WO1999011621A2 - Thiourea for increasing hdl-cholesterol levels, which are useful as anti-atherosclerotic agents - Google Patents

Abstract

Compounds are provided which have formula (I) wherein R is (II), (III), (IV) or (V), wherein R?7, R8, R9, R10 and R11¿ are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms; R?1 and R12¿ are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R?2, R3, R4, R5 and R6¿ are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.

Description

THIOUREA FOR INCREASING HDL-CHOLESTEROL LEVELS, WHICH ARE USEFUL AS ANTI-ATHEROSCLEROTIC AGENTS

FIELD OF THE INVENTION

This invention is directed to anti-atherosclerotic agents and more specifically to compounds, compositions and methods for treating atherosclerotic conditions, such as dyslipoproteinemias and coronary heart disease. This invention specifically relates to 1- aryl-3-heteroaryl thiourea derivatives that elevate HDL cholesterol concentration and which may be useful for the treatment of atherosclerotic conditions and coronary heart disease.

BACKGROUND OF THE INVENTION

Numerous studies have demonstrated that both the risk of coronary heart disease (CHD) in humans and the severity of experimental atherosclerosis in animals are inversely correlated with serum HDL cholesterol (HDL-C) concentrations (Russ et al., Am. J. Med.. ϋ, 480-483 (1951); Gofman et al., Circulation. 34, 679-697 (1966); Miller and Miller, Lancet. 1, 16-19 (1975); Gordon et al., Circulation. 79, 8-15 (1989); Stampfer et al.. N. Engl. J. Med.. 325, 373-381 (1991); Badimon et al., Lab. Invest.. 60. 455-461 (1989)). Atherosclerosis is the process of accumulation of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral arterial vessels and subsequent myocardial infarction and stroke. Angiographic studies have shown that elevated levels of some HDL particles in humans appear to be correlated to a decreased number of sites of stenosis in the coronary arteries of humans πyliller et al.. Br. Med. J .. 282. 1741-1744 (1981)).

There are several mechanisms by which HDL may protect against the progression of atherosclerosis. Studies in vitro have shown that HDL is capable of removing cholesterol from cells (Picardo et al., Arteriosclerosis. 6, 434-441 (1986)). Data of this nature suggest that one antiatherogenic property of HDL may lie in its ability to deplete tissue of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset, J. Lipid Res.. 9, 155-167 (1968)). This has been supported by experiments showing efficient transfer of cholesterol from HDL to the liver (Glass et al., J. Biol. Chem.. 258. 7161-7167 (1983); McKinnon et al., J. Biol. Chem., 26. 2548-2552 (1986)). In addition, HDL may serve as a reservoir in the circulation of apoproteins necessary for the rapid metabolism of triglyceride-rich lipoproteins (Grow and Fried, J. Biol. Chem.. 253, 1834-1841 (1978); Lagocki and Scanu, J. Biol. Chem.. 255. 3701-3706 (1980); Schaefer et al., J. Lipid Res.. 23, 1259-1273 (1982)). Accordingly, agents which increase HDL cholesterol concentrations would have utility as anti-atherosclerotic agents, useful particularly in the treatment of dyslipoproteinemias and coronary heart disease.

Ureas, thioureas, and numerous derivatives thereof are known to be useful for treating various conditions. For example, the use of urea and thiourea derivatives as tyrosine kinase inhibitors to inhibit cell proliferation and differentiation in the treatment of cancer is disclosed in WO 9640673-A1. The use of [(alkoxy) pyridinyl] amino derivatives to inhibit the secretion of gastric acid is disclosed in WO-9315055. The use of bis-aryl ureas and related compounds as cardiovascular agents is disclosed in CA-2132771, while the administration of ureas and thioureas for the treatment of ischaemia, asthma, Parkinson's disease, epilepsy and urinary incontinence is disclosed in U.S. Patent No, 5,547,966.

