ML-236B Derivatives and their preparation

• US 4,346,227 A
• Filed: 06/05/1981
• Issued: 08/24/1982
• Est. Priority Date: 06/06/1980
• Status: Expired due to Term

• Current Assignee: Sankyo Company Limited (Daiichi Sankyo Company Limited)
• Original Assignee: Sankyo Company Limited (Daiichi Sankyo Company Limited)
• Inventors: Tanaka, Minoru, Terahara, Akira
• Primary Examiner(s): Gerstl, Robert
• Application Number:
  US06/270,846
• Time in Patent Office: 445 Days
• Field of Search: 560/119, 560/256
• US Class Current: 560/119
• CPC Class Codes: C07D 309/30 Oxygen atoms, e.g. delta-lactones
• CPC Class Codes: C12N 1/145 Fungal isolates
• CPC Class Codes: C12N 1/205 Bacterial isolates
• CPC Class Codes: C12P 17/06 containing a six-membered hetero ring, e.g. fluorescein
• CPC Class Codes: C12P 7/62 Carboxylic acid esters
• CPC Class Codes: C12R 2001/465 Streptomyces
• CPC Class Codes: C12R 2001/645 Fungi ; Processes using fungi
• CPC Class Codes: C12R 2001/65 Absidia
• CPC Class Codes: C12R 2001/785 Mucor
• CPC Class Codes: C12R 2001/845 Rhizopus
• CPC Class Codes: Y10S 435/886 Streptomyces

Abstract

Compounds of formula (I): ##STR1## (wherein R represents a group of formula ##STR2## and the corresponding ring-closed lactones, salts (especially alkali metal salts) and esters (especially C₁ -C₅ alkyl esters) thereof may be prepared by subjecting ML-236B, or ML-236B carboxylic acid or a salt or ester thereof to enzymatic hydroxylation, which may be effected by means of microorganisms of the genera Mucor, Rhizopus, Zygorynchus, Circinella, Actinomucor, Gongronella, Phycomyces, Martierella, Pycnoporus, Rhizoctonia, Absidia, Cunninghamella, Syncephalastrum and Streptomyces, or cell-free, enzyme-containing extracts from said microorganisms. The compounds are capable of inhibiting biosynthesis of cholesterol and are thus useful in the treatment of hypercholesteraemia.

Claims

1. Compounds of formula (I):

##STR19## wherein R¹ represents a hydrogen atom or a C₁ -C₅ alkyl group, and R represents a group of the formula ##STR20## and pharmaceutically acceptable salts of the acid when R¹ represents a hydrogen atom.

2. Compounds as claimed in claim 1, having the formula (II) ##STR21## (in which R¹ represents a hydrogen atom or a C₁ -C₅ alkyl group) and pharmaceutically acceptable salts of the acid wherein R¹ represents a hydrogen atom.

3. Compounds as claimed in claim 2, wherein R¹ represents a hydrogen atom.

4. Compounds as claimed in claim 2, wherein R¹ represents a C₁ -C₅ alkyl group.

5. Compounds as claimed in claim 2, wherein R¹ represents a methyl group.

6. Compounds as claimed in claim 2, in the form of alkali metal salts.

7. Compounds as claimed in claim 6, in the form of the sodium salt.

8. Compounds as claimed in claim 2, having the configuration shown in formula (IV):

##STR22## (wherein R¹ is as defined in claim

     2) and pharmaceutically acceptable salts thereof.

9. Compounds as claimed in claim 8, wherein R¹ represents a hydrogen atom.

10. Compounds as claimed in claim 8, wherein R¹ represents a C₁ -C₅ alkyl group.

11. Compounds as claimed in claim 8, wherein R¹ represents a methyl group.

12. Compounds as claimed in claim 8, in the form of the alkali metal salts.

13. Compounds as claimed in claim 12, in the form of the sodium salt.

14. Compounds as claimed in claim 2, having the configuration shown in formula (VI):

##STR23## (wherein R¹ is as defined in claim

     2) and pharmaceutically acceptable salts thereof.

15. Compounds as claimed in claim 14, wherein R¹ represents a hydrogen atom.

16. Compounds as claimed in claim 14, wherein R¹ represents a C₁ -C₅ alkyl group.

17. Compounds as claimed in claim 14, wherein R¹ represents a methyl group.

18. Compounds as claimed in claim 14, in the form of the alkali metal salts.

19. Compounds as claimed in claim 18, in the form of the sodium salt.

20. Compounds as claimed in claim 1, which have the formula (VIII):

##STR24## (in which R¹ represents a hydrogen atom or a C₁ -C₅ alkyl group) and pharmaceutically acceptable salts of the acid wherein R¹ represents a hydrogen atom.

21. Compounds as claimed in claim 20, wherein R¹ represents a hydrogen atom.

22. Compounds as claimed in claim 20, wherein R¹ represents a C₁ -C₅ alkyl group.

23. Compounds as claimed in claim 20, wherein R¹ represents a methyl group.

24. Compounds as claimed in claim 20, in the form of the alkali metal salts.

25. Compounds as claimed in claim 24, in the form of the sodium salt.