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Pyrimidine derivatives

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USRE37314E1
USRE37314E1 US09141731 US14173198A USRE37314E US RE37314 E1 USRE37314 E1 US RE37314E1 US 09141731 US09141731 US 09141731 US 14173198 A US14173198 A US 14173198A US RE37314 E USRE37314 E US RE37314E
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Kentaro Hirai
Teruyuki Ishiba
Haruo Koike
Masamichi Watanabe
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Shionogi and Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic 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
    • C07D239/28Heterocyclic 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
    • C07D239/32One oxygen, sulfur or nitrogen atom
    • C07D239/42One nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic 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
    • C07D239/28Heterocyclic 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
    • C07D239/32One oxygen, sulfur or nitrogen atom
    • C07D239/34One oxygen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic 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
    • C07D239/28Heterocyclic 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
    • C07D239/32One oxygen, sulfur or nitrogen atom
    • C07D239/38One sulfur atom

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):

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.

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.

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.

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.

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)

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)

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)

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.

(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.

(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.

(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.

(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.

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.

[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).

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.

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):
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.
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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
KR100699757B1 (en) * 1999-02-06 2007-03-27 더 유니버시티 코트 오브 더 유니버시티 오브 애버딘 Use of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors for the manufacture of a medicament for the treatment of diabetic neuropathy
GB0001662D0 (en) * 1999-02-06 2000-03-15 Zeneca Ltd Pharmaceutical compositions
GB0000710D0 (en) 1999-02-06 2000-03-08 Zeneca Ltd Drug combination
CN1347320A (en) * 1999-02-06 2002-05-01 阿斯特拉曾尼卡有限公司 Use of cholesterol-lowering agent
GB9903472D0 (en) 1999-02-17 1999-04-07 Zeneca Ltd Chemical process
EP1035127B1 (en) * 1999-03-10 2003-10-08 Lonza AG Process for the preparation of N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorphenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethansulfonamide
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
ES2251392T3 (en) * 1999-07-13 2006-05-01 Lonza Ag Process for preparing 2-amino-4- (4-fluorophenyl) -6-alquilpirimidina-5-carboxylates.
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
US6403830B2 (en) 2000-03-24 2002-06-11 Pharmacia Corporation Amidino compound and salts thereof useful as nitric oxide synthase inhibitors
RU2002123591A (en) * 2000-04-03 2004-03-20 Астразенека Аб (Se) The new combination of a beta-blocker and an agent that lowers the cholesterol level
EP1272455A4 (en) 2000-04-13 2005-07-27 Pharmacia Corp Halogenated 2-amino-4, 5 heptenoic acid derivatives useful as nitric oxide synthase inhibitors
JP2003530412A (en) 2000-04-13 2003-10-14 ファルマシア・コーポレーション Useful halogenated 2-amino-3,4-heptenoic acid derivative as nitric oxide synthase inhibitors