The treatment of atherosclerosis with certain ureas, thioureas and derivatives thereof has been suggested in Japanese Patent 8301841 (the use of ureas and thioureas as inhibitors of squalene epoxidase); U.S. Patent No. 4,623,662 (the use of certain urea and thiourea compounds to lower serum lipids in warm-blooded animals); and U.S. Patent Nos. 4,387,105 and 4,387,106 (the use of di(aralkyl) ureas and di(aralkyl) thioureas to inhibit fatty acyl CoA: cholesterol acyl transferase). Canadian Patent No. 2,072,704 discloses certain N-phenyl thiourea derivatives and methods for the treatment of atherosclerosis therewith. However, the treatment of atherosclerosis, cardiovascular disease and dyslipoproteinemias, due to the elevation of serum HDL cholesterol concentrations through the use of the present urea and thiourea derivatives, has heretofore not been recognized.

SUMMARY OF THE INVENTION

In accordance with the present invention, there are provided l-(aryl- substituted)-3-(heteroaryl substituted) thioureas which are particularly useful as antiatherosclerotic agents. More particularly, this invention provides compounds of formula 1 having the structure

wherein

wherein

R⁷, R⁸, R¹⁰ and R¹¹ are each independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms;

R¹ and R¹² are each independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R², R³, R⁴, R⁵ and R⁶ are each independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.

This invention also provides methods of elevating the HDL concentration and treating or inhibiting atherosclerosis and related coronary heart disease or dyslipoproteinemias and improving the HDL/LDL cholesterol ratio in a mammal in need thereof which comprises administering to the mammal a compound of formula 1 having the structure

wherein

wherein

R⁷, R⁸, R¹⁰and R¹¹ are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms; R¹ and R¹² are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R², R³, R⁴, R⁵ and R⁶ are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

Preferably, the present compounds are those represented by formula 1 :

wherein

wherein

R⁷, R⁸, R⁹, R¹⁰and R" are each, independently, hydrogen, halogen, or methyl; R¹ and R¹² are hydrogen; and R², R³, R⁴, R⁵ and R⁶ are each, independently, hydrogen, halogen or methyl; or a pharmaceutically acceptable salt thereof.

As used in describing this invention, the term "lower alkyl" includes both straight chain as well as branched moieties. The term "halo" or "halogen" includes fluorine, chlorine, bromine, and iodine.

As used in describing this invention, the term "compounds of this invention" includes the broader description encompassing the formula used in accordance with the above methods, as well as the narrower description encompassing the formula used in accordance with the above novel compounds.

The pharmaceutically acceptable salts of the present compounds include those derived from organic and inorganic acids such as, but not limited to: acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methane sulfonic, toluene sulfonic and similarly known acceptable acids.

The most preferred compounds according to this invention are:

1 -(5-Chloro-2-methyl-phenyl)-3-(pyridin-2-yl)-thiourea; l-(5-Chloro-2-methyl-phenyl)-3-(pyridin-3-yl)-thiourea; l-(5-Chloro-2-methyl-phenyl)-3-(5-chloro-pyridin-2-yl)-thiourea; l-(5-Chloro-2-methyl-phenyl)-3-(pyrazin-2-yl)-thiourea; l-(5-Chloro-2-methyl-phenyl)-3-(5-methyl-pyridin-2-yl)-thiourea; 1 -(4-Chloro-2-methyl-phenyl)-3-(pyridin-2-yl)-thiourea; l-(2-Chloro-6-methyl-phenyl)-3-(pyridin-2-yl)-thiourea; l-(2-Chloro-6-methyl-phenyl)-3-(5-chloro-pyridin-2-yl)-thiourea; l-(4-Chloro-2-methyl-phenyl)-3-(5-chloro-pyridin-2-yl)-thiourea; l-(5-Chloro-2-methyl-phenyl)-3-(3-methyl-pyridin-2-yl)-thiourea; l-(2-Chloro-6-methyl-phenyl)-3-(3-methyl-pyridin-2-yl)-thiourea; and l-(4-Chloro-2-methyl-phenyl)-3-(3-methyl-pyridin-2-yl)-thiourea. The present invention provides a process for the preparation of a compound having formula I as defined and illustrated above or a pharmceutically acceptable salt thereof wherein

(a) an amine having the formula Rl^-H or a reactive derivative thereof is reacted with a thioacylating agent for introducing a thioacyl group having the formula R14-CS- in which one of R¹- and Rl4 is a group having the formula

where R R3, R4₅ R5₅ R6 _an£j R12 are as defined above and the other one of R¹^ and R 14 is a group having the formula -NRRI where R and R are as defined above; or

(b) a compound having formula I as defined and illustrated above is converted into a pharmaceutically acceptable salt by neutralization with an acid.

