Stromelysin inhibitors

Details Stromelysin inhibitors Stromelysin inhibitors

2000-12-15

2002-01-08

Killos, Paul J. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C560S068000, C560S067000, C560S070000, C514S765000

Reexamination Certificate

active

06337411

ABSTRACT:

The invention relates to stromemycin, stromemycin derivatives, processes for their preparation and use thereof as pharmaceuticals and stromelysin inhibitors.
Stromelysin (matrix metalloproteinase 3) is a matrix metalloproteinase which is substantially involved as an enzyme in the degradation of proteoglycans, which are important constituents of cartilaginous tissue (A. J. Fosang et al. J. Clin. Invest. 98 (1996) 2292-2299). Compounds which are structurally similar to stromemycin have been described by Yasuzawa et al. (The Journal of Antibiotics, Volume XLIII, No. 4, (1990), pages 336-343).
In the attempt to find efficacious compounds for the treatment of connective tissue disorders, it has now been found that the stromemycin according to the invention and the stromemycin derivatives are inhibitors of the matrix metalloproteinase stromelysin.
The invention therefore relates to the compound of the formula I
and/or a stereoisomeric form of the compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I, where
R
1
is selected from
a (C
3
-C
10
) linear or branched aklyl group which is unsubstituted, monosubstituted, disubstituted, or trisubstituted with a group selected from
—OR
3
where R
3
is selected from hydrogen and a (C
1
-C
4
)-alkyl;
NR
4
R
5
, where R
4
and R
5
are independently selected from hydrogen and a (C
1
-C
4
)-alkyl;
a halogen;
═O; and
—COOH; and
a (C
3
-C
10
) linear or branched alkenyl group which is unsubstituted, monosubstituted, disubstituted, or trisubstituted with a group selected from
—OR
3
where R
3
is selected from hydrogen and a (C
1
-C
4
)-alkyl;
NR
4
R
5
where R
4
and R
5
are independently selected from hydrogen and a (C
1
-C
4
)-alkyl;
a halogen;
═O; and
—COOH;
R
2
is selected from
a (C
3
-C
10
) linear or branched aklyl group which is unsubstituted, monosubstituted, disubstituted, or trisubstituted with a group selected from
—OR
3
where R
3
is selected from hydrogen and a (C
1
-C
4
)-alkyl;
NR
4
R
5
, where R
4
and R
5
are independently selected from hydrogen and a (C
1
-C
4
)-alkyl;
a halogen;
═O; and
—COOH; and
a (C
3
-C
10
) linear or branched alkenyl group which is unsubstituted or monosubstituted, disubstituted, or trisubstituted with a group selected from
—OR
3
where R
3
is selected from hydrogen and a (C
1
-C
4
)-alkyl;
NR
4
R
5
, where R
4
and R
5
are independently selected from hydrogen and a (C
1
-C
4
)-alkyl;
a halogen;
═O; and
—COOH; and
Z is a hexose which is in pyranoid form via a C-glycosidic bond.
A preferred compound of the formula I is one where
R
1
is nonadienyl,
R
2
is nonadienyl and
Z is D(+)-glucose, D(+)-mannose, D(+)-galactose or D(+)-talose.
Another preferred compound is
This compound is designated below as stromemycin.
The term hexose is understood as meaning all naturally occurring hexoses of the formula C
6
H
12
O
6
, for example D(+)-glucose, D(+)-mannose, D(+)-galactose or D(+)-talose.
The invention furthermore relates to a process for the preparation of the compound of the formula I and/or a stereoisomeric form of the compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I, which comprises
a) culturing the microorganism DSM 12038 or its mutants or variants in an aqueous nutrient medium and isolating and purifying the compound stromemycin, or
b) converting stromemycin by reductive hydrogenation into a compound of the formula I in which R
1
and R
2
are C
9
-alkyl, or
c) converting stromemycin by ozonolysis into a compound of the formula I in which R
1
and R
2
are
1.) —CH
2
CH
2
CH
2
—OH,
2.) —CH
2
CH
2
CHO or
3.) —CH
2
CH
2
COOH or
d) extending a compound of the formula I prepared by process c)2) by 1 to 7 methylene groups by reaction with alkylidenephosphoranes, where the side chains introduced can have functional groups such as hydroxyl, ether, amino groups or F, Cl, Br or I radicals,
