EP0876355A1 - Derives 2-thioxo-imidazolin-4-one et leur utilisation pour augmenter la cholesterolemie a lipoproteine de haute densite - Google Patents

Derives 2-thioxo-imidazolin-4-one et leur utilisation pour augmenter la cholesterolemie a lipoproteine de haute densite

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Publication number
EP0876355A1
EP0876355A1 EP96942118A EP96942118A EP0876355A1 EP 0876355 A1 EP0876355 A1 EP 0876355A1 EP 96942118 A EP96942118 A EP 96942118A EP 96942118 A EP96942118 A EP 96942118A EP 0876355 A1 EP0876355 A1 EP 0876355A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
thioxo
imidazolidin
ethyl
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96942118A
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German (de)
English (en)
Inventor
Hassan Mahmoud Elokdah
Sie-Yearl Chai
Theodore Sylvester Sulkowski
Donald Peter Strike
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
American Home Products Corp
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Filing date
Publication date
Priority claimed from US08/563,325 external-priority patent/US5554607A/en
Application filed by American Home Products Corp filed Critical American Home Products Corp
Publication of EP0876355A1 publication Critical patent/EP0876355A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to compounds for increasing HDL cholesterol concentration in the blood of a mammal, to their use in this method of treatment, to pharmaceutical compositions containing the compounds and to a process for preparation of the compounds.
  • 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.
  • Angiographical studies have shown that elevated levels of some HDL particles appears to be correlated with a decrease in the number of sites of stenosis in the coronary arteries of humans ( Miller et al. Br. Med. J .. 282 (1981 , 1741-1744).
  • 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 (1986) 434-441). Data of this nature suggests that one antiatherogenic property of HDL may lie in its ability to deplete tissues of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset. J. Lipid Res.. 9 (1968) 155-167). This has been supported by experiments showing efficient transfer of cholesterol from HDL to the liver (Glass et al, Circulation. 66 (Suppl. I) (1982) 102; MacKinnon et al, J. Biol. Chem..
  • HDL may serve as a reservoir in the circulation for apoproteins necessary for the rapid metabolism of triglyceride-rich lipoproteins (Grow and Fried, J. Biol. Chem.. 253 (1978) 1834-1841; Lagocki and Scanu, J. Biol. Chem.. 255 (1980) 3701-3706; Schaefer et al, J. Lipid Res.. 23 (1982) 1259-1273).
  • agents which increase HDL cholesterol concentrations are useful as anti-atherosclerotic agents, particularly in the treatment of dyslipoproteinemias and coronary heart disease.
  • Z is alkyl, phenylalkyl, phenyl or substituted phenyl, where the substituent is a halogen, alkyl, alkoxy or halogenated alkyl group
  • X is phenyl, halophenyl, alkyl, alkenyl, or alkynyl
  • Y is S or O.
  • EP 0584694 andWO 93/18057 disclose a group of imidazolidin-3-yl benzoyl or alkanoyl amino acid derivatives as inhibitors of cell-cell adhesion for use in inhibition of thrombocyte aggregation, metastasis and osteoclast formation. Chronic administration for prevention of arteriosclerosis and thrombosis is disclosed.
  • JP 04,297,461 discloses a group of 2-thiohydantoin compounds of the following formula, said to be useful as anti-bacterial, anti-viral, anti-inflammatory and anti-rheumatic agents:
  • R* is lower alkyl, lower alkenyl, phenyl(lower)alkyl or substituted phenyl with 1-3 groups chosen from lower alkyl, lower alkoxy, halogen, lower alkoxycarbonyl or hydroxy;
  • R2 is either hydrogen or alkanoyl; and R3 is hydrogen, lower alkyl, phenyl, phenyl (lower) alkyl, or a lower alkylthio, lower alkyl group that can be substituted with one to three phenyl groups that have had a lower alkoxy group.
  • EP 0578516 discloses a group of 2-thiohydantoins, said to be useful anti- androgenic agents for treatment of various cancer, of the formula :
  • X oxygen or sulfur
  • Y is oxygen, sulfur or NH
  • Rl and R ⁇ are cyano, nitro, halogen, trifluoromethyl, or a free or esterified carboxylic acid or salt;
  • R3 is hydrogen, alkyl, alkenyl, alkynyl, aryl or aryl-alkyl; R and R ⁇ are hydrogen, optionally substituted alkyl, or cycloalkyl.
