PAPYRACILLIC ACID, METHOD FOR PREPARATION AND ITS USE AS SYNTHON FOR BIOACTIVE SUBSTANCES

Abstract: This invention relates to a new biological active compound as shown in formula (I) and its biological active derivates; whereas derivates are produced by the reaction of formula (I) with nucleophiles.

Description: Papyracillic Acid, Method for Preparation and its Use as Synthon for Bioactive Substances Description This invention relates to a new biological active compound (I) The compound called papyracillic acid can be in an equilibrium of its open chain form. Due to its reactivity, compound (I) can be used as an educt for a wide range of new compounds. Possible derivatives of papyracillic acid are such where the hydrogen of the hydroxy group of C-l is substituted by a branched or an unbranched Cι-C4-Al ylester. Another possibility of derivatization of compound (I) is the reaction of (I) with different nucleophiles Y. The potency of (I) as an electrophile can be demonstrated by the reaction of (I) with the nucleophile cysteine or cysteine methyl ester. Both yield in essentially one respective product which is suφrisingly formed by nucleophic binding at C-9. The reaction between (I) and Ac 2 O in pyridin yields inter alia in a compound where Y symbolizes OAc. An introduction of an additional ring system into papyracillic structure can be demonstrated by the reaction of (I) with Trimethylsilyldiazomethane (TMSCHN 2 ). The reaction of (I) with TMSCHN 2 yields inter alia to products of 1 -3 dipolar cycloaddition. Again, the carbon on position C-9 of (I) is electrophilic. C-9 and C- 5 of (I) are members of the introduced ring system in papyracillic acid. An unexpected number of products was obtained under the acetylation conditions in pyridine and by the reaction of papycillic acid with glycine. Both reactions are illustrative examples that papyracillic acid can in addition be used as reactive electrophilic educt to create a diversity of products. This diversity of products can be used directly or after one or more separation steps as plurality of compounds like chemical libraries for the search of active principles as lead structures in drug discovery for further optimization. From such pluralities of compounds the active principle can be obtained by separation from the mixture. Such an active principle cannot only serve as lead structure but can be a pharmacophor or compound useful for plant protection by itself. Another aspect of the invention concerns the preparation of plurality of compounds by reacting papracillic acid with different reactive compounds, preferrable nuclephiles (which may be for example different heterocycles or with different amino acids). A method of determining whether a compound plurality or its subsets interact with a target of interest comprises a) providing a target of interest b) incubating said target with said compound or compound plurality c) determining whether said target exhibits a responsive change. Is such a compound selected for further lead structure optimization or pharmacophor identification as an additional step d), the variation of the structure of said compound can be performed. During the lead structure optimization and pharmacophor identification the variation of the structure can be done by conventional chemical means or molecular modelling. The same is true for steps a) to c) of the above-mentioned method which can be done by traditional biological/biochemical means or also by molecular modelling. Targets of interest are for example pharmaceutical or plant protection targets. Those targets include proteins (receptors, ion channels, signal transduction proteins, enzymes etc.), cells, parts of cells, DNA, RNA etc. Whether a compound or compound plurality shows a responsive change with the target of interest can be detected by, for example, colour reaction activation or inactivation of reactions etc. More particularly, this invention relates to papyracillic acid (I), derivatives and salts thereof especially their pharmaceutical acceptable salts, to process of preparation thereof and to bioactive, preferred pharmaceutical, compositions comprising the same. Further derivatives of papyracillic acid are obtained by reaction of (I) with alkylation agents. Prodrugs of papyracillic acid and its derivatives are included in this invention. For isolation and purification, pharmaceutical unacceptable salts can be used as well. The compound (I) and its derivatives can be solvated, especially hydrated. Hydration may happen during preparation or storage. Compound I and its derivatives show different asymmetric centres. The invention includes racemates and optically active forms of papyracillic acid. In addition it was found that papyracillic acid shows antibiotic activity. The invention includes fermentation fluids, extracts, and concentrated solutions which contain papyracillic acid or its derivatives. Papyracillic acid can be produced by cultuπng a papyracillic acid producing strain, e g Ascomycete Lachnum p pyraceum (Karst ) Karst in a nutrient medium containing CaBr 2 A related compound is Penicillic acid which is a classical mycotoxin produced by various fungi including the genera Penicillium and Aspergillus Together with patulin, isopatulin and ascladiol it constitutes a class of chemically relatively simple 