LV10423B - New bht ether compounds and their use as hypolipidemic and antiatherosclerotic drugs - Google Patents

Abstract

The pharmaceutically active BHT-ω pyridine ethers with formula<IMAGE>where -3-Pyr is<IMAGE>m - 1, 3;if m - 1, sum = 6-9;if m - 3, sum = 5-11;in total (sum) = [m+n+1(for oxygen)], where bonding between 2 carbon atoms in the (CH2)n part right next to the pyridine ring is single, double or triple; pharmaceutically compatible with them salts with incorporated acids; pharmaceutical compositions containing them; and treatment method for lipidemia and atherosclerosis.

Description

5 10 15 20 25

New BHT Ether Compounds and their Use as Hypolipidemic and Antiatherosclerotic Drugs LV10423 FIELD OF THE INVENTION Hypolipidemic and antiatherosclerotic compounds, pharmaceutical compositions thereof, and use thereof. BACKGROUND OF INVENTION AND PRIOR ART Since the beginning of medical history, athero-sclerosis has been described as an important disease. However, only in the twentieth century was it discovered that myocardial infarction is always associated with coronary atherosclerosis and thrombosis. Epidemiologic studies carried out in the seventies have shown that about fifty percent of ali mortalities in the Western industrial-ized countries are caused by cardiovascular disease. The most important factors in the development of atherosclerosis are known. The importance of elevated cholesterol and triglyceride concentrations was discovered early. Cholesterol and triglycerides are transported in the form of so-called lipoproteins, the cholesterol-rich low-density (LDL) &quot;and triglyceride-rich very low-density (VLDL) fractions of which are considered as atherogenic if their concentrations in the blood are increased. However, only recently was it discovered that in addition to their amount, the &quot;quality&quot; of LDL is also decisive. Thus, in animal experiments it could be shown that equally high concentrations of LDL cholesterol were more or less atherogenic depending upon the properties of , the drug applied to reduce the elevated LDL. cholesterol Ievel. The cause of this finding could also be shown by the authors, namely, a drug which was also able to reduce LDL oxidation was most effective in counteracting atherosclero- - 1 - v . % 30 sis. (Carew et al., Proc. Nat. Acad. Sci. USA 84, 7725-7729 (November 1987.)) This experiment impressively demonstrates the importance of LDL &quot;quality&quot;. In the body, LDL and VLDL are subject to continual oxidation which is physiologically balanced by natūrai so-called antioxidants such as toco-pherol or ascorbic acid. However, in the case of increased LDL (cholesterol) and VLDL (triglyceride) values, this homeostasis is disturbed and shifted in favor of an in-creasing tendency towards oxidation.

Therefore, the risk of development and manifestation of atherosclerosis is increased by two factors: - elevated concentration of so-called atherogenic lipoproteins (LDL, VLDL) and - their content of oxidation products (e.g., oxidized lipids).

Causal treatment must, therefore, influence both factors.

Apart from the humoral factors, namely the lipoproteins, the cellular constituents of the vascular wall play an important role in atherogenesis. Thus, in the case of mechanical or Chemical damage of the internai vascular coating, the endothelium, a proliferation impulse is generated to stimulate the underlying layer of smooth muscle celis. This process is particularly impressive after endothelial damage as a result of angioplasty. Within a relatively short time the induced proliferate can block the vessel to such an extent that an infarction may occur. In addition to mechanical endothelial damage, noxae such as oxidized LDL play also an important part.

Therefore, in addition to the two possibilities mentioned above, effective atherosclerosis intervention must be aimed at protecting the endothelium and reducing excessive proliferation of smooth muscle celis.

I W 4Α«Ι»&lt;Ι LV IVHM

Compounds fulfilling ali the above-mentioned require-ments should comprise two pharmacologically differently-acting moieties, at least: 5 - nicotinic acid or a suitable derivative thereof as the lipid-lowering principle. - an antioxidant as the antiatherosclerosis principle.

Nicotinic acid is the drug of choice as it acts not only on lipids but has been shovrn to have antiatheroscler-olic properties of its own. 10 15

Yet, for medication purposes, one must circumvent the known side effects of nicotinic acid, e.g., flush due to a too rapid increase of nicotinic acid concentration in the blood. In fact, it has been found that rapid increases and high Ievels of nicotinic acid are not necessary to achieve the lipid-lowering effect. Thus, low nicotinic acid concen-trations and sufficient reduction of lipids should be the main prerequisites of valuable compounds of the afore-mentioned type. 20 DE 2716125 discloses, as a.preferred compound, a BHT (butylated hydroxy toluene) ether derivative (herein named Mrz 3/156) of the formula: 25

3 30

When tested for the required properties, excessively high Ievels of nicotinic acid (cf. Table 1) were observed, thereby demonstrating that this compound does not fulfill the stated requirements.

Extensive and painstaking synthetic and pharmacologi-cal efforts have revealed that there are several structural prerequisites necessary to meet ali the criteria.

It was concluded that only compounds of the below-mentioned general formula are of interest.

It could be shovrn that the compounds according to the invention are - effective in reducing lipids without induction of excessively high Ievels of nicotinic acid; - effective in counteracting lipid and lipoprotein oxidation; - effective in reducing endothelial damage due to oxidized LDL; and - effective in reducing the proliferation of smooth muscle celis in the vascular wall.

OBJECTS OF THE INVENTION

It is an object of the invention to provide new and more effective hypolipidemic and antiatherosclerotic compounds, pharmaceutical compositions thereof, and method of treating hyperlipidemia and atherosclerdsis therewith. It is a further object of the invention to provide such novel compounds, compositions, and method which fulfill the foregoing theoretical requirements. Additional :objects will become apparent hereinafter, and stili other objects of the invention will be apparent to one skilled in the art. 4

I II ' L. V 1C423

SUMMARY OF THE INVENTION

The invention, then, comprises the following aspects, inter alia. singly or in combination: 5 a compound selected from those BHT-omega-pyridyl ether compounds of the formula: 10 cv,

