WO1991009848A1 - Pyridinones utilisees comme agents antiatherosclerotiques - Google Patents

Pyridinones utilisees comme agents antiatherosclerotiques Download PDF

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Publication number
WO1991009848A1
WO1991009848A1 PCT/US1990/007190 US9007190W WO9109848A1 WO 1991009848 A1 WO1991009848 A1 WO 1991009848A1 US 9007190 W US9007190 W US 9007190W WO 9109848 A1 WO9109848 A1 WO 9109848A1
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Prior art keywords
pyridinone
bis
fractions
methylene chloride
methyl
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PCT/US1990/007190
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English (en)
Inventor
Gilbert Arthur Youngdale
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The Upjohn Company
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Publication of WO1991009848A1 publication Critical patent/WO1991009848A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to novel substituted pyridinone compounds of the formula I and a method of using these compounds in mammals as therapeutic agents for the prevention or treatment of atherosclerosis and related diseases.
  • Atherosclerosis the most common form of arteriosclerosis, is a complex disease resulting in obstruction of arterial blood vessels. It is the major, chronic contributing factor to heart attacks, strokes, and other complications of impaired blood flow. These medical events are caused either directly by the presence of the vascular lesion or indirectly by creating an intravascular site of enhanced thrombogenicity.
  • potential target organs for therapy include not only the blood vessel itself but also liver, gut, and blood elements, all of which are involved in metabolism of cholesterol, (the lipid that accumulates in atherosclerotic lesions and which, along with proliferating and infiltrating cells and extracellular matrix, contributes to the mass of the vascular lesion).
  • cholesterol-lowering drugs are believed to exert their systemic effect by lowering LDL-cholesterol and/or raising HDL-cholesterol and/or preventing or reducing the deposition of cholesterol in the artery.
  • Lowering LDL-cholesterol to reduce the risk of coronary heart disease is well recognized in the medical community. Raising HDL- cholesterol to lower the risk of heart disease is becoming more widely acknowledged.
  • Preventing or reducing the deposition of cholesterol in the artery is another method of reducing the risk of coronary heart disease. Therefore, the compounds of the present invention are useful as therapeutic agents to prevent or treat atherosclerosis and related diseases by favorably affecting circulating lipid levels as described above.
  • J. Org. Chem., 33:2083 (1968) describes the preparation of various pyridone compounds by treating 3-, 4- and 6-methyl-2(1H)-pyridones with 2 equivalents of n- butyllithium followed by an electrophilic compound.
  • J. Med. Chem., 28:1790 (1985) discloses 1,2-dihydro-2-oxo-6-(2,2-dimethyl- propyl)-3-pyridinecarboxylic acid, certain analogues and derivatives thereof as oral hypoglycemic agents.
  • Chem. Ber., 93:61 (1960) discloses the preparation of 1.3-bis[2-oxo-1.2-dihydro- pyridyl-(1)]-propanol and of 1.3-bis-[2-oxo-1.2-dihydro-pyridyl-(1)]-acetone.
  • Chem. Ber., 71B:296 (1938) discloses the preparation of N,N'-2.2'-bis-[pyridon- (2)]-diethylether.
  • the present invention particularly provides:
  • n is one to four, inclusive; wherein p is zero to two, inclusive; wherein q is zero to four, inclusive; or pharmaceutically acceptable salts or hydrates thereof; provided that (1) when X 1 is -(CH 2 ) n -[Y 1 -(CH 2 ) n ] p -Y 1 -(CH 2 ) n -, Y 1 is -O-, and R 1 is -X 1 - pyridinone substituted by R 2 , p is 1 or 2;
  • a method for treating or preventing atherosclerosis or related diseases in a patient having or susceptible to said diseases which comprises administering to said patient an amount effective of a compound of the formula I wherein R 1 is
  • the present invention consists of the compounds described by the formula I, and their use in mammals as therapeutic agents for the prevention or treatment of atherosclerosis and related complications by, for example, lowering serum cholesterol, and/or altering the relative distribution of circulating high density and low density lipoprotein-bound cholesterol fractions, and/or reduction of cholesterol in arterial tissue.
  • the parenthetical term (C n -C m ) is inclusive such that a compound of (C 1 -C 4 ) would include compounds of 1 , 2, 3 and 4 carbons and their isomeric forms; and compounds containing a double bond may be in either the cis or trans configuration.
  • the scope of this invention includes the pharmacologically acceptable acid salts of the disclosed compounds. Acid salts are formed by reacting the compounds described herein with the appropriate acid in a suitable solvent.
  • Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, hydrobromic, hydroiodic, acetic, lactic, citric, succinic, benzoic, salicylic, palmoic, cyclohexansulfamic, methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, maleic, fumaric, or oxalic.
  • Chart A The compounds of the present invention are prepared as described in the following charts, where the variables are as defined above.
  • Chart A describes the preparation of compounds of the present invention.
  • the compound of formula A-1 which is commercially available or may be prepared by methods known in the literature is reacted with the compound of formula A-2 which is commercially available or may be prepared by methods known in the literature wherein substituent A 1 is Cl, Br, I, -OSO 2 CH 3 or -OSO 2 -tolyl in the presence of a solvent and a base.
  • the base used may be sodium bicarbonate, sodium carbonate, potassium carbonate, KO-t-butyl, sodium hydride, potassium hydride, sodium hydroxide, or potassium hydroxide.
  • the solvent used may be water, methanol, ethanol, ether, DMSO, dimethylformamide, or tetrahydrofuran wherein the solvent used depends on which base and compound of formula A-2 are used and would be apparent to one of ordinary skill in the art.
  • the compounds of the formula A-3 and A-4 are obtained.
