Method for producing pravastatin precursor, ML-236B

Details Method for producing pravastatin precursor, ML-236B Method for producing pravastatin precursor, ML-236B

1998-12-29

2001-03-20

Marx, Irene (Department: 1651)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing heterocyclic carbon compound having only o, n, s,...

Reexamination Certificate

active

06204032

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the invention
The present invention is related to a new method for producing ML-236B, a precursor of pravastatin sodium, in particular to a method for producing ML-236B lactone form(I), free acid form (II), and sodium salt(III) shown in the following formulae by using a new microorganism isolated from soil. ML-236B is obtained from the culture broth of this microorganism and it is used as a substrate of pravastatin sodium which is a potent cholesterol-lowering agent used in treatment for hypercholesterolemia.
2. Description of the Prior Art
It has been known that heart disease such as myocardial infarction, arteriosclerosis have been caused mainly by hyperlipidemia, especially hypercholesterolemia. It was reported by U.S. Pat. No. 3,983,140 and UK. Patent No. 1,453,425 that a cholesterol-lowering compound called ML-236B produced by a fungus Penicillium sp. had been discovered. ML-236B is produced by soil microorganisms or chemical conversion. It was reported that
Penicillium brevicompactin,
Penicilmyces sp.,
Trichoderma longibraiatum, Trichoderma pseudokoningi, Hyphomyces chrisopomus
and
Penicillium citrium
produced ML-236B(David et al., “Biotechnology of filamentous fungi”, p241; JP Publication No. Pyung 4-349034).
Particularly, Sankyo Pharmaceutical Company, Japan, had developed
Penicillium citrium
SANK 18767 by mutation of a strain
Penicillium citrium
NRRL-8082 which was reported in 1971. By continuing strain development for 14 years, they had obtained
Penicillium citrium
Thom SANK 13380. ML-236B productivity had risen from 1.75 mg/l to 42.5 mg/l.
However, the method above described required so much time about 14 years to develop a strain with high ML-236B productivity. It also needed a little long cultivation time, 14 days, and showed relatively low ML-236B productivity.
SUMMARY OF THE INVENTION
To overcome the problems described above in the prior art, the present inventors have made many efforts to screen a new microorganism with higher ML-236B productivity and to develop a new method for preparing ML-236B with high yield and purity.
Finally, they isolated a new microorganism Gliocladium sp. YJ-9515 which showed very high ML-236B productivity and short cultivation time. Consequently, this strain can be used directly for industrial production of ML-236B.


REFERENCES:
patent: 3983140 (1976-09-01), Endo et al.
patent: 4814324 (1989-03-01), Borris
patent: 5153124 (1992-10-01), Furuya et al.
patent: 0 070 649 A2 (1982-07-01), None
patent: 547 898 A2 (1992-12-01), None
patent: 0 605 230 A1 (1994-07-01), None
patent: 1453425 (1976-10-01), None
Patent Abstracts of Japan, vol. 17, No. 225 (C-1055), 1993, JP 4-360894 A.
A.G. Brown et al., “Crystal and Molecular Structure of Compactin, a New Antifungal Metabolite fromPenicillium brevicompactum,” J.C.S. Perkin I,1165-1170 (1976).*
A. Endo et al., ML-236A, ML-236B, And ML-236C, New Inhibitors Of Cholesterogenesis Produced byPenicillium citrinum, The Journal of Antibiotics,29:1346-1348 (Dec. 1976).*
Biotechnology of Filamentous fungi,Butterworth-Heinemann, Eds. D.B. Finkelstein et al., Chapter 10, P.S. Masurekar, “Therapeutic Metabolites” 241-301 (1992).

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