Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reissue Patent
1998-08-27
2001-08-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S318000, C544S322000
Reissue Patent
active
RE037314
ABSTRACT:
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 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.
In the specification, the term “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. 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 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.
The term “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.
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 R
1
, R
2
, and R
3
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, R
1
, R
2
, R
3
, and R
4
each 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, R
1
, R
2
, R
3
, and R
4
each has the same meaning as defined above.
(4) 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.
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 (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.
wherein C*, the dotted line, R
1
, R
2
, R
3
, and R
4
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 rout
Hirai Kentaro
Ishiba Teruyuki
Koike Haruo
Watanabe Masamichi
Pillsbury Madison & Sutro LLP Intellectual Property Group
Raymond Richard L.
Shionogi Seiyaku Kabushiki Kaisha
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