Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-06
2003-07-29
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S539000, C435S121000, C435S171000, C435S254100
Reexamination Certificate
active
06599930
ABSTRACT:
The present invention relates to a novel active substance, coniosetin, of the tetramic acid type, which is produced by the microorganism
Coniochaeta ellipsoidea
Udagawa (DSM 13856) during fermentation, to chemical derivatives derived from coniosetin, to a process for the preparation thereof, and to a method for using the novel tetramic acids as pharmaceuticals.
A relatively large number of antibiotics with a tetramic acid basic structure has already been described. Tetramic acid, 2,4-pyrrolidinedione, is the parent compound of various natural substances produced by some microorganisms and marine invertebrates. A description of harzianic acid, an antibiotic with very low activity, was published in 1994 (R. Sawa et al., J. Antibiotics 47:731-732 (1994)). A summary article by B. J. L. Royles described the natural tetramic acid derivatives published up to 1994 (Chem. Rev. 95:1981-2001 (1995)).
Further natural tetramic acids have been described since 1995, but only a few have antibacterial properties. Examples include:
reutericyclin (A. Höltzel et al., Angew. Chem. 112:2886-2888 (2000)), a compound with weak antibacterial activity;
rubrosides A-H (N. Sata et al., J. Org. Chem. 64:2331-2339 (1999));
aflastatins (M. Ono et al., J. Antibiotics 51:1019-1028 (1998));
F-10778 (A. Tanaka et al., Annu. Rep. Sankyo Res. Lab. 49:135-141 (1997));
ancorinoside A (S. Ohta et al., J. Org. Chem. 62:6452-6453 (1997));
physarorubinic acid (A. Nowak et al., Liebigs Ann./Recl. 1817-1821 (1997));
ascosalipyrrolidinone A (C. Osterhage et al., J. Org. Chem. 65:6412-6417 (2000));
talaroconvolutins (S. Suzuki et al., J. Nat. Prod. 63:768-772 (2000));
xanthobaccin A (Y. Hashidoko et al., Tetrahedron Lett. 40:2957-2960 (1999));
equisetin and phomasetin (S. S. Singh et al., Tetrahedron Lett. 39:2243-2246 (1998)), isomeric inhibitors of HIV-1 integrase;
cryptocin (J. Y. Li et al., Org. Lett. 2:767-770 (2000)), an antimycotic compound; and
vancoresmycin (N. V. S. Ramakrishna et al., Int. Patent Publikation No. WO 0028064), an antibiotic.
A large number of antibiotics are employed therapeutically for treating bacterial infectious diseases. The pathogens are, however, becoming increasingly resistant to the pharmaceuticals used, and there is in fact a great threat from so-called multiresistant organisms which not only have become resistant to single groups of antibiotics, such as, for example, &bgr;-lactam antibiotics, glycopeptides or macrolides, but also harbor more than one resistance. There are even pathogens which have become resistant to all commercially available antibiotics. Therapy is no longer possible for infectious diseases caused by such organisms. Thus, there is a great need for novel agents which can be employed for resistant organisms. Although many thousands of antibiotics have been described in the literature, most of them are too toxic to be employable as pharmaceuticals.
Surprisingly, it has been found that the strain
Coniochaeta ellipsoidea
Udagawa (DSM 13856) is able to produce at least one novel antibiotic, for example coniosetin, which not only has very good antibacterial activity but is also well-tolerated.
The invention consequently relates to the active substances produced by the strain
Coniochaeta ellipsoidea
Udagawa (DSM 13856) and their physiologically tolerated salts, esters, ethers and obvious chemical equivalents.
The invention accordingly relates to compounds of the formula I:
wherein
R, R
2
and R
3
are, independently of one another:
A. H, or
B. C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl or C
2
-C
6
-alkynyl, in which alkyl, alkenyl and alkynyl are straight-chain or branched and are optionally substituted once or twice by:
B.1 —OH,
B.2 ═O,
B.3 —O—C
1
-C
6
-alkyl, in which alkyl is straight-chain or branched,
B.4 —O—C
2
-C
6
-alkenyl, in which alkenyl is straight-chain or branched,
B.5 —aryl,
B.6 —NH—C
1
-C
6
-alkyl, in which alkyl is straight-chain or branched,
B.7 —NH—C
2
-C
6
-alkenyl, in which alkenyl is straight-chain or branched,
B.8 —NH
2
or
B.9 halogen,
in which substituents B.1 to B.9 may be further substituted by —CN, amide or oxime functions,
R
4
is C
1
-C
6
-alkyl, in which alkyl can be straight-chain or branched and is optionally substituted once or twice as described under B.1 to B.9, or C
2
-C
6
-alkenyl, in which alkenyl can be straight-chain or branched, and
R
5
is H or methyl, and
X, X
2
, X
3
and X
4
are, independently of one another, O, NH, N—C
1
-C
6
-alkyl,
N—C
2
-C
6
-alkenyl, N—C
2
-C
6
-alkynyl, N-acyl, N-aryl, N—O—R or S.