  • US 5,411 ,981 discloses compounds closely related to EP 0578516, supra, where R ⁇ and R ⁇ are both methyl.
  • R ⁇ and R ⁇ are hydrogen, chloro, bromo, fluoro or alkyl of 1-2 carbon atoms.
  • JP 73 87,030 discloses a group of 3-phenyl-2-thiohydantoin derivatives useful as herbicides.
  • US 4,473,393 discloses a group of pesticidal thiohydantoin compositions.
  • R is alkyl of 1 to 6 carbon atoms; a substituted or unsubstituted aromatic N, O or S heterocycle having 4 to 6 carbon and one hetero ring members; substituted or unsubstituted aryl of 6 to 10 carbon atoms, arylalkyi of 7 to 12 carbon atoms, benzhydryl or indanyl , in which the substituents are one to three members independendy selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon ations, alkylthio of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halo, perfluoroalkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms or hydroxy; and
  • Rl is aryl of 6 to 10 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms or substituted aryl of 6 to 10 carbon atoms where the substituents are one to three members independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon ations, alkylthio of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halo, perfluoroalkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms or hydroxy, for use in the treatment of mammals.
  • a preferred embodiment of the invention provides a compound of formula I in which R is substituted phenyl where the substituents are two members of the group consisting of alkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, halo, or ortho substituted trimethylene or tetramethylene and R ⁇ is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms.
  • Another preferred embodiment of the invention provides a compound of formula I in which R is substituted phenyl where the substituents are a halo and an alkyl group of 1 to 3 carbon atoms or ortho substituted trimethylene and R ⁇ is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms.
  • Another preferred embodiment of the invention provides a compound of formula I in which R is substituted phenyl where the substituents are chloro or fluoro in the 4- or 5- position and an alkyl group of 1 to 3 carbon atoms and R 1 is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms.
  • R is substituted phenyl where the substituents are chloro or fluoro in the 4- or 5- position and an alkyl group of 1 to 3 carbon atoms and R 1 is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms.
  • Rl is alkyl of 1 to 6 carbon atoms and R is alkyl of 1 to 6 carbon atoms, naphthyl, benzhydryl, fluorophenylmethyl, phenethyl, l-(fluorophenyl)ethyl, 5-chloro- 2-methoxyphenyl, trifluoromethoxyphenyl, trifluoromethylphenyl, methy lsulfanyl- phenyl, pyridyl or the group of formula II
  • R ⁇ , R ⁇ and R ⁇ together are 2-chloro, 4-fluoro, 2,4-chloro or 2,6- chloro, or
  • R2 is hydrogen, R ⁇ is a halogen in 3-position and R ⁇ is alkyl of 1 to 6 carbon atoms in
  • R ⁇ is alkyl of 1 to 6 carbon atoms and R ⁇ and R ⁇ are, independently, hydrogen or alkyl of 1 to 6 carbon atoms or R ⁇ is a halogen and R ⁇ is hydrogen; or
  • Rl is alkenyl of 2 to 6 carbon atoms
  • R is is the group of formula II where R ⁇ is alkyl of 1 to 6 carbon atoms and R ⁇ and R ⁇ are, independendy, hydrogen or alkyl of 1 to 6 carbon atoms, or R ⁇ is hydrogen and R ⁇ and R ⁇ taken together are ortho substituted trimethylene or tetramethylene, or R ⁇ is alkyl of 1 to 6 carbon atoms,
  • R3 is halogen and R ⁇ is hydrogen, or R ⁇ is hydrogen, R ⁇ is halogen in 3-position and
  • R is alkyl of 1 to 6 carbon atoms in 4-position; or when Rl is alkynyl of 2 to 6 carbon atoms, R is a group of formula II where any two of R ⁇ , R3 and R ⁇ are, independently, alkyl of 1 to 6 carbon atoms, halo, perfluoralkyl of 1 to 6 carbon atoms, perfluoralkoxy of 1 to 6 carbon atoms, or, taken together, are ortho substituted trimethylene or tetramethylene; or when Rl is aryl of 6 to 10 carbon atoms or arylalkyi of 7 to 12 carbon atoms, R is the group of formula II where R 2 is alkyl of 1 to 6 carbon atoms, R 3 is a halogen and R 4 is hydrogen, or R 2 is hydrogen, R 3 is a halogen in 3-position and R 4 is alkyl of 1 to 6 carbon atoms in 4- position.
