Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-07-21
2002-10-29
Horlick, Kenneth R. (Department: 1656)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C514S183000, C435S006120, C435S254100
Reexamination Certificate
active
06472158
ABSTRACT:
This application is a national stage filing under 35 U.S.C. § 371 of international application No. PCT/EP99/00288, filed on Jan. 19,1999.
The present invention relates to novel active substances (ustilipides) which are formed by the microorganism Ustilago maydis, FH 2634, DSM 11494, during fermentation, to a method for the production thereof, to the use thereof as pharmaceutical, to ustilipide-containing pharmaceuticals and to the microorganism Ustilago maydis, FH 2634, DSM 11494.
Schizophrenia (dementia praecox) is an endogenous, psychosomatic disorder with loss of the structural cohesion of the personality and with disconnection of thought, affect and perception. It is based on the interaction of psychological and somatic factors. Schizophrenia is associated with severe disorders of thought, disturbances of drive, delusions, hallucinations and disturbances of the perception of self. Treatment of schizophrenia at present is mainly by the administration of neuroleptics, and by psychotherapy. It can at present not yet be cured, or can be cured to only a limited extent. Because the possibility of treating this severe disorder is completely inadequate, there is an urgent need for novel medicines suitable for treating schizophrenia.
It has now been found that the strain Ustilago maydis, FH 2634, DSM 11494, is able to form novel, highly active substances which are suitable for treating schizophrenia or other diseases caused by dysfunction of dopamine metabolism, and which are also well tolerated.
The invention accordingly relates to the active substances (ustilipides) formed by the strain Ustilago maydis DSM 11494, and to their physiologically tolerated salts, esters and obvious chemical equivalents.
The invention thus relates to compounds of the formula I
where
R
2
, R
3
and R
4
are, independently of one another, acyl radicals with 2-25 carbon atoms, preferably with 2-20 carbon atoms, which are unsubstituted or are substituted, independently of one another, by 1, 2 or 3 (C
6
-C
12
)-aryl radicals; and
R is hydrogen or a radical defined under R
2
, R
3
and R
4
where in the case where R is hydrogen, then R
2
is an acyl radical with 3-25 carbon atoms, preferably with 3-20 carbon atoms, which is unsubstituted or substituted by 1, 2 or 3 (C
6
-C
12
)-aryl radicals;
and the physiologically tolerated salts thereof.
Preference is given to compounds of the formula I in which
R is hydrogen or an acyl radical with 2-25 carbon atoms, preferably with 2-20 carbon atoms;
R
2
is an acyl radical with 4-25 carbon atoms, preferably with 4-20 carbon atoms;
R
3
is an acyl radical with 10-25 carbon atoms, preferably with 15-20 carbon atoms; and
R
4
is an acyl radical with 2-25 carbon atoms, preferably with 2-20 carbon atoms;
and the physiologically tolerated salts thereof.
Preference is also given to compounds of the formula I in which R
3
is an acyl radical with 10-20 carbon atoms, preferably 15-18 carbon atoms, and R, R
1
, R
3
and R
4
are each, independently of one another, an acyl radical with 2-10 carbon atoms, particularly preferably with 2-6 carbon atoms, and the physiologically tolerated salts thereof.
The acyl radicals in the compounds of the formula I can be straight-chain or branched, saturated or unsaturated once, twice, three times, four times or five times.
An acyl radical with 2 carbon atoms means, for example, an acetyl radical.
Examples of saturated, unbranched acyl radicals are an acetic acid residue (C=2), propionic acid residue (C=3), butyric acid residue (C=4), valeric acid residue (C=5), caproic acid residue (C=6), enanthic acid residue (C=7), caprylic acid residue (C=8), pelargonic acid residue (C=9), capric acid residue (C=10), undecanoic acid residue (C=11), lauric acid residue (C=12), tridecanoic acid residue (C=13), myristic acid residue (C=14), pentadecanoic acid residue (C=15), palmitic acid residue (C=16), margaric acid residue (C=17), stearic acid residue (C=18), nonadecanoic acid residue (C=19), arachidic acid residue (C=20), behenic acid residue (C=22), lignoceric acid residue (C=24). Examples of saturated, branched acyl radicals are an isobutyric acid residue (C=4), isovaleric acid residue (C=5), tuberculostearic acid residue (C=19).
