USRE37314E1 - Pyrimidine derivatives - Google Patents

Pyrimidine derivatives Download PDF

Info

Publication number
USRE37314E1
USRE37314E1 US09/141,731 US14173198A USRE37314E US RE37314 E1 USRE37314 E1 US RE37314E1 US 14173198 A US14173198 A US 14173198A US RE37314 E USRE37314 E US RE37314E
Authority
US
United States
Prior art keywords
compound
amino
substituted
lower alkyl
sulfonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime, expires
Application number
US09/141,731
Inventor
Kentaro Hirai
Teruyuki Ishiba
Haruo Koike
Masamichi Watanabe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shionogi and Co Ltd
Original Assignee
Shionogi and Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=16216169&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=USRE37314(E1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Shionogi and Co Ltd filed Critical Shionogi and Co Ltd
Priority to US09/141,731 priority Critical patent/USRE37314E1/en
Application granted granted Critical
Publication of USRE37314E1 publication Critical patent/USRE37314E1/en
Adjusted expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom

Definitions

  • the present invention relates to 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor.
  • the compounds of the present invention inhibit the HMG-CoA reductase, which plays a main role in the synthesis of cholesterol, and subsequently they suppress the biosynthesis of cholesterol. Therefore, they are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis.
  • the present invention relates to compounds of the formula (I):
  • R 1 is lower alkyl, aryl or aralkyl, each of which may have one or more substituents: R 2 and R 3 each is independently hydrogen, lower alkyl, or aryl, and each of said lower alkyl and aryl may have one or more substituents; R 4 is hydrogen, lower alkyl, or a cation capable of forming a non-toxic pharmaceutically acceptable salt; X is sulfur, oxygen, or sulfonyl, or imino which may have a stubstituent; the dotted line represents the presence or absence of a double bond, or the corresponding ring-closed lactone.
  • This invention also provides a pharmaceutical composition comprising the same.
  • lower alkyl refers to a straight, branched, or cyclic C 1 to C 6 alkyl, including methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, n-hexyl, and isohexyl and the like.
  • the lower alkyl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, amino, and cyano.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • aryl refers to C 6 to C 12 aromatic group including phenyl, tolyl, xylyl, biphenyl, naphthyl, and the like.
  • the aryl may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, and cyano.
  • Preferred aryl is phenyl substituted by 1 to 3 halogens.
  • aralkyl refers to C 1 to C 6 lower alkyl substituted by C 6 to C 12 aromatic aryl group defined above. Examples of them are benzyl, phenethyl, phenylpropyl and the like, each of which may have 1 to 3 substituents independently selected from the group consisting of lower alkyl halogen, amino, cyano, and the like.
  • a cation capable of forming a non-toxic pharmaceutically acceptable salt refers to alkali metal ion, alkaline earth metal ion, and ammonium ion.
  • alkali metal examples are lithium, sodium, potassium, and cesium
  • alkaline earth metal examples are beryllium, magnesium, and calcium. Especially, sodium and calcium are preferred.
  • acyl examples are formyl acetyl, propionyl, butyryl, isobutyryl, valeryl, and isovaleryl.
  • substituents are acyl, optionally substituted amino, and substituted sulfonyl.
  • substituted amino as substituent means amino group substituted by sulfonyl and alkylsulfonyl. Examples of them are sulfonyl amino and methanesulfonyl amino.
  • substituted sulfonyl as substituent means sulfonyl group substituted by alkyl, amino, or alkylamino. Examples of them are methanesulfonyl, sulfamoyl, methylsulfamoyl, and N-methylsulfamoyl.
  • the compounds of the present invention can be prepared by the following method.
  • the carboxylate group of the compound a is converted into the alcohol group by the reduction in an appropriate inactive solvent such as THF, ether, and toluene in the presence of the reductant such as LiAlH and DIBAL-H.
  • the reaction is performed at ⁇ 70° to 50° C., preferably at near room temperature, for 10 minutes to 10 hours, preferably for 30 minutes to 3 hours.
  • the obtained alcohol is subjected to oxidation in an appropriate solvent such as methylene chloride in the presence of the oxidizing agent such as TPAP/4-methylmorpholin-N-oxide or pyridium chlorochromate to give aldehyde compound b.
  • the reaction is performed at 0°-60° C., preferably at near room temperature, for 10 minutes to 10 hours, preferably 30 minutes to 3 hours.
  • R 1 , R 2 , and R 3 each has the same meaning as defined above, and Alkyl means lower alkyl.
  • C* means asymmetric carbon atom
  • the dotted line means the presence or absence of the double bond
  • R 1 , R 2 , R 3 , and R 4 each has the same meaning as defined above.
  • Every sort of halogen can be used for hydrogen halogenide. Amongst all, hydrogen fluoride is preferred.
  • the same organic solvents as used in the step (2) may be employed. Acetonitrile is especially preferred.
  • the reaction is performed in a range of from 0° to 60° C., preferably at room temperature, for 0.5-10 hours, preferably for 1-2 hours.
  • the compound d is reacted with diethylmethoxyborane and NaBH 4 in an alcohol-organic solvent mixture and subjected to column chromatography of silica gel to give the compound (I) (in case R 4 is lower alkyl).
  • the reaction is performed at a temperature between ⁇ 100° to 20° C., preferably between ⁇ 85° to ⁇ 70° C. under cooling, for 10 minutes to 5 hours, preferably for 30 minutes to 2 hours.
  • the alcohol includes methanol, ethanol, propanol, and butanol; and the organic solvent includes the same as in the step (3).
  • the obtained compound may be subjected to saponification with the solution of metalic hydroxide (R 4 : cation), and after the saponification, the reaction mixture is neutralized with an acid and extracted with an organic solvent (R 4 : hydrogen).
  • the saponification is performed in a popular solvent such as water, acetonitrile, dioxane, acetone, and the mixture thereof, preferably in the presence of a base, by a conventional method.
  • the reaction is performed at 0° to 50° C., preferably at near room temperature.
  • As metalic hydroxide which may be used are sodium hydroxide, potassium hydroxide, and their analogue.
  • Acids which may be used include inorganic acids such as hydrochloric acid, sulfuric acid and the like.
  • the compound of the present invention can be administered orally or parenterally.
  • the compound of the present invention may be orally administered in the form of tablets, powders, capsules and granules, aqueous or oily suspension, or liquid form such as syrup or elixir, and parenterally in the form of aqueous or oily suspension.
  • preparations can be prepared in a conventional manner by using excipients, binders, lubricants, aqueous or oily solubilizers, emulsifier, suspending agents, and the like. And preservatives and stabilizers can be further used.
  • the dosages may vary with the administration route, age, weight, condition, and the kind of disease of the patients, but are usually 0.5-200 mg/day, preferably 1-100 mg/day through oral route, and 0.1-100 mg/day, preferably 0.5-50 mg/day through parenteral route. They may be used in a single or divided doses.
  • TPAP tetrapropylammonium perruthenate
  • HMPA hexamethylphosphoramide
  • DIBAL-H diisobutylaluminum hydride.
  • p-Fluorobenzaldehyde 81.81 g is reacted in the same manner as disclosed in the specification of JP Unexamed. Pat. Publn. No. 61-40272 to give 151.0 g (Yield: 86.7%) of the compound 1. Then the mixture of a solution of 44.68 g of the compound 1 in 65 ml of HMPA and 28.24 g of s-methylisourea hydrogen sulfate is stirred at 100° C. for 22 hours. Then the reaction mixture is extracted with ether, and washed with saturated sodium hydrogencarbonate and water in order. The organic layer is dried, and the solvent is distilled away. The obtained residue is subjected to column chromatography of silica gel to give 26.61 g (yield: 46.8%) of the compound 2.
  • the aqueous layer is extracted with 200 ml of methylene chloride, and each organic layer is washed with dil.HCl and brine in order. Each organic layer are collected and dried over anhydrous magnesium sulfate and evaporated to distill the solvent to give half ester compound.
  • This compound can be prepared by the method described at page 10 in the specification of KOKAI 2-250852.
  • the reaction mixture is stirred at 0° C. for 1 hour and cooled to ⁇ 78° C. and added dropwise to the solution of thus obtained active ester compound in ether.
  • the reaction mixture is washed with 5 ml of THF and stirred at 0° C. for 1 hour, and 10 ml of 5% sodium hydrogencarbonate is added thereto.
  • the reaction mixture is stirred for 5 minutes and extracted with ethyl acetate and the organic layer is separated and the remaining aqueous layer is extracted with ethyl acetate. Each organic layer is collected and washed with brine, dried over anhydrous magnesium sulfate and concentrated.
  • the obtained residue is subjected to column chromatography of silica gel eluting with ether-ethyl acetate and crystallized from ether-hexane to give objective compound.
  • each pyrimidine carboxylate (III) obtained in Reference Example 1-3 is reacted in the same manner as Example 1 or 2 to give the compound (I b) and (I a). Their physical constants are shown in Table 1-3.
  • Sprague-Dawley rats which were in free access to ordinary dietes containing 2% cholestyramine and water for 2 weeks, were used for the preparation of rat liver microsome.
  • the thus obtained microsome was the purified according to the manner by Juroda et al., Biochem. Biophys. Act, 486, 70 (1977).
  • the microsomal fraction obtained by centrifugation at 105,000 ⁇ g was washed once with a buffered solution containing 15 mM nicotinamide and 2 mM magnesium chloride (in a 100 mM potassium phosphate buffer, pH 7.4). It was homogenized with a buffer containing nicotinamide and magnesium chloride at the same weight as the liver employed. The thus obtained homogenate was cooled down and kept at ⁇ 80° C.
  • the rat liver microsome sample (100 ⁇ l), which was preserved at ⁇ 80° C., was fused at 0° C. and diluted with 0.7 ml of a cold potassium phosphate buffer (100 mM, pH7.4). This was mixed with 0.8 ml of 50 mM EDTA (buffered with the aforementioned potassium phosphate buffer) and 0.4 ml of 100 mM dithiothreitol solution (buffered with the aforementioned potassium phosphate buffer), and the mixture was kept at 0° C.
  • a cold potassium phosphate buffer 100 mM, pH7.4
  • the microsome solution (1.675 ml) was mixed with 670 ⁇ l of 25 mM NADPH (buffered with the aformentioned potassium phosphate buffer), and the solution was added to the solution of 0.5 mM [3 ⁇ 14 ](HMG-CoA (3mCi/mmol).
  • a solution (5 ⁇ l) of sodium salt of the test compound dissolved in potassium phosphate buffer is added to 45 ⁇ l of the mixture. The resulting mixture was incubated at 37° C. for 30 minutes and cooled. After termination of the reaction by addition of 10 ⁇ l of 2N ⁇ HCl, the mixture was incubated again at 37° C.
  • the compounds of the present invention exhibit HMG-CoA reductase inhibition activities superior to Mevinolin.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The compounds of the present invention inhibit the HMG-CoA reductase, and subsequently suppress the biosynthesis of cholesterol. And they are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis.