  • Chart B The compound of formula B-1 is reacted with the compound of formula B-2 wherein R 10 is (C 1 -C 4 )alkyl in a suitable solvent at reflux to obtain the compound of formula B-3 wherein R 10 is (C 1 -C 4 )alkyl .
  • Compounds B-1 and B-2 are commercially available or may be prepared by methods known in the literature.
  • Chart C The compound of formula C-1 is obtained by epoxidizing the appropriate alkenylpyridinone.
  • the alkenylpyridones are obtained by alkylating 2(1H)-pyridinone with the appropriate alkenyl halide, methanesulfonate, or 4-toluenesulfonate.
  • the compound of formula C-1 is reacted with the compound of formula C-2 wherein R 20 is (C 1 -C 4 )alkyl (commercially available or prepared by esterifying 4-hydroxybenzoic acid) to give the compound of formula C-3 wherein R 20 is (C 1 -C 4 )alkyl.
  • the acids of the compounds of formula C-3 may be prepared by basic hydrolysis followed by acidification.
  • the compound of formula C-3 is oxidized with common oxidizing agents, e.g., Jones reagent or Swern reagent, to give the compound of formula C-4 wherein R 20 is (C 1 -C 4 )alkyl .
  • the compounds of the present invention are useful to lower cholesterol in an affected patient and are therefore useful to treat diseases caused by abnormal blood cholesterol levels such as atherosclerosis and coronary heart disease.
  • the amount of the compounds of the present invention in the feed was such that the animal received the following doses: in the MHC quail test, 50 mg/kg/day; in the normal quail test, 50 mg/kg/day; in the normal rat test, 50 mg/kg/day; and in the atherosclerotic quail test, 100 mg/ kg/day: Normocholesterolemic Quail Lipoprotein Test
  • mice Male SEA Japanese quail, approximately 4 to 6 weeks of age, are reared at Miles Quail Farm, Gobies, MI, from a colony of animals originally derived at The Upjohn Company. Prior to drug testing, birds are randomly distributed into 10-15 groups of 10 quail each. They are housed in 10 cage units and and fed a commercial diet (Purina Game Bird Layena, Ralston Purina Co. , St. Louis, MO) for 7 days. Compounds are dissolved or suspended in 50 ml of 95 % ethanol and mixed with 1.2 kg of the diet. Control groups receive diet mixed with ethanol alone, and positive groups receive diet mixed with 1-propyl-2(1H)-pyridinone to provide a daily dose of 50 mg/kg.
  • a commercial diet Purina Game Bird Layena, Ralston Purina Co. , St. Louis, MO
  • each bird is bled from the right jugular vein and serum samples are obtained after low speed centrifugation. Food intake is determined for each group by subtracting the weight of diet remaining at the end of the experiment from the weight of the starting diet.
  • Beta- and alpha-lipoproteins are isolated from individual serum samples using PEG-8000 in glycine buffer, pH 9. Three hundred microliters of serum are mixed with
  • solution A 20 g of PEG-8000 + 100 ml of glycine buffer, pH 9).
  • each bird is bled from the right jugular vein and serum samples are obtained after low speed centrifugation.
  • Alpha- and beta-lipoproteins are isolated and analyzed from individual serum samples using the same method that is used for normocholesterolemic quail samples.
  • Food intake is determined for each group by subtracting the weight of diet remaining at the end of the experiment from the weight of the starting diet.
  • Normal Rat Test Normal male rats, 100-110g, are evenly distributed by weight into groups of 10. The animals are housed in stainless steel cages with 5 rats in each cage. Food and water are allowed ad libitum. Treatment is started on day 2 and continues for 7 days. The compounds are dissolved or suspended in 50 ml of 95% ethanol and mixed in 1.6 kg of rat diet (Purina 5002), which contains 20.7% protein, 5.84% fat, 4.08% fiber, 0.726% calcium, and 0.596% phosphorus. The control group receives diet mixed with 50 ml ethanol alone. Clofibrate at 150 mg/kg/day is used as positive standard. At the end of the experiment the animals are anesthetized with Cyclopal sodium (1 ml i.p.
  • Birds are randomly distributed into groups of 10, and are housed individually in 10 cage units. The birds are fed a diet consisting of 48.25% each of yellow corn and soybean meal, 0.5% sodium chloride, 2% cholesterol, and 1 % cholic acid. Drugs are dissolved or suspended in 200 ml of 95% ethanol and mixed into the diet. Two groups are controls and one group serves as the positive standard. Birds in the latter group are treated with 1-vinyl-2-pyrrolidinone. After 8 weeks on the diet, the birds are bled from the right jugular vein and decapitated. The left and right brachiocephalic arteries and the thoracic aortas are removed in one piece and placed in saline. The aortas are cleaned free of blood, fat, and adventitia, blotted dry, weighed, and frozen.
  • Frozen arteries are homogenized using a glass tissue grinder in 2 ml of Solution C (hexane:isopropanol 3:2) and the homogenate is rinsed with 2 ml of the same solution. All homogenized samples are poured into 13 ml conical glass test tubes. Then 3 ml of Solution D (Solution C + 1.5% Triton X-100) is added. The tubes are capped, mixed, and left at room temperature overnight. Samples are then centrifuged at 2000 RPM for 30 minutes at 6°C. The clear solution is poured into another 13 ml conical glass tube and the solvent is evaporated under nitrogen at 45 °C.
  • Solution C hexane:isopropanol 3:2
  • Serum samples are diluted 1 :5 with saline. Lipids in serum samples are analyzed using the same methods as for artery samples without modifications.