5-membered cyclic lactones, which due to their toxicity and carcinogenicity are considered to be a potential health hazard to animals and man [R J Cole, R H Cox, Handbook of Toxic Fungal Metabolites, p 510-526, Acadamic Press, New York, 1981] Penicillic acid (II) can be used to create a multitude of libaries in a very similar manner as papyracillic acid In the case of penicillic acid the reactive carbon for nucleophilic binding is C-6 π The micro-organism which can be used for the production of papyracillic acid is a papyracillic acid producing strain belonging to the genus Ascomycetes Morphological, biological, physiological and cultural charactenstics of Ascomycetes Lachnum papyraceum can be found in [Dennis, R W G A revision of British Hyaloscyphaceae with notes on related European species Mycol Papers 32 Kew 1949, Karsten, P A , Mycologia Femica Parsprima Discomycetes Bildrag till Kannedom of Finnlands Natural Folk, Helsingtors, pp 1-263, 1871] Synonyms used for Lachnum papyraceum are: Lachnum (syn. Dasyscyphella, Dasyscyphus, Dasyscypha) papyraceum (syn. papyraceus) (Karst.) P. Karst. [Ainsworth, G.C, Sparrow, F.K. & Sussman, A.S. (eds.) The fungi. An advanced treatise. Vol IV A: A taxonomic review with keys: Ascomycetes and Fungi Imperfecti. Academic Press New York London (1976), p. 297]. Ascomycetes Lachnum papyraceum, strain 48 ~ 88, was collected in 1988 in Hinterstein, Germany. A voucher specimen, which showed the characteristics of the genus and species according to Dennis and Karsten, and strain A 48 ~ 88 (obtained from the ascospores) are deposited in the herbarium and the culture collection of the Lehrbereich Biotechnology, University of Kaiserslautern. It is deposited as well with DSM, Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg lb, D-38124 Braunschweig, Germany, under accession number DSM 10201 (the deposition date is August 3, 1995). It is to be understood that the production of papyracillic acid is not limited to the use of the particular organism described herein, which is given for the illustrative purpose only. This invention also includes the use of any mutants which are capable of producing papyracillic acid including natural mutants as well as artificial mutants which can be produced from the described organism by conventional means such as irradiation of X-ray, ultra-violet radiation, treatment with N-methyl- N'-nitro-N-nitrosoguanidine, 2-aminopurine, and the like. For growth of Ascomycetes Lachnum papyraceum and therefore production of papyracillic acid, all suitable culturing methods can be used resulting in production of sufficient bio mass. In general, seeding of Ascomycetes Lachnum papyraceum and fermentation to papyracillic acid is independent of used container, fermentors and starter proceedings. Fermentation ofthe fungus was sucessful in MGP medium [Example 1, Lit. Stadler et al. J. Antibiotics 48, 149-154, 1995] with 100 mM calcium bromide, but other culture media like BAF medium [Singer, R. The Agaricales in modern taxonomy. Springer Verlag Berlin/Heidelberg/New York 1976), YMG media (glucose 0,4% or 1% respectively; malt extract 1,0%, yeast extract 0,4%, and malt extract medium (malt extract 0,5 - 5%) were also suitable for the production of papyracillic acid. The production of compounds I was also observed in Potato Dextrose broth, CMG broth, Czapek-Dox broth (with glucose or sucrose respectively) and cornmeal medium (if not specified otherwise, these culture media are described in the ATCC Media Handbook, American Type Culture Collection Rockville Md, USA 1984). Assays for antibiotic activity of the extracts of fermentations to which 100 mM CaBr2 was added at the onset ofthe secondary metabolism indicated that strongly active metabolites are formed during these conditions, and TLC analyses show that a new product that has not been observed during previous fermentations of the fiingus is formed in large amounts. The new product (I) was obtained by silica gel chromatography, and spectroscopic characterisation by NMR suggested that it is a mixture of four isomers (approximately 1 :1 :2:4 in chloroform according to the H NMR spectrum). Preferred fermentation conditions and media are given in example 1 Derivatives of papyracillic acid Derivatives of papyracillic acid, where C-7 of I is substituted by OR instead of OH with R equals Cι-C 4 -Alkyl are included in this invention. These compounds can be generally obtained by reaction of compound (I) under appropriate conditions (e.g. example 3). The methylation of papyracillic acid (I) with Trimethylsilydiazomethane (TMSCHN 2 ) in Benzene/Methanol 1 : 1 yielded an unexpected number of products (cf. Example 4-6). The methyl ester III is formed rapidly, and is the major product as long as reaction time is short (minutes). In addition, the two azo derivatives (IVa) and (IVb) were formed together with the ester (III). The formation of similar cyclic azo products (via a 1,3-dipoIar cycloaddition of the reagent to the double bond) when α,β- unsaturated carbonyl compounds are treated with diazomethane or TMS- diazomethane has been reported, although these normally are oxidised to pyrazoles or rearranged to pyrazolines. [Aoyama, T.; Iwamoto, Y.; Nishigaki, S.; Shiori, T. Chem. Pharm. Bull. 1989, 37, 253-256]. Papyrallic acid (I) can be used for synthesizing