Description

This application is a reissue of U.S. Pat. No. 5,260,440, issued Nov. 8, 1993.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor.
2. Prior Art
As the first generation of drugs for the treatment of atherosclerosis by inhibiting the activity of HMG-CoA reductase, there are known Mevinolin (U.S. Pat. No. 4,231,938), pravastatin sodium (U.S. Pat No. 4,346,227), and, simvastatin (U.S. Pat. No. 4,444,784), which are fungal metabolites or of the chemical modifications. Recently, synthetic inhibitors of HMG-CoA reductase such as fluvastatin (F. G. Kathawala et al., 8th Int'l Symp. on Atherosclerosis, Abstract Papers, p. 445, Rome (1988)) and BMY 22089 (GB Pat. No. 2,202,846) are developed as the second generation drugs.
SUMMARY OF THE INVENTION
The compounds of the present invention inhibit the HMG-CoA reductase, which plays a main role in the synthesis of cholesterol, and subsequently they suppress the biosynthesis of cholesterol. Therefore, they are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis.
DETAILED DESCRIPTION
The present invention relates to compounds of the formula (I):
Figure USRE037314-20010807-C00001
wherein R1 is lower alkyl, aryl or aralkyl, each of which may have one or more substituents: R2 and R3 each is independently hydrogen, lower alkyl, or aryl, and each of said lower alkyl and aryl may have one or more substituents; R4 is hydrogen, lower alkyl, or a cation capable of forming a non-toxic pharmaceutically acceptable salt; X is sulfur, oxygen, or sulfonyl, or imino which may have a stubstituent; the dotted line represents the presence or absence of a double bond, or the corresponding ring-closed lactone. This invention also provides a pharmaceutical composition comprising the same.
In the specification, the term “lower alkyl” refers to a straight, branched, or cyclic C1 to C6 alkyl, including methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, n-hexyl, and isohexyl and the like. Further, the lower alkyl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, amino, and cyano. Halogen means fluorine, chlorine, bromine and iodine.
The term “aryl” refers to C6 to C12 aromatic group including phenyl, tolyl, xylyl, biphenyl, naphthyl, and the like. The aryl may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, and cyano. Preferred aryl is phenyl substituted by 1 to 3 halogens.
The term “aralkyl” refers to C1 to C6 lower alkyl substituted by C6 to C12 aromatic aryl group defined above. Examples of them are benzyl, phenethyl, phenylpropyl and the like, each of which may have 1 to 3 substituents independently selected from the group consisting of lower alkyl halogen, amino, cyano, and the like.
The term “a cation capable of forming a non-toxic pharmaceutically acceptable salt” refers to alkali metal ion, alkaline earth metal ion, and ammonium ion. Examples of alkali metal are lithium, sodium, potassium, and cesium, and examples of alkaline earth metal are beryllium, magnesium, and calcium. Especially, sodium and calcium are preferred.
Examples of “acyl” are formyl acetyl, propionyl, butyryl, isobutyryl, valeryl, and isovaleryl.
In the term “imino which may have a substituent”, preferred substituents are acyl, optionally substituted amino, and substituted sulfonyl.
The term “substituted amino as substituent” means amino group substituted by sulfonyl and alkylsulfonyl. Examples of them are sulfonyl amino and methanesulfonyl amino.
The term “substituted sulfonyl as substituent” means sulfonyl group substituted by alkyl, amino, or alkylamino. Examples of them are methanesulfonyl, sulfamoyl, methylsulfamoyl, and N-methylsulfamoyl.
The compounds of the present invention can be prepared by the following method.
(1) The carboxylate group of the compound a is converted into the alcohol group by the reduction in an appropriate inactive solvent such as THF, ether, and toluene in the presence of the reductant such as LiAlH and DIBAL-H. The reaction is performed at −70° to 50° C., preferably at near room temperature, for 10 minutes to 10 hours, preferably for 30 minutes to 3 hours. Then the obtained alcohol is subjected to oxidation in an appropriate solvent such as methylene chloride in the presence of the oxidizing agent such as TPAP/4-methylmorpholin-N-oxide or pyridium chlorochromate to give aldehyde compound b. The reaction is performed at 0°-60° C., preferably at near room temperature, for 10 minutes to 10 hours, preferably 30 minutes to 3 hours.
Figure USRE037314-20010807-C00002
wherein R1, R2, and R3 each has the same meaning as defined above, and Alkyl means lower alkyl.
(2) The obtained compound b is subjected to reaction with (3R)-or (3S)-3-(tert-butyldimethylsilyloxy-5-oxo-6-triphenylphosphoranylidene hexanoic acid derivatives in an appropriate solvent such as acetonitrile, diethylether, tetrahydrofuran, and dimethylformamide to give the compound c. The reaction is performed for 1-30 hours, preferably for 10-15 hours under heating.
Figure USRE037314-20010807-C00003
wherein C* means asymmetric carbon atom, the dotted line means the presence or absence of the double bond, R1, R2, R3, and R4each has the same meaning as defined above.
(3) The compound c is subjected to elimination of the tertbutyldimethylsilyl group in an appropriate organic solvent in the presence of hydrogen halogenide to give the compound d.
Every sort of halogen can be used for hydrogen halogenide. Amongst all, hydrogen fluoride is preferred.
The same organic solvents as used in the step (2) may be employed. Acetonitrile is especially preferred.
The reaction is performed in a range of from 0° to 60° C., preferably at room temperature, for 0.5-10 hours, preferably for 1-2 hours.
Figure USRE037314-20010807-C00004
wherein C*, the dotted line, R1, R2, R3, and R4 each has the same meaning as defined above.
(4) The compound d is reacted with diethylmethoxyborane and NaBH4 in an alcohol-organic solvent mixture and subjected to column chromatography of silica gel to give the compound (I) (in case R4 is lower alkyl). The reaction is performed at a temperature between −100° to 20° C., preferably between −85° to −70° C. under cooling, for 10 minutes to 5 hours, preferably for 30 minutes to 2 hours.
Here, the alcohol includes methanol, ethanol, propanol, and butanol; and the organic solvent includes the same as in the step (3).
Further, if necessary, the obtained compound may be subjected to saponification with the solution of metalic hydroxide (R4: cation), and after the saponification, the reaction mixture is neutralized with an acid and extracted with an organic solvent (R4: hydrogen). The saponification is performed in a popular solvent such as water, acetonitrile, dioxane, acetone, and the mixture thereof, preferably in the presence of a base, by a conventional method. The reaction is performed at 0° to 50° C., preferably at near room temperature.
As metalic hydroxide which may be used are sodium hydroxide, potassium hydroxide, and their analogue.
Acids which may be used include inorganic acids such as hydrochloric acid, sulfuric acid and the like.
Figure USRE037314-20010807-C00005
wherein C*, the dotted line, R1, R2, R3, and R4 each has the same meaning as defined above.
Further, if necessary, the obtained compounds (I) are subjected to reflux under heating to give the corresponding lactones.
The compound of the present invention can be administered orally or parenterally. For example, the compound of the present invention may be orally administered in the form of tablets, powders, capsules and granules, aqueous or oily suspension, or liquid form such as syrup or elixir, and parenterally in the form of aqueous or oily suspension.
These preparations can be prepared in a conventional manner by using excipients, binders, lubricants, aqueous or oily solubilizers, emulsifier, suspending agents, and the like. And preservatives and stabilizers can be further used.
The dosages may vary with the administration route, age, weight, condition, and the kind of disease of the patients, but are usually 0.5-200 mg/day, preferably 1-100 mg/day through oral route, and 0.1-100 mg/day, preferably 0.5-50 mg/day through parenteral route. They may be used in a single or divided doses.
The present invention is illustrated by the following examples and reference examples, which are not to be considered as limiting.
The abbreviations used in examples and reference examples have the following meanings.
Me: methyl,
Et: ethyl,
i-Pr: isopropyl
t-Bu: tert-butyl,
Ph: phenyl,
DMF: dimethylformamide,
THF: tetrahydrofuran
DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
TPAP: tetrapropylammonium perruthenate
HMPA: hexamethylphosphoramide
DIBAL-H: diisobutylaluminum hydride.
REFERENCE EXAMPLE 1 Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methylthiopyrimidine-5-carboxylate (III-1) and Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methylsulfonylpyrimidine-5-carboxylate (III-2)
Figure USRE037314-20010807-C00006
p-Fluorobenzaldehyde 81.81 g is reacted in the same manner as disclosed in the specification of JP Unexamed. Pat. Publn. No. 61-40272 to give 151.0 g (Yield: 86.7%) of the compound 1. Then the mixture of a solution of 44.68 g of the compound 1 in 65 ml of HMPA and 28.24 g of s-methylisourea hydrogen sulfate is stirred at 100° C. for 22 hours. Then the reaction mixture is extracted with ether, and washed with saturated sodium hydrogencarbonate and water in order. The organic layer is dried, and the solvent is distilled away. The obtained residue is subjected to column chromatography of silica gel to give 26.61 g (yield: 46.8%) of the compound 2.
To a solution of the obtained compound 2 in 400 ml of benzene is added 21.64 g (0.095 mmol) or DDQ, and the mixture is stirred for 30 minutes. Then the mixture is subjected to column chromatography of silica gel to give 24.31 g (Yield: 91.9%) of the compound (III-1).
NMR (CDCl3) δ: 1.10 (t, J=7,3H): 1.31 (d, J=7,6 Hz); 2.61 (s, 3H); 3.18 (hept, J=7,1H); 4.18 (q, J=7,2H); 7.12 (m, 2H), 7.65 (m, 2H).
To a solution of 13.28 g (0.04 mmol) of the compound (III-1) in chloroform is added 17.98 g of m-chloroperbenzoic acid, and the reaction mixture is stirred at room temperature. Then it is washed with sodium sulfate and saturated sodium hydrogencarbonate in order. The solution is dried, and the solvent is distilled away and washed with n-hexane to give 13.93 g (Yield 95.7%) of the compound (III-2).
NMR (CDCl3) δ: 1.16 (t, J=7,3H); 1.37 (d, J=7,6H); 3.26 (hept, J=7,1H); 3.42 (s, 3H), 4.28 (q, 2H); 7.18 (m, 2H); 7.76 (m, 2H).
REFERENCE EXAMPLE 2
Another synthetic method of the compound (III-1)
To a solution of 200 mg (0.594 mmol) of the compound 2 in 5 ml of dichloromethane are added 0.5 g (6.10 equivalent) of potassium carbonic anhydride and 166 mg (1.1 equivalent) of iodine, and the mixture is stirred at room temperature for 2.5 hours. After reaction, to the mixture is added saturated sodium hydrogensulfite and extracted with ether. The organic layer is washed with water and dried. The solvent is distilled away under reduced pressure to give 166 mg (Yield: 83.6%) of the compound (III-1) as resinous substance.
NMR (CDCl3) δ: 1.10 (t, 3H, J=7); 1.31 (d, 6H, J=7); 2.61 (s, 3H) 3.17 (heptet, 1H, J=7); 4.18 (q, 2H, J=7); 7.07-7.17 (m, 2H); 7.61-7.69 (m, 2H)
REFERENCE EXAMPLE 3
Another synthetic method of the compound (III-2)
To a solution of 1.0 g (2.97 mmol) of the compound 2 in 10 ml of acetone is added 1.5 g (9.48 mmol) of potassium permanganate, and the mixture is stirred at room temperature for 15 minutes. Acetic acid 1.0 ml is added thereto, and the mixture is stirred at room temperature for further 30 minutes and water is added thereto. The reaction mixture is extracted with ether, washed with saturated sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent is distilled away under reduced pressure to give 1.07 g (2.94 mmol) (Yield: 99.1%) of the compound (III-2) as crystals.
REFERENCE EXAMPLE 4 Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl-sulfonylamino)pyrimidine-5-carboxylate (III-3) and Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-dimethylsulfamoylamino)pyrimidine-5-carboxylate (III-4)
Figure USRE037314-20010807-C00007
To a solution of 52.7 g (144 mmol) of the compound (III-2) in 500 ml of absolute ethanol is added gradually a solution of 71.9 ml of 5N methylamine in ethanol under ice-cooling. The reaction mixture is warmed to room temperature, stirred for 1 hour and evaporated under reduced pressure. To the residue is added water, and the mixture is extracted with ether, dried and evaporated under reduced pressure to give 46.9 g (Yield: 100%) of the compound 3. mp. 85°-86° C.
Anal Calcd. (%) for C17H20N3FO2: C,64.34; H,6.35; N,13.24: F,5.99. Found: C,64.42, H,6.46: N,13.30; F,6.14.
To a solution of 370 mg (1.213 mmol) of the compound 3 in 5 ml of DMF is added 60 mg of 60% NaH under ice-cooling, and the reaction mixture is stirred for 30 minutes. Methanesulfonyl chloride 208 mg is added thereto, and the mixture is warmed to room temperature and stirred for 2 hours further. To the mixture is added ice-water, and the mixture is extracted with ether. The organic layer is washed with water and dried. The solvent is evaporated under reduced pressure, and the resulting residue is washed with ether-n-pentane to give 322 mg (Yield: 57.6%) of the compound (III-3).
NMR (CDCl3) δ: 1.10 (t, J=7,3H); 1.32 (d, J=7,6H); 3.24 (hept,J=7,1H); 3.52 (s,3H); 3.60 (s, 3H); 4.19 (q, J=7,2H); 7.14 (m, 2H); 7.68 (m, 2H).
To a solution of 4.13 g (13.0 mmol) of the compound 3 in 40 ml of DMF is added 0.57 g of 60% NaH under ice-cooling, and the mixture is warmed to room temperature and stirred for 1 hours. After cooling again, dimethylsulfamoyl chloride 2.43 g (16.9 mmol) is dropwise added thereto, and the mixture is stirred for 2.5 hours. To the mixture is added icewater, and the mixture is extracted with ether washed with water, dried and evaporated under reduced pressure to distill ether. The resulting residue is washed with ether-hexane to give 4.10 g (Yield: 74.2%) of the compound (III-4). mp. 114°-116° C.
Anal Calcd. (%) for C19H25N4SFO4: C,53.76; H,5.94; N,13.20; F,4.48. Found: C,53.74: H,5.96; N,13.19; F,4.78.
REFERENCE EXAMPLE 5 Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxypyrimidine-5-carboxylate (III-5) and Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylhydrazino)pyrimidine-5-carboxylate (III-6)
Figure USRE037314-20010807-C00008
To a solution of 1.39 g (3.8 mmol) of the compound (III-2) in 60 ml of absolute methanol is added a solution of 0.41 g (7.6 mmol) of sodium methoxide under ice-cooling. The reaction mixture is warmed to room temperature gradually and stirred for 1 hour. The mixture is neutralized with acetic acid and extracted with ether. The organic layer is washed with sodium bicarbonate and water in order, dried and evaporated under reduced pressure to distill ether. The residue is subjected to column chromatography of silica gel to give 1.17 g (Yield: 96.7%) of the compound (III-5).
NMR (CDCl3) δ: 1.10 (t, 3H, J=7 Hz); 1.32 (d, 6H, J=6.6 Hz); 3.21 (m, 1H); 4.08 (s, 3H); 4.18 (q, 2H, J=7 Hz); 7.07-7.74 (m, 4H).
To a solution of 2.50 g (6.77 mmol) of the compound (III-2) in 50 ml of absolute ethanol is added 0.80 g (16.93 mmol) of methyl hydrazine under ice-cooling. The reaction mixture is warmed to room temperature and stirred for 2 hours and extracted with ether. The organic layer is washed with saturated brine and dried to distill the solvent. To a mixture of 2.37 g of the thus obtained compound and a mixture of anhydrous THF and anhydrous pyridine is added 1.03 g (7.84 mmol) of methanesulfonyl chloride under testing. The reaction mixture is warmed to room temperature and stirred for 1.5 hours. To the mixture are added 3 ml of anhydrous pyridine and 1.53 g (11.65 mmol) of methanesulfonyl chloride, and the mixture is stirred for 2 hours. To the reaction mixture is added ice-water and extracted with ether. The organic layer is washed with water and the resulting oily residue is subjected to column chromatography of silica gel to give 2.75 g (Yield: 94.0%) of the compound (III6).