  • Statistical Analysis Data are statistically analyzed as a one-way analysis of variance. All values are transformed to logarithms to achieve more homogenous within-group variances. The mean response to each test compound is compared with the mean observed in the control animals using the least significant difference test.
  • the amount of a compound of the present invention effective to favorably affect circulating lipid levels is from about 0.01 to about 15 g, administered from one to three times daily. The more preferred range is 0.1 to 3 g.
  • the compounds of the present invention may be supplied in capsules, tablets, suppositories, powders, or as fluid solutions and/or suspensions in aqueous or non- aqueous vehicles, or they can be added to food.
  • the compounds can be administered orally, intravenously, intramuscularly, intraarterially, intraperitoneally, subcutaneously, transdermally, sublingually, or bucally to man or to other animals.
  • the dosage will vary with the route of administration and the physical state of the recipient. Also, for example, the dosage by the oral route will depend on the frequency of administration and the weight of the recipient. The proper dosage would be apparent to one of ordinary skill in the art.
  • a 1 is Cl
  • a mixture of 46.2 g of 2(1H)-pyridinone, 24.3 g of sodium hydroxide, 11.2 g of tetrabutylammonium bromide, 34.8 g of 2-chloroethyl ether, and 400 ml of toluene is stirred and heated under reflux for 47 hours. The cooled mixture is washed with 150 ml of water and then with 50 ml of brine.
  • the combined aqueous phases are extracted with methylene chloride (3x200 ml).
  • the combined extracts are dried over magnesium sulfate. Evaporation of the solvent leaves 53.88 g of brown oil which solidifies upon standing overnight.
  • the solid is chromatographed on a 1100 g column of silica gel.
  • the column is eluted witb 10% methanol/methylene chloride and 200 ml fractions are collected.
  • the fractions are assayed by silica gel tic (1x4") (10% methanol/methylene chloride).
  • Fractions 17-27 are combined giving 44.64 g of solid.
  • the solid is chromatographed on a 2 kg column of silica gel.
  • the column is eluted with 10% methanol/methylene chloride and 200 ml fractions are collected, then assayed by silica gel tic (1x4") (10% methanol/methylene chloride). Fractions 32-42 are combined giving a solid which is crystallized from methylene chloride/hexane giving 20.17 g of large ivory prisms. Evaporation of the solvent from the filtrate leaves 20.06 g of solid. The 20.06 g is chromatographed on a 1100 g column of silica gel. The column is eluted with 7.5% methanol/methylene chloride and 200 ml fractions are collected.
  • fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol/methylene chloride). Fractions 32-33 are combined and crystallized from acetone/hexane giving 0.56 g of solid. The 0.56 g, the 20.17 g of crystallized solid from the preceding column, and fractions 25-31 are combined and crystallized from acetone/hexane giving 35.23 g of the title product as large ivory prismatic needles.
  • the 40.11 g and the 1.6 g are combined and chromatographed on a 2 kg column of silica gel.
  • the column is eluted with 5% (fractions 1-41), 7.5% (fractions 42-50), and 10% methanol/acetone (fractions 51-85) and 200 ml fractions are collected.
  • the fractions are assayed by silica gel thin layer chromatography (1x4") (5% methanol/methylene chloride). Fractions 27-30 are combined and distilled giving 6.0 g of the title product as a yellow oil.
  • Fractions 26-44 are combined giving 4.22 g of yellow oil.
  • the 4.22 g is combined with the 18.65 g from fractions 32-27, first column and chromatographed on a 1100 g column of silica gel. The column is eluted with 50% acetone/methylene chloride and 200 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (50% acetone/methylene chloride).
  • Fractions 18-33 are combined and distilled giving 15.63 g of the second title product as a yellow oil. Physical characteristics are as follows: BP: 204-221 °C/0.15 mm.
  • Example 4 1, 1 '-[1,2-Ethanediylbis(oxy-2, 1-ethanediyl)bis-2(1H)- pyridinone (Formula A-3: R 2 is Cl; X 1 is -(CH 2 ) 2 (O(CH 2 ) 2 ) 2 -) Refer to Chart A (wherein A, is Cl)
  • the column is eluted with 7.5 % methanol/methylene chloride and 200 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4")
  • Example 5 1-[2-[2-[2-[2-(2-Pyridinyloxy)ethoxy]ethoxy]-ethoxy]ethyl]-2(1H)- pyridinone hydrate (Formula A-4: X 1 is -(CH 2 ) 2 (O(CH 2 ) 2 ) 3 -, R 2 is
  • the cooled solution is extracted with methylene chloride (4x75 ml).
  • the combined extracts are dried over magnesium sulfate.
  • Evaporation of the solvent leaves 67.87 g of yellow-brown oil.
  • the aqueous phase is extracted with methylene chloride (4x75 ml).
  • the combined extracts are dried over magnesium sulfate.
  • Evaporation of the solvent leaves 3.27 g of yellow oil.
  • the 67.87 g of oil and the 3.27 g of oil are combined and chromatographed on a 2 kg column of silica gel. The column is eluted with 7.5% methanol/methylene chloride and 200 ml fractions are collected.
  • the 28.66 g, the 3.08 g, the 4.04 g, and the 4.49 g are combined and chromatographed on a 1100 g column of silica gel.
  • the column is eluted with 10% methanol/methylene chloride and 200 ml fractions are collected.
  • the fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol/ methylene chlor ide).
  • Fractions 27-40 are combined and crystallized from methylene chloride/ethanol/hexane giving 8.34 g of the second title product as small buff, needles. Physical characteristics are as follows: MP: 184-185°C. Analysis Found: C, 63.39; H, 5.60; N, 11.22.