a huge number of different compound pluralities by reaction of (I) with different nucleophiles Y. Compound pluralities consisting either of reaction products of (I) with a single nucleophile Yi or a number of different nucleophiles Yi, Y 2 ... Y n can be used for screening of new drugs or lead structures for drugs in different assays. In the case of desired results (e.g. activation or inhibition of a reaction of interest in a receptor or cell assay), sets of compound pluralities can be constructed. Such subsets are either produced by reducing the number of nucleophiles reacting or by separation of groups of products from the compound plurality by conventional means like chromotography, solvent extraction etc. If, for example, the multitude of individual products reduce the effective amount for the single product to a concentration to low for meaningful assaying either pure substances or subsets of substances can be used for assaying. Pure substances are obtained by conventional purification technology. Interesting compound libraries are produced by the reaction of a nucleophile Y with the electrophilic C-9 of (I). Examples of nucleophiles are amines, alcohols and thiols all of aliphatic or aromatic hydrocarbons which may be substituted by themselves. Other examples of nucleophiles are substituted or unsubstituted heterocycles. Such are for example pyridine, pyridazine, pyrimidine, pyrazine, thiazols, oxazols, imidazols, purins, chinolins, benzochinolins etc. In a similar way compound pluralities with penicillic acid (II) as electrophile are synthesized. An example of a single library with (I) is shown in the following scheme. (I) (V) a: R = H; b: R = CH 3 . The reaction between papyracillic acid (I) and cysteine and its methyl ester was fast and yielded essentially one respective product. No attack on C-3 of papyracillic acid (I) was observed. The structures of the adducts (Va) and (Vb) were determined by the HMBC correlations observed between 9-H2 and C-l 1, as well as between 11-H2 and C-9, and the NOESY correlations between 6-H and 5- H as well as 8-H3, between 9-H2 and IO-H3, and between 3-OCH3 and 5-H. In the case of reaction with Glycin a huge number of products is obtained. To illustrate the plurality of reactions which papyracillic acid (I) is able to undergo, (I) was acetylated in pyridine and it was observed that several products are formed. The major product was found to be compound (VI) which together with compound (Vila) may be formed by the addition of acetate to the electrophilic papyracillic acid (I). In addition, and unexpectedly, the three indolizine derivatives (VIII), (IX) and (X) were obtained, apparently formed after the nucleophilic attack by pyridine. The NMR chemical shifts of compounds (VIII), (IX) and (X) are in agreement with published data on indolizines and the structures ofthe compounds were determined by COSY, NOESY, HMQC and HMBC NMR experiments. Although pyridine is considered to be a weak nucleophile it can react with Michael-acceptors and the hypothetical compound (Vllb) could be a precursor of the indolizines. Compound (VIII) could then be formed after abstraction of 9-H of (Vllb), formation of a bond between C-4 and C-2' of the pyridyl residue, followed by hydrolysis ofthe enol ether and decarboxylation. The acetyl groups at C-3 of compounds (IX) and (X) are probably added during the reaction, as indolizines are known to be acetylated in this position by pyridine/acetic anhydride. However, the indolizine skeleton of compounds (IX) and (X) would appear to be formed after an attack by the cojugated enol of (Vila) on C-2' of the pyridyl residue. In addition, a series of transformations including deacetylation and oxidation would have to take place, and the methyl group at C-l in compounds (IX) and (X) would be the C-6 methyl group of papyracillic acid (I). VIII IX a: R = OAc; b: R = 1 -pyridyl. The proposed mechanism for the formation of VIII and IX is shown in the following scheme. As starting reaction the nucleophilic binding ofthe nucleophile at C-9 is suggested. In the case ofthe formation of VIII and IX the nucleophile is pyridine. The scheme illustrates two ofthe different reaction passes (I) can follow after initial nucleophilic binding of a nucleophile Y to C-9 of I. / Deacetylation Acetylation Oxidation IX As an additional example, penicillic acid (II) was also acetylated, and the major products were isolated and characterised. The corresponding products were obtained, compound (XI) corresponds to compound (VI), (XII) is similar to (VIII) except that (XII) also was acetylated at C-3, and in (XIII) the C-3 acetyl group has (as the enol) been acetylated while the hydrolysis/decarboxylation has not taken place. (XHI) was obtained pure as the ethyl ester (Xlllb), formed during the evaporation of pyridine which was expedited by the addition of ethanol. XI xπ xm R a: R = H; b: R = Et Preferred compound pluralities for search of lead structures and new drugs are obtained by reaction of I or II with heterocycles with nucleophilic activity more preferrable in addition to aceticanhydrid or chemical equivalents. Such libraries may have inter alia the following structure. where W-V are part of heterocycle backbone, one W or V is preferrable, a heteroatom N, S or O and the other represents a C or CH. a, b and