CH.V., ! wherein 3 ch3 h

15 wherein m = 1,3 for m = 1, Σ = 6 - 9 20 for m = 3, Σ = 5 - 11 Sum (Σ) = [m+n+1 (for oxygen)] wherein the bond between the two carbon atoms of the (CH2)n moiety most closely adjacent the pyridine ring is a single, double, or triple bond, pharmaceutically-acceptable acid 25 addition salts thereof, pharmaceutical compositions useful for combating hyperlipidemia and atherosclerosis comprising such a compound together with a pharmaceUtically-acceptable carrier or diluent, and a method of combating hyperlipi-demia and atherosclerosis comprising the step of adminis-30 tering to a li*ing animal, including a human being, in need thereof, an effective antihyperlipidemic and antiathero-sclerotic amount of such a compound. 5 5

GENERAL DESCRIPTION OF THE INVENTION

The present invention relates to ethers of a BHT-deri-vative (a butylated hydroxy toluene derivative) and an omega-pyridylalkyl-, -alkenyl-, or -alkinyl-alcohol as active hypolipidemic and antiatherosclerotic compound. More particularly, it relates to such an ether compound of the formula: 10

15

-3-Pyr = 20 wherein: m = 1, 3 25 for m = 1, Σ = 6 - 9 for m = 3, Σ = 5 - 11 Σ = [m+n+1 (for oxygen)] wherein (CH2)n may optionally include a double bond or a triple bond conj ugated to the 3-position of the pyridine ring, that is, the bond between the two carbon atoms of the (CH2)n moiety most closely adjacent the'pyridine ring may be a single, double, or triple bond, and a pharmaceutically-acceptable acid addition salt thereof, as well as a pharma-ceutical composition containing a compound of the invention as active ingredient, both of which are useful as antilipi-demic and antiatherosclerotic aģents, and a method of combating hyperlipidemia and atherosclerosis therewith. 6 30 LV10423

PHARMACOLOGY a) Kinetics of nicotinic acid 5

The kinetics of nicotinic acid released from the compounds under investigation was studied in the rat. A single dose (0.2 mmol/kg) of the tēst substance was administered to fasting normolipidemic rats by gavage. 240 and 360 minūtes thereafter, blood samples were taken and the concentration of nicotinic acid in serum was determined using a GC/MS method (n = 5 rats per time). 10

The data are given in table 1. 15 20 25

Table 1: Concentration of nicotinic acid (mg/1) in pooled serum samples after a single application of drug · Nicotinic acid Tēst compound Time Time 240' 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 30 b) Evidence of lipid-lowering properties.

The lipid-lowering properties of the compounds accord-ing to the invention were investigated in a rat modei. In this modei a single dose (0.2 mMol/kg) of the tēst substance was administered to fasting normolipidemic rats by the oral route. 240 and 360 minūtes after application, blood samples were taken, the concentrations of triglycer-ides being assessed by a Standard method (namely GPO-PAP method, E. Merck-system, Darnlstadt, Germany) (n = 5 rats per measurement time).

In Table 2 the mean changes are given in percent as compared to a solvent (cremophor, 30% in aqua dest) con-trol.

Table 2: Mean changes (Δ mean reduction) in percent of triglyceride concentrations 240 and 360 minūtes after a single application versus vehicle-treated control.

Trialvcerides Tēst Compound Time Time 240' 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 28 3/191 37 32 3/181 57 57 Control 0 0 8 LV10423 c) Evidence of antioxidant properties.

The antioxidant properties of the compounds according to the invention were studied in iņ-vitro tests. In these tests the substance was incubated with the substrate to be oxidized (synthe.tic triglyceride with unsaturated fatty acids, i.e., trilinolenine or human LDL). After the incuba-tion period, the degree of oxidation was determined using the so called thiobarbituric acid (TBA) assay. TBA reacts with raalondialdehyde (MDA), which is one of the essential oxidation products. The reaction product was assayed photometrically. cl). Trilinolenine assay 400 μΐ of trilinolenine was incubated for 3 h at 37°C with 2 ml HAM F 10 medium with vehicle (namely, ethanol, 0.5% final concentration) or tēst substance (concentration: 5 x 10'5 M) (oxidation is effected without special cata-lysts).

The total TBA-reactive material was determined in 1 ml of the incubate by adding 1.5 ml of 0.67% TBA solution to 0.05 N NāOH and 1.5 ml to a 20% trichloroacetic acid solution. The mixture was reacted for 60 min. on a boiling water bath. After cooling, absorption was determined at 532 nm.

Three preparations were tested per tēst compound. 9 c2) LDL assay LDL (d = 1.019 - 1.063) was obtained from human plasma by ultracentifugation under addition of EDTA. 100 μς of LDL was incubated with 0.5 ml of HAM F 10 5 medium for 24 h at 37°C with vehicle (namely ethanol, 0.5% final concentration) or tēst substance (concentration: 5 x 10-5 M) in the presence of 10 μΜ of Cu2\

The total TBA-reactive material was determined in accordance with the trilinolenine assay. 10 Three preparations were tested per tēst compound.

Tables 3a (trilinolenine assay) and 3b (LDL assay) represent the mean changes in percent as compared to solvent control.

Table 3; Mean change (Δ mean reduction) in percent of the 15 concentration of TBA-reactive material after 3-h (a: trilinolenine assay) and 24-h (b: LDL assay) incubation versus vehicle-treated control preparation. al · bl

20 Tēst Compound Trilinolenine LDL assay % assay % 3/161 58 79 3/187 71 82 25 3/192 74 86 3/179 79 73 3/188 66 71 3/124 76 90 3/190 72 89 30 3/191 76 86 3/181 76 , 76 Control 0 0 10 LV10423 d. Evidence of endothelial protection against cytotoxic effects of oxidized LDL.

Human endothelial celis of the umbilical vein were isolated after collagenase vascular treatment and cultured. 5 For the assay the celis were dispersed in a density of 50,000 per dish and cultivated for 4 days with Ham's F 12/DMEM medium (ratio: 4:1) under addition of 15% fetal calf serum, 5% horse serum and 10 ng/ml ECGF heparin.

After 4 days the celis were washed with serum-* free 10 medium and used in the cytotox assay.

For this assay the celis were incubated for 24 h at 37°C in 1 ml of Ham's F 10 medium (+ ECGF heparin) with LDL (200 μς/ταί). During this time period either the vehicle, namely, ethanol, 0.5% final concentration (control prepara-15 tion 1) or the tēst substance (2 x 10‘5M) was present. In parallel, one preparation was incubated without LDL and v/ithout any other substance and with vehicle (0.5% ethanol) to assess the maximum proliferation rāte (control preparation 2). 20 After 24 h the resultant TBA-reactive material was determined in the medium or the number of celis counted.

