Substituted biphenyl compounds for use as a medicament.

Start of patent duration: 1954 10 15 Longest possible duration:

Issued: 1935 05 23

Inventor:

© dependence:

AT 377 974 © Pamphlets contemplated for distinction from the prior art:

U.S. Patent 4,242,121

Nr.377974

The invention relates to a process for the preparation of novel aromatic carboxylic acids which find use in human and veterinary medicine. In particular, the invention relates to a process for the preparation of 2- {substituted phenyl) benzoic acids which are known in the art

Regulation or reduction of blood lipids.

⁵ Atherosclerosis is a pathological condition that is the major cause of occlusive vascular disease leading to myocardial infarction and stroke. This condition is associated with deposition of blood lipids in the walls of major arteries and is known to be common in individuals whose blood lipid levels are elevated over established standards. The distribution of lipids in the various lipoprotein components of blood determines this¹⁰ Level of risk / advantage of these materials. High cholesterol levels in low and very low density lipoproteins are associated with an increased risk of atherosclerotic coronary artery disease, while high levels of high density lipoprotein cholesterol are associated with reduced risks of this disease. The increase in blood triglyceride levels has also been shown to be a factor that increases the risk of developing these vascular¹⁵ illnesses increased. The strong association between the elevation of specific components of blood lipids and these major cardiovascular diseases has led to attempts to regulate blood lipid levels through the use of diet and remedial intervention. It has been found that certain compounds, particularly those of Formula (I) below, are effective in reducing the proportion of these lipoprotein components in the blood associated with Athero²⁰ Sclerosis related.

The invention thus relates to a process for the preparation of novel aromatic carboxylic acids of the general formula

Ar¹ - Ar² (I) wherein Ar * is a group of the formulas

<img file="AT377974B_D0001.tif" />

means and Ar² a group of formulas

<img file="AT377974B_D0002.tif" />

represents in which formulas RC_{? 5}Alkyl, perfluoro-Cj ₄alkyl or phenyl, and pharmaceutically acceptable salts thereof.

Preferred compounds within the scope of formula (I) are those of the formula

- 3 Nr.377974

<img file="AT377974B_D0003.tif" />

<img file="AT377974B_D0004.tif" />

where R has the above meaning.

In particular, it has been found that compounds wherein RC_{? G}-Alkyl or trifluoromethyl, have an activity equal to or greater than that of the standard antilipemic compound clofibrate.

The most preferred compound of formula (I) is 2- (4-trifluoromethylphenyl) benzoic acid. Suitable pharmaceutically acceptable acid addition salts are, for example, those derived from alkali metals (such as sodium or potassium) or alkaline earth metals (such as calcium or magnesium) and ammonium salts (such as NR.sup.5, where R is hydrogen or Cj₄-Alkyl, for example NH ^).

Certain compounds of the type of formula (I) have been widely reported in the literature (US Pat

No. 4,242,121) and a number of compounds specifically described, such as J. Chem. Soc. (C), 1968, 848 et seq. However, nowhere has it been taught or suggested that the compounds have pharmacological activity.

The compounds of formula (I) are useful in the treatment or prophylaxis of any condition in which the underlying etiology is associated with elevated blood lipid levels. Thus, the compounds of formula (I) are valuable in the treatment or prophylaxis of atherosclerosis, occlusive vascular diseases and for the reduction or regulation of blood lipids such as triglycerides and cholesterol.

The proportion of the active ingredient required for use in the above conditions varies according to the mode of administration, the condition to be treated and the patient to be treated, and ultimately is the decision of the physician. A suitable oral dose of the active ingredient for a mammal is 1 to 40 mg / kg body weight / day; Preferably, a suitable dose for a human is 2 to 10 mg / kg of body mass, suitably about 4 mg / kg of body mass / day.

The desired dose is preferably given in 1 to 3 sub-doses, which in suitable

Intervals are administered throughout the day. When 2 sub-doses are used, each is preferably in the range of 1 to 100 mg / kg of body mass; a typical underdose for a human is about 2 mg / kg of body mass.

Although it is possible to use the compounds of formula (I) as a raw chemical, preferably the active ingredient is presented as a pharmaceutical or veterinary formulation.

Pharmaceutical formulations or preparations contain the active ingredient together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic and / or prophylactic ingredients. The carrier (s) must be acceptable in the sense that they are compatible with the other ingredients of the formulation and for the

Recipients are not harmful.

