JP2000501100A - 2-Thioxo-imidazolidin-4-one derivatives and their use for increasing HDL cholesterol levels - Google Patents

Abstract

(57) Abstract: Compounds and methods for increasing HDL cholesterol levels in the blood of a mammal in need of elevated HDL cholesterol levels. The method comprises administering to the mammal a compound of formula (I) orally or parenterally. In the formula (I), R is alkyl; substituted or unsubstituted aromatic N, O or S heterocycle; substituted or unsubstituted aryl, arylalkyl, benzhydryl or indanyl (wherein the substituent is alkyl, alkoxy, R1 is aryl, alkyl, alkenyl, alkynyl or substituted aryl (herein, ^one to three substituents independently selected from the group consisting of alkylthio, alkenyl, alkynyl, halo, perfluoroalkyl, perfluoroalkoxy or hydroxy); Wherein the substituent is 1 to 3 substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, alkenyl, alkynyl, halo, perfluoroalkyl, perfluoroalkoxy or hydroxy.

Description

DETAILED DESCRIPTION OF THE INVENTION              2-thioxo-imidazolidin-4-one derivatives and          Use of them to increase HDL cholesterol levels   The present invention increases HDL cholesterol levels in mammalian blood Compounds, their use in the method of treatment, pharmaceutical compositions containing these compounds And a process for producing these compounds.   Numerous studies have identified the risks and risks of coronary heart disease (CHD) in humans. The severity of any experimental atherosclerosis in the serum It has been shown to be inversely correlated with terol (HDL-C) concentrations [Russ et al. American Journal of Medicine (Am . J. Med.),11(1951) 480-493; Gofman et al., Circulation (Circulation),34(1966) 679-697; Miller and Miller, Lancet (Lancet),1(1975) 16-19; Go Gordon et al., Circulation (Circulation),79(1989) 8-15; stamper (Stampfer) et al., New England Journal of Medicine (N . Engl . J. Med. ),325(1991) 373-381; Badimon et al., Laboratory Inve. Stigration (Lab . Invest.),60(1989) 455-461]. Atherosclerosis Is the process of cholesterol accumulation in the arterial wall, It results in obstruction or stenosis, eventually causing myocardial infarction and stroke. Blood vessels Contrast-enhanced studies show that elevated levels of HDL particles in humans Have been shown to be associated with a decrease in the number of stenotic sites [Miller et al., British Medical Journal (Br . Med. J.),282(1981) 1741-1744] .   There are several mechanisms by which HDL prevents the progression of atherosclerosis. In vitro studies show that HDL can remove cholesterol from cells [Picardo et al., Arteriosclerosis (Arteriosclerosis),6 (1986) 434-441]. Data on this property can be found in HDL, which suppresses atherogenesis. One of the properties of this is that it eliminates excess free cholesterol from tissues, and consequently Suggests that its capacity to deliver cholesterol to the liver [Glomset, Journal of Lipid Research (J . L ipid Res. ),9(1968) 155-167]. This means cholesterol from HDL to the liver [Glass et al., Circuit (Circulation),66(Addendum I(1982) 102; MacKinnon et al. Journal of Biological Chemistry (J . Biol. Chem.),261(1986) 2548-2552]. In addition, HDL is a rapid substitute for triglyceride-rich lipoproteins. Grow can serve as a reservoir in the circulation of apoproteins required for sickness [Grow And Fried, Journal of Biological Chemistry (J . Biol. Chem. ),253(1978) 1834-1841; Lagocki and Scanu ), Journal of Biological Chemistry (J . Biol. Chem.),255(19 80) 3701-3706; Schaefer et al., Journal of Lipid Lisa Reach (J . Lipid Res.)twenty three(1982) 1259-1273]. Therefore, HDL cholesterol concentration Drugs that increase blood pressure may be used as anti-atherosclerotic drugs, especially for low lipoprotein blood. It is useful for the treatment of coronary artery disease and coronary heart disease.   U.S. Pat. No. 5,137,904 has the formula: Wherein Z is alkyl, phenylalkyl, phenyl or substituted phenyl (where Wherein the substituent is a halogen, alkyl, alkoxy or halogenated alkyl group); X is phenyl, halophenyl, alkyl, alkenyl, or alkynyl; and And Y is S or O] Discloses a group of thiohydantoin derivatives. These compounds are Inhibits collagen-induced and ADP-induced platelet aggregation.   EP 0584694 and WO 93/18057 inhibit platelet aggregation, metastasis and osteoclastogenesis. A group of imidazolidine-3- as an inhibitor of cell-cell adhesion for use in harm Disclosed are ylbenzoyl or alkanoyl amino acid derivatives. Arteriosclerosis And long-term administration for the prevention of thrombosis. [Wherein, Y =-(CH_Two)_n-CO- or -Ph-CO-].   JP 04,297,461 is an antibacterial, antiviral, anti-inflammatory and antirheumatic drug. A group of 2-thiohydantoins which are said to be useful Disclosed are compounds. [Wherein, R¹Is lower alkyl, lower alkenyl, phenyl (lower) alkyl, Is lower alkyl, lower alkoxy, halogen, lower alkoxycarbonyl or Phenyl substituted with 1 to 3 groups selected from hydroxy;   R^TwoIs either hydrogen or alkanoyl; and   R^ThreeIs hydrogen, lower alkyl, phenyl, phenyl (lower) alkyl, or lower Alkylthio (where the lower alkyl group is 1 to 3 alkyl groups having a lower alkoxy group) May be substituted with a phenyl group of   EP 0578516 is said to be an antiandrogen useful in the treatment of various cancers The formula: Wherein X is oxygen or sulfur;   Y is oxygen, sulfur or NH;   R¹And R^TwoIs cyano, nitro, halogen, trifluoromethyl, or Release or ester type carboxylic acids or salts;   R^ThreeIs hydrogen, alkyl, alkenyl, alkynyl, aryl or aryl- Lequil;   R^FourAnd R^FiveIs hydrogen, optionally substituted alkyl, or Chloroalkyl] Discloses a group of 2-thiohydantoins.   US 5,411,981 discloses compounds closely related to EP 0578516 mentioned above, except that R^FourYou And R^FiveAre methyl).   US 3,923,994 discloses a class of 3-ants having anti-arthritic activity, represented by the formula: Discloses 2-thiohydantoin derivatives. [Wherein, R¹And R^TwoIs hydrogen, chloro, bromo, fluoro or C1-2 Alkyl]   JP 73 87,030 is a group of 3-phenyl-2-thiohydantes useful as herbicides In derivatives are disclosed.   U.S. Pat.No. 4,473,393 discloses a family of insecticidal thiohydantoin compositions. I have.   According to the present invention, formula I: [Where,   R is alkyl having 1 to 6 carbons; having 4 to 6 carbons and one hetero ring-constituting atom Substituted or unsubstituted aromatic N, O or S heterocyclic ring; Or unsubstituted aryl, arylalkyl having 7 to 12 carbon atoms, benzhydryl and the like. Or indanyl (where the substituent is an alkyl having 1 to 6 carbons, Alkoxy, alkylthio having 1 to 6 carbons, alkenyl having 2 to 6 carbons, carbon number 2 to 6 alkynyl, halo, C 1 to C 6 perfluoroalkyl, C 1 to C 6 independently selected from the group consisting of perfluoroalkoxy or hydroxy 1 to 3 substituents); and   R¹Is aryl having 6 to 10 carbons, alkyl having 1 to 6 carbons, and 2 to 6 carbons Alkenyl, alkynyl having 2 to 6 carbons or substituted aryl having 6 to 10 carbons ( Here, the substituent is alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, carbon Alkylthio having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms , Halo, C1-C6 perfluoroalkyl, C1-C6 perfluoro 1-3 substitutions independently selected from the group consisting of alkoxy or hydroxy Base)] A compound for use in treating a mammal, represented by formula (I), is provided.   A preferred embodiment of the present invention is a compound of the formula I wherein R is substituted phenyl (wherein And the substituent is alkyl having 1 to 6 carbons, perfluoroalkoxy having 1 to 6 carbons , Halo, or ortho-substituted trimethylene or tetramethylene. Two selected substituents);¹Is alkyl having 1 to 6 carbons, 2 to 6 carbons Which is alkenyl or alkynyl having 2 to 6 carbon atoms.   Another preferred embodiment of the present invention is represented by formula I wherein R is substituted phenyl (this Here, the substituent is halo and alkyl or ortho-substituted trimethyl having 1 to 3 carbon atoms. Len) and R¹Is alkyl having 1 to 3 carbons, alkenyl having 2 to 4 carbons or Is a compound having 2 to 4 carbon atoms.   Another preferred embodiment of the present invention is represented by formula I wherein R is substituted phenyl (this Here, the substituent is chloro or fluoro at the 4- or 5-position and C1-C3. Alkyl) and R¹Is alkyl having 1 to 3 carbons, alkenyl having 2 to 4 carbons Or a compound which is an alkynyl having 2 to 4 carbon atoms is provided.   Certain of the compounds of the present invention are novel and constitute a further aspect of the present invention. I do. Thus, according to a further aspect of the present invention, there is provided a compound of formula I above, wherein R¹Is Alkyl having 1 to 6 carbons, R is alkyl having 1 to 6 carbons, naphthyl, benzhydr Ryl, fluorophenylmethyl, phenethyl, 1- (fluorophenyl) ethyl, 5-chloro-2-methoxyphenyl, trifluoromethoxyphenyl, trifluoro Lomethylphenyl, methylsulfanylphenyl, pyridyl or formula II: [Wherein, R^Two, R^ThreeAnd R^FourAre 2-chloro, 4-fluoro, 2,4-chloro Or 2,6-chloro, or R^TwoIs hydrogen, R^ThreeIs halogen at the 3-position, R^FourIs the 4th charcoal An alkyl having a prime number of 1 to 6, or R^TwoIs an alkyl having 1 to 6 carbons, R^ThreeAnd R^Four Is independently hydrogen or alkyl having 1 to 6 carbons, or R^ThreeIs halogen, R^FourIs hydrogen] A group represented by;   Alternatively, R¹Is an alkenyl having 2 to 6 carbon atoms, and R is a group of the formula II (where R^TwoIs charcoal Alkyl of a prime number 1 to 6, R^ThreeAnd R^FourIs independently hydrogen or an alkyl having 1 to 6 carbons Kill or R^TwoIs hydrogen, R^ThreeAnd R^FourAre ortho-substituted trimethylene Or tetramethylene, or R^TwoIs an alkyl having 1 to 6 carbons, R^ThreeIs haloge N, R^FourIs hydrogen or R^TwoIs hydrogen, R^ThreeIs halogen at the 3-position, R^FourIs the number of carbon atoms at position 4. 1-6 alkyl);   Alternatively, R¹Is alkynyl having 2 to 6 carbon atoms, R is a group of the formula II wherein R^Two , R^ThreeAnd R^FourIs independently alkyl having 1 to 6 carbon atoms, halo, charcoal Perfluoroalkyl having 1 to 6 carbon atoms, perfluoroalkoxy having 1 to 6 carbon atoms, Or together, ortho-substituted trimethylene or tetramethylene);   Alternatively, R¹Is aryl having 6 to 10 carbons or aryl having 7 to 12 carbons When alkyl, R is a group of formula II wherein R^TwoIs an alkyl having 1 to 6 carbons, R^ThreeIs Halogen, R^FourIs hydrogen or R^TwoIs hydrogen, R^ThreeIs halogen at the 3-position, R^FourIs a compound represented by the formula (1):   R, R¹, R^Two, R^ThreeOr R^FourIt is preferred when any of is alkyl Or alkyl having 1 to 3 carbon atoms, especially methyl or ethyl, or R^Two, R^ThreeAnd And R^FourAny two of which are ortho-substituted trimethylene or tetramethyl Len.   