c are part of the backbone of papyracillic or penicillic acid, where the carbons a, b, c are C-4, C-5 and C-6 of penicillic acid or a, b, c are C-4, C-5, C- 9 of papyracillic acid respectively. Rι, R and R 3 represent either residues of papyracillic acid or residues formed by decarboxylation, acetylation, solvolysis etc. between the c-carbon and V is optionally a double bond. Biological activity of papyracillic acid Papyracillic acid and its derivatives show interesting pharmaceutical properties in different test systems. For example antibacterial activity (< 10 μg/ml) was found for (I) against Bacillus brevis, Bacillus substilis, Micrococcus luteus and Enterobacter dissolvens. Antifungal activity is observed with less or about 5 μg/ml against Nematosopra coryli. It is less active (10 μg/ml) with Mucor miehei, Penicillium notatum, Paecilomyces varioti. The cytotoxic activity (IC 0) is determined to be in the range of 2-5 μg/ml. The plate diffusion test was performed as described in "Biology of Antibioties", Springer Verlag, N.Y. 1972. The nutrient broth for bacteria was obtained from DIFCO. The growth medium for fungi and yeast contained 4 g yeastextract, 10 g Maltose, 4 g Glucose and 20 g Agar per 1 1 water. Biological activity of libraries with papyracillic acid as educt and deconvolution of libraries for identification of a single compound as drug or lead structure. A compound plurality was obtained as given in example 8. This compound plurality was active in assay (here fibrinogen-lowering assay). The compound plurality shows a fibrinogen synthesis inhibition of about 75% at 100 μg/ml. This compound plurality was deconvoluted into subsets by chromotographical extraction in 10 single compounds. One of them, compound (X), shows a very effective fibrinogen-lowering activity. The test principle is the inhibition of fibrinogen synthesis in the human hepatoma cell line HepG2. HepG2 cells were grown in culture flasks in MEM culture medium containing 10% fetal calf serum. 10 5 cells ml were seeded in 96-well-microtiter plates (Maxisorb®). The test substance was diluted in cell culture medium and added in increasing concentrations to the cells immediately after seeding. After a 48 hours' incubation period the supernatant is removed from the cells and the fibrinogen content was determined by ELISA. Plates were first coated overnight with 100 μl of a monospecific polyclonal antibody directed against fibrinogen. After removing the excess antibody, the plates were washed three times with PBS/0.05% Tween®- 20 and were subsequently incubated at room temperature for 1 hour in PBS/0.1% casein to block unspecific binding sites. After another wash 100 μl aliquots of the appropriately diluted supernatant were added per well in triplicate and immunocomplexing as well as detection of the complexes formed were performed using a horseradish peroxidase (POD)-labelled monoclonal antibody directed against the E-domain of fibrin for immunodetection. ABTS® reduction catalyzed by POD was used for quantification, monitoring the absorbance at 405 nm by means of an ELISA reader. Inhibition of fibrinogen synthesis was calculated as percentage of the fibrinogen content in the supernatant of wells containing untreated cells (controls) on the same microtiter plate. Control Fibrinogen 840 ng/ml Fibrinogen Synthesis Inhibition Compound (X) 10 μg/ml 3 μg/ml 1 μg/ml 0.3 μg/ml 0.1 μg/ml IC 50 μg/ml 77 30 10 6 1 5 Pharmaceutical compositions of papyracillic acid and its derivate. In order to produce pharmaceutical agents, the compounds of the general formula (I) or its derivates are mixed in a know manner with suitable pharmaceutical carrier substances, aromatics, flavourings and dyes and are formed for example into tablets or coated tablets or they are suspended or dissolved in water or an oil such as e.g. olive oil with addition of appropriate auxiliary substances. The substance ofthe general formula (I) or its derivates can be administered orally or parenterally in a liquid or solid form. Water is preferably used as the injection medium which contains the stabilizing agents, solubilizers and/or buffers which ar usually used for injection solutions. Such additives are for example tartrate or borate buffers, ethanol, dimethylsulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular polymers (such as liquid polyethylene oxide) for the regulation of the viscosity or polyethylene oxide) for the regulation ofthe viscosity or polyethylene derivatives of sorbitol anhydrides. Solid carrier substances are e.g. starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acid, higher molecular fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular polymers (such as polyethylene glycols). Suitable formulations for the oral application can if desired contain flavourings and sweeteners. The administered dose depends on the age, the health and the weight of the recipient, the extent ofthe disease, the type of treatments which are possibly being carried out concurrently, the frequency ofthe treatment and the type ofthe desired effect. The daily dose of the active compound is usually 0.1 to 50 mg/kg body weight. Normally 0.5 to 40 and preferably 1.0 to 20 mg/kg/day in one or several applications per day are effective in order to obtain the desired results. Structure of papyracillic acid