Pharmaceutical formulations thus contain a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier therefor. The active ingredient (s) may conveniently be presented (as a pharmaceutical formulation) in unit dosage form. A convenient unit dose formulation contains the active compound (s) in a proportion of 1 to 10 mg.

Pharmaceutical formulations are suitable for oral, rectal or parenteral (including intramuscular and intravenous) administration, although oral administration is preferred. The formulations may, if appropriate, be presented in single dosage units and prepared by methods known in the pharmaceutical art. All such methods include

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Combining the active ingredient with liquid carriers or finely divided solid carriers or both and, if necessary, shaping the product into the desired formulation.

Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules, cachets or tablets each containing a predetermined level of active ingredient. A tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in free-flowing form, such as powder or granules, optionally in admixture with a binding, lubricating, inert diluent, lubricating, surface-active or dispersing agent, in a suitable device. Molded tablets can be made by molding an inert liquid diluent. Optionally, tablets may be coated and, if uncoated, they may be scored. Capsules may be prepared by charging the active ingredient, either alone or in admixture with one or more accessory ingredients, into the capsule containers and then capping them in a conventional manner. Cachets are analogous capsules, wherein the active ingredient is sealed together with any auxiliary ingredient (s) in a rice paper wrapper.

Pharmaceutical formulations suitable for oral administration and wherein the carrier is a liquid may be presented as a solution or suspension in an aqueous or non-aqueous liquid, such as an oil-in-water or water-in-oil emulsion.

Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably prepared as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly employed; the suppositories may conveniently be formed by mixing the active ingredient with the softened or melted carrier (s) and then cooling and shaping in suitable molding equipment.

Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of the active ingredient in aqueous or oily vehicles. Such preparations are conveniently presented in unit dose or multi-dose containers, which are sealed after introduction of the formulation until needed for use.

It will be understood that in addition to the abovementioned excipients, the pharmaceuticals described above also include, as appropriate, one or more other excipients such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like. and finally also substances entered for the purpose of rendering the formulation isotonic with the blood of the recipient.

The inventive method is characterized in that in a compound of general formula

Ar¹ - Ar (II), where Ar * has the above meaning and Ar is a group of formulas

- 5 No.377974

G'

<img file="AT377974B_D0005.tif" />

or

<img file="AT377974B_D0006.tif" />

and G is the group of the formula

<img file="AT377974B_D0007.tif" />

which hydrolyzes group G, or in a compound of formula (II) wherein Ar and Ar¹ have the above meaning and G is an aldehyde group, the group G to the group

CO₂H selectively oxidized, after which a resulting free acid is converted, if desired, into a pharmaceutically acceptable salt.

Compounds of formula (II) can be prepared according to methods known for the preparation of such compounds. Furthermore, compounds of the formula (II) in which G represents an aldehyde group, by reacting compounds of the formula

ArM (III), wherein M represents a metal, such as lithium, or MgX, wherein X is halogen (in particular chlorine or bromine) and Ar has the above meaning, with a compound of formula

Ar¹ J (IV) wherein Ar¹ has the above meaning.

The compounds of formula (II) wherein G is oxazoline may be prepared by reacting a compound of formula

Ar¹ - Μ (V), wherein M and Ar¹ have the above meaning, with a compound of the formula

H₃CO - Ar (VI), wherein Ar has the above meaning, provided that G represents only oxazoline.

Compounds of formula (III) or formula (V) are prepared from the corresponding halogen compound (eg, bromine compound) by the well-known method of producing Grignard 25 reagents. The compound of formula (VI) is prepared from the corresponding acid by the method of Meyers et al., JACS 97, 7383 (1975).

The following examples are intended to illustrate the invention in more detail, without this being intended to be limited thereto.