Three preparations were tested per tēst compound.

Table 4a represents the mean changes in percent versus appropriate control preparation 1. 25 Table 4b shows the number of celis in percent as compared to appropriate control preparation 2.

Table 4a: Mean change (Δ mean reduction) in percent of the concentration of TBA-reactive material after incubation of 30 endothelial celis for 24 h with LDL versus appropriate control preparation 1. 11 5

Table 4b: Mean number of celis in percent after 24-h incubation with LDL as compared to appropriate control preparation 2. al bl Tēst TBA-reactive material Number of endothelial celis % % 10 15 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 &lt;3-oo 20 e. Evidence of the antiproliferative effect on smooth muscle celis in vitro 25

Smooth muscle celis, obtained after isolation from the aorta of balloon-catheterized rats, were cultivated i'n DMEM under addition of 10% of fetal calf serum and subject to passages.

For the assay 10,000 celis of one passage were inocu-lated per dish and incubated for 3 days with vehicle (namely DMSO, 0.5% final concentration) or tēst compound (5 x 10'5 M) 4 h after innoculation. After 3 days a celi count was made. Six preparations were tested per tēst compound. \

Table 5 shows the mean changes in percent versus solvent control. 12 30 !_V 10423

Table 5: Mean change (A mean reduction) in percent of the number of smooth vascular muscle celis after incubation with tēst substance for 3 days as compared to vehicle-treated control preparation. 5 10 15 Tēst compound 3/161 3/187 3/192 3/179 3/188 3/124 3/190 3/191 3/181

Number of celis _%_ 98 93 95 55 63 7i 91 79 81 20 SYNTHESIS OF THE COMPOUNDS OF THE INVENTION The preparation of the compounds of the invention is carried out starting from an omega-pyridylalkyl-/ alkenyl-, or alkynyl-alcohol, which is reacted with 3,5-ditert.-butyl-4-hydroxy-benzyl alcohol in the form of its acetate: 25 30

I. 13 wherein further details and meanings are as previously defined. P(Ph)a + aKCHzL,-™5

The co-pyridyl-alkyl-alcohol is prepared by' a Wittig-reaction starting from pyridyl-3-aldehyde and a phosphonium salt, synthesized from the corresponding halo-alkylalcohol. The resulting unsaturated G)-pyridyl-alkyl-alcohol is directly - or after hydrogenation - converted into a claimed ether. H C = 0

KPhV^HCH^-OTVP

• Cf

Alternatively, the starting ω-pyridyl-alkyl-alcohol can be prepared by reacting 3-bromopyridine and the corresponding omega-alkynyl alcohol. The resulting (o-pyridyl-alkynyl-alcohol is converted directly - or after hydrogen-ation to an o)-pyridyl-alkenyl- or (ū-pyridyl-alkyl-alcohol-into a claimed compound of Formula I„

Br *

+ HC = C -(CH^-O-THP

C = C—(CHj^-OH

14

bV ' «10423

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

The compounds of Formula I include specifically the following compounds: 5 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) 10 3. 2,6-Di-tert-butyl-4-[7-(3-pyridyl)-2-oxaheptyl]phenol (Mrz 3/192) 4. (Z)-2,6-Di- ter t -bu tyl - 4 - [ 8 - (3 -pyridy 1) - 2 -oxaoct- 7 -eny 1 ] -phenol (Mrz 3/181) 5. 2,6-Di-tert-butyl-4-[9-(3-pyridyl)-2-oxanonyl]phenol 15 (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 (Mrz 3/190) 20 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 2,6-Di-tert-butyl-4-[8-(3-pyridyl)-2-oxaoctyl]phenol and 2,6-Di-tert-butyl-4-[5-(3-25 pyridyl)-4-oxapentyl]phenol are preferred. 15

The following Examples are given to illustrate the preparation of the compounds of the present invention, but are not to be construed as limiting. EXAMPLE 1

Synthesis of 2,6-Di-tert-butyl-4- [8-(3-pyridyl) -2-oxa-octy 1]phenol STEP 1 3,5-Di-tert-butyl-4-hydroxybenzylacetate 102.1 g (1 mol) of acetic anhydride is slowly added to a stirred solution of 118 g (0.5 mol) of 3,5-di-tert-butyl-4-hydroxybenzylalcohol in 90 ml pyridine at 0°C. After 15 minūtes, the cooling-bath is removed and the solution reacted an additional two hours at ambient temperature. Then, the reaction mixture is poured under vigorous stir-ring into ice-water. After 15 minūtes the precipitated product is collected by filtration, washed with water, dried and recrystallized from hexanes, yielding 110 g (80%) of 3,5-di-tert-butyl-4-hydroxybenzylacetate as a yellowish cystalline solid, m.p. 108°C. (C17 H2603; Formula Weight (F.W.) 278.2)

Rf: 0.5,7 (Si02 60; n-hexane/diethyl ether 3:1) STEP 2 6-(3-Pyridyl)hexanol A solution of 45 ml (0.47 mol) of 3-bromopyridine and 52 g (0.53 mol) of 5-hexyn-l-ol in 150 ml of triethylamine and 500 ml of dichloromethane is degassed for 15 = minūtes with argon, and 3 g (4.3 mmol) of bis(triphenylphosphine)-palladium(II)chloride and 450 mg of cuprous iodide is added. The mixture is heated at reflux for 3 h. The cooled reaction mixture is diluted with 1 liter of dichloromethane and is washed with water and brine, dried (K2C03), concentrated and bulb-to-bulb distilled (b.p. 120- 16