Examples of unbranched acyl radicals which are unsaturated once are an acrylic acid residue (C=3), crotonic acid residue (C=4), palmitoleic acid residue (C=16), oleic acid residue (C=18), erucic acid residue (C=22).
Examples of unbranched acyl radicals which are unsaturated twice are a sorbic acid residue (C=6) and linoleic acid residue (C=18).
Examples of unbranched acyl radicals which are unsaturated three times are a linolenic acid residue (C=18) or eleostearic acid residue (C=18).
An example of an unbranched acyl radical which is unsaturated four times is an arachidonic acid residue (C=20).
An example of an unbranched acyl radical which is unsaturated five times is a clupanodonic acid residue (C=22). (C
6
-C
12
)-aryl means, for example, phenyl, naphthyl or biphenylyl. Phenyl is preferred.
The invention further relates to
a) a compound of the formula (II)
where n is 11 (=ustilipide A: molecular formula: C
36
H
64
O
13
, MW: 704) and the physiologically tolerated salts thereof;
b) a compound of the formula (III)
where n is 11 (=ustilipide B: molecular formula: C
34
H
60
O
13
, MW: 676) and the physiologically tolerated salts thereof; and
c) a compound of the formula (IV)
wherein n is 11 (ustilipide C, molecular formula: C
32
H
58
O
12
, MW: 634) and the physiologically tolerated salts thereof.
Centers of chirality in the compounds of the formula I-IV may, unless indicated otherwise, be present in the R or 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.
Of the compounds according to the invention of the formula I-IV, all of which have a saccharide framework, the preferred compounds are those in which the configuration of the saccharide framework corresponds to that of 1-O-&bgr;-D-manno-pyranosyl-(2R,3S)-erythritol (formula V):
Some glycolipids with a mannopyranosyl-erythritol framework have already been mentioned in the literature (G. Deml et al. Phytochemistry, 19, 83-87, 1980). The schizonellins A and B described therein, which differ in their structure from the compounds according to the invention of the formula (I) to (IV), have weak antibiotic activity and a strong hemolytic effect.
The invention also relates to a method for the production of said compounds of the formula I to IV, which comprises cultivating the microorganism Ustilago maydis FH 2634 (DSM 11494) or mutants and variants thereof in an aqueous nutrient medium, and then isolating and purifying the target compounds.
The microorganism Ustilago maydis FH 2634 (DSM 11494) was isolated from a soil sample. Said microorganism was deposited on Apr. 14, 1997, under the conditions of the Budapest treaty at the Deutsche Sammlung von Mikroorganismen und Zelikulturen, Mascheroder Weg 1b, D-38124 Braunschweig under the number DSM 11494.
Ustilago maydis DSM 1494 has white aerial mycelium and gray spore chains. It forms characteristic spore chains. In a nutrient solution containing a source of carbon and a source of nitrogen and the usual inorganic salts, Ustilago maydis DSM 11494 produces ustilipides.
In place of the strain DSM 11494 it is also possible to employ its mutants and variants as long as they synthesize the compounds according to the invention. Such mutants can be generated in a manner known per se by physical means, for example irradiation, such as with ultraviolet rays or X-rays, or chemical mutagens such as, for example, ethylmethanesulfonate (EMS); 2-hydroxy-4-methoxybenzophenone (MOB) or N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). Screening for mutants and variants
Kurz Michael
Noelken Gerhard
Vértesy László
Wink Joachim
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner LLP
Horlick Kenneth R.
Maupin Christine
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