US6545170B2 (en) 2000-04-13 2003-04-08 Pharmacia Corporation 2-amino-5, 6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors
US6787668B2 (en) 2000-04-13 2004-09-07 Pharmacia Corporation 2-amino-4,5 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
JP2003530435A (en) 2000-04-13 2003-10-14 ファルマシア・コーポレーション Useful halogenated 2-amino-5,6-heptenoic acid derivative as nitric oxide synthase inhibitors
GB0011163D0 (en) * 2000-05-10 2000-06-28 Astrazeneca Ab Chemical compound
US20030191177A1 (en) * 2000-06-22 2003-10-09 Goran Berglund Fomulation
EP1320371A2 (en) * 2000-07-31 2003-06-25 Ottawa Heart Institute Research Corporation Charged phospholipid 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
JP5009480B2 (en) 2000-09-15 2012-08-22 ファルマシア コーポレーション Useful as nitric oxide synthase inhibitors 2-amino-2-alkyl-5-heptenoic acid and heptynoic acid derivatives
EP1317416A2 (en) 2000-09-15 2003-06-11 Pharmacia Corporation 2-amino-2-alkyl-4 hexenoic and hexynoic acid derivatives useful as nitric oxide synthase inhibitors
KR100830018B1 (en) * 2000-10-12 2008-05-15 교와 가부시키가이샤 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 Amino acid complexes of c-aryl for the treatment of diabetes and procedure glucosides.
JP4359141B2 (en) 2001-07-13 2009-11-04 アストラゼネカ・ユーケイ・リミテッドAstraZeneca UK Limited Preparation of aminopyrimidine compounds
RU2353625C2 (en) * 2001-10-18 2009-04-27 Бристол-Маерс Сквибб Компани Mimetics of human glucan-like peptide-1 and their application in treating diabetes and related states
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
US20060229321A1 (en) * 2001-10-19 2006-10-12 Hans Basun Rosuvastatin in pre demented states
WO2003043624A1 (en) * 2001-11-16 2003-05-30 Bristol-Myers Squibb Company 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
EP1504525A2 (en) * 2002-05-14 2005-02-09 Siemens Aktiengesellschaft 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
US20050222415A1 (en) * 2002-05-21 2005-10-06 Yatendra Kumar Process 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
JP2006512086A (en) * 2002-09-20 2006-04-13 ダイヴァーサ コーポレイション Enzymatic chemical methods for the synthesis of statins and statin intermediates
US20050171207A1 (en) * 2003-09-26 2005-08-04 Myriad Genetics, Incorporated Method and composition for combination treatment of neurodegenerative disorders
EP1553937B1 (en) * 2002-10-23 2010-06-02 Bristol-Myers Squibb Company Glycinenitrile-based inhibitors of dipeptidyl peptidase iv
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
GB0229243D0 (en) 2002-12-16 2003-01-22 Avecia Ltd Compounds and process
CA2509344C (en) 2002-12-16 2011-10-04 Astrazeneca Uk Limited Process for the preparation of pyrimidine compounds
WO2004066929A3 (en) * 2003-01-24 2004-12-16 Wei Meng Cycloalkyl containing anilide ligands for the thyroid receptor
JP2006516623A (en) * 2003-01-24 2006-07-06 カロ・バイオ・アクチボラゲットKaro Bio Ab Thyroid receptor for replacement anilide ligands
US7276536B2 (en) * 2003-03-17 2007-10-02 Japan Tobacco Inc. Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino) phenyl] 2-methylpropanethioate
DK1603553T3 (en) * 2003-03-17 2012-01-30 Japan Tobacco Inc Pharmaceutical compositions of CETP inhibitors
US20050261237A1 (en) * 2003-04-25 2005-11-24 Boojamra Constantine G Nucleoside phosphonate analogs
US7429565B2 (en) 2003-04-25 2008-09-30 Gilead Sciences, Inc. Antiviral phosphonate analogs
US7407965B2 (en) * 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
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
CA2522845A1 (en) * 2003-04-25 2004-11-11 Gilead Sciences, Inc. Kinase inhibitor phosphonate conjugates
US20090247488A1 (en) * 2003-04-25 2009-10-01 Carina Cannizzaro Anti-inflammatory phosphonate compounds
ES2421520T3 (en) * 2003-04-28 2013-09-03 Daiichi Sankyo Co Ltd Potentiator adiponectin production
WO2004096276A9 (en) * 2003-04-28 2005-03-31 Sankyo Co Sugar intake-ability enhancer
JP2006525360A (en) * 2003-05-02 2006-11-09 日本たばこ産業株式会社 S- [2 - ([[1- (2- ethylbutyl) cyclohexyl] carbonyl] amino) phenyl] 2-methylpropanethioate and combination comprising the HMG-CoA reductase inhibitor