R¹When is alkenyl having 2 to 6 carbon atoms, it is preferably allyl . R^TwoAnd R^ThreeWhen is halogen, they are preferably independently chlorine or fluorine. Nitrogen, especially at the 2nd, 4th and / or 6th position. R^TwoOr R^ThreeBut Perfluoroalkyl having 1 to 6 carbon atoms, perfluoroalkoxy having 1 to 6 carbon atoms When R¹Is alkynyl having 2 to 6 carbon atoms, it is preferably ethynyl, pro- Pargyl or butynyl, especially prop-2-ynyl.   When R is aryl having 6 to 10 carbon atoms, it is preferably phenyl or Naphthyl, the latter being preferably 2-naphthyl. R has 7 to 12 carbon atoms When it is aralkyl, it is preferably benzyl or phenethyl.   When R is fluorophenylmethyl, it is preferably 4-fluorophenyl Nylmethyl.   When R is 1- (fluorophenyl) ethyl, it is preferably 1- (4-fluoro) Lophenyl) ethyl. When R is trifluoromethoxyphenyl, It is preferably 4-trifluoro-methoxyphenyl. R is methylsulfa When it is phenyl, it is preferably 2-methylsulfanylphenyl is there. When R is pyridyl, it is preferably 3-pyridyl.   The most preferred compounds of the invention are those compounds in standard experimental test models. Based on potency and total activity profile:   3- (5-chloro-2-methylphenyl) -1-methyl-2-thioxo-imidazolidine- 4-ON   3- (3-chloro-2-methylphenyl) -1-methyl-2-thioxo-imidazolidine- 4-ON   3- (4-chloro-2-methylphenyl) -1-methyl-2-thioxo-imidazolidin- 4-ON   3- (indan-5-yl) -1-methyl-2-thioxo-imidazolidin-4-one   3- (2,6-diisopropylphenyl) -1-methyl-2-thioxo-imidazolidine -4-on   3- (2-ethyl-6-isopropylphenyl) -1-methyl-2-thioxo-imidazo Lysine-4-one   3- (2-ethyl-6-methylphenyl) -1-methyl-2-thioxo-imidazolidine- 4-ON   3- (5-chloro-2-methylphenyl) -1-ethyl-2-thioxo-imidazolidine- 4-ON   3- (2,6-dichlorophenyl) -1-ethyl-2-thioxo-imidazolidin-4-o In   1-ethyl-3- (4-fluorophenyl) -2-thioxo-imidazolidin-4-one   1-ethyl-2-thioxo-3- (4-trifluoromethoxyphenyl) -imidazoli Gin-4-on   3- (2,6-dimethylphenyl) -1-ethyl-2-thioxo-imidazolidin-4-o In   1-ethyl-3-isobutyl-2-thioxo-imidazolidin-4-one   3- (2-chlorophenyl) -1-ethyl-2-thioxo-imidazolidin-4-one   1-ethyl-3- (2-tolyl) -2-thioxo-imidazolidin-4-one   3- (2-chloro-6-methylphenyl) -1-ethyl-2-thioxo-imidazolidine- 4-ON   1-ethyl-3- (5-fluoro-2-methylphenyl) -2-thioxo-imidazolidy N-4-ON   3- (2,6-diisopropylphenyl) -1-ethyl-2-thioxo-imidazolidy N-4-ON   1-ethyl-2-thioxo-3- (2-trifluoromethylphenyl) -imidazolide N-4-ON   1-ethyl-3- (2-ethyl-6-methylphenyl) -2-thioxo-imidazolidine- 4-ON   3- (2-chloro-4-methylphenyl) -1-ethyl-2-thioxo-imidazolidine- 4-ON   3- (2,4-dichlorophenyl) -1-ethyl-2-thioxo-imidazolidin-4-o In   3- (2,4-dimethylphenyl) -1-ethyl-2-thioxo-imidazolidin-4-o In   3- (2,5-dimethylphenyl) -1-ethyl-2-thioxo-imidazolidin-4-o In   1-ethyl-2-thioxo-3- (2,4,5-trimethylphenyl) -imidazolidine- 4-ON   1-ethyl-3- (2-isopropylphenyl) -2-thioxo-imidazolidine-4- on   1-ethyl-3- (2-ethylphenyl) -2-thioxo-imidazolidin-4-one   3- (5-chloro-2-methylphenyl) -1-phenyl-2-thioxo-imidazolidy N-4-ON   3- (5-chloro-2-methylphenyl) -1-isopropyl-2-thioxo-imidazo Lysine-4-one   3- (2,6-dimethylphenyl) -1-isopropyl-2-thioxo-imidazolidine -4-on   3- (2-ethyl-6-methylphenyl) -1-isopropyl-2-thioxo-imidazo Lysine-4-one   1-butyl-3- (4-fluorophenyl) -2-thioxo-imidazolidin-4-one   1-allyl-3- (2,6-dimethylphenyl) -2-thioxo-imidazolidin-4-o In   3- (2,6-dimethylphenyl) -1- (prop-2-ynyl) -2-thioxo-imidazo Lysine-4-one   3- (3-chloro-4-methylphenyl) -1-methyl-2-thioxo-imidazolidin- 4-ON   3- (2-ethylphenyl) -1-methyl-2-thioxo-imidazolidin-4-one   1-methyl-3- (2-isopropylphenyl) -2-thioxo-imidazolidine-4- on   3- (4-t-butylphenyl) -1-methyl-2-thioxo-imidazolidin-4-one   1-allyl-3- (5-chloro-2-methylphenyl) -2-thioxo-imidazolidine- 4-ON   3- (5-chloro-2-methylphenyl) -1- (prop-2-ynyl) -2-thioxo-i Midazolidine-4-one   1-ethyl-3- (2-ethyl-6-isopropylphenyl) -2-thioxo-imidazo Lysine-4-one   A preferred use of the compounds of formula I, i.e. a method of treatment with these compounds, is For increasing HDL cholesterol levels in the blood of mammals The mammal may have a substituted 2-thioxo-imidazolidin-4-o as defined herein. Is administered in an amount sufficient to raise such HDL cholesterol levels. It is implemented by doing. And this represents a further aspect of the invention.   The compounds of the present invention utilize readily available starting materials, reagents and conventional synthetic methods. Can be easily prepared according to the following reaction scheme or a modification thereof. . Variations of these manufacturing processes (known per se, fully prepared by medicinal chemists (Within the scope of technology) can also be used. In the following reaction scheme , R^TwoIs hydrogen or alkyl having 1 to 6 carbons, and X is halogen.  The N-substituted amino acid (2a) reacts the corresponding α-halo acid (1) with the appropriate amine (excess). Prepared. This reaction can be performed as is or in water at room temperature. For 18 hours. One equivalent of amine is an amine hydrogen halide as a by-product The hydrohalide formed during the alkylation to form the acid salt (2b) is captured. The N-alkyl amino acid (2a) is purified by crystallization from a suitable solvent or Or isothiocyanate as a mixture of crude products containing amine hydrohalides Reacted with The reaction between 2a and isothiocyanate is carried out using triethylamine, etc. In chloroform or methylene chloride in the presence of a base. This mixture Heat to reflux for 3-18 hours. Reaction is thiourea (3a) or direct thiohydantoin (4) (R¹Depending on the nature of the). Cyclization of 3a to thiohydantoin (4) Reflux in ethanol in the presence of a base (triethylamine) for 2-3 hours. And is carried out. The crude product mixture (2a & 2b) is reacted with isothiocyanate. When formed, thiourea (3b) is formed together with 4 as a by-product. Purification of 4 1) fractional crystallization, 2) flash chromatography, 3) extraction of 3b into 2N hydrochloric acid Or 4) 3b as its hydrochloride in ethyl acetate or diethyl ether. By precipitation from a suitable solvent such as toluene.   The present invention further relates to a 2-thioxoimidazolidin-4-one derivative alone or Combination with excipients (ie pharmaceutically acceptable substances without pharmacological action) And a pharmaceutical composition comprising: Such a composition may be a composition treated with the compound. In raising serum high density lipoprotein levels in dairy animals, low lipoprotein It is useful in the treatment of atherosclerotic conditions such as bloodemia and coronary heart disease.   The exact dose to be adopted depends on the patient (whether veterinary or human), The nature and severity of the condition, the mode of administration, and the particular active substance employed. Depends on several factors. The compounds described above are preferred by conventional routes, especially enterally. Preferably, it is administered orally in the form of tablets or capsules. Administration The compound is suitable for use as a medicament, especially for atherosclerosis and sequelae (angina Disease, myocardial infarction, arrhythmia, heart failure, renal failure, stroke, peripheral artery occlusion, and related Free form, as appropriate for prophylactic or curative treatment of Or a pharmaceutically acceptable salt form. These treatments are Slows the progression of the state and helps the body reverse its direction naturally.   Pharmaceutical compositions can be prepared using suitable carriers known in the art. . In such compositions, the carrier can be any solid, liquid, or mixture of solid and liquid. It may be. Solid compositions include powders, tablets and capsules. Solid carriers include flavoring agents, lubricants, solubilizing agents, suspending agents, binders, and disintegrants. One or more substances that can also act as For powder , The carrier is a finely divided solid, also with the finely divided active ingredient Mixed. In the case of tablets, the active ingredient is composed of a carrier having the necessary compressibility and a suitable Are mixed in proportions and formed into the desired shape and dimensions. Suitable solid carriers are carbonated Magnesium, magnesium stearate, talc, sugar, lactose, pectin, de Xistrin, starch, gelatin, tragacanth, methylcellulose, hydroxy Cimethylcellulose, sodium carboxymethylcellulose, low melting wax , Cocoa butter and the like. Employ an encapsulating material with the compound of the present invention The term "composition" may refer to the encapsulating material, optionally with other carriers. It is intended to include as a formulation the active ingredient in combination with. Anti-Athero of the present invention Cachets may be used for delivery of mucosal atherosclerotic drugs.   Sterile liquid compositions include solutions, suspensions, emulsions, syrups and elixirs. Agents. The compound of the present invention may be a pharmaceutically acceptable carrier such as sterile water May be dissolved or suspended in a sterile organic solvent or a mixture of both. Parenteral Liquid carriers suitable for injection are preferred. If these compounds are sufficiently soluble If necessary, an appropriate organic solvent (eg, propylene glycol or polyethylene) Can be directly dissolved in normal saline using renglycol). As needed And pulverize the suspension of the finely divided compound into starch or carboxymethyl cellulose. Prepared in an aqueous solution of sodium salt or in a suitable oil (eg, peanut oil) Can be Liquid pharmaceutical compositions, which are sterile solutions or suspensions, are administered intramuscularly, It can be utilized by intraperitoneal or subcutaneous injection. Often a liquid composition May be used in place of the preferred solid oral administration method.   It is preferable to prepare the compounds in unit dosage form for a standard dosage regime. Scratch Thus, the composition may be readily divided into smaller doses at the direction of a physician. Can be. For example, a unit dose may be suitable for dispensing, vials or ampoules. Or a capsule or tablet. Composition of these unit dosage forms The active compound present in the product may be administered once daily or multiple times, depending on the particular needs of the patient. For several administrations, it may be present in amounts from about 1 g to about 15 g or more. Activity The daily dose of the compound will depend on the route of administration, patient size, age and gender, and the severity of the disease state. Depending on the response to therapy, as tracked by blood analysis, and the rate of patient recovery Change. By starting a treatment regimen with a minimum daily dose of about 1 g, Use of DL blood levels and patient symptomatic palliative analysis may require higher dosage You just have to decide if you want to do that. Based on the data shown below, humans and animals Estimated daily doses for both medical uses are from about 10 to about 200 mg / kg / day. It is. However, in general, satisfactory results are in the range of about 400 mg to about 2000 mg. Daily dose (for convenience, administered 2-4 times a day in divided doses). Is shown.   