The thioacylation step is preferably carried out in an aprotic solvent for example, ethyl acetate. The amine R1-1H may be used as such or as a reactive derivative, for example, a potassium or sodium salt. The thioacylating agent may be a thiocarbamoyl chloride having the formula

particularly where R 2 is lower alkyl of 1 to 6 carbon atoms and R^, R3_; R4_^ R5 ^ R6 are as defined above or a thiocarbamoyl chloride having the formula R^RN-CS-Cl particularly where R* is lower alkyl of 1 to 6 carbon atoms and R is as defined above. Where Rl2 is hydrogen, an optionally substituted phenyl isothiocyanate may be used as thioacylating agent. Where R^ is hydrogen, an isothiocyanate having the formula R-N=C=S may be used as thioacylating agent.

The l-(aryl substituted)-3-(heteroaryl substituted) thioureas of this invention may be prepared by the reaction of an appropriately substituted aryl isothiocyanate with an appropriately substituted amino heterocycle (see, e.g., J. March, Advanced Organic Chemistry. 3rd Ed., Wiley-Interscience, NY, pages 802-803). The reaction may take place in an aprotic organic solvent such as dichloromethane or ethyl acetate at temperatures ranging from ambient to the reflux temperature of the solvent as shown in Scheme 1.

Scheme 1

wherein R, R¹, R², R³, R⁴, R⁵, and R⁶ are as described above.

The appropriately substituted aryl isothiocyanates useful as starting materials in the reaction described above are either commercially available, known in the art, or can be readily prepared by procedures analogous to those in the literature for known compounds. Likewise, the appropriately substituted heterocyclic amines useful as starting materials in this reaction are either commercially available, known in the art, or can be readily prepared by procedures analogous to those described in the literature for known compounds.

Representative compounds of this invention were evaluated in an in vivo standard pharmacological test procedure which measured the ability of the compounds of this invention to elevate HDL cholesterol levels. The following briefly describes the procedure used and results obtained. Male Sprague-Dawley rats weighing 200-225 g were housed two per cage and fed Purina Rodent Chow Special Mix 5001-S supplemented with 0.25% cholic acid and 1.0% cholesterol and water ad libitum for 8 days. Each test substance was administered to a group of six rats fed the same diet with the test diet mixed in as 0.005-0.1% of the total diet. Body weight and food consumption were recorded prior to diet administration and at termination. Typical doses of the test substances were 5-100 mg/kg/day.

At termination, blood was collected from anesthetized rats and the serum was separated by centrifugation. Total serum cholesterol was assayed using the Sigma Diagnostics enzymatic kit for the determination of cholesterol, Procedure No. 352, modified for use with ninety-six well microtiter plates. After reconstitutiton with water the reagent contains 300 U/l cholesterol oxidase, 100 U/l cholesterol esterase, 1000 U/l horse radish peroxidase, 0.3 mmol/1 4-aminoantipyrine and 30.0 mmol/1 p- hydroxybenzene sulfonate in a pH 6.5 buffer. In the reaction cholesterol was oxidized to produce hydrogen peroxide which was used to form a quinoneimine dye. The concentration of dye formed was measured spectrophotometrically by absorbance at 490 nm after incubation at 25°C for 30 minutes. The concentration of cholesterol was determined for each serum sample relative to a commercial standard from Sigma.

HDL cholesterol concentrations in serum were determined by separation of lipoprotein classes by fast protein liquid chromatography (FPLC) by a modification of the method of Kieft et al. (J. Lipid Res.. 32, 859-866 (1991)). Using this methodology, 25 mL of serum was injected onto Superose 12 and Superose 6 (available from Pharmacia), in series, with a column buffer of 0.05 M Tris (2-amino-2- hydroxymethyl-l,3-propanediol) and 0.15 M sodium chloride at a flow rate of 0.5 mL/min. The eluted sample was mixed on line with Boehringer-Mannheim cholesterol reagent pumped at 0.2 mL/min. The combined eluents were mixed and incubated on line through a knitted coil (available from Applied Biosciences) maintained at a temperature of 45°C. The eluent was monitored by measuring absorbance at 490 nm and gives a continuous absorbance signal proportional to the cholesterol concentration. The relative concentration for each lipoprotein class was calculated as the percent of total absorbance. HDL cholesterol concentration in serum was calculated as the percent of total cholesterol as determined by FPLC multiplied by the total serum cholesterol concentration. The test compounds were administered at a dose of 100 mg/kg (Table I) and the duration of treatment was eight days. The results obtained in this standard pharmaceutical test procedure are shown below in Table 1.

