WO1990000897A1 - Methode et composition pour enrayer l'hyperlipidemie - Google Patents

Methode et composition pour enrayer l'hyperlipidemie Download PDF

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Publication number
WO1990000897A1
WO1990000897A1 PCT/US1989/003246 US8903246W WO9000897A1 WO 1990000897 A1 WO1990000897 A1 WO 1990000897A1 US 8903246 W US8903246 W US 8903246W WO 9000897 A1 WO9000897 A1 WO 9000897A1
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Prior art keywords
substituted
dione
phenyl
triazolidine
alkyl
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PCT/US1989/003246
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English (en)
Inventor
Robert A. Izydore
Iris H. Hall
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University Of North Carolina At Chapel Hill
North Carolina Central University
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Priority claimed from US07/224,680 external-priority patent/US5034528A/en
Priority claimed from US07/224,679 external-priority patent/US4866058A/en
Application filed by University Of North Carolina At Chapel Hill, North Carolina Central University filed Critical University Of North Carolina At Chapel Hill
Publication of WO1990000897A1 publication Critical patent/WO1990000897A1/fr

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    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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

Definitions

  • the present invention relates to compositions having hypolipidemic activity and methods for their use in controlling hyperlipidemia in mammals. Specifically, the present invention is directed to methods for controlling hyperlipidemia by treating mammals, especially humans, with a class of hypolipidemic agents selected from 1,2,4- triazolidine-3,5-diones, 1,3,5- triazabicyclo[3.1.0]hexane-2,4-diones and 1,3,5- triazine-2,4(1H,3H)-diones.
  • a class of hypolipidemic agents selected from 1,2,4- triazolidine-3,5-diones, 1,3,5- triazabicyclo[3.1.0]hexane-2,4-diones and 1,3,5- triazine-2,4(1H,3H)-diones.
  • Cholesterol is commonly found in all the tissues and blood of mammals, especially humans. Manufactured in the liver and other cells as a substrate for other steroids and membrane synthesis; cholesterol is a normal constituent of bile. As will be appreciated, many familiar foods contain cholesterol, with some containing more than others. Maintaining proper levels of cholesterol in the body has become an important factor in todays diet, since medical science has proven that certain afflictions such as hypothyroidism, diabetes and the intake of foods having a high cholesterol content may result in high levels of cholesterol in the blood.
  • hyperlipidemia A condition which is associated with elevated levels of cholesterol, phospholipids, and/or triglycerides in the blood serum of mammals is commonly referred to as hyperlipidemia (i.e. as used herein, reference to hyperlipidemia is intended to be inclusive of both hypercholesterolemia and hypertriglyceremia, and hence, compounds having a hypolipidemic effect will exhibit activity to lower both cholesterol and triglyceride lipid levels) .
  • Hyperlipidemia can lead to serious health problems such as arthereosclerosis. We know that serum lipoprotein in mammals is composed of cholesterol together with triglyceride, phospholipid and apoproteins.
  • Lipoprotein is composed of several fractions-the very low density lipoprotein (VLDL) , the low density lipoprotein (LDL) and the high density lipoprotein (HDL) depending on the specific gravity of the apoprotein components of the fraction. Medical evidence points to the VLDL and LDL fractions as being associated with atherosclerosis. In contrast, the HDL fraction appears to- carry cholesterol from the blood vessels to the liver where it is processed and excreted in the bile. As hyperlipidemic states increase in atherosclerosis the LDL cholesterol increases and
  • U.S. Patent No. 4,639,444 describes 3,5- dialkyl-4,6-diaryltetrahydro-2H-l,3,5-thiadiazine-2- thione derivatives as useful hypolipidemic agents.
  • U.S. Patent No. 4,681,893 teaches that certain trans-6-[2-(3- or 4-carboxamido-substituted pyrrol- 1-yl)alkyl]-4-hydroxypyran-2-ones and their ring opened acids are potent hypolipidemic agents.
  • U.S. Patent No. 4,351,844 describes hypocholesterolae ic lactone compounds and their free acids which are derived from the natural fermentation product evinolin.