The ability of the compounds of the invention to increase serum HDL levels is determined by HDL cholesterol Established by the following standard experimental method for measuring oil.   Male Sprague-Dawley rats weighing 200-225 g 2 per cage, 0.25% choline and 1.0% cholesterol Purina Rodent Chow Special Mix (Purina Rodent  Chow Special Mix) 5001-S and water ad libitum for 8 days. Same diet (test diet) Is a mixture of 0.005% to 0.1% of the total diet). Is administered with each test substance. Weight and food consumption before and at the end of food administration. Record. Typical doses of test substance are between 5 and 100 mg / kg / day.   At the end point, blood is collected from anesthetized rats and serum is centrifuged. Sigma ma) diagnostic enzyme kit for cholesterol measurement, Sigma Procedure No. 352 (9 (Modified for use in 6-well microtiter plates) using whole serum cholesterol. Analyze the role. After reconstitution with water, the reagents were placed in pH 6.5 buffer at 300 U / l cholesterol oxidase, 100 U / l cholesterol esterl , 1000 U / l horseradish peroxidase, 0.3 mmol / l 4-amino Antipyrine and 30.0 mmol / l p-hydroxybenzenesulfonate contains. In this reaction, cholesterol is oxidized to produce hydrogen peroxide. The quinone imine dye is formed using this. The concentration of the dye formed is 25 After incubation at 30 ° C. for 30 minutes, absorbance at 490 nm was measured using a spectrophotometer. Measured by luminosity. Cholesterol levels are commercially available from Sigma. It was measured for each serum sample relative to the standard.   Serum HDL cholesterol levels can be determined by the method of Kieft et al. [Journal Le of lipid research (J . Lipid Res.),32(1991) 859-866] Of lipoprotein class by high-performance liquid chromatography (FPLC) Measure by separation. 0.05M Tris (2-amino-2-hydroxymethyl-1,3- Using propanediol) and 0.15M sodium chloride column buffer. At a rate of 0.5 ml / min, 25 μl of serum was transferred to Superose 12 and shoe. Inject sequentially into Superose 6 (Pharmacia). Eluted The Boehringer-Mnheim (Boehringer-M) fed the sample at a rate of 0.2 ml / min. Mix online with a cholesterol reagent from Armheim). The combined eluate A knitting coil mixed and maintained at a temperature of 45 ° C. (Applied Biosciences (A pplied Biosciences). The eluate is Monitor by measuring absorbance at 490 nm, but cholesterol Gives a continuous absorbance signal proportional to the concentration of the protein. Aspects of each lipoprotein class The relative concentration is calculated as a percentage (%) of the total absorbance. HDL choles in serum Terol concentration is the percentage of total cholesterol measured by FPLC (%) Multiplied by the total serum cholesterol concentration.   Test compounds were administered in an amount of 100 mg / kg. Duration of treatment was 8 days . Compounds of the invention increase HDL cholesterol levels as shown in Table I .   The following examples are not intended to be a limitation on the scope of Applicants' invention, but rather to Provided to illustrate the preparation of representative compounds useful in the method.                                 Example 1 3- (5-chloro-2-methylphenyl) -1-methyl- 2-thioxo-imidazolidin-4-one   Sarcosine ethyl ester hydrochloride (7.68 g), 5-chloro-2-methylphenyl -Isothiocyanate (9.18 g), triethylamine (12 g) and chloropho The mixture of rum (200 mL) was heated at reflux for 5 hours. The mixture is cooled to room temperature, After washing with 1N HCl (2 × 200 mL), it was washed with water (200 mL). Organic phase Evaporated to dryness. The residue was crystallized from ethanol to give the title compound (9.2 g) as a yellowish brown. Color solid Obtained as a form. 132-134 ° C. Elemental analysis: C₁₁H₁₁ClN_TwoOS Calculated: C, 51.87; H, 4.35; N, 11.00; 51.79; H, 4.12; N, 10.73. Mass spectrum (EI, M.⁺) m / z2 54/256.                                 Example 2 3-benzhydryl-1-methyl-2-thioxo-imidazolidin-4-one   11.25 g of benzhydryl-isothiocyanate, sarcosine ethyl ester 7.68 g of hydrochloride, 12 g of triethylamine and 200 mL of chloroform And the title compound was prepared by the method described in Example 1. The title compound is Obtained as an off-white solid (7.40 g). 139-141 ° C. element Analysis result: C₁₇H₁₆N_TwoCalculated value for OS: C, 68.89; H, 5.44; N, 9.45; Found: C, 68.92; H, 5.43; N, 9.58. Mass spec Toll (EI, M.⁺) m / z 296.                                 Example 3 1-methyl-3- (pyridin-3-yl) -2-thioxo-imidazolidin-4-one   Sarcosine ethyl ester hydrochloride (7.68 g), pyridin-3-yl-isothiosi Anate (6.8 g), triethylamine (10.1 g) and chloroform (200 g) (mL) of the mixture was heated at reflux for 3.5 hours. The solvent was distilled off. Residue in ethyl acetate ( (300 mL) and washed with water (2 × 200 mL). The organic phase is anhydrous magnesium sulfate And dried with um. The solvent was distilled off. Crystallization from ethyl acetate gave the title compound ( 4.1 g) were obtained as an off-white solid. Melting point 149-151 [deg.] C. Elemental content Analysis result: C₉H₉N_ThreeAs OS, calculated values: C, 52.16; H, 4.38; N, 20.28, found: C, 52.16; H, 4.05; N, 20.06. Mass spec Toll (EI, M.⁺) m / z 207.                                 Example 4 3- (5-chloro-2-methoxyphenyl) -1-methyl- 2-thioxo-imidazolidin-4-one   Sarcosine ethyl ester hydrochloride (7.68 g), 5-chloro-2-methoxyphenyl L-isothiocyanate (10.0 g), triethylamine (10.0 g) and chloroform A mixture of loform (150 mL) was heated at reflux for 4.5 hours. Bring this mixture to room temperature Cool. Collect the precipitated solid, wash with chloroform, air dry and The compound (11.8 g) was obtained as an off-white solid. 245-247 ° C . Elemental analysis: C₁₁H₁₁ClN_TwoO_TwoCalculated as S: C, 48.80; H , 4.10; N, 10.35, found: C, 48.42; H, 3.96; N, 10. 33. Mass spectrum (EI, M.⁺) m / z 270.                                 Example 5 3- (3-chloro-2-methylphenyl) -1-methyl- 2-thioxo-imidazolidin-4-one   13.2 g of 3-chloro-2-methylphenyl-isothiocyanate, sarcosine 11.0 g of tyl ester hydrochloride, 25 g of triethylamine, and chloroform The title compound was prepared by the method described in Example 1 using 300 mL. The Crystallization from ethyl ether gave the title compound (15.2 g) as a tan solid. I got it. 122-124 ° C. Elemental analysis: C₁₁H₁₁ClN_TwoAs OS , Calculated: C, 51.87; H, 4.35; N11.00, Found: C, 51.96. H, 4.21; N, 11.05. Mass spectrum (EI, M.⁺) m / z 254/25 6.                                 Example 6 3- (3-chloro-4-methylphenyl) -1-methyl- 2-thioxo-imidazolidin-4-one   18.3 g of 3-chloro-4-methylphenyl-isothiocyanate, sarcosine 15.3 g of tyl ester hydrochloride, 25 g of triethylamine, and chloroform The title compound was prepared by the method described in Example 1 using 300 mL. vinegar Crystallization from ethyl acid gave the title compound (14.5 g) as an off-white solid I got it. Melting point 178-180 [deg.] C. Elemental analysis: C₁₁H₁₁ClN_TwoAs OS Calculated: C, 51.87; H, 4.35; N11.00, found: C, 51.8. 9; H, 4.20; N, 10.95. Mass spectrum (+ FAB, [M + H]⁺) m / z 255/257.Example 7               3-( 4-chloro-2-methylphenyl) -1-methyl- 2-thioxo-imidazolidin-4-one   9.18 g of 4-chloro-2-methylphenyl-isothiocyanate, sarcosine 7.68 g of tyl ester hydrochloride, 12.0 g of triethylamine, and chloroform The title compound was prepared by the method described in Example 1 using 300 mL of the compound. Crystallization from diethyl ether gave the title compound (7.5 g) as an off-white solid. Obtained as a form. 113-115 ° C. Elemental analysis: C₁₁H₁₁ClN_TwoO As S, calculated values: C, 51.87; H, 4.35; N11.00, actual values: C, 51.72; H, 4.17; N, 10.88. Mass spectrum (EI, M.⁺) m / z2 54/256.                                 Example 8 3- (indan-5-yl) -1-methyl-2-thioxo-imidazolidin-4-one   7.7 g of indan-5-yl-isothiocyanate, sarcosine ethyl ester salt Using 6.7 g of acid salt, 12 g of triethylamine, and 300 mL of chloroform The title compound was prepared by the method described in Example 1. Crystal from ethyl acetate To give the title compound (7.9 g) as a tan solid. Melting point 158-160 ° C. Elemental analysis: C₁₃H₁₄N_TwoCalculated value for OS: C, 63.39; H, 5 .73; N 11.37; Found: C, 63.30; H, 5.81; N, 11.31. Mass spectrum (EI, M.⁺) m / z 246.                                 Example 9 3- (2,6-diisopropylphenyl) -1-methyl- 2-thioxo-imidazolidin-4-one   8.3 g of 2,6-diisopropylphenyl-isothiocyanate, sarcosine ethyl Ester hydrochloride 5.8 g, triethylamine 14.5 g, and chloroform 2 The title compound was prepared by the method described in Example 1 using 00 mL. Jie Crystallization from a tyl ether / hexane mixture gave the title compound (6.6 g) as a tan. Obtained as a solid. Melting point 174-176 [deg.] C. Elemental analysis: C₁₆H_{twenty two}N_TwoOS Calculated: C, 66.17; H, 7.63; N 9.64, found: C, 66. 39; H, 7.63; N, 9.59. Mass spectrum (+ FAB, [M + H]⁺) m / z 269/271.                                Example 10 3- (2-ethyl-6-isopropylphenyl) -1-methyl- 2-thioxo-imidazolidin-4-one   10.25 g of 2-ethyl-6-isopropylphenyl-isothiocyanate, monkey 7.68 g of cosin ethyl ester hydrochloride, 14.8 g of triethylamine, and The title compound was prepared by the method described in Example 1 using 200 mL of loroform. Made. Crystallization from a diethyl ether / hexane mixture gave the title compound (8.9). 5g) was obtained as a tan solid. 132-134 ° C. Elemental analysis results: C₁₅H₂₀N_TwoAs OS, calculated values: C, 65.18; H, 7.29; N10.13, Found: C, 65.11; H, 7.31; N, 10.05. Mass spectrum (PBE I, M.⁺) m / z 276.                                 Example 11 3- (2-ethyl-6-methylphenyl) -1-methyl- 2-thioxo-imidazolidin-4-one   8.9 g of 2-ethyl-6-methylphenyl-isothiocyanate, sarcosine ethyl Ester hydrochloride 7.68 g, triethylamine 12.5 g, and chloroform The title compound was prepared by the method described in Example 1 using 250 mL. The Crystallize from ethyl ether to give the title compound (7.45g) as a pink solid Obtained. 106-108 ° C. Elemental analysis: C₁₃H₁₆N_TwoCalculated as OS Value: C, 62.87; H, 6.49; N 11.28, found: C, 62.52; H, 6.61; N, 11.29. Mass spectrum (+ ESI, [M + H]⁺) m / z 269/2 71.                                 