EP1624871B1 (en) 2003-05-15 2009-07-15 Merck & Co., Inc. (a New Jersey corp.) Method of treating atherosclerosis, dyslipidemias and related conditions and pharmaceutical compositions
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
JP4037898B2 (en) * 2003-06-18 2008-01-23 テバ ファーマシューティカル インダストリーズ リミティド Fluvastatin sodium crystal Form xiv, LXXIII, LXXIX, LXXX and xxxvii type, processes for their preparation, compositions and methods for their use containing them
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
CN1838942A (en) * 2003-07-11 2006-09-27 普罗医药公司 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
EP1663989B1 (en) 2003-09-10 2009-04-15 AstraZeneca UK Limited CRYSTALLINE FORM OF BIS (E)-7- 4-(4-FLUOROPHENYL)-6-IS OPROPYL-2- METHYL(METHYLSULFONYL)AMINO PYRIMIDIN-5-YL&r sqb;(3R,5S)-3,5-DIHYDROXYHEPT-6 -ENOICACID CALCIUM SALT
GB0321127D0 (en) 2003-09-10 2003-10-08 Astrazeneca Uk Ltd Chemical compounds
GB0321827D0 (en) * 2003-09-18 2003-10-15 Astrazeneca Uk Ltd Chemical compounds
GB0322552D0 (en) 2003-09-26 2003-10-29 Astrazeneca Uk Ltd Therapeutic treatment
CN1886383A (en) * 2003-10-22 2006-12-27 兰贝克赛实验室有限公司 Process for the preparation of amorphous rosuvastatin calcium
US7432273B2 (en) * 2003-10-24 2008-10-07 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
GB0324791D0 (en) 2003-10-24 2003-11-26 Astrazeneca Ab Chemical process
CA2543596A1 (en) * 2003-11-07 2005-05-26 Jj Pharma, Inc. Hdl-boosting combination therapy complexes
US7674913B2 (en) * 2003-11-12 2010-03-09 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
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
WO2005054207A1 (en) * 2003-12-04 2005-06-16 Glenmark Pharmaceuticals Limited Process for the preparation of pyrimidine derivatives
EP1699760B1 (en) 2003-12-23 2017-05-17 Merck Sharp & Dohme Corp. Anti-hypercholesterolemic compounds
KR20060135712A (en) * 2003-12-24 2006-12-29 테바 파마슈티컬 인더스트리즈 리미티드 Process for preparation of statins with high syn to anti ratio
EP1702626B1 (en) 2003-12-30 2011-11-30 Kowa Company, Ltd. Screening method for gamma-secretase inhibitors
US20070161700A1 (en) * 2004-12-28 2007-07-12 Kowa Company, Ltd. Inhibitor for the formation of y-secretase complex
DE602004004679D1 (en) * 2004-01-16 2007-03-22 Zentiva As A process for the preparation of the hemicalcium salt of (E) -7-ä4- (4-fluorophenyl) -6-isopropyl-2-ämethyl (methylsulfonyl) aminoüpyrimidin-5-ylü (3R, 5S) -3,5-dihydroxy-6-heptenoic acid
WO2005077917A1 (en) * 2004-01-19 2005-08-25 Ranbaxy Laboratories Limited Amorphous salts of rosuvastatin
US20070078109A1 (en) * 2004-02-13 2007-04-05 David Platt Compositions and methods used to treat acne and candida
JP4711952B2 (en) * 2004-02-25 2011-06-29 日産化学工業株式会社 Nuclear transfer promoter and screening methods of the Rac proteins
EP1719525B1 (en) * 2004-02-25 2014-12-10 Kowa Company, Ltd. Nuclear transfer promoter for cdc42 protein and method of screening the same
US20070293535A1 (en) * 2005-02-24 2007-12-20 Kowa Company, Ltd. Nuclear Transfer Promoter for Ddc42 Protein and Method of Screening the Dame
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
CA2569124C (en) 2004-06-07 2013-04-23 Merck & Co., Inc. 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
US7534763B2 (en) 2004-07-02 2009-05-19 Bristol-Myers Squibb Company Sustained release GLP-1 receptor modulators
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
US7417028B2 (en) * 2004-07-02 2008-08-26 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 modulators and their use in treatment of diabetes and related conditions
US7786163B2 (en) * 2004-07-12 2010-08-31 Forest Laboratories Holdings Limited (BM) Constrained cyano compounds
US7572805B2 (en) 2004-07-14 2009-08-11 Bristol-Myers Squibb Company Pyrrolo(oxo)isoquinolines as 5HT ligands
WO2006110157A9 (en) 2004-07-27 2007-03-08 Gilead Sciences Inc Nucleoside phosphonate conjugates as anti hiv agents