  • R' is hydrogen, a C, to C Pain alkyl or 'substituted alkyl, a C 2 to C Trust alkenyl or substituted alkenyl, a C 2 to C, 8 alkynyl or substituted alkynyl, ⁇ C, to C 10 cycloalkyl or substituted cycloalkyl, a C 4 to C 10 cycloalkenyl or substituted cycloalkenyl, phenyl, a substituted phenyl, cyano, phenalkyl, -CO-R 9 or -Y-CO-R 9 ;
  • R 2 is hydrogen, a C, to C Pain alkyl or 'substituted alkyl, a C 2 to C Force alkenyl or substituted alkenyl, a C 2 to C, 8 alkynyl or substituted alkynyl, ⁇ C, to C 10 cycloalkyl or substituted cycloalkyl, a C 4
  • R 3 and R * can be the same or different and are each the same as R 1 ;
  • R 5 , R 6 and R 7 can be the same or different and are each hydrogen, a C, to C 18 al'yl or . substituted alkyl, a C 2 to C Principal alkenyl or substituted alkenyl, a C, to C Conduct alkynyl or substituted alkynyl, a C to C, profession cycloalkyl or substituted cycloalkyl, a C 4 to C I0 cycloalkenyl or substituted cycloalkenyl, phenyl or substituted phenyl, phenalkyl, -CO-R 9 , or -Y-CO-R 9 , with the proviso that R 5 and R 6 together cannot be so bulky as to cause the compound to decompose;
  • R ⁇ is hydrogen, a C, to C 5 alkyl, a C to C t0 cycloalkyl, -CO-R 9 , or -Y-CO-R 9 ;
  • R 9 is hydrogen, a C, to C 5 alkyl or substituted alkyl, a C 2 to C 5 alkenyl or substituted alkenyl, a C 2 to C 5 alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C, to C 5 alkoxy or substituted alkoxy, a C 4 to C, 0 cycloalkyl or substituted cycloalkyl, a C.
  • R 10 and R" can be the same or different and are each hydrogen, a C, to C 5 alkyl or substituted alkyl, phenyl or substituted phenyl;
  • Y is a C, to C 10 alkylene or substituted alkylene; and the pharmaceutically acceptable salts, and mixtures thereof.
  • the present invention provides for pharmaceutical compositions for use in controlling hyperlipidemia in mammals which comprises a hypolipidentically effective amount of a compound having hypolipidemic activity and a structural formula (I) or a pharmaceutically acceptable salt thereof as shown above in combination with a pharmaceutically acceptable carrier.
  • hypolipidemic activity is intended to refer to the ability of the compounds of formula (I) to lower levels of serum cholesterol and/or triglycerides in mammals to which the compound is administered.
  • hypolipidemic agents Many of the above-described compounds which may be used as hypolipidemic agents are new, and hence, as a further embodiment*of the present invention there is provided a novel class of compounds having hypolipidemic activity and the structural formula:
  • R 1 is hydrogen, a C, to C. 8 alkyl or substituted alkyl, a C 2 to C Pain alkenyl or substituted alkenyl, a C 2 to C Conduct alkynyl or substituted alkynyl, a C 4 to C 10 cycloalkyl or substituted cycloalkyl, a C to C t0 cycloalkenyl or substituted cycloalkenyl, phenyl, a substituted phenyl, cyano, phenalkyl, -CO-R 9 or -Y-CO-R 9 ;
  • R 3 and R 4 may be the same or different and are each the same as R';
  • R 9 is hydrogen, a C f to C 5 alkyl or substituted alkyl, a C 2 to C 5 alkenyl or substituted alkenyl, a C 2 to C 5 alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C, to C 5 alkoxy or substituted alkoxy, a C 4 to C, 0 cycloalkyl or substituted cycloalkyl, a C 4 to C 10 cycloalkenyl or substituted cycloalkenyl, -NHC 6 C 5 , -NR'°R n wherein R 10 And R" can be the same or different and are each hydrogen, a C, to C 5 alkyl or substituted alkyl, phenyl or substituted phenyl, and
  • Y is a C, to C 10 alkylene or substituted alkylene; provided that R 3 and R 4 are not both hydrogen and further provided that neither R 3 nor ' is hydrogen when R' is phenyl.
  • a second class of novel hypolipidemic agents according to this invention have the structural formula:
  • R' is hydrogen, a C, to C l8 alkyl or substituted alkyl, a C 2 to C, 8 alkenyl or substituted alkenyl, a C 2 to C 18 alkynyl or substituted alkynyl, a C 4 to C 10 cycloalkyl or substituted cycloalkyl, a C to C )0 cycloalkenyl or substituted cycloalkenyl, phe- nyl, a substituted phenyl, cyano, phenalkyl, -CO-R 9 or -Y-CO-R 9 ;
  • R 5 and R 6 can be the same or different and are each hydrogen, a C, to C f8 alkyl or substituted alkyl, a C 2 to C 18 alkenyl or substituted alkenyl, a C 2 to C 18 alkynyl or substituted alkynyl, a C to C, 0 cycloalkyl or substituted cycloalkyl, a C to C 10 cycloalkenyl or substituted cycloalkenyl, phenyl or substituted phenyl, phenalkyl, -CO-R 9 , or -Y-CO-R 9 , with the proviso that R 5 and R 6 together cannot be so bulky as to cause the compound to decompose;
  • R 9 is hydrogen, a C, to C s alkyl or substituted alkyl, a C 2 to C 5 alkenyl or substituted alkenyl, a C 2 to C s alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C t to C 5 alkoxy or substituted alkoxy, a C to C t0 cycloalkyl or substituted cycloalkyl, a C 4 to C 10 cycloalkenyl or substituted cycloalkenyl,
  • R 10 and R" can be the same or different and are each hydrogen, a C, to C s alkyl or substituted alkyl, phenyl or substituted phenyl; and Y is a C, to C, o alkylene or substituted alkylene; and the pharmaceutically acceptable salts thereof, and mixtures thereof; provided that R' is not phenyl or chlorophenyl when R s is hydrogen, R 6 is -CO-R 9 , and R" is ethoxy or when R 6 is hydrogen, RR S is -CO-R 9 , and R 9 is ethoxy; and further provided that R' is not phenyl when RR 5 is hydrogen, R 6 is -CO-R 9 , and R 9 is methoxy or when R 6 is hydrogen, R 5 is -CO-R 9 , and R 9 is methoxy.
