LT3339B - New bht ether compounds and their use as hypolipidemic and antiatherosclerotic drugs - Google Patents

Abstract

The discovered pharmaceutically active butyl hydroxytoluene (BHT) omega - pyridyl ethers, selected from BHT omega-pyridyl compounds, are described by the formula:<IMAGE>wherem = 1.3when m = 1, Ε = 6-9when m = 3, Ε = 5-11Sum (Ε) = [m + n + 1 (for oxygen)],where the connection between two carbonic atoms of (CH2)n part, next to the pyridine ring, is a single, double or triple connection; and its pharmaceutically acceptable acid connection saline, its pharmaceutical compositions, fight against lipidemia and arteriosclerosis.

Description

FIELD OF THE INVENTION The present invention relates to hypolipidemic and antiaterosclerotic compounds, their pharmaceutical compositions and their use.

Atherosclerosis has been described as an important disease since the beginning of medical history. However, it was not until the twentieth century that myocardial infarction was always associated with coronary artery atherosclerosis and thrombosis. Epidemiological studies in the 1970s showed that about fifty percent of all deaths in Western industrialized countries were due to cardiovascular disease.

The most important factors for the development of atherosclerosis are known. The importance of elevated cholesterol and triglyceride levels was revealed early. Cholesterol and triglycerides are transported in the form of so-called lipoproteins, whose cholesterol-rich low-density (LDL) and triglyceride-rich very low-density (LMTL) fractions are considered atherogenic if their blood levels are elevated.

However, it has only recently been revealed that besides their quantity, the quality of LDL is also decisive. And yes, in animal experiments, it could be shown that equally high LDL cholesterol levels were more or less atherogenic depending on the drugs used to reduce elevated LDL cholesterol. The reason for this discovery could also be demonstrated by the authors, namely that drugs that could also reduce LDL oxidation were most effective in counteracting atherosclerosis. (Carew et al., Proc. Nat.

Acad. Sci. USA 84, 7725-7729 (November 1987). This experiment impressively demonstrates the importance of LDL quality. In the body, LDL and LMTL are dependent on continuous oxidation, which is physiologically balanced by natural so-called antioxidants such as tocopherol or ascorbic acid. However, at elevated levels of LDL (cholesterol) and LMTL (triglycerides), this homeostasis is disrupted and pushed toward an increasing trend in favor of oxidation.

Thereby, the risk of developing and developing atherosclerosis is increased by two factors:

- increased levels of so-called atherogenic lipoproteins (LDL, LMTL);

the content of their oxidation products (eg lipids).

to oxidize

The causal factor.

treatment in this way must influence both

In addition to these humoral factors, namely lipoproteins, the cellular components of the vascular wall will play an important role in atherosclerosis. In this way, in the case of internal vascular, endothelial, mechanical or chemical damage, a fertile impulse is generated to stimulate the smooth muscle cell lower layer. This process is particularly impressive after endothelial injury as a result of plastic surgery. In the short term, induced delivery can block the blood vessels to such an extent that it can cause infarction. In addition to mechanical endothelial damage, a noxious factor such as oxidized LDL also plays a role.

Therefore, in addition to the two options mentioned above, an effective effect on atherosclerosis must be achieved by protecting the endothelium and reducing excessive proliferation of smooth muscle cells.

Compounds meeting all of the above requirements should have two pharmacologically distinct moieties, at least:

- nicotinic acid or a suitable derivative thereof as a lipid-lowering primer;

- antioxidant as an anti-atherosclerotic primer.

Nicotinic acid is best because it not only acts on lipids, but has been shown to have anti-atherosclerotic properties.

Medical uses require known side effects of nicotinic acid, such as sudden redness due to too fast increases in blood levels, found that rapid increases and acid levels are not necessary to achieve lipid lowering effects. Thus, low concentrations of nicotinic acid and sufficient lipid reduction should be the basic preconditions for the valuable compounds of the above type.

However, the disruptive effects of nicotinic acid were, in fact, high in nicotine

DE no. No. 2716125 discloses a BHT (butylated hydroxytoluene) ether derivative (herein called Mrz 3/156) as a preferred compound of the formula

When the required properties were tested, very high levels of nicotinic acid were observed (Table 1), demonstrating that this compound did not meet the above requirements.

Extensive and meticulous synthesis and pharmacological tests have shown that there are several structural assumptions necessary to meet all these criteria.

It was concluded that only compounds of the general formula mentioned below could be of interest.

It has been possible to show that the compounds of the present invention are present

- effective in reducing lipids without causing very high levels of nicotinic acid;

- effective in inhibiting lipid and lipoprotein oxidation;

- effective in reducing endothelial damage due to oxidized LDL;

and

- effective in reducing the proliferation of smooth muscle cells in the vascular wall.

It is an object of the present invention to provide novel, more effective hypolipidemic and anti-atherosclerotic compounds, pharmaceutical compositions thereof for the treatment of hyperlipidemia and concomitant atherosclerosis. It is a further object of the present invention to provide such novel compounds, mixtures and method which satisfy the above theoretical requirements. Additional objects will become apparent below, and further objects of the invention will be apparent to those skilled in the art.

The present invention encompasses the following aspects, inter alia, singly or in combination:

- a compound selected from those BHT omega-pyridyl ether compounds of the formula

in which

m = 1.3 when m = 1, 6- = 6-9 when m = 3, Σ = 5-11

The sum (Σ) = [m + n + 1 (for oxygen)] wherein the bond between the (CH ₂ ) _n moiety closest to the pyridine ring, the two carbon atoms, is a single, double or triple bond, its pharmaceutically acceptable acid addition salts, compositions useful in combating hyperlipidemia and atherosclerosis, comprising such a compound in association with a pharmaceutically acceptable carrier or diluent.