US20080286251A1 (en) * 2004-08-02 2008-11-20 Propharmaceuticals, 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
WO2006026273A3 (en) * 2004-08-25 2006-09-08 Merck & Co Inc Method of treating atherosclerosis, dyslipidemias and related conditions
EP1791852B8 (en) * 2004-09-23 2009-04-01 Brystol-Myers Squibb Company C-aryl glucoside sglt2 inhibitors and method for their production
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
KR101021828B1 (en) 2004-10-27 2011-03-17 다이이찌 산쿄 가부시키가이샤 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
DE602005023347D1 (en) 2004-12-23 2010-10-14 Hui Yao Pyrimidinone, their production and their use
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
WO2006076598A3 (en) * 2005-01-12 2006-08-24 William R Ewing Bicyclic heterocycles as cannabinoid receptor modulators
US7368458B2 (en) * 2005-01-12 2008-05-06 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
US7361766B2 (en) 2005-01-12 2008-04-22 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
US20060160850A1 (en) * 2005-01-18 2006-07-20 Chongqing Sun 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
WO2006079611A1 (en) * 2005-01-31 2006-08-03 Ciba Specialty Chemicals Holding Inc. Crystalline forms of rosuvastatin calcium salt
WO2006083012A1 (en) * 2005-02-02 2006-08-10 Ajinomoto Co., Inc. Method for producing pyrimidine compound
ES2319461T3 (en) * 2005-02-10 2009-05-07 Bristol-Myers Squibb Company Dihidroquinazolinonas as modulators of 5HT.
JP2008521836A (en) * 2005-10-04 2008-06-26 テバ ファーマシューティカル インダストリーズ リミティド Preparation of rosuvastatin
EP1863773A1 (en) * 2005-03-22 2007-12-12 Unichem Laboratories Limited Process for preparation of rosuvastatin
EP1869005A1 (en) * 2005-04-04 2007-12-26 Unichem Laboratories Limited Process for preparation of calcium salt of rosuvastatin
WO2006113261A3 (en) 2005-04-14 2006-11-30 Christopher B Cooper Inhibitors of 11-beta hydroxysteroid dehydrogenase type i
US7521557B2 (en) 2005-05-20 2009-04-21 Bristol-Myers Squibb Company Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods
US20060275356A1 (en) * 2005-05-25 2006-12-07 Burgess James W Pharmaceutical compositions for treating or preventing coronary artery disease
US7825139B2 (en) * 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV
KR20080026117A (en) * 2005-05-26 2008-03-24 브리스톨-마이어스 스큅 컴퍼니 N-terminally modified glp-1 receptor modulators
WO2006128954A1 (en) * 2005-06-01 2006-12-07 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
US7572808B2 (en) * 2005-06-17 2009-08-11 Bristol-Myers Squibb Company Triazolopyridine cannabinoid receptor 1 antagonists
US7452892B2 (en) * 2005-06-17 2008-11-18 Bristol-Myers Squibb Company Triazolopyrimidine cannabinoid receptor 1 antagonists
US7317012B2 (en) * 2005-06-17 2008-01-08 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoind-1 receptor modulators
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
EP1912952B1 (en) 2005-06-24 2014-10-15 LEK Pharmaceuticals d.d. Process for preparing amorphous rosuvastatin calcium free of impurities
CN101203496B (en) 2005-06-24 2011-04-20 力奇制药公司 Process for preparing pure amorphous rosuvastatin calcium
WO2007000121A1 (en) * 2005-06-29 2007-01-04 Zentiva, A.S. A method for the production of the hemi-calcium salt of (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid
GB0514078D0 (en) 2005-07-08 2005-08-17 Astrazeneca Uk Ltd Chemical process
JP2009502959A (en) * 2005-07-28 2009-01-29 ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company Substitution of the serotonin receptor agonists and antagonists tetrahydro -1h- pyrido [4,3, b] indole
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
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
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
EP1943215A2 (en) 2005-10-31 2008-07-16 Brystol-Myers Squibb Company 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
JP5235676B2 (en) * 2005-12-20 2013-07-10 レツク・フアーマシユーテイカルズ・デー・デー (E)-7-[4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] - (3r, 5s)-3,5-dihydroxy-hept - a pharmaceutical composition comprising a 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