NMR (CDCl3) δ: 1.08 (t, J=7,3H); 1.29 (d, J=7,6H); 2.96 (s, 3H); 3.24 (hept, J=7,1H); 3.59 (s, 3H); 4.16 (q, J=7,2H); 7.14 (m, 2H), 7.63 (m, 2H).
REFERENCE EXAMPLE 6 Methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanate
(1) (3R)-3-(tert-butyldimethylsilyloxy)glutaric acid-1-((R)-(−)mandelic acid ester*1 65 g (164 mmol) is dissolved into 60 ml of methanol, a solution of sodium methoxide in methanol (28% methanol 310 ml, 1.6 mol) is added dropwise thereto under nitrogen atmosphere at 0° C. for 45 minutes at internal temperature under 7° C. The reaction mixture is stirred at 0° C. for 30 minutes and poured into a mixture of 150 ml of conc.HCl, 300 ml of water, and 500 ml of methylene chloride being stirred under ice-cooling and the organic layer is collected. The aqueous layer is extracted with 200 ml of methylene chloride, and each organic layer is washed with dil.HCl and brine in order. Each organic layer are collected and dried over anhydrous magnesium sulfate and evaporated to distill the solvent to give half ester compound.
*1: This compound can be prepared by the method described at page 10 in the specification of KOKAI 2-250852.
1HNMR(CDCl3) δ: 0.08 (s, 3H); 0.09 (s, 3H); 0.86 (s, 9H); 2.52-2.73 (m, 4H); 3.08 (s, 3H); 4.55 (quint, 1H, J=6Hz).
IR (CHCl3): 2880, 1734, 1712, 1438, 1305, 1096, 836 cm−1.
[α]D=−5.0±0.4° (C=1.04, 23.5° C., CHCl3).
Rf 0.32 (CHCl3/MeOH=9/1).
(2) To a solution of the thus obtained half ester compound in 10 ml of ether are added dropwise triethylamine and ethyl chlorocarboxylate in order under nitrogen atmosphere at −78° C. The resulting white suspension is stirred at 0° C. for 1 hour and cooled to −78° C. The resulting precipitate is filtered under nitrogen atmosphere and the filtrate is washed with 15 ml of ether. To a suspension of 1.29 g ( 3.6 mmol) of methyl bromide triphenylphosphonium in 5 ml of THF is added dropwise butyllithium (1.6M hexane, 2.25 ml, 3.6 mmol) under nitrogen atmosphere at −78° C. The reaction mixture is stirred at 0° C. for 1 hour and cooled to −78° C. and added dropwise to the solution of thus obtained active ester compound in ether. The reaction mixture is washed with 5 ml of THF and stirred at 0° C. for 1 hour, and 10 ml of 5% sodium hydrogencarbonate is added thereto. The reaction mixture is stirred for 5 minutes and extracted with ethyl acetate and the organic layer is separated and the remaining aqueous layer is extracted with ethyl acetate. Each organic layer is collected and washed with brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue is subjected to column chromatography of silica gel eluting with ether-ethyl acetate and crystallized from ether-hexane to give objective compound.
1HNMR (CDCl3)δ: 0.04 (s, 3H); 0.06 (s, 3H); 0.83 (s, 9H); 2.4-2.9 (m, 4H); 3.64 (s, 3H); 3.74 (d, 1H); 4.5-4.7 (m, 1H); 7.4-7.8 (m, 15H).
IR (CHCl3): 2380, 1730, 1528, 1437, 1250, 1106, 835 cm −1.
[α]D=−6.2° (C=1.27, 22.0° C., CHCl3).
mp.:77.5°-78.5° C., Rf=0.48 (CHCl3/MeOH=9/1).
Anal Calcd. (%) for C31H39O4PS: C, 69.63; H,7.35; P,5.79. Found: C, 69.35; H,7.35; P,6.09.
EXAMPLE 1 Sodium (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate (I a-1)
(1) To a solution of 322 mg of the compound (III-3) obtained in Reference Example 2 in 7 ml of anhydrous toluene is added dropwise 1.4 ml of DIBAL-H in 1.5M toluene at −74° C., and the reaction mixture is stirred for 1 hour and acetic acid is added thereto. The mixture is extracted with ether, and the organic layer is washed with sodium bicarbonate and water, dried and evaporated under reduced pressure to distil ether. The obtained residue is subjected to column chromatography of silica gel eluting with methylene chloride/ether (20/1) to give 277 mg (Yield: 96.1%) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol 4.
Figure USRE037314-20010807-C00009
(2) A suspension of 277 mg of the thus obtained compound 4, 190 mg of 4-methylmorpholin-N-oxide, 6 mg of TPAP, 1.0 g of powder molecular sieve 4A, and 10 ml of methylene chloride is stirred for 2 hours. The insoluble matter is filtered off and the two-thirds of the filtrate is distilled away under reduced pressure. The resulting residue is subjected to column chromatography of silica gel eluting with methylene chloride to give 196 mg (Yield: 71.2%) of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-pyrimidinecarbardehyde as crystals.
Figure USRE037314-20010807-C00010
(3) A solution of 190 mg of the compound 5, 450 mg of methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanate (Reference Example 6), and 5 ml of acetonitrile is refluxed under heating for 14 hours and evaporated under reduced pressure to distill acetonitrile. The resulting residue is subjected to column chromatography of silica gel eluting with methylene chloride to give 233 mg (Yield: 71.3%) of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate 6 as syrup.
Figure USRE037314-20010807-C00011
(4) To a solution of 16 g of the compound 6 in 100 ml of acetonitrile is added dropwise a solution of 48% hydrogen flouride in 400 ml of acetonitrile (1:19) under ice-cooling, and the mixture is warmed to room temperature and stirred for 1.5 hours. The reaction mixture is neutralized with sodium bicarbonate and extracted with ether. The organic layer is washed with sodium chloride, dried and evaporated under reduced pressure to distil ether to give 13 g (Yield: 100%) of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate 7 as syrup.
Figure USRE037314-20010807-C00012
(5) To a solution of 13 g of the compound 7 in 350 ml of anhydrous THF and 90 ml of methanol is added a solution of 29.7 ml of 1M diethylmethoxyborane-THF at −78° C., and the mixture is stirred at the same temperature for 30 minutes. To the mixture is added 1.3 g of NaBH4, and the mixture is stirred for 3 hours. Acetic acid 16 ml is added thereto, and the mixture is adjusted to pH 8 with saturated sodium bicarbonate and extracted with ether. The organic layer is washed with water, dried and evaporated ether under reduced pressure. To the resulting residue is added methanol and the mixture is evaporated under reduced pressure for three times. The resulting residue is subjected to column chromatography of silica gel eluting with methylene chloride/ether (3/1) to give 11.4 g (Yield: 85.2%) of methyl 7-[4-(4-fluorophenyl)-6-iso-propyl-2-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate as syrup.
Figure USRE037314-20010807-C00013
NMR (CDCl3) δ: 1.27 (d, J=7,6H); 1.53 (m, 2H); 2.47 (d, J=6,2H); 3.36 (hept, J=2H); 3.52 (s, 3H); 3.57 (s, 3H); 3.73 (s, 3H); 4.20 (m, 1H); 4.43 (m, 1H); 5.45 (dd, J=5,16, 1H); 6.64 (dd, J=2,16, 1H); 7.09 (m, 2H); 7.64 (m, 2H).
(6) To a solution of 11.4 g of the compound (I b-1) in 160 ml of ethanol is added 223 ml of 0.1N sodium hydroxide under ice-cooling. The reaction mixture is warmed to room temperature and stirred for 1 hour. The solvent is distilled away under reduced pressure, and ether is added to the resulting residue and the mixture is stirred to give 11.0 g (Yield: 95.0%) of the objective compound (I a-1) as powdery crystals.
Figure USRE037314-20010807-C00014
[α]D=+18.9±0.6° (C=1.012, 25.0° C., H2O).
NMR (CDCl3) δ: 1.24 (d, J=7,6H); 1.48 (m, 1H); 1.65 (m, 1H); 2.27 (dd,J=2,6.2H); 3.41 (hept, J=7,1H); 3.48 (s, 3H); 3.59 (s, 3H); 3.73 (m, 1H); 4.32 (m 1H); 5.49 (dd, J=7,16 1H); 6.62 (d, J=16,1H); 7.19 (m, 2H); 7.56 (m, 2H).
EXAMPLE 2 Sodium (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-acetyl-N-methylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate (I a-2)
(1) Ethyl 4-(4-fluorophenyl-6-isopropyl-2-methylaminopyrimidine-5-carboxylate 3 838 mg obtained in Reference Example 4 is allowed to react in the same manner as in Example 1 (1) and (2) to give 157 mg of 4-(4-fluorophenyl)-6-isopropyl-2-methylaminopyrimidine-5-carbaldehyde.
(2) A solution of 157 mg of thus obtained aldehyde compound in 4 ml of anhydrous DMF is reacted with 25 mg of 60% NaH under ice-cooling for 30 minutes, 0.05 ml of acetylchloride is added thereto and the mixture is stirred for 1 hour. The mixture is added with ice and extracted with ether. The organic layer is washed with water and dried and concentrated to distill the solvent to give 167 mg (Yield: 93.4%) of 4-(4-fluorophenyl)-6-isopropyl-2-(N-acetyl-N-methylamino)pyrimidine-5-carbardehyde. Thus obtained aldehyde compound is reacted in the same manner as in Example 1 (3)-(5) to give methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-acetyl-N-methylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate (I b-2).
NMR (CDCl3)δ: 1.27 (d, J=7,6H); 1.54 (m, 2H); 2.48 (d, J=6,2H); 2.52 (s, 3H); 3.39 (hept, J=7, 1H); 3.60 (s, 3H); 3.58 (brs, 1H); 3.74 (s, 3H): 4.21 (m, 1H); 4.48 (m, 1H); 5.50 (dd, J=5,16, 1H); 6.66 (dd, J=2,16); 7.11 (m, 2H); 7.61 (m, 2H).
(3) The thus obtained compound (I b-2) is reacted in the same manner as Example 1 (6) to give the objective compound (I a-2).
Figure USRE037314-20010807-C00015
NMR (CDCl3)δ: 1.27 (d, J=7,6H); 1.57 (m, 2H): 2.17 (s, 3H); 2.27 (d, J=6,2H); 3.72 (s, 3H); 3.50 (hept, J=7, 1H); 3.70 (m, 1H); 4.35 (q, J=6,1H); 5.59 (dd, J=5,16, 1H); 6.54 (d, J=16, 1H); 7.24 (m, 2H): 7.59 (m, 2H).
EXAMPLE 3-6
As a starting material, each pyrimidine carboxylate (III) obtained in Reference Example 1-3 is reacted in the same manner as Example 1 or 2 to give the compound (I b) and (I a). Their physical constants are shown in Table 1-3.
Figure USRE037314-20010807-C00016
TABLE 1
Ex. Startup Product
No. material NMR δ
3 (Ill-1) 1b-3(X: S)Yield 96.0% (CDCl3,
1.26(d, J = 7.6H): 1.52(m, 2H): 2.47(d, J = 6,
2H): 2.60(s, 3H): 3.33(hept, J = 7, 1H): 3.73
(s, 3H): 4.18(m, 1H): 4.44(m, 1H): 5.44(dd,
J = 5, 16, 1H): 6.60(dd, J = 2, 16, 1H), 7.07(m,
2H): 7.58(m, 2H)
1a-3(X: S)Yield 87.3% (D2O)
1.20(d, J = 7, 6H): 1.47(m, 1H): 1.61(m, 1H):
2.26(m, 2H), 2.54(s, 3H): 3.36(hept, J = 7, 1H):
3.71(m, 1H): 4.29(m, 1H): 5.43(dd, J = 6, 16,
1H): 6.55(d, J = 16, 1H): 7.16(m, 2H), 7.47
(m, 2H)
4 (Ill-2) 1b-4(X: SO2): Yield 93.7% (CDCl3)
1.31(d, J = 7, 6H): 1.52(m, 2H): 2.48(d, J = 6,
2H): 3.40(s, 3H); 3.47(hept, J = 7, 1H); 3.74
(s, 3H): 3.87(brs, 1H): 4.23(m, 1H): 4.49
(m, 1H); 5.59(dd, J = 5, 16H, 1H); 6.74(d, d, J =
2, 16, 1H); 7.12(m, 2H): 7.69(m, 2H)
1a-4(X: SO2): Yield 70.9% (D2O)
1.27(d, d, J = 7, 2, 6H); 1.60(m, 2H); 2.25(J =
6, d, 2H): 3.44(s, 3H): 3.51(hept, J = 7, 1H):
3.70(m, 1H): 4.33(q, J = 6, 1H): 5.65(d, d, J = 5,
16, 1H): 6.71(d, J = 16, 1H): 7.23(m, 2H); 7.60
7.60(m, 2H)
TABLE 1
Ex. Startup Product
No. material NMR δ
3 (Ill-1) 1b-3(X: S)Yield 96.0% (CDCl3,
1.26(d, J = 7.6H): 1.52(m, 2H): 2.47(d, J = 6,
2H): 2.60(s, 3H): 3.33(hept, J = 7, 1H): 3.73
(s, 3H): 4.18(m, 1H): 4.44(m, 1H): 5.44(dd,
J = 5, 16, 1H): 6.60(dd, J = 2, 16, 1H), 7.07(m,
2H): 7.58(m, 2H)
1a-3(X: S)Yield 87.3% (D2O)
1.20(d, J = 7, 6H): 1.47(m, 1H): 1.61(m, 1H):
2.26(m, 2H), 2.54(s, 3H): 3.36(hept, J = 7, 1H):
3.71(m, 1H): 4.29(m, 1H): 5.43(dd, J = 6, 16,
1H): 6.55(d, J = 16, 1H): 7.16(m, 2H), 7.47
(m, 2H)
4 (Ill-2) 1b-4(X: SO2): Yield 93.7% (CDCl3)
1.31(d, J = 7, 6H): 1.52(m, 2H): 2.48(d, J = 6,
2H): 3.40(s, 3H); 3.47(hept, J = 7, 1H); 3.74
(s, 3H): 3.87(brs, 1H): 4.23(m, 1H): 4.49
(m, 1H); 5.59(dd, J = 5, 16H, 1H); 6.74(d, d, J =
2, 16, 1H); 7.12(m, 2H): 7.69(m, 2H)
1a-4(X: SO2): Yield 70.9% (D2O)
1.27(d, d, J = 7, 2, 6H); 1.60(m, 2H); 2.25(J =
6, d, 2H): 3.44(s, 3H): 3.51(hept, J = 7, 1H):
3.70(m, 1H): 4.33(q, J = 6, 1H): 5.65(d, d, J = 5,
16, 1H): 6.71(d, J = 16, 1H): 7.23(m, 2H); 7.60
7.60(m, 2H)
TABLE 3
Ex. Starting Product
No. material NMR δ
7 (Ill-6) 1b-7(X: N—NHSO2Me): Yield: 87.8% (CDCl3)
1.24(d, J = 7, 6H): 1.51(m, 2H): 2.47(d, J = 6,
2H); 2.95(s, 3H); 3.35(hept, J = 7, 1H); 3.46
(d, J = 2, 1H): 3.55(s, 3H); 3.66(d, J = 2, 1H): 3.74
(s, 3H): 4.18(m, 1H): 4.44(m, 1H): 5.41
(dd, J = 5, 16, 1H); 6.58(dd, J = 2, 16, 1H); 7.09(m,
2H); 7.58(m, 2H), 7.70(s, 1H)
1a-7(X: N—NHSO2Me): Yield: 74.7% (D2O)
1.23(d, J = 7, 6H): 1.51(m, 2H): 2.26(d, J = 6, 2H)
3.10(s, 3H); 3.37(hept, J = 7, 1H): 3.44
(s, 3H): 3.70(m, 1H). 4.29(q, J = 6, 1H): 5.39
(dd, J = 5, 16, 1H): 6.58(d, J = 16, 1H): 7.19(m,
2H):7.52(m, 2H)
EXAMPLE 7
Calcium salt of the compound (I a-1) (sodium salt) 1.50 g (3.00 mmol) is dissolved in 15 ml of water and stirred at room temperature under nitrogen atmosphere, successively 3.00 ml (3.00 mmol) of 1 mol/L calcium chloride 3.00 ml (3.00 mmol) is added dropwise thereto over 3 minutes. The reaction mixture is stirred at the same temperature for 2 hours, and the resulting precipitate is collected, washed with water and dried to give 1.32 g of calcium salt as powdery. This compound started to melt at a temperature of 155° C., but the definitive melting point is ambiguous.
[α]D=+6.3° ±0.2° (C=2.011, 25.0° C., MeOH).
Anal Calcd. (%) for C22H27N3O6SF . 0.5Ca . 0.5H2O: C,51.85; H,5.53; N,8.25; F,3.73; Ca,3.93. Found: C,51.65; H,5.51; N,8.47; F,3.74; Ca,4.07.
Biological Activity Experiment The HMG-CoA reductase inhibitory effect
(1) Preparation of rat liver microsome
Sprague-Dawley rats, which were in free access to ordinary dietes containing 2% cholestyramine and water for 2 weeks, were used for the preparation of rat liver microsome. The thus obtained microsome was the purified according to the manner by Juroda et al., Biochem. Biophys. Act, 486, 70 (1977). The microsomal fraction obtained by centrifugation at 105,000×g was washed once with a buffered solution containing 15 mM nicotinamide and 2 mM magnesium chloride (in a 100 mM potassium phosphate buffer, pH 7.4). It was homogenized with a buffer containing nicotinamide and magnesium chloride at the same weight as the liver employed. The thus obtained homogenate was cooled down and kept at −80° C.
(2) Measurement of the HMG-CoA reductase inhibitory activities
The rat liver microsome sample (100 μl), which was preserved at −80° C., was fused at 0° C. and diluted with 0.7 ml of a cold potassium phosphate buffer (100 mM, pH7.4). This was mixed with 0.8 ml of 50 mM EDTA (buffered with the aforementioned potassium phosphate buffer) and 0.4 ml of 100 mM dithiothreitol solution (buffered with the aforementioned potassium phosphate buffer), and the mixture was kept at 0° C. The microsome solution (1.675 ml) was mixed with 670 μl of 25 mM NADPH (buffered with the aformentioned potassium phosphate buffer), and the solution was added to the solution of 0.5 mM [3−14](HMG-CoA (3mCi/mmol). A solution (5 μl) of sodium salt of the test compound dissolved in potassium phosphate buffer is added to 45 μl of the mixture. The resulting mixture was incubated at 37° C. for 30 minutes and cooled. After termination of the reaction by addition of 10 μl of 2N·HCl, the mixture was incubated again at 37° C. for 15 minutes and then 30 μl of this mixture was applied to thin-layer chromatography of silica gel of 0.5 mm in thickness (Merck AG, Art 5744). The chromatograms were developed in toluene/acetone (1/1) and the spot, whose Rf value was between 0.45 to 0.60, were scraped. The obtained products were put into a vial containing 10 ml of scintillator to measure specific radio-activity with scintillation counter. The activities of the present compounds are shown in Table 4 as comparative ones based on the assumption that the activity of Mevinolin (sodium salt) as reference drug is 100.
TABLE 4
Test Compound HMG-CoA reductase inhibitory activities
1a-1 442
1a-3 385
1a-5 279
1a-7 260
Mevinolin Na 100
From the test data, the compounds of the present invention exhibit HMG-CoA reductase inhibition activities superior to Mevinolin.