Example 1: Preparation of 4 '- (trifluoromethyl) -2-biphenylcarboxylic acid 30 a. Preparation of 2- (4,4-dimethyl-2-oxazolin-2-yl) -4'-trifluoromethylbiphenyl

A mechanically stirred solution of 5.1 g (0.21 mol) of magnesium turnings (Mallinckrodt for Grignard reactions) and 41 g (0.2 mol) of 2- (2-methoxyphenyl) -4,4-dimethyl-2-oxazoline in 50 ml of dry tetrahydrofuran was prepared under nitrogen. To this was added a crystal of iodine, 1 ml of dibromoethane and 2 ml of pure p-bromotrifluoromethylbenzene to pass the Grignard reaction to No. 3777974. Upon initiation of the reaction, the remainder of the p-bromotrifluoromethylbenzene (50 g, 0.22 mole total) in 100 mL dry tetrahydrofuran was added dropwise at a rate sufficient to maintain the reaction at a gentle reflux. The addition lasted 1 h. At the end of the additional period, the reaction mixture was heated at reflux for 3 hours. The reaction mixture was then cooled to room temperature and 10 ml of water was added dropwise to coagulate the salts. The tetrahydrofuran was decanted and the remaining solids were slurried twice with 300 ml of ethyl ether and twice with 300 ml of dichloromethane. Each organic extract was decanted from the solids and combined and then evaporated under reduced pressure to an oil.

This oil was redissolved in 300 ml of dichloromethane, washed once with 100 ml of water and once with 10 ml of saturated sodium chloride solution, dried and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure (5.32 Pa, 95 ° C) to give 2- (4,4-dimethyl-2-oxazolin-2-yl) -4'-trifluoromethylbiphenyl in a yield of 33% , A sample was recrystallized from petroleum ether (bp 30-60 ° C), mp 50-51 ° C.

Elemental analysis for C_lgH_lgF_GNO:

Calculated: Found:

67.70%

67.62%

5.05%

5.09%

4.39%

4.39%

b. Preparation of 4 '- (trifluoromethyl) -2-biphenylcarboxylic acid 20 A solution of 3.5 g (0.011 mol) of 2- (4,4-dimethyl-2-oxazolin-2-yl) -4'-trifluoromethylbiphenyl in 60 ml of 6n Hydrochloric acid was stirred for 2 hours at high reflux. The reaction mixture was then cooled to room temperature and extracted with methylene chloride. The organic extracts were dried and concentrated under reduced pressure to give a solid. By recrystallization from ethyl ether / pentane was 4 '- (trifluoromethyl) -2-biphenylearbonsäure in 86% yield, mp. 167-169 ° C.

Elemental analysis for CH _GF_G O_G:

Calculated: Found:

63.16%

63.12%

3.41%

3.42%

Thin layer chromatography (lined container), 10% methanol / chloroform, 1 spot,

R_f 0.33, silica gel 60 (trade name of Whatman Co., Clifton, New Jersey) plate.

Example 2: Preparation of 4- (n-butyl) -2-biphenylcarboxylic acid

a. Preparation of 2- (4,4-dimethyl-2-oxazolin-2-yl) -4'-n-butylbiphenyl

A mechanically stirred solution of 3.75 g (0.154 mol) of magnesium turnings (Mallinckrodt, for Grignard reaction) and 30 g (0.146 mol) of 2- (2-methoxyphenyl) -4,4-dimethyl-2-oxazoline in 50 ml of dry Tetrahydrofuran was prepared under nitrogen. To this was added 1 iodine crystal, 1 ml dibromoethane and 2 ml of pure p-iodo-n-butylbenzene to initiate the Grignard reaction. After heating to initiate the reaction, the remainder of 40 g (0.154 mol) of p-iodo-n-butylbenzene in 50 ml of dry tetrahydrofuran was added dropwise at a rate to maintain the reaction at a gentle reflux. The addition took 1 h and the reaction mixture was then refluxed for 3 h. Then the reaction mixture was cooled to room temperature and 15 ml of water was added dropwise to coagulate the salts. The tetrahydrofuran was decanted and the remaining solids were sliced ​​twice with 200 ml of ethyl ether and twice with 300 ml of dichloromethane. Every organic

Extract was decanted from the solids and combined and evaporated under reduced pressure to an oil. The oil was redissolved in 300 ml of dichloromethane, washed once with 100 ml of saturated sodium chloride solution, dried and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure (3.59 Pa, 130 ° C) to give 2- (4,4-dimethyl-2-oxazolin-2-yl) -4'-n-butylbiphenyl as an oil, yield 25%.

b. Preparation of 4 '- (n-butyl) -2-biphenylcarboxylic acid

- 7 no.377974

A solution of 12 g (0.039 mol) of 2- (4,4-dimethyl-2-oxazolin-2-yl) -4'-n-butylbiphenyl in 200 ml of 6N hydrochloric acid was stirred at high reflux for 48 hours. The reaction mixture was then cooled to room temperature and extracted with dichloromethane. The organic extracts were dried and concentrated under reduced pressure to give an oil. chromatographic⁵ Graphite with a mixture of acetone-petroleum ether gave a solid. Recrystallization from acetone / petroleum ether gave 4- (n-butyl) -2-biphenylcarboxylic acid in 20% yield,

Mp 74-76 ° C.