  • a third class of novel hypolipidemic agents according to this invention have the structural formula:
  • R' is hydrogen, a C, to C 18 alkyl or substituted alkyl, a C 2 to C Community alkenyl or substituted alkenyl, a C 2 to C, s alkynyl or substituted alkynyl, a C 4 to C, 0 cycloalkyl or substituted cycloalkyl, a C 4 to C 10 cycloalkenyl or substituted cycloalkenyl, phenyl, a substituted phenyl, cyano, phenalkyl, -CO-R 9 or -Y-CO-R 9 ;
  • R 7 is hydrogen, a C, to C 18 alkyl or substituted alkyl, a C 2 to C I8 alkenyl or substituted alkenyl, a C 2 to C I8 alkynyl or substituted alkynyl, a C 4 to C 10 cycloalkyl or substituted cycloalkyl, a C 4 to C t0 cycloalkenyl or substituted cycloalkenyl, phenyl or substituted phenyl, phenalkyl, -CO-R 9 , or -Y-CO-R 9 , R8 is hydrogen, a C, to C 5 alkyl, a C 4 to
  • R 9 is hydrogen, a C, to C 5 alkyl or substituted alkyl, a C 2 to C 5 alkenyl or substituted alkenyl, a C 2 to C 5 alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C, to C 5 alkoxy or substituted alkoxy, a C 4 to C 10 cycloalkyl or substituted cycloalkyl, a C 4 to C, 0 cycloalkenyl or substituted cycloalkenyl, -NHC 6 C 5 , -NR ,0 R 1 ' wherein R'° and R" can be the same or different and are each hydrogen, a C, to C 5 alkyl or substituted alkyl, phenyl or substituted phenyl -OH; R 12 is -CO, -COH, -CS, -CSH, or a C. to C 4 alkylene group
  • Y is a C, to C 10 alkylene or substituted alkylene; with the proviso that when R ⁇ is hydrogen and R 7 is ethoxy, R' is not phenyl, chlorophenyl, methoxyphenyl, or n-butyl.
  • Pharmaceutically acceptable salts and mixtures of the above-described compounds are expected to have similar activity.
  • mammals as used herein is intended in its normal sense, and hence is inclusive of not only mice, rats, dogs, cats, horses, pigs, sheep, cows and other animals, but humans as well.
  • hypolipidemic agents of the present invention we observed the inhibition of activity of the rate limiting enzyme of cholesterol synthesis (HMG CoA reductase) as well as the lowering of the acyl CoA cholesterol acyl transferase (cholesterol ester) , acetyl CoA carboxylase (fatty acid) , sn glycerol-3- phosphate acyl transferase and phosphatidylate phosphohydrolase (triglyceride) and heparin induced lipoprotein lipase (release of triglycerides for apoproteins) .
  • HMG CoA reductase the rate limiting enzyme of cholesterol synthesis
  • acetyl CoA carboxylase fatty acid
  • sn glycerol-3- phosphate acyl transferase and phosphatidylate phosphohydrolase triglyceride
  • heparin induced lipoprotein lipase release of triglycerides for apoprotein
  • hypolipidemic agents of the present invention afford reduction in both serum cholesterol and triglycerides and can be used in lower dosage amounts than commercially available agents such as nicotinic acid derivatives, clofibrate, cholestyramine and cholesripol.
  • agents of the present invention we have observed significant increases in HDL-cholesterol and reduced levels of LDL cholesterol with an acceleration of lipid excretion via the feces with clearance of lipids from the blood compartment and tissues, e.g. the aorta wall.
  • alkyl refers to carbon containing substituents that may be straight chain or branched.
  • substituted alkyl refers to carbon containing substituents that may be straight chain or branched.
  • substituted alkyl refers to carbon containing substituents that may be straight chain or branched.
  • substituted alkyl include alkyl, cycloalkyl, alkenyl, cycloalkenyl alkynyl and alkoxy substituted with at least one common functional substituent selected from but not limited to the group consisting of alkoxy, oxo, alkoxy carbonyl, halogen, nitro, aryl, carbamoyl, amino, amido, acyloxy, hydroxy, carboxy, alkylthio, sulfoxide, sulfone, thiol, sulf
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and n-pentyl.