UV 130°C/0.05 mbar), to give 63 g of 6-(3-pyridyl)hex-5-ynol as a yellow oil, which is dissolved in 300 ml of isopropanol and hydrogenated for 16 h over 6 g 10% palladium on carbon in a Parr-hydrogenator. The crude product is evaporatively 5 distilled (b.p. 120-130°C/0.05 mbar), yielding 61.8 g (65%) of 6-(3-pyridyl)hexanol as a faintly yellow, viscous liquid. (CuH17N0; F.W. 179.3) STEP 3 10 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-buty-l-4-hydroxybenzylacetate, 895 mg (5 mmol) of 6-(3-pyridy-l)hexanol and 30 mg of tetrakis(triphenylphosphine) palladium(O) in 60 ml of degassed, dry acetonitrile is 15 stirred at room-temperature under a nitrogen-atmosphere for 5 days. The solvent is evaporated, the residue partitioned between ether and saturated aqueous bicarbonate, and the dried extract separated by column-chromatography on silica gel after concentration. The yield of 2,6-di-tert-butyl-20 4-[8-(3-pyridyl )-2-oxaoctyl]phenol amounts to 59% yellowish viscous oil, slowly crystallizing, m.p. 63°C. (C26h39N02; F.W. 397.6)

Rf: 0.6 (Si02 60; n-hexane/ethyl acetate 3:1) 17 EXAMPLE 2

Synthesis of 2,6-Di-tert-butyl-4-[6-(3-pyridyl)-2-oxa-hexyl]phenol 5 STEP 1 2,(3-Bromopropyloxy) tetrahydropyran

To a solution of 35 g (0.251 mol) of 3-bromopropanol and 1^ g of p-toluenesulphonic acid in 500 ml of diethylether, 32.5 ml (0.357 mol) of 3,4-dihydro-2H-pyran 10 is added dropwise under cooling with ice water and the solution is stirred for 2 hours at room temperature. The mixture is neutralized with saturated aqueous bicarbonate. washed with brine and conceņtrated after drying, affording 56 g of 2-(3-bromopropyloxy)tetrahydropyran in practically 15 quantitative yield as a viscous liquid, which may be used without further purification. (C8H15Br02; F.W. 223.1)

Rf: 0.9 (Si02 60; n-hexane/ethyl acetate 1:1) STEP 2 20 3-(Tetrahydropyranyloxy )propyl-triphenylphosphoniunbromide 66.5 g (0.298 mol) of 2-(3-bromopropyloxy)tetrahydrop-yran is refluxed together with 82 g (0.312 mol) of triphe-nylphosphine and 1 g of tetrabutylammonium iodide in 500 ml of acetonitrile for 24 hours. After evaporation of the 25 solvent, the residue is triturated several times with boiling diethylether. 144 g (100%) of 3-(tetrahydropyra-nyloxy)propyl-triphenylphosphonium br'omide is obtained as heavy oil, (C26H30BrN02P; F.W. 485.4) v - 18 - LV10423 STEP 3 2-[4-(3-Pyridyl)but-3-enoxy]tetrahydropyran

To a solution of 33.6 ml (0.24 mol) of diisopr'opylam-ine in 300 ml of dry tetrahydrofuran, 149 ml (0.244 mol; 5 15% solution in hexanes) of butyllithium is added dropwise under an atmosphere of nitrogen at 78°C. After stirring for an additional 15 minūtes, 115 g (0.237 mol) of 3-(tetra-hydropyranyloxy)propyl-triphenylphosphonium bromide, dissolved in 400 ml of dry tetrahydrofuran, is added slowly 10 to the mixture, followed after 30 minūtes by a solution of 19 ml (0.199 mol) of freshly-distilled pyridine-3-aldehyde. The reaction mixture is then stirred for 3 hours at -78°C followed by reaction at ambient temperature for an additional 16 hours. After usual work-up, 87 g (79%) of 2-[4— 15 (3-pyridyl)but-3-enoxy]tetrahydropyran is isolated as viscous liquid by chromatographic separation of the crude product mixture. (C14H19N02; F.W. 233.3)

Rf; 0.2 (Si02 60; n-hexane/diethyl ether 1:1) 20 STEP 4 4-(3-Pyridyl)butanol 10 g (43 mmol) of 2-[4-(3-pyridyl)but-3-enoxy]tetrah-ydropyran in 200 ml of methanol/water 1:1 (v/v) is acidif-ied by 2N hydrochloric acid and hydrogenated for 16 hours 25 over 2 g 10% palladium on carbon. After filtration, the solvent is removed, the remaining residue is neutralized by saturated aqueous bicarbonate, and the product is extraced with several portions* of ether. Purification of the crude product by column chromatography on silica gel yields 15.7 30 g (87%) of 4-(3-pyridyl)butanol as colourless viscous oil. (C9H13NO; F.W. 151.2)

Rf: 0.2 (Si0260; n-hexane/ethyl acetate 1:1) 19 STEP 5 2, 6-Di-tert-buty1-4-[6-(3-pyridy1)-2-oxahexy1]phenol according to EXAMPLE 1 STEP 3 2, 6-di-tert-butyl-4-[6-(3-pyridyl)-2-oxahexyl)phenol 5 is obtained as an amber oil in 62% yield for the final etherification step. (C24H35N02; F.W. 369.6)

Rf: 0.42 (Si02 60; n-hexane/ethyl acetate 3:2) EXAMPLE 3 10 Synthesisof 2,6-Di-tert-butyl-4-[7-(3-pyridyl)-2-oxa- heptyl]phenol according to EXAMPLE 1, STEP 2 (starting from 4-pentyn-l-ol; E.R.H. Jones et al., Org. Synthesis Coll. Vol. 4, 755 (1963)) to STEP 3, 2,6-di-tert-butyl-4-[7-(3-pyridyl)-2-oxaheptyl)phenol is obtained as a heavy yellow 15 syrup in 59% yield in the final etherification step. (C25H37N02; F.W. 383.6)