  • R 1 ' R 2 , R 3 or R 4 is alkyl it is preferably alkyl of 1 to 3 carbon atoms, especially methyl or ethyl, or any two of R 2 , R3 and R 4 when taken together are ortho substituted trimethylene or tetramethylene.
  • Rl is alkenyl of 2 to 6 carbon atoms it is preferably allyl
  • R 2 or R 3 are halogen they are preferably independendy, chlorine or fluorine, especially in the 2-, 4-, and/or -6 positions.
  • R 2 or R 3 are perfluoralkyl of 1 to 6 carbon atoms, perfluoralkoxy of 1 to 6 carbon atoms
  • Rl is alkynyl of 2 to 6 carbon atoms it is preferably ethynyl, propargyl or butynyl, especially prop-2-ynl.
  • R is aryl of 6 to 10 carbon atoms it is preferably, phenyl or naphthyl, the latter being preferably, 2-naphthyl.
  • R is aralkyl of 7 to 12 carbon atoms, it is preferably benzyl or phenethyl.
  • R is fluorophenylmethyl, it is preferably 4-fluorophenylmethyl.
  • R When R is l-(fluorophenyl)ethyl, it is preferably l-(4-fluorophenyl)ethyl. When R is trifluoromethoxyphenyl, it is preferably 4-trifluoro-methoxyphenyl. When R is methylsulfanylphenyl, it is preferably 2-methylsulfanylphenyl. When R is pyridyl, it is preferably 3-pyridyl.
  • a preferred use of the compounds of formula I or method of treatment using the compounds is for increasing HDL cholesterol concentration in the blood of a mammal, by administering to said mammal an amount of a substituted 2-thioxo-imidazolidin-4- one as herein defined, sufficient to increase that HDL cholesterol concentration, and this represents further aspects of the present invention.
  • the compounds of the invention can be prepared readily according to the following reaction scheme or modification thereof using readily available starting materials, reagents and conventional synthetic procedures. It is also possible to make use of variants of these process steps, which in themselves are known to and well within the preparatory skill of the medicinal chemist.
  • R is hydrogen or alkyl of 1 to 6 carbon atoms and X is a halogen.
  • N-Substituted amino acids (2a) were prepared by reacting the corresponding ⁇ - halo acids (1) with the appropriate amines (excess). The reaction was carried out either neat or in water at ambient temperature for 18 hours. One equivalent of the amine scavenges the hydrohalide formed during the alkylation forming the amine hydrohalide (2b) as a side product.
  • the N-alkyl amino acids (2a) were either purified by crystallization from an appropriate solvent, or reacted with the isothiocyanates as crude product mixtures containing the amine hydrohalide salt. Reaction of 2a with isothiocyanates is carried out in chloroform or methylene chloride in the presence of a base such as triethyl amine.
  • compositions comprised of uie 2- thioxo imidazolidin-4-one derivatives either alone or in combination with excipients (i.e. pharmaceutically acceptable materials with no pharmacological effects).
  • excipients i.e. pharmaceutically acceptable materials with no pharmacological effects.
  • Such compositions are useful in the treatment of atherosclerotic conditions such as dyslipoproteinemias and coronary heart disease, in that they increase the blood serum high density lipoprotein concentration of mammals treated with the compounds.
  • the precise dosage to be employed depends upon several factors including the host, whether in veterinary medicine or human medicine, the nature and severity of the condition being treated, the mode of administration and the particular active substance employed.
  • the compounds may be administered by any conventional route, in particular enterally, preferably orally in the form of tablets or capsules.
  • Administered compounds can be in the free form or pharmaceutically acceptable salt form as appropriate, for use as a pharmaceutical, particularly for use in the prophylactic or curative treatment of atherosclerosis and sequelae (angina pectoris, myocardial infarction, arrhythmias, heart failure, kidney failure stroke, peripheral arterial occlusion, and related disease states). These measures will slow the rate of progress of the disease state and assist the body in reversing the process direction in a natural manner.
  • the carrier may be a solid, liquid or mixture of a solid and a liquid.
  • Solid compositions include powders, tablets and capsules.
  • a solid carrier can be one or more substances which may also act as a flavoring agent, lubricant, solubilizer, suspending agent, binder, or tablet disintegrant.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like.
  • Encapsulating materials may also be employed with the compounds of this invention, and the term "composition" is intended to include the active ingredient in combination with an encapsulating material as a formulation, with or without other carriers.