  • alkoxy groups include methoxy and ethoxy.
  • suitable cycloalkyl groups are cyclobutyl, cyclopentyl or cyclohexyl. The terms "substituted phenyl" and
  • substituted phenoxy refer to the presence on the aromatic ring of at least one common functional substituent selected from but not limited to the group of C, to C 5 alkyl, substituted C, to C 5 alkyl, C, to C 5 alkoxy, benzoyl, alkanoyl, alkoxy carbonyl, halogen, nitro, carbamoyl, amino, amido, acyloxy, hydroxy, carboxy, alkylthio, sulfoxide, sulfone, thiol, sulfonyl, sulfano, phosphono and silyl.
  • Halogen groups may be selected from bromine, chlorine, fluorine and iodine, and preferably from chlorine and bromine.
  • Our invention provides a method for treating hypolipidemia in mammals by administering a hypolipidemically effective amount of a compound of formula (I) .
  • R 2 is (a) are those wherein R' is selected from the group consisting of phenyl, halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; and R 3 and R' may be the same or different and are each selected from the group consisting of hydrogen, alkylcarbonyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxycarbonyl wherein the alkoxy group has from 1 to 5 carbon atoms, and N-phenylcarbamoy1.
  • R 2 is (a) include 4- phenyl-l-methylcarbonyl-1,2,4-triazolidine-3,5- dione, 4-phenyl-l,2-dimethylcarbonyl-l,2,4- triazolidine-3,5-dione, 4-phenyl-l-N- * phenylcarbamoyl-l,2,4-triazolidine-3,5-dione, 4- phenyl-l-ethoxycarbonyl-1,2,4-triazolidine-3,5- dione, 4-(4-chlorophenyl)-l-methylcarbonyl-l,2,4- triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1,2,4- triazolidine-3,5-dione, 4-n-butyl-l,2,4- triazolidine-3,5-dione, 4-(4-nitrophenyl)-l,2,4- triazolidine-3,5-
  • R 2 is (b)
  • R r is selected from the group consisting of phenyl, halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; and R 5 and R ⁇ are the same or different and are each selected from the group consisting of hydrogen, alkoxycarbonyl wherein the alkoxy group has from 1 to 5 carbon atoms, alkylcarbonyl wherein the alkyl group has from 1 to 5 carbon atoms, phenoxycarbonyl, carbamoyl and substituted carbamoyl. It is appreciated that, if R 5 and R 6 are too bulky, such as in the case when both are aromatic, the compound wherein R 2 is (b) may decompose. Thus those compounds are intended to be excluded from the invention.
  • Exemplary of compounds of formula (I) wherein R 2 is (b) are 3-(4-chlorophenyl)-6- ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4- dione, 3-phenyl-6-ethoxycarbonyl-l,3,5- triazabicyclo[3.1.0]hexane-2,4-dione, 3-(4- methoxyphenyl)-6-ethoxycarbonyl-l,3,5- triazabicyclo[3.1.0]hexane-2,4-dione, 4-n-butyl-6- ethoxycarbonyl-1,3 ,5-triazabicyclo[3.1.0]hexane-2,4- dione, 3-phenyl-6-methoxycarbonyl-l,3,5-triazabi ⁇ cyclo[3.1.0]hexane-2,4-dione and pharmaceutically acceptable salts and mixtures thereof.
  • R 1 is selected from the group consisting of phenyl, halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms;
  • R 7 is an alkoxy having from 1 to 5 carbon atoms or phenoxy;
  • R 8 is hydrogen or a C, to C 5 alkyland R' 2 is -CO.
  • Exemplary of the compounds of formula (I) wherein R 2 is (c) are 3-phenyl-6-ethoxycarbonyl-l,3,5-triazine-2,4(1H,3H)- dione; 3-(4-chlorophenyl)-6-ethoxycarbonyl-l,3,5- triazine-2,4(lH,3H)-dione; and pharmaceutically acceptable salts and mixtures thereof.
  • our invention provides novel compounds of formula (II) as defined above with the proviso that provided that both R 3 and R 4 are not hydrogen and that R' is not phenyl when either R 3 and R 4 is hydrogen and further provided that R 9 is not -NHC 6 H 5 when R' is phenyl.
  • Our invention further provides novel compounds of
  • R 1 is not phenyl or chlorophenyl when R 5 is hydrogen, R 6 is -CO-R 9 , and R 9 is ethoxy or when R s is hydrogen, RR 5 is -CO-R 9 , and R' is ethoxy; and further provided that R 1 is not phenyl when RR 5 is hydrogen, R ⁇ is -CO- R 9 , and R 9 is methoxy or when R 6 is hydrogen, R 5 is - CO-R 9 , and R 9 is methoxy.