  • Example 7 1-[(2-Oxo-1,3-dioxolan-4-yl)methyl]-2(1H)-pyridinone and 1,1'-(2-Oxo- 1,3-propanediyl)bis-2(1H)-pyridinone
  • 10 ml of standard Jones reagent To a stirred solution of 3 g of the second title product of Example 6 in 25 ml of water is added 10 ml of standard Jones reagent. The mixture is stirred for 24 hours at ambient temperature and then for 4 hours while heated on a steam bath. Then while the mixture is still heated on the steam bath an additional 10 ml of Jones reagent is added during 5 minutes. The heating is continued for 3 hours. The mixture is then allowed to stand at room temperature for 17 hours.
  • the mixture is diluted with 100 ml of water and basified by the cautious addition of solid sodium carbonate.
  • the mixture is extracted with chloroform (3x100 ml).
  • the combined extracts are dried over magnesium sulfate. Evaporation of the solvent leaves 1.04 g of yellow solid.
  • the solid is chromatographed on a 50 g column of silica gel. The column is eluted with 10% methanol/methylene chloride and 40 ml fractions are collected. The fractions are assayed by silca gel thin layer chromatography (1x4") (10% methanol/methylene chloride). Fraction 6 gives 0.26 g of ivory solid. Fractions 7-10 are combined giving 0.43 g of yellow solid.
  • Fractions 15-24 are combined giving 21.2 g of dark brown oil.
  • the oil is chromatographed on a 1100 g column of silica gel.
  • the column is eluted with 5% methanol/methylene chloride and 200 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (5 % methanol/methylene chloride).
  • Fraction 24 is crystallized from methylene chloride/hexane giving 0.37 g of yellow-brown crystals.
  • Fraction 29 is crystallized from methylene chloride/hexane giving 1.3 g of cream crystals.
  • the 0.37 g and the 1.3 g are combined with fractions 25-28 and crystallized from methylene chloride/hexane giving 8.36 g of the first title product as small ivory crystals.
  • Example 8 1 , 1 '-(1 ,4-Phenylenedimethylene)bis-2(1H)-pyridinone
  • the toluene layer is dried over magnesium sulfate. Evaporation of the solvent leaves 0.80 g of yellow oil which is discarded.
  • the aqueous layer which contains solid is extracted with methylene chloride (3x100 ml).
  • Example 9 1, 1 '-(2-Hydroxy-2-methyl-1,3-propanediyl)bis-2(1H)-pyridinone and 1-[2-hydroxy-2-methyl-3-(2-pyridyloxy)propyl]-2(1H)- pyridinone Hydrate
  • 2(1H)-pyridinone To a stirred mixture of 27.1 g of potassium tert butoxide in 200 ml of dry tetrahydrofuran is added 41.84 g of 2(1H)-pyridinone. The mixture becomes warm upon mixing. The mixture is stirred for 2 hours.
  • a solution of 23.44 g of 1-chloro-2,3- epoxy-2- methylpropane in 50 ml of dry tetrahydrofuran is added during 15 minutes.
  • the mixture is then stirred and heated under reflux for 91 hours.
  • the solvent is evaporated.
  • the residue is treated with 200 ml of water and 40 ml of 50% aqueous sodium hydroxide solution.
  • the mixture is extracted with methylene chloride (3x100 ml).
  • the combined extracts are washed with 25 ml of brine and dried over magnesium sulfate. Evaporation of the solvent leaves a brown oil.
  • the oil is chromatographed on a 2 kg column of silica gel. The column is eluted with 5% methanol/acetone and 200 ml fractions are collected.
  • Fractions 21-33 are combined giving 8.73 g of yellow-green oil which is chromatographed on a 700 g column of silica gel. The column is eluted with 20% acetone/methylene chloride and 200 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (20% acetone/methylene chloride. Fractions 26-37 are combined giving 4.54 g of the second title product as a viscous yellow oil.
  • the solid present in the mixture is collected by filtration, washed with water and methylene chloride, and dried giving 28.75 g of brown solid.
  • the solid is chromatographed on an 1100 g column of silica gel. The column is eluted with 10% methanol-methylene chloride and 200 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol-methylene chloride). Fraction 18 is slurried in hot tetrahydrofuran and filtered to remove a small amount of insoluble material. The filtrate is concentrated and hexane is added. Cooling gives 2.29 g of cream leaflets.
  • Fraction 22 is slurried in hot acetone and filtered to remove a small amount of insoluble material. The filtrate is concentrated and hexane is added. Cooling gives 3.60 g of small buff plates. The 2.29 g and the 3.60 g are combined with fractions 19-21 and dissolved in hot tetrahydrofuran. The solution is filtered. The filtrate is concentrated and hexane is added. Cooling gives 23.64 g of the title product as an ivory solid.
  • a mixture of 2.67 g of the second title product of Example 6, 6 g of silver oxide, 10 ml of methyl iodide, and 150 ml of methylene chloride is stirred and heated under reflux for 23 hours.
  • the mixture is filtered.
  • the filter cake is washed well with methylene chloride. Evaporation of the solvent from the combined filtrate and washing leaves a sticky solid.
  • the solid is chromatographed on a 400 g column of silica gel. The column is eluted with 10% methanol-methylene chloride and 100 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol-methylene chloride).
  • a mixture of 15.22 g of 2( 1 H)-pyridinone, 10 g of 3-chloro-2-chloromethyl-1- propene, 22.1 g of potassium carbonate, and 300 ml of acetone is stirred and heated under reflux for 51 hours. After cooling to room temperature the mixture is filtered. The filter cake is washed with methylene chloride.