WO2007082264A3 (en) * 2006-01-11 2007-12-21 Squibb Bristol Myers Co Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
US20100274014A1 (en) * 2006-01-30 2010-10-28 Cadila Healthcare Limited Process for manufacturing rosuvastatin potassium and crystalline and amorphous forms thereof
US7553836B2 (en) * 2006-02-06 2009-06-30 Bristol-Myers Squibb Company Melanin concentrating hormone receptor-1 antagonists
ES2383767T3 (en) 2006-03-07 2012-06-26 Verenium Corporation Aldolases, nucleic acids encoding them and methods for producing and using the same
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
US9174945B2 (en) * 2006-04-13 2015-11-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Rosuvastatin zinc salt
US8455640B2 (en) * 2006-05-03 2013-06-04 Msn Laboratories Limited Process for statins and its pharmaceutically acceptable salts thereof
US20100022457A1 (en) * 2006-05-26 2010-01-28 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
US20080044326A1 (en) * 2006-07-04 2008-02-21 Esencia Co., Ltd. Sterilizer for baby products
EP2040707B1 (en) 2006-07-05 2011-11-30 Nycomed GmbH Combination of atorvastatin with a phosphodiesterase 4 inhibitor 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
ES2357263T3 (en) * 2006-09-18 2011-04-20 Richter Gedeon Nyrt. Pharmaceutical compositions containing rosuvastatin calcium.
ES2567171T3 (en) 2006-10-09 2016-04-20 Msn Laboratories Private Limited New process for the preparation of statins and pharmaceutically acceptable salts thereof
WO2008057862A3 (en) 2006-11-01 2008-10-16 Squibb Bristol Myers Co MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-ϰB ACTIVITY AND USE THEREOF
WO2008093205A3 (en) * 2007-01-31 2009-02-26 Upparapalli Sampath Kumar A method for the purification of rosuvastatin intermediate
WO2008130951A1 (en) 2007-04-17 2008-10-30 Bristol-Myers Squibb Company Fused heterocyclic 11-beta-hydroxysteroid dehydrogenase type i inhibitors
CN101687793B (en) 2007-04-20 2014-05-07 百时美施贵宝公司 Crystal forms of saxagliptin and processes for preparing same
US20100086615A1 (en) 2007-04-27 2010-04-08 Kyushu University, National University Corporation Agent for treatment of pulmonary disease
CN101754972A (en) * 2007-05-18 2010-06-23 百时美施贵宝公司 Crystal structures of SGLT2 inhibitors and processes for preparing same
WO2009023059A3 (en) 2007-06-01 2010-01-07 The Trustees Of Princeton University Treatment of viral infections by modulation of host cell metabolic pathways
JP2010530419A (en) 2007-06-20 2010-09-09 メルク・シャープ・エンド・ドーム・コーポレイション Diphenyl-substituted alkanoic
US20090011994A1 (en) * 2007-07-06 2009-01-08 Bristol-Myers Squibb Company Non-basic melanin concentrating hormone receptor-1 antagonists and methods
CN101808995A (en) * 2007-07-27 2010-08-18 百时美施贵宝公司 Novel glucokinase activators and methods of using same
EP2022784A1 (en) 2007-08-08 2009-02-11 LEK Pharmaceuticals D.D. Process for the preparation of methyl ester of rosuvastatin
WO2009026558A1 (en) 2007-08-23 2009-02-26 Amgen Inc. Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (pcsk9)
CA2696381A1 (en) * 2007-08-28 2009-03-05 Ratiopharm Gmbh Process for preparing pentanoic diacid derivatives
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
WO2009047576A1 (en) * 2007-10-12 2009-04-16 EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság Process for preparation of pharmaceutical intermediates
WO2009047577A1 (en) * 2007-10-12 2009-04-16 EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság Process for preparation of rosuvastatin zinc salt
CN101910171A (en) 2007-11-01 2010-12-08 百时美施贵宝公司 Nonsteroidal compounds useful as modulators of glucocorticoid receptor AP-1 and/or NF-kappa B activity and use thereof
KR20170060173A (en) 2008-01-11 2017-05-31 리타 파마슈티컬스 잉크. Synthetic triterpenoids and methods of use in the treatment of disease
WO2009091346A3 (en) * 2008-01-15 2009-10-01 Bilim Ilac Sanayi Ticaret A . S . Stable pharmaceutical formulation and preparation methods