Elemental analysis for C ,, H..0 .:

1 / Io CH ⁰ Calculated: 80.28% 7.13%

Found: 80.00% 7.15%

Thin Layer Chromatography (lined container), 10% methanol / chloroform, 1 spot, Rp. 0.48, Silica gel 60 plate.

Example 3: Preparation of 2- (4-biphenyl) benzoic acid

a. Preparation of 2- (4,4-dimethyl-2-oxazolin-2-yl) -4'-phenylbiphenyl

A mechanically stirred solution of 2.95 g (0.12 mol) of magnesium turnings (Mallinckrodt, for Grignard reaction) and 23.4 g (0.114 mol) of 2- (2-methoxyphenyl) -4,4-dimethyl-2-oxazoline in 100 ml of dry tetrahydrofuran was prepared under nitrogen. To this end, 1 iodine crystal, 1 ml of dibromoethane and 2 ml of pure p-bromophenylbenzene (also known as p-bromobiphenyl) were added to initiate the Grignard reaction. After initiating the reaction, the remainder of 28 g (0.12 mole total) of p-bromophenyl benzene in 100 mL dry tetrahydrofuran was added dropwise at a rate sufficient to maintain the reaction at a gentle reflux. The addition took 1 h, after which the reaction mixture was heated at reflux for 4 h and then stirred overnight at room temperature. Then, the reaction mixture was worked up by adding 15 ml of water to the stirred reaction mixture to coagulate the salts. The tetrahydrofuran was decanted and the remaining solids were slurried twice with 300 ml of ethyl ether and twice with 300 ml of dichloromethane. Each organic extract was decanted from the solids and they were combined and evaporated under reduced pressure to an oil.

The oil was redissolved in 300 ml of dichloromethane, washed once with 100 ml of water and once with 100 ml of saturated chloride solution, dried and concentrated under reduced pressure to an oil. The oil was chromatographed eluting with ethyl acetate / petroleum ether to give a solid. Recrystallization from acetone / petroleum ether gave 2- (4,4-dimethyl-2-oxazolin-2-yl) -4'-phenylbiphenyl in 16% yield, m.p. 95-97 ° C.

b. Preparation of 2- (4-biphenyl) benzoic acid

A solution of 6.3 g (0.019 mol) of 2- (4,4-dimethyl-2-oxazolin-2-yl) -4'-phenylbiphenyl in

100 6 ml hydrochloric acid was stirred at high reflux for 24 h. The reaction mixture was then cooled to room temperature and extracted with dichloromethane. The organic extracts were dried and concentrated under reduced pressure to give an oil. Chromatography of the oil in acetone / petroleum ether gave a solid. Recrystallization of the solid from acetone / petroleum ether gave 2- (4-biphenyl) benzoic acid in 28% yield, m.p. 194-195 ° C.

<td colspan="4">Elemental analysis for ^_lgH₁₄O₂:</td>

<td></td><td colspan="2">C</td><td>H</td>

<td>45</td><td>Calculated:</td><td>83.19%</td><td>5.14%</td>

<td></td><td>Found:</td><td>83.19%</td><td>5.10%</td>

<td></td><td colspan="2">TLC</td><td>(lined container), 10% methanol / chloroform, 1 spot,</td>

R_f 0.4, Silica gel 60 (brand name) plate.

Example 4: Process variant for the preparation of 4 '- (trifluoromethyl) -2-biphenylcarboxylic acid 50 a. Preparation of 2-bromobenzaldehyde dimethyl acetal

Nr.377974

- 8 A solution of 451.9 g (2.44 mol) of 2-bromobenzaldehyde, 324 g (3.05 mol) of trimethyl orthoformate and 4.0 ml (0.05 mol) of conc. Hydrochloric acid in 2 liters of methanol was refluxed for 4 hours.