and its derivatives The structure determination of papyracillic acid (I) and its derivatives is based on 2D NMR experiments, and pertinent HMBC correlations. No molecular ion could, as expected, be observed in the EI or CI mass spectra of the two azo derivatives (IVa) and (IVb), however, by decreasing the temperature of the ion source from 250 °C to 110 °C the ion M+NHj "1" (m/z 300) was approximately as abundant as the M-N 2 +NH 4 + (m/z 272) in the CI (NH 3 ) mass spectra of both compounds. In addition, the ions for M2+NH + (m/z 582), M2-N 2 +NH4 + ( /z 554) and M2- N4+NH4 + (m/z 526) became stronger (3-5 % of the base peak). The relative stereochemistry of (IVa) and (IVb) was suggested by the NOESY correlations observed and the chemical shifts of the C-6 methyl groups in the l H NMR spectrum. IO-H3 correlate strongly to one of protons of C-9 and one of C-l 1 in both compounds, while 8-H3 do not, suggesting that the C-6 methyl group is positioned above the five-membered ring in the most stable conformation of the two compounds. This is further supported by the weaker NOESY correlation observed between the C-3 methoxy protons and 6-H. The chemical shift for IO-H3 is shifted upfield with 0.4 ppm in compound (IVa) compared to compound (IVb), and this could be explained by the stronger anisotropic effect of the azo function on IO-H3 of compound (IVa). The following examples are given for the purpose of illustrating this invention. Example 1 Strain A 48 ~ 88 of Lachnum papyraceum was maintained and cultivated on MGP medium (maltose 2%, glucose 1%, soypeptone 0.1%, yeast extract 0.1%, KH 2 PO 4 0.1%, MgSO 4 0.005%, CaCl 2 xH 2 O lOmM, FeCl 3 6μM, ZnSO 4 7H 2 O 6μM) and in the presence of 50-500 mM CaBr 2 . Fermentations were carried out in a 20-liter fermentor (Braun Biostat U) at 24°C with an aeration rate of 3.2 liters/minute and agitation (140 φm). Oxygen saturation of the culture broth was measured using a Braun Oxygen electrode. Aliquots of the culture fluid (100ml) were extracted twice with ethyl acetate. The combined extracts were dried with Na 2 SO 4 . An extract of Lachnum papyraceum was dissolved in methanol (50 ml), and subjected to flash chromatography on a silica gel column eluted with ethyl acetate/ eptane 1 :1. The fractions were analysed by TLC on silica gel plates in toluene: acetone 7:3, the Rf value of papyracillic acid in this system is 0.60 and upon spraying the plate with anisy aldehyde/sulfuric acid it gives a deep-green coloured spot. The fractions containing papyracillic acid were purified once more in the same system (silica gel column eluted with ethyl acetate: heptane 1 :1) whereafter pure papyracillic acid was obtained from recrystallisation in methanol: water 1:5. The NMR spectra were recorded with a Bruker ARX500 spectrometer, the UV spectra with a Perkin Elmer λl6, the IR spectra with a Bruker IFS48, and the mass spectra with a Jeol SX102 spectrometer. Example 2 Papyracillic acid (I) was obtained as white crystals, m.p. 97-99°C. [CX]D 0° (c 1.0 in methanol). UN (methanol) ^ (ε): 226 nm (6,200). IR (KBr): 3450, 2920, 1770, 1640, 1360, 1210, 940 and 860 cnr 1 . l H ΝMR (500 MHz in CDC1 3 ), δ, mult. J (Hz): 5.23-5.05, 2-H and 9-H 2 ; 3.89, 3.85, 3.84 and 3.83, 4s, 3-OCH 3 ; 2.89, dm, J6-10=7.2; 2.84, 2.75 and 2.66, ddq, J 6 -9a=3, J6-9b=3, Jό-10=7, 6-H; 1.57, 1.54, 1.38 and 1.36, 4s, 8-H3; 1.14, 1.13, 1.13 and 1.10, 4d, J6-ιo=7, IO-H3. 13 C ΝMR (125 MHz in CDCI3), δ: 178.2, 177.9, 176.7 and 176.2 C-3; 170.4, 170.3, 170.2 C-l; 149.4, 148.3, 148.2 and 147.8 C-5; 111.4, 111.3, 111.2 and 110.9 C-9; 109.5, 109.2, 107.3 and 107.3 C-7; 107.3, 107.3, 107.1 and 106.2 C-4; 91.1, 90.2, 88.8, 88.4 C-2; 60.1, 60.0, 60.0, 59.8 OCH3; 47.9, 47.4, 47.0 and 45.1 C-6; 25.1, 24.4, 22.6 and 22.4 C-8; 15.2, 12.7, 10.9 and 10.4 C-10. MS (EI, 70 eV), m/z: 209.0791 (M + - OH, 100%, C 11 H 1 3O 4 requires 209.0814), 184 (12 %), 166 (56 %), 139 (29 %), 123 (13 %), 69 (18 %), 43 (24 %). Example 3 The reaction of I yielding Acetals is performed in a usual manner by katalyzing with acid. The methylated compound of (I) (OCH 3 @ C-7 of (I)) was obtained by stirring at room temperature leaving Papyracillic acid (I) in Methanol with traces of trifluoracetic acid present. A mixture of isomers was obtained, from which the methylated compound could be isolated as the major isomer. White crystals, m.p. 116-118°C. [α]p 42° (c 1.3 in methanol). UV (methanol) λ-^ (ε): 224 nm (9,800). IR (KBr): 2940, 1770, 1640, 1460, 1360, 1210, 950 and 870 cm-1. *H NMR (500 MHz in CDC1 3 ), δ, mult. J (Hz): 5.12, d, J6-9a=3, 9-HA; 5.10, d, j 6 -9b =3, 9-Hb; 5.01, s, 2-H; 3.81, s, 3- OCH3; 3.23, s, 7-OCH3, ddq, J 6 -9a =3, τ 6-9b =3, M0-6.8, 6-H; 1.43, s, 8-H3, 1.08, d, J6-10=6.8, IO-H 3 . 13 C NMR (125 MHz in CDCI3), δ: 178.0 C-3; 170.1 C- 1; 148.5 C-5; 109.6 C-9; 109.1 C-7; 106.8 C-4; 88.1 C-2; 59.6 3-OCH3; 49.2 7- OCH3; 48.5 C-6; 18.7 C-8; 10.3 C-10. MS (EI, 70 eV), m/z: 209.0788 (M+ - OCH3, 54%, C11H13O4 requires 209.0814), 166 (100%), 151 (29 %), 123 (31%), 69 (39%), 43 (43%). Example 4 Methyl papyracillate (III) was obtained as a colourless oil. [α]o +25 ° (c 1.0 in chloroform). UV (methanol) k^ (ε): 224 nm (11,700). IR (KBr): 2950, 1715, 1685, 1620, 1370, 1195, 1145 and 1020 cm' 1 . l H NMR (500 MHz in CDCI3), δ, mult. J (Hz): 6.00 and 5.95, 2s, 9-H 2 ; 5.23, s, 2-H; 3.82, q, J6-ιo=7.2, 6-H; 3.70, s, 3-OCH3; 3.56, s, I-OCH 3 ; 2.15, s, 8-H 3 ; 1.19, d, J 6 -io=7.2, IO-H3. 