Example 12 3- (2-chloro-6-methylphenyl) -1-methyl- 2-thioxo-imidazolidin-4-one   9.2 g of 2-chloro-6-methylphenyl-isothiocyanate, sarcosine ethyl Ester hydrochloride 7.68 g, triethylamine 12 g, and chloroform 2 The title compound was prepared by the method described in Example 1 using 00 mL. Eta Crystallization from methanol gave the title compound (7.1 g) as an orange solid (7.1 g). Was. 142-145 ° C. Elemental analysis: C₁₁H₁₁ClN_TwoOS Calculated: C, 51.87; H, 4.35; N11.00; found: C, 51.96; H , 4.26; N, 10.97. Mass spectrum (EI, M.⁺) m / z 254.                                Example 13 3- (2-ethylphenyl) -1-methyl-2-thioxo-imidazolidin-4-one   16.3 g of 2-ethylphenyl-isothiocyanate, sarcosine ethyl ester Hydrochloride 15.3 g, triethylamine 20.2 g, and chloroform 300 m The title compound was prepared by the method described in Example 1 using L. Title compound (20.4 g) were obtained as an off-white solid. 135-137 ° C. Elemental analysis: C₁₂H₁₄N_TwoCalculated value for OS: C, 61.51; H, 6.0 N; 11.96; Found: C, 61.11; H, 5.92; N, 11.71. mass Spectrum (EI, M.⁺) m / z 234.                                Example 14 1-methyl-3- (2-isopropylphenyl)- 2-thioxo-imidazolidin-4-one   14.2 g of 2-isopropylphenyl-isothiocyanate, sarcosine ethyl 12.29 g of ester hydrochloride, 16.0 g of triethylamine, and chloroform The title compound was prepared by the method described in Example 1 using 200 mL. The Crystallization from ethyl ether gave the title compound (15.9 g) as a pink solid. Obtained. 129-131 ° C. Elemental analysis: C₁₃H₁₆N_TwoCalculated as OS H, 6.49; N 11.28, found: C, 62.89; H, 6.38; N, 11.28. Mass spectrum (EI, M.⁺) m / z 248.                                Example 15 3- (2,6-dichlorophenyl) -1-methyl-2-thioxo-imidazolidin-4-one   14.28 g of 2,6-dichlorophenyl-isothiocyanate, sarcosine ethyl 10.75 g of ester hydrochloride, 14.5 g of triethylamine, and chloroform The title compound was prepared by the method described in Example 1 using 200 mL. The Crystallization from ethyl ether gave the title compound (16.9 g) as a light pink solid. As obtained. 207-209 ° C. Elemental analysis: C_TenH₈Cl_TwoN_TwoOS and And calculated: C, 43.65; H, 2.93; N 10.18, found: C, 43.65. 57; H, 2.61; N, 10.14. Mass spectrum (EI, M.⁺) m / z 274.                                Example 16 3- (5-chloro-2-methylphenyl) -1-ethyl 2-thioxo-imidazolidin-4-one   2-Chloroacetic acid (27.5 g) was added with stirring to a 70% aqueous solution of ethylamine (5%). 00 mL). The addition was performed over 30 minutes. Put this mixture in the room Stir at warm for 18 hours. The mixture is then evaporated to a viscous oily A residue (55 g) was obtained. This crude product is composed of N-ethylglycine and ethylamine It consisted of a 1: 1 mixture of hydrochlorides. This product mixture can be further purified Without preparing, the preparation of the title compound in the next paragraph, as well as in Example 17 Used in the preparation of the title compound described in Example 42 and Example 58.   Crude N-ethylglycine (9.23 g), 5-chloro-2-methylphenyl-iso Thiocyanate (9.18 g), triethylamine (10 g) and chloroform (2 g) (50 mL) was heated at reflux for 18 hours. The solvent was distilled off. The residue is treated with ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1 N HCl (00 mL) and evaporated to dryness. Purification is achieved by crystallization from ethanol. It was carried out. The title compound (7.6 g) was obtained as a light pink solid. Fusion Points 152-154 ° C. Elemental analysis: C₁₂H₁₃ClN_TwoCalculated value as OS: C, 53.63; H, 4.88; N 10.42, found: C, 53.36; H, 4. 79; N, 10.35. Mass spectrum (EI, M.⁺) m / z 268/270.                                Example 17 3- (2,6-dichlorophenyl) -1-ethyl-2-thioxo-imidazolidin-4-one   10.2 g of 2,6-dichlorophenyl-isothiocyanate, N-ethylglycine Using 7.4 g, 10 g of triethylamine and 250 mL of chloroform, The title compound was prepared by the method described in Example 16. Purification from ethanol The crystallization was carried out. The title compound (6.5 g) was obtained as a tan solid. Was. 170-172 ° C. Elemental analysis: C₁₁H_TenCl_TwoN_TwoOS Calculated: C, 45.69; H, 3.48; N 9.69, Found: C, 45.53; H, 3.19; N, 9.62. Mass spectrum (EI, M.⁺) m / z 288/290/292 .                                Example 18 1-ethyl-3- (4-fluorophenyl) -2-thioxo-imidazolidin-4-one   7.65 g of 4-fluorophenyl-isothiocyanate, N-ethylglycine 9. Performed using 32 g, 10 g of triethylamine, and 250 mL of chloroform The title compound was prepared by the method described in Example 16. Purification from ethanol Performed by crystallization. The title compound (6.6 g) was obtained as a pink solid. Was. Melting point 149-151 [deg.] C. Elemental analysis: C₁₁H₁₁FN_TwoCalculated as OS Value: C, 55.45; H, 4.65; N 11.76, found: C, 55.31; H, 4.51; N, 10.82. Mass spectrum (EI, M.⁺) m / z 238.                                Example 19 3- (5-chloro-2-methoxyphenyl) -1-ethyl- 2-thioxo-imidazolidin-4-one   N-ethylglycine (9.2 g), 5-chloro-2-methoxyphenyl-isothiocyan Nate (10 g), triethylamine (10.1 g), and methylene chloride (150 m The mixture of L) was heated at reflux for 3.5 hours. The mixture was evaporated to dryness. Collect residue And washed with hot ethanol and dried. The title compound (7.6 g) is cream colored As a solid. Melting point 171-174 [deg.] C. Elemental analysis: C₁₂H₁₃ClN_Two O_TwoCalculated as S: C, 50.61; H, 4.60; N 9.84, found: C , 50.33; H, 4.50; N, 9.69. Mass spectrum (EI, M.⁺) m / z2 84/286.Example 20 1-ethyl-2-thioxo- 3- (4-trifluoromethoxyphenyl) -imidazolidin-4-one   9.2 g of N-ethylglycine, 4-trifluoromethoxyphenyl-isothiocyan 10.9 g of nitrate, 10.1 g of triethylamine, and 150 mL of methylene chloride And the title compound was prepared by the method described in Example 19. Purification Performed by flash chromatography on mage (methylene chloride). table The title compound (4.6 g) was obtained as a cream colored solid. Melting point 116-119 ° C . Elemental analysis: C₁₂H₁₁F_ThreeN_TwoO_TwoCalculated as S: C, 47.37; H, 3.64; N 9.21, found: C, 47.20; H, 3.50; N, 9.13. quality Quantitative spectrum (EI, M.⁺) m / z 304.                                Example 21 3- (2,6-dimethylphenyl) -1-ethyl-2-thioxo-imidazolidin-4-one   9.2 g of N-ethylglycine, 2,6-dimethylphenyl-isothiocyanate 8. Using 2 g, 10.1 g of triethylamine and 150 mL of methylene chloride, The title compound was prepared by the method described in Example 19. Purification from ethanol The crystallization was carried out. The title compound (2.3 g) was obtained as a white solid (2.3 g). I got it. 128-131 ° C. Elemental analysis: C₁₃H₁₆N_TwoAs OS, Calculated: C, 62.87; H, 6.49; N 11.28, found: C, 62.83; H, 6.50; N, 11.25. Mass spectrum (EI, M.⁺) m / z 248.                                Example 22 1-ethyl-3- (4-fluorobenzyl) -2-thioxo-imidazolidin-4-one   9.2 g of N-ethylglycine, 8.4 4-fluorobenzyl-isothiocyanate g, 10.1 g of triethylamine, and 150 mL of methylene chloride. The title compound was prepared by the method described in Example 19. Purification is ethyl acetate / hex Performed by crystallization from a sun mixture. The title compound (4.85 g) was Obtained as a solid. 73-76 ° C. Elemental analysis: C₁₂H₁₃FN_TwoOS and Calculated: C, 57.12; H, 5.19; N11.10, found: C, 56. 97; H, 5.15; N, 11.06. Mass spectrum (EI, M.⁺) m / z 252.                                Example 23 1-ethyl-3-isobutyl-2-thioxo-imidazolidin-4-one   9.2 g of N-ethylglycine, 5.7 g of isobutyl-isothiocyanate, The procedure described in Example 19 was repeated using 10.1 g of tylamine and 150 mL of methylene chloride. The title compound was prepared by the method described. Flash purification on silica gel Performed by chromatography (methylene chloride). The title compound (2.3 g) Obtained as an oil. Elemental analysis: C₉H₁₆N_TwoCalculated value as OS: C, 53 .97; H, 8.05; N 13.99, found: C, 54.01; H, 8.21; N , 14.00. Mass spectrum (EI, M.⁺) m / z 200.                                Example 24 3- (2-chlorophenyl) -1-ethyl-2-thioxo-imidazolidin-4-one   9.2 g of N-ethylglycine, 8.48 of 2-chlorophenyl-isothiocyanate g, 10.1 g of triethylamine, and 150 mL of methylene chloride. The title compound was prepared by the method described in Example 19. Purification from ethanol Performed by crystallization. The title compound (3.85 g) was obtained as an orange solid. . 142-145 ° C. Elemental analysis: C₁₁H₁₁ClN_TwoCalculated as OS H, 4.35; N11.00, found: C, 51.96; H, 4.26; N, 10.97. Mass spectrum (EI, M.⁺) m / z 254.                                Example 25 1-ethyl-3- (2-tolyl) -2-thioxo-imidazolidin-4-one   9.2 g of N-ethylglycine 7.4 g of 2-tolyl-isothiocyanate, triet The procedure described in Example 19 was repeated using 10.1 g of tylamine and 150 mL of methylene chloride. The title compound was prepared by the method described. Purification by crystallization from ethanol It was carried out. The title compound (3.6 g) was obtained as a cream colored solid. Melting point 105-108 ° C. Elemental analysis: C₁₂H₁₄N_TwoAs OS, calculated value: C, 6 1.51; H6.02; N11.93, found: C, 61.22; H, 5.96; N , 11.89. Mass spectrum (EI, M.⁺) m / z 234.Example 26 1-ethyl-3- (naphthalen-2-yl) -2-thioxo-imidazolidin-4-one   9.2 g of N-ethylglycine, 9.3 g of 2-naphthyl-isothiocyanate, Example 19 was prepared using 10.1 g of ethylamine and 150 mL of methylene chloride. The title compound was prepared by the method described. Purification for crystallization from ethanol Therefore, it was implemented. The title compound (4.7 g) was obtained as a light pink solid. . 156-159 ° C. Elemental analysis: C₁₅H₁₄N_TwoCalculated value as OS: C, 66.64; 5.22; N 10.36, found: C, 66.69; H, 5.24. N, 10.42. Mass spectrum (EI, M.⁺) m / z 270.                                Example 27 3- (2-chloro-6-methylphenyl) -1-ethyl- 2-thioxo-imidazolidin-4-one   9.2 g of N-ethylglycine, 2-chloro-6-methylphenyl-isothiocyanate Using 9.1 g of triethylamine, 10.1 g of triethylamine, and 150 mL of methylene chloride. The title compound was prepared by the method described in Example 19. Purification is silica gel Performed by flash chromatography (methylene chloride) above. Ethanor The title compound (5.4 g) was obtained as a cream solid by crystallization from toluene. Was. 124-126 ° C. Elemental analysis: C₁₂H₁₃ClN_TwoOS Calculated: C, 53.63; H 4.87; N 10.42; found: C, 53.43; H, 4.79; N, 10.28. Mass spectrum (EI, M.⁺) m / z 268/270.                                