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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/20—Spiro-condensed ring systems
• • 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
• • 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
• • 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
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61P3/06—Antihyperlipidemics
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D211/74—Oxygen atoms
  • C07D211/76—Oxygen atoms attached in position 2 or 6
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
  • C07D211/86—Oxygen atoms
  • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/22—Bridged ring systems
  • C07D221/24—Camphidines

Definitions

• This invention relates to the use of certain cyclic lactam compounds as drugs for treating atherosclerotic conditions, for lowering total cholesterol in blood fractions and/or for treatment to beneficially alter the relative distribution and ratios of circulating high density (HDL) and low density (LDL) lipoprotein bound cholesterol fractions in the blood and arteries of valuable, warmblooded animal patients, including humans, and to some of such compounds as new compounds per se.
• HDL high density
• LDL low density
• this invention provides the use of a below defined class of cyclic lactam compounds, termed 2-(1H)-pyridinone and 2-piperidone derivative compounds which we have discovered to have useful ranges of drug activity to treat atherosclerosis, to control total cholesterol, and/or to beneficially alter the ratio of HDL/LDL lipoprotein bound cholesterol in the blood of warm-blooded animals.
• 2-(1H)-pyridinone and 2-piperidone derivative compounds which we have discovered to have useful ranges of drug activity to treat atherosclerosis, to control total cholesterol, and/or to beneficially alter the ratio of HDL/LDL lipoprotein bound cholesterol in the blood of warm-blooded animals.
• LDL low density lipoproteins
• lovastatin sold under the trademark MevAcor ® , is described in the
• Carney 3,895,032 discloses ⁇ -(cyclic tert-amino ⁇ henoxy)alkanoic acids for hypolipidemic drug use.
• Nadelson 4,000,307 discloses alkanoyl isoindolenylmethylphenones as hypolipidemic agents.
• Hall et al 4,395,471 discloses the use of a variety of cyclic imides, diones and partially reduced diones to treat diseases associated with increased serum cholesterol or triglycerides.
• Hall et al 4,689,326 discloses the use of 3,4,5,6-dibenzohomopiperidine and certain deviatives thereof for controlling hyperlipidemia.
• Ienaga et al 4,683,240 discloses the use of certain imidazolidinetrione derivatives as having hypolipidemic effects.
• D.E. 1670-570-A discloses 3,3-dialkyl-2-piperidone production from the corresponding 4-cyano-butyraldehyde.
• the products are said to be pharmaceutical or intermediates.
• D.E. 1670-521-A discloses the production of some 2- piperidone ring compounds said to be useful as pharmaceutical or as intermediates for plastic production.
• Japan 3065-897 discloses some benzo(a)quinolizines prepared from some 4-oxobenzo-(a)quinolizines which starting materials have a modified lactam linkage in the polycyclic reactant.
• 71-37117S/22 DE1958424-A discloses 6-(p-hydroxy ⁇ henyl)-2-piperidones as intermediates in the preparation of plastics and as stabilizers for oxidation-sensitive plastics.
• Belgian 896,678 discloses 5- or 6-aryl-3-(cyano, amido or amino)-2-pyridones as cardiotonic agent drugs.
• EP 89.022A discloses 5-alkanoyl-6-alkyl-2-(1H)-pyridinone derivatives as cardiotonic drugs.
• EP 74,091 discloses 6-phenyl-2-(1H)pyridinone as cardiotonic drugs, and
• WO 8601-202-A discloses 2-pyridone derivative compounds as cardiotonic drugs.