  • Novel compounds of formula (IV) as defined above are also provided with the provio that when R' is hydrogen and R 7 is ethoxy, R' is not chlorophenyl, methoxyphenyl, or n-butyl.
  • R' is selected from the group consisting of halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 - carbon atoms, alkoxyphenyl wherein the alkoxy group .has from 1 to 5 carbon atoms, and nitrophenyl; and R 3 • and R* are each selected from the group consisting of hydrogen, alkylcarbonyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxycarbonyl wherein the alkoxy group has from 1 to 5 carbon atoms, and a carbamoyl or substituted carbamoyl with the proviso that both R 3 and R 4 are not both hydrogen.
  • novel hypolipidemic compounds of formula (II) are 4-phenyl-l-methylcarbonyl-l,2,4- triazolidine-3,5-dione, 4-phenyl-l,2- dimethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4- chlorophenyl)-1-methylcarbonyl-l,2,4-triazolidine- 3,5-dione, 4-(4-methoxyphenyl)-1,2-dimethylcarbonyl- 1,2,4 -triazolidine-3,5-dione, 4-(4-methoxyphenyl- 1,2-di-n-pentylcarbonyl-l,2,4-triazolidine-3,5- dione, 4-(4-methoxyphenyl)-1,2-diethylcarbonyl- 1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1,2- diethylcarbonyl-1,2,4-triazolidine ⁇
  • Novel compounds from within the class defined by formula (III) include those wherein R' is selected from the group consisting of phenyl, halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; and R 5 and R 6 may be the same or different and are each selected from the group consisting of hydrogen and alkoxycarbonyl wherein the alkoxy group has from 1 to 5 carbon atoms.
  • novel hypolipidemic compounds of formula (III) are 3-(4-methoxyphenyl)-6- "ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4- dione, 3-n-butyl-6-ethoxycarbonyl-l,3,5- triazabicyclo[3.1.0]hexane-2,4-dione and pharmaceu ⁇ tically acceptable salts and mixtures thereof.
  • R' is selected from the group consisting of halophenyl, nitrophenyl and alkoxyphenyl wherein the alkoxy group contains from 1 to 5 carbon atoms but is not ethoxy when R' is chlorophenyl.
  • the pharmaceutically acceptable salts of the compounds of formulas (I) through (IV) can be used.
  • These salts may be acid addition salts formed from inorganic or organic, e.g. hydrochlorides, sulfates, phosphates, benzoates or acetates, or salts formed with bases, e.g. alkali metal salts such as sodium or potassium salts.
  • hypolipidemically active compound as defined by formulas (I) through (IV)
  • a suitable dose of the active compound is in the range of from about 1 to about 100 mg/kg body weight per day; preferably from about 4 to about 16 mg/kg daily.
  • a typical unit or sub-dose of the active compound is about 150 mg.
  • the form of the dose is not critical and may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or inefflation. Oral administration is preferred.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose or maize-starch; lubricants, for example, magnesium stearate or stearic acid; disintegrants, for example, potato starch, croacarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral li»guid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or another suitable vehicle before use.
  • Such "liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup or carboxymethyl cellulose; emulsifying agents, for example, sorbitan mono-oleate; non- aqueous vehicles (which may include edible oils) , for example, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p- hydroxybenzoates or sorbic acid.
  • suspending agents for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup or carboxymethyl cellulose
  • emulsifying agents for example, sorbitan mono-oleate
  • non- aqueous vehicles which may include edible oils
  • preservatives for example, methyl or propyl p- hydroxybenzoates or sorbic acid.
  • a 1% aqueous solution of carboxymethylcellulose may be employed.
  • the compounds of formulas (I) through (IV) or their salts may also be formulated _ as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formulas (I) through (IV) and their physiologically acceptable acid addition or basic salts may be formulated for parenteral administration by injection or continuous infusion and may be presented in unit dose form in ampoules, or in multi-dose forms with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the compounds of formulas (I) through (IV) or their pharmaceutically acceptable salts may be used in the manufacture of a medicament for the treatment of human or animal subjects suffering from hyperlipidemia.
  • derivatives of 1,2,4- triazolidine-3,5-diones may be synthesized by reacting 4- substituted 1,2,4-triazolidine-3,5-diones synthesized by the tepwise procedure of Cookson, Gupte, Stevens, and Watts, Org. Syn. 1871, 5_l, 121, with carboxylic acid anhydrides or alkoxy chloroformates wherein the alkoxy group has from 1 to 5 carbon atoms in the presence of soium hydride, or aryl isocyanates in the presence of sodium hydride.
  • 1- and 1,2-alkyl subtituted derivatives can be made by reacting 4-substituted 1,2,4- triazolidine-3,5-diones with alkyl halides or cycloalkyl halides in the presence of a based, e.g. KOH.
