Basic proline-amide derivatives of GE 2270 and GE 2270-like anti

Details Basic proline-amide derivatives of GE 2270 and GE 2270-like anti Basic proline-amide derivatives of GE 2270 and GE 2270-like anti

1997-07-31

2000-11-07

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514 9, 530317, 540451, A61K 3805, C07K 506, C07K 756

Patent

active

061437395

DESCRIPTION:

BRIEF SUMMARY
The present invention refers to basic amide derivatives of GE 2270 and GE 2270-like antibiotics of general formula I ##STR2## wherein:
R.sup.1 represents hydrogen, (C.sub.1 -C.sub.4)alkyl or di(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkylene,
alk represents (C.sub.1 -C.sub.4)alkylene or (C.sub.2 -C.sub.5)alkylene-carbonyl,
R.sup.2 represents a NR.sup.3 R.sup.4 group wherein -C.sub.4)alkylene, or di(C.sub.1 -C.sub.4)alkylamino-(C.sub.1 -C.sub.4)alkylene, and -C.sub.4)alkylamino-(C.sub.1 -C.sub.4)alkylene or hydroxy(C.sub.1 -C.sub.4)alkylene, optionally a further heteroatom selected from nitrogen and oxygen, optionally substituted with a group selected from (C.sub.1 -C.sub.4)alkyl, hydroxy(C.sub.1 -C.sub.4)alkylene, di(C.sub.1 -C.sub.4)alkylamino and di(C.sub.1 -C.sub.4)alkylamino-(C.sub.1 -C.sub.4)alkylene;
or R.sup.1 and alk-R.sup.2 together with the adiacent nitrogen atom form a five or six membered heterocycle ring optionally containing a further heteroatom selected from oxygen and nitrogen, optionally substituted with a group selected from (C.sub.1 -C.sub.4)alkyl, di(C.sub.1 -C.sub.4)alkylamino, di(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkylene, hydroxy(C.sub.1 -C.sub.4)alkylene and a alk.sub.2 -R.sup.5 group wherein
alk.sub.2 is (C.sub.1 -C.sub.4)alkyl and
R.sup.5 is a NR.sup.6 R.sup.7 group wherein -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkylene and -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkylene heteroatoms selected from nitrogen and oxygen, optionally substituted with a group selected from (C.sub.1 -C.sub.4)alkyl, hydroxy(C.sub.1 -C.sub.4)alkylene, di(C.sub.1 -C.sub.4)alkylamino and di(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkylene
and the group of formula ##STR3## represents the antibiotic core portion of formula ##STR4## wherein:
W.sup.1 represents phenyl
W.sup.2 represents hydroxy
or both W.sup.1 and W.sup.2 represent methyl,
X.sup.1 represents hydrogen or methyl,
X.sup.2 represents hydrogen, methyl or methoxymethylen,
with the proviso that when both W.sup.1 and W.sup.2 are methyl, then X.sup.1 is methyl and X.sup.2 is hydrogen,
or a pharmaceutical acceptable salt thereof.
The present invention refers also to the processes for preparing the compounds of formula I and to the carboxylic acid and protected carboxylic acid derivatives of the above compounds, i.e. the precursors of the compounds of formula I wherein the amidic group: ##STR5## is substituted by the group --COOY, wherein Y represents hydrogen or (C.sub.1 -C.sub.4)alkyl.
Antibiotic GE 2270 is prepared by culturing a sample of Planobispora rosea ATCC 53773 or a producing variant or mutant thereof and isolating the desired antibiotic substance from the mycelium and/or the fermentation broth. Planobispora rosea ATCC 53773 was isolated from a soil sample and deposited on Jun. 14, 1988 with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Md. 20852 Maryland, U.S.A., under the provisions of the Budapest Treaty. The strain has been accorded accession number ATCC 53773.
Antibiotic GE 2270 factor A is the main component of the antibiotic GE 2270 complex. Antibiotic GE 2270 factor A and Planobispora rosea ATCC 53773 are described in U.S. Pat. No. 5,139,778.
At present, a number of minor factors of antibiotic GE 2270 have been isolated, namely factors B.sub.1, B.sub.2, C.sub.1, C.sub.2, D.sub.1, D.sub.2, E and T disclosed in European Patent Application Publication no. 451486 and factor which has as its equivalent, U.S. Pat. No. 5,747,295 C.sub.2a is disclosed in European Patent Application Publication no. 529410 which has as its equivalent U.S. Pat. No. 5,514,649. Also degradation products of GE 2270 factor A are known, namely factors A.sub.1, A.sub.2, A.sub.3 and H disclosed in U.S. Pat. No. 5,139,778.
Among these compounds, factor A, B.sub.2, C.sub.1 and C.sub.2 may be employed as suitable starting materials for preparing the compounds of the present invention.
The above factors may be represented by the following formula II: ##STR6## wherein ##STR7## is a group as above defined wherein
W.sup.1 is phen

REFERENCES:
patent: 5139778 (1992-08-01), Selva et al.
patent: 5202241 (1993-04-01), Selva et al.
patent: 5514649 (1996-05-01), Selva et al.
patent: 5599791 (1997-02-01), Tavecchia et al.
patent: 5891869 (1999-04-01), Lociuro et al.
"Novel Antibiotics, Amythiamicins III. Structure Elucidations of Amythiamicins A, B and C" The Journal of Antibiotics, vol. 47, No. 10, pp. 1153-1159, (1994).

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