The volatile components were removed by rotary evaporation and the residue was dried over anhydrous potassium carbonate, filtered and distilled (66-72 ° C at 13.3-26.6 Pa) to give 474.1 g (84%) of 2-bromobenzaldehyde dimethyl acetal colorless oil were obtained.

NMR (CDC1₃): 3.35 (s, 6, OCHg), 5.50 (s, 1, CH), 7.5 (m, 4, Ar-H).

b. Preparation of iodo (4-trifluoromethylphenyl) bis (triphenylphosphine) palladium (II)

To a slurry of 12.61 g (10.9 mmol) of tetrakis (triphenylphosphine) palladium in 35 ml of dry benzene under nitrogen was added a solution of 2.97 g (10.9 mmol) of 4-iodobenzotrifluoride in 35 ml of benzene , 1 h after dissolution, the solvent was evaporated and the residue was triturated with cold diethyl ether. The iodo (4-trifluoromethylphenyl) bis (triphenylphosphine) palladium (II) compound (9.58 g, 97%) was filtered, dried in vacuo and stored in a brown bottle under nitrogen.

c. Preparation of 4'-trifluoromethyl-2-biphenylcarbaldehyde

To 1.23 g (50.7 mmol) of magnesium turnings in a dry flask was added under nitrogen 10 ml of anhydrous tetrahydrofuran. The mixture was mechanically stirred while a solution of 1.22 g (6.5 mmol) of 1,2-bromoethane in 10 ml of tetrahydrofuran was added dropwise. Upon completion, a solution of 3.0 g (13.0 mmol) of dimethylacetal of 2-bromobenzaldehyde and 2.44 g (13.0 mmol) of 1,2-dibromoethane in 10 ml of tetrahydrofuran was added at a rate to give a slight reflux maintain. Upon completion, another 1.22 g (6.5 mmol) of 1,2-dibromoethane in 10 ml of tetrahydrofuran was added dropwise. The mixture was then refluxed for an additional 20 minutes and placed in an addition funnel attached to the second reaction flask and a solution of 2.72 g (10.0 mmol) of 4-iodobenzotrifluoride and 0.21 g (0.9 mmol). Iodine-4- (trifluoromethyl) bis (triphenylphosphine) palladium (II) in 20 ml of refluxing tetrahydrofuran, decanted. The Grignard reagent was added dropwise and the mixture was refluxed for 1 1/2 hours. After cooling to room temperature, 30 ml of 3N hydrochloric acid were added and the tetrahydrofuran was evaporated on a rotary evaporator. The residue was extracted with diethyl ether. The Ätherextrakt was washed with 20 ml of 3N hydrochloric acid, four times with 25 ml of water and 10 ml of saturated sodium chloride solution. The ether solution was then dried (MgSO 4), treated with charcoal, filtered and evaporated to give 3.41 g of a dark yellow oil. This was chromatographed on Waters Prep 500 HPLC using a 1: 1 mixture of methylene chloride and hexane. The product was isolated after evaporation of the solvent as a light yellow oil: 2.41 g, 96.4%.

NMR: (CDC1₃): 7.6 (m, 7, Ar-H), 8.0 (m, 1, 3-H), 9.9 (s, 1, CHO).

Elemental analysis for C₁₄H_GF₃O:

CH

Calculated: 67.20% 3.62%

Found: 67.39% 3.69%

d. Preparation of 4'-trifluoromethyl-2-biphenylcarboxylic acid

To a solution of 1.08 g (4.32 mmol) of 4'-trifluoromethyl-2-biphenylcarbaldehyde in 15 ml of tert-butanol at 80 ° C was added a solution of 0.89 g (5.62 mmol) of potassium permanganate in 25 ml Added water. After stirring for 2 h at 80 ° C, the mixture was cooled, a solution of 2 ml of 3N sodium hydroxide was added and the manganese dioxide filtered off. The filtrate was diluted with 15 ml of water and acidified with 6N hydrochloric acid to precipitate 1.05 g (91.2%) of the titled compound. Dissolution in 15 ml of 0.3 N sodium hydroxide and subsequent treatment with activated charcoal, filtration and precipitation with 6N hydrochloric acid gave 0.85 g (85%) of the purified 4-trifluoromethyl-2-biphenylcarboxylic acid compound.

NMR (CDClg): 7.5 (m, 7, ArH), 8.0 (m, 1, 3-H), 9.5 (broad s, 1, CO₂H).