Claims (8)

What is claimed is:
1. A compound represented by the formula (I):
Figure USRE037314-20010807-C00017
wherein
R1 is (1) lower alkyl which may have 1 to 3 substitutents independently selected from the group consisting of halogen, amino, and cyano, (2) C6 to C12 aromatic group which may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, and cyano, or (3) C1 to C6 lower alkyl substituted by C6 to C12 aromatic group which may have 1 to 3 substituents independently sel-ected from the group consisting of lower alkyl, halo-gen, amino, and cyano; R2 and R3 each is independently (1) hydrogen, (2) lower alkyl which may have 1 to 3 substituents independently selected from the group consisting of halogen, amino, and cyano, or (3) C6 to C12 aromatic group which may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, and cyano; R4 is (1) hydro-gen, (2) lower alkyl, or a cation capable of forming a non-toxic pharmaceutically acceptable salt; X is sulfur, oxygen, or sulfonyl, or imino which may be substituted by formyl, acetyl, propionyl, butyryl, isobutyryl, vale-ryl, isovaleryl, amino substituted by sulfonyl or alkyl-sulfonyl, and sulfonyl substituted by alkyl, amino or alkylamino, the dotted line represents the presence or absence of a double bond, or the corresponding ring-closed lactone.
2. The compound claimed in claim 1, wherein X is imino which may be substituted by formyl, acetyl, pro-pionyl, butyryl, isobutyryl, valeryl, isovaleryl, amino substituted by sulfonyl or alkylsulfonyl, or sulfonyl substituted by alkyl, amino or alkylamino.
3. The compound claimed in claim 2, wherein X is imino which may be substituted by formyl, acetyl, pro-pionyl, butyryl, isobutyryl, valeryl, isovaleryl, alkylsul-fonylamino, or alkylsulfonyl.
4. The compound claimed in claim 1 having the (3R, 5S)-dihydroxy configuration.
5. A pharmaceutical composition comprising an ef-fective amount of the compound claimed in claim 1 as an active ingredient, in combination with a pharmaceu-tical excipient.
6. The compound 7-( 4 -( 4 -fluorophenyl)- 6 -isopropyl- 2 -(N-methyl-N-methylsulfonylamino)pyrimidin- 5 -yl)-( 3R,5S)-dihydroxy-(E)- 6 -heptenoic acid in the form of a non-toxic pharmaceutically acceptable salt thereof.
7. The compound of claim 6 in the form of a sodium salt.
8. The compound of claim 6 in the form of a calcium salt.
US09/141,731 1991-07-01 1998-08-27 Pyrimidine derivatives Expired - Lifetime USRE37314E1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US09/141,731 USRE37314E1 (en) 1991-07-01 1998-08-27 Pyrimidine derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP18801591 1991-07-01
JP3-188015 1991-07-01
US07/897,793 US5260440A (en) 1991-07-01 1992-06-12 Pyrimidine derivatives
US09/141,731 USRE37314E1 (en) 1991-07-01 1998-08-27 Pyrimidine derivatives