Rf: 0.49 (Si02 60; n-hexane/ethyl acetate 3:2) EXAMPLE 4 20 Synthesis of (Z )-2, 6-Di-tert-butly-4-[8-*(3-pyridyl)-2-oxa“ oct-7-eny1]phenol STEP 1 (Z)-6-(3-Pyridyl)hex-5-enol 25 A solution of 45 ml (0.47 mol) of 3-bromopyridine and 52'g (0.53 mol) of 5-hexyn-l-ol in 150 ml of triethylamine and 500 ml of · dichloromethane is degāssed for 15 minūtes with argon, and 3. g (4,3 mmol) of bis(triphenylphosph-ine)palladium(II)chloride and 450 mg of cuprous iodide is 30 added. The mixture is heated at reflux for 3 h. The cooled reaction mixture is diluted with 1 liter of dichloromethane and is washed with water and brine, dried (K2C03), concentr-ated and bulb-to-buLb distilled (b.p. 120-130°C/0.05 mbar), 20 5 10 15 20 25 LV10423 to give 63 g of 6-(3-pyridyl)hex-5-ynol 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 h over 6 g Lindlar catalyst (Pb-poisoned Pd catalyst) in a Parrhy-drogenator. The crude product is evaporatively distilled (b.p. 120-130°C/0.05 mbar), yielding 61 g (73%) of (Z)-6-(3-pyridyl)hex-5-enol as a colourless viscous liquid. (0ηΉι5Ν0; F.W. 177.3) Rf: 0.21 (Si02 60; CH2Cl2/MeOH 97:3) STEP 2 ( Z)-2,6-Di-tert-butyl-4-[8-(3-pyridyl)-2-oxaoct-7-eny-l]phenol according to EXAMPLE 1 STEP 3, uging (Z)-6-(3-pyr-idyl)hex-5-enol as the alcohol component in the etherific-atiort reaction. The yield of (Z)-2,6-di-tert-butyl-4-[8-(3-pyridyl)-2-oxaoct-7-enyl]phenol amounts to 49%; yellow-ish viscous oil, slowly crystallizing, m.p. 44°C. (C26H39N02; F.W. 397.6) Rf: 0.4 (Si02 60; n-hexane/ethyl acetate 2:1) EXAMPLE 5 Synthesis of 2,6-Di-tert-butyl-4-[9-(3-pyridyl)-2-oxanon-yl]phenol The starting material 7-(3.pyridyl)heptanol was prepared via a Wittig-route from 6-bromohexanol and nico-tine aldehyde, analogous to EXAMPLE 2, STEP 1 to STEP 4. Etherification like in EXAMPLE 1, STEP-3 afforded 2,6-di-tert-butyl-4-[9-(3-pyridyl)-2-oxanonyl]phenol (43%); amber coloured viscous liquid. (C27H41N02; F.W. 411.6) Rf: 0.48 (Si02 60; n-hexane/ethyl acetate 3:2) 21 30 EXAMPLE 6

Synthesis of 2,6-Di-tert-butyl-4-[5-(3-pyridyl)-4-oxa-penty1]phenol STEP 1 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propanol A solution of 57.76 g (0.2 mol; 70% soln. in toluene) of sodium bis(2-methoxyethoxy)aluminium hydride in 100 ml of dry toluene is prepared in a 1 liter three-necked flask fitted with a mechanical stirrer, a condenser equipped with a nitrogen inlet, and a 500-ml. pressure-equalizing drop-ping funnel. The mixture is stirred under cooling with an ice-bath and maintained under a nitrogen atmosphere while 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 anhydrous toluene is added slowly over 30 minūtes. Stirring is continued after addition for a 30-minute period at ambient temperature followed by 80 minūtes at reflux. The cooled reaction mixture, which has deposited a viscous glassy precipitate in the course of the reaction, is carefully quenched with 1 liter of 3M hydro-chloric acid. After usual work-up, the oily crude product is evaporatively bulb-to-bulb distilled at 145-150°C (1 Torr) providing 25.7 g (97%) 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanol as a colourless solid, m.p. 69-70°C after recrystallization from n-hexane. (C17H2802; F.W. 264,4)

Rf: 0.49 (Si02 60; TOl/i-PrOH 9:1) 3-(3,5-Di-tert-butyl-4-hydroxyphenyl )-1-( tetrahydropyran-2-yloxy)propane

An ice-cold, stirred solution of 31.06 g (0.117 mol) of 3-(3,5-di-tert-buytl-4-hydroxyphenyl)propanol and 500 mg of pyridinium p-toluenesulphonate (PPTS) in 120 ml of anhydrous dichloromethane is treated over a 15-minute period dropwise with 11.91 g (0.142 mol) of 3,4-dihydro-2H-pyran and, after further 60 minūtes in the cooling-bath, is reacted at room temperature overnight. The reaction mixture is washed with saturated aqueous bicarbonate and brine, dried over Na2S04 and concentrated iņ vacuo. leaving 40.74 g (pract. 100%) 3-(3,5-di-tert-butyl-4-hydroxy- phenyl)-1-(tetrahydropyran-2yloxy)propane as a yellow oil, which is used without further purification. (C22H3603; F.W. 348.5)

Rf: 0.57 (Si0260; Tol/i-PrOH 9:1) STEP 3 3-( 4-Acetoxy-3,5-di-tert-butylphenyl)-l-(tetrahydropyran-2-yloxy)propane A vigourously stirred mixture of 40.74 g (0.117 mol) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-l-( tetrahydropy-ran-2-yloxy)propane and 5.85 g (16.7 mmol) of tetrabutylam-monium hydrogen sulphate in 250 ml of dichloromethane and 250 ml of 50% aqueous sodium hydroxide is treated at 0°C dropwise with 14.32 g (0.140 mol) of* acetic anhydride, dissolved in 100 ml of dichloromethane, under a nitrogen atmosphere. After addition is complete, the mixture is reacted for an additional 4-hour period at ambient temperature. Following usual extractive work-up, 42.69 g (93%) of 3- (4-acetoxy-3,5-di-tert-butylphenyl )-1-( tetrahydropyran-2-yloxy)propane is obtained as a brown viscous liguid, Which 5 is used for the following deprotection step without further purification. (C24H3804; F.W. 390.6)

Rf: 0.52 (Si02 60; Tol/i-PrOH 9:1) STEP 4 3-(4-Acetoxy-3,5-di-tert.-butylphenyl)-propanol 10 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 together with 1 g of amberlyst 15 (H’-form) for 2 hours at 45°C and maintained at room temperature overnight. After dilution of the suspen-sion with 100 ml of methanol, the catalyst is removed by filtration and the filtrate evaporated at reduced pressure 9 15 leaving 11.53 g of crude product, which is purified by flashchromatography over silica gel with H/AcOEt'3:l as the eluent. 6.96 g (61%) of 3-(4-acetoxy-3,5-di-tert-butyl-phenyl)propanol is isolated from the product-containing fractions as a faintly yellowish oil, which gradually crystallizes upon standing, m.p. 93-95°C. (C19H3003; F.W. 20 306.4)

