Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
  • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
  • C07D251/08—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • 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

• This invention is in the field of anti-atherosclerotic agents and specifically relates to compounds, compositions and methods for treating atherosclerotic conditions such as dysliproteinimias and coronary heart disease.
• This invention specifically relates to substituted tetrahydro-l,3,5-triazin-2[lH]-thione derivatives that elevate HDL cholesterol concentration and which may be useful for the treatment of atherosclerotic conditions and coronary heart disease.
• Atherosclerosis is the process of accumulation of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral arterial vessels and subsequent myocardial infarction and stroke.
• Angiographic studies have shown that elevated levels of some HDL particles in humans appear to be correlated to a decreased number of sites of stenosis in the coronary arteries of humans (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 suggest that one antiatherogenic property of HDL may lie in its ability to deplete tissue of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset, J. Lipid Res.. 9 (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. L (1982), 102; McKinnon 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 would be of utility as anti-atherosclerotic agents, useful particularly in the treatment of dyslipoproteinimias and coronary heart disease.
• U.S. Patent No. 3,505,057 and U.S. Patent No. 3,505,323 disclose l-aryl-tetrahydro-s-triazin-2[lH]-thiones and their use as herbicidal agents.
• this invention provides antitherosclerotic agents of formula 1 having the structure
• R 1 , R 2 , R 3 , R 4 , and R 5 are each independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, phenylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy of 7-12 carbon atoms, fluoroalkoxy of 1-6 carbon atoms, trifluoromethyl, alkylthio of 1-3 carbon atoms, alkylsulfonyl of 1-3 carbon atoms, -SCF 3 , nitro, alkylamino in which the alkylamino moiety has 1-6 carbon atoms, or dialkylamino in which each alkyl group has 1-6 carbon atoms;
• R 6 is hydrogen; and R 7 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, or arylalkyl of 7-12 carbon atoms or a pharmaceutically acceptable salt thereof.
• R 1 , R 2 , R 3 , R 4 , and R 5 are each independently, hydrogen, halogen, or alkyl of 1-6 carbon atoms. More preferably each is independently hydrogen, fluorine, chorine, methyl, methoxy, dimethylamine, nitro or trifluoromethyl. Preferably three of R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen and the other two are each independently hydrogen, fluorine, chorine, methyl, methoxy, dimethylamine, nitro or trifluoromethyl.
• R 7 is preferably alkyl of 1-6 carbon atoms or arylalkyl of 7-12 carbon atoms; more preferably methyl or benzyl.
• This invention also provides a method of treating or inhibiting atherosclerosis, cardiovascular disease, or dyslipoproteinimias, and improving the HDL/LDL cholesterol ratio in a mammal in need thereof which comprises administering a compound of formula 1 having the structure
• R 1 , R 2 , R 3 , R 4 , and R 5 are each independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, phenylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy of 7-12 carbon atoms, fluoroalkoxy of 1-6 carbon atoms, trifluoromethyl, alkylthio of 1-3 carbon atoms, alkylsulfonyl of 1-3 carbon atoms, -SCF3, nitro, alkylamino in which the alkylamino moiety has 1-6 carbon atoms, or dialkylamino in which each alkyl group has 1-6 carbon atoms; R 6 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, or arylal
• R 6 is alkyl of 1-6 carbon atoms; that R 6 is alkyl of 1-6 carbon atoms, and R 1 , R 2 , R 3 , R 4 , and R 5 are each, independently, hydrogen, halogen, or alkyl of 1-6 carbon atoms. It is more preferred that R 6 is hydrogen, methyl, ethyl, isopropyl, isobutyl or benzyl . Most preferably R 6 is methyl.
• R 1 , R 2 , R 3 , R 4 , and R 5 are preferably each independendy, hydrogen, halogen, or alkyl of 1-6 carbon atoms. More preferably each is independently hydrogen, fluorine, chorine, methyl, methoxy, dimethylamine, nitro or trifluoromethyl. Preferably three of R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen and the other two are each independendy hydrogen, fluorine, chorine, methyl, methoxy, dimethylamine, nitro or trifluoromethyl.
• R 7 is preferably alkyl of 1-6 carbon atoms or arylalkyl of 7-12 carbon atoms; more preferably methyl or benzyl.
• alkyl, alkenyl, and alkynyl include both straight chain as well as branched moieties, examples include methyl, ethyl, isopropyl, n-propyl, n-butyl, s-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, ethenyl and ethynyl.
• halo includes fluorine, chlorine, bromine, and iodine.
• Fluoroalkoxy includes mono-, di-, tri-, and polyfluorinated alkoxy moieties such as -OCF3, -OCH2F, -OCHF2, -OCH2CF3, and the like.
• the aryl moiety of the arylalkyl and aryloxy substituents include radicals such as benzyl, phenyl and naphthyl.
• Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• the term "compounds of this invention” includes the broader description encompassing the formula used in accordance with the above methods, as well as the narrower description encompassing the formula used in accordance with the above novel compounds.
• the pharmaceutically acceptable salts are those derived from organic and inorganic acids such as, but not limited to: acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, toluenesulfonic and similarly known acceptable acids.
• l-(aryl substituted)-3,5-disubstituted tetrahydro-triazin-2[lH]thiones of this invention are preferentially prepared by reacting an appropriately substituted aromatic thiourea with formaldehyde and an amine (Mannich reaction; see J. Marsh,
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R are as described above for formula 1.
• Representative compounds of this invention were evaluated in an in vivo standard pharmacological test procedure which measured the ability of the compounds of this invention to elevate HDL cholesterol levels. The following briefly describes the procedure used and results obtained.