Example 28 1-ethyl-3- (5-fluoro-2-methylphenyl)- 2-thioxo-imidazolidin-4-one   Crude N-ethylglycine (11.5 g), 5-fluoro-2-methylphenyl-iso Thiocyanate (10.42 g), triethylamine (12.5 g) and chloroform (300 mL) was heated at reflux for 6 hours. The solvent was distilled off. The residue was treated with acetate Dissolved in chill (500 mL) and washed with water (500 mL). The organic phase was evaporated to dryness. Remaining Dissolve the residue in ethanol (50 mL) and dilute with diethyl ether (200 mL) did. The solution was saturated with hydrogen chloride. This mixture was filtered. Discard solids Was. The filtrate was evaporated to dryness. Dissolve the residue in diethyl ether (300 mL) and wash with water (200 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. D Crystallization from ethanol gave the title compound (6.5 g) as a pink solid. . 98-100 ° C. Elemental analysis: C₁₂H₁₃FN_TwoCalculated value as OS: C, 57.13; H, 5.19; N 11.10, found: C, 56.88; H, 5. 17; N, 11.05. Mass spectrum (EI, M.⁺) m / z 252.                                Example 29 3- (2,6-diisopropylphenyl) -1-ethyl- 2-thioxo-imidazolidin-4-one   2,1.9 g of 2,6-diisopropylphenyl-isothiocyanate, 18.4 g of lysine, 20.2 g of triethylamine, and 300 mL of chloroform And the title compound was prepared by the method described in Example 16. Purification is eta Performed by crystallization from knol. The title compound (8.2 g) was a light yellow Obtained as a solid. Melting point 159-161 [deg.] C. Elemental analysis: C₁₇H_{twenty four}N_TwoOS Calculated: C, 67.07; H 7.94; N 9.20, found: C, 66.9. 2; H, 8.03; N, 9.13. Mass spectrum (PBEI, M.⁺) m / z 304.                                Example 30 1-ethyl-2-thioxo- 3- (2-trifluoromethylphenyl) -imidazolidin-4-one   9.2 g of N-ethylglycine, 2- (trifluoromethyl) -phenyl-isothiocy 10.2 g of anate, 10.1 g of triethylamine and 150 m of methylene chloride The title compound was prepared by the method described in Example 19 using L. Residue Further purification by flash chromatography on mica gel (methylene chloride) did. Crystallization from ethanol gave the title compound (2.7 g). Melting point 8 2-85 ° C. Elemental analysis: C₁₂H₁₁F_ThreeN_TwoAs OS, calculated value: C, 50. H, 3.85; N, 9.72; found: C, 50.00; H, 3.61; N, 9. 61. Mass spectrum (EI, M.⁺) m / z 288.Example 31 1-ethyl-3- (2-ethyl-6-isopropylphenyl)- 2-thioxo-imidazolidin-4-one   20.5 g of 2-ethyl-6-isopropylphenyl-isothiocyanate, N-ethyl Luglycine 18.4 g, triethylamine 20.2 g, and chloroform 300 The title compound was prepared by the method described in Example 28 using mL. Purification Flash chromatography on silica gel (5-10% acetic acid in hexane) Chill). Pure by crystallization from diethyl ether / hexane The stylish title compound (7.5 g) was obtained as a white solid. 77-79 ° C. element Analysis result: C₁₆H_{twenty two}N_TwoCalculated as OS: C, 66.17; H 7.64; N 9.65, found: C, 66.12; H, 7.77; N, 9.69. Mass spectrum (EI, M.⁺) m / z 290.                                Example 32 1-ethyl-3- (2-ethyl-6-methylphenyl)- 2-thioxo-imidazolidin-4-one   17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, N-ethylglycol 18.4 g of syn, 20.2 g of triethylamine and 300 mL of chloroform And the title compound was prepared by the method described in Example 28. Residue is silica Flash chromatography on gel (20% ethyl acetate in hexane) And further purified. The title compound was obtained as a light pink solid (8.6 g). 82-84 ° C. Elemental analysis: C₁₄H₁₈N_TwoAs OS, calculated value: C, 6 4.09; H 6.92; N 10.68, found: C, 64.27; H, 7.04; N , 10.60. Mass spectrum (EI, M.⁺) m / z 262.                                Example 33 3- (2-chloro-4-methylphenyl) -1-ethyl- 2-thioxo-imidazolidin-4-one   18.3 g of 2-chloro-4-methylphenyl-isothiocyanate, N-ethylglycol 18.4 g of syn, 20.2 g of triethylamine and 300 mL of chloroform And the title compound was prepared by the method described in Example 28. Ethyl acetate Crystallization provided the title compound (5.8 g) as a pink solid. Melting point 1 26-128 ° C. Elemental analysis: C₁₂H₁₃ClN_TwoAs OS, calculated value: C, 53.63; H 4.88; N 10.42, found: C, 53.50; H, 4.76; N, 10.28. Mass spectrum (+ FAB, [M + H]⁺) m / z 269/271.                                Example 34 1-ethyl-3- [1- (4-fluorophenyl) -ethyl]- 2-thioxo-imidazolidin-4-one   18.1 g of 1- (4-fluorophenyl) -ethyl-isothiocyanate, N-ethyl Glycine 18.4 g, triethylamine 20.2 g, and chloroform 300 m The title compound was prepared by the method described in Example 16 using L. Ethyl acetate The title compound (8.8 g) was obtained as a light yellow solid by crystallization from Was. 93-95 ° C. Elemental analysis: C₁₃H₁₅FN_TwoCalculated value as OS: C, 58.63; H 5.68; N 10.52, found: C, 58.69; H, 5.6. 4: N, 10.58. Mass spectrum (EI, M.⁺) m / z 266.                                Example 35 3- (2,4-dichlorophenyl) -1-ethyl-2-thioxo-imidazolidin-4-one   20.4 g of 2,3-dichlorophenyl-isothiocyanate, N-ethylglycine Using 18.4 g, 20.2 g of triethylamine, and 300 mL of chloroform The title compound was prepared by the method described in Example 16. Purification is silica gel By flash chromatography on the above (20% ethyl acetate in hexane) Carried out. The title compound (8.8 g) was obtained as a light pink solid. Melting point 144 １４146 ° C. Elemental analysis: C₁₁H_TenCl_TwoN_TwoCalculated value as OS: C, 45 .69; H 3.49; N 9.69, found: C, 45.81; H, 3.40; N, 9. 58. Mass spectrum (CI, [M + H]⁺) m / z 289/291/293.                                Example 36 1-ethyl-3-phenethyl-2-thioxo-imidazolidin-4-one   16.3 g of phenethyl-isothiocyanate, 18.4 g of N-ethylglycine, Example 16 was prepared using 20.2 g of triethylamine and 300 mL of chloroform. The title compound was prepared by the method described in Purification is carried out on silica gel. Performed by Chromatography (20% ethyl acetate in hexane). table The title compound (15.0 g) was obtained as an off-white solid. Melting point 66-68 ° C . Elemental analysis: C₁₃H₁₆N_TwoCalculated value for OS: C, 62.87; H6.4 9; N 11.28; found: C, 63.03; H, 6.49; N, 11.32. mass Spectrum (EI, M.⁺) m / z 248.                                Example 37 3- (2,3-dimethylphenyl) -1-ethyl-2-thioxo-imidazolidin-4-one   16.3 g of 2,3-dimethylphenyl-isothiocyanate, N-ethylglycine Using 18.4 g, 20.2 g of triethylamine, and 250 mL of chloroform The title compound was prepared by the method described in Example 16. From ethanol Crystallization provided the title compound (10.3 g) as a light pink solid. . 120-121 ° C. Elemental analysis: C₁₃H₁₆N_TwoCalculated value as OS: C, 62.87; H 6.49; N 11.28, found: C, 62.72; H, 6.4. 4: N, 11.47. Mass spectrum (EI, M.⁺) m / z 248.                                Example 38 3- (2,4-dimethylphenyl) -1-ethyl-2-thioxo-imidazolidin-4-one   16.3 g of 2,4-dimethylphenyl-isothiocyanate, N-ethylglycine Using 18.4 g, 20.2 g of triethylamine, and 250 mL of chloroform The title compound was prepared by the method described in Example 16. From ethanol Crystallization provided the title compound (10.8 g) as a light pink solid. Fusion Points 161-162 ° C. Elemental analysis: C₁₃H₁₆N_TwoAs OS, calculated value: C, H 6.49; N 11.28, found: C, 62.63; H, 6.45; N, 11.17. Mass spectrum (EI, M.⁺) m / z 248.                                 Example 39 3- (2,5-dimethylphenyl) -1-ethyl-2-thioxo-imidazolidin-4-one   16.3 g of 2,5-dimethylphenyl-isothiocyanate, N-ethylglycine Using 18.4 g, 20.2 g of triethylamine, and 250 mL of chloroform The title compound was prepared by the method described in Example 16. From ethyl acetate Crystallization gave the title compound (10.6 g) as an off-white solid. . Melting point 176-178 [deg.] C. Elemental analysis: C₁₃H₁₆N_TwoCalculated value as OS: C, 62.87; H 6.49; N 11.28, found: C, 62.70; H, 6.4. 6; N, 11.27. Mass spectrum (EI, M.⁺) m / z 248.                                Example 40 1-ethyl-2-thioxo- 3- (2,4,5-trimethylphenyl) -imidazolidin-4-one   17.7 g of 2,4,5-trimethylphenyl-isothiocyanate, N-ethylglycol 18.4 g of syn, 20.2 g of triethylamine and 250 mL of chloroform And the title compound was prepared by the method described in Example 16. Ethanol Crystallization of the title compound (15.3 g) as an off-white solid Obtained. 162-164 ° C. Elemental analysis: C₁₄H₁₈N_TwoCalculated as OS Value: C, 64.09; H, 6.92; N, 10.68; found: C, 64.21; H, 6 .93; N, 10.80. Mass spectrum (EI, M.⁺) m / z 262.                                Example 41 1-ethyl-3- (2-isopropylphenyl)- 2-thioxo-imidazolidin-4-one   15.42 g of 2-isopropylphenyl-isothiocyanate, N-ethylglyci 16.05 g, 12 g of triethylamine and 200 mL of chloroform The title compound was prepared by the method described in Example 16. Purification is silica gel Chromatography (5-20% ethyl acetate in hexane) Therefore, it was implemented. The title compound (9.8 g) was isolated by crystallization from ethanol. Obtained as a colored solid. 125-127 ° C. Elemental analysis: C₁₄H₁₈N_Two As OS, calculated values: C, 64.09; H, 6.91; N, 10.68; H. 6.93; N, 10.71. Mass spectrum (EI, M.⁺) m / z2 62.Example 42 1-ethyl-3- (2-ethylphenyl) -2-thioxo-imidazolidin-4-one   16.3 g of 2-ethylphenyl-isothiocyanate, 18.2-N-ethylglycine. 4 g, 20.2 g of triethylamine and 200 mL of chloroform. The title compound was prepared by the method described in Example 16. Purification on silica gel By flash chromatography (5-10% ethyl acetate in hexane) Carried out. The title compound (9.12 g) was obtained by crystallization from diethyl ether. Obtained as a white solid. 71-73 ° C. Elemental analysis: C₁₃H₁₆N_TwoO Calculated as S: C, 62.87; H 6.49; N 11.28, found: C, 6 2.81; H, 6.43; N, 11.17. Mass spectrum (EI, M.⁺) m / z24 8.                                Example 43 3- (5-chloro-2-methylphenyl) -1-phenyl- 2-thioxo-imidazolidin-4-one   N-phenylglycine ethyl ester (8.95 g), 5-chloro-2-methylphen Mixture of Nyl-isothiocyanate (9.18 g) and chloroform (200 mL) The material was heated at reflux for 24 hours. The solvent was distilled off. Residue mixed with ethyl acetate / hexane Crystallized from the product. The solid is collected, dried and treated with 2- [3- (5-chloro-2-methyl Phenyl-1-thioureido] -acetic acid ethyl ester As a solid. 148-150 ° C. Elemental analysis: C₁₈H₁₉ClN_Two O_TwoAs S, calculated values: C, 59.58; H 5.28; N, 7.72; 59.79; H, 5.38; N, 7.65. Mass spectrum (EI, M.⁺) m / z26 2/264.   2- [3- (5-chloro-2-methylphenyl) -1-phenyl-thioureido] -acetic acid Butyl ester (9.5 g), triethylamine (1 mL), and ethanol (150 g) (mL) of the mixture was heated to reflux for 2 hours. Concentrate the mixture to half volume and bring to room temperature And cooled. Collect the solid and air dry to give the title compound (6.1 g) off-white Obtained as a colored solid. Melting point 168-170 [deg.] C. Elemental analysis: C₁₆H₁₃C 1N_TwoCalculated value for OS: C, 60.66; H 4.14; N 8.84, actual value: C , 60.81; H, 4.16; N, 8.81. Mass spectrum (EI, M.⁺) m / z3 16/318.                                