Rf: 0.47 (Si02 60; Tol/i-PrOH 9:1) STEP 5 2,6-Di-tert-butyl~4-[5-(3-pyridyl)-4-oxapentyl]phenol 25 A solution of 19.74 g (64.42 mmol) of 3-(4-acetoxy-3,5-di-tert-butylphenyl)propanol, 12.68 g (77.3 mmol) of 3-picolylchloride hydrochloride and 5 g of tetrabutylammon-ium hydrogen sulphate in 250 ml of toluene is treated with 250 ml of 50% aqueous sodium hydroxide with vigorous stirring (&gt;· 400 rpm) under a nitrogen atmosphere and external cooling with a water-bath. Stirring of the dark reaction mixture is continued for an additional 5 hours at room temperature. After usual extractive work-up, the crude 24 30

I I VI0423

product (26.3 g) is purified by flash-chromatography over silica gel with AcOEt/H 2:1 as the eluent, yielding 16.9 g (66%) of 2,6-di-tert-butyl-4-[5-(3-pyridyl)-4-oxapentyl]-phenyl acetate as a colourless oil, which is dissolved in 5 100 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) lithium aluminium hydride in 100 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred overnight in the gradually-warming 10 cooling bath, maintained for 2 hours at 40°C, and quenched under vigorous stirring and external cooling with ice-water by sequential, careful addition of 1.77 g of water, 1.77 g of 15% aqueous sodium hydroxide and a final portaionn of 5.31 g of water. After 1 hour, the resulting suspension is 15 diluted with 200 ml of THF, dried with 20 g of Na2S04 and the aluminate precipitate is removed by filtration through a fritted glass funnel and the solvent evaporated at reduced pressure, to give 12.9 g of crude 2,6-di-tert-buty-l-4-[5-(3-pyridyl)-4-oxapentyl)phenol as a yellow solid, 20 leaving 11.49 g (76% for the deprotection step) of pure product, m.p. 105°C, after recrystallization with n-hexane/ ethyl acetate. (C23H33N02; F.W. 355.5)

Rf: 0.37 (Si02 60; Tol/i-PrOH 9:1) 25 25 ΕΧΑΜΡΙιΕ 7

Synthesis of 2,6-Di-tert-butyl-4-[7-(3-pyridyl)-4-oxa-heptyl]phenol STEP 1 3-(4-Acetoxy-3, 5-di-tert-butylpheny1)-1-(tosyloxy)propane To 8.41 g (27.44 nunol) of 3-(4-acetoxy-3,5-di-tert-bu-tylphenyl)-propanol (see EXAMPLE 6, STEP 3 to STEP 4), dissolved in 125 ml of anhydrous pyridine, is added 5.49 g (28.80 mmol) of p-toluenesulphonyl chloride at 0°C. The reaction mixture is stirred for 1.5 hours at this tempera-ture and stored overnight in the refrigerator and worked up extractively in the usual way. The crude 3-(4-acetoxy- 3.5- di-tert-butylphenyl)-l-(tosyloxy)propane is purified by flash-chromatography over silica gel with n-hexan/AcOEt 4:1 as the eluent, affording 8.28 g (66%) of pure tosylate as a colourless viscous liquid. (C26H36S05; F.W. 460.6)

Rf: 0.42 (Si0260; Tol/i-PrOH 9:1) STEP 2 2.6- Di-tert-butyl-4-[7-(3-pyridyl)-4-oxaheptyl]phenol . A solution of 3.66 g (26.68 nunol) of 3-(3-pyridyl)pro-panol in 30 ml anhydrous THF and 3.5 ml dry HMPA is added via syringe to a stirred suspension of 2.56 g (60% oil dispersion, 53.33 mmol) of NaH in 35 ml of anhydrous THF under an inert atmosphere at 0°C, followed by a 2 h period at reflux. The sodium alcoholate solutiori is then recooled to 0°C and 10.68 g (23.19 mmol) of 3-(4-acetoxy-3,5-di-tert-butylphenyl)-1-(tosyloxy)propane, dissolved in 35 ml of anhydrous THF, is added, followed by refluxing for 2 h and stirring overnight at room temperature. After usual workup, the crude product (9.88 g; brown oil) is purified by flash-chromatography over silica gel, eluting with n- I Μ -4Λ4Α4 L V IV4£0 hexane/ethyl acetate 3:1, yielding 2.88 g (62% of 2,6-di-tert-butyl-4-[7-(3-pyridyl)-4-oxaheptyl]phenol as amber oil. (C25H37N02; F.W. 383.6)

Rf: 0.44 (Si02 60; n-hexane/ethyl acetate 3:2) EXAMPLE 8

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

Starting with 5-(3-pyridyl)pentanol (preparation: see EXAMPLE 1, step 2, starting with 4-pentyn-l-ol (E.R.H. Jones et al., Org. Synthesis Coll. 4, 755 (1963)), etheri-fication as described above (see EXAMPLE 7), afforded 2,6-di-tert-butyl-4-[9-(3-pyridyl)-4-oxanonyl]phenol in 57% yield as yellowish viscous oil. (C27H41N02; F.W. 411.6)

Rf: 0.52 (Si02 60; n-hexane/ethyl acetate 3:2) EXAMPLE 9

Synthesis of 2,6-di-tert.-butyl-4-[8-(3-pyridyl)-2-oxaoct-7-ynyl]phenol

According to EXAMPLE 1 Step 2 (without hydrogenation step) to Step 3, 2,6-di-tert-butyl-4-[8-(3-pyridyl)-2- oxaoct-7-ynyl]phenol is obtained as yellow viscous oil in 62% yield in the final step. (C26H35N02; F.W. 393.6)

Rf: 0.48 (Si0260; n-hexane/ethyl acetate 2:1) ACID ADDITION SALTS'

