Derivatives of physiologically active substance ML-236B and proc

Details Derivatives of physiologically active substance ML-236B and proc Derivatives of physiologically active substance ML-236B and proc

1989-10-03

1993-09-14

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

560194, C07D30930, C07C 6934

Patent

active

052450503

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel compounds with a three-membered cyclic structure having a cholesterol synthesis inhibitory activity, and processes for the production thereof. According to the present invention, stable, novel compounds can be easily produced.


BACKGROUND ART

In 1971, the present inventors established an efficient method of developing a cholesterol synthesis inhibiting agent aimed at a compound produced by a microorganism, and screening was carried out, and in 1973 found that a compound designated as ML-236B having the desired activity is produced by a microorganism of the genus Penicillium (Japanese Examined Patent Publication, Kokoku, No. 56-12114); in 1981 by a microorganism of the genus Paecilomyces (Japanese Examined Patent Publication, Kokoku, No. 59-45360; in 1982 by a microorganism of the genus Hypomycess (Japanese Examined Patent Publication, Kokoku, No. 62-19158); by a microorganism of the genus Trichoderma (Japanese Examined Patent Publication, Kokoku, No. 62-19519; and by a microorganism of the genus Eupenicillium. Attention has been paid to compounds belonging to this class as therapeutic agents for arteriosclerosis and coronary heart disease, because these compounds specifically inhibit HMG-CoA reductase and repress the synthesis of cholesterol.
Although, as stated above, the compounds belonging to this class exhibit a specific and notable therapeutic efficacy, they are relatively unstable, and therefore, difficult modification steps are necessary for the production thereof.


DISCLOSURE OF THE INVENTION

On the basis of the above, the present invention relates to useful novel compounds and simple processes for the production thereof. More specifically, the conventional ML-236B compound of microbial origin is heated in the presence of a cyclopropanating agent to saturate a double bond and to form a three-membered cyclic structure, resulting in a remarkably stable compound.
Among the present compounds are those represented by the following general formula: ##STR2## wherein R.sub.1 and R.sub.2 are the same or different and represent a hydrogen or halogen atom, as well as free acids, amides and salts thereof.
The present compound can be produced by heating the ML-236B compound represented by the following formula: ##STR3## in the presence of a cyclopropanating agent to obtain a halogenated compound containing a three-membered cyclic moiety, and if desired, reducing the halogenated compound partially or totally for dehalogenation. Ring-opened free acids, amides and salts can be easily produced by treating the halogenated compound or dehalogenated compound by an usual base such as ammonia or sodium hydroxide, similar to other compounds belonging to the same class.


BEST MODE OF CARRYING OUT THE INVENTION

According to the present invention, effective cyclopropanating agents include methane derivatives capable of forming carbene, as well as alkaline metal salts of chlorodifluoroacetic acid, dichlorofluoromethane, iodoform, chloroform and bromoform; and effective dehalogenating agents particularly include tributyl tin hydride. As a solvent for the cyclopropanation, diethyleneglycol dimethyl ether (Diglyme), chloroform, and dichloromethane are preferable.
Salts of the present compounds are, for example, salts of alkali metals, such as potassium and sodium; salts of alkali earth metals such as magnesium and calcium; and ammonium salts.


HMG-CoA Reductase Inhibitory Activity

The HMG-CoA reductase activity can be determined by using [.sup.14 C] HMG-CoA as a substrate and measuring the resulting [.sup.14 C] mevalonic acid (Kuroda and Endo, Biochem Biophys Acta, 486, 70-81), as described in detail in the following.
A reaction mixture contains 100 mM of potassium phosphate buffer (pH 7.4), 10 mM of EDTA, 10 mM of dithiothreitol, 10 mM of NADPH, 0.11 mM of DL-[3-.sup.14 C] HMG-CoA (4.5 mCi/mmol), and 0.6 mg/ml of rat liver microsome fraction. The final volume of reaction mixture is 50 .mu.l including 1 .mu.l of a methanol solution of a test sample. A reaction is s

REFERENCES:
patent: 4137322 (1979-01-01), Endo et al.
patent: 4937259 (1990-06-01), Lee
C. H. Kuo et al., J. Org. Chem. 1983, 48, 1991-1998.
Endo, Journal of Antibiotics, 33(3):334-336 (Mar. 1980).

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