13 C NMR (125 MHz in CDCI3), δ: 207.8 C-7; 191.0 C-4; 167.2 C-3; 166.2 C-l; 146.1 C-5; 129.2 C-9; 93.1 C-2; 56.8 3-OCH 3 ; 51.1 I-OCH 3 ; 45.4 C-6; 28.4 C-8; 15.1 C-10. MS (EI, 70 eV), m/z: 240.0976 (M + , 20 %, C15H22O2 requires 240.0998), 208 (42 %), 198 (99 %), 166 (60 %), 139 (100 %), 123 (29 %), 69 (42 %), 43 (73 %). Example 5 Compound (IVa) was obtaines as white crystals, m.p. 97-99°C, in 10% yield after methylation of papyracillic acid (I) with TMS-diazomethane in methanol: benzene 1:1 at room temperature for 5 h. [α]o +34 ° (c 0.6 in chloroform). UV (methanol) λmax (ε): 222 n (7,800). IR (KBr): 2920, 1710, 1700, 1620, 1445, 1360, 1200, 1140, 1070 and 815 cm" 1 . *H NMR (500 MHz in CDCI3), δ, mult. J (Hz): 5.14, s, 2-H; 4.66, ddd, J9a-lla=64, j 9 b-lla=10.2, Jlia-llb=18 2, 11-Ha; 4.56, ddd, j 9a - llb=9-9, J9b-llb=5.7, j πa . l lb =18.2, 11-Hb, 4.01, q, J 6 -10=7.0, 6-H; 3.80, s, 3- OCH3; 3.57, s, 1-OCH3; 2.23, s, 8-H3; 2.12, ddd, J 9a . 9b =13.9, J a -n a =6.4, J 9a . H b =9.9, 9-Ha; 2.04, ddd, J 9a - 9 b=13.9, J 9 b-l l a=10.1, J 9b -llb=5.7; 0.79, d, J 6 - 10 =7.0, 10-H3. 13C NMR (125 Mhz in CDCL3), : 208. C-7; 197.7 C-4; 167.5 C- 3; 166.9 C-l; 105.2, C-5; 93.0 C-2; 79.1 C-l l; 57.4 3-OCH3; 51.6 1-OCH3; 47.3 C-6; 31.2 C-8; 20.3 C-9; 11.2 C-10. MS (EI, 79 eV), m/z: 254.1137 (m+-N2, 5%, C13H18O5 requires 254.1154), 222 (8%), 212 (32%), 211 (19%), 179 (17%), 153 (100%), 137 (18%), 111 (21%), 69 (26%), 43 (50%). MS (CI, nH3, ion source temperature 20°C ), m/z: 272 (m-N2+NH4+, 82%), 255 (m-N2+H+, 13%), 237 (32 %). Example 6 Compound (IVb) was obtained as a colourness oil in 10% yield after methylation of papyracillic acid (I) (vide supra). [α]o +10 ° (c 0.5 in chloroform). UV (methanol) k^ (ε): 222 nm (8,400). IR (KBr): 2920, 1700, 1615, 1435, 1360, 1190 and 1140 cm" 1 . *H NMR (500 MHz in CDC1 3 ), δ, mult. J(Hz): 5.15, s, 2-H; 4.66, ddd, J 9a -lla=6.3, J 9 b-lla=8 5, Jlla-llb=18 1, H-Ha; 4.63, ddd, J9a-1 lb=7 9, 6-H; 3.84, s, 3OCH3; 3.55, s, 1-OCH3; 2.13, s, 8-H3; 2.07, ddd, J 9a . 9b =12.7, d, J 9b -ii a =8.5, J 9 b-l l b=7 0, 1.17, d, τ 6-io=7.2, 10-H3 13C NMR data were not recorded. MS (EI, 70 eV), m z: 254.1159 (m+-N2, 7%, C13H18O5 requires 254.1154), 223 (12%), 212 (38&), 211 (59%), 179 (30%), 153 (100%), 137 (28%), 111 (37%), 69 (38%), 43 (72%). MS (CI, NH3, ion source temperature 250 o C), m/z: 272 (m-N2+NH4+, 100%), 255 (M-N2+H+, 27%), 237 (34%). MS (CI, NH3, ion source temperature 110 o C), m/z: 300 (M+NH4+, 100%), 272 (M-N2+NH4+, 85%), 255 (m- N2+H+, 8%), 237 (23%). Example 7 The compounds (V) were obtained as a mixture (library) or as single compounds as follows: Compound (Va) was obtained as yellowish oil in 42% yield after the reaction between papyracillic acid (I) (29 mg, 0.13 nmol) and cysteine (29 mg, 0.12 nmol) in 1 ml Phosphatpuffer pH7, 0.1M at 37° C for 15 mins and purification by reversed phase HPLC (O to 30% methanol in water during 60 min) and repeated silica gel chromatography (MTBE:MeOH 8: 1). [α]o -125° (c 1.0 in methanol). UV (methanol) λ,^ (e): 224 nm (6,400). LR (KBr): 3420, 1750, 1640, 1390 and 870 cm- 1 . l H NMR, 500 MHz in CD 3 OD (δ, mult., J): 5.26, s, 2-H; 3.96, s, 3-OCH 3 ; 3.70, dd, Jna-12=3.6, 11- Ha; 2.87, dd, Ju a - l lb=14.6, Jn b -12=8.8, 11-Hb; 2.83, dd, J 5 - 9 a=3.8, J 9a - 9b =13.5, 9-Ha; 2.74, m, 5-H; 2.59, dd, J 5 .9b=10.2, J 9a . 9b =13.5, 9-Hb; 2.03, dq, J 5 -6=11.5, J6-10=6.7, 6-H; 1.47, s, 8-H3; 1.11, d, J6-io=6 7, IO-H3. 13 C NMR, 125 MHz in CD3OD (δ): 180.1 C-3; 172.8 and 172.7 C-l and C-13; 110.0 C-4; 108.8 C-7; 91.3 C-2; 60.7 3-OCH 3 ; 54.8 C-12; 49.1 C-5; 47.6 C-6; 34.7 C-l l; 29.8 C-9; 26.6 C-8; 12.2 C-10. MS (FAB positive ions), m/z: 370 (M + Na + ) and 348 (M + IT). The cysteine methyl ester adduct Compound (Vb) was obtained as a yellow oil in 52 % yield after the reaction between papyracillic acid (I) (29 mg, 0.13 mmol) and cysteine methyl ester (21 mg, 0.12 mmol) in 1 ml Phosphatpuffer pH7, 0.1M at 37° C for 15 mins and purification by reversed phase HPLC (O to 30% methanol in water during 60 min) and repeated silica gel chromatography (MTBE:MeOH 8:1). [α] D -106° (c 1.0 in methanol). UV (methanol) k^ (ε): 222 nm (8,200). IR (KBr): 3400, 2950, 1750, 1640, 1450, 1380, 1220, 1020 and 870 cm" 1 . Η NMR, 500 MHz in CDCI3 (δ, mult., J): 5.07, s, 2-H; 3.90, s, 3-OCH3; 3.70, s, I3-OCH3; 3.60 J dd, Jι la . 12 =4.7, J U b-i2=7.2, 12-H; 2.83, dd, Jn a -iib=13.5, Jιι a .ι 2 =4.7, 11- Ha; 2.70, dd, Jπ a -nb=13.5, Jnb-12=7.2, 1 1-Hb; 2.67-2.52, , 9-Ha, 5-H and 9- Hb; 2.00, dq, J 5 -6=H 5, J 6 -io=6.7, 6-H; 1.49, s, 8-H3; 1.08, d, J 6 -io=6 7, IO-H3. 13 C NMR, 125 MHz in CDCl 3 (δ): 177.1 C-3; 174.1 C-13; 169.6 C-l; 108.1 C-4; 107.2 C-7; 90.4 C-2; 59.7 3-OCH ; 53.6 C-12; 52.3 13-OCH 3 ; 48.2 C-5; 46.0 C- 6; 37.8 C-l l; 29.5 C-9; 26.2 C-8; 11.7 C-10. MS (FAB, positive ions) m/z: 362 (M + H * ). Example 8 Compounds (VI) - (X) were obtained after the treatment of papyracillic acid (I) with acetic anhydride:pyridine (1:5) at room temperature for 16 hours. The yields after separation were 63 % of (VI), 9 % of (VII), 5 % of compound (VIII), 3 % of (IX), and 7 % of (X). Compound (VI), 5-Acetoxy-4-methoxy-5-(l-(l-methyl-2-oxopropyl)vinyl)-2,5- dihydro-2-furanone was obtained as white crystals, m.p. 55-57 °C, as a 3:2 epimeric mixture. [α]o +25 ° (c 1.1 in chloroform). UV (methanol) ^ (ε): 230 nm (7,400). LR (KBr): 1776, 1716, 1343, 1197, 1178, 1070 and 1028 cm" 1 . l NMR, 500 MHz in CDC1 3 (δ, mult., J): 5.55 and 5.21, m, 9-H 2 ; 5.20 and 5.13, s, 3-H; 3.85 and 3.87, s, 2-OCH3; 3.27 and 3.43, q, J6-io=7.0, 6-H; 2.10 and 2.06, s, 8-H3; 2.04 and 2.01, s, 4-OAc; 1.12 and 1.19, d, J6-ιo=7.0, IO-H3. 