Table I

Example Number HDL-CholesteroI Level Increase (%)

Example 1 67 Example 2 87 Example 3 16 Example 4 114 Example 5 21 Example 6 513 Example 7 398 Example 8 272 Example 9 83 Example 10 154 Example 11 413 Example 12 399

The results set forth in Table I demonstrate that the compounds of the present invention are useful in raising the concentration of HDL cholesterol, and are therefore, useful for treating or inhibiting atherosclerosis, related cardiovascular disease, or dyslipoproteinemias, and for improving the HDL/LDL cholesterol ratio. Moreover, in light of their ability to elevate HDL cholesterol concentrations, the present compounds are useful in treating several metabolic conditions associated with low concentrations of HDL, such as low HDL-cholesterol levels in the absence of dyslipidemia, metabolic syndrome, non- insulin dependent diabetes mellitus (NIDDM), familial combined hyperlipidemia, familial hypertriglyceridemia, and dyslipidemia in peripheral vascular disease (PVD).

The compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. The invention provides a pharmaceutical composition comprising a compound of this invention in association or combination with a pharmaceutically acceptable carrier. The invention also provides a process for the preparation of such a pharmaceutical composition by bringing a compound of this invention into association or combination with a pharmaceutically acceptable carrier. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The compounds of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be either liquid or solid composition form.

Preferably, the pharmaceutical composition containing the present compounds is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient. The unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form may also be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The therapeutically effective amount of the compounds of this invention that is administered and the dosage regimen depends on a variety of factors, including the weight, age, sex, medical condition of the subject, the severity of the disease, the route and frequency of administration, and the specific compound employed, and thus may vary widely. However, it is believed that the pharmaceutical compositions may contain the present compounds in the range of about 0.1 to about 2000 mg, preferably in the range of about 0.5 to about 500 mg and most preferably between about 1 and about 100 mg. Projected daily dosages of active compound are about 0.01 to about 100 mg/kg body weight. The daily dose can be conveniently administered two to four times per day.

The following non-limiting examples illustrate the preparation of representative compounds of this invention.

Example 1 l-(5-Chloro-2-methyl-phenyI)-3-(pyridin-2-yl)-thiourea

2-Aminopyridine (40 mmol, 3.76 g) was added to a cold solution of 5-chloro-2-methyl phenylisothiocyanate (40 mmol, 7.32 g) in dry dichloromethane (50 mL). The mixture was stirred overnight at room temperature and then refluxed for 6 hours. After cooling, the precipitate was collected, washed with hexane and dried in vacuo (5.62 g, 51%). The product was recrystallized from dichloromethane-acetonitrile to provide after washing with hexane and drying in vacuo a white solid, mp 188-190°C.

Η NMR (CDC1₃, 400 MHz): 5 2.34 (s, 3H, CH₃), 6.91-6.93 (m, 1H, ArH), 7.00-

7.03 (m, 1H, ArH), 7.17-7.22 (m, 2H, ArH), 7.68-7.72 (m, 1H, ArH), 7.83 (m, 1H, ArH), 8.19-8.20 (m, 1H, ArH), 9.19 (1H, NH), 13.46 (1H, NH) MS (El, m z): 277/279 [M]⁺

Anal. Calcd. for C₁₃H₁₂C1N₃S: C, 56.21; H, 4.35; N, 15.13. Found: C, 55.89; H, 4.16; N, 15.27 Example 2 l-(5-Chloro-2-methyl-phenyl)-3-(pyridin-3-yl)-thiourea

3-Aminopyridine (40 mmol, 3.76 g) was added to a solution of 5-chloro-2-methyl phenylisothiocyanate (40 mmol, 7.32 g) in dry dichloromethane (50 mL). The mixture was stirred for 24 hours at room temperature, cooled in an ice bath for 30 minutes and the precipitate collected and dried (6.77 g, 61%). The product was recrystallized from warm acetonitrile to provide a white solid, mp 144-146°C. "H NMR (CDC1₃, 400 MHz): δ 2.32 (s, 3H, CH₃), 7.24-7.28 (m, 2H), 7.35-7.39