• one aspect of this invention provides a process or method for treating a valuable warm-blooded animal patient to lower the total cholesterol content and/or to beneficially alter the distribution of high density lipoprotein-bound cholesterol (HDL) relative to the amount of low density lipoprotein-bound cholesterol
• HDL high density lipoprotein-bound cholesterol
• LDL lactam compound of formula I (see the General Structural Formula sheets, infra) wherein
• R is hydrogen or C 1 to C 6 -alkyl
• X is oxygen (-O-) or bivalent sulfur (-S-)
• Y is hydrogen or C 1 to C 6 -alkyl, or -XY taken together represent hydrogen or C 1 to C 6 -alkyl, or -XY is part of a double bond between the 5- or 6-position carbon atoms of the ring when R 2 is also part of that double bond
• R 1 is hydrogen or C 1 to C 6 -alkyl
• R 2 is part of the double bond between the 5- and 6-position lactam ring carbon atoms when -XY is part of that same double bond
• R 3 is hydrogen, C 1 to C 6 -alkyl or phenyl; or
• R 2 and R 3 are independently selected from the group consisting of hydrogen, C 1 to C 6 -alkyl and phenyl
• R 4 and R 5 are independently selected from the group consisting of hydrogen, C 1 to C 6 -alkyl, or phenyl, and when one of R 4 and R 5 is phenyl, the other is hydrogen; or R 4 and R 5 are taken together with the carbon to which they are bonded to complete a spiro-cycloalkyl ring having from 4 to 6 methylene carbon atoms therein;
• R 6 and R 7 are independently selected from the group consisting of hydrogen and C 1 to C 6 -alkyl, or phenyl and when one of R 6 or R 7 is phenyl, the other is hydrogen; and wherein R 3 and R 6 can be taken together to form a -(CH 2 ) n bridge ring forming connections where n is 2 to 3, across the lactam ring, provided that (I) when -XY and R 2 form a double bond between the ring carbon atoms in the 5- and 6- positions, R 1 is hydrogen and R 3 is selected from the group consisting of hydrogen, C 1 to C 6 -alkyl and phenyl; and
• HDL/LDL ratio in a sample of that patient's blood before such treatment began.
• Another aspect of this invention provides a group of specific new compounds, within the above Formula I definitions, which have the same valuable cholesterol lowering, anti-atherosclerosis and/or HDL/LDL cholesterol-altering property, although not all to the same degree.
• the compounds believed to be new include 1,4-dimethyl-6-ethoxy-2-piperidinone, 1,4-dimethyl-3,4-dihydro-2-pyridinone, 6-hydroxy-1,4-dimethyl-2-piperidinone, 9-hydroxy-8-methyl-8-azaspiro[4.5]-decan-7-one, 8-methyl-8-azaspiro[4.5]decan-9-ene-7-one, 9-ethoxy-8-methyl-8-azaspiro[4/5]-decan-7-one, 6-hydroxy-1,4,4-trimethyl-2-piperidinone, 6-hydroxy-1,3,3-trimethyl-2-piperidinone, 1,3,3-trimethyl-3,4-dihydro-2-pyridinone, 3,4-dihydro-1-
• R is hydrogen or C 1 to C 6 -alkyl; R 1 and R 3 are hydrogen;
• R 4 and R 5 are independently selected from the group consisting of hydrogen and C 1 to C 6 -alkyl and phenyl, or
• R 4 and R 5 are taken together with the carbon to which they are bonded to complete a spiro cycloalkyl ring having from 4 to 6 methylene carbon atoms therein;
• R 6 and R 7 are hydrogen, C 1 -C 6 alkyl or phenyl. Examples of such compounds include :
• R 2 and R 3 are each hydrogen, C 1 -C 6 alkyl or phenyl; R 4 is C 1 to C 6 -alkyl and R 5 is hydrogen; or
• R 4 and R 5 are taken together with the carbon to which they are bonded to complete a spiro cycloalkyl ring having from 4 to 6 methylene carbon atoms therein;
• R 6 and R 7 are each hydrogen, C 1 to C 6 -alkyl or phenyl.