As acids suitable for the formation of acid addition salts according to conventional procedure, there may be mentioned from the mineral series the following acids: hydrochloric, hydrobromic, methanesulfonic, isothionic, sulfuric, phosphoric, and sulfamic acids and, from the organic series: acetic, propionic, maleic, fumaric, tartar- - 27 - 5 5 10 ic, citric, oxalic, and benzoic acids, to name a few. Preferred acids are hydrochloric, citric, and maleic. Other pharmaceutically-acceptable acid addition salts may be prepared, if desired, and one acid addition salt may be converted into another by neutralizing one salt, for example, the hydrochloride, and reacidifying with a differ-ent selected mineral or organic acid, to prepare another pharmaceutically-acceptable acid addition salt, as already explained in the foregoinģ and as is conventional in the art. 15 20 25 PHARMACEUTICAL COMPOSITIONS The compounds according to the present invention may be processed into pharmaceutical compositions comprising a pharmaceutically-acceptable carrier. or diluent in addition to the active compound of the present invention. Such compositions can be administered to a living animal, especially a living human, by the oral or the parenteral route. For example, solid preparations or pharmaceutical compositions for oral administration may take the form of capsules, tablets, pilis, powders, or granulates. In such solid pharmaceutical formulations, the active substance or a prodrug therefor is mixed with at least one pharmaceuti-cally-acceptable diluent or carrier such as cane sugar, lactose, starch, talc, or synthetic or natūrai gums, a binder such as gelatin, a lubricant such as sodium sterate, and/or a disintegrant such as sodium bicarbonate. To enable a sustained-release effect, a substance such as a hydrocolloid or other polymer may be incorporated into the pharmaceutical composition. Additional substances such as lubricants or buffers may also be added, as is conventional in the art. The tablets, pilis, or granulates may be subjected to enteric coating, if desired. Liguids for oral 28 30 LV10423 application may be in the form of liposomes, emulsions, Solutions, or suspensions, containing commonly-used inert diluents such as water. Additionally, such liquid pharmaceutical compositions may also contain wetting, emulsify-ing, dispersing, or generally surface-active aģents as well as sweetening, flavoring,' or fragrance-imparting substances.

Suitable preparations for parenteral application may be, among others, sterile aqueous or non-aqueous Solutions, suspensions, liposomes, or emulsions. Additional substances, of which there are many, already known for this form of presentation of a pharmaceutical composition, may be em-ployed as pharmaceutically-acceptable diluent or carrier material.

Depending upon the intended mode of application and duration of treatment, the exact dosage of the active compounds in the preparations of the invention may be varied, especially as deemed appropriate by the attending physician or veterinarian. The active aģents of the present invention may obvio'usly be combined for administra-tion wi.th other pharmacologically-active aģents.

In the compositions of the present invention, the proportions of the active aģent or aģents in the composition may be varied widely, it being necessary only that the active ingredient of the invention or a prodrug therefor constitute or provide an effective amount, i.e., such that a suitable effective dose will be obtained consistent with the dosage form employed. Obviously several dosage forms as well· as several individual active compounds may be administered at or about the same time or even in the same pharmaceutical composition or formulation. - 29 -

METHOD-OF-TREATING

As previously indicated, the compounds of the present invention are suitable, especially in the forra of pharma-ceutical compositions or formulations thereof, for oral or 5 parenteral administration, the exact individual dosages as well as daily dosages in a particular case of course being determined according to well-established medical and/or veterinarian principles in accord with the directions of the physician or veterinarian in charge. 10 In addition to oral and parenteral administration, rectal and/or intravenous administration māy be employed, the dosages generally being considerably reduced where parenteral administration is involved, although oral administration is preferred. An amount of approximately 15 one to three grams per day in the form of repeated dosages is suitable. Broader ranges of about 0.5 to about 10 grams per day may also be employed, depending upon the circum-stances of an individual case. Although 500 mg of active principle has been found especially suitable for use in 20 tablets, individual dosages may vary from about 200 to 1,000 mg, dfnd the 500 mg suggested for use in tablets may of course be administered orally, for example, from one to three times a day. It goes without saying that more than one tablet may be administered in a single dose, as would 25 be required to attain the above-identified suggested daily oral administration amounts of one to three grams per day.

As already stated, a compound of the invention or a prodrug therefor may be administered to the living animal including a living human in any one of numerous ways, for 30 example, orally as in capsules or tablets, parenterally in the form of sterile Solutions or suspensions, or by peliet implantation, and in some cases intravenously in the form of sterile Solutions. Other obvious modes of administra-

I - 30 - LV10423 tion are cutaneously, subcutaneously, bucally, intramus-cularly, and intraperitoneally, and the. particular mode of administration will as usual be selected by the physician or veterinarian in charge. 5 It is thus seen that the present invention provides novel antilipidemic and antiatherosclerotic BHT-omega pyridyl ether compounds and pharmaceutical compositions thereof, as well as a method of combating hyperlipidemia and atherosclerosis therewith, these collectively providing 10 a long-awaited solution to a previously-existing problem not adequately solved by the prior art.

It is to be understood that the present invention is not to be limited to the exact compounds, compositions, methods, or procedures disclosed, as numerous modifications 15 and changes therein will immediately become apparent to one skilled in the art to which this invention pertains, where£ore the present invention is to be understood as limited only by the full scope which can be legally accord-ed to the appended claims. 20 - 31 -

Ue claim I Μ ·*ΛΛΛ&lt;1 UV I ΜΗ Ati 1 Α compound selected from BHT-omega-pyridyl ether compounds of the formula: CH3 -ch3

^CHj H HCH2)m-0-(CH2)n3-3-Pyr wherein

wherein m = 1,3 for m = 1, Σ = 6 - 9 for m = 3, Σ » 5 - 11 Sum (Σ) = [m+n+1 (for oxygen)] wherein the bond between the two carbon atoms of the (CH2)n moiety most closely adjacent the pyridine ring is a single, double, or triple bond, and pharmaceutically-acceptable acid addition salts thereof. - 32 2 A compound of Claim 1 selected from the group consist-ing 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)-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]phe-nol (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-ynyl]phenol (Mrz 3/179). . - 3 - A compound of Claim 1 which is 2,6-Di-tert,butyl-4-[8·-(3-pyridyl)-2-oxaoctyl]phenol. - 4 - A compound of Claim 1 which is 2,6-Di-tert-butyl-4-[5-(3-pyridyl)-4-oxapentyl]phenol. - 5 -

