Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-18
2004-03-16
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C540S456000
Reexamination Certificate
active
06706727
ABSTRACT:
The invention relates to macrolides, particularly to macrolactam macrolides. It concerns the compounds of formula I
wherein either
R
1
is hydroxy in the &bgr;-configuration; and
R
2
is methyl and
one of R
3
and R
4
is ethyl and the other is methyl; or
R
1
is chloro in the &agr;-configuration; and
one of R
2
, R
3
and R
4
is ethyl and the others are methyl;
in free form and, where such forms exist, in salt form, hereinafter briefly named “the compound of the invention”.
When R
1
in formula I is in the &agr;-configuration it is above, and when it is in the &bgr;-configuration it is below, the plane of the paper. R
1
preferably is chloro in the &agr;-configuration. R
3
or R
4
, particularly R
3
, preferably is ethyl.
The compounds of the invention are hereinafter briefly named as follows:
when R
1
is hydroxy and
R
3
is ethyl: 21-ethyl-ascomycin; or
R
4
is ethyl: 27-ethyl-ascomycin;
when R
1
is chloro and
R
2
is ethyl: 19-ethyl-ASM; or
R
3
is ethyl: 21-ethyl-ASM; or
R
4
is ethyl: 27-ethyl-ASM;
i.e. they are, respectively:
(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E-2-[(1R,3R,4R)-4hydroxy-3-methoxycyclohexyl]-1-methylvinyl]-17,21-diethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,27-trimethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0
4,9
]octacos-18-ene-2,3,10,16-tetrone;
(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E-2-[(1R,3R,4)-4-hydroxy-3-methoxycyclohexyl]-1-methylvinyl]-17,27-diethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21-trimethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0
4,9
]octacos-18-ene-2,3,10,16-tetrone;
(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E-2-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-1-methylvinyl]-17,19-diethyl-1,14-dihydroxy-23,25-dimethoxy-13,21,27-trimethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0
4,9
]octacos-18-ene-2,3,10,16-tetrone;
(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E-2-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-1-methylvinyl]-17,21-diethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,27-trimethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0
4,9
]octacos-18-ene-2,3,10,16-tetrone; and
(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E-2-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-1-methylvinyl]-17,27-diethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21-trimethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0
4,9
]octacos-18-ene-2,3,10,16-tetrone.
21-Ethyl-ascomycin and 27-ethyl-ascomycin are higher homologues of ascomycin. 19-Ethyl-ASM, 21-ethyl-ASM and 27-ethyl-ASM are higher homologues of pimecrolimus (ASM) (33-epichloro-33-desoxy-ascomycin).
The compounds of the invention can be prepared by a process comprising
a) for the preparation of the compounds of formula I as defined above wherein R
1
is hydroxy in the &bgr;-configuration,
cultivating an appropriate microorganism and isolating from the resultant culture medium the corresponding compounds of formula I wherein R
1
is hydroxy in the &bgr;-configuration; or
b) for the preparation of the compounds of formula I as defined above wherein R
1
is chloro in the &agr;-configuration,
replacing under epimerization hydroxy with chloro in a corresponding compound of formula I wherein R
1
is hydroxy in the &bgr;-configuration,
and recovering the resultant compounds in free form or, where such forms exist, in salt form
The process of the invention is effected in conventional manner.
In variant a) any ascomycin-producing microorganism strain may be used which produces higher homologues of ascomycin, e.g. as impurities, preferably a Streptomyces hygroscopicus strain. Such strains are known and available from public depositories. Preferably, strains are used which produce significant amounts of higher homologues of ascomycin, or cultivation conditions are chosen which allow preparation of enhanced amounts of higher homologues of ascomycin. Such strains are known and readily accessible, such as
Streptomyces hygroscopicus
subsp.
ascomyceticus
(e.g. ATCC 14891, ATCC 53855, ATCC 55087, ATCC 55276, ATCC 55558, DSM 5085),
Streptomyces tsukubaensis
No. 9993 (FERM BP-927),
Streptomyces hygroscopicus
subsp.
yakushimaensis
No. 7238 (FERM BP-928, NRRL 18488); or natural or artificial mutants thereof, and cultivation conditions for enhanced higher homologues production are known or can readily be determined in conventional manner therefrom Conveniently, appropriate mutant strains may be created exhibiting enhanced higher homologues production, or selected, in conventional manner, or culture may be effected under modified conditions, such as with increased concentration of the C4 precursor sodium butyrate in the culture medium.
Variant b) is a substitution reaction under simultaneous or concomittant epimerization. It is effected e.g. as described in EP 427680. It preferably is effected in an inert solvent such as tetrahydrofurane or toluene. Preferably the reaction is effected with tetrachloromethane or N-chloro-succmimide in the presence of triphenylphosphine, conveniently in an alkaline medium such as collidine.
The resultant compounds of the invention may be isolated from the cultivation or reaction mixture and purified in accordance with known methods. However, it has been found that, surprisingly, use of a chiral stationary phase such as Kromasil® during chromatographic purification may greatly facilitate isolation of, in particular, the compounds of the invention wherein R
1
is chloro.
The starting materials and intermediate compounds are either known or can be prepared according to known methods or analogously to known methods or analogously as described in the Examples.
REFERENCES:
patent: 0 427 680 (1991-05-01), None
Junker B., et al., “Secondary metabolite scale-up to minimize homolog impurity levels,” Boitechnology and Bioengineering, vol. 59(5), pp. 595-604 (1998).
Hersperger R., et al., “Ascomycin Derivatives and Their Use as Immunosuppressive Agents,” Drugs of the Future, Barcelona, ES, vol. 25(3), pp. 269-277 (2000).
Fleissner Gerhard
Häcker Helmut
Küsters Ernst
Penn Gerhard
Brouillette D. Gabrielle
Kifle Bruck
Novartis AG
LandOfFree
Macrolides does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Macrolides, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Macrolides will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3225570