  • Cachets may also be used in the delivery of the anti-atherosclerotic medicament of this invention.
  • Sterile liquid compositions include solutions, suspensions, emulsions, syrups and elixirs.
  • the compounds of this invention may be dissolved or suspended in the pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
  • the liquid carrier is one suitable for parental injection.
  • the compounds are sufficiendy soluble they can be dissolved directly in normal saline with or without the use of suitable organic solvents , such as propylene glycol or polyethylene glycol.
  • suitable organic solvents such as propylene glycol or polyethylene glycol.
  • dispersions of the finely divided compounds can be made-up in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, such as arachis oil.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by intramuscular, intraperitoneal or subcutaneous injection. In many instances a liquid composition form may be used instead of the preferred solid oral method of administration.
  • unit dosage forms of the compounds for standard administration regimens.
  • the composition can be subdivided readily into smaller doses at the physicians direction.
  • unit dosages may be made up in packeted powders, vials or ampoules and preferably in capsule or tablet form.
  • the active compound present in these unit dosage forms of the composition may be present in an amount of from about one gram to about fifteen grams or more, for single or multiple daily administration, according to the particular need of the patient.
  • the daily dose of active compound will vary depending upon the route of administration, the size, age and sex of the patient, the severity of the disease state, and the response to the therapy as traced by blood analysis and the patients recovery rate.
  • the blood levels of HDL and the patients symptomatic relief analysis may be used to determine whether a larger dose is indicated.
  • the projected daily dose for both human and veterinary use will be from about 10 to about 200 milligrams/kilogram per day. However, in general, satisfactory results are indicated to be obtained at daily dosages in the range of from 400 milligrams to about 2000 milligrams, conveniendy administered in divided doses two to four times a day.
  • the ability of the compounds of this invention to increase blood serum HDL levels was established by the following standard experimental procedure for determination of HDL cholesterol:
  • Test substances Male Sprague-Dawley rats weighing 200-225 g are 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 is 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 are recorded prior to diet administration and at termination. Typical doses of the test substances are 5 - 100 mg/kg/day. At termination, blood is collected from anesthetized rats and the serum is separated by centrifugation.
  • Total serum cholesterol is assayed using the Sigma Diagnostics enzymatic kit for the determination of cholesterol, Sigma Procedure No. 352, modified for use with ninety-six well microtiter plates. After reconstitution with water the reagent contains 300 U/1 cholesterol oxidase, 100 U ⁇ cholesterol esterase, 1000 U/1 horse radish peroxidase, 0.3 mmoles/l 4-aminoantipyrine and 30.0 mmoles/l p-hydroxybenzenesulfonate in a pH 6.5 buffer. In the reaction cholesterol is oxidized to produce hydrogen peroxide which is used to form a quinoneimine dye. The concentration of dye formed is measured spectrophotometrically by absorbance at 490 nm after incubation at 25C 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 are 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.. 2 (1991) 859-866. 25 ul of serum is injected onto Superose 12 and Superose 6 (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 is mixed on line with Boehringer-Mannheim cholesterol reagent pumped at 0.2 ml/min.
  • FPLC fast protein liquid chromatography
  • the combined eluents are mixed and incubated on line through a knitted coil (Applied Biosciences) maintained at a temperature of 45C.
  • the eluent is monitored by measuring absorbance at 490 nm and gives a continuous absorbance signal proportional to the cholesterol concentration.
  • the relative concentration of each lipoprotein class is calculated as the per cent of total absorbance.
  • HDL cholesterol concentration, in serum is calculated as the per cent of total cholesterol as determined by FPLC multiplied by the total serum cholesterol concentration.
  • Test compounds were administered at a dose of 100 mg/kg. The duration of treatment was eight days.
  • the compounds of the present invention increase HDL cholesterol concentrations as summarized in Table I:
  • the title compound was prepared by the procedure described in Example 1 using 13.2 g of 3-chloro-2-methylphenyl-isothiocyanate, 11.0 g of sarcosine ethyl ester hydrochloride, 25 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the tide compound (15.2 g) as a tan solid, m.p. 122-124° C.