An antilipidemic and antiatherosclerotic pharmaceuti-cal composition containing as active ingredient an effec-tive antilipidemic and antisclerotic amount of a compound, - 33 LV10423 selected frora BHT-omega-pyridyl ether compounds of the formula:

***mCf

N wherein m = 1,3 for m = 1, Σ = 6 - 9 for m = 3, Σ = 5 - 11 Sum (Σ) = [m+n+1 (for oxygen)] wherein the bond between the two carbon atoms of the (CH2)n moiety most closely adjacent the pyridine ring is a single, double, or triple bond, and pharmaceutically-acceptable acid addition salts thereof, together with a pharmaceuti-cally-acceptable carrier or excipient. - 6 - A pharmaceutical composition of 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), 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]phe-nol (Mrz 3/181), - 34 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-ynyl)phenol (Mrz 3/179). - 7 - A pharmaceutical composition of Claim 5 wherein the active ingredient is 2,6-Di-tert-butyl-4-[8-(3-pyridyl)-2-oxaoctyl]phenol. - 8 - A pharmaceutical composition of Claim 5 wherein the active ingredient is 2,6-Di-tert-butyl-4-[5-(3-pyridyl)-4-oxapentyl]phenol. - 9 - A method of preparing a pharmaceutical composition suitable for combating lipidemia and atherosclerosis in a living animal comprising the step of admixing together an effective antilipidemic and antiatherosclerotic amount of a compound selected from BHT-omega-pyridyl ether compounds of the formula:

35 LV10423 wherein m = 1,3 for m=l, Σ=6-9 for m = 3, Σ = 5 - 11 Sum (Σ) - [ra+n+1 (for oxygen)] wherein the bond between the two carbon atoms of the (CH2)n moiety most closely adjacent the pyridine ring is a single, double, or triple bond, and pharmaceutically-acceptable acid addition salts thereof, and a pharmaceutical-accept-able carrier or excipient and formulating the admixture into the form of a pharmaceutical composition thereof. - 10 - A method of 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)-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]phe-nol (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), 2, 6-Di-tert-butyl-4- [8-(3-pyridyl)-2-oxaoct-7-ynyl]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. - 36 -

Claims (10)

Formula 1. A compound formed from BHT-omega-pyridyl ether compounds of the formula m = 1.3, if m = 1, Σ = 6 - 9, if m = 3, Σ = 5 -11 total (Σ) = [m + n + 1 (for oxygen)], where the bond between 2 carbon atoms ( CH2) in the n-part close to the pyridine ring has simple, double or triple and pharmaceutically acceptable salts with added acids. A compound as described in claim 1, consisting of groups consisting of: 2.6-di- tert -butyl-4- [8- (3-pyridyl) -2-oxo-octyl] phenol (Mrz 3/161), 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-oxo-7-enyl] phenol (Mrz 3/181) , 2,6-di-tert-butyl-4- [9- (3-pyridyl) -2-oxananyl] phenol (Mrz 3/188), 2.6-d-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-oxananyl] phenol (Mrz 3/191) and 2.6-dichlorophen-butyl-1- [8- (3-pyridyl) ) -2-Coxoc-7-nylphenol (Mrz 3/179). The compound of claim 1, which is 2,6-di-tert-butyl-4- [8- (3-pyridyl) -2-oxooctyl] phenol. The compound of claim 1, which is 2,6-di-tert-butyl-4- [5- (3-pyridyl) -4-oxapentyl] phenol. 5. An anti-lipid and anti-sclerotrophic pharmaceutical composition comprising, as an active ingredient, an effective amount of an anti-lipidemic and anti-sclerotic compound formed of BHT-omega-pyridyl ether compounds of the formula: m = 1.3, if m = 1, Σ = 6 - 9, if m = 3, Σ = 5 -11 total (Σ) = [m + n + 1 (oxygen)] where the bond between carbon atoms (CH2 ) In part n, close to the pyridine ring has a simple, double or triple and pharmaceutically acceptable salts with added acids together with a pharmaceutically acceptable carrier or diluent. 6. The pharmaceutical composition of claim 5, wherein the active ingredient is composed of the group consisting of: 2,6-di-tert-butyl-4- [8- (3-pyridyl) -2-oxo-octyl] phenol (Mrz 3/161) ), 2,6-Di- tert -butyl-4- [6- (3-pyridyl) -2-oxahexyl] phenol (Mrz 3/187), 2 LV 10423 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-oxo-7-enyl] phenol (Mrz 3/181), 2,6-di- tert -butyl-4- [9- (3-pyridyl) -2-oxananyl] 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-oxananyl] phenol (Mrz 3/191) and 2.6-di- tert -butyl-4- [8- (3-pyridyl)] -2-oxaoc-7-ynyl] phenol (Mrz 3/179). The pharmaceutical composition described in claim 5, wherein the active ingredient is 2,6-di-tert-butyl-4- [8- (3-pyridyl) -2-oxooctylphenol. 8. The pharmaceutical composition described in claim 5, wherein the active ingredient is 2,6-di-tert-butyl-4- [5- (3-pyridyl) -4-oxapentylphenol. 9. A method for preparing a pharmaceutical composition comprising the step of mixing anti-lipid and anti-sclerotrophic compounds, which are formed from BHT-omega-pyridyl ether compounds of the formula: m = 1.3, if m = 1, Σ = 6 - 9, if m = 3, Σ = 5 -11 total (Σ) = [m + n + 1 (for oxygen)], where the bond between 2 carbon atoms ( In the CHgJn portion, the pyridine ring is closely adjacent to the simple, double or triple and pharmaceutically acceptable salts with attached acids and a pharmaceutically acceptable carrier or diluent and therefore the formulation is formulated in the form of a pharmaceutical composition. The method of claim 9, wherein the compound is composed of the group consisting of: 2.6-di- tert -butyl-4- [8- (3-pyridyl) -2-oxooctyl] phenol (Mrz 3/161), 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-oxo-7-enyl] phenol (Mrz 3 / 181), 2,6-di- tert -butyl-4- [9- (3-pyridyl) -2-oxananyl] 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- tert-butyl 4- [9- (3-pyridyl) -4-oxananyl] phenol (Mrz 3/191) and 2.6-di-tert-butyl-4- [8- (3-pyridyl) -2-oxo-octane] 7-Inyl] phenol (Mrz 3/179).