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ML-236B, Mevastatin (compactin)

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Mevastatin2DCSD.svg

Mevastatin (compactin, ML-236B) is a hypolipidemic agent that belongs to the statins class.

It was isolated from the mold Penicillium citrinum by Akira Endo in the 1970s, and he identified it as a HMG-CoA reductase inhibitor,[1] i.e., a statin. Mevastatin might be considered the first statin drug;[2] clinical trials on mevastatin were performed in the late 1970s in Japan, but it was never marketed.[3] The first statin drug available to the general public was lovastatin.

In vitro, it has antiproliferative properties.[4]

A British group isolated the same compound from Penicillium brevicompactum, named it compactin, and published their results in 1976.[5] The British group mentions antifungal properties with no mention of HMG-CoA reductase inhibition.

High doses inhibit growth and proliferation of melanoma cells.[6]

Systematic (IUPAC) name
(1S,7R,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2-methylbutanoate
Clinical data
Identifiers
73573-88-3 
None
PubChem CID: 64715
IUPHAR/BPS 3031
DrugBank DB06693 Yes
ChemSpider 58262 Yes
UNII 1UQM1K0W9X Yes
KEGG C13963 Yes
ChEBI CHEBI:34848 
ChEMBL CHEMBL54440 Yes
Chemical data
Formula C23H34O5
390.513 g/mol
Mevastatin
Title: Mevastatin
CAS Registry Number: 73573-88-3
CAS Name: (2S)-2-Methylbutanoic acid (1S,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-7-methyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
Additional Names: 7-[1,2,6,7,8,8a-hexahydro-2-methyl-8-(methylbutyryloxy)naphthyl]-3-hydroxyheptan-5-olide; 2b-methyl-8a-(2-methyl-1-oxobutoxy)mevinic acid lactone; compactin; 6-demethylmevinolin
Manufacturers’ Codes: CS-500; ML-236 B
Molecular Formula: C23H34O5
Molecular Weight: 390.51
Percent Composition: C 70.74%, H 8.78%, O 20.49%
Literature References:
Fungal metabolite which is a potent inhibitor of HMG-CoA reductase, the rate controlling enzyme in cholesterol biosynthesis. Isoln from Penicillium citrinum: A. Endo et al., DE 2524355 corresp to US 3983140 (1975, 1976 to Sankyo).
Isoln from P. brevicompactum, crystal and molecular structure: A. G. Brown et al., J. Chem. Soc. Perkin Trans. 1 1976,1165.
Inhibition of HMG-CoA reductase activity: A. Endo et al., FEBS Lett. 72, 323 (1976); M. S. Brown et al., J. Biol. Chem. 253,1121 (1978).
Therapeutic effects in primary hypercholesterolemia: A. Yamamoto et al., Atherosclerosis 35, 259 (1980).
Total synthesis: N. Y. Wang et al., J. Am. Chem. Soc. 103, 6538 (1981); M. Hirama, M. Uei, ibid. 104, 4251 (1982); N. N. Girotra, N. L. Wendler, Tetrahedron Lett. 23, 5501 (1982); C.-T. Hsu et al., J. Am. Chem. Soc. 105, 593 (1983); P. A. Grieco et al., ibid. 1403; D. L. J. Clive et al., J. Am. Chem. Soc. 110, 6914 (1988). Review of syntheses: T. Rosen, C. H. Heathcock, Tetrahedron 42,4909-4951 (1986).
Review of mevastatin and related compounds: A. Endo, J. Med. Chem. 28, 401-405 (1985).
Properties: Crystals from aq ethanol, mp 152°. [a]D22 +283° (c = 0.48 in acetone). uv max: 230, 237, 246 nm (log e 4.28, 4.30, 4.11).
Melting point: mp 152°
Optical Rotation: [a]D22 +283° (c = 0.48 in acetone)
Absorption maximum: uv max: 230, 237, 246 nm (log e 4.28, 4.30, 4.11)