The compound of the present invention is intended for use as ethers of BHT (butylated hydroxytoluene) derivative and omega-pyridylalkyl, alkenyl or -alkynyl alcohol as active hypolipidemic and antiatherosclerotic compounds. More specifically, it is for an ether compound represented by the formula

in which

m = 1.3 when m = 1, Σ = 6-9 when m = 3, Σ = 5-11

The sum (Σ) = [m + n + 1 (for oxygen)], where (CH ₂ ) _n can contain a double bond or a triple bond conjugated to the 3-position of the pyridine ring, that is, the bond between the (CH ₂ ) _n moiety closest to the pyridine for a ring, the two carbon atoms may be single, double or triple bond, and its pharmaceutically acceptable acid addition salts, as well as a pharmaceutical composition containing the compound of the invention as an active component, both of which are useful as antilipidemic and anti-atherosclerotic agents.

a) Dynamics of nicotinic acid

The dynamics of nicotinic acid derived from the compounds tested are investigated in the rat. A single dose of the test compound (0.2 mmol / kg) was administered into the fasted state in normal lipidemic rats by gavage. After 240 and 360 minutes, blood samples and serum nicotinic acid levels were determined using the GC / MS method (n = 5 rats / time).

The data are shown in Table 1.

Table: Concentration of nicotinic acid (mg / l)

in pooled serum samples after using the imo Nicotinic acid one medication Test compound Time 240 ' Time 360 ' 3/156 4.8 5.0 3/161 0.2 0.2 3/187 0.58 0.23 3/192 0.54 0.85 3/179 0.21 0.15 3/188 0.17 0.18 3/124 0.67 0.61 3/190 0.18 0.13 3/191 0.47 0.44 3/181 0.23 0.12

b) Demonstration of lipid lowering properties

The lipid-lowering properties of the compounds of the present invention were investigated in a rat model. In this model, a single dose (0.2 mmol / kg) of the test compound was administered orally into the empty stomach. Blood samples were taken 240 and 360 minutes after administration and triglyceride concentrations were assessed by a standard method (e.g., GPO-PAP method, E. Merck system, Darmstadt, Germany) (n = 5 rats per measurement time).

Table 2 shows the mean changes in percent relative to the control of the solvent (cremophor, 30% in distilled water).

Table 1: Mean changes in triglyceride concentrations (Δ avg. decrease) at 240 and 360 minutes after a single administration compared to a control experiment.

Triglycerides

Test compound Time 240 ' Time 360 ' 3/161 60 67 3/187 65 55 3/192 44 53 3/179 57 70 3/188 53 40 3/124 73 76 3/190 56 28th 3/191 37 32 3/181 57 57 Control 0 0

(c) Demonstration of antioxidant properties

The compound of the present invention was tested for antioxidant properties in in vitro assays. In these assays, the substance is incubated with the substrate to be oxidized (synthetic triglyceride with unsaturated fatty acids, i.e. trilinolenin or human LDL). After the incubation period, the degree of oxidation was determined using so-called thiobarbituric acid (TBR) fineness. TBR reacts with malondialdehyde (MDA), one of the essential oxidation products. The reaction product was determined photometrically.

io cl) Trilinolenin test

400 ml of trilinolenin was incubated for 3 hours at 37 ° C with 2 ml HAM F 10 medium with solvent (eg ethanol, 0.5% final concentration) or test substance (concentration 5x10 ⁵ M) (oxidation is achieved without special catalysts).

All TBR reactant was determined in 1 mL incubate by adding 1.5 mL of 0.67% TBR in 0.05 N NaOH and 1.5 mL in 20% trichloroacetic acid. The mixture reacted for 60 minutes in a boiling water bath. After cooling, measure the absorbance at 532 nm.

The test compound was tested three times.

c2) LDL test

LDL (d = 1.019 - 1.063) was obtained from human plasma by ultracentrifugation with EDTA.

100 µg LDL was incubated with 0.5 ml HAM F 10 medium for 24 h at 37 ° C with solvent (namely, ethanol, 0.5% final concentration) or test substance (concentration: 5x10 ⁵ M) in 10 μΜ Cu ²⁺ .

All TBR reactants were determined by the trilinolenin assay.

The test compound was tested 3 times.

Tables 3a (trilinolenin assay) and 3b (LDL assay) present mean percent changes compared to solvent control.

Table I: Mean percentage change (Δ avg) of TBR-reactive substance concentration after 3 hours of incubation (a: trilinolenin assay) and 24 hours (b: LDL assay) as compared to the control experiment.

Test compound a) Trilinolenin Test% b) LDL test% 3/161 58 79 3/187 71 82 3/192 74 86 3/179 79 73 3/188 66 71 3/124 76 90 3/190 72 89 3/191 76 86 3/181 76 76 Control 0 0

d) Demonstration of endothelial protection against cytotoxic effects of oxidized LDL

Human umbilical vein endothelial cells were isolated after vascular treatment with collagenase and culture.

For the test, cells were plated at 50,000 plates and cultured for 4 days in Ham's F 12 / DMEM medium (4: 1 ratio) with 15% fetal calf serum, 5% horse serum and 10 mg / ml ECGF heparin.

After 4 days, the cells were washed in serum-free medium and used in a cytotoxic assay.

For this assay, cells were incubated for 24 hours at 37 ° C in 1 ml Ham's F 10 medium (+ ECGF heparin) with LDL (200 µg / ml). During this time, either the solvent, namely ethanol, 0.5% final concentration (control 1) or test substance (2 x 10 ⁵ M) is co-incubated. In parallel, one sample was incubated with LDL without any other material and with solvent (0.5% ethanol) to assess maximal delivery rate (Control 2).

After 24 hours, the TBR-reacted substance was detected in the medium or the cells were counted.

The test compound was tested 3 times.

Table 4a shows the mean percentage changes compared to typical control 1.

Table 4b shows the percentage of cells compared with typical control 2.