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US07/897,793 Reissue US5260440A (en) 1991-07-01 1992-06-12 Pyrimidine derivatives

Publications (1)

Publication Number Publication Date
USRE37314E1 true USRE37314E1 (en) 2001-08-07

Family

ID=16216169

Family Applications (2)

Application Number Title Priority Date Filing Date
US07/897,793 Ceased US5260440A (en) 1991-07-01 1992-06-12 Pyrimidine derivatives
US09/141,731 Expired - Lifetime USRE37314E1 (en) 1991-07-01 1998-08-27 Pyrimidine derivatives

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US07/897,793 Ceased US5260440A (en) 1991-07-01 1992-06-12 Pyrimidine derivatives

Country Status (19)

Country Link
US (2) US5260440A (en)
EP (1) EP0521471B1 (en)
JP (1) JP2648897B2 (en)
KR (1) KR960005951B1 (en)
AT (1) ATE197149T1 (en)
CA (1) CA2072945C (en)
CL (1) CL2010000113A1 (en)
CY (2) CY2226B1 (en)
DE (2) DE69231530T2 (en)
DK (1) DK0521471T3 (en)
ES (1) ES2153824T3 (en)
GE (1) GEP20022693B (en)
GR (1) GR3035189T3 (en)
HK (1) HK1011986A1 (en)
HU (2) HU220624B1 (en)
LU (1) LU91042I2 (en)
NL (1) NL300125I2 (en)
PT (1) PT521471E (en)
TW (1) TW203044B (en)

Cited By (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030181500A1 (en) * 2000-08-30 2003-09-25 Sankyo Company, Limited Medicinal compositions for the prevention or treatment of cardiac failure
US20040132771A1 (en) * 2002-12-20 2004-07-08 Pfizer Inc Compositions of choleseteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors
US6777552B2 (en) 2001-08-16 2004-08-17 Teva Pharmaceutical Industries, Ltd. Processes for preparing calcium salt forms of statins
US20050085497A1 (en) * 2003-09-25 2005-04-21 Saleem Ahmad HMG-CoA reductase inhibitors and method
US20050131066A1 (en) * 2003-11-24 2005-06-16 Valerie Niddam-Hildesheim Crystalline ammonium salts of rosuvastatin
US20050187234A1 (en) * 2003-12-02 2005-08-25 Nina Finkelstein Reference standard for characterization of rosuvastatin
US20060019269A1 (en) * 2002-10-17 2006-01-26 Decode Genetics, Inc. Susceptibility gene for myocardial infarction, stroke, and PAOD, methods of treatment
WO2006091771A3 (en) * 2005-02-22 2007-01-11 Teva Pharma Ltd Preparation of rosuvastatin
US20070037979A1 (en) * 2005-02-22 2007-02-15 Valerie Niddam-Hildesheim Preparation of rosuvastatin
US20070048351A1 (en) * 2005-09-01 2007-03-01 Prescient Medical, Inc. Drugs coated on a device to treat vulnerable plaque
WO2007040940A1 (en) * 2005-10-03 2007-04-12 Teva Pharmaceutical Industries Ltd. Diastereomeric purification of rosuvastatin
WO2007050425A2 (en) 2005-10-21 2007-05-03 Bristol-Myers Squibb Company Lxr modulators
US20070099994A1 (en) * 2005-08-16 2007-05-03 Valerie Niddam-Hildesheim Rosuvastatin calcium with a low salt content
WO2007062314A2 (en) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Heterocyclic cetp inhibitors
US20070123550A1 (en) * 2005-08-16 2007-05-31 Valerie Niddam-Hildesheim Crystalline rosuvastatin intermediate
US20070142418A1 (en) * 2004-07-13 2007-06-21 Teva Pharmaceuticals Usa, Inc. Process for the preparation of rosuvastatin
US20070167625A1 (en) * 2005-02-22 2007-07-19 Anna Balanov Preparation of rosuvastatin
US20070179166A1 (en) * 2003-12-24 2007-08-02 Valerie Niddam-Hildesheim Process for preparation of statins with high syn to anti ratio
US20070254897A1 (en) * 2006-04-28 2007-11-01 Resolvyx Pharmaceuticals, Inc. Compositions and methods for the treatment of cardiovascular disease
US7396927B2 (en) 2003-08-28 2008-07-08 Teva Pharmaceutical Industries Ltd. Process for preparation of rosuvastatin calcium
EP1961419A1 (en) 2002-12-20 2008-08-27 Pfizer Products Inc. Dosage forms comprising a CETP inhibitor and an HMG-CoA reductase inhibitor
US20080206328A1 (en) * 2004-02-03 2008-08-28 Ferrer International, S.A. Hypocholesterolemic Compositions Comprising a Statin and an Antiflatulent Agent
US20080234302A1 (en) * 2004-09-27 2008-09-25 Mohammad Rafeeq Novel Processes for Preparing Amorphous Rosuvastatin Calcium and a Novel Polymorphic Form of Rosuvastatin Sodium
US20080249156A1 (en) * 2007-04-09 2008-10-09 Palepu Nageswara R Combinations of statins and anti-obesity agent and glitazones
US20080249141A1 (en) * 2007-04-06 2008-10-09 Palepu Nageswara R Co-therapy with and combinations of statins and 1,4-dihydropyridine-3,5-dicarboxydiesters
US20080248115A1 (en) * 2007-04-09 2008-10-09 Palepu Nageswara R Combinations of statins and anti-obesity agent
US20080269270A1 (en) * 2003-12-24 2008-10-30 Valerie Niddam-Hildesheim Triol form of rosuvastatin and synthesis of rosuvastatin
US20080293750A1 (en) * 2002-10-17 2008-11-27 Anna Helgadottir Susceptibility Gene for Myocardial Infarction, Stroke, Paod and Methods of Treatment
US20090069563A1 (en) * 2007-07-12 2009-03-12 Valerie Niddam-Hildesheim Rosuvastatin intermediates and their preparation
US20090076292A1 (en) * 2007-04-18 2009-03-19 Teva Pharmaceutical Industries Ltd. Rosuvastatin intermediates and process for the preparation of rosuvastatin
US20090312547A1 (en) * 2007-02-08 2009-12-17 Ramesh Dandala Process for preparation of rosuvastatin calcium field of the invention
US20100029940A1 (en) * 2006-12-13 2010-02-04 Ramesh Dandala Process for preparing rosuvastatin calcium
US20100048899A1 (en) * 2006-10-31 2010-02-25 Ramesh Dandala Process for preparing rosuvastatin calcium
US20100069635A1 (en) * 2006-11-29 2010-03-18 Dr. Reddy's Laboratories Ltd. Rosuvastatin dehydroabietylamine salt
WO2010093601A1 (en) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Novel sulfonic acid-containing thyromimetics, and methods for their use
US20100216863A1 (en) * 2004-01-30 2010-08-26 Decode Genetics Ehf. Susceptibility Gene for Myocardial Infarction, Stroke, and PAOD; Methods of Treatment
WO2011019326A2 (en) 2009-07-02 2011-02-17 Mahmut Bilgic Solubility and stability enchancing pharmaceutical formulation
WO2011018185A2 (en) 2009-08-13 2011-02-17 Synthon B.V. Pharmaceutical tablet comprising rosuvastatin calcium
US20110178296A1 (en) * 2008-09-30 2011-07-21 Sambhu Prasad Sarma Mallela Process for preparing pyrimidine propenaldehyde
WO2011141934A1 (en) 2010-05-13 2011-11-17 Matrix Laboratories Ltd. An improved process for the preparation of an intermediate of hmg-coa reductase inhibitors
WO2012027331A1 (en) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
EP2428516A1 (en) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics
US8158362B2 (en) 2005-03-30 2012-04-17 Decode Genetics Ehf. Methods of diagnosing susceptibility to myocardial infarction and screening for an LTA4H haplotype
WO2012063115A2 (en) 2010-11-11 2012-05-18 Jubilant Life Sciences Ltd. Process for the preparation of rosuvastatin calcium via novel amine intermediate
WO2012073256A1 (en) 2010-11-29 2012-06-07 Cadila Healthcare Limited Salts of rosuvastatin
WO2013080219A2 (en) 2011-11-28 2013-06-06 Mylan Laboratories Ltd NOVEL PROCESS FOR THE PREPARATION OF INTERMEDIATES OF HMG-CoA REDUCTASE INHIBITORS
US8476432B2 (en) 2010-07-01 2013-07-02 Yuhan Corporation Process for the preparation of HMG-COA reductase inhibitors and intermediates thereof
US8524914B2 (en) 2009-06-05 2013-09-03 Chong Kun Dang Pharmaceutical Corp. Method for preparing rosuvastatin, intermediate compounds useful for preparing same, and method for preparing same
US8673881B2 (en) 2009-04-13 2014-03-18 A.T. Resolve Sarl Compositions and methods for the treatment of inflammation
US8729092B2 (en) * 2012-09-24 2014-05-20 Terence J. Scallen Rosuvastatin enantiomer compounds
WO2014108795A2 (en) 2013-01-10 2014-07-17 Aurobindo Pharma Limited An improved process for the preparation of chiral diol sulfones and statins
WO2014142521A1 (en) 2013-03-12 2014-09-18 주식회사 엘지생명과학 Complex preparation including valsartan and rosuvastatin calcium and manufacturing method therefor
US8846915B2 (en) 2009-08-17 2014-09-30 Aurobindo Pharma Ltd. Process for the manufacture of rosuvastatin calcium using crystalline rosuvastatin ethyl ester
WO2014170786A1 (en) 2013-04-17 2014-10-23 Pfizer Inc. N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases
WO2015001573A1 (en) 2013-07-05 2015-01-08 Cadila Healthcare Limited Synergistic compositions
WO2015008294A1 (en) 2013-07-16 2015-01-22 Suven Life Sciences Limited Process for the preparation of rosuvastatin calcium and preparation of its novel intermediates
WO2016055901A1 (en) 2014-10-08 2016-04-14 Pfizer Inc. Substituted amide compounds
CN107698518A (en) * 2017-06-20 2018-02-16 迪沙药业集团（天津）药物研究有限公司 A kind of preparation method of rosuvastain calcium epimer impurity
WO2019094311A1 (en) 2017-11-08 2019-05-16 Merck Sharp & Dohme Corp. Prmt5 inhibitors
WO2020033282A1 (en) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Prmt5 inhibitors
WO2020033284A1 (en) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Prmt5 inhibitors
WO2020150473A2 (en) 2019-01-18 2020-07-23 Dogma Therapeutics, Inc. Pcsk9 inhibitors and methods of use thereof
WO2021019493A1 (en) 2019-07-31 2021-02-04 Intas Pharmaceuticals Ltd. Pharmaceutical composition comprising hmg-coa reductase inhibitors and fenofibrate
WO2021126731A1 (en) 2019-12-17 2021-06-24 Merck Sharp & Dohme Corp. Prmt5 inhibitors
US11576859B2 (en) 2015-10-23 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained release of therapeutic agents and methods of use thereof
US11576866B2 (en) 2016-09-30 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained delivery of adamantane-class drugs
US11992552B2 (en) 2015-12-08 2024-05-28 Lyndra Therapeutics, Inc. Geometric configurations for gastric residence systems