  • a mixture of 11.2 g of sodium hydroxide in 25 ml of water, 10.58 g of 2- mercaptobenzoxazole, 27.17 g of 1-(2-chloroethyl)-2-(1H)-pyridinonehydrochloride and 175 ml of ethanol is refluxed for 3.5 hours. A large amount of solid separates. An additional 4 g of sodium hydroxide is added. The refluxing is continued for 19 hours. The solvent is evaporated. The residue is mixed with 150 ml of water. The mixture is extracted with methylene chloride (4x100 ml). The combined extracts are dried over magnesium sulfate. Evaporation of the solvent leaves 7.52 g of orange oil.
  • the aqueous phase is extracted with chloroform (4x100 ml). The combined extracts are dried over magnesium sulfate. Evaporation of the solvent leaves 3.36 g of orange oil.
  • the 3.36 g and the 7.52 g are combined and chromatographed on a 700 g column of silica gel. The column is eluted with 10% methanol-methylene chloride and 200 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (5 % methanol-acetone). Fractions 1 1- 14 are combined giving 4.27 g of orange-brown oil. The oil is chromatographed on a 400 g column of silica gel.
  • fractions 41-46 had the same Rf as the title product of Example 18.
  • Fractions 26, 33, 34 and 35 are crystallized from acetone-hexane giving 0.08 g, 0.1 g, 0.07 g, and 0.04 g of buff needles, respectively. These solids are combined with fractions 27-32 and crystallized from acetone-hexane giving 1.16 g of the title product as buff needles.
  • Fractions 12-15 are combined giving 3.03 g of yellow oil.
  • the oil is chromato- graphed on a 400 g column of silica gel.
  • the column is eluted with 5% methanol/acetone and 100 ml fractions are collected.
  • the fractions are assayed by silica gel thin layer chromatography (1x4") ( 10% methanol/methylene chloride).
  • Fractions 30-47 are combined and crystallized from acetone/hexane giving 1.24 g of the title product as a mixture of large ivory crystalline lumps and ivory needles. .
  • a mixture of 29.14 g of 1 , 1 , 1-tris(hydroxymethyl)ethanetris-4-p-toluenesulfonate ester and 17.56 g of the sodium salt of 2(1H)-pyridinone are ground together.
  • This mixture and 300 ml of xylene is stirred and heated under reflux for 4.7 days.
  • the cooled mixture is shaken with 10 ml of 50% sodium hydroxide solution and 100 ml of water.
  • the layers are separated.
  • the xylene layer is washed with 50 ml of water.
  • the combined aqueous phases are extracted with methylene chloride (3x100 ml).
  • the combined extracts are dried over magnesium sulfate. Evaporation of the solvent leaves 9.16 of brown oil.
  • the aqueous phase is extracted with methylene chloride (2x100 ml).
  • the combined extracts are dried over magnesium sulfate. Evaporation of the solvent leaves 0.51 g of yellow solid.
  • the 9.16 g and the 0.51 g are combined and chromatographed on a 700 g column of silica gel. The column is eluted with 5% methanol/acetone and 200 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol/methylene chloride).
  • Fraction 17 is crystallized from acetone/hexane giving 0.51 g of solid.
  • the solid is recrystallized from methylene chloride/hexane giving 0.37 g of solid.
  • the solid is combined with fractions 18-28 and crystallized from methylene chloride/hexane giving 3.41 g of the title product as small buff needles.
  • the aqueous phase is saturated by addition of solid potassium carbonate.
  • the layers are separated.
  • the organic phase is dried over magnesium sulfate. Evaporation of the solvent leaves 31.94 g of orange- brown oil.
  • the oil is chromatographed on an 1100 g column of silica gel. The column is eluted with 10% methanol/methylene chloride and 200 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol- /methylene .chloride).
  • Fraction 22 is crystallized from acetone/hexane giving 1.56 g of ivory needles.
  • Fraction 23 is crystallized from acetone/ hexane giving 2.41 g of small ivory needles.
  • Fraction 24 is crystallized from acetone/hexane giving 1.32 g of small pale pink needles.
  • Fraction 25 is crystallized from acetone/hexane giving 0.89 g of small pale orange needles.
  • Fraction 26 is crystallized from acetone/ hexane giving 0.68 g of a mixture of pale orange needles and a solid.
  • the 1.56 g from fraction 22 is recrystallized from acetone-hexane giving 1.34 g of ivory needles.
  • the 1.34 g is combined with the crystallized solids from fractions 23-26 and crystallized from acetone/hexane giving 6.02 g of the title product as small ivory needles.
  • Example 21 1,1'-[2-(2-Oxo-1,2-dihydropyrid-1-yl)methyl]-1,3-propanediyl]bis-2(1H)- pyridinone
  • a mixture of 8 g of 1, 1'-(2-chloroethyl-1 ,3-propanediyl)-bis-2(1H)-pyridinone hydrate and 4.04 g of the sodium salt of 2(1H)-pyridinone is crushed and stirred. The mixture is heated beginning at 170°C and ending at 195 °C (oil bath temperature) for 1.5 hours with occasional stirring. Upon cooling, the reaction mixture forms a hard dark brown mass. The material is dissolved in 105 ml of warm water.
  • the solution is shaken with 6 ml of 50% sodium hydroxide solution and 250 ml of methylene chloride. The layers are separated. The aqueous layer is extracted with methylene chloride (2x75 ml). The combined organic phases are dried over magnesium sulfate. Evaporation of the solvent leaves 8.62 g of oily solid. The aqueous phase is saturated with sodium chloride and then extracted with methylene chloride (3x100 ml). The combined extracts are dried over magnesium sulfate. Evaporation of the solvent leaves 0.4 g of yellow oil. The 8.62 g and the 0.4 g are combined and chromatographed on a 700 g column of silica gel. The column is eluted with 10% methanol/ methylene chloride and 100 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol-methylene chloride).