Table 4a: Mean change in concentration (Δ avg) of TBR-reactive material after incubation of endothelial cells with LDL for 24 hours compared with typical control 1.

i

Table 4b: Percentage average cell number after 24 hours incubation with LDL compared to 2 representative controls.

Test compound a) TBR-reactive material b) % Endothelial cells 3/187 53 80 3/192 47 79 3/161 64 107 3/181 65 122 3/179 43 76 3/188 54 79 3/124 57 118 3/190 36 65 3/191 33 63 Control 0 100

(e) Demonstration of in vivo inhibition of smooth muscle cell growth.

Smooth muscle cells obtained after isolation from the aorta of 10 balloon catheterized rats were cultured in DMEM with 10% embryonic calf serum and subjected to passages.

The assay was inoculated with 10,000 single passage cells / 15 wells and incubated for 3 days with solvent (namely, DMSO,

0.5% final concentration) or test compound (5 x 10 ⁵ M) 4 hours after inoculation. After 3 days, cells were counted. 6 samples were tested for the test compound.

the table shows the mean percentage changes relative to the solvent control.

Table: Mean percentage change (Δ avg) of vascular smooth muscle cell number after days of incubation with test substance relative to solvent-treated control.

Test compound Cell Number% 3/161 98 3/187 93 3/192 95 3/179 55 3/188 63 3/124 71 3/190 91 3/191 79 3/181 81

SYNTHESIS OF THE INVENTION COMPOUNDS

The preparation of the compounds of this invention is carried out starting with omega-pyridylalkyl, alkenyl or alkynyl15 alcohol which is treated with 3,5-di-tert-butyl-4-hydroxy-benzyl alcohol acetate.

i

where further details are defined above.

and the values are those as ω-pyridyl-alkyl-alcohol obtained in the Witting reaction, from the pyridyl-3-aldehyde and the phosphonium salt synthesized from the corresponding haloalkyl alcohol.

The resulting unsaturated w-pyridyl-alkyl alcohol is converted into the ether of the invention immediately or after hydrogenation.

PCPh>

Br-CCH 1 2 n

P <Ph>> -O-THP

2 n-2

THP

Tetrahidi-opi ranil

Alternatively, the starting ω-pyridyl-alkyl alcohol may be prepared by reacting 3-bromopyridine and the corresponding omega-alkynyl alcohol. The resulting ω-pyridylalkynyl alcohol is converted immediately (or after hydrogenation) to ω-pyridyl-alkenyl or ω-pyridyl-alkyl alcohol) into the compound of formula I of the invention.

the invention also includes pharmaceutically acceptable acid addition salts of the above compounds.

The compounds of formula I include in particular the following compounds:

1. 2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoctyl] phenol (Mrz 3/161)

2. 2,6-Di-tert-butyl-4- [6- (3-pyridyl) -2-oxahexyl] phenol (Mrz 3/187)

3. 2,6-Di-tert-butyl-4- [7- (3-pyridyl) -2-oxaheptyl] phenol (Mr 3/192)

4. (Z) -2,6-Di-tert-Butyl-4- [8- (3-pyridyl) -2-oxaoct-7-enyl] phenol (Mrz 3/181)

5. 2,6-Di-tert-butyl-4- [9- (3-pyridyl) -2-oxanonyl] phenol (Mrz 3/188)

6. 2,6-Di-tert-butyl-4- [5- (3-pyridyl) -4-oxapentyl] phenol (Mrz 3/124)

7. 2,6-Di-tert-butyl-4- [7- (3-pyridyl) -4-oxaheptyl] phenol (Mr 3/190)

8. 2,6-Di-tert-butyl-4- [9- (3-pyridyl) -4-oxanonyl] phenol (Mrz 3/191)

9. 2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoct-7-ynyl] phenol (Mrz 3/179), of which 2,6Di-tert-butyl-4 is preferred. - [8- (3-pyridyl) -2-oxaoctyl] phenol and 2,6-Di-tert-butyl-4- [5- (3-pyridyl) -4-oxapentyl] phenol.

The following examples illustrate the preparation of the compounds of the present invention, but are not intended to limit the invention.

EXAMPLE

Synthesis of 2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoctyl] phenol

3,5-Di-tert-butyl-4-hydroxybenzyl] acetate

102.1 g (1 mol) of acetic anhydride are slowly added to a stirred solution of 118 g (0.5 mol) of 3,5-di-tert-butyl-4-hydroxybenzyl alcohol in 90 ml of pyridine at 0 ° C. After 15 minutes remove the freezing bath, and

the solution reacts for an additional two hours at ambient temperature. The reaction mixture is then poured into iced water with vigorous stirring. After 15 minutes, the precipitated product is collected by filtration, washed with water, dried and recrystallized from hexanes to give 110 g (80%) of 3,5-di-tert-butyl-4-hydroxybenzyl acetate as a yellowish crystalline solid, m.p. 108 ° C (C ₁₇ H ₂₆ O ₃ ; molecular weight (M.sv.) 278.2)

R f: 0.57 (SiO ₂ 60; n-hexane / diethyl ether 3: 1)

6- (3-Pyridine) hexanol A solution of 3-bromopyridine (52 mL, 0.47 mol) and 5-hexin-1-ol (52 g, 0.53 mol) is degassed with 150 mL of triethylamine and 500 mL of dichloromethane with argon for 15 minutes. ) bis (triphenylphosphine) palladium (II) chloride and 450 mg copper iodide. The mixture is refluxed for 3 hours. The cooled reaction mixture is diluted with 1 liter of dichloromethane and washed with water and brine, dried (K ₂ CO ₃ ), concentrated and distilled (boiling).

120-130 ° C / 0.05 mbar) to give 63 g of 6- (3-pyridyl) hex5-inol as a yellow oil which is dissolved in 300 ml of isopropanol and hydrogenated for 16 hours over 6 g.

10% Pd / C in Parr hydrogenation apparatus. The crude product is concentrated by distillation (boiling at 120130 ° C / 0.05 mbar) to give 61.8 g (65%) of 6- (3-pyridyl) hexanol as a slightly yellow viscous liquid.