Families Citing this family (314)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69527684T2 (en) 1994-09-06 2002-11-28 Ube Industries Preparation of 3-oxy-5-oxo-6-heptenoic acid derivatives
US5952331A (en) * 1996-05-23 1999-09-14 Syntex (Usa) Inc. Aryl pyrimidine derivatives
TW440563B (en) * 1996-05-23 2001-06-16 Hoffmann La Roche Aryl pyrimidine derivatives and a pharmaceutical composition thereof
US5958934A (en) * 1996-05-23 1999-09-28 Syntex (U.S.A.) Inc. Aryl pyrimidine derivatives and uses thereof
US6376476B1 (en) * 1996-12-13 2002-04-23 Zymogenetics Corporation Isoprenoid pathway inhibitors for stimulating bone growth
GB9900339D0 (en) * 1999-01-09 1999-02-24 Zeneca Ltd Chemical compounds
GB0001662D0 (en) * 1999-02-06 2000-03-15 Zeneca Ltd Pharmaceutical compositions
AR022462A1 (en) * 1999-02-06 2002-09-04 Astrazeneca Uk Ltd USE OF AN AGENT THAT DECREASES CHOLESTEROL
GB0000710D0 (en) * 1999-02-06 2000-03-08 Zeneca Ltd Drug combination
GB9903472D0 (en) 1999-02-17 1999-04-07 Zeneca Ltd Chemical process
US6160115A (en) * 1999-03-10 2000-12-12 Lonza Ag Process for preparing N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin -2-yl]-N-methylmethanesulfonamide
SK284027B6 (en) * 1999-03-10 2004-08-03 Lonza Ag Process for the preparation of N-[5-(diphenylphosphinoylmethyl)- 4-(4-fluorphenyl)-6-isopropylpyrimidin-2-yl]-N- methylmethansulfonamide
PL211797B1 (en) * 1999-07-13 2012-06-29 Lonza Ag Process for preparing 2-amino-4-(4-fluorphenyl)-6-alkylpyrimidine-5-carboxylate
GB0001621D0 (en) * 2000-01-26 2000-03-15 Astrazeneca Ab Pharmaceutical compositions
GB0003305D0 (en) * 2000-02-15 2000-04-05 Zeneca Ltd Pyrimidine derivatives
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
KR100835265B1 (en) 2000-03-24 2008-06-09 파마시아 코포레이션 Amidino compound and salts thereof useful as nitric oxide synthase inhibitors
AR030414A1 (en) * 2000-04-03 2003-08-20 Astrazeneca Ab PHARMACEUTICAL COMBINATION THAT INCLUDES A BLOCKING BETA AND A REDUCED HMG-COA INHIBITOR, PHARMACEUTICAL FORMULATION, TRANSPORTABLE PARTS EQUIPMENT, USE OF THIS COMBINATION AND THIS FORMULATION TO PREPARE MEDICATIONS
US6787668B2 (en) 2000-04-13 2004-09-07 Pharmacia Corporation 2-amino-4,5 heptenoic acid derivatives useful as nitric oxide synthase inhibitors
AR032318A1 (en) 2000-04-13 2003-11-05 Pharmacia Corp HALOGENATED DERIVATIVE COMPOUND OF HEPTENOIC ACID 2-AMINO-5,6; PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE IN THE MANUFACTURE OF A USEFUL MEDICINAL PRODUCT AS AN INHIBITOR OF NITRICAL SYNTHEASE OXIDE
AR030416A1 (en) 2000-04-13 2003-08-20 Pharmacia Corp HALOGENATED DERIVATIVE COMPOUND OF HEPTENOIC ACID 2-AMINO-3,4, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE IN THE MANUFACTURE OF A USEFUL MEDICINAL PRODUCT AS AN INHIBITOR OF SYNTHETIC NITRIC OXIDE
US6545170B2 (en) 2000-04-13 2003-04-08 Pharmacia Corporation 2-amino-5, 6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors
US6956131B2 (en) 2000-04-13 2005-10-18 Pharmacia Corporation 2-amino-3, 4 heptenoic compounds useful as nitric oxide synthase inhibitors
AR034120A1 (en) 2000-04-13 2004-02-04 Pharmacia Corp HALOGENATED DERIVATIVE COMPOUND OF HEPTENOIC ACID 2-AMINO-4,5, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND THE USE OF SUCH COMPOUND AND SUCH COMPOSITION IN THE MANUFACTURE OF A MEDICINAL PRODUCT TO INHIBIT OR MODULATE NITRIC ACID SYNTHESIS
GB0011163D0 (en) * 2000-05-10 2000-06-28 Astrazeneca Ab Chemical compound
SE0002354D0 (en) * 2000-06-22 2000-06-22 Astrazeneca Ab New formulation
AU7833601A (en) * 2000-07-31 2002-02-13 Daniel L Sparks Charged lipid compositions and methods for their use
EP1305293A1 (en) 2000-08-01 2003-05-02 Pharmacia Corporation Hexahydro-7-imino-1h-azepin-2-yl-hexanoic acid derivatives as inhibitors of inducible nitric oxide synthase
AR031129A1 (en) 2000-09-15 2003-09-10 Pharmacia Corp DERIVATIVES OF ACIDS 2-AMINO-2-ALQUIL-4-HEXENOICO AND -HEXINOICO USEFUL AS INHIBITORS OF NITRICO OXIDE SYNTHEASE
MY131964A (en) 2000-09-15 2007-09-28 Pharmacia Corp 2-amino-2-alkyl-5 heptenoic and heptynoic acid derivatives useful as nitric oxide synthase inhibitors
SK4112003A3 (en) * 2000-10-12 2004-01-08 Nissan Chemical Ind Ltd Preventives and remedies for complications of diabetes
GB0028429D0 (en) * 2000-11-22 2001-01-10 Astrazeneca Ab Therapy
EP1365029A4 (en) 2001-02-02 2009-07-29 Mitsubishi Chem Corp Process for producing (3r,5s)-(e)-7- 2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl -3,5-dihydroxyhept-6-enic acid esters
ES2258141T3 (en) 2001-04-11 2006-08-16 Bristol-Myers Squibb Company C-ARILO GLUCOSIDE AMINO ACIDS COMPLEX FOR DIABETES TREATMENT AND PROCEDURE.
DK1417180T3 (en) * 2001-07-13 2007-04-10 Astrazeneca Uk Ltd Preparation of Aminopyrimidine Compounds
IL160917A0 (en) * 2001-10-18 2004-08-31 Bristol Myers Squibb Co Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US7238671B2 (en) * 2001-10-18 2007-07-03 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
SE0103509D0 (en) * 2001-10-19 2001-10-19 Astrazeneca Ab Rosuvastatin in pre-demented states
EP1443919A4 (en) * 2001-11-16 2006-03-22 Bristol Myers Squibb Co Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein
US6835838B2 (en) * 2002-01-28 2004-12-28 Novartis Ag Process for the manufacture of organic compounds
KR101069781B1 (en) * 2002-05-14 2011-10-05 프라샌트 인베스트먼츠, 엘엘씨 Method for producing a transmission signal
US7057046B2 (en) * 2002-05-20 2006-06-06 Bristol-Myers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
AR039836A1 (en) * 2002-05-21 2005-03-02 Ranbaxy Lab Ltd PROCESS FOR THE PREPARATION OF A PIRIMIDINE ALDEHIDO USEFUL FOR THE PREPARATION OF ROSUVASTATIN
US20050182106A1 (en) * 2002-07-11 2005-08-18 Sankyo Company, Limited Medicinal composition for mitigating blood lipid or lowering blood homocysteine
US20050182036A1 (en) * 2002-08-02 2005-08-18 Sankyo Company, Limited Medicinal composition containing an HMG-CoA reductase inhibitor
US20050187204A1 (en) * 2002-08-08 2005-08-25 Sankyo Company, Limited Medicinal composition for lowering blood lipid level
GB0218781D0 (en) 2002-08-13 2002-09-18 Astrazeneca Ab Chemical process
US7414119B2 (en) * 2002-09-20 2008-08-19 Verenium Corporation Aldolases, nucleic acids encoding them and methods for making and using them
WO2004037181A2 (en) * 2002-10-23 2004-05-06 Bristol-Myers Squibb Company Glycinenitrile-based inhibitors of dipeptidyl peptidase iv and methods
US7098235B2 (en) 2002-11-14 2006-08-29 Bristol-Myers Squibb Co. Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds
DE60239428D1 (en) * 2002-12-10 2011-04-21 Ranbaxy Lab Ltd
DK1578731T3 (en) 2002-12-16 2010-02-15 Astrazeneca Uk Ltd Process for Preparation of Pyrimidine Compounds
GB0229243D0 (en) * 2002-12-16 2003-01-22 Avecia Ltd Compounds and process
TW200504021A (en) * 2003-01-24 2005-02-01 Bristol Myers Squibb Co Substituted anilide ligands for the thyroid receptor
US20040176425A1 (en) * 2003-01-24 2004-09-09 Washburn William N. Cycloalkyl containing anilide ligands for the thyroid receptor
KR20050110017A (en) * 2003-03-17 2005-11-22 니뽄 다바코 산교 가부시키가이샤 Method for increasing the oral bioavailability of s-'2-(''1-(2-ethylbutyl)cyclohexyl!carbonyl!amino)phenyl!-2-methylpropanethioate
PL1603553T3 (en) * 2003-03-17 2012-04-30 Japan Tobacco Inc Pharmaceutical compositions of cetp inhibitors
US7470724B2 (en) * 2003-04-25 2008-12-30 Gilead Sciences, Inc. Phosphonate compounds having immuno-modulatory activity
US7452901B2 (en) * 2003-04-25 2008-11-18 Gilead Sciences, Inc. Anti-cancer phosphonate analogs
US7407965B2 (en) * 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
SG182849A1 (en) 2003-04-25 2012-08-30 Gilead Sciences Inc Antiviral phosphonate analogs
EA200501676A1 (en) * 2003-04-25 2006-04-28 Джилид Сайэнс, Инк. PHOSPHONATE-CONTAINING KINASE INHIBITORS (OPTIONS), METHOD FOR THEIR RECEIVING, PHARMACEUTICAL COMPOSITION, PHARMACEUTICAL FORM ON THEIR BASIS AND METHOD FOR INHIBING KINASE IN MOLOPYTIC TREATMENT THEM
US20050261237A1 (en) * 2003-04-25 2005-11-24 Boojamra Constantine G Nucleoside phosphonate analogs
US20090247488A1 (en) * 2003-04-25 2009-10-01 Carina Cannizzaro Anti-inflammatory phosphonate compounds
US9345671B2 (en) * 2003-04-28 2016-05-24 Daiichi Sankyo Company, Limited Adiponectin production enhancer
AU2004233691B2 (en) * 2003-04-28 2007-09-20 Sankyo Company, Limited Sugar intake-ability enhancer
TWI393560B (en) * 2003-05-02 2013-04-21 Japan Tobacco Inc Combination comprising s-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]2-methylpropanethioate and an hmg coa reductase inhibitor
AR041089A1 (en) 2003-05-15 2005-05-04 Merck & Co Inc PROCEDURE AND PHARMACEUTICAL COMPOSITIONS TO TREAT ATEROSCLEROSIS, DYSLIPIDEMIAS AND RELATED AFFECTIONS
US7166638B2 (en) * 2003-05-27 2007-01-23 Nicox S.A. Statin derivatives
GB0312896D0 (en) * 2003-06-05 2003-07-09 Astrazeneca Ab Chemical process
US7459474B2 (en) * 2003-06-11 2008-12-02 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor and method
EP1726583A3 (en) * 2003-06-18 2007-05-09 Teva Pharmaceutical Industries Ltd Fluvastatin sodium crystal form LXXIX, processes for preparing it, compositions containing it and methods of using it.
US7368468B2 (en) * 2003-06-18 2008-05-06 Teva Pharmaceutical Industries Ltd. Fluvastatin sodium crystal forms XIV, LXXIII, LXXIX, LXXX and LXXXVII, processes for preparing them, compositions containing them and methods of using them
WO2005007110A2 (en) * 2003-07-11 2005-01-27 Pro-Pharmaceuticals, Inc. Compositions and methods for hydrophobic drug delivery
US6995183B2 (en) * 2003-08-01 2006-02-07 Bristol Myers Squibb Company Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
WO2005021511A1 (en) * 2003-08-27 2005-03-10 Hetero Drugs Limited A novel process for amorphous rosuvastatin calcium
US20050053664A1 (en) * 2003-09-08 2005-03-10 Eliezer Zomer Co-administration of a polysaccharide with a chemotherapeutic agent for the treatment of cancer
UY28501A1 (en) * 2003-09-10 2005-04-29 Astrazeneca Uk Ltd CHEMICAL COMPOUNDS
GB0321827D0 (en) * 2003-09-18 2003-10-15 Astrazeneca Uk Ltd Chemical compounds
US20050171207A1 (en) * 2003-09-26 2005-08-04 Myriad Genetics, Incorporated Method and composition for combination treatment of neurodegenerative disorders
GB0322552D0 (en) 2003-09-26 2003-10-29 Astrazeneca Uk Ltd Therapeutic treatment
WO2005040134A1 (en) * 2003-10-22 2005-05-06 Ranbaxy Laboratories Limited Process for the preparation of amorphous rosuvastatin calcium
GB0324791D0 (en) * 2003-10-24 2003-11-26 Astrazeneca Ab Chemical process
WO2005044308A1 (en) * 2003-10-24 2005-05-19 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
ATE428411T1 (en) * 2003-11-07 2009-05-15 Jj Pharma Inc HDL-BOOSTING COMBINATION THERAPY COMPLEXES
US7317109B2 (en) * 2003-11-12 2008-01-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7576121B2 (en) * 2003-11-12 2009-08-18 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
CA2545311C (en) * 2003-11-12 2012-01-03 Phenomix Corporation Heterocyclic boronic acid compounds
US7767828B2 (en) * 2003-11-12 2010-08-03 Phenomix Corporation Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
WO2005054207A1 (en) * 2003-12-04 2005-06-16 Glenmark Pharmaceuticals Limited Process for the preparation of pyrimidine derivatives
AU2004308332B2 (en) 2003-12-23 2008-04-10 Merck Sharp & Dohme Corp. Anti-hypercholesterolemic compounds
WO2005063728A2 (en) * 2003-12-24 2005-07-14 Teva Pharmaceutical Industries Ltd. Process for preparation of statins with high syn to anti ratio
US20070161700A1 (en) * 2004-12-28 2007-07-12 Kowa Company, Ltd. Inhibitor for the formation of y-secretase complex
JPWO2005063294A1 (en) 2003-12-30 2007-12-13 興和株式会社 γ-secretase complex formation inhibitor
CZ200486A3 (en) * 2004-01-16 2005-08-17 Zentiva, A.S. Process for preparing hemicalcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6-heptenoic acid
WO2005077917A1 (en) * 2004-01-19 2005-08-25 Ranbaxy Laboratories Limited Amorphous salts of rosuvastatin
EP1718146A2 (en) * 2004-02-13 2006-11-08 Pro-Pharmaceuticals, Inc. Compositions and methods used to treat acne and candida
WO2005079847A1 (en) * 2004-02-25 2005-09-01 Kowa Company, Ltd. NUCLEAR TRANSFER PROMOTER FOR Cdc42 PROTEIN AND METHOD OF SCREENING THE SAME
US8309574B2 (en) * 2004-02-25 2012-11-13 Kowa Company, Ltd. Nuclear transfer promoter for Rac protein and method of screening the same
US7241800B2 (en) 2004-03-17 2007-07-10 Mai De Ltd. Anhydrous amorphous form of fluvastatin sodium
GB0406757D0 (en) 2004-03-26 2004-04-28 Avecia Ltd Process and compounds
UA87854C2 (en) 2004-06-07 2009-08-25 Мерк Энд Ко., Инк. N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators
CN1323665C (en) * 2004-06-16 2007-07-04 鲁南制药集团股份有限公司 Composition for treating hyperlipemia
US7161004B2 (en) * 2004-06-21 2007-01-09 Dr. Reddy's Laboratories Limited Processes to produce intermediates for rosuvastatin
US7145040B2 (en) * 2004-07-02 2006-12-05 Bristol-Myers Squibb Co. Process for the preparation of amino acids useful in the preparation of peptide receptor modulators
TW200611704A (en) * 2004-07-02 2006-04-16 Bristol Myers Squibb Co Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
US7534763B2 (en) 2004-07-02 2009-05-19 Bristol-Myers Squibb Company Sustained release GLP-1 receptor modulators
CA2573848A1 (en) * 2004-07-12 2006-02-16 Phenomix Corporation Constrained cyano compounds
US7572805B2 (en) 2004-07-14 2009-08-11 Bristol-Myers Squibb Company Pyrrolo(oxo)isoquinolines as 5HT ligands
CZ298330B6 (en) * 2004-07-19 2007-08-29 Zentiva, A. S. Process for preparing 4-(4--fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)-5-pyrimidinecarbaldehyde and use thereof
EP2258376B1 (en) 2004-07-27 2019-02-27 Gilead Sciences, Inc. Phosphonate analogs of HIV inhibitor compounds
WO2006017417A2 (en) * 2004-08-02 2006-02-16 Pro-Pharmaceuticals, Inc. Compositions and methods for the enhancement of chemotherapy with microbial cytotoxins
CN100412065C (en) * 2004-08-13 2008-08-20 天津天士力集团有限公司 4-(p-fluorophenyl)-6-isopropyl-2-methylaminopyrimidine-5-methyl formate synthesis method
US20070244107A1 (en) * 2004-08-25 2007-10-18 Waters M Gerard Method of Treating Atherosclerosis, Dyslipidemias and Related Conditions
AR051446A1 (en) * 2004-09-23 2007-01-17 Bristol Myers Squibb Co C-ARYL GLUCOSIDS AS SELECTIVE INHIBITORS OF GLUCOSE CONVEYORS (SGLT2)
US7517991B2 (en) * 2004-10-12 2009-04-14 Bristol-Myers Squibb Company N-sulfonylpiperidine cannabinoid receptor 1 antagonists
CN1763015B (en) * 2004-10-22 2011-06-22 四川抗菌素工业研究所有限公司 Preparation method and intermediate of rosuvastatin and its pharmaceutical salts
WO2006046593A1 (en) 2004-10-27 2006-05-04 Daiichi Sankyo Company, Limited Benzene compound having 2 or more substituents
US7816347B2 (en) * 2004-12-15 2010-10-19 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions comprising NEP-inhibitors, inhibitors of the endogenous endothelin producing system and HMG CoA reductase inhibitors
EP1845092B1 (en) 2004-12-23 2010-09-01 Hui Yao Pyrimidinone compounds, their preparation and use thereof
GB0428328D0 (en) * 2004-12-24 2005-02-02 Astrazeneca Uk Ltd Chemical process
US7635699B2 (en) * 2004-12-29 2009-12-22 Bristol-Myers Squibb Company Azolopyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US7589088B2 (en) * 2004-12-29 2009-09-15 Bristol-Myers Squibb Company Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US7314882B2 (en) * 2005-01-12 2008-01-01 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
WO2006076597A1 (en) * 2005-01-12 2006-07-20 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
WO2006076568A2 (en) 2005-01-12 2006-07-20 Bristol-Myers Squibb Company Thiazolopyridines as cannabinoid receptor modulators
WO2006078697A1 (en) * 2005-01-18 2006-07-27 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
CN100351240C (en) * 2005-01-19 2007-11-28 安徽省庆云医药化工有限公司 Rosuvastatin calcium synthesis method
US7932387B2 (en) * 2005-01-31 2011-04-26 Basf Se Crystalline forms of rosuvastatin calcium salt
JPWO2006083012A1 (en) * 2005-02-02 2008-06-26 味の素株式会社 Method for producing pyrimidine compound
ATE421518T1 (en) * 2005-02-10 2009-02-15 Bristol Myers Squibb Co DIHYDROQUINAZOLINONES AS 5HT MODULATORS
US20070293535A1 (en) * 2005-02-24 2007-12-20 Kowa Company, Ltd. Nuclear Transfer Promoter for Ddc42 Protein and Method of Screening the Dame
EP1863773A1 (en) * 2005-03-22 2007-12-12 Unichem Laboratories Limited Process for preparation of rosuvastatin
WO2006106526A1 (en) * 2005-04-04 2006-10-12 Unichem Laboratories Limited Process for preparation of calcium salt of rosuvastatin
EP2527337A1 (en) 2005-04-14 2012-11-28 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type I
CN1307187C (en) * 2005-05-16 2007-03-28 浙江海正药业股份有限公司 Method for preparing Rosuvastain and its intermediate
US7521557B2 (en) 2005-05-20 2009-04-21 Bristol-Myers Squibb Company Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods
US7825139B2 (en) * 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US20060275356A1 (en) * 2005-05-25 2006-12-07 Burgess James W Pharmaceutical compositions for treating or preventing coronary artery disease
JP2008542292A (en) * 2005-05-26 2008-11-27 ブリストル−マイヤーズ スクイブ カンパニー N-terminal modified GLP-1 receptor modulator
EP1893585A1 (en) * 2005-06-01 2008-03-05 Fermion Oy Process for the preparation of n-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-n-methylmethanesulfonamide
US7632837B2 (en) * 2005-06-17 2009-12-15 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid-1 receptor modulators
US7317012B2 (en) * 2005-06-17 2008-01-08 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoind-1 receptor modulators
US7452892B2 (en) * 2005-06-17 2008-11-18 Bristol-Myers Squibb Company Triazolopyrimidine cannabinoid receptor 1 antagonists
US7629342B2 (en) * 2005-06-17 2009-12-08 Bristol-Myers Squibb Company Azabicyclic heterocycles as cannabinoid receptor modulators
US20060287342A1 (en) * 2005-06-17 2006-12-21 Mikkilineni Amarendra B Triazolopyrimidine heterocycles as cannabinoid receptor modulators
US7572808B2 (en) * 2005-06-17 2009-08-11 Bristol-Myers Squibb Company Triazolopyridine cannabinoid receptor 1 antagonists
CN102807530B (en) 2005-06-24 2015-08-05 力奇制药公司 Prepare the method for unformed ZD-4522 free from foreign meter
CA2611920C (en) * 2005-06-24 2015-05-05 Lek Pharmaceuticals D.D. Process for preparing pure amorphous rosuvastatin calcium
CZ299215B6 (en) * 2005-06-29 2008-05-21 Zentiva, A. S. Process for preparing hemi-calcium salt of rosuvastatin, i.e. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6-heptenoic acid
GB0514078D0 (en) * 2005-07-08 2005-08-17 Astrazeneca Uk Ltd Chemical process
BRPI0614485A2 (en) * 2005-07-28 2011-03-29 Bristol-Myers Squibb Company tetrahydro-1h-pyrido [4, 3, b] substituted indoles as serotonin receptor agonists and antagonists
CN100436428C (en) * 2005-08-22 2008-11-26 鲁南制药集团股份有限公司 Preparation method of rosuvastain and its salt
CN100352821C (en) * 2005-08-22 2007-12-05 鲁南制药集团股份有限公司 Rosuvastain calcium intermediate preparation method
US7795436B2 (en) * 2005-08-24 2010-09-14 Bristol-Myers Squibb Company Substituted tricyclic heterocycles as serotonin receptor agonists and antagonists
US20080139457A1 (en) * 2005-09-16 2008-06-12 Virginia Commonwealth University Therapeutic compositions comprising chorionic gonadotropins and HMG CoA reductase inhibitors
CA2625290A1 (en) * 2005-10-04 2007-04-12 Teva Pharmaceutical Industries Ltd. Preparation of rosuvastatin
US8618115B2 (en) * 2005-10-26 2013-12-31 Bristol-Myers Squibb Company Substituted thieno[3,2-d]pyrimidinones as MCHR1 antagonists and methods for using them
US7488725B2 (en) 2005-10-31 2009-02-10 Bristol-Myers Squibb Co. Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase IV and methods
CN1958593B (en) * 2005-11-03 2010-05-05 上海医药工业研究院 Method for preparing intermediate of synthesizing rosuvastatin calcium
CN101330919B (en) * 2005-12-20 2012-12-05 力奇制药公司 Pharmaceutical composition including (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrim idin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-enoic acid
US7592461B2 (en) 2005-12-21 2009-09-22 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
EP1976873A2 (en) * 2006-01-11 2008-10-08 Brystol-Myers Squibb Company Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
EP1979330A2 (en) * 2006-01-30 2008-10-15 Cadila Healthcare Limited A process for manufacturing rosuvastatin potassium
US7553836B2 (en) * 2006-02-06 2009-06-30 Bristol-Myers Squibb Company Melanin concentrating hormone receptor-1 antagonists
AU2007223086B2 (en) 2006-03-07 2013-09-26 Basf Enzymes Llc Aldolases, nucleic acids encoding them and methods for making and using them
