dioxane, diethyl ether or preferably tetrahydrofuran. The reaction temperature is preferably about -20° to +40°C, especially 0 to 25°C. The reaction takes about 3 to 24 hours, for example.
Preferably it is carried out over a period of about 12 to 16 hours. Reaction step (a) can suitably be carried out under an inert atmosphere, for example nitrogen, and in the presence of an aprotic solvent. The boron reagent contains at least one active hydrogen, e.g. _BH3 or an alkyl borohydride, or other borohydrides commonly used in hydroboration, e.g.

9-borabicyclo[3,3,1]nonane of [formula] or structural formula

[Formula] is catechol-borane. This reagent is preferably a tetrahydrofuran/borane reagent (1:1),
For example, it is used in the form of _BH3.THF . Suitable aprotic solvents are ethers such as diethyl ether or tetrahydrofuran, the latter being particularly preferred. The reaction temperature is preferably about -78° to +100°C, especially about -10° to +30°C. The reaction is carried out for example for about 5 minutes to 12 hours, preferably for about 15 minutes to 1 hour.
It takes place over a period of time. Although the product can be recovered by conventional techniques, it is preferable to use the compound as it is in the preparation of the compound without isolation. Many of the compounds are known or can be prepared by conventional techniques, for example by replacing halogens in silicon with metal organics. Compounds of formulas and are known and can be prepared from available materials by conventional methods. The formulas and compounds in which R ₁ represents (C _5-22 )alkyl, especially (C _8-18 )alkyl, are new. Among the novel compounds, compounds of further particular interest are those in _which R ₁ is branched at a _point other than an alpha _carbon atom; ₁₈ ) Those in which R 2 and R 3 are both methyl are preferred, and those in which R ₂ and R ₃ are both methyl are preferred. The compounds of formula may exist in the form of optically active isomers, eg enantiomers. It will be appreciated that this can be prepared from optically active compounds and separated and recovered by conventional techniques, ie resolution. Such isomeric forms are also included within the scope of this invention. Compounds of the formula of this invention are pharmacologically active. In particular, the compounds of the formula are used to control the cholesterol ester content of mammalian arterial walls and are therefore particularly used as anti-atherosclerotic agents, i.e. for the prevention of atherosclerosis. It can be used as a drug in the treatment and control of atherosclerotic conditions due to the accumulation of cholesterol esters in the walls of arteries. Such ability of compounds of formula can be illustrated by known test methods showing that the total cholesterol ester content of cultured cells is reduced by the test compound compared to untreated cells. This test method is carried out, for example, by the following method: (A) Cell culture K. Fischer-Dzoga et al. [Experimental and Mo-
lecular Pathology, 18 , 162-176 (1973)], rhesus monkey smooth muscle cells (from the walls of arteries, e.g. the aorta) were cultured in basal essential medium (Mi −nimum
Essential Medium）〔Ee−gle〕
were routinely grown in 75 cm ² tissue culture flasks. A 75 cm ² flask containing near confluent cell growth was selected for testing. Cells were removed from the flask surface by gentle enzymatic treatment with pronase. After centrifuging and decanting the enzyme solution, the cell pellet was resuspended in an appropriate volume of media for seeding the desired number of 60 mm tissue culture dishes. After inoculation, the dish is labeled with the cell type, date and flask number of origin, and placed in a high humidity incubator at approximately 5%
Cultured at 37 °C under a _CO2 atmosphere. When the cultures were confluent, actual drug testing began. Test compounds were also dissolved in 100% ethanol. The same amount of ethanol was added to the control group as well.
Tissue culture dishes were randomly divided into groups. Hyper-lipemic rabbit serum (HRS) was added to one group at 5% by volume (control group). The remaining groups received 5% HRS and test compound.
0.1-1 mg/100ml of vehicle was added. The dishes were then returned to the incubator for an additional 24 hours. All operations leading up to the final culture were performed using sterilization methods in a laminar flow hood. After the incubation period, the dishes were placed in a Zeiss
Axiomat) was used to observe the state of the culture microscopically.
In particular, the size, number and shape of cytoplasmic inclusions and cell morphology were recorded. Media was removed from the culture and 0.9% sodium chloride solution was added. Cells were removed from the flask with a rubber policeman and transferred to a conically textured centrifuge tube. Cells were suspended in isotonic salt solution and washed three times by centrifuging at 800xg for 10 minutes and aspirating the supernatant. (B) Cell extraction method Next, add an appropriate amount of isopropyl alcohol (approximately 1 ml/mg of protein) to the cell pellet.
Bronwell Biosonique
The samples were sonicated in a microtube (140 x 3 mm) for 10 seconds under the "LO" set 50 of the Biosonik model. After centrifugation at 800xg for 15 minutes,
The clear supernatant was decanted and a portion was taken for cholesterol analysis. The residue was dissolved in 0.1N sodium hydroxide and a portion was taken for protein quantification by the method of Lowry et al. (J. Biol. Chem. 193 , 265; 1951). (C) Analysis Free cholesterol: Standard, sample and blank (isopropyl alcohol only) isopropyl alcoholic solvents were treated in a similar manner. Free reagent (Reagent A in Table 1 below) was added to a 10 x 75 mm disposable glass test tube to which 20μ of isopropyl alcoholic solution was added and mixed.