(C _n H ₁₇ NO; M.sv. 179.3)

Stage I

2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoctyl] phenol

A solution of 1.53 g (5.5 mmol) of 3,5-di-tert-butyl-4-hydroxybenzyl acetate, 895 mg (5 mmol) of 6- (3-pyridyl) hexanol and 30 mg of tetrakis (triphenylphosphine) palladium (O) in 60 mL of degassed, of dry acetonitrile is stirred at room temperature under nitrogen for 5 days.

The solvent is evaporated, the residue is partitioned between ether and saturated bicarbonate aqueous solution and the dried extract is separated by silica gel column chromatography, after concentration of 2,6-di-tert-butyl-4- [8- (3-pyridyl) -2-oxooctyl] phenol. consisting of 59% yellowish viscous oil, slowly crystallizing, m.p. 63 ° C.

(C ₂₆ H ₃₉ NO ₂ ; M.Sv. 397.6)

R f: 0.6 (SiO ₂ 60; n-hexane / ethyl acetate 3: 1)

EXAMPLE

Synthesis of 2,6-Di-tert-butyl-4- [6- (3-pyridyl) -2-oxahexyl] phenol

2, (3-Bromopropyloxy) tetrahydropyran

To a solution of 35 g (0.251 mol) of 3-bromopropanol and 1 g of p-toluenesulfonic acid in 500 ml of diethyl ether was added 32.5 ml (0.357 mol) of 3,4-dihydro-2H-pyran dropwise with ice-cold cooling, and the solution was stirred

2 hours at room temperature. The mixture is neutralized with saturated aqueous bicarbonate solution, washed with brine and concentrated after drying to give 56 g of 2- (3-bromopropyloxy) tetrahydropyran in a practically quantitative yield as a viscous liquid which can be used without purification (C ₈ H ₁₅ BrO ₂ ; M.W. 223.1)

Rf: 0.9 (SiO ₂ 60; n-hexane / ethyl acetate 1: 1)

3- (Tetrahydropyranyloxy) propyltriphenylphosphine onobromide

66.5 g (0.298 mol) of 2- (3-bromopyloxy) tetrahydropyran are refluxed with 82 g (0.312 mol) of triphenylphosphine and 1 g of tetrabutylammonium iodide in 500 ml of acetonitrile. After evaporation of the solvent, the residue is triturated several times with boiling diethyl ether. 144 g (100%) of 3-tetrahydropyranyloxy) propyltriphenylphosphonium bromide are obtained as a fixed oil.

(C ₂₆ H ₃₀ BrNO ₂ P; M.W. 485.4)

2- [4- (3-Pyridyl) but-3-enoxy] tetrahydropyran

To a solution of 33.6 ml (0.24 mol) of diisopropylamine in 300 ml of dry tetrahydrofuran was added 149 ml (0.244 mol;

15% solution in hexanes) under a nitrogen atmosphere at a temperature of 78 ° C. After stirring for an additional 15 minutes, 115 g (0.237 mol) is slowly added to the mixture.

3- (Tetrahydropyranyloxy) propyltriphenylphosphonium bromide dissolved in 400 ml dry tetrahydrofuran followed by

19 ml (0.199 mol) of freshly distilled pyridine-3-aldehyde are added over 30 minutes. The reaction mixture was then stirred for 3 hours at -78 ° C, followed by an additional 16 hours at ambient temperature. After the usual completion, chromatographic separation of the crude product gives 87 g of 2- [4- (3-pyridyl) but-3-enoxy] tetrahydropyran as a viscous liquid.

(C ₁₄ H ₁₉ NO ₂ ; M.Sv. 233.3)

Rf: 0.2 (SiO ₂ 60; n-hexane / diethyl ether 1: 1) step

4- (3-Pyridyl) butanol g (43 mol) A solution of 2- [4- (3-pyridyl) but-3-enoxy] tetrahydropyran in 200 ml methanol / water 1: 1 (v / v) is acidified with 2N salt acid and hydrogenated over 2 g at 10% Pd / C for 16 hours. After filtration, the solvent is removed, the residue is neutralized with saturated aqueous bicarbonate solution and the product is extracted with several portions of ether. Purification of the crude product by silica gel chromatography yields

15.7 g (87%) of 4- (3-pyridyl) butanol as a colorless viscous oil.

(C ₉ H ₁₃ NO; F.sv. 151.2)

Rf: 0.2 (SiO _2, 60; n-hexane / ethyl acetate 1: 1) of the process

2,6-Di-tert-butyl-4- [6- (3-pyridyl) -2-oxahexyl] phenol according to Example 1, Step 3.

2,6-Di-tert-butyl-4- [6- (3-pyridyl) -2-oxahexyl] phenol is obtained as an amber oil in 62% yield for the final etherification step (C ₂₄ H ₃₅ NO ₂ ; M.Sv. 369.6).

R f: 0.42 (SiO ₂ 60; n-hexane / ethyl acetate 3: 2)

EXAMPLE

Synthesis of 2,6-di-tert-butyl-4- [7- (3-pyridyl) -2-oxaheptyl] phenol according to Step 2 Example 1 (starting with 4-pentyl-1-ol; ERH Jones et al., Organ Synthesis Coli Vol. 4, p. 755 (1963) and step 3 gave 2,6-di-tert-butyl-4- [7- (3-pyridyl) -2-oxa-heptyl) -phenol as a heavy yellow syrup in 59% yield in the final etherification step.