  • This letter method can also be used to prepare alkenyl, cycloalkenyl and alkynyl derivatives so long as the multiply bonded group is not dirrectly attached to the ring nitrogen.
  • phenylhydrazine should be used to cyclize the triazolidine-3,5-dione ring.
  • Compounds of formula (I) (c) and (IV) may be synthesized by heating a solution of a compound of formula (I) (b) or (III) in chlorobenzene at reflux for 2 weeks.
  • Alkycarbonyl-4-substituted-l.2.4-triazolidine-3,5- diones To a stirred suspension of the 4- substituted 1,2,4-triazolidine-3,5-dione (30 mmol) in 150 to 200 ml of chloroform at room temperature was added dropwise the carboxylic acid anhydride or other appropriate acylating agent (450 mmol) . The reaction mixture was stirred at room temperature or heated under reflux, as required, for one to five days. The reaction mixture was filtered to remove the 1-acylated 4-substituted l,2,4-triazolidine-3,5- dione and unreacted l,2,4-triazolidiine-3,5-dione.
  • 1,2.4-triazolidine-3.5-dione To a suspension of 5.3 g (30 mmol) of 4-phenyl-l,2,4-triazolidine-3,5-dione in 175 ml of chloroform was added dropwise over a 15 minute period 45.9 g (450 mmol) of acetic anhydride ⁇ with stirring. The reaction mixture was stirred at room temperature for five days. The reaction mixture was filtered to remove a white precipitate which was washed with 30 ml of chloroform to give 3.55 g (54.0 %) of l-methylcarbonyl-4-phenyl-l,2,4- triazolidine-3,5-dione as white solid, m.p. 215- 218.5 °C.
  • the filtrate was washed with three 100 ml portions of water and three 80 ml portions of 10% sodium carbonate.
  • the carbonate washings were Q acidified with concentrated hydrochloric acid. No precipitate was formed.
  • the chloroform solution was .. dried (Na 2 S0) and evaporated under reduced pressure to give a liquid residue containing acetic anhydride.
  • the filtered solid was recrystallized 5 from 95% ethanol to yield pure l-methylcarbonyl-4- phenyl-1,2,4-triazolidine-3,5-dione: m.p.
  • the carbonate washings were acidified with concentrated hydrochloric acid to yield a precipitate of the triazolidine-3'.5-dione product.
  • a precipitate which was presumably the sodium salt of the triazolidine-3,5- dione, formed in the sodium carbonate washings prior to acidification.
  • the precipitate was filtered from the carbonate washings and dissolved in hot water prior to acidification.
  • the chloroform solution was dried (Na 2 S0 4 ) and evaporated under reduced pressure to give a liquid residue containing acetic anhydride.
  • the chloroform solution was dried (Na 2 S0 4 ) and evaporated under reduced pressure to give a solid-liquid residue.
  • the residue was filtered and the filtered solid was washed with 25 ml of 95% ethanol to give 2.75 g (35.1%) of the 1,2,4-triazolidine-3,5-dione product as a white solid.
  • the solution was stirred at room temperature for five hours.
  • the clear solution was washed three times with 20 ml portions of water and three times with 15 ml portions of 10% sodium carbonate.
  • the sodium carbonate washings were acidified with concentrated hydrochloric acid. No precipitate was obtained.
  • the chloroform solution was dried (Na 2 S0 4 ) and evaporated to dryness under reduced pressure to give a solid-liquid residue.
  • the residue was washed with five ml of 95% ethanol and recrystallized from methanol to give pure 1,2-dimethylcarbonyl-4-(4-chlorophenyl)-1,2,4- triazolidine-3,5-dione: m.p.
  • Methyl diazoacetate was synthesized by the procedure of Searle, U.S. Patent No. 2,490,714 (1949) and Che . Abstr. 1950, 44, 3519. Aromatic devices of III can't be prepared.
  • the 4-substituted 3-H-l,2,4-triazoline-3,5-diones were prepared by the stepwise procedure of Cookson, Gupte, Stevens, and Watts, Or ⁇ . Svmth.. 191, 51, 121 t-butyl hypochlorite was prepared using the method of Teeter and Bell, Or ⁇ . Svnth. Coll. Vol. IV. 1963, 125. Ethyl diazoacetate was purchased commercially.
  • the product was purified by heating it in 20 ml of hot carbon tetrachloride, adding chloroform dropwise until the solid had dissolved, cooling the solution to room temperature, and adding petroleum ether (40- 60 °C) dropwise with swirling to precipitate pure 6- ethoxycarbonyl-3-phenyl-l,3,5-triaza- bicyclo[3.1.0]hexane-2,4-dione: m.p. 175-177 °C (decomp.); IR (Nujol) 1745 cm " ' (CO); HNMR (400
  • the solid was purified by heating it in 10 ml of hot carbon tetrachloride, adding chloroform (approximately 10 ml) to the mixture dropwise until the solid dissolved, cooling the solution to room temperature, and adding petroleum ether (b.p. 40-60 °C) dropwise with vigorous mixing.