e) separating a compound of the formula I, which on account of its chemical structure occurs in enantiomeric form, prepared by process a), b), c) or d) into the pure enantiomers by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the diastereomers thus obtained, and removal of the chiral auxiliary groups, or
f) either isolating the compound of the formula I prepared by process a), b), c), d) or e) in free form or, in the case of the presence of acidic or basic groups, converting it into physiologically tolerable salts.
The microorganism DSM 12038 belongs to the group consisting of the fungi and was deposited on Mar. 4, 1998 under the conditions of the Budapest Convention at the German Collection for Microorganisms and Cell Cultures, Mascheroder Weg 1b, D-38124 Brunswick under the number DSM 12038.
Variants of DSM 12038 are understood as meaning strains of DSM 12038 which have been obtained by isolation from a culture of DSM 12038, insofar as they produce stromemycin. Mutants of DSM 12038 are understood as meaning strains of DSM 12038 which were obtained from a culture of DSM 12038 after mutation, insofar as they produce stromemycin. Mutants of DSM 12038 can be produced in a manner known per se by physical means, for example irradiation such as ultraviolet or X-ray radiation or by chemical mutagens, for example ethyl methanesulfonate (EMS); 2-hydroxy-4-methoxybenzophenone (MOB) or N-methyl-N′-nitro-N-nitrosoguanidine (MNNG).
The mutants are found, for example, by taking samples from the culture medium and determining the inhibiting action on stromelysin. Stromemycin is produced by culturing DSM 12038. The nutrient solution contains carbon sources such as sucrose, cornstarch, dextrose, lactose, D-mannitol, molasses or malt extract and nitrogen sources such as soybean flour, groundnut flour, proteins, peptones, peptides, tryptones, meat extract, yeast extract or ammonium salts or nitrates.
The nutrient solution also contains inorganic salts such as sodium hydrogenphosphate, sodium chloride, calcium chloride, calcium sulfate, calcium carbonate, magnesium sulfate or potassium hydrogenphosphate. Fat such as methyl oleate or soybean oil can furthermore be added to the nutrient medium. In addition, trace elements such as iron, manganese, copper, zinc, cobalt or other metal salts are also added.
A preferred nutrient solution contains approximately from 0.1% to 2% of casein peptone, preferably from 0.3% to 1%, from approximately 0.1% to 2% of meat peptone, preferably from 0.3% to 2%, from 0.5% to 5% of glucose, preferably from 0.5% to 2%, and from 0.5% to 5% of maltose, preferably from 0.3% to 2%. The percentages relate to the weight of the total nutrient solution.
DSM 12038 is cultured at temperatures from 20° C. to 35° C., preferably at 23° C. to 28° C. and at pHs of 5 to 9, preferably at 4 to 6. Culturing is initially carried out aerobically in a shake flask and thereafter in a fermenter with stirring and aeration with air or pure oxygen. The microorganisms in the fermenters are cultured for a period of 48 to 240 hours, preferably of 15 to 72 hours, in particular of 15 to 30 hours. The formation of stromemycin reaches its maximum after approximately 15 to 30 hours.
Stromemycin is isolated directly from the nutrient solution or after separation of the cells, for example, by centrifugation or filtration. Stromemycin can be isolated by extraction with solvents or by adsorption on resins such as XAD 16, HP 20, MCI Gel® CHP20P or ion exchangers. Purification is carried out, for example, by chromatography on adsorption resins such as on Diaion® HP-20 (Mitsubishi Casei Corp., Tokyo), on Amberlite® XAD 7 (Rohm and Haas, USA), on Amberchrom® CG (Toso Haas, Philadelphia, USA). The separations can be carried out in a wide pH range. The range from pH 1 to pH 9, preferably from pH 2 to pH 8, is preferred. Reverse phase supports, which are employed in high-pressure liquid chromatography (HPLC), are moreover suitable. A further isolat

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