(C ₂₅ H ₃₇ NO ₂ ; M.Sv. 383.6)

R f: 0.49 (SiO ₂ 60; n-hexane / ethyl acetate 3: 2)

EXAMPLE Synthesis of (Z) -2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoct-7-enyl] phenol Step (Z) -6- (3-pyridyl) hex-5- A solution of enol ml (0.47 mol) of 3-bromopyridine and 52 g (0.53 mol) of 5hexin-1-ol in 150 ml of triethylamine and 500 ml of dichloromethane is degassed with argon for 15 minutes and 3 g (4.3 mmol) of bis (triphenylphosphine) palladium are added. II) chloride and 450 g of copper iodide. The mixture was heated under reflux for 3 hours. The cooled reaction mixture was diluted with 1 L dichloromethane and washed with water and brine, dried (K ₂ CO ₃ ), concentrated and distilled (boiling point 120130 ° C / 0.05 mbar) to give 63 g of 6- (3-pyridyl) hex. -5inol as a yellow oil, which is dissolved in 500 ml of ethyl acetate and, after addition of 15 ml of quinoline, is hydrogenated for 5 hours over 6 g of Lindlar catalyst (Pb-poisoned Pd catalyst) in a Parr hydrogenator. The crude product is distilled (boiling point 120130 ° C / 0.05 mbar) to give 61 g (73%) of (Z) -6- (3-pyridyl) hex-5-enol as a colorless viscous liquid.

(C _u H ₁₅ NO; M.Sv. 177.3)

Rf: 0:21 (SiO ₂ 60 CH ₂ Cl ₂ / MeOH 97: 3) of the process (Z) -2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oksaokt-7enil] phenol according to Example 1, Step 3, using (Z) -6- (3-pyridyl) hex-5-enol as the alcohol component in the etherification reaction. (Z) -2,6-di-tert-butyl-4- [8 (3-pyridyl) -2-oxaoct-7-enyl] phenol yields up to 49%; yellowish viscous oil, slowly crystallizing, m.p. 44 ° C. (C ₂₆ H ₃₉ NO ₂ ; M.Sv. 397.6)

R f: 0.4 (SiO ₂ 60; n-hexane / ethyl acetate 2: 1)

EXAMPLE

Synthesis of 2,6-Di-tert-butyl-4- [9- (3-pyridyl) -2-oxanonyl] phenol

The starting material 7- (3-pyridyl) heptanol was prepared by the Witting method from 6-bromohexanol and nicotine aldehyde analogous to Example 2, Steps 1-4. Step 3 etherification similar to Example 1 gave 2,6-ditret-butyl-4- [9- (3-pyridyl) -2-oxanonyl] phenol (43%) as an amber viscous liquid.

(C ₂₁ H ₄₁ NO ₂ ; M.Sv. 411.6)

R f: 0.48 (SiO ₂ 60; n-hexane / ethyl acetate 3: 2)

EXAMPLE

2,6-Di-tert-butyl-4- [5- (3-pyridyl) -4-oxapentyl] phenol step

3- (3,5-Di-tert-butyl) -4-hydroxyphenyl) propanol

A solution of 57.76 g (0.2 mol; 70% in toluene) of sodium bis (2-methoxyethoxy) aluminum hydride in 100 ml of dry toluene is prepared in a 1 L flask fitted with a mechanical stirrer, a condenser equipped with a nitrogen inlet and a pressure equalizing drip funnel. The mixture was stirred under ice-cooling and kept under nitrogen until slowly over 30 min. of a solution of 29.24 g (0.1 mol) of methyl 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate (Ιοηοχ 520; Shell Chemie GmbH) in 300 ml of dry toluene are added. Stirring is continued after addition for 30 minutes at ambient temperature and then refluxed for 80 minutes. Cool the reaction mixture, which has a viscous glassy precipitate, carefully add 1 1 3M hydrochloric acid. After normal treatment, the oily crude product is distilled at 145-150 ° C (1 Torr) to give

25.7 g (97%) of 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propanol as a colorless solid, m.p. 69-70 ° C by recrystallization from n-hexane.

(C ₁₇ H ₂₈ O ₂ ; M.Sv. 264.4)

R f: 0.49 (SiO ₂ 60; Tol / i-PrOH 9: 1)

3- (3,5-Di-tert-butyl-4-hydroxyphenyl) -1 (tetrahydropyran-2-yloxy) propane.

A solution of 31.06 g (0.117 mol) of 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propanol and 500 mg of pyridine p-toluenesulfonate (PPTS) in 120 ml of dry dichloromethane is cooled and stirred dropwise over a period of 15 minutes. 0.142 mol) of 3,4-dihydro-3H-pyran and left to react at room temperature overnight after further cooling in a cooling bath. The reaction mixture was washed with saturated bicarbonate aqueous solution and brine, dried over Na ₂ SO ₄ and concentrated in vacuo, leaving 40.74 g (practically 100%) of 3- (3,5-di-tert-butyl-4-hydroxy-phenyl) - 1-tetrahydropyran-2-yloxy) propane as a yellow oil which is used without further purification.

(C ₂₂ H ₃₆ O ₃ ; M.S. 348.5)

Rf: 0.57 (SiO ₂ 60; Tol / i-PrOH 9: 1)

3- (4-Acetoxy-3,5-di-tert-butylphenyl) -1 (tetrahydropyran-2-yloxy) propane

A vigorous mixture of 40.74 g (0.117 mol) of 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1- (tetrahydropyran-2-yloxy) propane and 5.85 g (16.7 mmol) of tetrabutylammonium hydrosulphate in 250 ml of dichloromethane and 250 ml 50% aqueous sodium hydroxide is treated at 0 [deg.] C. with the dropwise addition of 14.32 g (0.140 mol) of acetic anhydride dissolved in 100 ml of dichloromethane under a nitrogen atmosphere. When the addition is complete, the mixture reacts for a further 4 hours at ambient temperature. Standard work-up gave 42.69 g (93%) of 3- (4-acetoxy-3,5-ditret-butyl-phenyl) -1- (tetrahydropyran-2-yloxy) -propane as a brown viscous liquid which was used in the next deprotection step without further purification. .