(m, 2H), 7.92-7.96 (m, 2H), 8.14-8.16 (m, 1H), 8.42-8.44 (m, 1H), 8.54-8.55 (m, 1H)

MS (EI, m/z): 277/279 [M]⁺

Anal. Calcd. for C₁₃H₁₂C1N₃S: C, 56.21; H, 4.35; N, 15.13. Found: C, 56.40; H, 4.21; N, 15.24

Example 3 l-(5-Chloro-2-methyl-phenyl)-3-(5-chloro-pyridin-2-yl)-thiourea

To a solution of 2-amino-5-chloropyridine (40 mmol, 5.14 g) in ethyl acetate (40 mL) was added 5-chloro-2-methyl phenylisothiocyanate (48 mmol, 8.8 g). The mixture was refluxed for 6 hours and then stirred at room temperature overnight. The precipitate was collected, washed with ethyl acetate and dried (10.2 g, 81.7%). The product was recrystallized from hot ethyl acetate-methanol to provide a fluffy white solid, mp 215- 217°C.

Η NMR (CDC1₃, 400 MHz): δ 2.32 (s, 3H, CH₃), 6.87-6.88 (m, 1H, ArH), 7.18-

7.20 (m, 2H, ArH), 7.66-7.69 (m, 1H, ArH), 7.79-7.80 (m, 1H, ArH), 8.17 (m, 1H, ArH), 9.07 (1H, NH), 12.9 (1H, NH) MS (EI, m/z): 311/313/315 [M]⁺ Anal. Calcd. for C₁₃H_πCl₂N₃S: C, 50.01; H, 3.55; N, 13.46. Found: C, 49.74; H, 3.40; N, 13.23

Example 4 l-(5-Chloro-2-methyl-phenyl)-3-(pyrazin-2-yl)-thiourea

5-Chloro-2-methyl phenylisothiocyanate (48 mmol, 8.8 g) was added to a solution of 2-aminopyrazine (40 mmol, 3.8 g) in ethyl acetate (20 mL). The mixture was refluxed for 8 hours, cooled and the precipitate was collected, washed with ethyl acetate and dried (8.19 g, 73.5%). The product was recrystallized from hot acetonitrile containing a small amount of dichloromethane to provide an off-white solid, mp 212-213°C.

Η NMR (DMSO-d₆, 400 MHz): δ 2.24 (s, 3H, CH₃), 7.24-7.26 (m, IH, ArH), 7.31-7.33 (m, IH, ArH), 7.83-7.84 (m, IH, ArH), 8.29-8.31 (m, 2H ArH), 8.63- 8.64 (m, IH, ArH), 11.33 (IH, NH), 12.69 (IH, NH) MS (EI, m/z): 278/280 [M]⁺

Anal. Calcd. for C₁₂H_πClN₄S: C, 51.70; H, 3.98; N, 20.10. Found: C, 51.94; H, 3.98; N, 20.31

Example 5 l-(5-Chloro-2-methyl-phenyl)-3-(5-methyl-pyridin-2-yl)-thiourea

2-Amino-5-methylpyridine (40 mmol, 4.12 g) was added to a solution of 5-chloro-2- methyl phenylisothiocyanate (48 mmol, 8.8 g) in ethyl acetate (55 mL). The mixture was stirred at room temperature for 24 hours and the precipitate was collected, washed with ethyl acetate and dried (10.25 g, 88%). The product was recrystallized from ethyl acetate containing small amounts of dichloromethane and methanol to provide a fluffy white solid, mp 203-204°C. Η NMR (DMSO-d₆, 400 MHz): δ 2.23 (s, 3H, CH,), 2.26 (s, 3H, CH,), 7.16-7.21

(m, 2H, ArH), 7.29-7.31 (m, IH, ArH), 7.66-7.69 (m, IH, ArH), 8.04-8.05 (m, IH, ArH), 8.11 (m, IH, ArH), 10.94 (IH, NH), 13.64 (IH, NH) MS (EI, m/z): 291/ 293 [M]⁺

Anal. Calcd. for C₁₄H₁₄C1N₃S: C, 57.63; H, 4.84; N, 14.40. Found: C, 57.50; H, 4.72; N, 14.54