US20070238770A1 (en) * 2006-04-05 2007-10-11 Bristol-Myers Squibb Company Process for preparing novel crystalline forms of peliglitazar, novel stable forms produced therein and formulations
HU227696B1 (en) * 2006-04-13 2011-12-28 Egyt Gyogyszervegyeszeti Gyar Zinc salt of rosuvastatin, process for its preparation and pharmaceutical compositions containing it
ES2564250T3 (en) * 2006-05-03 2016-03-21 Msn Laboratories Private Limited New process for statins and their pharmaceutically acceptable salts thereof
WO2007139589A1 (en) 2006-05-26 2007-12-06 Bristol-Myers Squibb Company Sustained release glp-1 receptor modulators
US7919598B2 (en) 2006-06-28 2011-04-05 Bristol-Myers Squibb Company Crystal structures of SGLT2 inhibitors and processes for preparing same
JPWO2008001499A1 (en) 2006-06-29 2009-11-26 興和株式会社 Drugs for preventing and / or treating rheumatoid arthritis
US20080044326A1 (en) * 2006-07-04 2008-02-21 Esencia Co., Ltd. Sterilizer for baby products
CN102764440A (en) 2006-07-05 2012-11-07 奈科明有限责任公司 Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases
US7795291B2 (en) 2006-07-07 2010-09-14 Bristol-Myers Squibb Company Substituted acid derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents and method
EP2066644A2 (en) * 2006-08-04 2009-06-10 Glenmark Pharmaceuticals Limited Salts of rosuvastatin and processes for their preparation
US7727978B2 (en) 2006-08-24 2010-06-01 Bristol-Myers Squibb Company Cyclic 11-beta hydroxysteroid dehydrogenase type I inhibitors
HU227610B1 (en) * 2006-09-18 2011-09-28 Richter Gedeon Nyrt Pharmaceutical compositions containing rosuvastatin potassium
HUE028475T2 (en) 2006-10-09 2016-12-28 Msn Laboratories Private Ltd Novel process for the preparation of statins and their pharmaceutically acceptable salts thereof
EP2089355A2 (en) 2006-11-01 2009-08-19 Brystol-Myers Squibb Company Modulators of glucocorticoid receptor, ap-1, and/or nf- kappa b activity and use thereof
WO2008093205A2 (en) * 2007-01-31 2008-08-07 Orchid Chemicals & Pharmaceuticals Limited A method for the purification of rosuvastatin intermediate
AR065809A1 (en) 2007-03-22 2009-07-01 Bristol Myers Squibb Co PHARMACEUTICAL FORMULATIONS CONTAINING AN SGLT2 INHIBITOR
WO2008130951A1 (en) 2007-04-17 2008-10-30 Bristol-Myers Squibb Company Fused heterocyclic 11-beta-hydroxysteroid dehydrogenase type i inhibitors
PE20090696A1 (en) 2007-04-20 2009-06-20 Bristol Myers Squibb Co CRYSTALLINE FORMS OF SAXAGLIPTIN AND PROCESSES FOR PREPARING THEM
CN101668542B (en) 2007-04-27 2012-06-27 国立大学法人九州大学 Agent for treatment of pulmonary disease
WO2008144346A2 (en) * 2007-05-18 2008-11-27 Bristol-Myers Squibb Company Crystal structures of sglt2 inhibitors and processes for their preparation
CA2687964A1 (en) 2007-06-01 2009-02-19 The Trustees Of Princeton University Treatment of viral infections by modulation of host cell metabolic pathways
US20100190761A1 (en) 2007-06-20 2010-07-29 Anthony Ogawa Diphenyl substituted alkanes
US20090011994A1 (en) * 2007-07-06 2009-01-08 Bristol-Myers Squibb Company Non-basic melanin concentrating hormone receptor-1 antagonists and methods
JP2010534722A (en) * 2007-07-27 2010-11-11 ブリストル−マイヤーズ スクイブ カンパニー Novel glucokinase activator and method of use thereof
EP2022784A1 (en) * 2007-08-08 2009-02-11 LEK Pharmaceuticals D.D. Process for the preparation of methyl ester of rosuvastatin
JOP20080381B1 (en) 2007-08-23 2023-03-28 Amgen Inc Antigen Binding Proteins to Proprotein Convertase subtillisin Kexin type 9 (pcsk9)
EA201000214A1 (en) * 2007-08-28 2010-10-29 Рациофарм Гмбх METHOD OF OBTAINING DERIVATIVE PENTADICARBONIC ACID
CN101376647B (en) * 2007-08-31 2010-12-08 中山奕安泰医药科技有限公司 Method for synthesizing rosuvastatin intermediate and rosuvastatin
US20090082380A1 (en) * 2007-09-25 2009-03-26 Protia, Llc Deuterium-enriched rosuvastatin
HU230637B1 (en) * 2007-10-12 2017-05-29 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Process for producing intermediates of rosuvastatin
HU230981B1 (en) * 2007-10-12 2019-08-28 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Process for producing rosuvastatin salt
EP2209780B1 (en) 2007-11-01 2014-01-01 Bristol-Myers Squibb Company Nonsteroidal compounds useful as modulators of glucocorticoid receptor ap-1 and/or nf- kappa b activity and use thereof
JP4923146B2 (en) 2008-01-11 2012-04-25 リアタ ファーマシューティカルズ インコーポレイテッド Synthetic triterpenoids and methods of use in the treatment of disease
TR200800269A2 (en) * 2008-01-15 2009-08-21 Bi̇li̇m İlaç Sanayi̇ Ti̇caret A.Ş. Stable pharmaceutical formulation and preparation methods
CA2725052C (en) 2008-05-27 2014-09-16 Changzhou Pharmaceutical Factory Co., Ltd. Preparation method of rosuvastatin calcium and its intermediates
CN101591302B (en) * 2008-05-27 2011-08-31 常州制药厂有限公司 Preparation technique of heptenoic acid ester derivative
CN101591301B (en) * 2008-05-27 2011-01-12 常州制药厂有限公司 Preparation method of 3, 5-dihydroxy heptyl-6-gadoleic acid derivative
PE20091928A1 (en) * 2008-05-29 2009-12-31 Bristol Myers Squibb Co HAVE HYDROXYSUSTITUTED PYRIMIDINES AS NON-BASIC MELANIN-CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS
EP2138165A1 (en) 2008-06-27 2009-12-30 KRKA, tovarna zdravil, d.d., Novo mesto Pharmaceutical composition comprising a statin
SI2309992T1 (en) 2008-06-27 2018-03-30 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical composition comprising a statin
US8658617B2 (en) 2008-07-08 2014-02-25 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
EP2161024A1 (en) 2008-09-05 2010-03-10 Universitätsklinikum Hamburg-Eppendorf Combination product for the treatment of cancer
US20130064834A1 (en) 2008-12-15 2013-03-14 Regeneron Pharmaceuticals, Inc. Methods for treating hypercholesterolemia using antibodies to pcsk9
JO3672B1 (en) 2008-12-15 2020-08-27 Regeneron Pharma High Affinity Human Antibodies to PCSK9
EP2373609B1 (en) 2008-12-19 2013-10-16 KRKA, D.D., Novo Mesto Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates
EP2327682A1 (en) 2009-10-29 2011-06-01 KRKA, D.D., Novo Mesto Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates
SI2387566T1 (en) 2009-01-14 2014-07-31 Krka, Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of rosuvastatin
WO2010082072A1 (en) 2009-01-15 2010-07-22 Egis Gyógyszergyár Process for the preparation of rosuvastatin salts
WO2010089770A2 (en) 2009-01-19 2010-08-12 Msn Laboratories Limited Improved process for the preparation of highly pure (3r,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-3,5-dihydroxy-6(e)-heptenoic acid and pharmaceutically acceptable salts thereof
EP2264015A1 (en) 2009-02-02 2010-12-22 LEK Pharmaceuticals d.d. Key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof
KR101160152B1 (en) * 2009-02-24 2012-06-27 한미사이언스 주식회사 Novel process for preparing statin compound or its salt and intermediate used therein
GB0904104D0 (en) 2009-03-10 2009-04-22 Bradford Pharma Ltd Atorvastatin and rosuvastatin derivatives
GB0904100D0 (en) 2009-03-10 2009-04-22 Bradford Pharma Ltd Use of rosuvastatin lactols as medicaments
TR200902077A2 (en) 2009-03-17 2010-01-21 Sanovel İlaç San.Veti̇c.A.Ş. Stable rosuvastatin compositions
SG174504A1 (en) 2009-03-27 2011-10-28 Bristol Myers Squibb Co Methods for preventing major adverse cardiovascular events with dpp-iv inhibitors
US8470805B2 (en) 2009-04-30 2013-06-25 Kaohsiung Medical University Processes for preparing piperazinium salts of KMUP and use thereof
HUP0900285A2 (en) 2009-05-07 2011-01-28 Egis Gyogyszergyar Nyilvanosan Mukoedoe Reszvenytarsasag Rosuvastatin salts and preparation thereof
TR200904341A2 (en) 2009-06-03 2010-12-21 Bi̇lgi̇ç Mahmut Stable pharmaceutical compositions containing rosuvastatin calcium.
US20120294936A1 (en) 2009-11-13 2012-11-22 Astrazeneca Uk Limited Reduced mass metformin formulations
AU2010319377B2 (en) 2009-11-13 2014-10-23 Astrazeneca Ab Immediate release tablet formulations
CA2780939C (en) 2009-11-13 2018-06-12 Bristol-Myers Squibb Company Bilayer tablet formulations
AR079336A1 (en) * 2009-12-11 2012-01-18 Irm Llc ANTAGONISTS OF THE PRO-PROTEIN CONVERTASE-SUBTILISINE / TYPE 9 QUEXINE (PCSK9)
US20130115622A1 (en) 2009-12-14 2013-05-09 Kyoto University Pharmaceutical composition for prevention and treatment of amyotrophic lateral sclerosis
EP2336116A1 (en) 2009-12-16 2011-06-22 LEK Pharmaceuticals d.d. Process for the preparation of key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof
WO2011074016A1 (en) 2009-12-17 2011-06-23 Matrix Laboratories Ltd Novel polymorphic forms of rosuvastatin calcium and process for preparation of the same
WO2011086584A2 (en) 2010-01-18 2011-07-21 Msn Laboratories Limited Improved process for the preparation of amide intermediates and their use thereof
TWI562775B (en) 2010-03-02 2016-12-21 Lexicon Pharmaceuticals Inc Methods of using inhibitors of sodium-glucose cotransporters 1 and 2
CN102212082B (en) * 2010-04-05 2015-03-04 重庆博腾制药科技股份有限公司 Rosuvastatin calcium intermediate and preparation method thereof
CN102219749B (en) * 2010-04-14 2013-07-17 上海京新生物医药有限公司 Method for preparing rosuvastatin calcium
CN102971313A (en) 2010-04-14 2013-03-13 百时美施贵宝公司 Novel glucokinase activators and methods of using same
US8372877B2 (en) 2010-04-16 2013-02-12 Cumberland Pharmaceuticals Stabilized statin formulations
US8536330B2 (en) 2010-04-23 2013-09-17 Ranbaxy Laboratories Limited Intermediates for the preparation of HMG-CoA reductase inhibitors
EP2566465A2 (en) 2010-05-04 2013-03-13 Mahmut Bilgic Stable rosuvastatin formulations
EP2575757A1 (en) 2010-06-03 2013-04-10 Mahmut Bilgic Water soluble formulation comprising a combination of amlodipine and a statin
TR201005326A2 (en) 2010-06-30 2012-01-23 Bi̇lgi̇ç Mahmut Multiple dosage forms.
EP2423195A1 (en) 2010-07-26 2012-02-29 LEK Pharmaceuticals d.d. Process for the preparation of key intermediates for the synthesis of statins or pharmaceutically acceptable salts thereof
CN101955463B (en) * 2010-08-04 2012-01-04 重庆博腾制药科技股份有限公司 Method for preparing rosuvastatin calcium intermediate
MX2010011006A (en) * 2010-10-06 2012-04-18 Senosiain S A De C V Lab New salt of a pyrimidin derivative.
EP2626069A4 (en) 2010-10-06 2014-03-19 Univ Tokyo Prophylactic and/or therapeutic agent against lymphedema
TWI462739B (en) 2010-11-02 2014-12-01 Univ Kaohsiung Medical Processes for preparing piperazinium salts of sildenafil-analogues and use thereof
TR201009399A2 (en) 2010-11-11 2012-05-21 Bi̇lgi̇ç Mahmut Rapidly soluble effervescent rosuvastatin formulations.
HU230737B1 (en) 2010-11-16 2018-01-29 EGIS Gyógyszergyár Nyrt Process for preparation of rosuvastatin salt
HU230987B1 (en) 2010-11-29 2019-08-28 Egis Gyógyszergyár Nyrt. Process for the preparation of pharmaceutical intermediates with high purity
HU229260B1 (en) 2010-11-29 2013-10-28 Egis Gyogyszergyar Nyrt Process for preparation of rosuvastatin salts
TWI631963B (en) 2011-01-05 2018-08-11 雷西肯製藥股份有限公司 Compositions comprising and methods of using inhibitors of sodium-glucose cotransporters 1 and 2
CN102584717B (en) * 2011-01-17 2014-12-10 浙江九洲药业股份有限公司 Intermediate for preparing rosuvastatin and preparation method and application thereof
CN103313983B (en) 2011-01-18 2016-06-29 中化帝斯曼制药有限公司荷兰公司 The method preparing statin compound in the presence of a base
US8933113B2 (en) 2011-01-20 2015-01-13 Merck Sharp & Dohme Corp. Mineralocorticoid receptor antagonists
CN103476796A (en) 2011-01-28 2013-12-25 赛诺菲 Human antibodies to pcsk9 for use in methods of treating particular groups of subjects
EP2697203B1 (en) 2011-04-13 2017-05-24 Merck Sharp & Dohme Corporation Mineralocorticoid receptor antagonists
EP2699552A1 (en) * 2011-04-18 2014-02-26 Basf Se Multicomponent crystalline system of rosuvastatin calcium salt and vanillin
KR20200003219A (en) 2011-05-20 2020-01-08 아스트라제네카 유케이 리미티드 Pharmaceutical composition of rosuvastatin calcium
WO2012172564A1 (en) * 2011-05-25 2012-12-20 Dr. Reddy's Laboratories Limited Process for preparation of rosuvastatin calcium
AR087305A1 (en) 2011-07-28 2014-03-12 Regeneron Pharma STABILIZED FORMULATIONS CONTAINING ANTI-PCSK9 ANTIBODIES, PREPARATION METHOD AND KIT
WO2013046222A2 (en) * 2011-08-10 2013-04-04 Glenmark Generics Limited A process for the preparation of amorphous rosuvastatin calcium
EP3536712B1 (en) 2011-09-16 2023-05-31 Regeneron Pharmaceuticals, Inc. Methods for reducing lipoprotein(a) levels by administering an inhibitor of proprotein convertase subtilisin kexin-9 (pcsk9)
WO2013055606A1 (en) 2011-10-13 2013-04-18 Merck Sharp & Dohme Corp. Mineralocorticoid receptor antagonists
EP2602249B1 (en) 2011-12-06 2015-08-12 F.I.S. Fabbrica Italiana Sintetici S.p.A. Synthesis of rosuvastatin by means of co-crystals
BR112014016154A8 (en) 2011-12-29 2017-07-04 Tufts College functionalization of biomaterials to control responses to regeneration and inflammation
CN104902892A (en) 2012-02-02 2015-09-09 悉尼大学 Improvements in tear film stability
PL2844233T3 (en) 2012-05-01 2020-09-07 Althera Life Sciences, Llc Oral tablet formulation consisting of fixed combination of rosuvastatin and ezetimibe for treatment of hyperlipidemia and cardiovascular diseases
CA2875096A1 (en) 2012-06-15 2013-12-19 Genentech, Inc. Anti-pcsk9 antibodies, formulations, dosing, and methods of use
CN103709107B (en) * 2012-09-29 2016-04-20 安徽省庆云医药化工有限公司 New crystal of Rosuvastatin methyl esters and preparation method thereof
CN103044339A (en) * 2012-10-15 2013-04-17 武汉市江润精细化工有限责任公司 Preparation method of rosuvastatin calcium intermediate
DK3489226T3 (en) 2012-11-20 2021-04-26 Lexicon Pharmaceuticals Inc Inhibitors of sodium glucose cotransport 1
ITVI20130039A1 (en) 2013-02-20 2014-08-21 F I S Fabbrica Italiana Sint I S P A PROCESS FOR THE PREPARATION OF KEY INTERMEDIATES FOR STATIN SYNTHESIS
JP6068765B2 (en) 2013-03-14 2017-01-25 ボリュン ファーマスーティカル カンパニー リミテッド Pharmaceutical combination preparation
US10111953B2 (en) 2013-05-30 2018-10-30 Regeneron Pharmaceuticals, Inc. Methods for reducing remnant cholesterol and other lipoprotein fractions by administering an inhibitor of proprotein convertase subtilisin kexin-9 (PCSK9)
EA201592267A1 (en) 2013-06-07 2016-04-29 Ридженерон Фармасьютикалз, Инк. METHODS OF INHIBITING ATHEROSCLEROSIS BY MEANS OF PCSK9 INHIBITOR INTRODUCTION
WO2014203045A1 (en) 2013-06-20 2014-12-24 Lupin Limited A novel, green and cost effective process for synthesis of tert-butyl (3r,5s)-6-oxo-3,5-dihydroxy-3,5-o-isopropylidene-hexanoate
US9593113B2 (en) 2013-08-22 2017-03-14 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
AU2014348765A1 (en) 2013-11-12 2016-06-09 Regeneron Pharmaceuticals, Inc. Dosing regimens for use with PCSK9 inhibitors
JP6536871B2 (en) 2013-12-02 2019-07-03 国立大学法人京都大学 Preventive and therapeutic agent for FGFR3 disease and method of screening the same
CN103724278B (en) * 2013-12-12 2019-03-29 江苏阿尔法药业有限公司 The preparation method of Statins intermediate and its derivative
KR20150079373A (en) 2013-12-30 2015-07-08 한미약품 주식회사 Composite formulation for oral administration comprising ezetimibe and rosuvastatin
EP3103878A4 (en) 2014-02-06 2017-08-16 API Corporation Rosuvastatin calcium and process for producing intermediate thereof
CN114404427A (en) 2014-02-13 2022-04-29 配体药物公司 Prodrug compound and use thereof
WO2015131405A1 (en) * 2014-03-07 2015-09-11 凯莱英医药集团（天津）股份有限公司 Intermediate compound for preparing rosuvastatin calcium and method for preparing rosuvastatin calcium therefrom
CN103896979B (en) * 2014-03-31 2015-03-18 南京欧信医药技术有限公司 Compound synthetic method
CN103951552B (en) * 2014-04-11 2015-09-30 浙江宏元药业有限公司 Rosuvastatin intermediate and preparation method thereof
CN104151252B (en) * 2014-05-07 2016-09-28 兰州大学 One prepares the method for [6-isopropyl-4-(4-fluorophenyl)-2-sulfenyl-5-base] formic acid esters
BR112016027778A2 (en) 2014-05-30 2017-08-15 Pfizer USES OF CARBONITRIL DERIVATIVES, THEIR COMBINATION AND THEIR PHARMACEUTICAL COMPOSITION
JP2017528427A (en) 2014-07-16 2017-09-28 サノフィ・バイオテクノロジー Method for treating a patient having heterozygous familial hypercholesterolemia (heFH)
JP6649263B2 (en) * 2014-10-10 2020-02-19 株式会社エーピーアイ コーポレーション Method for purifying statins
CN104356155B (en) * 2014-10-20 2017-01-18 浙江新东港药业股份有限公司 Preparation method of (S)-tert-butyldimethylsilyloxy-glutaramate
CN104529909B (en) * 2014-12-26 2016-08-24 江西富祥药业股份有限公司 A kind of method for crystallising of rosuvastain calcium intermediate
CN104592130A (en) * 2014-12-30 2015-05-06 江苏阿尔法药业有限公司 Novel method for preparing rosuvastatin main chain
CN104628653B (en) * 2015-01-28 2018-04-03 湖北益泰药业有限公司 The method of synthesizing rosuvastatin spit of fland calcium key intermediate
KR20160126700A (en) 2015-04-24 2016-11-02 미래파인켐 주식회사 New Statin intermediate, the preparation of the same and the preparation of Rosuvastatin using the same
CN104829600B (en) * 2015-05-05 2017-11-07 浙江新东港药业股份有限公司 A kind of synthesis technique of the intermediate in synthesizing rosuvastatin spit of fland
CN107922507B (en) 2015-08-18 2022-04-05 瑞泽恩制药公司 anti-PCSK 9 inhibitory antibodies for treating hyperlipidemic patients receiving lipoprotein apheresis
CN105367502A (en) * 2015-12-07 2016-03-02 浙江宏元药业有限公司 Rosuvastatin calcium intermediate and method for preparing rosuvastatin calcium intermediate and rosuvastatin calcium
HUE061878T2 (en) 2016-04-18 2023-08-28 Morepen Laboratories Ltd New polymorphic form of crystalline rosuvastatin calcium&novel processes for crystalline as well as amorphous rosuvastatin calcium
BR112019015107A2 (en) 2017-01-23 2020-03-10 Dong Wha Pharm. Co., Ltd. COMPLEX FORMULATION UNDERSTANDING HMG-COA REDUCTASE AND CLOPIDOGREL INHIBITOR
PL3661937T3 (en) 2017-08-01 2021-12-20 Gilead Sciences, Inc. Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) for treating viral infections
EP3737676B1 (en) * 2018-01-09 2024-03-06 Ligand Pharmaceuticals, Inc. Acetal compounds and therapeutic uses thereof
WO2019216313A1 (en) 2018-05-08 2019-11-14 国立大学法人岡山大学 Medication useful for cardiovascular diseases
US20210299331A1 (en) 2018-07-19 2021-09-30 Kyoto University Pluripotent stem cell-derived plate-shaped cartilage and method for producing the same
SG11202102498UA (en) 2018-09-26 2021-04-29 Lexicon Pharmaceuticals Inc Crystalline forms of n-(1 -((2-(dimethylamino)ethyl)amino)-2-m ethyl-1 -oopropan-2-yl)-4-(4-(2-methyl-5- (2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2h-pyran-2-yl)benzyl) phenl)butanamide and methods of their synthesis
EP3900787A4 (en) 2018-12-21 2022-02-23 Kyoto University Lubricin-localized cartilage-like tissue, method for producing same and composition comprising same for treating articular cartilage damage
CN109796414B (en) * 2019-02-26 2022-05-20 中国药科大学 Method for continuously preparing rosuvastatin intermediate by adopting micro-channel modular reaction device
WO2020184703A1 (en) 2019-03-13 2020-09-17 国立大学法人浜松医科大学 Pharmaceutical composition for treating aortic aneurysm
BR112022001783A2 (en) 2019-07-31 2022-03-22 Tecnimede Soc Tecnico Medicinal Sa Immediate release multi-unit solid oral compositions, their methods and uses.
WO2021100848A1 (en) 2019-11-22 2021-05-27 株式会社エーピーアイ コーポレーション Carbonyl reductase, nucleic acid encoding same, and method for producing optically active compound using same
US20230172996A1 (en) 2020-02-21 2023-06-08 Yoshikazu NAKAOKA Composition for alleviating pulmonary hypertension, method for predicting prognosis of pulmonary hypertension, method for assisting in determining severity of pulmonary hypertension, and method for assisting in diagnosing pulmonary hypertension
TW202302090A (en) * 2021-04-30 2023-01-16 大陸商江蘇恒瑞醫藥股份有限公司 Dosage regimen for thrombopoietin receptor agonist
WO2023275715A1 (en) 2021-06-30 2023-01-05 Pfizer Inc. Metabolites of selective androgen receptor modulators
GB2622822A (en) 2022-09-28 2024-04-03 Novumgen Ltd A rapidly disintegrating tablet of rosuvastatin and its process of preparation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330057A2 (en) 1988-02-25 1989-08-30 Bayer Ag Substituted pyrimidines
US4868185A (en) 1987-12-10 1989-09-19 Warner-Lambert Company 6-[[Substituted)pyrimidinyl)ethyl]- and ethenyl]tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US4925852A (en) 1987-07-10 1990-05-15 Hoechst Aktiengesellschaft 3-demethylmevalonic acid derivatives, and pharmaceutical products based on these compounds
EP0367895A1 (en) 1988-10-06 1990-05-16 Sandoz Ag Pyrimidinyl-substituted hydroxyacids, lactones and esters and pharmaceutical compositions containing them
US5026708A (en) 1987-09-12 1991-06-25 Nissan Chemical Industries Ltd. Pyrimidine type mevalonolactones