References

  1. Endo, Akira; Kuroda M.; Tsujita Y. (December 1976). “ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium”. Journal of Antibiotics (Tokyo) 29 (12): 1346–8. doi:10.7164/antibiotics.29.1346. PMID 1010803.
  2.  “The story of statins”.
  3.  Endo, Akira (Oct 2004). “The origin of the statins”. Atheroscler Suppl. 5 (3): 125–30. doi:10.1016/j.atherosclerosissup.2004.08.033.PMID 15531285.
  4.  Wachtershauser, A.; Akoglu, B; Stein, J (2001). “HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2”. Carcinogenesis 22 (7): 1061–7. doi:10.1093/carcin/22.7.1061. PMID 11408350.
  5.  Brown, Allan G.; Smale, Terry C.; King, Trevor J.; Hasenkamp, Rainer; Thompson, Ronald H. (1976). “Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum.”. J. Chem. Soc., Perkin Trans. 1 (11): 1165–1170.doi:10.1039/P19760001165. PMID 945291.
  6. ^ Glynn, Sharon A; O’Sullivan, Dermot; Eustace, Alex J; Clynes, Martin; O’Donovan, Norma (2008). “The 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors, simvastatin, lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells”. BMC Cancer8: 9. doi:10.1186/1471-2407-8-9. PMC 2253545. PMID 18199328.

The present invention

http://www.google.com/patents/US6204032

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.

Figure US06204032-20010320-C00001

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.

culturing, in a culture medium, Gliocladium sp. YJ-9515 having the accession number KCTC 0252 BP; and
recovering said at least one compound of ML-236B; wherein the compound of formula I is the lactone form of ML-236B represented by

Figure US06204032-20010320-C00002
wherein the compound of formula II is the free acid form of ML-236B represented by

Figure US06204032-20010320-C00003
and
wherein the compound of formula III is the sodium salt form of ML-236B represented by

Figure US06204032-20010320-C00004

The invention will be described in more detail in the drawings.

FIG. 1 is the IR spectrum of ML-236B obtained from this invention;

and

FIG. 2 is the 13C-NMR spectrum of ML-236B obtained from this invention.

The physical properties such as appearance, melting point. molecular weight, elemental analysis, formular, UV spectrum, IR spectrum, solubility and specific rotation of ML-236B obtained from Example 2, 3 and Comparative Example are described in Table 1.

TABLE 1
COMPARATIVE
Article EXAMPLE 2, 3 EXAMPLE
Appearance white crystal white crystal
Melting point (° C.) 150˜152 150˜152
Molecular weight calculated 390.2635 experimental 390.2392
experimental 390.2392
Elemental C 70.74, H 8.77, O 20.49 C 70.74, O 20.49, H 8.77
Analysis (%) C 70.55 , H 8.69
calculated C 70.85 , H 8.02
experimental
Formula C23H34O5 C23H34O5
UV spectrum 230, 237, 246 230, 237, 246
(nm, MeOH)
IR spectrum 3509, 2964, 2938, 2884, 3509, 2964, 2938, 2884,
(cm−1, KBr ) 1744, 1698, 1445, 1385, 1744, 1699, 1445, 1385,
1236, 1206, 1182, 1151, 1236, 1206, 1182, 1150,
1077, 1056 1076, 1056
Solubility methanol, chloroform, methanol, chloroform,
soluble ethanol, ethyl acetate ethanol, ethyl acetate
insoluble water water
Specific rotation +283n +283n
[α]D

13C NMR data of ML-236B are shown in Table 2 and FIG. 2.

TABLE 2
The δ c(ppm) The δ c(ppm)
number EX- COMPAR- number EX- COMPAR-
of AMPLE ATIVE of AMPLE ATIVE
carbon 2,3 EXAMPLE carbon 2,3 EXAMPLE
C-1 171.50 170.67 C-13 124.48 123.33
C-2 39.31 38.44 C-14 134.35 133.38
C-3 63.18 62.12 C-15 128.96 127.96
C-4 36.88 35.84 C-16 133.49 132.37
C-5 77.22 76.26 C-17 31.66 30.70
C-6 33.75 32.82 C-18 14.66 13.64
C-7 24.83 23.78 C-19
C-8 37.66 36.67 C-20 177.79 176.55
C-9 38.31 37.40 C-21 42.56 41.50
C-10 68.45 67.51 C-22 27.55 26.48
C-11 27.06 26.30 C-23 12.59 11.49
C-12 21.74 20.74 C-24 17.74 16.64

By using a new microorganism which was obtained from this invention, the productivity of pravastatin precursor was elevated highly and the pravastatin precursor could be prepared in a simple way in short time.

Therefore, the present invention could be used effectively in production of pravastatin precursor.

DR ANTHONY MELVIN CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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