13 C NMR, 125 MHz in CDCI3 (δ): 207.1 and 207.6 C-7, 177.1 and 177.7 C-2; 168.2 and 168.2 C- 1; 167.2 and 167.2 4-OAc; 142.2 and 142.7 C-5; 117.7 and 117.4 C-9; 101.0 and 100.9 C-4; 90.5 and 89.8 C-3; 59.8 and 59.9 2-CH 3 ; 46.5 and 47.7 C-6; 27.7 and 27.3 C-8; 21.1 and 21.1 4-OAc; 17.1 and 16.5 C-10. MS (EI, 70 eV), m z: 226.0860 (M + - CH 2 CO, 12 %, C11H14O5 requires 226.0841), 209 (6 %), 208 (6 %), 166 (100 %), 151 (14 %), 139 (25 %), 123 (21 %). MS (CI, NH3), m/z: 286 (M + NH4 + , 100 %). Compound (Vila), 5-(l-Acetoxymetyl-2-methyl-3-oxo-(Z)-butylidene)-4- methoxy-2,5-dihydro-2-furanone was obtained as white crystals, m.p. 54-56 °C. [α]D +250 ° (c 1.1 in chloroform). UV (methanol) k^ (ε): 263 nm (11,400). IR (KBr): 1782, 1745, 1717, 1607, 1441, 1366, 1229, 1027 and 970 cnr 1 . Η NMR, 500 MHz in CDCI3 (δ, mult., J): 5.38, s, 2-H; 5.10, d, J 9a . 9b =12.9, 9-Ha; 4.86, d, J 9a . 9b =12.9, 9-Hb; 3.94, s, 2-OCH3; 3.93, q, J 6 -io=7.0, 6-H; 2.13, s, 8-H3; 1.97, s, 4-OAc; 1.22, d, J6-io=7.0, IO-H3. 1 C NMR, 125 MHz in CDCI3 (δ): 206.0 C- 7; 170.4 4-OAc; 170.1 C-2; 166.6 C-l; 143.1 C-4; 120.3 C-5; 92.0 C-3; 59.7 2- CH3; 58.2 C-9; 47.6 C-6; 28.3 C-8; 20.5 4-OAc; 12.9 C-10. MS (EI, 70 eV), m/z: 268 (M + , 2 %), 226.0852 (M + - CH 2 CO, 33 %, C11H1 4 O5 requires 226.0841), 209 (3 %), 166 (100 %), 151 (1 1 %), 137 (14 %), 123 (16 %). MS (CI, NH 3 ), m/z: 286 (M + NH 4 + , 100 %). Compound (VIII), l-Acetyl-2-(l-methyl-2-oxo-propyl)-indolizine was obtained as a greenish oil. [α]o +428 ° (c 1.2 in chloroform). UV (methanol) k^^ (ε): 233 nm (20,200), 271 nm (4,000), 280 nm (4, 000), 350 nm (11,900). IR (KBr): 1711, 1622, 1501, 1426, 1352, 1238, 1158 and 963 cm' 1 . •H NMR, 500 MHz in CDCI3 (δ, mult., J): 7.97, d, J 5 - 6 =6.8, 5-H; 7.84, d, J 7 - 8 =9.2, 8-H; 7.18, d, J -io=0.8, 3- H; 7.08, dd, J 6 . 7 =7, J 7 . 8 =9, 7-H; 6.71, dd, J 5 - 6 =J6- 7 =7, 6-H; 4.62, dd, J -io=0.8, J10-13=7.2, 10-H; 2.61, s, 15-H 3 ; 2.31, s, 12-H 3 ; 1.47, d, Jιo- l 3=7.2, 13-H 3 . 1 C NMR, 125 MHz in CDCI3 (δ): 209.9 C-1 1; 192.0 C-14; 136.3 C-9; 132.1 C-2; 126.4 C-5; 123.4 C-7; 119.0 C-8; 114.1 C-3; 112.2 C-6; 112.2 C-l; 45.0 C-10; 31.0 C-14; 28.8 C-12; 16.4 C-13. MS (EI, 70 eV), m/z: 229.1105 (M + , 87 %, C1 4 H 1 5O2N requires 229.1103), 214 (10 %), 212 (8 %), 186 (100 %), 172 (65 %), 170 (28 %), 144 (79 %), 143 (39 %). MS (CI, NH 3 ), m/z: 230 (M + H + , 100 %). Compound (DQ, 5-(3-Acetyl-l-methyl-2-indolizinyl)-5-acetoxy-4-methoxy-2,5- dihydro-2-furanone was obtained as a greenish oil. [α]o +84 ° (c 0.4 in chloroform). UV (methanol) k^ (ε): 231 nm (28,400), 377 nm (6,700). IR (KBr): 1775, 1648, 1453, 1370, 1339, 1198, 1159 and 1013 cm" 1 . l H NMR, 500 MHz in CDCI3 (δ, mult., J): 8.95, d, J5-6=7.3, 5-H; 7.43, d, J7-8=9 0, 8-H; 6.94, dd, J6- 7 =6.5, J 7 -8=9.0, 7-H; 6.71, dd, J 5 -6=J6- 7 =7, 6-H; 5.33, s, 12-H; 3.94, s, 11- OCH 3 ; 2.69, s, I6-CH3; 2.31, s, M-H3; 2.14, s, 10-OAc. 13 C NMR, 125 MHz in CDCI3 (δ): 192.9 C-15; 177.8 C-11; 168.4 C-13; 167.4 10-OAc; 133.6 C-9; 126.1 C-5; 122.7 C-2; 122.4 C-3; 121.1 C-7; 117.2 C-8; 113.8 C-6; 109.1 C-l; 101.0 C- 10; 90.6 C-12; 60.0 I I-OCH3; 31.9 C-16; 21.5 10-OAc; 9.8 C-14. MS (EI, 70 eV), m/z: 343.1059 (M + , 88 %, Cι 8 Hι 7 O 6 N requires 343.1056), 300 (8 %), 283 (20 %), 258 (79 %), 242 (100 %), 200 (45 %). MS (CI, NH3), m/z: 344 (M + H + , 59 %), 284 (100 %). Compound (X), 5-(3-Acetyl- 1 -methyl-2-indolizinyl)-4-methoxy-2,5-dihydro-2- furanone was obtained as a greenish oil. [α]o +239 ° (c 1.5 in chloroform). UV (methanol) ^ (ε): 230 nm (17,400), 259 nm (7,900), 378 nm (4, 800). IR (KBr): 1754, 1632, 1458, 1375, 1235 and 1158 cnr 1 . } H NMR, 500 MHz in CDCI3 (δ, mult., J): 9.81, d, J 5 -6=7.3, 5-H; 7.47, d, J 7 - 8 =8.8, 8-H; 7.11, dd, J 6 . 7=7.7, J 7 -8=8.8, 7-H; 6.84, dd, J 5 -6=J6-7=7, 6-H; 6.66, d, Jιo-l2=l-3, 10-H; 5.31, , J10-12=1.3, 12-H; 3.90, s, I I-OCH3; 2.68, s, I6-CH3; 2.21, s, H-CH3. 1 C NMR, 125 MHz in CDCI3 (δ): 186.3 C-15; 180.3 C-11; 172.1 C-13; 136.2 C-9 128.3 C-5; 124.2 C-2; 123.3 C-7; 122.1 C-3; 116.5 C-8; 114.4 C-6; 111.2 C-l 89.4 C-12; 74.8 C-10; 59.8 I I-OCH3; 31.2 C-16; 8.8 C-14. MS (EI, 70 eV), m/z 285.1009 (M + , 65 %, Cι 6 Hι 5 O N requires 285.1001), 259 (11 %), 243 (100 %), 242 (70 %), 228 (48 %), 200 (17 %), 158 (14 %), 154 (15 %), 130 (20 %). MS (CI, NH3), m/z: 303 (M + NH 4 + , 15 %), 284 (M + H + , 100 %). Example 9 Compounds (XI) - (XIII) were obtained after the treatment of penicillic acid (II) with acetic anhydride:pyridine (1:5) at room temperature for 16 hours. The yields after separation were 58 % of (XI), 2 % of (XII) and 5 % of (XIII). Compound (XI), 5- Acetoxy-5-( 1 -methyl- 1 -ethenyl)-4-methoxy-2, 5-dihydro-2- furanone was obtained as white crystals, m.p. 72-74 °C. UV (methanol) k^n (ε): 230 nm (10,100). IR (KBr): 3125, 1765, 1640, 1460, 1370, 1350, 1270, 1225, 1200, 1120, 1100, 1030, 950, 910, 840 and 800 cm" 1 . ! H NMR, 500 MHz in CDCI3 (δ, mult., J): 5.34, m, 6-Ha; 5.15, s, 2-H; 5.13, m, 6-Hb; 3.88, s, 3-OCH 3 ; 2.08, s, 4-OAc; 1.79, , 7-H 3 . 