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4925852A (en) 1987-07-10 1990-05-15 Hoechst Aktiengesellschaft 3-demethylmevalonic acid derivatives, and pharmaceutical products based on these compounds
US5026708A (en) 1987-09-12 1991-06-25 Nissan Chemical Industries Ltd. Pyrimidine type mevalonolactones
US4868185A (en) 1987-12-10 1989-09-19 Warner-Lambert Company 6-[[Substituted)pyrimidinyl)ethyl]- and ethenyl]tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
EP0330057A2 (en) 1988-02-25 1989-08-30 Bayer Ag Substituted pyrimidines
EP0367895A1 (en) 1988-10-06 1990-05-16 Sandoz Ag Pyrimidinyl-substituted hydroxyacids, lactones and esters and pharmaceutical compositions containing them

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
B. Roth et al., J. Med. Chem., 34, 463-466 (1991).
G. Beck et al., J. Med. Chem., 33, 52-60 (1990).
Moore et al, J. Am. Chem. Soc., vol. 107, pp. 3694-3701, 1985.*

Cited By (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030181500A1 (en) * 2000-08-30 2003-09-25 Sankyo Company, Limited Medicinal compositions for the prevention or treatment of cardiac failure
US20050197501A1 (en) * 2000-11-16 2005-09-08 Teva Pharmaceutical Industries Ltd. Processes for preparing calcium salt forms of statins
US6777552B2 (en) 2001-08-16 2004-08-17 Teva Pharmaceutical Industries, Ltd. Processes for preparing calcium salt forms of statins
US20040176615A1 (en) * 2001-08-16 2004-09-09 Valerie Niddam-Hildesheim Processes for preparing calcium salt forms of statins
US20080293750A1 (en) * 2002-10-17 2008-11-27 Anna Helgadottir Susceptibility Gene for Myocardial Infarction, Stroke, Paod and Methods of Treatment
US20060019269A1 (en) * 2002-10-17 2006-01-26 Decode Genetics, Inc. Susceptibility gene for myocardial infarction, stroke, and PAOD, methods of treatment
US20040132771A1 (en) * 2002-12-20 2004-07-08 Pfizer Inc Compositions of choleseteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors
EP1961419A1 (en) 2002-12-20 2008-08-27 Pfizer Products Inc. Dosage forms comprising a CETP inhibitor and an HMG-CoA reductase inhibitor
US7396927B2 (en) 2003-08-28 2008-07-08 Teva Pharmaceutical Industries Ltd. Process for preparation of rosuvastatin calcium
US20050085497A1 (en) * 2003-09-25 2005-04-21 Saleem Ahmad HMG-CoA reductase inhibitors and method
US7371759B2 (en) 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
EP2428516A1 (en) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics
US20090036680A1 (en) * 2003-11-24 2009-02-05 Ranbaxy Laboratories Limited Salts of hmg-coa reductase inhibitors and use thereof
US7777034B2 (en) 2003-11-24 2010-08-17 Teva Pharmaceutical Industries Ltd. Crystalline ammonium salts of rosuvastatin
US20050131066A1 (en) * 2003-11-24 2005-06-16 Valerie Niddam-Hildesheim Crystalline ammonium salts of rosuvastatin
US7692009B2 (en) 2003-12-02 2010-04-06 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US20050187234A1 (en) * 2003-12-02 2005-08-25 Nina Finkelstein Reference standard for characterization of rosuvastatin
US7692010B2 (en) 2003-12-02 2010-04-06 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US7692008B2 (en) 2003-12-02 2010-04-06 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US7244844B2 (en) 2003-12-02 2007-07-17 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US7741482B2 (en) 2003-12-02 2010-06-22 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US8487097B2 (en) 2003-12-02 2013-07-16 Teva Pharmacedutical Industries Ltd. Reference standard for characterization of rosuvastatin
US20070255059A1 (en) * 2003-12-02 2007-11-01 Teva Pharmaceuticals Usa, Inc. Reference standard for characterization of rosuvastatin
US20070244321A1 (en) * 2003-12-02 2007-10-18 Teva Pharmaceuticals Usa, Inc. Reference standard for characterization of rosuvastatin
US20070249831A1 (en) * 2003-12-02 2007-10-25 Teva Pharmaceutical Industries Ltd. Reference for characterization of rosuvastatin
US20070249830A1 (en) * 2003-12-02 2007-10-25 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US7851624B2 (en) 2003-12-24 2010-12-14 Teva Pharamaceutical Industries Ltd. Triol form of rosuvastatin and synthesis of rosuvastatin
US20070179166A1 (en) * 2003-12-24 2007-08-02 Valerie Niddam-Hildesheim Process for preparation of statins with high syn to anti ratio
US20080269270A1 (en) * 2003-12-24 2008-10-30 Valerie Niddam-Hildesheim Triol form of rosuvastatin and synthesis of rosuvastatin
US20100216863A1 (en) * 2004-01-30 2010-08-26 Decode Genetics Ehf. Susceptibility Gene for Myocardial Infarction, Stroke, and PAOD; Methods of Treatment
US20080206328A1 (en) * 2004-02-03 2008-08-28 Ferrer International, S.A. Hypocholesterolemic Compositions Comprising a Statin and an Antiflatulent Agent
US7655796B2 (en) 2004-07-13 2010-02-02 Teva Pharmaceutical Industries Ltd. Process for the preparation of rosuvstatin
US20070142418A1 (en) * 2004-07-13 2007-06-21 Teva Pharmaceuticals Usa, Inc. Process for the preparation of rosuvastatin
US20080234302A1 (en) * 2004-09-27 2008-09-25 Mohammad Rafeeq Novel Processes for Preparing Amorphous Rosuvastatin Calcium and a Novel Polymorphic Form of Rosuvastatin Sodium
US7612203B2 (en) 2005-02-22 2009-11-03 Teva Pharmaceutical Industries Ltd. Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof
US20070191436A1 (en) * 2005-02-22 2007-08-16 Valerie Niddam-Hildesheim Diastereomeric purification of rosuvastatin
WO2006091770A3 (en) * 2005-02-22 2007-05-31 Teva Pharma Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof
US20070037979A1 (en) * 2005-02-22 2007-02-15 Valerie Niddam-Hildesheim Preparation of rosuvastatin
US20070167625A1 (en) * 2005-02-22 2007-07-19 Anna Balanov Preparation of rosuvastatin
WO2006091771A3 (en) * 2005-02-22 2007-01-11 Teva Pharma Ltd Preparation of rosuvastatin
US8063211B2 (en) 2005-02-22 2011-11-22 Teva Pharmaceutical Industries, Ltd. Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof
US7582759B2 (en) 2005-02-22 2009-09-01 Teva Pharmaceutical Industries Ltd. Diastereomeric purification of rosuvastatin
US8158362B2 (en) 2005-03-30 2012-04-17 Decode Genetics Ehf. Methods of diagnosing susceptibility to myocardial infarction and screening for an LTA4H haplotype
US20090240054A1 (en) * 2005-08-16 2009-09-24 Teva Pharmaceuticals Usa, Inc. Rosuvastatin calcium with a low salt content
US20090215806A1 (en) * 2005-08-16 2009-08-27 Valerie Niddam-Hildesheim Rosuvastatin calcium with a low salt content
US7868169B2 (en) 2005-08-16 2011-01-11 Teva Pharmaceutical Industries, Ltd. Crystalline rosuvastatin intermediate
US20070099994A1 (en) * 2005-08-16 2007-05-03 Valerie Niddam-Hildesheim Rosuvastatin calcium with a low salt content
US20070123550A1 (en) * 2005-08-16 2007-05-31 Valerie Niddam-Hildesheim Crystalline rosuvastatin intermediate
US20070048351A1 (en) * 2005-09-01 2007-03-01 Prescient Medical, Inc. Drugs coated on a device to treat vulnerable plaque
US20090187026A1 (en) * 2005-10-03 2009-07-23 Teva Pharmaceuticals Usa, Inc. Diastereomeric purification of rosuvastatin
US20100197916A1 (en) * 2005-10-03 2010-08-05 Teva Pharmaceutical Industries Ltd. Diastereomeric purification of rosuvastatin
WO2007040940A1 (en) * 2005-10-03 2007-04-12 Teva Pharmaceutical Industries Ltd. Diastereomeric purification of rosuvastatin
EP2392567A1 (en) 2005-10-21 2011-12-07 Bristol-Myers Squibb Company Benzothiazine derivatives and their use as lxr modulators
WO2007050425A2 (en) 2005-10-21 2007-05-03 Bristol-Myers Squibb Company Lxr modulators
WO2007062314A2 (en) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Heterocyclic cetp inhibitors
US20070254897A1 (en) * 2006-04-28 2007-11-01 Resolvyx Pharmaceuticals, Inc. Compositions and methods for the treatment of cardiovascular disease
US20100048899A1 (en) * 2006-10-31 2010-02-25 Ramesh Dandala Process for preparing rosuvastatin calcium
US8318933B2 (en) 2006-10-31 2012-11-27 Aurobindo Pharma Ltd Process for preparing rosuvastatin calcium
US20100069635A1 (en) * 2006-11-29 2010-03-18 Dr. Reddy's Laboratories Ltd. Rosuvastatin dehydroabietylamine salt
US20100029940A1 (en) * 2006-12-13 2010-02-04 Ramesh Dandala Process for preparing rosuvastatin calcium
US8212034B2 (en) 2006-12-13 2012-07-03 Aurobindo Pharma Ltd. Process for preparing rosuvastatin calcium
US20090312547A1 (en) * 2007-02-08 2009-12-17 Ramesh Dandala Process for preparation of rosuvastatin calcium field of the invention
US8212035B2 (en) 2007-02-08 2012-07-03 Aurobindo Pharma Ltd. Process for preparation of rosuvastatin calcium field of the invention
US20080249141A1 (en) * 2007-04-06 2008-10-09 Palepu Nageswara R Co-therapy with and combinations of statins and 1,4-dihydropyridine-3,5-dicarboxydiesters
US20080248115A1 (en) * 2007-04-09 2008-10-09 Palepu Nageswara R Combinations of statins and anti-obesity agent
US20100234443A1 (en) * 2007-04-09 2010-09-16 Scidose Llc Combinations of statins and anti-obesity agent
US20080249156A1 (en) * 2007-04-09 2008-10-09 Palepu Nageswara R Combinations of statins and anti-obesity agent and glitazones
US20090076271A1 (en) * 2007-04-18 2009-03-19 Vinod Kumar Kansal Process for preparing intermediates of HMG-CoA reductase inhibitors
US7687660B2 (en) 2007-04-18 2010-03-30 Teva Pharmaceutical Industries Ltd. Process for preparing intermediates of HMG-CoA reductase inhibitors
US7964748B2 (en) 2007-04-18 2011-06-21 Teva Pharmaceutical Industries, Ltd. Process for preparing intermediates of HMG-CoA reductase inhibitors
US20090076292A1 (en) * 2007-04-18 2009-03-19 Teva Pharmaceutical Industries Ltd. Rosuvastatin intermediates and process for the preparation of rosuvastatin
US20090209779A1 (en) * 2007-04-18 2009-08-20 Teva Pharmaceutical Industries Ltd. Process for preparing intermediates of HMG-CoA reductase inhibitors
US20100160663A1 (en) * 2007-04-18 2010-06-24 Teva Pharmaceutical Industries Ltd. PROCESS FOR PREPARING INTERMEDIATES OF HMG-CoA REDUCTASE INHIBITORS
US20090069563A1 (en) * 2007-07-12 2009-03-12 Valerie Niddam-Hildesheim Rosuvastatin intermediates and their preparation
US7884226B2 (en) 2007-07-12 2011-02-08 Teva Pharmaceutical Industries, Ltd. Purification of rosuvatatin intermediate by thin film evaporation and chemical method
US20090099383A1 (en) * 2007-07-12 2009-04-16 Tamar Nidam Purification of rosuvatatin intermediate by thin film evaporation and chemical method
US20110178296A1 (en) * 2008-09-30 2011-07-21 Sambhu Prasad Sarma Mallela Process for preparing pyrimidine propenaldehyde
WO2010093601A1 (en) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Novel sulfonic acid-containing thyromimetics, and methods for their use
US9315447B2 (en) 2009-04-13 2016-04-19 A.T. Resolve Sarl Compositions and methods for the treatment of inflammation
US8673881B2 (en) 2009-04-13 2014-03-18 A.T. Resolve Sarl Compositions and methods for the treatment of inflammation
US8524914B2 (en) 2009-06-05 2013-09-03 Chong Kun Dang Pharmaceutical Corp. Method for preparing rosuvastatin, intermediate compounds useful for preparing same, and method for preparing same
WO2011019326A2 (en) 2009-07-02 2011-02-17 Mahmut Bilgic Solubility and stability enchancing pharmaceutical formulation
WO2011018185A2 (en) 2009-08-13 2011-02-17 Synthon B.V. Pharmaceutical tablet comprising rosuvastatin calcium
US8846915B2 (en) 2009-08-17 2014-09-30 Aurobindo Pharma Ltd. Process for the manufacture of rosuvastatin calcium using crystalline rosuvastatin ethyl ester
WO2011141934A1 (en) 2010-05-13 2011-11-17 Matrix Laboratories Ltd. An improved process for the preparation of an intermediate of hmg-coa reductase inhibitors
US8476432B2 (en) 2010-07-01 2013-07-02 Yuhan Corporation Process for the preparation of HMG-COA reductase inhibitors and intermediates thereof
WO2012027331A1 (en) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
WO2012063115A2 (en) 2010-11-11 2012-05-18 Jubilant Life Sciences Ltd. Process for the preparation of rosuvastatin calcium via novel amine intermediate
WO2012073256A1 (en) 2010-11-29 2012-06-07 Cadila Healthcare Limited Salts of rosuvastatin
WO2013080219A2 (en) 2011-11-28 2013-06-06 Mylan Laboratories Ltd NOVEL PROCESS FOR THE PREPARATION OF INTERMEDIATES OF HMG-CoA REDUCTASE INHIBITORS
US8729092B2 (en) * 2012-09-24 2014-05-20 Terence J. Scallen Rosuvastatin enantiomer compounds
US9296702B2 (en) 2012-09-24 2016-03-29 Terence J. Scallen Rosuvastatin enantiomer compounds
WO2014108795A2 (en) 2013-01-10 2014-07-17 Aurobindo Pharma Limited An improved process for the preparation of chiral diol sulfones and statins
WO2014142521A1 (en) 2013-03-12 2014-09-18 주식회사 엘지생명과학 Complex preparation including valsartan and rosuvastatin calcium and manufacturing method therefor
WO2014170786A1 (en) 2013-04-17 2014-10-23 Pfizer Inc. N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases
WO2015001573A1 (en) 2013-07-05 2015-01-08 Cadila Healthcare Limited Synergistic compositions
US9518028B2 (en) 2013-07-16 2016-12-13 Suven Life Sciences Limited Process for the preparation of Rosuvastatin calcium and preparation of its novel intermediates
WO2015008294A1 (en) 2013-07-16 2015-01-22 Suven Life Sciences Limited Process for the preparation of rosuvastatin calcium and preparation of its novel intermediates
WO2016055901A1 (en) 2014-10-08 2016-04-14 Pfizer Inc. Substituted amide compounds
US11576859B2 (en) 2015-10-23 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained release of therapeutic agents and methods of use thereof
US11992552B2 (en) 2015-12-08 2024-05-28 Lyndra Therapeutics, Inc. Geometric configurations for gastric residence systems
US11576866B2 (en) 2016-09-30 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained delivery of adamantane-class drugs
CN107698518A (en) * 2017-06-20 2018-02-16 迪沙药业集团（天津）药物研究有限公司 A kind of preparation method of rosuvastain calcium epimer impurity
WO2019094311A1 (en) 2017-11-08 2019-05-16 Merck Sharp & Dohme Corp. Prmt5 inhibitors
WO2020033284A1 (en) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Prmt5 inhibitors
US11981701B2 (en) 2018-08-07 2024-05-14 Merck Sharp & Dohme Llc PRMT5 inhibitors
US11993602B2 (en) 2018-08-07 2024-05-28 Merck Sharp & Dohme Llc PRMT5 inhibitors
WO2020033282A1 (en) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Prmt5 inhibitors
WO2020150473A2 (en) 2019-01-18 2020-07-23 Dogma Therapeutics, Inc. Pcsk9 inhibitors and methods of use thereof
EP4115879A1 (en) 2019-07-31 2023-01-11 Intas Pharmaceuticals Ltd. Pharmaceutical composition comprising hmg-coa reductase inhibitors and fenofibrate
WO2021019493A1 (en) 2019-07-31 2021-02-04 Intas Pharmaceuticals Ltd. Pharmaceutical composition comprising hmg-coa reductase inhibitors and fenofibrate
WO2021126731A1 (en) 2019-12-17 2021-06-24 Merck Sharp & Dohme Corp. Prmt5 inhibitors

Also Published As

Publication number Publication date
EP0521471A1 (en) 1993-01-07
CY2004008I2 (en) 2016-10-05
CA2072945C (en) 2001-07-31
CL2010000113A1 (en) 2010-07-02
JP2648897B2 (en) 1997-09-03
HU9202179D0 (en) 1992-10-28
DE122009000017I2 (en) 2010-10-21
DE69231530T2 (en) 2001-06-13
EP0521471B1 (en) 2000-10-25
TW203044B (en) 1993-04-01
JPH05178841A (en) 1993-07-20
KR930002325A (en) 1993-02-23
DK0521471T3 (en) 2001-02-05
HUT61531A (en) 1993-01-28
CY2226B1 (en) 2003-04-18
PT521471E (en) 2001-04-30
ATE197149T1 (en) 2000-11-15
CA2072945A1 (en) 1993-01-02
CY2004008I1 (en) 2010-07-28
DE122009000017I1 (en) 2009-11-05
KR960005951B1 (en) 1996-05-06
NL300125I2 (en) 2003-08-01
HU220624B1 (en) 2002-03-28
US5260440A (en) 1993-11-09
NL300125I1 (en) 2003-07-01
DE69231530D1 (en) 2000-11-30
HU0004863D0 (en) 2001-02-28
GEP20022693B (en) 2002-05-10
LU91042I2 (en) 2003-11-24
GR3035189T3 (en) 2001-04-30
HU219407B (en) 2001-04-28
HK1011986A1 (en) 1999-07-23
ES2153824T3 (en) 2001-03-16

Similar Documents

Publication Publication Date Title
USRE37314E1 (en) Pyrimidine derivatives
US4929620A (en) 5-pyrimidinyl-3,5-dihydroxy-6-heptenoic acid compounds useful as inhibitors of cholesterol biosynthesis
US4950675A (en) Pyridine di-mevalono-lactones as inhibitors of cholesterol biosynthesis
EP0235164B1 (en) Imidazole analogs of mevalonolactone and derivatives thereof
US4925852A (en) 3-demethylmevalonic acid derivatives, and pharmaceutical products based on these compounds
US4957940A (en) Bicyclo heptane and bicyclo octane substituted inhibitors of cholesterol synthesis
JPH0347167A (en) Heterocyclic homologue of mevaronolactone
US4906657A (en) Bicyclo heptane and bicyclo octane substituted inhibitors of cholesterol synthesis
HU210056B (en) Process for producing substituted 2-pyridone derivatives and pharmaceutical compositions comprising them
US20030225075A1 (en) Novel pyrimidone derivatives
US5011947A (en) Antihypercholesterolemic alkylene compounds
JP3181054B2 (en) 2- and 5-alkyl and phenyl-substituted 4- (1-hydroxy, 1-acyloxy or 1-carbamoyloxy) -5hydroxy-2 (5H) -furanone as anti-inflammatory agents
KR0167781B1 (en) Pyrrol derivatives
US6136815A (en) Antiviral 2,4-pyrimidinedione derivatives and process for the preparation thereof
US4868185A (en) 6-[[Substituted)pyrimidinyl)ethyl]- and ethenyl]tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US4751235A (en) Anti-atherosclerotic indolizine derivatives
WO1990010624A1 (en) Pyrimidine type mevalonolactones
US20040009975A1 (en) Novel pyrimidinedione derivatives
JPH06256318A (en) Method for synthesizing 5-carboalkoxypyrimidine derivative
KR910000415B1 (en) Acyl derivatives of hydroxypyrimidine
US3835132A (en) Morpholino-piperazinyl pyrimidines
EP0303348A1 (en) 2-Amino-5-hydroxy-4-pyrimidones
HU201911B (en) Process for producing new biphenyl derivatives and pharmaceutical compositions containing them
JPH03112967A (en) Isoquinolone derivative
JPH0224269B2 (en)

Legal Events

Date Code Title Description
PTEF Application for a patent term extension

Free format text: PRODUCT NAME: CRESTOR (ROSUVASTATIN CALCIUM); REQUESTED FOR 1304 DAYS

Filing date: 20031010

Expiry date: 20120612

FPAY Fee payment

Year of fee payment: 12

PTEG Grant of a patent term extension

Free format text: PRODUCT NAME: CRESTOR (ROSUVASTATIN CALCIUM)

Filing date: 20031010

Expiry date: 20120612