  • Fraction 33 is crystallized from methylene chloride-hexane giving 0.07 of ivory needles.
  • Fraction 34 is crystallized from methylene chloride/hexane giving 0.18 g of ivory needles. The 0.07 g and the 0.18 g are combined with fractions 35-53 and crystallized from methylene chloride/hexane giving 1.77 g of the title product as an ivory solid.
  • Example 22 1, 1'-(1,2-Phenylengdimethylene)bis-2(1H)-pyridinone (Formula A-3: R 2 is H; X 1 is -CH 2 -phenyl-CH 2 -) Refer to Chart A (wherein A 1 is Br).
  • a mixture of 22.82 g of 2(1H)-pyridinone, 31.67 % of ⁇ , ⁇ '-dibromo-o-xylene, 33.2 g of potassium carbonate, and 400 ml of acetone is stirred and heated under reflux for 4 days. The mixture is filtered. The filter cake is washed with acetone.
  • Example 23 1, 1 '-(1 ,3-Phenylenedimethylene)bis-2(1H)-pyridinone (Formula A-3: R 2 is H; X 1 is -CH 2 -phenyl-CH 2 -) Refer to Chart A (wherein A 1 is Br).
  • Example 24 1,1'-(2-Hydroxy-1 ,3-propanediyl)bis-2(1H)-pyridinone and (2,3-Dihydroxypropyl)-2(1H)-pyridinone
  • a stirred solution of 28 g of sodium hydroxide in 400 ml of water is added 95.1 g of 2(1H)-pyridinone.
  • a stirred solution is added 46.27 g of epichlorohydrin.
  • the mixture is stirred and heated under reflux for 3 days.
  • the reaction mixture is cooled in an ice bath and acidified with concentrated hydrochloric acid.
  • sodium carbonate monohydrate is added cautiously until the mixture is basic. The majority of the water is evaporated and the residue is dried.
  • the residue is slurried 3 times in 400 ml of boiling methylene chloride and filtered.
  • the insoluble material is slurried three times with 200 ml of boiling methylene chloride and filtered.
  • the insoluble material is slurried with 200 ml of boiling 10% methanol/methylene chloride and filtered. Evaporation of the solvent from the filtrates leaves, respectively: 62.56 g, 19.44 g, 22.71 g, 20.13 g, and 6.01 g.
  • the combined solids are chromatographed on a 2 kg column of silica gel. The column is eluted with 10% methanol/methylene chloride and 200 ml fractions are collected.
  • fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol-methylene chloride).
  • Fraction 58 is crystallized from methylene chloride/ethanol/hexane giving 1.51 g of small white needles.
  • the 1.51 g is combined with fractions 59-83 and crystallized from methylene chloride/ethanol/hexane giving 25.13 g of the second title product as ivory needles, MP 113-115°C, undepressed mixed MP with authentic second title product.
  • Fraction 40 is crystallized from methylene chloride/ethanol/ hexane giving 1.27 g of small ivory plates.
  • Fraction 41 is crystalized from methylene chloride-ethanolhexane giving 3.82 g of small ivory plates.
  • Fraction 53 is crystallized from methylene chloride/ ethanol/hexane giving 0.65 g of small ivory plates.
  • the 1.27 g, 3.82 g, and 0.65 g are combined with fractions 42-52 and crystallized from methylene chloride/ethanol/hexane giving 43.22 g of the title product as small ivory plates.
  • Physical characteristics of the first title product are as follows: MP: 184-185°C. The melting point is the same as that of authentic first title product.
  • Example 25 1, 1'-(2-Methoxy-1 ,3-propanediyl)bis-2(1H)-pyridinone To a stirred solution of 41.57 g of 1 , 1 '-(2-hydroxy-1,3-propanediyl)bis-
  • 2(1H)pyridinone prepared as described below, in 500 ml of water is added 150 ml of dimethyl sulfate in one portion followed by 254 ml of 50% sodium hydroxide solution during 4 hours. The mixture becomes hot during the addition. The mixture is heated at reflux for one hour. The mixture is diluted with 100 ml of water and cooled to room temperature. An additional 100 ml of dimethyl sulfate is added during 55 minutes. The mixture is stirred for 16 hours. An additional 100 ml of dimethyl sulfate is added during 35 minutes. An additional 70 ml of dimethyl sulfate is added during 30 minutes. Then 50 ml of 50% sodium hydroxide is added during 30 minutes.
  • the mixture is diluted with 400 ml of water and extracted with methylene chloride (3x200 ml).
  • the combined extracts are dried over magnesium sulfate. Evaporation of the solvent leaves 37.62 g of yellow oil. Repeating the extraction procedure gives 4.08 g of yellow oil.
  • the 37.62 g and 4.08 g are combined and chromatographed on a 2 kg column of silica gel. The column is eluted with 10% methanol/methylene chloride and 200 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography 1x4") (10% methanol/ methylene chloride). Fraction 33 is crystallized from acetone/hexane giving 0.61 g of white prisms.
  • the 0.61 g is combined with fractions 34-47 and crystallized from acetone-hexane giving 30.53 g of pale pink crystalline solid. Concentration of the filtrate gives 3.61 g of ivory crystalline solid.
  • the total yield of the title product is 34.14 g.
  • the 34.14 g is combined with 22 g of the title product prepared in a similar manner and crystallized from acetone/hexane giving 50.72 of the title product as a pale pink crystalline solid.