  • the tide compound was prepared by the procedure described in Example 1 using 18.3 g of 3-chloro-4-methylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 25 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded the tide compound (14.5 g) as an off-white solid, m.p. 178-180°
  • the tide compound was prepared by the procedure described in Example 1 using 9.18 g of 4-chloro-2-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (7.5 g) as an off-white solid, m.p. 113-
  • the tide compound was prepared by the procedure described in Example 1 using 7.7 g of indan-5-yl-isothiocyanate, 6.7 g of sarcosine ethyl ester hydrochloride, 12 g of trieuiyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded uie tide compound (7.9 g) as a tan solid, m.p. 158-160° C. Anal. Calcd. for Cl3 Hi4 N2 O S: 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.
  • the tide compound was prepared by the procedure described in Example 1 using 8.3 g of 2,6-diisopropylphenyl-isothiocyanate, 5.8 g of sarcosine ethyl ester hydrochloride, 14.5 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl edier/hexane mixture afforded the title compound (6.6 g) as a tan solid, m.p. 174-176° C.
  • Mass spectrum (+FAB, [M+H]+) m/z 269/271.
  • the tide compound was prepared by d e procedure described in Example 1 using 8.9 g of 2-euiyl-6-meuiylphenyl-isouiiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.5 g of trieuiyl amine, and 250 mL of chloroform. Crystallization from diethyl ether afforded die title compound (7.45 g) as a peach solid, m.p. 106-108° C. Anal. Calcd. for Ci3 Hi6 N2 O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.52;
  • the tide compound was prepared by the procedure described in Example 1 using 9.2 g of 2-chloro-6-methylphenyl-isouiiocyanate, 7.68 g of sarcosine euiyl ester hydrochloride, 12 g of triethyl amine, and 200 mL of chloroform. Crystallization from ethanol afforded the title compound (7.1 g) as an orange solid (7.1 g), m.p. 142-145°
  • the tide compound was prepared by die procedure described in Example 1 using 16.3 g of 2-ethylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 20.2 g of triethyl amine, and 300 mL of chloroform.
  • the tide compound (20.4 g) was obtained as an off-white solid, m.p. 135-137° C.
  • the tide compound was prepared by d e procedure described in Example 1 using 14.2 g of 2-isopropylphenyl-isouiiocyanate, 12.29 g of sarcosine ethyl ester hydrochloride, 16.0 g of trieuiyl amine, and 200 mL of chloroform. Crystallization from diethyl ether afforded the title compound (15.9 g) as a peach solid, m.p. 129-131° C.
  • the tide compound was prepared by the procedure described in Example 1 using 14.28 g of 2,6-dichlorophenyl-isothiocyanate, 10.75 g of sarcosine etiiyl ester hydrochloride, 14.5 g of trieuiyl amine, and 200 mL of chloroform. Crystallization from diediyl euier afforded the tide compound (16.9 g) as a light peach solid, m.p.
  • the tide compound was prepared by die procedure described in Example 16 using 10.2 g of 2,6-dichlorophenyl-isothiocyanate, 7.4 g of N-e ⁇ iyl glycine, 10 g of trieuiyl amine, and 250 mL of chloroform. Purification was achieved through crystallization from ethanol. The tide compound (6.5 g) was obtained as a tan solid, m.p. 170-172° C. Anal. Calcd. for. Cn Hio Cl2 N2 O S: C, 45.69; H, 3.48; N,
  • the tide compound was prepared by d e procedure described in Example 16 using 7.65 g of 4-fluorophenyl-isothiocyanate, 9.32 g of N-etivyl glycine, 10 g of triethyl amine, and 250 mL of chloroform. Purification was achieved through crystallization from ethanol. The tide compound (6.6 g) was obtained as a pink solid, m.p. 149-151° C. Anal. Calcd. for. C11 H11 F N2 O S: C, 55.45; H, 4.65; N.1 1.76.
  • the tide compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 10.9 g of 4-trifluoromethoxyphenyl-isod ⁇ iocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Tide compound (4.6 g) was obtained as a creamy solid, m.p. 116-119° C. Anal. Calcd. for. C12 Hn F3 N2 O2 S: C, 47.37; H, 3.64; N, 9.21. Found: C, 47.20; H, 3.50; N, 9.13. Mass spectrum (EI, M.+) m/z 304.