CN101591302B (en) 2008-05-27 2011-08-31 常州制药厂有限公司 Preparation technique of heptenoic acid ester derivative
EP2298745B1 (en) * 2008-05-27 2014-09-03 Changzhou Pharmaceutical Factory Preparation method of rosuvastatin calcium and its intermediates
US7989433B2 (en) * 2008-05-29 2011-08-02 Bristol-Myers Squibb Company Substituted thieno[3,2-D]pyrimidines as 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
EP2309992B1 (en) 2008-06-27 2017-10-25 KRKA, tovarna zdravil, d.d., Novo mesto Pharmaceutical composition comprising a statin
US20100093667A1 (en) * 2008-07-08 2010-04-15 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
WO2010077854A8 (en) 2008-12-15 2011-07-07 Regeneron Pharmaceuticals, Inc. High affinity human antibodies to pcsk9
US20130064834A1 (en) 2008-12-15 2013-03-14 Regeneron Pharmaceuticals, Inc. Methods for treating hypercholesterolemia using antibodies to pcsk9
WO2010069593A1 (en) 2008-12-19 2010-06-24 Krka, D. D., Novo Mesto Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates
WO2010081861A1 (en) 2009-01-14 2010-07-22 Krka, Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of rosuvastatin
EP2389365A1 (en) 2009-01-15 2011-11-30 Egis Gyógyszergyár Nyilvánosan Müködö Process for the preparation of rosuvastatin salts
US8487105B2 (en) 2009-01-19 2013-07-16 Msn Laboratories Limited Process for preparing pitavastatin, intermediates and pharmaceuctically 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
EP2233133B1 (en) 2009-03-17 2012-07-25 Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi Stable Rosuvastatin Compositions
WO2010111665A1 (en) 2009-03-27 2010-09-30 Bristol-Myers Squibb Company 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
WO2010128346A3 (en) 2009-05-07 2011-01-13 Egis Gyógyszergyár Nyilvánosan Mukodo Reszvenytársaság Rosuvastatin manganse, copper, iron and zinc salts with high photochemical stability
WO2010140992A1 (en) 2009-06-03 2010-12-09 Mahmut Bilgic Stable pharmaceutical compositions containing rosuvastatin calcium
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
CA2780939A1 (en) 2009-11-13 2011-05-19 Bristol-Myers Squibb Company Bilayer tablet formulations
JP5798123B2 (en) 2009-11-13 2015-10-21 ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company Low mass of metformin formulation
JP5784623B2 (en) 2009-11-13 2015-09-24 アストラゼネカ・アクチエボラーグAstrazeneca Aktiebolag Rapid-release tablet formulation
KR20120098873A (en) * 2009-12-11 2012-09-05 노파르티스 아게 Pcsk9 antagonists
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
US8987444B2 (en) 2010-01-18 2015-03-24 Msn Laboratories Private Limited Process for the preparation of amide intermediates and their use thereof
US20110218159A1 (en) 2010-03-02 2011-09-08 Philip Manton Brown 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 preparation and intermediates
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
ES2559209T3 (en) 2010-04-14 2016-02-11 Bristol-Myers Squibb Company New glucokinase activators and methods of use thereof
US8372877B2 (en) 2010-04-16 2013-02-12 Cumberland Pharmaceuticals Stabilized statin formulations
WO2011132172A1 (en) 2010-04-23 2011-10-27 Ranbaxy Laboratories Limited NOVEL INTERMEDIATES FOR THE PREPARATION OF HMG-CoA REDUCTASE INHIBITORS
WO2011139256A3 (en) 2010-05-04 2012-05-18 Bilgic Mahmut Stable rosuvastatin formulations
EP2575757A1 (en) 2010-06-03 2013-04-10 Mahmut Bilgic Water soluble formulation comprising a combination of amlodipine and a statin
WO2012002921A1 (en) 2010-06-30 2012-01-05 Mahmut Bilgic Multiple dosage forms comprising fenofibrate or fenofibric acid in combination with hmg co a reductase inhibitors such as statins
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
WO2012046772A1 (en) 2010-10-06 2012-04-12 国立大学法人東京大学 Prophylactic and/or therapeutic agent against lymphedema
CA2813388A1 (en) * 2010-10-06 2012-04-12 Laboratorios Senosiain S.A. De C.V. New salt of a pyrimidin derivative