  • a mixture of 21.6 g of the first title product of Example 6, 10.53 g of 2(1H)- pyridinone, and a few crystals of potassium fluoride dihydrate is stirred and heated at 155-165° (oil bath temperature) for 3 hours.
  • the reaction mixture is combined with the materials from a 10.83 mmolar reaction and a 12.41 mmolar reaction and chromatographed on an 1100 g column of silica gel.
  • the column is eluted with 10% methanol/methylene chloride and 200 ml fractions are collected.
  • the fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol/methylene chloride).
  • a mixture of 52.16 g of the second title product of Example 24, 1.5 g of potassium carbonate, and 300 ml of diethyl carbonate is stirred and heated under reflux for 15 minutes. Then the ethanol which is produced is allowed to distill during 2.25 hours. The mixture is then heated under gentle reflux for 15.25 hours. The excess diethyl carbonate is evaporated from the dark brown mixture. The residue is treated with 100 ml of water and extracted with methylene chloride (4x200 ml). The combined extracts are dried over magnesium sulfate. Evaporation of the solvent leaves 56 g of dark brown oil. The oil is chromatographed on an 1100 g column of silica gel.
  • the column is eluted with 10% methanol/methylene chloride and 200 ml fractions are collected.
  • the fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol/methylene chloride).
  • Fractions 1 1-15 are combined giving 32.41 g of dark brown oil.
  • Fractions 16-24 are combined giving 16.92 of dark brown oil which is chromatographed on an 1100 g column of silica gel.
  • the column is eluted with 5% methanol/acetone and 200 ml fractions are collected.
  • the fractions are assayed by silica gel thin layer chromatography (1x4") (5 % methanol/acetone).
  • Fractions 26-35 are combined and crystallized from methylene chloride/hexane (charcoal) giving 2.73 g of small buff needles.
  • the 2.73 g is recrystallized from methylene chloride-hexane giving 2.12 g of the first title product as small buff needles.
  • Fractions 11-12 are combined with the 32.41 g from fractions 11-15, first column giving 34.26 g of dark brown oil. The oil is chromatographed on an 1100 g column of silica gel. The column is eluted with 50% acetone/Skellysolve B and 200 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (50% acetone/Skellysolve B). Fractions 19-22 are combined and crystallized from methylene chloride/hexane giving 9.6 g of slightly impure second title product as small pale pink needles. Fractions 23-27 are combined giving 17.03 g of yellow-brown solid.
  • the solid is chromatographed on an 1100 g column of silica gel.
  • the column is eluted with 50% acetone/Skellysolve B and 200 ml fractions are collected.
  • the fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol/methylene chloride).
  • Fraction 23 is crystallized from methylene chloride/hexane giving a mixture of yellow solid and small white needles.
  • the yellow solid is separated mechanically from the white needles.
  • the white needles (0.75 g) are combined with fractions 19-22 and crystallized from methylene chloride/hexane giving 7.87 g of long white needles.
  • the 7.87 g is recrystallized from methylene chloride/hexane giving 6.14 g of the pure second title product as long white needles.
  • Physical characteristics are as follows:
  • Example 27 2-[S-[2-(2-Oxo-1,2-dihydropyrid-1-yl)ethyl]thio]benzoxazoleand 1-[2-(2- Oxo-1,2-dihydropyrid-1-yl)ethyl]benzoxazolin-2-thione
  • To a stirred solution of 2.07 g of 1-(2-hydroxyethyl)-2(1H)-pyridinonein 300 ml of methylene chloride is added 23 ml of triethylamine. Then a solution of 13 ml of methanesulfonyl chlofide in 50 ml of methylene chloride is added during 35 minutes. The resulting solution is stirred for 4.5 hours.
  • fractions are assayed by silica gel thin layer chromatography (1x4") (10% methanol/methylene chloride). Fractions 15-30 are combined giving 37.48 g of light brown solid. The solid is chromatographed on an 1100 g column of silica gel. The column is eluted with 10% methanol/methylene chloride and 200 ml fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (5% methanol/ methylene chloride). Fractions 11-13 are combined giving 13.65 g of brown oil. Fractions 14-15 are combined giving 12.91 g of crude first title product as a yellow-brown oil.
  • Fractions 18-19 are combined giving 4.77 g of crude first title product as a yellow-brown oil.
  • Fractions 16-17 are combined and crystallized from methylene chloride/hexane giving 5.11 g of ivory needles.
  • the 5.1 1 g is recrrstallized from methylene chloride/hexane giving 3.74 g of first title product as ivory needles.
  • fractions 1 1-13 The 13.65 g from fractions 1 1-13 is chromatographed on an 1100 g column of silica gel. The column is eluted with 5% methanol/methylene chloride and 200 ml (fractions 1-21) and 100 ml (fractions 22-39) fractions are collected. The fractions are assayed by silica gel thin layer chromatography (1x4") (5% methanol/methylene chloride). Fractions 21-23 are combined and crystallized from methylene chloride/hexane giving 0.85 g of small cream needles. The 0.85 g is recrystallized from methylene chloride/hexane giving 0.74 g of the second title product as small ivory needles. Physical characteristics are as follows:
  • Fractions 24-38 are combined giving 1 1.8 g of yellow-brown oil. This material is combined with the 12.91 g from fractions 14-15, second column; the 4.77 g from fractions 18-19, second column; the materials from the crystallization filtrates from fractions 16-17, second column; and the materials from the crystallization filtrates from fraction 21-23, third column, giving a total of 31.47 g of crude first title product as a pale brown solid.
  • A (wherein A, is Cl).