Example 6 l-(4-Chloro-2-methyl-phenyl)-3-(pyridin-2-yl)-thiourea

A solution of 4-chloro-2-methyl phenylisothiocyanate (34.5 mmol, 6.3 g) and 2- aminopyridine (34.8 mmol, 3.3 g) in ethyl acetate (30 mL) was stirred at room temperature for 18 hours. The precipitate was collected, washed with ethyl acetate and dried to provide the title compound (6.1 g, 63.7%) as a pale yellow solid, mp 189- 190°C. Η NMR (DMSO-d₆): δ 2.26 (s, 3H, CH₃), 7.08-7.11 (m, IH, ArH), 7.23-7.28 (m,

2H, ArH), 7.38 (m, IH, ArH), 7.73-7.75 (m, IH, ArH), 7.81-7.86 (m, IH, ArH),

8.27-8.29 (m, IH, ArH), 11.0 (IH, NH), 13.5 (IH, NH)

MS (EI, m/z): 277 [M]⁺

Anal. Calcd. for C₁₃H₁₂C1N₃S: C, 56.21; H, 4.35; N, 15.13. Found: C, 56.05; H,

4.13; N, 15.27

Example 7 l-(2-Chloro-6-methyl-phenyl)-3-(pyridin-2-yl)-thiourea

A solution of 2-chloro-6-methyl phenylisothiocyanate (33.2 mmol, 6.1 g) and 2-amino pyridine (33.4 mmol, 3.1 g) in ethyl acetate (30 mL) was stirred at room temperature for 18 hours. The precipitate was collected, washed with ethyl acetate and dried to provide the title compound (2.45 g, 26.6%) as a white solid, mp 214-215°C. "H NMR (DMSO-d₆, 400 MHz): δ 2.26 (s, 3H, CH₃), 7.06-7.10 (m, IH, ArH),

7.19-7.28 (m, 3H, ArH), 7.36-7.38 (m, IH, ArH), 7.81-7.85 (m, IH, ArH), 8.24- 8.27 (m, IH, ArH), 11.02 (IH, NH), 13.2 (IH, NH) MS (ESI, m/z): 278 [M+H]⁺

Anal. Calcd. for C₁₃H₁₂C1N,S: C, 56.21; H, 4.35; N, 15.13. Found: C, 56.03; H, 4.07; N, 15.16

Example 8 l-(2-Chloro-6-methyl-phenyl)-3-(5-chloro-pyridin-2-yl)-thiourea

A solution of 2-chloro-6-methyl phenylisothiocyanate (33.2 mmol, 6.1 g) and 2-amino- 5-chloropyridine (33.4 mmol, 4.3 g) in ethyl acetate (20 mL) was stirred at 50°C for 17 hours. The reaction was cooled, the precipitate was collected, washed with ethyl acetate and dried to provide the title compound (6 g, 58%) as a white solid, mp 226-227°C.

Η NMR (DMSO-d₆, 400 MHz): δ 2.24 (s, 3H, CH₃), 7.22-7.30 (m, 3H, ArH), 7.36-7.38 (m, IH, ArH), 7.94-7.97 (m, IH, ArH), 8.31-8.32 (m, IH, ArH), 11.2

(IH, NH), 12.65 (IH, NH)

MS (+FAB, m/z): 312 [M+H]⁺

Anal. Calcd. for C₁₃H_πCl₂N₃S: C, 50.01; H, 3.55; N, 13.46. Found: C, 50.05; H,

3.25; N, 13.45 Example 9 l-(4-Chloro-2-methyl-phenyl)-3-(5-chIoro-pyridin-2-yI)-thiourea

A solution of 4-chloro-2-methyl phenylisothiocyanate (27.6 mmol, 5.1 g) and 2-amino- 5-chloroρyridine (28 mmol, 3.6 g) in ethyl acetate (20 mL) was stirred at 50°C for 65 hours. The reaction was cooled, the precipitate was collected, washed with ethyl acetate and dried to provide the title compound (7 g, 81.2%) as a white solid, mp 203-205°C.