• examples of such compounds include: 6-ethoxy-1-methyl-2-piperidinone, 6-hydroxy-1-methyl-2-piperidinone, 6-ethoxy-1,4-dimethyl-2-piperidinone, 6-hydroxy-1,4-dimethyl-2-piperidinone, 9-hydroxy-8-methyl-8-azaspiro[4.5]-decan-7-one, 9-ethoxy-8-methyl-8-azaspiro[4.5]-decan-7-one, 6-hydroxy-1,4,4-trimethyl-2-piperidinone, 6-hydroxy-1,3,3-trimethyl-2-piperidinone, and (c) compounds of the formula (IV) wherein R is C 1 to C 6 -alkyl;
• X is oxygen or bivalent sulfur
• Y is hydrogen or C 1 to C 6 -alkyl
• R 1 Is hydrogen
• R 2 Is hydrogen or C 1 to C 6 -alkyl
• R 4 and R5 are hydrogen or methyl
• R 7 is hydrogen or C 1 to C 6 -alkyl, n is 2 or 3.
• glutaric acid anhydride compound can be treated with the selected primary amine, e.g., a C 1 to C 3 -alkylamine such as methylamine, as a concentrated solution of the amine in water, say 30% to 45% V/V concentration followed by heating the mixture sufficiently to effect an imidation reaction, say 150° to 275°C., to obtain the N-substituted-piperidindione (imide) compound 6 in good yield.
• the selected primary amine e.g., a C 1 to C 3 -alkylamine such as methylamine
• This resulting imide compound 6 intermediate can be isolated) or treated in its reaction mixture) and then reduced and etherified by known methods, e.g., by the sodium borohydride/ethanol or thioethanol imide reduction method of Speckamp [Hubert, J.C., Wynberg, J.P.B.A. and W.N. Speckamp, W.N. , TETRAHEDRON. 31 (1975), pp. 1437-41] to convert the imide compound 6. to the corresponding alkyl ether compounds 2 after workup in acidic ethanol in good yields (60% to 85%). Other alkanols or thioalkanols can be used to make the other ether compounds.
• substituted piperidin-2,6-dione compounds 6 such as the 3-phenylpiperidin-2,6-dione or the 3,3-dimethylpiperidin-2,6-diones are separable by silica gel chromatography procedures to afford the desired ethyl ether, 1,5,5-trimethyl-6-ethoxy-2-pi ⁇ eridinone 7 where R 7 is ethyl and smaller amount of the useful ether compound, 1,3,3-trimethyl-6-ethoxy-2-pyridinone.
• the 3-phenylsubstituted imides gives inseparable mixtures which require further heat treatment with toluene and p-toluene-sulfonic acid (TsOH) to yield the separatable desired 1-methyl-3-phenyl-3,4-dihydro-2-pyridinone and the 1-methyl-5-phenyl-3,4-dihydro-2-pyridinone type compounds, 8.
• TsOH p-toluene-sulfonic acid
• N-alkyl-6-alkyloxy-2-piperidinones 7 and the enamides 8 are all, in general, active as anti-atherosclerotic drug compounds in standard laboratory animal tests, but some are preferred over others.
• the chemical process can be carried further to hydrolyze the 6-alkoxy or 6-alkylthlo ether type compounds 7 to the corresponding 6-hydroxy- or 6-mercapto.
• N-alkyl-2-pi ⁇ eridinone compounds (hydroxy or mercapto lactam compounds) 9.
• TsOH means p-toluenesulfonic acid
• EtOH means ethanol or ethyl alcohol
• KOH means potassium hydroxide
• CH 2 CI 2 means methylene chloride
• 1 3 C NMR (CDCI 3 , ppm) means carbon 13 nuclear magnetic resonance spectrum analysis in parts per million scale units
• EtOAc means ethyl acetate
• a common solvent CH 3 NH 2 means methylamine
• H 2 O means water
• AcOH means acetic acid
• Et 2 O means diethyl ether
• DMF means N.N-dimethylformamide
• CH 3 I means methyl iodide
• HI RES MS means high resolution mass spectral analysis
• TLC means thin layer chromatography analysis procedures
• Et 3 N means triethylamine
• MgSO 4 means a common organic liquid drying form of magnesium sulfate.
• step B piperidinone (10 g. , 63.7 mmol), TsOH (0.16g.) and benzene (300 mL) were heated to reflux.