US8497370B2 (en) 2010-11-02 2013-07-30 Kaohsiung Medical University Processes for preparing amine salts of sildenafil-analogues and use thereof
WO2012064306A3 (en) 2010-11-11 2012-08-09 Bilgic Mahmut Effervescent formulations of rosuvastatin
WO2012066365A3 (en) 2010-11-16 2012-08-02 EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság Crystalline pharmaceutically active ingredients
JP2013543884A (en) 2010-11-29 2013-12-09 エギシュ ヂョヂセルヂャール ニルヴァーノサン ミケデ レースヴェーニタールササーグ Preparation of high-purity of pharmaceutical intermediates
EP2646419B1 (en) 2010-11-29 2017-10-18 Egis Gyógyszergyár Nyilvánosan Müködö Részvény-Társaság Method for preparing rosuvastatin salts
RU2013136384A (en) 2011-01-05 2015-02-10 Лексикон Фармасьютикалз, Инк. Composition containing glucose cotransporter inhibitors sodium 1 and 2 and methods for their use
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
EP2665723B1 (en) 2011-01-18 2015-07-22 DSM Sinochem Pharmaceuticals Netherlands B.V. Process for the preparation of statins in the presence of base
RU2598842C2 (en) 2011-01-20 2016-09-27 Мерк Шарп Энд Домэ Корп. Mineralocorticoid receptor antagonists
KR20140012075A (en) 2011-01-28 2014-01-29 사노피 Pharmaceutical compositions comprising human antibodies to pcsk9
WO2012139495A1 (en) 2011-04-13 2012-10-18 Merck Sharp & Dohme Corp. Mineralocorticoid receptor antagonists
DE202012011888U1 (en) * 2011-04-18 2013-03-21 Basf Se Crystalline multicomponent system of rosuvastatin calcium salt and vanillin
WO2012172564A1 (en) * 2011-05-25 2012-12-20 Dr. Reddy's Laboratories Limited Process for preparation of rosuvastatin calcium
WO2013046222A3 (en) * 2011-08-10 2013-06-20 Glenmark Generics Limited A process for the preparation of amorphous rosuvastatin calcium
US9505730B2 (en) 2011-10-13 2016-11-29 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
JP6224624B2 (en) 2012-02-02 2017-11-01 ザ・ユニバーシティ・オブ・シドニー Improvement in tear film stability
WO2013188855A1 (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 Methyl ester of rosuvastatin preparing a new crystal form and
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
CN104854096A (en) 2012-11-20 2015-08-19 莱西肯医药有限公司 Inhibitors of sodium glucose cotransporter 1
EP2769979A1 (en) * 2013-02-20 2014-08-27 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Process for the preparation of key intermediates for the synthesis of Statins
EP2974719A4 (en) 2013-03-14 2016-08-03 Boryung Pharm Pharmaceutical combination drug
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
WO2015027021A1 (en) 2013-08-22 2015-02-26 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
US20160327544A1 (en) 2013-12-02 2016-11-10 Kyoto University Prophylactic and therapeutic agents for fgfr3 diseases and screening method for the same
WO2015119261A1 (en) 2014-02-06 2015-08-13 株式会社エーピーアイ コーポレーション Rosuvastatin calcium and process for producing intermediate thereof
JP6240346B2 (en) * 2014-03-07 2017-11-29 ▲凱▼菜英医▲薬▼集▲団▼(天津)股▲フン▼有限公司 Process for preparing rosuvastatin calcium from intermediate compounds for preparing the rosuvastatin calcium, and it
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 intermediates and preparation method
CN104151252B (en) * 2014-05-07 2016-09-28 兰州大学 A method for the preparation of [6-isopropyl-4- (4-fluorophenyl) -2-5-yl] methyl ester
US20170252352A1 (en) 2014-05-30 2017-09-07 Pfizer Inc. Methods of use and combinations
WO2016056658A1 (en) * 2014-10-10 2016-04-14 株式会社エーピーアイ コーポレーション Method for purifying statin compound
CN104356155B (en) * 2014-10-20 2017-01-18 浙江新东港药业股份有限公司 One kind of (S) - tert-butyldimethylsilyloxy - Preparation glutaric acid monoamide
CN104529909B (en) * 2014-12-26 2016-08-24 江西富祥药业股份有限公司 The method of one kind of rosuvastatin atorvastatin calcium crystalline intermediates
CN104628653A (en) * 2015-01-28 2015-05-20 湖北益泰药业有限公司 Method for synthesizing key intermediate of rosuvastatin calcium
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 synthetic statin rosuvastatin synthesis of intermediates
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