Example 44 3- (3-chloro-2-methylphenyl) -1-phenyl- 2-thioxo-imidazolidin-4-one   N-phenylglycine ethyl ester (8.95 g), 3-chloro-2-methylphen Mixture of Nyl-isothiocyanate (9.18 g) and chloroform (200 mL) The material was heated at reflux for 18 hours. The solvent was evaporated to dryness. The residue was ethanol (15 0 mL) and triethylamine (3 mL). Heat this mixture for 3 hours Refluxed. The solvent was distilled off. Dissolve the residue in ethyl acetate (300 mL) and add 1N H After washing with Cl (2 × 200 mL), it was washed with water (200 mL). The organic phase is sulfuric anhydride Dry over magnesium and evaporate to dryness. The residue was treated with diethyl ether. The solid was collected by filtration and air dried to give the title compound (5.3 g) as an off-white solid. I got it. Mp 154-156 ° C. Elemental analysis: C₁₆H₁₃ClN_TwoAs OS Calculated: C, 60.66; H 4.14; N 8.84, found: C, 60.48; H, 4.05; N, 8.76. Mass spectrum (+ FAB, [M + H]⁺) m / z 317 / 319.                                Example 45 3- (5-chloro-2-methylphenyl) -1-isopropyl 2-thioxo-imidazolidin-4-one   2-Chloroacetic acid (69.0 g) was added with stirring to isopropylamine (431.5). g) was added little by little. The addition was performed over 30 minutes. This mixture is brought to room temperature for 1 hour. Stir for 8 hours. Excess isopropylamine was distilled off, resulting in a viscous, clear oil. A solid (182.0 g) remained which solidified on standing. This crude product is From a 1: 1 mixture of N-isopropylglycine and isopropylamine hydrochloride Was composed. This product mixture was used without further purification in the next paragraph. For the preparation of the title compound in Example 46 and in Example 46 to Example 52. Used for compound preparation.   Crude N-isopropylglycine (21.2 g), 5-chloro-2-methylphenyl- Isothiocyanate (18.3 g), triethylamine (21.0 g) and chloropho The mixture of rum (300 mL) was heated at reflux for 4 hours. The solvent was distilled off. Acetic acid residue Dissolved in ethyl (400 mL) and water (300 mL). The organic phase was washed with 2N HCl (2 × 300 mL) and then with water. Dry the organic phase over anhydrous magnesium sulfate And evaporated to dryness. Crystallization from ethanol gave the title compound (15.4 g). Obtained as a pink solid. 142-144 ° C. Elemental analysis: C₁₃H₁₅C 1N_TwoCalculated value for OS: C, 55.21; H, 5.35; N 9.91, actual value: C, 55.07; H, 5.20; N, 9.82. Mass spectrum (+ FAB, [M + H]⁺) m / z 283/285.                                Example 46 3- (2,6-dimethylphenyl) -1-isopropyl- 2-thioxo-imidazolidin-4-one   16.3 g of 2,6-dimethylphenyl-isothiocyanate, N-isopropyl Lysine 21.2 g, triethylamine 21.0 g, and chloroform 300 mL And the title compound was prepared by the method described in Example 45. ethanol Crystallization from afforded the title compound (12.9 g) as a white solid. Fusion 135-137 ° C. Elemental analysis: C₁₄H₁₈N_TwoAs OS, calculated value: C, H. 6.92; N 10.68, found: C, 63.99; H, 6.72; N, 10.67. Mass spectrum (+ FAB, [M + H]⁺) m / z 263.                                Example 47 3- (2,6-diisopropylphenyl) -1-isopropyl- 2-thioxo-imidazolidin-4-one   21.9 g of 2,6-diisopropylphenyl-isothiocyanate, N-isopro Pyrglycine 21.2 g, triethylamine 21.0 g, and chloroform 30 The title compound was prepared by the method described in Example 45 using 0 mL. Eta The title compound (11.7 g) was obtained as a white solid by crystallization from phenol. Was. Melting point 175-177 [deg.] C. Elemental analysis: C₁₈H₂₆N_TwoCalculated value as OS : C, 67.88; H 8.23; N 8.80, found: C, 68.03; H, 8.0. 9; N, 8.81. Mass spectrum (+ FAB, [M + H]⁺) m / z 319.                                Example 48 3- (4-fluorophenyl) -1-isopropyl- 2-thioxo-imidazolidin-4-one   15.3-g of 4-fluorophenyl-isothiocyanate, N-isopropylglyci 21.2 g of triethylamine, 21.0 g of triethylamine and 300 mL of chloroform The title compound was prepared by the method described in Example 45. From ethanol Crystallization of afforded the title compound (12.6 g) as a pink solid. Melting point 1 84-186 ° C. Elemental analysis: C₁₂H₁₃FN_TwoAs OS, calculated value: C, 5 7.12; H5.19; N11.10, found: C, 56.98; H, 5.09; N , 11.06. Mass spectrum (+ FAB, [M + H]⁺) m / z 253.                                Example 49 3- (indan-5-yl) -1-isopropyl-2-thioxo-imidazolidin-4-one   17.5 g of indan-5-yl-isothiocyanate, N-isopropylglycine Using 21.2 g, 21.0 g of triethylamine, and 300 mL of chloroform The title compound was prepared by the method described in Example 45. From ethanol Crystallization provided the title compound (9.9 g) as a white solid. Melting point 178 ~ 180 ° C. Elemental analysis: C₁₅H₁₈N_TwoCalculated value as OS: C, 56.66 H, 6.61; N, 10.21, found: C, 56.70; H, 6.67; N, 10. 22. Mass spectrum (EI, M.⁺) m / z 274.                                Example 50 3- (2-ethyl-6-methylphenyl) -1-isopropyl- 2-thioxo-imidazolidin-4-one   17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, N-isopropyl Luglycine 21.2 g, triethylamine 21.0 g, and chloroform 300 The title compound was prepared by the method described in Example 45 using mL. Etano The title compound (13.0 g) was converted to a light yellow solid by crystallization from I got it. 132-134 ° C. Elemental analysis: C₁₅H₂₀N_TwoOS Calculated: C, 65.18; H 7.29; N 10.14, found: C, 65.06; H, 7.37; N, 10.20. Mass spectrum (EI, M.⁺) m / z 276.                                Example 51 3- (2-ethylphenyl) -1-isopropyl- 2-thioxo-imidazolidin-4-one   16.3 g of 2-ethylphenyl-isothiocyanate, N-isopropylglycine Using 21.2 g, 21.0 g of triethylamine, and 300 mL of chloroform The title compound was prepared by the method described in Example 45. Diethyl ether Crystallization from afforded the title compound (6.8 g) as a white solid. Melting point 103-105 ° C. Elemental analysis: C₁₄H₁₈N_TwoAs OS, calculated value: C, 6 4.09; H 6.92; N 10.68, found: C, 64.08; H, 6.92; N , 10.62. Mass spectrum (EI, M.⁺) m / z 262.                                Example 52 1-isopropyl-3- (2-isopropylphenyl)- 2-thioxo-imidazolidin-4-one   10.0 g of 2-isopropylphenyl-isothiocyanate, N-isopropyl Lysine 11.9 g, triethylamine 12.0 g, and chloroform 200 mL And the title compound was prepared by the method described in Example 45. ethanol To give the title compound (6.8 g) as a light pink solid Obtained. 112-114 ° C. Elemental analysis: C₁₅H₂₀N_TwoCalculated as OS Value: C, 65.18; H 7.29; N 10.13, found: C, 65.51; H, 7 .25; N, 10.32. Mass spectrum (EI, M.⁺) m / z 276.                                Example 53 1-benzyl-3- (4-butylphenyl) -2-thioxo-imidazolidin-4-one   N-benzylglycine (8.7 g), 4-n-butylphenyl-isothiocyanate ( 8.55 g), triethylamine (5.5 g), and chloroform (150 mL). The mixture was heated at reflux for 5 hours. The solvent was distilled off. The residue was ethyl acetate (300 mL) And dissolved in water (2 × 200 mL). The organic phase is dried over anhydrous magnesium sulfate. And evaporated to dryness. Crystallization from ethyl acetate gave off the title compound (11.4 g). Obtained as a white solid. Melting point 149-151 [deg.] C. Elemental analysis: C₂₀ H_{twenty two}N_TwoCalculated value for OS: C, 70.97; H 6.55; N 8.28, actual value: C, 70.81; H, 6.76; N, 8.32. Mass spectrum (EI, M.⁺) m / z 338.                                Example 54 1-butyl-3- (5-chloro-2-methylphenyl)- 2-thioxo-imidazolidin-4-one   2-Chloroacetic acid (47.3 g) was added with stirring to n-butylamine (500.0 g). Was added little by little. The addition was performed over 30 minutes. 18 hours at room temperature While stirring. When excess n-butylamine was distilled off, a viscous and clear oily substance (1) was obtained. 20.0 g), which solidified on standing. The crude product is N-butyl It consisted of a 1: 1 mixture of luglycine and butylamine hydrochloride. this The product mixture was prepared without further purification in the preparation of the title compound in the next paragraph. And for the preparation of the title compounds described in Examples 55 to 56. .   N-butylglycine (12.0 g), 5-chloro-2-methylphenyl-isothiocyan Nate (9.15 g), triethylamine (12.0 g) and chloroform (200 g). (mL) of the mixture was heated at reflux for 5 hours. The solvent was distilled off. Residue in diethyl ether (400 mL). This mixture was filtered. The solid is diethyl ether And then discarded. The filtrate was evaporated to dryness. Crystallize from ethanol and add The title compound (6.0 g) was obtained as a tan solid. 102-103 ° C. element Analysis result: C₁₄H₁₇ClN_TwoCalculated value for OS: C, 56.65; H, 5.7 7; N 9.44; found: C, 56.41; H, 5.97; N, 9.36. Mass spec Kutor (EI, M.⁺) m / z 296/298.                                Example 55 1-butyl-3- (4-fluorophenyl) -2-thioxo-imidazolidin-4-one   7.7 g of 4-fluorophenyl-isothiocyanate, N-butylglycine 12. 0 g, 15.0 g of triethylamine, and 250 mL of chloroform. The title compound was prepared by the method described in Example 54. Crystals from ethanol The title compound (5.9 g) was obtained as an off-white solid. Melting point 92-93 ° C. Elemental analysis: C₁₃H₁₅FN_TwoCalculated value for OS: C, 58. 62; H 5.68; N 10.52, found: C, 58.23; H, 5.65; N, 1 0.56. Mass spectrum (EI, M.⁺) m / z 266.                                Example 56 1-butyl-3- (2-fluoro-6-methylphenyl)- 2-thioxo-imidazolidin-4-one   6.5 g of 2-chloro-6-methylphenyl-isothiocyanate, N-butylglyci 8.5 g of triethylamine, 10.0 g of triethylamine, and 150 mL of methylene chloride. The title compound was prepared by the method described in Example 54. Purification is silica gel Performed by flash chromatography (methylene chloride) above. Ethanor The title compound (3.85 g) was converted to a light pink solid by crystallization from I got it. 97-100 ° C. Elemental analysis: C₁₄H₁₇ClN_TwoAs OS Calculated: C, 56.65; H 5.77; N 9.44, found: C, 56.45; H , 5.67; N, 9.33. Mass spectrum (+ FAB, [M + H]⁺) m / z 297.                                Example 57 3- (4-t-butylphenyl) -1-methyl-2-thioxo-imidazolidin-4-one   Sarcosine ethyl ester hydrochloride (7.68 g), 4-tert-butylphenyl-isothi Osocyanate (9.6 g), triethylamine (10.1 g) and chloroform (2 g) (50 mL) was heated at reflux for 3 hours. The mixture is cooled to room temperature and 2N H After washing with Cl (2 × 200 mL), it was washed with water (200 mL). The organic phase is sulfuric anhydride Dry over magnesium and evaporate to dryness. The residue was crystallized from ethanol and The title compound (9.9 g) was obtained. 156-158 ° C. Elemental analysis: C₁₄H₁₈ N_TwoCalculated value for OS: C, 64.09; H, 6.91; N, 10.68, actual measurement Values: C, 63.83; H, 7.15; N, 10.53. Mass spectrum (EI, M.⁺) m / z 262.                                