Η NMR (DMSO-d₆, 400 MHz): δ 2.24 (s, 3H, CH₃), 7.25-7.29 (m, 2H, ArH), 7.37-

7.38 (m, IH, ArH), 7.67-7.70 (m, IH, ArH), 7.93-7.96 (m, IH, ArH), 8.34-8.35 (m, IH, ArH), 11.11 (IH, NH), 12.94 (IH, NH) MS [+FAB, m/z]: 312 [M+H]⁺

Anal. Calcd. for C_I3H_πCl₂N₃S: C, 50.01 ; H, 3.55; N, 13.46. Found: C, 50.17; H, 3.34; N, 13.70

Example 10 l-(5-ChIoro-2-methyl-phenyl)-3-(3-methyl-pyridin-2-yl)-thiourea

A solution of 5-chloro-2-methyl phenylisothiocyanate (48.7 mmol, 8.9 g) and 2-amino- 3-methylpyridine (48.6 mmol, 5.25 g) in ethyl acetate (40 mL) was stirred at room temperature for 18 hours. The precipitate was collected, washed with ethyl acetate and dried to provide the title compound (9.3 g, 65.6%) as a white solid, mp 125-127°C.

NMR (DMSO-d₆, 400 MHz): δ 2.26 (s, 3H, CH,), 2.36 (s, 3H, CH₃), 7.09-7.12 (m,

IH, ArH), 7.20-7.23 (m, IH, ArH), 7.30-7.32 (m, IH, ArH), 7.71-7.74 (m, IH, ArH), 7.94 (m, IH, ArH), 8.18-8.19 (m, IH, ArH), 9.22 (IH, NH). 13.56 (IH, NH) MS [El, m/z]: 291 [M]⁺

Anal. Calcd. for C₁₄H₁₄C1N₃S: C, 57.63; H, 4.84; N, 14.40. Found: C, 57.48; H, 4.87; N, 14.40

Example 11 l-(2-Chloro-6-methyl-phenyl)-3-(3-methyl-pyridin-2-yl)-thiourea

A solution of 2-chloro-6-methyl phenylisothiocyanate (33.2 mmol, 6.1 g) and 2-amino- 3-methylpyridine (33.7 mmol, 3.6 g) in ethyl acetate (20 mL) was stirred at room temperature for 18 hours. The precipitate was collected and the filtrate was concentrated in vacuo to give a yellow oil. Trituration of the oil with ether/hexane provided the title compound (2.1 g, 21.7%) as a white crystalline solid, mp 159-160°C. NMR (DMSO-d₆, 400 MHz): δ 2.26 (s, 3H, CH₃), 2.37 (s, 3H, CH,), 7.07-7.10 (m,

IH, ArH), 7.22-7.27 (m, 2H, ArH), 7.36-7.38 (m, IH, ArH), 7.71-7.72 (m, IH, ArH), 8.16-8.17 (m, IH, ArH), 9.28 (IH, NH), 13.14 (IH, NH) MS [+FAB, m/z]: 292 [M+H]⁺ Anal. Calcd. for C₁₄H₁₄C1N₃S: C, 57.63; H, 4.84; N, 14.40. Found: C, 57.54; H, 4.75; N, 14.34

Example 12 l-(4-Chloro-2-methyl-phenyl)-3-(3-methyl-pyridin-2-yl)-thiourea

A solution of 4-chloro-2-methyl phenylisothiocyanate (42.6 mmol, 6.1 g) and 2-amino- 3-methylpyridine (42.7 mmol, 4.6 g) in ethyl acetate (20 mL) was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo to give a yellow oil. Trituration with ether led to crystallization of the product. The white cystalline solid was collected, washed with ether and dried to provide the title compound (2.6 g, 16%), mp 109-110°C.

NMR (DMSO-d₆, 400 MHz): δ 2.26 (s, 3H, CH,), 2.35 (s, 3H, CH₃), 7.08-7.1 1 (m,

2H, ArH), 7.25-7.28 (m, IH, ArH), 7.37-7.38 (m, IH, ArH), 7.70-7.72 (m, IH, ArH), 8.17-8.19 (m, IH, ArH), 9.17 (IH, NH), 13.38 (IH, NH) MS [+FAB, m/z]: 292 [M+H]⁺

Anal. Calcd. for C₁₄H_!4C1N,S: C, 57.63; H, 4.84; N, 14.40. Found: C, 57.78; H, 4.78; N, 14.34

The present invention may be embodied in other specific forms without departing from the spirit and essential attributes thereof and accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.