  • a stirred mixture of 95. 1 g of 2( 1 H)-pyridinone, 62.5 g of trans- 1,4-dichloro-2- butene, 138.2 g of anhydrous potassium carbonate, and 600 ml of methanol is heated under reflux for 4 days. The solygnt is evaporated. The residue is treated with 600 ml of water and 100 ml of 50% sodium hydroxide. The mixture is warmed until no solid is present. Two layers are present. After cooling to room temperature the mixture (some crystals separate) is extracted with methylene chloride (3x400 ml). The combined extracts are dried over magnesium sulfate. The solution is concentrated and Skellysolve B is added.
  • Example 29 4,4'-(1,2-Ethanediyl)-1 , 1 '-[2-(2-oxo-1 ,2-dihydro ⁇ yrid-1-yl)ethyl]bispiperidine A mixture of 10.33 g of 4,4'-ethylenedipiperidine dihydrochloride, 12.1 g of 1-
  • Example 30 Methyl4-[3-(1 ,2-Dihydro-2-oxopyridin-1-yl)-2-hydroxypropoxy]benzoate (Formula B-3: R 2 is H; R 10 is CH 3 ) Refer to Chart B. A mixture of 10.55 g of methyl 4-(2,3-epoxypropoxy)-benzoate, 4.82 g of 2(1H)- pyridinone, 2 drops of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBu) and 200 ml of acetonitrile is heated under reflux for 12 days. The solution is cooled at 5°C for 4 hours.
  • DBu 1,8-diazabicyclo(5.4.0)undec-7-ene
  • MP Begins softening at 60°C, is nearly melted at 80°C; nearly resolidified, and melted clear at 176°C.
  • a signified an increase in HDL or LDL compared to non-treated control animals.
  • a signified a decrease in HDL or LDL compared to non-treated control animals.
  • ⁇ signified no significant change in HDL or LDL compared to non-treated control animals.
  • b + signified a decrease in arterial cholesterol compared to non- treated control animals.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés de la formule (I), ainsi qu'un procédé d'utilisation de ces composés chez les mammifères comme agents thérapeutiques pour la prévention ou le traitement de l'athérosclérose et des maladies associées. Dans ladite formule, R1 comprend les substances suivantes: pyridinones, pyridinyloxy, benzoxazoles et benzoxazolin-2-thiones substitués; et cis-CH=CHCH2OC(O)O(C1-C4)alkyle, -(CH2)nCH(OH)CH2O-phényle-CO2R3, et -(CH2)nC(=O)CH2O-phényle-CO2R3.
PCT/US1990/007190 1989-12-22 1990-12-12 Pyridinones utilisees comme agents antiatherosclerotiques WO1991009848A1 (fr)

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EP0882778A2 (fr) * 1997-06-04 1998-12-09 Nalco/Exxon Energy Chemicals, L.P. Méthode et composition pour l'adoucissement d'hydrocarbures gazeux ou liquides, des systèmes aqueux et de leurs mélanges
WO2007120528A2 (fr) * 2006-03-31 2007-10-25 La Jolla Pharmaceutical Company Inhibiteurs d'adhérence médiée par l'amine oxydase sensible aux semi-carbazides (ssao) et la vap-1 utilisés dans le traitement et la prévention de maladies
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US20160002204A1 (en) * 2014-07-03 2016-01-07 Board Of Regents, The University Of Texas System Gls1 inhibitors for treating disease
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US9809588B2 (en) 2014-07-03 2017-11-07 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10125128B2 (en) 2015-06-30 2018-11-13 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10150753B2 (en) 2015-12-22 2018-12-11 Board Of Regents, The University Of Texas System Salt forms and polymorphs of (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyrdin-2-yl)acetamido) pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide
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DE2637477A1 (de) * 1976-08-20 1978-02-23 Hoechst Ag Dihydro-oxo-nicotinsaeuren und verfahren zu ihrer herstellung

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EP0882778A2 (fr) * 1997-06-04 1998-12-09 Nalco/Exxon Energy Chemicals, L.P. Méthode et composition pour l'adoucissement d'hydrocarbures gazeux ou liquides, des systèmes aqueux et de leurs mélanges
EP0882778A3 (fr) * 1997-06-04 1999-05-06 Nalco/Exxon Energy Chemicals, L.P. Méthode et composition pour l'adoucissement d'hydrocarbures gazeux ou liquides, des systèmes aqueux et de leurs mélanges
US9266834B2 (en) 2006-03-15 2016-02-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
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US10344025B2 (en) 2014-07-03 2019-07-09 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10125128B2 (en) 2015-06-30 2018-11-13 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10738043B2 (en) 2015-06-30 2020-08-11 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US11713313B2 (en) 2015-06-30 2023-08-01 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10899740B2 (en) 2015-12-22 2021-01-26 Board Of Regents, The University Of Texas System Salt forms and polymorphs of (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide
US10150753B2 (en) 2015-12-22 2018-12-11 Board Of Regents, The University Of Texas System Salt forms and polymorphs of (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyrdin-2-yl)acetamido) pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide
US11603365B2 (en) 2015-12-22 2023-03-14 Board Of Regents, The University Of Texas System Salt forms and polymorphs of (r)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido) pyridazin-3-yl)-2-fluorobutyl)-n-methyl-1H-1,2,3-triazole-4-carboxamide
US11045443B2 (en) 2017-10-18 2021-06-29 Board Of Regents, The University Of Texas System Glutaminase inhibitor therapy
US11786500B2 (en) 2017-10-18 2023-10-17 Board Of Regents, The University Of Texas System Glutaminase inhibitor therapy
US10722487B2 (en) 2017-10-18 2020-07-28 Board Of Regents, The University Of Texas System Glutaminase inhibitor therapy

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