  • the precipitated solid was filtered and dried to yield 2.50 g (92%) of pure 6-methoxycarbonyl-3- phenyl-1,3,5-triazabicyclo [3.1.0]hexane-2,4-dione as a white solid: M.P. 176-177 e (decomp.).
  • the pale yellow solution was filtered and evaporated to dryness under reduced pressure to give 3.08 g (95%) of the crude bicyclic product as a light yellow solid.
  • the solid was purified by heating it in 30 ml of hot carbon tetrachloride, adding chloroform (approximately 25 ml) dropwise until the solid dissolved, cooling the solution to room temperature, and adding petroleum ether (b.p. 40-60 °C) dropwise with mixing.
  • the precipitated solid was filtered and dried to yield pure 6- ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5- triazabicyclo[3.1.0]hexane-2,4-d-tpne as a white solid: M.p.
  • the pale yellow solution was filtered and evaporated to dryness under reduced pressure to give 2.38 g (90%) of the crude bicyclic product as a light yellow solid.
  • the solid was purified by dissolving it in 20 ml of carbon tetrachloride and adding cyclohexane dropwise with mixing to effect precipitation. The precipitated solid was filtered and dried to yield pure 6-ethoxycarbonyl-3-n-butyl-l,3,5- triazabicyclo[3.1.0]hexane-2,4-dione as a white solid: m.p. 94-96 e.
  • the filtered solid was washed with an additional 50 ml of dichloromethane to give 1.5 g (35%) of 2,6- diphenyltriazolo[1,2-a]triazole-1,3,5,7-tetraone: m.p. greater than 310 °C.
  • the combined methylene chloride washings were evaporated under reduced pressure to yield 1.5 g (21%) of crude 6- ethoxycarbonyl-3-phenyl-l,3,5-triazine-2,4(1H,3H)- dione: m.p. 158-164 °C (decomposition).
  • the 1,3,5- triazinedione product was purified as follows: A quantity weighing 1.00 g of the 1,3,5-triazinedione
  • the 1,3,5-triazinedione product was recrystallized by heating 0.50 g of the product in 60 ml of boiling carbon tetrachloride, with stirring. A total of 55 ml of chloroform was ' then added in five ml portions to dissolve the solid. The hot solution was filtered, and then filtrate was cooled to room temperature. The cooled filtrate was added dropwise to 200 ml of cyclohexane with stirring to precipitate 0.21 g of an off-white solid: m.p. 203-205 °C. It was generally observed that addition of cyclohexane to the carbon tetrachloride-chlorofor filtrate led to the formation of a gummy precipitate.
  • an untreated control group of six mice were similarly tested on Days 9 and ?& to determine their serum cholesterol and trigylceride blood levels. Based on the results obtained for the untreated control group, the percent control, based on serum cholesterol and serum triglyceride levels of the treated mice compared to the untreated mice, was obtained. Table 1 reports this percent control, including standard deviation, indicating the level of confidence of these numbers.
  • mice A group of six CF 1 male mice (about 25 g) were placed on a commercial diet (U.S. Biochemical Corporation BAsal Atherogenic Test Diet) which produced a "hyperlipidemic" state. That is, the average serum cholesterol level in the group of treated mice was raised from 122 to 375 g percent and triglyceride levels were raised from 137 to 367 mg/dL.
  • mice Upon reaching these hyperlipidemic levels, the mice were administered Compounds A, J, M and N in a concentration of 20 mg/kg/d [LD 50 value in mice as single injection IP>500mg/kg for these compounds] intraperitoneally for 14 days while continuing the hyperlipidemic diet.
  • LD 50 value in mice as single injection IP>500mg/kg for these compounds intraperitoneally for 14 days while continuing the hyperlipidemic diet.
  • serum cholesterol and serum triglyceride levels were measured in accordance with the procedure of Example 6. The following results were obtained:
  • a test solution of Compounds A, F, J, M, N and 0 were suspended in an aqueous solution of 1% CMC, homogenized and administered orally to six Sprague-Dawley male rats, which each weighted approximately 350 grams. Administration of the compounds was by an intubation needle. The rats were each fed with 20 milligrams of Compounds A, F, J, M, N and 0 per kilogram of body weight per day for 14 days. Similarly, six Sprague-Dawley male rats of approximately the same weight (that used for testing F weighed approximately 160 grams) were fed similar volumes of the same aqueous 1% CMC solution without the active agents, also orally, administered by intubation needle.
  • the active compound is finely ground and intimately mixed with the powdered excipients (lactose, corn starch, and magnesium stearate) .
  • the formulation is then compressed in a die to produce the tablet.
  • the finely ground active compound is mixed with the powdered excipients and packed into a two part gelatin capsule.