Example 58 1-ethyl-3- (2-methylsulfanylphenyl 2-thioxo-imidazolidin-4-one   N-ethylglycine (9.23 g), 2- (methylthio) -phenyl-isothiocyane (9.1 g), triethylamine (10.1 g), and methylene chloride (150 m The mixture of L) was heated at reflux for 3 hours. The mixture was evaporated to dryness. Etano the residue The title compound (6.5 g) was obtained as a cream solid. 128-131 ° C. Elemental analysis: C₁₂H₁₄N_TwoS_TwoAs O, calculated value: C , 52.11; H, 5.30; N 10.52, found: C, 52.28; H, 5.2. 6; N, 10.54. Mass spectrum (EI, M.⁺) m / z 266.                                 Example 59 1-allyl-3- (2,6-dimethylphenyl) -2-thioxo-imidazolidin-4-one   Chloroacetic acid (27.5 g) was added to allylamine (114 g) in water (100 mL). ) Was added in portions over 5 minutes. The reaction mixture is added at room temperature for 48 hours. Stirred for hours. The mixture was then evaporated to a viscous oily residue (3. 5 g) were obtained. This crude product is composed of N-allylglycine and allylamine hydrochloride. It consisted of a 1: 1 mixture. This product mixture may be further purified. And in the preparation of the title compound in the next paragraph, as well as in the table described in Example 60. Used for the preparation of the title compound.   N-allylglycine (17.4 g), 2,6-dimethylphenyl-isothiocyanate (20 g), triethylamine (20.2 g), and methylene chloride (150 mL) Was heated to reflux for 3 hours. The reaction mixture was evaporated to dryness. Residual gum The product was dissolved in diethyl ether and treated with ether containing hydrogen chloride. White Of solids formed. This solid was filtered and discarded. The filtrate was concentrated to give a residue. The residue is chromatographed on silica gel (CH_TwoCl_Two) The compound (5.2 g) was obtained as an orange solid. 43-46 ° C. Result of elemental analysis Fruit: C₁₄H₁₆N_TwoCalculated value for OS: C, 64.59; H, 6.19; N10.7 6, found: C, 64.52; H, 6.08; N, 10.66. Mass spectrum (E I, M.⁺) m / z 260.                                Example 60 1-allyl-3- (5-chloro-2-methylphenyl)- 2-thioxo-imidazolidin-4-one   N-allylglycine (17.4 g), 5-chloro-2-methylphenyl-isothiocyan (20.1 g), triethylamine (20.2 g) and methylene chloride (15 g). (0 mL) was heated at reflux for 2 hours. The reaction mixture was evaporated to dryness. Purification Was performed by flash chromatography on silica gel (methylene chloride). Was. The title compound (4.8 g) was recrystallized from hexane-EtOAc to a yellow color. Obtained as a solid. 106-109 ° C. Elemental analysis: C₁₃H₁₃N_TwoOC Calculated as 1S: C, 55.61; H, 4.67; N 9.98, found: C, 55.45; H, 4.56; N, 9.72. Mass spectrum (EI, M.⁺) m / z28 0.                                Example 61 3- (2,6-dimethylphenyl) -1- (prop-2-ynyl)- 2-thioxo-imidazolidin-4-one   Cooling ethyl bromoacetate (37.6 g) in diethyl ether (75 mL) To the solution was added propargylamine (25 g). This mixture is kept at 0-5 ° C for 3 hours Stirred. The reaction mixture was warmed to room temperature and kept stirring for 18 hours. Solid is raw I did This solid was filtered and discarded. The filtrate was evaporated to dryness and the crude title compound ( 30.1 g). This crude product was used without further purification in the next paragraph. And the title compound described in Example 62 and Example 63 It was used for the preparation of the compound.   Ethyl N-propargylaminoacetate (14.1 g), 2,6-dimethylphenyl-i Sothiocyanate (16.3 g), triethylamine (10.1 g) and methyl chloride A mixture of ren (150 mL) was heated at reflux for 3 hours. Cool the reaction mixture to room temperature And washed with 1N HCl (100 mL) and then with water. Separate the organic phase and dry After drying over magnesium sulfate, it was evaporated to dryness. The remaining oil is Both were ground. The solid was collected by filtration. Recrystallize from hexane-EtOAc to give the title The compound (12.5 g) was obtained as a yellow solid. 117-121 ° C. Elemental content Analysis result: C₁₄H₁₄N_TwoS_TwoCalculated as O: C, 65.09; H, 5.46; N 10.84, found: C, 65.23; H, 5.43; N, 10.88. Mass spec Toll (EI, M.⁺) m / z 258.                                Example 62 3- (5-fluoro-2-methylphenyl) -1- (prop-2-ynyl)- 2-thioxo-imidazolidin-4-one   Ethyl N-propargylaminoacetate (7.0 g), 5-chloro-2-methylphenyl Isothiocyanate (9.2 g), triethylamine (5.0 g), and methyl chloride (100 mL) was heated to reflux for 3 hours. The reaction mixture is cooled to room temperature After washing with 1N HCl (50 mL), it was washed with water. The organic layer is treated with anhydrous magnesium sulfate. And dried by evaporation. The remaining oil was triturated with hexane . The solid was collected by filtration. Recrystallize from EtOAc to give the title compound (5.1 g) as a yellow As a solid. 131-134 ° C. Elemental analysis: C₁₃H₁₁N_TwoO Calculated for ClS: C, 56.01; H, 3.98; N 10.05, found: C, 55.90; H, 3.77; N, 9.92. Mass spectrum (EI, M.⁺) m / z 278.                                Example 63 3- (4-fluoro-2-methylphenyl) -1- (prop-2-ynyl)- 2-thioxo-imidazolidin-4-one   Ethyl N-propargylaminoacetate (10.0 g), 4-chloro-2-methylphenyl Lysothiocyanate (12.9 g), triethylamine (7.1 g) and methyl chloride A mixture of Tylene (150 mL) was heated at reflux for 3 hours. Cool the reaction mixture to room temperature The mixture was washed with 1N HCl (100 mL), and then washed with water. The organic layer is After drying with gnesium, it was evaporated to dryness. Trim the remaining oil with hexane. Crushed. The solid was collected by filtration. Recrystallized from hexane-EtOAc to give the title compound ( 5.2 g) were obtained as a yellow solid. Melting point 99-102 <0> C. Elemental analysis: C₁₃ H₁₁N_TwoCalculated for OCLS: C, 56.01; H, 3.98; N 10.05. , Found: C, 55.61; H, 3.83; N, 10.0. Mass spectrum (EI, M.⁺) m / z 278.

────────────────────────────────────────────────── ─── Continuation of front page    (31) Priority claim number 60 / 007,658 (32) Priority date November 28, 1995 (November 28, 1995) (33) Priority country United States (US) (31) Priority claim number 60 / 007,661 (32) Priority date November 28, 1995 (November 28, 1995) (33) Priority country United States (US) (31) Priority claim number 60 / 007,665 (32) Priority date November 28, 1995 (November 28, 1995) (33) Priority country United States (US) (31) Priority claim number 60 / 007,666 (32) Priority date November 28, 1995 (November 28, 1995) (33) Priority country United States (US) (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, S Z, UG), UA (AM, AZ, BY, KG, KZ, MD , RU, TJ, TM), AL, AU, BA, BB, BG , BR, CA, CN, CU, CZ, EE, GE, HU, IL, IS, JP, KP, KR, LC, LK, LR, L T, MG, MK, MN, MX, NO, NZ, PL, RO , SG, SI, SK, TR, TT, UA, UZ, VN (72) Inventor Surukowski, Theodore Sylvester             United States 19087 Pennsylvania             No. 316, Rockland Road (72) Inventor Strike, Donald Peter             United States 19087 Pennsylvania             David Davids, Iven Avenue             No. 445

Claims (1)

[Claims]   1. Formula I: [Where,   R is alkyl having 1 to 6 carbons; having 4 to 6 carbons and one hetero ring-constituting atom Substituted or unsubstituted aromatic N, O or S heterocyclic ring; Or unsubstituted aryl, arylalkyl having 7 to 12 carbon atoms, benzhydryl and the like. Or indanyl (where the substituent is an alkyl having 1 to 6 carbons, Alkoxy, alkylthio having 1 to 6 carbons, alkenyl having 2 to 6 carbons, carbon number 2 to 6 alkynyl, halo, C 1 to C 6 perfluoroalkyl, C 1 to C 6 independently selected from the group consisting of perfluoroalkoxy or hydroxy 1 to 3 substituents); and   R¹Is aryl having 6 to 10 carbons, alkyl having 1 to 6 carbons, and 2 to 6 carbons Alkenyl, alkynyl having 2 to 6 carbons or substituted aryl having 6 to 10 carbons ( Here, the substituent is alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, carbon Alkylthio having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms , Halo, C1-C6 perfluoroalkyl, C1-C6 perfluoro 1-3 substitutions independently selected from the group consisting of alkoxy or hydroxy Base)] A compound for use in the treatment of mammals, represented by the formula:   2. Mammals in which the treatment requires elevated HDL cholesterol blood levels Claims for increasing HDL cholesterol concentration in the blood of children Item 7. The compound according to Item 1.   3. The compound is of the formula I wherein R is substituted phenyl (wherein the substituent is a carbon Alkyl having 1 to 6 carbon atoms, perfluoroalkoxy having 1 to 6 carbon atoms, halo, or Two positions selected from the group consisting of ortho-substituted trimethylene or tetramethylene Substituent) and R¹Is alkyl having 1 to 6 carbons, alkenyl having 2 to 6 carbons or Is an alkynyl having 2 to 6 carbon atoms.   4. The compound is of the formula I, wherein R is substituted phenyl, wherein the substituent is halo. And alkyl or ortho substituted trimethylene having 1 to 3 carbon atoms)¹But Alkyl having 1 to 3 carbons, alkenyl having 2 to 4 carbons or alkyl having 2 to 4 carbons 3. The compound according to claim 1, which is quinyl.   5. The compound is represented by Formula I, wherein R is substituted phenyl (where the substituent is at the 4-position Or chloro or fluoro at the 5-position and alkyl having 1 to 3 carbons)¹ Is an alkyl having 1 to 3 carbons, an alkenyl having 2 to 4 carbons or an alkyl having 2 to 4 carbons. 3. The compound according to claim 1, which is ruquinyl.   