(C ₂₄ H ₃₈ O ₄ ; M.S. 390.6)

Rf: 0.52 (SiO ₂ 60; Tol / i-PrOH 9: 1) step

3- (4-Acetoxy-3,5-di-tert-butylphenyl) -propanol

A solution of 14.6 g (37.38 mmol) of 3- (4-acetoxy-3,5-di-tert-butylphenyl) -1- (tetrahydropyran-2-yloxy) propane in 80 ml of anhydrous methanol is stirred with 1 g of amberlyst 15 (H + -form) ) for two hours at 45 ° C and stored at room temperature overnight. After diluting the suspension with 100 mL of methanol, the catalyst is removed by filtration and the filtrate is evaporated under reduced pressure to leave 11.53 g of crude product which is purified by chromatography on silica gel with H / AcOEt 3: 1 as eluent. 6.96 (61%) of 3- (4-acetoxy-3,5-di-tert-butyl-phenyl) -propanol is isolated from the product-containing fractions as a pale yellow oil which gradually crystallizes on melting, m.p. 93-95 ° C.

(C ₁₉ H ₃₀ O ₃ ; M.S. 306.4)

R f: 0.47 (SiO ₂ 60; Tol / i-PrOH 9: 1)

2,6-Di-tert-butyl-4- [5- (3-pyridyl) -4-oxapentyl] phenol

A solution of 19.74 g (64.62 mmol) of 3- (4-acetoxy-3,5-di-tert-butylphenyl) propanol, 12.69 g (77.3 mmol) of 3-picolyl chloride hydrochloride and 5 g of tetrabutylammonium hydrosulphate in 250 ml of toluene is treated with 250 ml of 50% aqueous sodium hydroxide with vigorous stirring (> 400 rpm) under ice-cooling in an ice bath. Stirring of the dark reaction mixture was continued for another 5 hours at room temperature. After the usual treatment, the crude product (26.2 g) is purified by silica gel flash chromatography with AcOEt / H 2: 1 as eluent to give 16.9 g (66%) of 2,6-di-tert-butyl-4- [5- (3-pyridyl). -4-Oxapentyl] -phenyl acetate as a colorless oil, dissolved in 100 ml of dry tetrahydrofuran and added dropwise at -78 ° C (acetone / dry ice) under inert conditions to a stirred suspension of 1.77 g (46.76 mmol) of lithium aluminum hydride 100 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred overnight in a gradually warmed cooling bath, held for 2 hours at 40 ° C, quenched with vigorous stirring and external freezing with ice water, successively adding 1.77 g of water to 1.77 g of 15% aqueous sodium hydroxide and finally 5.31 g of water. After 1 hour, the resulting suspension was diluted with 200 mL of THF, dried with 20 g of Na ₂ SG-, and the aluminum precipitate was removed by filtration through a frit glass funnel, and the solvent was evaporated under reduced pressure to give 12.9 g of crude 2, 6-di-tert-butyl. 4- [5- (3-Pyridyl) -4-oxapentyl) phenol as a yellow solid, leaving 11.49 g (76% for the deprotection step) of pure product, m.p. 105 ° C after recrystallization from n-hexanoethyl acetate.

(C ₂₃ H ₃₃ O ₂ ; M.Sv. 355.5)

R f: 0.37 (SiO ₂ 60; Tol / i-PrOH 9: 1)

EXAMPLE

2,6-Di-tert-butyl-4- [7- (3-pyridyl) -4-oxaheptyl] phenol step

3- (4-Acetoxy-3,5-di-tert-butylphenyl) -1 (tosyloxy) propane

To 8.41 g (27.44 mmol) of 3- (4-acetoxy-3,5-di-tert-butylphenyl) propanol (see Example 6, Steps 3-4) dissolved in 125 mL of anhydrous pyridine was added 5.49 g (28.8 mmol) of p-toluenesulfonyl. of chloride at 0 ° C. The reaction mixture was stirred for 1.5 hours at this temperature and kept overnight in a refrigerator, which was subjected to conventional extraction. The crude 3- (4-acetoxy-3,5-di-tert-butylphenyl) -1- (tosyloxy) propane is purified by silica gel flash chromatography with n-hexane / AcOEt 4: 1 as eluent to give 8.28 g (66%) of pure tosylate as a colorless viscous liquid.

(C ₂₆ H ₃₆ SO ₅ ; M.S. 460.6)

R f: 0.42 (SiO ₂ 60; Tol / i-PrOH 9: 1) step

2,6-Di-tert-butyl-4- [7- (3-pyridyl) -4-oxaheptyl] phenol

A solution of 3.66 g (26.68 mmol) of 3- (3-pyridyl) propanol in 30 ml of anhydrous THF and 3.5 ml of dry HMPA is added via syringe to a stirred suspension of 2.56 g (60% oily dispersion 53.33 mmol) of NaH in 35 ml of anhydrous THF, At 0 ° C, then reflux for 2 hours. The sodium alcoholate solution was again cooled to 0 ° C and 10.68 g (23.19 mmol) of 3- (4-acetoxy-3,5-ditret-butylphenyl) -1- (tosyloxy) propane dissolved in 35 ml of anhydrous THF was added, followed by reflux for hours and stir at room temperature overnight. After the usual work-up, the crude product (9.88 g; brown oil) is purified by silica gel flash chromatography eluting with n-hexane / ethyl acetate 3: 1 to give 2.88 g (62%) of 2,6-di-tert-butyl4- [ 7- (3-pyridyl) -4-oxaheptyl] phenol as an amber oil.

(C ₂₅ H ₃₇ NO ₂ ; M.Sv. 383.6)

R f: 0.44 (SiO ₂ 60; n-hexane / ethyl acetate 3: 2)

EXAMPLE

Synthesis of 2,6-Di-tert-butyl-4- [9- (3-pyridyl) -4-oxanonyl] phenol

2,6-Di-tert-butyl-4- [9- (3-pyridyl) -4-oxanonyl] phenol

Etherification of 5- (3-pyridyl) pentanol (synthesis: see Example 1, from 4-pentyl-1-ol (ERH Jon et al., Org. Synthesis Coli. 4, 755 (1963)), as described above (See Example 7) gave 2,6-di-tert-butyl-4- [9- (3-pyridyl) -4-oxanonyl] phenol in 57% yield as a viscous viscous oil.