  • the tide compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.2 g of 2,6-dimethylphenyl-isod ⁇ iocyanate, 10.1 g of triethylamine, and 150 mL of metiiylene chloride. Purification was achieved through crystallization from ethanol. Title compound (2.3 g) was obtained as a white solid (2.3 g). m.p. 128-131° C. Anal. Calcd. for. C13 Hi6 N2 O S: C, 62.87; H, 6.49; N,
  • the tide compound was prepared by d e procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.4 g of 4-fluorobenzyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of metiiylene chloride. Purification was achieved through crystallization from ethyl acetate/hexane mixture. Tide compound (4.85 g) was obtained as a white solid, m.p. 73-76° C. Anal. Calcd. for. C12 Hi 3 F N2 O S: C, 57.12; H, 5.19; N, 11.10 Found: C, 56.97; H.5.15; N, 11.06. Mass spectrum (EI, M.+) m/z 252.
  • the tide compound was prepared by d e procedure described in Example 19 using 9.2 g of N-etiryl glycine, 5.7 g of isobutyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of metiiylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Titie compound (2.3 g) was obtained as an oil. Anal. Calcd. for. C9 Hi6 N2 O S: C, 53.97; H, 8.05; N, 13.99.
  • the tide compound was prepared by die procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.48 g of 2-chlorophenyl-isouiiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Tide compound (3.85 g) was obtained as an orange solid, m.p. 142-145° C. Anal. Calcd. for. Cn Hn Cl N2 O S: C, 51.87; H, 4.35; N ,
  • the tide compound was prepared by die procedure described in Example 19 using 9.2 g of N-ethyl glycine, 7.4 g of 2-tolyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of metiiylene chloride. Purification was achieved through crystallization from edianol. Title compound (3.6 g) was obtained as a creamy solid, m.p. 105-108°
  • the tide compound was prepared by the procedure described in Example 19 using 9.2 g of N-ediyl glycine, 9.3 g of 2-naphthyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of metiiylene chloride. Purification was achieved dirough crystallization from ethanol. Title compound (4.7 g) was obtained as a light pink solid, m.p. 156-159° C. Anal. Calcd. for. C15 H14 N2 O S: C, 66.64; H, 5.22; N, 10.36
  • the tide compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 9.1 g of 2-chloro-6-methylphenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the tide compound (5.4 g) as a creamy solid, m.p. 124-126° C. Anal. Calcd. for. C12 H13 Cl N2 O S: 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.
  • the titie compound was prepared by the procedure described in Example 16 using 21.9 g of 2,6-diisopropylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Purification was achieved through crystalUzation from ethanol. The title compound (8.2 g) was obtained as light yellow solid, m.p. 159-161° C. Anal. Calcd. for. C17 H24 N2 O S: C, 67.07; H, 7.94; N ,
  • EXAMPLE 30 1 -Ethvl.2-thioxo-3-f2-trifl ⁇ oromethvlnhenvn-imidazolidin.4-one.
  • the tide compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 10.2 g of 2-(trifluoromethyl)-phenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. The residue was further purified by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded d e titie compound (2.7 g), m.p. 82-85° C. Anal. Calcd. for. Cl2 H F3 N2 O S: C, 50.00; H, 3.85; N.9.72. Found: C, 50.00; H, 3.61; N, 9.61.
  • the tide compound was prepared by d e procedure described in Example 28 using 20.5 g of 2-ethyl-6-isopropylphenyl-isouiiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-10 % ethyl acetate in hexane). CrystalUzation from diethyl ether/hexane afforded pure title compound (7.5 g) as a white solid, m.p. 77-79° C. Anal. Calcd. for. Ci6 H22 N2 O S: 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.
  • the tide compound was prepared by the procedure described in Example 28 using 17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of trieuiyl amine, and 300 mL of chloroform. The residue was further purified by flash chromatography on silica gel (20 % etfiyl acetate in hexane). The title compound was obtained (8.6 g) as a light peach solid, m.p. 82-84° C. Anal. Calcd. for. C14 H s N2 O S: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.27; H, 7.04; N, 10.60. Mass spectrum (EI, M. + ) m/z 262.
  • the tide compound was prepared by the procedure described in Example 28 using 18.3 g of 2-chloro-4-methylphenyl-isothiocyanate, 18.4 g of N-etivyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded the titie compound (5.8 g) as a peach solid, m.p. 126-128° C. Anal. Calcd. for. C12 H13 Cl N2 O S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.50; H, 4.76; N,
  • the tide compound was prepared by the procedure described in Example 16 using 18.1 g of l-(4-fluorophenyl)-ethyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded die tide compound (8.8 g) as a Ught yellow solid, m.p. 93-95° C. Anal.