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 (99)

* 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
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
US20090036680A1 (en) * 2003-11-24 2009-02-05 Ranbaxy Laboratories Limited Salts of hmg-coa reductase inhibitors and use thereof
US20070249830A1 (en) * 2003-12-02 2007-10-25 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
US7692010B2 (en) 2003-12-02 2010-04-06 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
US7692009B2 (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
US20050187234A1 (en) * 2003-12-02 2005-08-25 Nina Finkelstein Reference standard for characterization of rosuvastatin
US20070244321A1 (en) * 2003-12-02 2007-10-18 Teva Pharmaceuticals Usa, Inc. Reference standard for characterization of rosuvastatin
US20070255059A1 (en) * 2003-12-02 2007-11-01 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
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
US20070142418A1 (en) * 2004-07-13 2007-06-21 Teva Pharmaceuticals Usa, Inc. Process for the preparation of rosuvastatin
US7655796B2 (en) 2004-07-13 2010-02-02 Teva Pharmaceutical Industries Ltd. Process for the preparation of rosuvstatin
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
US7582759B2 (en) 2005-02-22 2009-09-01 Teva Pharmaceutical Industries Ltd. Diastereomeric purification of rosuvastatin
WO2006091771A3 (en) * 2005-02-22 2007-01-11 Anna Balanov Preparation of rosuvastatin
US20070167625A1 (en) * 2005-02-22 2007-07-19 Anna Balanov Preparation of rosuvastatin
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
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
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
US8158362B2 (en) 2005-03-30 2012-04-17 Decode Genetics Ehf. Methods of diagnosing susceptibility to myocardial infarction and screening for an LTA4H haplotype
US20070123550A1 (en) * 2005-08-16 2007-05-31 Valerie Niddam-Hildesheim Crystalline rosuvastatin intermediate
US7868169B2 (en) 2005-08-16 2011-01-11 Teva Pharmaceutical Industries, Ltd. Crystalline rosuvastatin intermediate
US20090215806A1 (en) * 2005-08-16 2009-08-27 Valerie Niddam-Hildesheim Rosuvastatin calcium with a low salt content
US20090240054A1 (en) * 2005-08-16 2009-09-24 Teva Pharmaceuticals Usa, Inc. Rosuvastatin calcium with a low salt content
US20070099994A1 (en) * 2005-08-16 2007-05-03 Valerie Niddam-Hildesheim Rosuvastatin calcium with a low salt content
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
US20100197916A1 (en) * 2005-10-03 2010-08-05 Teva Pharmaceutical Industries Ltd. Diastereomeric purification of rosuvastatin
US20090187026A1 (en) * 2005-10-03 2009-07-23 Teva Pharmaceuticals Usa, Inc. 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
US20080249156A1 (en) * 2007-04-09 2008-10-09 Palepu Nageswara R Combinations of statins and anti-obesity agent and glitazones
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
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
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
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
US7884226B2 (en) 2007-07-12 2011-02-08 Teva Pharmaceutical Industries, Ltd. Purification of rosuvatatin intermediate by thin film evaporation and chemical method
US20090069563A1 (en) * 2007-07-12 2009-03-12 Valerie Niddam-Hildesheim Rosuvastatin intermediates and their preparation
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
US8673881B2 (en) 2009-04-13 2014-03-18 A.T. Resolve Sarl Compositions and methods for the treatment of inflammation
US9315447B2 (en) 2009-04-13 2016-04-19 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
US9296702B2 (en) 2012-09-24 2016-03-29 Terence J. Scallen Rosuvastatin enantiomer compounds
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
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

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