• the flask was equipped with a Dean-Stark trap filled with 4A molecular sieves. After five hours the solvent was removed in vacuo. The residue was vacuum distilled bulb to bulb to give the titled -2-pyridinone, (4.7 g. , 66.4%) b 40 95oC.
• Example 4 6-Hydroxy-1,4-dimethyl-2-Piperidinone.
• A By reduction of 1,4-dimethylglutarimide. A 30.0 g (2.3 mmole) portion of the 1,4-dimethylglutarimide prepared as described, for example, in Example 2, part A hereinabove, at -78°C in CH 2 Cl 2 (600 mL), was treated with a 425 mL (425 mmole) portion of lithium triethylborohydride (Super Hydride) to obtain the titled compound, m.p. 79o-83°C.
• Super Hydride lithium triethylborohydride
• 3,3-Dimethylglutaric anhydride (25.0 g, 0.176 mol) was added to 40% CH 3 NH 2 in H 2 O (150 mL). The solution temperature was kept between 10o and 15oC. Following the addition the solution was allowed to warm to room temperature. After 18 hours the H 2 O was removed in vacuo. The residue was heated to 200oC. and the formed H 2 O was removed by distillation. The pot residue was distilled under vacuum bulb to bulb (90oC, 0.6 mm) to yield the subtitled imide (14.9 g, 55%): mp 47-50oC (Lit.
• Example 8 6-Hydroxy-1,4,4-trimethyl-2-piperidinone.
• the anhydride, 3-phenylglutaric anhydride, (5.0 g, 26.3 mmol) was added to 40% CH 3 NH 2 in H 2 O (50 mL) at 5oC. After the addition, the solution was warmed to room temperature and stirred overnight. The H 2 O was removed by evaporation and the residue was heated to 240oC. for five hours. The pot residue was distilled bulb to bulb (b 1 . 2 110oC) to give the subtitled compound as a yellow solid.
• the ( ⁇ ) glutaric anhydride derivative precursor compound (41.1 g. 0.225 mol) was added portionwise to 40% CH 3 NH 2 in water (200 mL) at 5°C. After the addition, the solution was warmed to room temperature for one hour followed by concentration in vacuo. The residue was heated to 200°C for one hour followed by bulb to bulb distillation of the residue (b 1.0 105oC) to afford the subtitled imide as a white crystalline solid (28.8 g, 65.6%): mp 48-50oC; 1 H NMR (CDCl 3 ) ⁇
• Lithium triethylborohydride must be stored and handled under nitrogen. 2. Lithium triethylborohydride reacts with dichlormethane at room temperature. Therefore, the reaction temperature should notexceed 40°C.
• the compounds described herein for use in the process of this invention are expected to be useful as the active drug ingredient in drug formulations used to treat a valuable warm-blooded animal patient including, humans, horses, dogs, cats, goats, pigs, and the like, for the reduction or prevention and control of atherosclerosis, for lowering serum cholesterol, for altering the relative distribution of circulating and esterified high density and low density lipo-protein-bound cholesterol fractions, and for the reduction of cholesterol in arterial tissues.
• the selected drug compound used in this invention can be administered orally or systemically, neat, but most usually in combination with one or more pharmaceutical composition ingredients in the form of tablets, hard or soft filled gelatin capsules and/or in sterile solutions, administered by sterile intramuscular or intravenous procedures.
• the effective dosage of one or more of these selected compounds will usually range from about 0.5 to about 50 mg. of drug compound per kilogram of body weight of the patient per day depending upon the drug compound selected, the patient body weight , the severity of the condition being treated, and other factors of concern to the patient's physician, until the HDL/LDL ratio in blood serum samples improves or until the atherosclerotic condition of the patient improves.
• SEA Susceptible to Experimental Atherosclerosis
• Compounds (0.5 g for 50 mg/kg dose, 0.15 g for 15 mg/kg dose, 0.05 g for 5 mg/kg dose, etc.) were dissolved or dispersed in 50 ml of 95% ethanol and mixed with 1.2 kg of the diet.
• Control groups received diet mixed with ethanol alone, and positive control groups received diet mixed with 1-pro ⁇ yl-2(1H)pyridone at 50 mg/kg.