  • the tide compound was prepared by the procedure described in Example 16 using 20.4 g of 2,3-dichlorophenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Purification was achieved by flash chromatography on silica gel (20 % etiiyl acetate in hexane) The tide compound (8.8 g) was obtained as a light peach solid, m.p. 144-146° C. Anal. Calcd. for. Cn Hio Cl2 N2 O S: 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.
  • the tide compound was prepared by the procedure described in Example 16 using 16.3 g of phenethyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of trieuiyl amine, and 300 mL of chloroform. Purification was achieved by flash chromatography on silica gel (20 % ethyl acetate in hexane) The title compound (15.0 g) was obtained as an off-white solid, m.p. 66-68° C. Anal. Calcd. for. C13 Hi6 N2 O S: C, 62.87; H,
  • the tide compound was prepared by tiie procedure described in Example 16 using 16.3 g of 2,3-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (10.3 g) as a light pink solid, m.p. 120-121° C. Anal. Calcd. for. C13 Hi6 N2 O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.72; H, 6.44; N, 11.47. Mass spectrum (EI, M. + ) m/z 248.
  • EXAMPLE 38 3-f2.4-DimethvlDhenvn-l-ethvl-2-thioxo-imida7.olidin-4.one
  • the tide compound was prepared by the procedure described in Example 16 using 16.3 g of 2,4-dimethylphenyl-isothiocyanate, 18.4 g of N-ediyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. CrystalUzation from ethanol afforded the title compound (10.8 g) as a light peach solid, m.p. 161-162° C. Anal. Calcd. for. C13 Hi6 N2 O S: C62.87; H, 6.49; N, 11.28. Found: C, 62.63; H, 6.45; N, 1 1.17. Mass spectrum (EI, M. + ) m/z 248.
  • EXAMPLE 39 3. .->-nimethvlDhenvn-l-ethvl-2-thioxo-imida7 lidin-4-one
  • the tide compound was prepared by the procedure described in Example 16 using 16.3 g of 2,5-dimed ⁇ ylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethyl acetate afforded the tide compound (10.6 g) as an off-white solid, m.p. 176-178° C. Anal. Calcd. for.
  • the tide compound was prepared by d e procedure described in Example 16 using 17.7 g of 2,4,5-trimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of trieuiyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded d e tide compound (15.3g) as an off-white solid, m.p. 162-164° C. Anal. Calcd. for.
  • the tide compound was prepared by d e procedure described in Example 16 using 15.42 g of 2-isopropylphenyl-isothiocyanate, 16.05 g of N-ethyl glycine, 12 g of trieuiyl amine, and 200 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-20 % ethyl acetate in hexane) CrystalUzation from ethanol afforded the tide compound (9.8 g) as a white solid, m.p. 125-127° C. Anal. Calcd. for. Ci4 Hi8 N2 O S: C, 64.09; H, 6.91; N, 10.68. Found: C, 64.19 H, 6.93; N, 10.71. Mass spectrum (EI, M.+) m/z 262.
  • the tide compound was prepared by die procedure described in Example 16 using 16.3 g of 2-ed ⁇ ylphenyl-isod ⁇ iocyanate, 18.4 g of N-ethyl glycine, 20.2 g of trieuiyl amine, and 200 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-10 % etiiyl acetate in hexane) Crystallization from diediyl etiier afforded the title compound (9.12 g) as a white solid, m.p. 71-73° C. Anal. Calcd. for. Ci3 Hi6 N2 O S: C62.87; H, 6.49; N, 11.28. Found: C, 62.81; H,
  • the tide compound was prepared by die procedure described in Example 45 using 21.9 g of 2,6-diisopropylphenyl-isoti ⁇ ocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. CrystaUization from etiianol afforded d e tide compound (11.7 g) as a white solid, m.p. 175-177° C. Anal. Calcd. for. Ci8 H26 2 O S: C, 67.88; H, 8.23; N, 8.80. Found: C, 68.03; H, 8.09; N , 8.81. Mass spectrum (+FAB, [M+H] + ) m/z 319. EXAMPLE 4ft
  • the tide compound was prepared by d e procedure described in Example 45 using 17.5 g of indan-5-yl-isod iocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of trieuiyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (9.9 g) as a white solid, m.p. 178-180° C. Anal. Calcd. for. C15 Hi8 N2 O S: 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 21 A.
