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Details for Patent: 4,410,629

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Details for Patent: 4,410,629

Title: ML-236B Derivatives and their preparation
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 C.sub.1 -C.sub.5 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, Gongornella, 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.
Inventor(s): Terahara; Akira (Tokyo, JP), Tanaka; Minoru (Tokyo, JP)
Assignee: Sankyo Company Limited (Tokyo, JP)
Filing Date:Feb 24, 1982
Application Number:06/351,974
Claims:1. A process for preparing a compound of the formula (I). ##STR19## wherein R represents a group of formula ##STR20## or a ring-closed lactone, salt or ester thereof which comprises enzymatically hydroxylating a substrate selected from ML-236B having the formula ##STR21## or ML-236B carboxylic acid having the formula ##STR22## or a salt or ester of said ML-236B carboxylic acid with a microorganism of the genera Mucor, Rhizopus, Zygorynchus, Circinella, Actinomucor, Gongronella, Phycomyces, Martierella, Pycnoporus, Rhizoctonia, Absidia, Cunninghamella, Syncephalastrum and Streptomyces or with a cell-free, enzyme containing extract from said microorganisms to produce said compound of the formula (I), and recovering said compound of the formula (I).

2. A process as claimed in claim 1, wherein said microorganism is selected from the group consisting of:

Absidia coerulea

Cunninghamella echinulata

Syncephalastrum racemosum

Streptomyces roseochromogenus

Mucor hiemalis f. hiemalis

Mucor bacilliformis

Mucor circinellodes f. circinelloides

Mucor hiemalis f. corticolus

Mucor dinorphosporus

Mucor fragilis

Mucor genevensis

Mucor globosus

Mucor circinelloides f. griseo-cyanus

Mucor heterosporus

Mucor spinescens

Rhizopus chinensis

Rhizopus circinans

Rhizopus arrhizus

Zygorynchus moelleri

Circinella muscae

Circinella rigida

Circinella umbellata

Actinomucor, elegans

Phycomyces blakesleeanus

Martierella isbellina

Gongronella butleri

Pycnoporus coccineus

Rhizoctonia solani

Syncephalastrum nigricans

Absidia glauca var. paradoxa

3. A process as claimed in claim 2, wherein said microorganism is selected from the group consisting of:

Absidia coerulea IFO-4423

Cunninghamella echinulata IFO-4445

Cunninghamella echinulata IFO-4444

Cunninghamella echinulata ATCC-9244

Syncephalastrum racemosum IFO-4814

Syncephalastrum racemosum IFO-4828

Streptomyces roseochromogenus NRRL-1233

Streptomyces roseochromogenus IFO-3363

Streptomyces roseochromogenus IFO-3411

Mucor hiemalis f. hiemalis IFO-5834

Mucor hiemalis f. hiemalis IFO-5303

Mucor hiemalis f. hiemalis IFO-8567

Mucor hiemalis f. hiemalis IFO-8449

Mucor hiemalis f. hiemalis IFO-8448

Mucor hiemalis f. hiemalis IFO-8565

Mucor hiemalis f. hiemalis CBS-117.08

Mucor hiemalis f. hiemalis CBS-109.19

Mucor hiemalis f. hiemalis CBS-200.28

Mucor hiemalis f. hiemalis CBS-242.35

Mucor hiemalis f. hiemalis CBS-110.19

Mucor hiemalis f. hiemalis CBS-201.65

Mucor bacilliformis NRRL-2346

Mucor circinelloides f. circinelloides IFO-4554

Mucor circinelloides f. circinelloides IFO-5775

Mucor hiemalis f. corticolus NRRL-12473

Mucor dimorphosporus IFO-4556

Mucor fragilis CBS-236.35

Mucor genevensis IFO-4585

Mucor globosus NRRL-12474

Mucor circinelloides f. griseo-cyanus IFO-4563

Mucor heterosporus NRRL-3154

Mucor spinescens IAM-6071

Rhizopus chinensis IFO-4772

Rhizopus circinans ATCC-1225

Rhizopus arrhizus ATCC-11145

Zygorynchus moelleri IFO-4833

Circinella muscae IFO-4457

Circinella rigida NRRL-2341

Circinella umbellata NRRL-1713

Circinella umbellata IFO-4452

Circinella umbellata IFO-5842

Phycomyces blakesleeanus NRRL-12475

Martierella isabellina IFO-6739

Gongronella butleri IFO-8080

Pycnoporus coccineus NRRL-12476

Rhizoctonia solani NRRL-12477

Syncephalastrum nigricans NRRL-12478

Syncephalastrum nigricans NRRL-12479

Syncephalastrum nigricans NRRL-12480

Absidia glauca var. paradoxa IFO-4431

Actinomucor elegans ATCC-6476

4. A process as claimed in claim 3, wherein there is separated from the reaction mixture a compound selected from the group consisting of M-4, M-4', IsoM-4', a salt, ester or lactone of M-4, M-4' IsoM-4 or IsoM-4' or a mixture thereof.