• Beta and alpha lipoproteins were isolated from individual serum samples using PEG-8000 (polyethyleneglycol of about 8000 molecular weight) and glycine buffer, pH 9. Three hundred microliters of serum were mixed with 300 microliters of solution A (20 gram of PEG-8000 + 100 ml of glycine buffer, pH 9) using a Micromedic automatic pipette. Samples were allowed to stand at room temperature for 10 minutes and were centrifuged for 20 minutes at 2000 x g at 4oC. The resulting beta-lipoprotein pellet was dissolved in 300 microliters of solution B (10 ml Triton X-100 + 1000 ml distilled water).
• Cholesterol, triglycerides and total protein in alpha and beta lipoproteins were measured using Demand Autoanalyzer system Model AU 500 (Cooper Biomedical Inc.) and Standard Enzymatic reagents (Olympus Demand). All data were statistically analyzed using a one-way classification design (G. W. Snedecor et al, "Statistitcal Method", ISU Press, Ames, IA (1969), pp. 258-296). All values were transformed to logarithms to achieve more homogenous within-group variances. The mean response for each test compound was compared with mean observed in the control animals and the LSD test (E. S. Pearson et al, Biometrika. 38, (1951), pp. 112-130).
• Treated/control ratios of antilogs of the log means are presented. A P-value less than 0.004 is significantly different from control (g x 2000 means centrifugation at 2000 the force of gravity).
• the test results are presented in groups of tables for representative compounds used according to this invention. Data for the following compounds, in terms of ratios of the effect of test compound treated diet-fed quail to control diet-fed quails (T/C) for alpha-cholesterol (HDL), beta-cholesterol (LDL) and total cholesterol in the serum are provided in TABLE 1, attached hereinafter.
• the data indicate that at a dosage of 50 mg./kg./day compound 2 lowered the beta-cholesterol (LDL) fraction approximately 30% (100-62-38), raised the alpha-cholesterol (HDL) fraction approximately 22% (100+22) and the total cholesterol content stayed even (1.00).
• the data for compound 4 in Table 1 indicate that compound 4 lowered the beta cholesterol (LDL) fraction, raised the alpha-cholesterol (HDL) fraction and the total cholesterol fraction stayed even.
• test drug compound diet T
• T test drug compound diet
• C control diet group
• the T/C ratio for the total cholesterol analysis for the given test compound be no higher than 1, indicating that the total cholesterol content in the test animal be no more in the drug treated animal, but preferably less than one than what appears in the control group animals for that test, that is, that the total cholesterol in the serum has not increased over the control.
• Selected compounds are also tested in a more advanced eight-week quail test wherein the diet is intentionally increased in cholesterol content according to the following procedure:
• Adult, male, SEA Japanese quail were raised in gang cages on a commercial diet (Purina Game Bird Layena, Ralston Purina Company, St. Louis, MO) until five-six weeks of age.
• One hundred birds were randomly distributed into groups of 10 birds. These were housed individually in 10-cage units (Sani Battery unit B6010, Marsh Manufacturing, Garden Gover, CA) and fed a diet consisting of 48.25% each of yellow corn and soybean meal 0.5% NaCl, 2% cholesterol and 1% cholic acid.
• Drugs were mixed into the diet using a feed mixer (Hobart A-200) for 20 minutes. Two groups were controls and one group served as the positive standard. Birds in the latter group were treated with 1-vinyl-2-pyrrolidinone.
• the birds were bled via the right jugular vein and decapitated.
• the left and right brachiocephalic arteries and the thoracic aortas were removed in one piece and placed in saline.
• the aortas were cleaned free of blood, fat and adventitia, blotted dry, weighed and frozen.
• Frozen arteries were homogenized using a glass grinder in 2 ml of Solution A (hexane: isopropanol 3:2 V/V) and the homogenate was rinsed with 2 ml of the same solution. All homogenized samples were poured into 13 ml conical, glass test tubes. Then 3 ml of Solution B (solution A + 1.5% Triton X-100 surfactant) was added. The tubes were capped, mixed and left at room temperature overnight. Samples were then centrifuged at 2000 RPM for 30 minutes at 6oC. The clear solution was poured into another 13 ml conical, glass tube and the solvent was evaporated under nitrogen at 45°C.