The invention further relates to stereoisomeric forms of the compound of the formula I and/or mixtures of these forms in any ratio, and/or physiologically tolerated salts of the compound of the formula I.
The invention relates not only to compounds of the formula I (coniosetin and coniosetin derivatives) but also to obvious chemical equivalents as defined below.
In formula I,
C
1
-C
6
-alkyl is a straight-chain or branched alkyl having 1 to 6 carbon atoms, preferably having 1 to 4 carbon atoms, such as methyl, ethyl, i-propyl, tert-butyl and hexyl,
C
2
-C
6
-alkenyl is a straight-chain or branched alkenyl having 2 to 6 carbon atoms, which is saturated once, twice or three times, such as, for example, allyl, crotyl, 1-propenyl, penta-1,3-dienyl and pentenyl, and
C
2
-C
6
-alkynyl is a straight-chain or branched alkynyl having 2 to 6 carbon atoms, which is unsaturated once or twice, such as, for example, propynyl, butynyl and pentynyl.
Aryl can be, for example, phenyl, benzyl or 1- or 2-naphthyl, which may also be substituted, for example, by halogen such as chlorine, bromine, fluorine, by alkyl having 1-4 carbon atoms, such as methyl, by hydroxyl, by alkoxy having 1-4 carbon atoms, such as methoxy and/or by trifluoromethyl.
Acyl can be aliphatic or aromatic acyl radicals. Aliphatic acyl has 1-7, generally 1-4, carbon atoms, such as, for example, formyl, acetyl, propionyl, butyryl, hexanoyl, acryloyl, crotonoyl, propioloyl, which may also be further substituted, for example, by halogen, such as chlorine, bromine, fluorine, by amino, and/or by alkylamino having 1-4 carbon atoms, preferably methyl- or ethylamino groups. Aromatic acyl can be, for example, benzoyl or naphthoyl, which may be further substituted, for example, by halogen, such as chlorine, bromine, fluorine, by alkyl having 1-4 carbon atoms, such as methyl, by hydroxyl, by amino groups such as, for example, ethylamino, or by alkoxy groups having 1-7, generally 1-4, carbon atoms, such as methoxy.
In one embodiment of the invention, compounds of the formula I are those wherein:
R
3
is H,
R
4
is penta-1,3-dienyl,
R
5
is CH
3
,
R
2
X
2
is OH,
X
3
, X
4
is ═O, and
RX is OH,
and the physiologically tolerated salts thereof.
In yet another embodiment of the invention, compounds of the formula I are those in which R
3
is H and R
4
is penta-1,3-dienyl.
The invention further relates to a compound of the formula II
(coniosetin: molecular formula: C
25
H
35
NO
4
; MW 413.56) and the physiologically tolerated salts thereof.
Chirality centers in the compounds of the formula I or II may, unless indicated otherwise, be in the R or in the S configuration. The invention relates both to the optically pure compounds and to mixtures of stereoisomers, such as mixtures of enantiomers and mixtures of diastereomers, in any ratio.
Preferred novel compounds of the formula I are those compounds in which the configuration corresponds to the substituted hydrogenated naphthyl structure of the formula III:
The invention therefore further relates to a compound of the formula IIIA:
and the physiologically tolerated salts thereof.
The invention additionally relates to a compound of the molecular formula: C
25
H
35
NO
4
(coniosetin) obtainable by fermentation of
Coniochaeta ellipsoidea
Udagawa (DSM 13856) or one of its variants and/or mutants until the compound coniosetin accumulates in the culture broth and subsequent isolation of the compound, and the pharmacologically acceptable salts thereof.
The invention further relates to chemical derivatives derived from a compound of the molecu
Fassy Florence
Knauf Martin
Markus-Erb Astrid
Raynal-Wetzel Marie-Cecile
Toti Luigi
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner LLP
McKane Joseph K.
Small Andrea D.
LandOfFree
Coniosetin and derivatives thereof, process for the... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Coniosetin and derivatives thereof, process for the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Coniosetin and derivatives thereof, process for the... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3011241