6. Wherein the compound is   3- (5-chloro-2-methylphenyl) -1-methyl-2-thioxo-imidazolidine- 4-on;   3- (3-chloro-2-methylphenyl) -1-methyl-2-thioxo-imidazolidine- 4-on;   3- (4-chloro-2-methylphenyl) -1-methyl-2-thioxo-imidazolidin- 4-on;   3- (indan-5-yl) -1-methyl-2-thioxo-imidazolidin-4-one;   3- (2,6-diisopropylphenyl) -1-methyl-2-thioxo-imidazolidine -4-on;   3- (2-ethyl-6-isopropylphenyl) -1-methyl-2-thioxo-imidazo Lysine-4-one;   3- (2-ethyl-6-methylphenyl) -1-methyl-2-thioxo-imidazolidine- 4-on;   3- (5-chloro-2-methylphenyl) -1-ethyl-2-thioxo-imidazolidine- 4-on;   3- (2,6-dichlorophenyl) -1-ethyl-2-thioxo-imidazolidin-4-o N;   1-ethyl-3- (4-fluorophenyl) -2-thioxo-imidazolidin-4-one ;   1-ethyl-2-thioxo-3- (4-trifluoromethoxyphenyl) -imidazoli Gin-4-one;   3- (2,6-dimethylphenyl) -1-ethyl-2-thioxo-imidazolidin-4-o N;   1-ethyl-3-isobutyl-2-thioxo-imidazolidin-4-one;   3- (2-chlorophenyl) -1-ethyl-2-thioxo-imidazolidin-4-one;   1-ethyl-3- (2-tolyl) -2-thioxo-imidazolidin-4-one;   3- (2-chloro-6-methylphenyl) -1-ethyl-2-thioxo-imidazolidine- 4-on;   1-ethyl-3- (5-fluoro-2-methylphenyl) -2-thioxo-imidazolidy N-4-ON;   3- (2,6-diisopropylphenyl) -1-ethyl-2-thioxo-imidazolidine -4-on;   1-ethyl-2-thioxo-3- (2-trifluoromethylphenyl) -imidazolide N-4-ON;   1-ethyl-3- (2-chloro-6-methylphenyl) -2-thioxo-imidazolidine- 4-on;   3- (2-ethyl-4-methylphenyl) -1-ethyl-2-thioxo-imidazolidine- 4-on;   3- (2,4-dichlorophenyl) -1-ethyl-2-thioxo-imidazolidin-4-o N;   3- (2,4-dimethylphenyl) -1-ethyl-2-thioxo-imidazolidin-4-o N;   3- (2,5-dimethylphenyl) -1-ethyl-2-thioxo-imidazolidin-4-o N;   1-ethyl-2-thioxo-3- (2,4,5-trimethylphenyl) -imidazolidine- 4-on;   1-ethyl-3- (2-isopropylphenyl) -2-thioxo-imidazolidine-4- on;   1-ethyl-3- (2-ethylphenyl) -2-thioxo-imidazolidin-4-one;   3- (5-chloro-2-methylphenyl) -1-phenyl-2-thioxo-imidazolidy N-4-ON;   3- (5-chloro-2-methylphenyl) -1-isopropyl-2-thioxo-imidazo Lysine-4-one;   3- (2,6-dimethylphenyl) -1-isopropyl-2-thioxo-imidazolidine -4-on;   3- (2-ethyl-6-methylphenyl) -1-isopropyl-2-thioxo-imidazo Lysine-4-one;   1-butyl-3- (4-fluorophenyl) -2-thioxo-imidazolidin-4-one ;   1-allyl-3- (2,6-dimethylphenyl) -2-thioxo-imidazolidin-4-o N;   3- (2,6-dimethylphenyl) -1- (prop-2-ynyl) -2-thioxo-imidazo Lysine-4-one;   3- (3-chloro-4-methylphenyl) -1-methyl-2-thioxo-imidazolidin- 4-on;   3- (2-ethylphenyl) -1-methyl-2-thioxo-imidazolidin-4-one;   1-methyl-3- (2-isopropylphenyl) -2-thioxo-imidazolidine-4- on;   3- (4-t-butylphenyl) -1-methyl-2-thioxo-imidazolidin-4-one ;   1-allyl-3- (5-chloro-2-methylphenyl) -2-thioxo-imidazolidine- 4-on;   3- (5-chloro-2-methylphenyl) -1- (prop-2-ynyl) -2-thioxo-i Midazolidin-4-one;   1-ethyl-3- (2-ethyl-6-isopropylphenyl) -2-thioxo-imidazo Lysine-4-one;   3- (2-chloro-6-methylphenyl) -1-methyl-2-thioxo-imidazolidine- 4-on; and   3- (2,6-dimethylphenyl) -1-methyl-2-thioxo-imidazolidin-4-o 3. The compound according to claim 1, which is selected from the group consisting of:   7. In the blood of mammals that require elevated HDL cholesterol blood levels Claims 1 to 6 for the manufacture of a medicament for raising HDL cholesterol levels in Use of a compound of formula I as defined elsewhere.   8. A compound of formula I as defined in any of claims 1 to 6 and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising a body.   9. In the blood of mammals that require elevated HDL cholesterol blood levels For increasing HDL cholesterol levels in a mammal, comprising: Administering the compound of formula I as defined in any of items 1 to 6 orally or parenterally A method consisting of:   10. Formula I: [Where,   R¹Is alkyl having 1 to 6 carbons, R is alkyl having 1 to 6 carbons, naphthyl, Nshydryl, fluorophenylmethyl, phenethyl, 1- (fluorophenyl) Ethyl, 5-chloro-2-methoxyphenyl, trifluoromethoxyphenyl, Trifluoromethylphenyl, methylsulfanylphenyl, pyridyl or formula II :[Wherein, R^Two, R^ThreeAnd R^FourAre 2-chloro, 4-fluoro, 2,4-chloro Or 2,6-chloro, or R^TwoIs hydrogen, R^ThreeIs halogen at the 3-position, R^FourIs the 4th charcoal An alkyl having a prime number of 1 to 6, or R^TwoIs an alkyl having 1 to 6 carbons, R^ThreeAnd R^Four Is independently hydrogen or alkyl having 1 to 6 carbons, or R^ThreeIs halogen, R^FourIs hydrogen] A group represented by;   Alternatively, R¹Is an alkenyl having 2 to 6 carbon atoms, and R is a group of the formula II (where R^TwoIs charcoal Alkyl of a prime number 1 to 6, R^ThreeAnd R^FourIs independently hydrogen or an alkyl having 1 to 6 carbons Kill or R^TwoIs hydrogen, R^ThreeAnd R^FourAre ortho-substituted trimethylene Or tetramethylene, or R^TwoIs an alkyl having 1 to 6 carbons, R^ThreeIs haloge N, R^FourIs hydrogen or R^TwoIs hydrogen, R^ThreeIs halogen at the 3-position, R^FourIs the number of carbon atoms at position 4. 1-6 alkyl);   Alternatively, R¹Is alkynyl having 1 to 6 carbon atoms, R is a group of the formula II (provided that R is^Two , R^ThreeAnd R^FourIs independently alkyl having 1 to 6 carbon atoms, halo, charcoal Perfluoroalkyl having 1 to 6 carbon atoms, perfluoroalkoxy having 1 to 6 carbon atoms, Or together, ortho-substituted trimethylene or tetramethylene);   Alternatively, R¹Is aryl having 6 to 10 carbons or aryl having 7 to 12 carbons When alkyl, R is a group of formula II wherein R^TwoIs an alkyl having 1 to 6 carbons, R^ThreeIs Halogen, R^FourIs hydrogen or R^TwoIs hydrogen, R^ThreeIs halogen at the 3-position, R^FourIs fourth place Alkyl having 1 to 6 carbon atoms)] A compound represented by the formula:   11. formula:[Where,   R¹Is alkyl having 1 to 6 carbons or alkenyl having 2 to 6 carbons;   R^TwoIs an alkyl having 1 to 6 carbons, R^ThreeAnd R^FourIs independently hydrogen or carbon number 1 Alkyl of 6 to 6;^TwoIs hydrogen, R^ThreeAnd R^FourAre together Exchanged trimethylene or tetramethylene] The compound according to claim 10, which is represented by the formula:   12. R^ThreeAnd R^FourIs hydrogen, R¹Is methyl or ethyl, R^TwoHas 1 to 3 carbon atoms The compound according to claim 11, which is alkyl.   13.3- (2-Ethylphenyl) -1-methyl-2-thioxo-imidazolidin-4- on;   1-methyl-3- (2-isopropylphenyl) -2-thioxo-imidazolidine-4- on;   1-ethyl-3- (2-tolyl) -2-thioxo-imidazolidin-4-one;   1-ethyl-3- (2-isopropylphenyl) -2-thioxo-imidazolidine-4- On; or   1-ethyl-3- (2-ethylphenyl) -2-thioxo-imidazolidin-4-one 13. A compound according to claim 11 or claim 12.   14． R^FourIs hydrogen, R¹Is methyl, ethyl or allyl, R^TwoHas 1 to 3 carbon atoms Alkyl, R^ThreeIs an alkyl having 1 to 3 carbons, or R^TwoIs hydrogen, R^ThreeAnd R^FourBut The compound according to claim 11, which is an ortho-substituted trimethylene or tetramethylene.   15.3- (2-Ethyl-6-methylphenyl) -1-methyl-2-thioxo-imidazo Lysine-4-one;   3- (2,6-dimethylphenyl) -1-ethyl-2-thioxo-imidazolidin-4-o N;   3- (2,6-dimethylphenyl) -1-isopropyl-2-thioxo-imidazolidine -4-on;   1-allyl-3- (2,6-dimethylphenyl) -2-thioxo-imidazolidin-4-o N;   3- (2-ethyl-6-isopropylphenyl) -1-methyl-2-thioxo-imidazo Lysine-4-one; or   1-ethyl-3- (2-ethyl-6-isopropylphenyl) -2-thioxo-imidazo 15. The compound according to claim 14, which is lysin-4-one.   16. R¹Is methyl, ethyl or allyl, R^Two, R^ThreeAnd R^FourBut independently carbon The compound according to claim 11, which is an alkyl having the formulas 1 to 3.   17.1-Ethyl-2-thioxo-3- (2,4,5-trimethylphenyl) -imidazo 17. The compound according to claim 16, which is lysin-4-one.   18. formula: [Where,   R¹Is alkyl having 1 to 6 carbons;   R^TwoAnd R^ThreeRepresents 2,4-dichloro or 2,6-dichloro;   Or R^TwoIs 2-chloro or 4-chloro, R^ThreeIs hydrogen] The compound according to claim 10, which is represented by the formula:   19.3- (2,6-Dichlorophenyl) -1-ethyl-2-thioxo-imidazolidine -4-on;   1-ethyl-3- (4-fluorophenyl) -2-thioxo-imidazolidin-4-one ;   3- (2-chlorophenyl) -1-ethyl-2-thioxo-imidazolidin-4-one;   3- (2,4-dichlorophenyl) -1-ethyl-2-thioxo-imidazolidin-4-o N;   3- (4-fluorophenyl) -1-isopropyl-2-thioxo-imidazolidin-4 -On; or   1-butyl-3- (4-fluorophenyl) -2-thioxo-imidazolidin-4-one 19. The compound according to claim 18, which is   20. formula: [Where,   R¹Is alkynyl having 2 to 6 carbon atoms;   R^TwoAnd R^ThreeIs independently an alkyl having 1 to 6 carbons, a halo, a pel having 1 to 6 carbons Fluoroalkyl, perfluoroalkoxy having 1 to 6 carbon atoms, or Tte R^TwoAnd R^ThreeIs ortho-substituted trimethylene or tetramethylene The compound according to claim 10, which is represented by the formula:   21. R¹Is ethynyl, propargyl or butynyl. Compound.   22.3- (2,6-dimethylphenyl) -1- (prop-2-ynyl) -2-thioxo-i Midazolidin-4-one;   3- (5-chloro-2-methylphenyl) -1- (prop-2-ynyl) -2-thioxo-i Midazolidin-4-one; or   3- (4-chloro-2-methylphenyl) -1- (prop-2-ynyl) -2-thioxo-i 22. The compound according to claim 20 or 21, which is midazolidin-4-one.   23. formula:[Where,   R¹Is alkyl having 1 to 6 carbons, alkenyl having 2 to 6 carbons, 6 to 1 carbons Aryl having 0 or arylalkyl having 7 to 12 carbon atoms;   R^TwoIs an alkyl having 1 to 6 carbons, R^ThreeIs halogen, R^FourIs hydrogen; or   R^TwoIs hydrogen, R^ThreeIs halogen at the 3-position, R^FourIs alkyl having 1 to 6 carbon atoms at position 4. The compound according to claim 10, which is represented by the formula:   24. R¹Is an alkyl, allyl or phenyl having 1 to 3 carbon atoms, R^TwoHas 1 carbon Alkyl of ~ 3, R^ThreeIs chloro or fluoro, R^Four24. is hydrogen. Compound.   25.3- (5-Chloro-2-methylphenyl) -1-methyl-2-thioxo-imidazo Lysine-4-one;   3- (3-chloro-2-methylphenyl) -1-methyl-2-thioxo-imidazolidine- 4-on;   3- (4-chloro-2-methylphenyl) -1-methyl-2-thioxo-imidazolidin- 4-on;   3- (5-chloro-2-methylphenyl) -1-ethyl-2-thioxo-imidazolidine- 4-on;   3- (2-chloro-6-methylphenyl) -1-ethyl-2-thioxo-imidazolidine- 4-on;   1-ethyl-3- (5-fluoro-2-methylphenyl) -2-thioxo-imidazolidy N-4-ON;   3- (5-chloro-2-methylphenyl) -1-phenyl-2-thioxo-imidazolidy N-4-ON;   3- (5-chloro-2-methylphenyl) -1-isopropyl-2-thioxo-imidazo Lysine-4-one; or   1-allyl-3- (5-chloro-2-methylphenyl) -2-thioxo-imidazolidine- 25. The compound according to claim 23 or 24, which is 4-one.   26. Formula I [where R¹Is an alkyl having 1 to 6 carbons; R is an alkyl having 1 to 6 carbons Alkyl, naphthyl, benzhydryl, fluorophenylmethyl, phenethyl, 1 -(Fluorophenyl) ethyl, 5-chloro-2-methoxyphenyl, trifluoromethyl Toxiphenyl, trifluoromethylphenyl, methylsulfanylphenyl, etc. Or pyridyl].   27. R¹Is alkyl having 1 to 6 carbons; R is alkyl having 1 to 6 carbons, 2-naph Butyl, benzhydryl, 4-fluorophenylmethyl, phenethyl, 1- (4-fur Orophenyl) ethyl, 5-chloro-2-methoxyphenyl, 4-trifluoromethoate Xyphenyl, 2-trifluoromethylphenyl, 2-methylsulfanylphenyl 27. The compound according to claim 26, which is benzyl or 3-pyridyl.   28.3-benzhydryl-1-methyl-2-thioxo-imidazolidin-4-one;   1-methyl-3- (pyridin-3-yl) -2-thioxo-imidazolidin-4-one;   3- (5-chloro-2-methoxyphenyl) -1-methyl-2-thioxo-imidazolidy N-4-ON;   3- (5-chloro-2-methoxyphenyl) -1-ethyl-2-thioxo-imidazolidy N-4-ON;   1-ethyl-2-thioxo-3- (4-trifluoromethoxyphenyl) -imidazoli Gin-4-one;   1-ethyl-3- (4-fluorobenzyl) -2-thioxo-imidazolidin-4-one ;   1-ethyl-3-isobutyl-2-thioxo-imidazolidin-4-one;   1-ethyl-3- (naphthalen-2-yl) -2-thioxo-imidazolidin-4-one;   1-ethyl-2-thioxo-3- (2-trifluoromethylphenyl) -imidazolide N-4-ON;   1-ethyl-3- [1- (4-fluorophenyl) -ethyl] -2-thioxo-imidazoli Gin-4-one;   1-ethyl-3-phenethyl-2-thioxo-imidazolidin-4-one; or   1-ethyl-3- (2-methylsulfanylphenyl) -2-thioxo-imidazolide 28. The compound according to claim 26 or 27, which is 1-4-one.   29. A method for producing a compound as defined in any of claims 1 to 28, The corresponding formula A: [Wherein, R^TwoIs the same as defined in any one of claims 1 to 28, and X is halogen. Is a compound represented by R¹-NH_Two(Where R¹Agrees with any of claims 1 to 28 ) And reacting with formula 2 (a): [Wherein, R¹And R^TwoIs as defined above] And reacting the compound of formula 2 (a) with R-NCS in the presence of a base. Let equation (3a): Or equation (4):To obtain a compound of formula (3a) in the presence of a base A process comprising cyclizing to a compound of formula (4) by refluxing.