Claims

WHAT IS CLAIMED IS:

1. A compound of the structure:

wherein

wherein

R , R , R , R and R are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms;

R and R are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and

R², R , R , R and R are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein:

wherein

R⁷, R⁸, R⁹, R¹⁰and R¹¹ are each, independently, hydrogen, halogen, or methyl; R¹ and R¹² are hydrogen; and

R², R³, R⁴, R⁵ and R⁶ are each, independently, hydrogen, halogen or methyl; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, which is l-(5-chloro-2-methyl-phenyl)-3-(pyridin-2- yl)-thiourea.

4. The compound of claim 1, which is l-(5-chloro-2-methyl-phenyl)-3-(pyridin-3- yl)-thiourea.

5. The compound of claim 1, which is l-(5-chloro-2-methyl-phenyl)-3-(5-chloro- pyridin-2-yl)-thiourea.

6. The compound of claim 1, which is l-(5-chloro-2-methyl-phenyl)-3-(pyrazin-2- yl)-thiourea.

7. The compound of claim 1 , which is l-(5-chloro-2-methyl-phenyl)-3-(5-methyl- pyridin-2-yl)-thiourea.

8. The compound of claim 1, which is l-(4-chloro-2-methyl-phenyl)-3-(pyridin-2- yl)-thiourea.

9. The compound of claim 1, which is l-(2-chloro-6-methyl-phenyl)-3-(pyridin-3- yl)-thiourea.

10. The compound of claim 1, which is l-(2-chloro-6-methyl-phenyl)-3-(5-chloro- pyridin-2-yl)-thiourea.

1 1. The compound of claim 1, which is l-(4-chloro-2-methyl-phenyl)-3-(5-chloro- pyridin-2-yl)-thiourea.

12. The compound of claim 1 , which is l-(5-chloro-2-methyl-phenyl)-3-(3-methyl- pyridin-2-yl)-thiourea.

13. The compound of claim 1 , which is l-(2-chloro-6-methyl-phenyl)-3-(3-methyl- pyridin-2-yl)-thiourea.

14. The compound of claim 1, which is l-(4-chloro-2-methyl-phenyl)-3-(3-methyl- pyridin-2-yl)-thiourea.

15. A method of treating atherosclerosis in a mammal in need thereof, which comprises administering to said mammal an anti-atherosclerotic effective amount of a compound of the structure:

wherein

wherein

7 8 9 10 I I

R , R , R , R and R are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms; R¹ and R ^" are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R², R\ R , R and R are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.

16. A method of elevating the HDL cholesterol concentration in a mammal in need thereof, which comprises administering to said mammal an HDL cholesterol elevating effective amount of a compound of the structure:

wherein

wherein

R , R , R , R and R are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms;

R¹ and R¹ are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R , R , R , R and R are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.

17. A method of treating dyslipoproteinemia in a mammal in need thereof, which comprises administering to said mammal an anti-dyslipoproteinemic effective amount of a compound of the structure:

wherein R , R , R , R and R are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms;

R 1 and R 12 are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R , R , R , R and R are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.

18. A method of treating cardiovascular disease in a mammal in need thereof, which comprises administering to said mammal an anti-cardiovascular disease effective amount of a compound of the structure:

wherein

wherein

R , R , R , R and R are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms; R and R are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R , R , R , R and R are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition, which comprises a compound of the structure:

wherein R 7 , R 8 , R 9 , R 10 and R 11 are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms; R and R are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R , R , R , R and R are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.

20. Use of a compound of the structure:

wherein

wherein

7 8 10 1 1 R , R , R and R are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms;

R 1 and R 12 are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R , R , R , R and R are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof to prepare a medicament for treating atherosclerosis.

21. Use of a compound of the structure:

wherein

wherein

R 7 , R 8 , R 10 and R 11 are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms;

R 1 and R 12 are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R², R , R , R and R are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof to prepare a medicament for elevating the HDL cholesterol concentration.

22. Use of a compound of the structure:

wherein

wherein

R 7 , R 8 , R 10 and R 11 are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms;

R¹ and R¹² are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R , R , R , R and R are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof to prepare a medicament for treating dyslipoproteinemia.

23. Use of a compound of the structure:

wherein

7 8 10 1 1

R , R , R and R are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms;

1 12

R and R are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R², R³, R⁴, R⁵ and R are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof to prepare a medicament for treating cardiovascular disease.