• Male Sprague-Dawley rats weighing 200-225 g were housed two per cage and fed Purina Rodent Chow Special Mix 5001-S supplemented with 0.25% cholic acid and 1.0% cholesterol and water ad libitum for 8 days.
• Each test substance was administered to a group of six rats fed the same diet with the test diet mixed in as 0.005-0.1% of the total diet. Body weight and food consumption were recorded prior to diet administration and at termination. Typical doses of the test substances were 5-100 mg kg/day.
• HDL cholesterol concentrations in serum were determined by separation of lipoprotein classes by fast protein liquid chromatography (FPLC) by a modification of the method of Kieft et al. f.T. Linid Res.. 32 (1991), 859-866].
• FPLC fast protein liquid chromatography
• 25 ml of serum was 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 was mixed on line with Boehringer-Mannheim cholesterol reagent pumped at 0.2 mL/min.
• the combined eluents were mixed and incubated on line through a knitted coil (Applied Biosciences) maintained at a temperature of 45°C.
• the eluent was monitored by measuring absorbance at 490 nm and gave a continous absorbance signal proportional to the cholesterol concentration.
• the relative concentration for each lipoprotein class was calculated as the percent of total absorbance.
• HDL cholesterol concentration in serum was calculated as the percent of total cholesterol as determined by FPLC multiplied by the total serum cholesterol concentration.
• Test compounds were administered at a dose of 100 mg kg or as indicated in parenthesis (Table I). The duration of treatment was eight days. The results obtained in this standard pharmaceutical test procedure are shown below in Table 1. Table I
• Example 3 145 Example 4 478 (75) Example 5 445 Example 6 78 (75) Example 7 94 (50) Example 8 165 (50) Example 9 170 (50) Example 10 98 (50) Example 11 345 (50) Example 12 35 (50)
• the compounds of this invention raised the concentration of HDL cholesterol, and are therefore useful for treating or inhibiting atherosclerosis, cardiovascular disease, or dysUpoproteinimias, and improving the HDL/LDL cholesterol ratio, and several metabolic conditions associated with low concentrations of HDL such as low HDL- cholesterol levels in the absence of dyslipidemia, metabolic syndrome, non-insulin dependent diabetes mellitus (NIDMM), familial combined hyperlipidemia, familial hypertriglyceridemia, and dyslipidemia in peripheral vascular disease (PVD).
• NDMM non-insulin dependent diabetes mellitus
• PVD peripheral vascular disease
• the compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
• Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material.
• 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 compression properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably, contain up to 99% of the active ingredient.
• Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
• Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
• the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
• the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
• suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
• cellulose derivatives preferably sodium carboxymethyl cellulose solution
• alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
• oils e.g. fractionated coconut oil and arachis oil
• the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
• Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
• Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
• the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
• the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package 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 analyusis and the patients recovery rate.
• the blood levels of HDL and the patient sympomatic relief analysis may be used to determine whether a larger dose is indicated.
• the projected daily dose for both human and veterinary use wil 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, conveniently administered in divided doses two to four times a day.
• Procedure A To a mixture of the appropriately substituted thiourea (29.4 mmol) in EtOH (20 mL), is added 40% aqueous methylamine (32.3 mmol, 1.1 molar eq) and 37% aqueous formaldehyde (64.7 mmol, 2.2 molar eq). The solution is refluxed under nitrogen until complete by TLC (10% MeOH/CH 2 Cl 2 or 2:1 Hex/EtOAc). The reaction mixture is cooled to room temperature and the precipitated product is filtered, washed with 50% aqueous ethanol and recrystallized, if necessary (recrystallization solvent provided in parenthesis); Procedure B. Identical to procedure A except that the solvent is removed under vacuum and the residue is recrystallized (recrystallization solvent provided in parenthesis)
• Procedure C Identical to procedure A except that the reaction is run in water;
• Procedure D Identical to procedure A except that the solvent is removed under vacuum and the residue is chromatographed on silica gel eluting with 20% ethyl acetate in hexane;
• Procedure E Identical to procedure A except that the reaction is run in dioxane. The solvent is removed under vacuum and the residue is washed with water and recrystallized;
• Procedure F Identical to procedure A except that the reaction is run in dioxane. The solvent is removed under vacuum and residue is chromatographed on silica gel eluting with dichloromethane;
• Procedure G Identical to procedure A except that the reaction is run in dioxane. The reaction mixture is poured into water and extracted with dichloromethane. The extracts are evaporated in vacuo and the residue is chromatographed on silica gel with 30% ethyl acetate in hexane;
• Procedure H Identical to procedure G except that the desired product crystallizes directly upon concentration of the dichloromethane extracts.

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• 1997
  • 1997-11-10 AU AU51706/98A patent/AU5170698A/en not_active Abandoned
  • 1997-11-10 JP JP52266598A patent/JP2001503769A/ja active Pending
  • 1997-11-10 WO PCT/US1997/020233 patent/WO1998021190A1/en not_active Application Discontinuation
  • 1997-11-10 CA CA002271728A patent/CA2271728A1/en not_active Abandoned
  • 1997-11-10 EP EP97946555A patent/EP0938480A1/en not_active Withdrawn
  • 1997-11-13 AR ARP970105309A patent/AR010068A1/es unknown
  • 1997-11-13 ZA ZA9710265A patent/ZA9710265B/xx unknown

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