5. A process as claimed in claim 4, wherein said ester is a C.sub.1 -C.sub.5 alkyl ester.

6. A process as claimed in claim 4, wherein said ester is the methyl ester.

7. A process as claimed in claim 4, wherein said salt is an alkali metal salt.

8. A process as claimed in claim 4, wherein said salt is a sodium salt.

9. A process as claimed in claim 1, wherein said microorganism is selected from the group consisting of:

Absidia coerulea

Cunninghamella echinulata

Syncephalastrum racemosum

Mucor hiemalis f. hiemalis

Mucor bacilliformis

Mucor circinellodies f. circinelloides

Mucor hiemalis f. corticolus

Mucor dimorphosporus

Mucor fragilis

Mucor genevensis

Mucor globosus

Mucor circinellodies f. griseo-cyanus

Mucor heterosporus

Mucor spinescens

Pycnoporus coccineus

Rhizoctonia solani

Syncephalastrum nigricans

10. A process as claimed in claim 1, wherein said microorganism is selected from the group consisting of:

Absidia coerulea IFO-4423

Cunninghamella echinulata IFO-4445

Cunninghamella echinulata IFO-4444

Cunninghamella echinulata ATCC-9244

Syncephalastrum racemosum IFO-4814

Syncephalastrum racemosum IFO-4828

Mucor hiemalis f. hiemalis IFO-5834

Mucor hiemalis f. hiemalis IFO-5303

Mucor hiemalis f. hiemalis IFO-8567

Mucor hiemalis f. hiemalis IFO-8449

Mucor hiemalis f. hiemalis IFO-8448

Mucor hiemalis f. hiemalis IFO-8565

Mucor hiemalis f. hiemalis CBS-117.08

Mucor hiemalis f. hiemalis CBS-109.19

Mucor hiemalis f. hiemalis CBS-200.28

Mucor hiemalis f. hiemalis CBS-242.35

Mucor hiemalis f. hiemalis CBS-110.19

Mucor hiemalis f. hiemalis CBS-201.65

Mucor bacilliformis NRRL-2346

Mucor circinelloides f. circinelloides IFO-4554

Mucor circinelloides f. circinelloides IFO-5775

Mucor hiemalis f. corticolus NRRL-12473

Mucor dimorphosporus IFO-4556

Mucor fragilis CBS-236.35

Mucor genevensis IFO-4585

Mucor globosus NRRL-12474

Mucor circinelloides f. griseo-cyanus IFO-4563

Mucor heterosporus NRRL-3154

Mucor spinescens IAM-6071

Pycnoporus coccineus NRRL-12476

Rhizoctonia solani NRRL-12477

Syncephalastrum nigricans NRRL-12478

Syncephalastrum nigricans NRRL-12479 and

Syncephalastrum nigricans NRRL-12480.

11. A process as claimed in claim 1, wherein said microorganism is selected from the group consisting of:

Mucor hiemalis f. hiemalis

Mucor circinelloides. f. circinelloides

Mucor fragilis

Mucor genevensis

Mucor circinelloides f. griseo-cyanus

Pycnoporus coccineus and

Rhizoctonia solani.

12. The process of claim 1, wherein said microorganism is cultivated in a culture medium and said ML-236B or said ML-236B carboxylic acid or salt or ester thereof is added to said culture medium to produce said compound of the formula (I).

13. A process is for preparing a compound having the formula (a): ##STR23## (wherein R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.5 alkyl group), pharmaceutically acceptable salts of the acid wherein R.sup.1 represents a hydrogen atom, and compounds of formula (b): ##STR24## by enzymatically hydroxylating a substrate selected from the group consisting of ML236B or ML236B carboxylic acid with a microorganism selected from the group consisting of Syncephalastrum nigricans and Syncephalastrum racemosum and recovering said compounds.

14. A process as claimed in claim 13, wherein R.sup.1 represents a hydrogen atom.

15. A process as claimed in claim 13, wherein R.sup.1 represents a C.sub.1 -C.sub.5 alkyl group.

16. A process as claimed in claim 13, wherein R.sup.1 represents a methyl group.

17. A process as claimed in claim 13, wherein said salt is an alkali metal salt.

18. A process as claimed in claim 17, wherein said salt is a sodium salt.

19. A process for preparing a compound having the formula (c): ##STR25## (wherein R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.5 alkyl group), pharmaceutically acceptable salts of the acid wherein R.sup.1 represents a hydrogen atom, and compounds of formula (d): ##STR26## by enzymatically hydroxylating a substrate selected from the group consisting of ML236B or ML236B carboxylic acid with a microorganism selected from the group consisting of Absidia coerulea and Cunninghamella echinulata and recovering said compounds.

20. A process as claimed in claim 19, wherein R.sup.1 represents a hydrogen atom.

21. A process as claimed in claim 19, wherein R.sup.1 represents a C.sub.1 -C.sub.5 alkyl group.

22. A process as claimed in claim 19, wherein R.sup.1 represents a methyl group.

23. A process as claimed in claim 19, wherein said salt is an alkali metal salt.

24. A process as claimed in claim 23, wherein said salt is a sodium salt.
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