(C ₂₇ H ₄₁ NO ₂ ; M.Sv. 411.6)

R f: 0.52 (SiO ₂ 60; n-hexane / ethyl acetate 3: 2)

EXAMPLE

2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoct-7-yl] phenol

According to Steps 2 (without hydrogenation) and 3 of Example 1, 2,6-di-tert-butyl-4- [8- (3-pyridyl) -2-oxooct is obtained.

7-inyl] phenol as a yellow viscous oil in 62% yield in the final step (C ₂₆ H ₃₅ NO ₂ ; M.S.v. 393.6) Rf: 0.48 (SiO ₂ 60; n-hexane / ethyl acetate 2: 1).

As acids suitable for the formation of salts by addition of an acid according to the usual procedure, the following may be mentioned from the mineral series: hydrochloric, hydrobromic, methanesulfonic, isothionic, sulfuric, phosphoric, sulfamic acids, and from the organic series: acetic, propionic, maleic, fumaric, tartaric, citric, oxalic, benzoic acids, to name a few. The acids to be preferred are hydrochloric, citric and maleic acids. Other pharmaceutically acceptable acid addition salts may be prepared as needed and the acid salt may be converted to another by neutralization of one salt, such as hydrochloride, and re-acidification with a different selected mineral or organic acid to yield another pharmaceutically acceptable acid salt. , as explained above and as adopted in the art.

PHARMACEUTICAL COMPOSITIONS

The compounds of the present invention may be formulated into pharmaceutical compositions containing, in addition to the active compound of the present invention, a pharmaceutically acceptable carrier or diluent. Such compositions may be administered to a live animal, particularly a human, orally or parenterally. For example, solid preparations or pharmaceutical compositions for oral administration may be in the form of capsules, tablets, powders or granules. In such solid pharmaceutical formulations, the active ingredient or prodrug is mixed with at least one pharmaceutically acceptable diluent or carrier, such as cane sugar, lactose, starch, talc or synthetic or natural gums such as gelatin, ointment such as sodium stearate and / or disintegrant. , such as sodium bicarbonate. For a sustained release effect, a substance such as a hydrocolloid or other polymer may be incorporated into a pharmaceutical composition. Additional materials such as grease or bumpers may be added as is commonly accepted in the art. The tablets, pills or granules may be coated as needed. Liquids for oral administration may be liposomes, emulsions, solutions or suspensions containing commonly used diluents such as water. In addition, such liquid pharmaceutical compositions may contain wetting, emulsifying, dispersing or general surfactants as well as sweetening, perfuming or aromatic substances.

Suitable formulations for parenteral administration include, but are not limited to, sterile aqueous or nonaqueous solutions, suspensions, liposomes, or emulsions. Auxiliaries, many of which are already known for such a pharmaceutical formulation, may be used as a pharmaceutically acceptable diluent or carrier.

Depending on the intended mode of administration and the duration of treatment, the exact dosage of the active compound in the formulations of the present invention may vary, in particular as it may seem appropriate to the attending physician or veterinarian. The active agents of the present invention may obviously be mixed for administration with other pharmaceutically active agents.

The proportions of the active agent or agents in the compositions of the present invention may vary widely in the composition, it is only necessary that the active ingredient or prodrug of the invention release or provide an effective amount, i. y. such that a suitable effective dosage will be obtained in constant dosage with the dosage form employed. It will be appreciated that multiple dosage forms, as well as several individual active compounds, may be administered at the same time or even in the same pharmaceutical composition or formulation.

As noted above, the compounds of the present invention are suitable, in particular in the form of pharmaceutical compositions or pharmaceutical preparations thereof for oral or parenteral administration, for accurate individual dosing as well as daily dosing according to well-known medical and / or veterinary principles, as directed by your doctor or veterinarian.

In addition to oral administration and parenteral administration, rectal and / or intravenous administration may be used, with dosage generally being reduced when parenteral administration is used, although oral administration is preferred. A quantity of about 1-3 grams per day in the form of a repeated dosage is suitable. Wider ranges of about 0.5 to 10 g / day may also be applied, depending on the circumstances of the individual case. Although it has been found that 500 mg of the active compound is particularly suitable for tablet use, individual dosage ranges may range from 200 to 500 mg, and 500 mg offered as tablets may, of course, be administered orally, e.g., 1 to 3. times a day. Without saying it is clear that more than one tablet can be given in a single dose when one should receive the previously suggested daily oral intakes of 1 to 3 grams per day.

As stated above, a compound of the present invention or a prodrug thereof may be administered to a live animal, including a human, by one of a variety of routes, e.g., oral capsules and tablets, parenterally in sterile liquid or suspension, or subcutaneous implantation and in some cases intravenously sterile. in the form of solutions. Other clear routes of administration are via the skin, subcutaneous, transbuccal, intramuscular, intraperitoneal, and the particular route of administration will, as usual, be prescribed by the attending physician or veterinarian.

Thus, the present invention provides novel anti-lipidemic and anti-atherosclerotic BHT omega-10 pyridyl ether compounds and pharmaceutical compositions thereof for combating hyperlipidemia and concomitant atherosclerosis, thereby collectively providing a long-awaited solution to the problem of the prior art.

It should be understood that the specific compounds, the present invention, the compositions, the disclosed procedures, as not limited to the methods, or numerous modifications and modifications thereof, will be readily apparent to one skilled in the art to which the present invention relates. be legally consistent with the attached claim.