Example 5: Following the procedure described in Example 1, the following compounds were prepared:

Nr.377974

- 9 2- (4-ethylphenyl) benzoic acid, mp 129-131 ° C,

2- (4-isopropylphenyl) benzoic acid, m.p. 106.5 to 107.5 ° C,

2- (4-tert-butylphenyl) benzoic acid, m.p. 129-131.5 ° C, 1- (4-trifluoromethylphenyl) -2-naphthoic acid, m.p. 227-228.5 ° C, 1- (4-ethylphenyl ) -2-naphthoic acid, mp 152-154 ° C.

Effect of 2- (4-trifluoromethylphenyl) benzoic acid on the hypercholesterolemic male rat

Hypercholesterolemia was induced in male rats after 3 days diet with 0.4% cholesterol and 0.2% sodium cholate. Each group contained 4 rats. The tested compounds 10 were administered orally twice daily for 3 days and once on the 4th day. Control animals received the vehicle methylcellulose. Treatment with the cholesterol diet and with the compound started the same day. The animals were bled prior to diet administration and treatment with the compound and 3 hours after the last dose of the compound on the 4th day. All blood was taken after a fasting period of 4 hours. Total serum cholesterol, triglyceride and high density lipoprotein cholesterol (HDL) were determined according to the method and test equipment of Dow Diagnostics (trade name of Dow Chemical Co. Laboratories, Indianapolis, IN). Very low and low density lipoprotein cholesterol (VLDL &amp; LDL) were determined by the difference between total and HDL cholesterol. Table I shows the effect of 2- (4-trifluoromethylphenyl) benzoic acid and clofibrate on serum total cholesterol and triglyceride levels. Table II shows the effect of 2- (4-trifluoromethylphenyl) benzoic acid and clofibrate on HDL and VLDL &amp; LDL cholesterol.

Table I

Inhibition of diet-induced hypercholesterolemia

<td>connection</td><td>dose mg / kg / day</td><td>% Modification from the K cholesterol</td><td>in the serum ontrol triglyceride</td>

<td>IA (R = CF₃)</td><td>150</td><td>-40</td><td>-60</td>

<td>IA (R = CF₃)</td><td>100</td><td>-51</td><td>-57</td>

<td>IA (R = CF₃)</td><td>50</td><td>-56</td><td>-53</td>

<td>IA (R = CF₃)</td><td>25</td><td>-40</td><td>-43</td>

<td>clofibrate</td><td>200</td><td>-28</td><td>-40</td>

<td>clofibrate</td><td>100</td><td>0</td><td>-33</td>

<td>clofibrate</td><td>50</td><td>0</td><td>-31</td>

<td>clofibrate</td><td>25</td><td>0</td><td>0</td>

Nr.377974

Effect on HDL and VLDL &amp; LDL cholesterol

Table II

<td rowspan="2">connection</td><td rowspan="2">dose mg / kg / day</td><td colspan="2">% Change in serum from the control</td>

<td>VLDL &amp; LDL</td><td>HDL</td>

<td>I (R = CF₃)</td><td>150</td><td>-52</td><td>-15</td>

<td>I (R = CF₃)</td><td>50</td><td>-64</td><td>+10</td>

<td>I (R = CF₃)</td><td>25</td><td>-46</td><td>- 6</td>

<td>clofibrate</td><td>200</td><td>-29</td><td>-28</td>

<td>clofibrate</td><td>100</td><td>0</td><td>-21</td>

Effect of Compounds of Formula (IA) on Cholesterol and Triglyceride Levels in Rats Following the method described above, various compounds were used

Investigated formula (IA) for its ability to reduce rat cholesterol and triglyceride levels. The compounds were compared in efficacy with clofibrate. The results are shown in Table III.

Table III

<td>R in formula (IA)</td><td>cholesterol lowering</td><td>lowering of triglycerides</td>

<td>^CF3</td><td>A</td><td>A</td>

<td>nC₄H_G</td><td>A</td><td>A</td>

<td>^c2 H ₅</td><td>A</td><td>A</td>

<td>iC₃H₇</td><td>A</td><td>A</td>

<td>¹- 4 °^Η3</td><td>M</td><td>A</td>

In = inactive in the tested dose A = activity&gt; clofibrate M = activity £ clofibrate