  • the tide compound was prepared by die procedure described in Example 45 using 16.3 g of 2-ethylphenyl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of trieuiyl amine, and 300 mL of chloroform. CrystaUization from diediyl ether afforded die tide compound (6.8 g) as a white solid, m.p. 103-105° C. Anal. Calcd. for. C14 Hi8 N2 O S: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.08; H, 6.92; N, 10.62. Mass spectrum (EI, M. + ) m/z 262.
  • the title compound was prepared by the procedure described in Example 45 using 10.0 g of 2-isopropylphenyl-isothiocyanate, 11.9 g of N-isopropyl glycine, 12.0 g of triethyl amine, and 200 mL of chloroform. Crystallization from ethanol afforded die tide compound (6.8 g) as a light pink solid, m.p. 112-1 14° C. Anal. Calcd. for.
  • the tide compound was prepared by d e procedure described in Example 54 using 6.5 g of 2-chloro-6-methylphenyl-isothiocyanate, 8.5 g of N-butyl glycine, 10.0 g of tried yl amine, and 150 mL of metiiylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). CrystaUization from ethanol afforded die tide compound (3.85 g) as a Ught pink solid, m.p. 97-100° C. Anal. Calcd. for. C14 H ⁇ Cl N2 O S : 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.

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Abstract

Composés et procédé permettant d'augmenter la concentration en cholestérol à lipoprotéines de haute densité (HDL) dans le sang d'un mammifère nécessitant une concentration accrue de cholestérol HDL, ledit procédé consistant à administrer audit mammifère, par voie orale ou parentérale, un composé de formule (I). Dans la formule (I), R représente alkyle; un hétérocycle N, O, ou S aromatique substitué ou non; aryle, arylalkyle, benzhydryle ou indanyl substitué ou non dans lequel les substituants peuvent être un, deux ou trois éléments indépendamment sélectionnés dans le groupe formé par: alkyle, alcoxy, akylthio, alcényle, alcynyle, halo, perfluoroalkyle, perfluoroalcoxy ou hydroxy; et R1 représente aryle, alkyle, alcényle, alcynyle ou aryle substitué dans lequel les substituants peuvent être un, deux ou trois éléments indépendamment sélectionnés dand le groupe formé par: alkyle, alcoxy, alkythio, alcényle, alcynyle, halo, perfluoroalkyle, perfluoroalcoxy ou hydroxy.
EP96942118A 1995-11-28 1996-11-25 Derives 2-thioxo-imidazolin-4-one et leur utilisation pour augmenter la cholesterolemie a lipoproteine de haute densite Withdrawn EP0876355A1 (fr)

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US766695P 1995-11-28 1995-11-28
US7665P 1995-11-28
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US563325 1995-11-28
US08/563,325 US5554607A (en) 1995-11-28 1995-11-28 Use of 2-thioxo-imidazolin-4-one derivatives in the treatment of atherosclerosis
US7658P 1995-11-28
PCT/US1996/019164 WO1997019932A1 (fr) 1995-11-28 1996-11-25 Derives 2-thioxo-imidazolin-4-one et leur utilisation pour augmenter la cholesterolemie a lipoproteine de haute densite

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US6455566B1 (en) 1997-09-03 2002-09-24 Wyeth Substituted 1-aryl-3-heteroaryl-thioureas (or isothioureas) as antiatherosclerotic agents
AU775606B2 (en) * 1998-08-31 2004-08-05 Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The Methimazole derivatives and tautomeric cyclic thiones to treat autoimmune diseases
EP1426046A4 (fr) 2001-09-14 2005-11-02 Shionogi & Co Nouvelle utilisation de composes tricycliques
FR2845385B1 (fr) * 2002-10-04 2004-12-31 Fournier Lab Sa Composes derives de la 2-thiohydantoine et leur utilisation en therapeutique
FR2845384B1 (fr) * 2002-10-04 2004-12-31 Fournier Lab Sa Composes derives de la 2-thiohydantoine et leur utilisation en therapeutique
EP1546111A2 (fr) * 2002-10-04 2005-06-29 Laboratoires Fournier S.A. Composes derives de la 2-thiohydantoine et leur utilisation pour le traitement du diabete

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JPH0629943B2 (ja) * 1983-10-31 1994-04-20 富士写真フイルム株式会社 画像形成方法
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FR2694290B1 (fr) * 1992-07-08 1994-09-02 Roussel Uclaf Nouvelles phénylimidazolidines éventuellement substituées, leur procédé de préparation, leur application comme médicaments et les compositions pharmaceutiques les renfermant.
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