A 0.4 ml portion was added. After standing at room temperature for about 5 minutes, 0.8 ml of 0.5N sodium hydroxide (Reagent C in Table 1 below) was added and mixed. Fluorescence was then measured on an Aminco-Bowman fluorescence spectrometer with an absorption wavelength of 325 nm and an emission wavelength of 415 nm. In this case a xenon lamp, an IP28 phototube and a cuvette with a 1 cm light path under a 2 mm slit were used. Total Cholesterol: Total cholesterol was measured according to the same method as described above for free cholesterol, except that Test A was replaced by the total reagent (Reagent B in Table 1 below). The sample is
0.5N sodium hydroxide solution (Reagent C in Table 1 below)
The cells were incubated at 37°C for 20 minutes before addition of . Other analysis for cholesterol, i.e. process
The above step (C)) obtained from (A) and (B) can also be carried out by the method of Ishikawa et al. (J. Lipid Res. 15 , 286; 1974). The amount of cholesterol esters is obtained by subtracting the amount of free cholesterol of the cells determined in the assay by the total cholesterol content. A lower value of cholesterol esters in the cell group to which the test compound has been added compared to the control group (untreated) indicates that the test compound is active in reducing cholesterol esters in the cells. Table 1 Composition of reagents for the determination of cholesterol A Reagent for free cholesterol Sodium phosphate buffer PH 7.0 0.05M Cholesterol oxidase 0.08 U/ml Horseradish peroxidase 30.00 U/ml p-hydroxyphenyl Acetic acid 0.10mg/ml B Total cholesterol reagent Sodium phosphate buffer PH7.0 0.05M Cholesterol ester hydrolase
0.08U/ml Cholesterol Oxidase 0.08U/ml Forceradyl Peroxidase
30.00U/ml Sodium taurocholate 5.00mM Carbowax-6000 0.17mM p-Hydroxyphenylacetic acid 0.15mg/ml C Sodium hydroxide solution 0.5N A suitable daily dosage for the above application is 10mg
~5000 mg, suitably administered in divided doses of 2.5 to 2500 mg over 2 to 4 times per day or in slow-release form. A suitable daily dosage using a compound of formula a is from about 10 to about 1000 mg, suitably 2 mg per day.
Administered in ~4 divided doses of 2.5-500 mg or in slow-release form. A suitable daily dosage for a compound of formula b is from about 100 to about 5000 mg, preferably from about 100 to 2000 mg, suitably from 25 to 2500 mg two to four times per day.
Administered in divided doses or in slow-release form. The compounds can be mixed with conventional pharmaceutically acceptable diluents and carriers and optionally other excipients, and can be administered in the form of tablets or capsules. The following Preparations and Examples illustrate the invention. Preparation example 1 4,4-dimethyl-4-sila-tetradecene-
1. Compound Magnesium ribbon 73g under nitrogen
(3.04 mol), 570 ml of anhydrous tetrahydrofuran, and 183 g (172 ml, 1.42 mol) of dimethyldichlorosilane were added with 1- 205 g (0.928 mol) of bromdecane was added. After the addition and completion of the exothermic reaction, the mixture was stirred at 40° C. for 1 hour. When the sample was subjected to the Gilman test, all of the Grignard reagent had been consumed. The resulting mixture was concentrated under strictly anhydrous conditions and vacuum. The resulting semi-solid material was then mixed with 218 g (1.8 g) of allyl bromide.
mol) and 400 ml of anhydrous tetrahydrofuran while stirring at about 45-65°C. This exothermic reaction was controlled by cooling. Stirring was continued at 60°C for 16 hours. The mixture was then cooled, 2 portions of hexane were added, and the contents were poured into 318 g of aluminum chloride dissolved in ice water. The organic phase was separated after adding some ligroin. Then the product is 3
Washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was rectified using a packed column to obtain a fraction of 4,4-dimethyl-4-silatetetradecene-1: boiling point 69-81°/0.015-0.030 mm.
Hg. Preparation Example 2 4,4-dimethyl-4-silatetetradecanol. Compound Under nitrogen, keeping the temperature below 25℃,
166.4 g of 4,4-dimethyl-4-silatetetradecene-1 in 550 ml of anhydrous tetrahydrofuran
(0.69 mol) of 1M borane in tetrahydrofuran
270ml (0.81 equivalents) was added. The reaction mixture was left at 20° C. for 1/2 hour, then 10 ml of water was carefully added to decompose the excess hydride (H ₂ evolution). When gas evolution had ceased, 140 g (0.39 mol) of triethylamine were added followed by 93 g (1.03 mol) of tert-butyl hydroperoxide while cooling to 5-10°C (due to exotherm). The reaction mixture was left at 20°C for 16 hours and concentrated under vacuum and below 40°C. This concentrate was partitioned between toluene and dilute aqueous sodium hydroxide, the organic phase was washed twice with water and slightly acidic (HCl) ferrous sulfate solution (to remove any remaining peroxide). 2 times with dilute hydrochloric acid and once with sodium bicarbonate solution,
Dry over sodium sulfate, filter, and concentrate under vacuum to give a colorless oil. This oil was then rectified under vacuum through a column containing stainless steel overhanging packings to give the title product; boiling point 110-114°C/0.035mm. Preparation Example 3 4,4-dimethyl-4-silatotradecanoic acid.
Compound A solution of 143.4 g (0.554 mol) of 4,4-dimethyl-4-silatetradecanol in 0.2 acetone was cooled to -10<0>C. Cool to -10° to 0°C and add Jones reagent (Jones) while stirring.
reagent) (8N oxidation equivalent of chromic acid in aqueous sulfuric acid)
302 ml (4.36 x 0.554 electron equivalents) was added over 30 minutes. Stirring was then continued for 45 minutes at -10° to 0°C and for 1 hour at 0° to 5°C. The mixture was warmed to 10° C. with stirring for 1/2 hour, then poured into ice and heptane. The resulting organic phase was washed three times with half-saturated sodium chloride solution and twice with water, dried over sodium sulfate, filtered and concentrated under vacuum to give an oil. Most of the resulting material is rectified through a column filled with stainless steel protruding packings,
The title product was obtained; boiling point 138-140°C/0.05mm. Preparation Examples 4-21 By following the method described above and using equivalent amounts of the corresponding starting materials, the following products (with the exception of R ₂ and
_R3 is _CH3 ) obtained:

[Table] Example 1 (+)-4,4-dimethyl-4-sila-tetradecanoyl-1'-phenylamide. Compound Methylene chloride while keeping the temperature between 20° and 30°C
14.3 g (128.5 mmol) of triethylamine were added to 35 g (128.5 mmol) of 4,4-dimethyl-4-sila-tetradecanoic acid in 200 ml (exothermic).
The resulting clear solution was maintained at 0 DEG to -20 DEG C. while adding 15.4 g (128.5 mmol) of ethyl chloroformate in 100 ml of methylene chloride to give a mixed anhydride of formula. The resulting mixture was then brought to a temperature of 15° C. for 3/4 hour and then 34.4 g (+)-α-methylbenzylamine (2× 1.1 x 128.5 mmol) was added. The mixture was stirred at 20°C for 3 hours and poured onto ice. The organic phase was washed twice with 1N hydrochloric acid and once with a mixture of sodium bicarbonate and sodium carbonate solution, dried over sodium sulfate,
Filtration and concentration under vacuum gave 47.2 g of oil.
Rectification using a “Kugelrohr” apparatus yields the title product of analytical purity from 170 to 177
Obtained as the last fraction at °C/0.06 mmHg; melting point 32
~34℃. Example 2 (±)-4,4-dimethyl-4-sila-tetradecanoyl-1'-phenyl-2'-p-tolyl-
Ethylamide (compound) In a dry flask, add 4,4-dimethyl-4-
3.17 g (11.6 mmol) of sylar tetradecanoic acid,
2.53 g (23.2 mmol) triethylamine and 5 ml methylene chloride were added. The resulting solution was cooled in an ice bath. 1.385 ethyl chloroformate in 3 ml of methylene chloride while stirring and keeping the temperature at 0°C.
g (12.8 mmol) of solution was added in about 1 minute,
The resulting solution was then treated with 2 ml of methylene chloride. The resulting white slurry was stirred for 1 hour at 0°C. A solution of 2.45 g (11.6 mmol) of (±) 1-phenyl-2-p-tolylethylamine in 3 ml of methylene chloride was then added with stirring in an ice solution, followed by washing with 2 ml of methylene chloride. The resulting mixture was allowed to warm to room temperature while stirring. Furthermore
Gentle stirring was continued for 48 hours. The reaction mixture was then washed with approximately 25 ml of water, followed by extraction of the organic phase with dilute hydrochloric acid until the aqueous extract became acidic. The organic phase was then washed with sodium bicarbonate solution (PH=8), dried over anhydrous sodium, filtered and concentrated under vacuum at 40° C. to give a colorless oil. Chromatography of this oil on silica gel, eluting with 1:1 hexane:chloroform, afforded the title compound; mp 39-42°. By following the methods of Examples 1 and 2 and using approximately equivalent amounts of the corresponding starting materials, compounds of the following formula, where R ₂ and R ₃ are methyl, were obtained:

【table】

【table】

[Table] The table below shows the NMR values of the oily compounds of the present invention. Values are expressed in PPM relative to the reference compound tetramethylsilane at 0 PPM, and the solvent is CDCl ₃ (D=deuterium). In the table, the following symbols are used: S - singlet, D
- doublet, Q-quartet, M-multiplet and B-broad. The number in the box is the number of protons.

【table】

【table】

Claims (1)

[Claims] 1 formula [In the formula, R ₁ is (C _1-22 ) alkyl, R is the formula (a) is an aralkyl group, and Ra is hydrogen, fluorine, chlorine, bromine or iodine,
(C _1-4 ) alkyl or alkoxy or trifluoromethyl, Rc is hydrogen, (C _1-4 ) alkyl or and Y′ is hydrogen, fluorine, chlorine, bromine or iodine,
or (C _1-4 )alkyl, or R is the formula (b) is an indolyl group, and R ₄ is (C _1-4 )alkyl]. 2 formula a [In the formula, R′ ₁ is C _1-22 alkyl which may be branched at a point other than the α-carbon atom, Ra has the same meaning as described in claim 1, and Rc ₁ is [Formula ], where Y″ is fluorine, chlorine, bromine or iodine, or (C _1-4 )alkyl]. 3 Formula b [In the formula, R' ₁ and Ra have the same meanings as described in claim 2, and Rc ₂ is (C _1-4 ) alkyl] compound. 4. The compound according to claim 1, which is 4,4-dimethyl-4-sila-tetradecanoyl-1'-phenyl-2'-p-tolyl-ethylamide. 5 formula [In the formula, R ₁ is (C _1-22 ) alkyl, R is the formula (a) is an aralkyl group, and Ra is hydrogen, fluorine, chlorine, bromine or iodine,
(C _1-4 ) alkyl or alkoxy or trifluoromethyl, Rc is hydrogen, (C _1-4 ) alkyl or and Y′ is hydrogen, fluorine, chlorine, bromine or iodine,
or (C _1-4 )alkyl, or R is the formula (b) and R ₄ is (C _1-4 )alkyl, together with a pharmaceutically acceptable diluent or carrier. 6 formula [In the formula, R ₁ is (C _1-22 ) alkyl, R is the formula (a) is an aralkyl group, and Ra is hydrogen, fluorine, chlorine, bromine or iodine,
(C _1-4 ) alkyl or alkoxy or trifluoromethyl, Rc is hydrogen, (C _1-4 ) alkyl or [Formula], Y′ is hydrogen, fluorine, chlorine, bromine or iodine,
or (C _1-4 )alkyl, or R is the formula (b) is an indolyl group, and R ₄ is (C _1-4 )alkyl] A method for producing a compound of the formula H ₂ NR... [wherein R is as defined above] formula the compound [wherein R ₁ has the same meaning as defined above] A method for producing a compound of the formula, characterized by acylation with the compound of the formula or a reactive derivative thereof.