  • the sodium lauryl sulfate, hydroxypropylmethylcellulose, flavor and color are triturated with the active compound. This mixture is then blended with 0.5 ml water and sucrose, and additional water is added to make the total volume 1.0 ml of suspension.
  • hypolipodemic compounds of the present invention when administered to 'mammals provide for " a significant increase in the HDL cholesterol content (table 4) coupled with a desireable reduction of the LDL cholesterol content. Furthermore, the very.low density lipoprotein, which generally is high in triglyceride and neutral lipid content, and which carries these lipids to the tissues from the liver, is markedly reduced by the agents.

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Abstract

Compositions pharmaceutiques comprenant des dérivés hypolipidémiants de 1,2,4-triazolidine-3,5-diones, 1,3,5-triazabicyclo[3.1.0]hexane-2,4-diones, et 1,3,5-triazine-2,4(1H,3H)-diones dans un véhicule pharmaceutiquement acceptable pour le traitement de l'hyperlipidémie chez les mammifères, en particulier chez l'homme. La présente invention porte également sur une méthode pour enrayer l'hyperlipidémie chez les mammifères, consistant à administrer à un mammifère une quantité, suffisante pour enrayer l'hyperlipidémie, d'un composé hypolipidémiant selon la formule développée (I), où R1 est hydrogène, un alkyle ou alkyle susbstitué C¿1? à C18, un alkényle ou alkényle substitué C2 à C18, un alkynyle ou alkynyle substitué C2 à C18, un cycloalkyle ou cycloalkyle substitué C4 à C10, un cycloalkényle ou cycloalkényle substitué C4 à C10, phényle, un phényle substitué, cyano, phénylalkyle, -CO-R?9¿ ou -Y-CO-R9; R2 est (a), (b), (c); R3 et R4 peuvent être identiques ou différents et représentent chacun la même chose que R?1; R5, R6 et R7¿ peuvent être identiques ou différents et représentent chacun hydrogène, un alkyle ou alkyle substitué C¿1? à C18, un alkényle ou alkényle substitué C2 à C18, un alkynyle ou alkynyle substitué C1 à C18, un cycloalkyle ou cycloalkyle substitué C4 à C10, un cycloaklényle ou cycloalkényle substitué C4 à C10, phényle ou phényle substitué, phénylalkyle, -CO-R?9¿ ou -Y-CO-R9, à la condition que R5 et R6 ne soient, ensemble, pas assez volumineux pour provoquer la décomposition du composé; R8 est hydrogène, un alkyle C¿1? à C5, un cycloalkyle C4 à C10, -CO-R?9¿ ou -Y-CO-R9; R9 est hydrogène, un alkyle ou alkyle substitué C¿1? à C5, un alkényle ou alkényle substitué C2 à C5, un alkynyle ou alkynyle substitué C2 à C5, phényle ou phényle substitué, phénoxy ou phénoxy substitué, un alkoxy ou alkoxy substitué C1 à C5, un cycloalkyle ou cycloalkyle substitué C4 à C10, un cycloalkényle ou cycloalkényle substitué C4 à C10, -NHC6C5, -NR?10R11, où R10 et R11¿ peuvent être identiques et différents et représentent chacun hydrogène, un alkyle ou alkyle substitué C¿1? à C5, phényle ou phényle substitué; Y est un alkylène ou alkylène substitué C1 à C10; R?12¿ est -CO, -COH, -CS, -CSH ou un groupe alkylène C¿1? à C4; et les sels et mélanges pharmaceutiquement acceptables dudit composé.
PCT/US1989/003246 1988-07-27 1989-07-27 Methode et composition pour enrayer l'hyperlipidemie WO1990000897A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999007352A2 (fr) * 1997-08-12 1999-02-18 Sumitomo Pharmaceuticals Company, Limited Procede permettant de favoriser l'expression du gene du recepteur de la lipoproteine de basse densite (ldl)
US6264938B1 (en) 1997-11-05 2001-07-24 Geltex Pharmaceuticals, Inc. Combination therapy for treating hypercholestrolemia

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999007352A2 (fr) * 1997-08-12 1999-02-18 Sumitomo Pharmaceuticals Company, Limited Procede permettant de favoriser l'expression du gene du recepteur de la lipoproteine de basse densite (ldl)
WO1999007352A3 (fr) * 1997-08-12 1999-05-14 Sumitomo Pharma Procede permettant de favoriser l'expression du gene du recepteur de la lipoproteine de basse densite (ldl)
US6264938B1 (en) 1997-11-05 2001-07-24 Geltex Pharmaceuticals, Inc. Combination therapy for treating hypercholestrolemia
US6365186B1 (en) 1997-11-05 2002-04-02 Geltex Pharmaceuticals, Inc. Combination therapy for treating hypercholesterolemia
US7638524B2 (en) 1997-11-05 2009-12-29 Genzyme Corporation Combination therapy for treating hypercholesterolemia

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