Claims (10)

DEFINITION OF INVENTION A compound selected from butylated hydroxytoluene (BHT) omega-pyridyl ether compounds of the formula wherein m = 1.3; when m = Ι, Σ = 6-9 when m = 3, E = 5-ll The sum (Σ) = [m + n + 1 (oxygen)], wherein the bond between the two carbon atoms of (CH ₂ ) _n closest to the pyridine ring is a single, double or triple bond, and its pharmaceutically acceptable acid addition salts. 2. A compound according to claim 1, which is selected from the group consisting of: 2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoctyl] phenol (Mrz 3/161), I 2,6-Di-tert-butyl-4- [6- (3-pyridyl) -2-oxahexyl] phenol (Mrz 3/187), 2,6-Di-tert-butyl-4- [7- (3-pyridyl) -2-oxaheptyl] phenol (Mrz 3/192), (Z) -2,6-Di-tert-butyl-4- [ 8- (3-pyridyl) -2-oxaoct-7-enyl] phenol (Mrz 3/181), 2,6-Di-tert-butyl-4- [9- (3-pyridyl) -2-oxanonyl] phenol (Mrz 3/188), 2,6-Di-tert-butyl-4- [5- (3-pyridyl) -4-oxapentyl] phenol (Mrz 3/124), 2,6-Di-tert-butyl-4- [7- (3-pyridyl) -4-oxaheptyl] phenol (Mrz 3/190), 2. 6-Di-tert-butyl-4- [9- (3-pyridyl) -4-oxanonyl] phenol (Mrz 3/191), and 2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoct-7-vinyl] phenol (Mrz 3/179). 3. A compound according to claim 1 which is 2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoctyl] phenol. 4. A compound according to claim 1 which is 2,6-Di-tert-butyl-4- [5- (3-pyridyl) -4-oxapentyl] phenol. An anti-lipidemic and anti-sclerotic pharmaceutical composition comprising an active component and a pharmaceutically acceptable carrier or binder, wherein the active component is an effective anti-lipidemic and anti-sclerotic amount of a compound selected from BHT omega-pyridyl ether compounds of the formula -3-Pvr where m = 1.3; for m = l, Z = 6- 9 for m = 3, Σ = 5 - 11 The sum (Σ) = [m + n + 1 (for oxygen)], wherein the bond between the two carbon atoms of (CH ₂ ) _n closest to the pyridine ring is a single, double or triple bond and its pharmaceutically acceptable acid addition salts. 6. A pharmaceutical composition according to claim 5, wherein the active ingredient is selected from the group consisting of: 2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoctyl] phenol (Mrz 3/161), I 2,6-Di-tert-butyl-4- [6- (3-pyridyl) -2-oxahexyl] phenol (Mrz 3/187), 2,6-Di-tert-butyl-4- [7- (3-pyridyl) -2-oxaheptyl] phenol (Mrz 3/192), (Z) -2,6-Di-tert-butyl-4- [ 8- (3-pyridyl) -2-oxaoct-7-ynyl] phenol (Mrz 3/181), 2,6-Di-tert-butyl-4- [9- (3-pyridyl) -2-oxanonyl] phenol (Mrz 3/188), 2,6-Di-tert-butyl-4- [5- (3-pyridyl) -4-oxapentyl] phenol (Mrz 3/124), 2,6-Di-tert-butyl-4- [7- (3-pyridyl) -4-oxaheptyl] phenol (Mr 3/190), 2,6-Di-tert-butyl-4- [9- (3-pyridyl) -4-oxanonyl] phenol (Mrz 3/191), and 2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoct-7-vinyl] phenol (Mrz 3/179). 7. The pharmaceutical composition of claim 5, wherein the active component is 2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoctyl] phenol. 8. The pharmaceutical composition of claim 5, wherein the active ingredient is 2,6-Di-tert-butyl-4- [5- (3-pyridyl) -4-oxapentyl] phenol. 9. A process for the preparation of a pharmaceutical composition for combating lipidemia and atherosclerosis in live animals, comprising mixing an effective antilipidemic and antisclerotic amount of a compound selected from BHT omega-pyridyl ether compounds of the formula wherein m = 1.3; when m = l, E = 6- 9 when m = 3, E = 5-ll The sum (Σ) = [m + n + 1 (for oxygen)] where the bond between the two carbon atoms of (CH ₂ ) _n closest to the pyridine ring is a single, double or triple bond and its acceptable acid addition salts, carriers or binders to form a pharmaceutical composition. pharmaceutically pharmaceutically and thereafter i 10. A process for preparing a pharmaceutical composition according to claim 9, wherein the compound is selected from the group consisting of: 2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoctyl] phenol (Mrz 3/161), 2,6-Di-tert-butyl-4- [6- (3-pyridyl) -oxahexyl] phenol (Mrz 3/187), 2,6-Di-tert-butyl-4- [7- (3-pyridyl) -2-oxaheptyl] phenol (Mrz 3/192), (Z) -2,6-Di-tert-butyl-4- [ 8- (3-pyridyl) -2-oxaoct-7-enyl] phenol (Mrz 3/181), 2,6-Di-tert-butyl-4- (9- (3-pyridyl) -2-oxanonyl] phenol (Mrz 3/188), 2,6-Di-tert-butyl-4- [5- (3-pyridyl) -4-oxapentyl] phenol (Mrz 3/124), 2,6-Di-tert-butyl-4- [7- (3-pyridyl) -4-oxaheptyl] phenol (Mr 3/190), 2,6-Di-tert-butyl-4- [9- (3-pyridyl) -4-oxanonyl] phenol (Mrz 3/191), 2,6-Di-tert-butyl-4- [8- (3-pyridyl) -2-oxaoct-7-vinyl] phenol (Mrz 3/179), especially 2,6-Di-tert-butyl-4- (8 - (3-pyridyl) -2-oxaoctyl] phenol, or 2,6-Di-tert-butyl-4- (5- (3-pyridyl) -4-oxapentyl] phenol.