ML-236B Derivatives and their preparation

Claim 2

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).

Claim 3

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

Claim 4

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

Claim 5

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.

Claim 6

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

Claim 7

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

Claim 8

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

Claim 9

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

Claim 10

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

Claim 11

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.

Claim 12

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.

Claim 13

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).

Claim 14

A process is for preparing a compound having the formula (a): ##STR23## (wherein R 1 represents a hydrogen atom or a C 1 -C 5 alkyl group), pharmaceutically acceptable salts of the acid wherein R 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.

Claim 15

A process is for preparing a compound having the formula (a): ##STR23## (wherein R 1 represents a hydrogen atom or a C 1 -C 5 alkyl group), pharmaceutically acceptable salts of the acid wherein R 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.

Claim 16

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

Claim 17

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

Claim 18

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

Claim 19

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

Claim 20

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

Claim 21

A process for preparing a compound having the formula (c): ##STR25## (wherein R 1 represents a hydrogen atom or a C 1 -C 5 alkyl group), pharmaceutically acceptable salts of the acid wherein R 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.

Claim 22

A process for preparing a compound having the formula (c): ##STR25## (wherein R 1 represents a hydrogen atom or a C 1 -C 5 alkyl group), pharmaceutically acceptable salts of the acid wherein R 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.

Claim 23

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

Claim 24

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

Claim 25

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

Claim 26

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

Claim 27

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