• Solution A hexane: isopropanol 3:2 V/V
• Serum samples were diluted 1:5 with saline. Lipids and total protein in serum were analyzed using the same methods as described previously for serum samples.
• This invention also relates to compositions containing a formula I compound as an active ingredient in a pharmaceutical carrier.
• compositions are useful in pharmaceutical dosage unit forms of the formula I compounds for systemic administration (oral, rectal and parenteral administration form) in therapy for treating and alleviating symptoms of atherosclerosis, elevated cholesterol levels and/or other than normal HDL/LDL lipoprotein-bound cholesterol ratios, in blood serum fractions in humans and valuable animals, including dogs, cats and other commercially valuable and domestic animals.
• dosage unit form refers to physically discrete units suitable as unitary dosages for mammalian subjects, each unit containing a predetermined quantity for the essential active ingredient compound of this invention calculated to produce the desired effect, in combination with the required pharmaceutical means which adapt the said ingredient for systemic administration.
• suitable dosage unit forms in accordance with this invention are tablets, capsules, orally administered liquid preparations in suitable liquid vehicles, sterile preparations in suitable liquid vehicles for intramuscular and intravenous administration, sup positories and sterile dry preparations for the extemporaneous preparation of sterile injectable preparations in a suitable liquid vehicle.
• Suitable solid diluents or carriers for the solid oral pharmaceutical dosage unit forms are selected from the group consisting of lipids, carbohydrates, proteins and mineral solids, for example, starch, sucrose, lactose, kaolin, dicalcium phosphate, gelatin, acacia, corn syrup, corn starch, talc and the like.
• Capsules, both hard and soft, are filled with compositions of the selected formula I compound or salt thereof ingredients in combination with suitable diluents and excipients, for example, edible oils, talc, calcium carbonate and the like and also calcium stearate.
• Liquid preparations for oral administration are prepared in water or aqueous vehicles which advantageously contain suspending agents, for example, methylcellulose, acacia, polyvinylpyrrolidone, polyvinyl alcohol and the like.
• suspending agents for example, methylcellulose, acacia, polyvinylpyrrolidone, polyvinyl alcohol and the like.
• the injectable formulation must be sterile and must be fluid to the extent that easy syringeabiliity exists.
• Such preparations must be stable under the conditions of manufacture and storage, and ordinarily contain in addition to the basic solvent or suspending liquid, preservatives in the nature of bacteriostatic and fungistatic agents, for example, parabens, chlorobutanol, benzyl alcohol, phenol, thimerosal, and the like.
• osmotically active agents for example sugars or sodium chloride in isotonic concentrations.
• Carriers and vehicles include vegetable oils, ethanol, polyols, for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like. Any solid preparations for subsequent extemporanoues preparation of sterile injectable preparations are sterilized, preferably by exposure to a sterilizing gas, for example, ethylene oxide.
• a sterilizing gas for example, ethylene oxide.
• the aforesaid carriers, vehicles, diluents, excipients, preservatives, isotonic agents and the like constitute the pharmaceutical means which adapt the preparations for systemic administration.
• the pharmaceutical dosage unit forms are prepared in accordance with the preceding general description to provide from about 0.5 mg to about 50 mg of the essential active ingredient per dosage unit form, for administration to the patient one or more times per day, or slowly but continuously by intravenous drip methods in severe cases, depending upon the medical condition being treated, the age and weight of the patient and other factors of concern to the patient or his or her physician.
• T/C T/C (p Value) T/C (p value) Number (mg/kg/day) Alpha Chol. Beta Chol. Total Chol.
• Applicant for all designated States except US: THE UPpatent), NL (European patent), NO, SE (European pa JOHN COMPANY [US/US]; 301 Henrietta Street, Kaltent), SU, US. amazoo, MI 49001 (US).

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