13 C NMR, 125 MHz in CDCI3 (δ): 178.0 C-3; 169.0 C-l; 167.7 4-OAc; 138.3 C-5; 116.0 C-6; 101.3 C-4; 89.7 C-2; 59.9 3- OCH3; 21.3 4-OAc; 17.3 C-7. MS (EI, 70 eV), m/z: 212.0662 (M + , 42 %, C10H12O 5 requires 212.0685), 169 (61 %), 152 (39 %), 142 (27 %), 126 (39 %), 124 (28 %), 100 (94 %), 68 (84 %), 43 (100 %). Compound (XII), l,3-Diacetyl-2-methylindolizine was obtained as yellow oil. UV (methanol) Ji^ (ε): 234 nm (8,300), 260 (8,600), 290 (5,100), 336 (6,400) and 348 (6,600). LR (KBr): 2920, 1770, 1640, 1610, 1490, 1410, 1390, 1200 and 910 cm- 1 . Ϊ H NMR, 500 MHz in CDC1 3 (δ, mult., J): 10.00, d, J 5 -6=7.1, 5-H; 8.30, d, J 7 -8=9.0, 8-H; 7.38, dd, J 6 - 7 =6.8, J 7 -8=9.0, 8-H; 6.97, dd, J 5 -6=J6- 7 =7, 6-H; 2.87, s, I2-H 3 ; 2.65, s, I I-H3; 2.65, s, 14-H 3 . 13 C NMR, 125 MHz in CDCI3 (δ): 192.8 C-13; 189.1 C-10; 138.5 C-9; 135.3 C-2; 128.9 C-5; 127.8 C-7; 123.2 C-3; 118.7 C-8; 115.5 C-l; 114.8 C-6; 31.9 C-14; 31.6 C-1 1; 14.9 C-12. MS (EI, 70 eV), m/z: 215.0954 (M + , 39 %, C13H13NO2 requires 215.0946), 200 (100 %), 186 (6 %), 172 (10 %), 158 (11 %), 143 (8 %), 130 (15 %), 43 (13 %). Compound (XIII), 3-(3-( 1 -Acetoxy- 1 -ethenyl)-2-methyI- 1 -indolizinyl)-3-methoxy- (E)-2-propenoic acid ethyl ester was obtained as a yellow oil. UN (methanol) k-^^ (ε): 230 nm (21,100), 260 (15,000), 330 (8,700) and 352 (8,700). IR (KBr): 2975, 2930, 1760, 1710, 1605, 1520, 1490, 1370, 1195, 1 140, 1125, 1100 and 1050 cm" l . l H ΝMR, 500 MHz in CDCI 3 (δ, mult., J): 8.12, d, J5-6=7.1, 5-H; 7.24, d, J 7 . 8 =9.0, 8-H; 6.81, dd, J 6 - 7 =6.6, J 7 - 8 =9.0, 7-H; 6.55, dd, J 5 - 6 =J6-7=7, 6-H; 5.41, d, ^15a-15b=1 5, 15-Ha; 5.40, s, 11-H; 5.21, d, Jι 5a -15b=l 5, 15-Hb; 4.01, q, J=7.1, I2-OCH2CH3; 3.82, s, IO-OCH3; 2.28, s, 13-H 3 ; 2.11, s, 17-H 3 ; 1.08, t, J= 7.1, I2-OCH 2 CH3. 13 C ΝMR, 125 MHz in CDCI3 (δ): 168.8 C-16; 166.8 C-12; 166.0 C-10; 144.6 C-14; 132.6 C-9; 126.2 C-2; 124.2 C-5; 119.8 C-7; 118.0 C-8; 117.8 C-3; 111.1 C-6; 109.0 C-15; 107.7 C-l; 93.5 C-11; 59.4 12-OCH 2 CH 3 ; 55.9 10- OCH3; 20.8 C-17; 14.2 I2-OCH2CH3; 11.1 C-13. MS (EI, 70 eV), m/z: 343.1431 (M + , 100 %, Cι 9 H 2 ιΝO 5 requires 343.1420), 314 (22 %), 300 (47 %), 286 (46 %), 284 (52 %), 272 (45 %), 256 (32 %), 240 (29 %), 228 (22 %), 212 (41 %), 198 (50 %), 182 (33 %), 168 (26 %), 154 (30 %).

Claims: Claims 1. Compound ofthe formula (I) its tautomers, optically active forms, and their pharmacologically acceptable salts. 2. Derivates of compound I ofthe formula (!') r where R represents a branched or unbranched alky group and its tautomers, optically active forms and their pharmaceutically acceptable salts. 3. A method for the preparation of compounds I of claim 1 which comprises culturing of a strain belonging to genus Ascomyces which produces substances according to claim 1 in a nutrient medium containing in addition CaBr 2 . 4. A method as claimed in claim 3, wherein the substance producing strain is Ascomecetes Lachnum papyraceum (Karst.) Karst. strain 44 ~ 88. 5. Method of making a compound plurality by reaction of compound I of claim 1 or compound I' of claim 2 with one or more nucleophils Y. 6. Method of making a compound plurality by a reaction of compound II, H its tautomers or optically active forms with one or more nucleophils Y. 7. A method of reducing a compound plurality obtainable by a method of any one of claims 5 or 6 by separation of a subplurality of compounds by conventional means. 8. A method of isolating a single compound comprising a) providing a compound plurality obtainable by a method of any one of claims 5, 6 or 7 b) isolating said compound from said compound plurality by conventional means. 9. A method of determining whether a compound or compound plurality obtainable by a method of any one of claims 5-8 interact with a target of interest which comprises a) providing a target of interest, b) incubating said target with said compound or compound plurality and c) determining whether said target exhibits a responsive change 10. A method for identifying a pharmacophor by using a compound or compound plurality obtainable by the method of any one of claims 5-8 which comprises a) providing a target of interest, b) incubating said target with said compound or compound plurality, c) determining whether said target exhibits a responsive change, d) variation ofthe structure of said compound or compound plurality whereby the responsive change may not be reduced. 11. A method of claim 10 comprising an additional step e) repeating steps a) to d) using the identified pharmacophor obtainable by a method of claim 10 instead ofthe compound or compound plurality. 12. Compound or compound plurality obtainable by the method of any one of claims 3 to 11. 13. A single compound obtainable by the method of any one of claims 3, 4, 8, 10 or 11 for use in medicine. 15. A method of making a pharmaceutical composition comprising combining a compound obtainable by the method of any one of claims 3-5 or 8-11 and a pharmaceutical acceptable carrier, where said pharmaceutical composition shows a fibrinogen-lowering, antibacterial, antifungal or cytotoxic activity.

Inventors: ANKE HEIDRUN, DOERGE LIESEL, HANSSKE FRITZ, SHAN RUDONG, STADLER MARC, STERNER OLOV, ANKE, HEIDRUN, DOERGE, LIESEL, HANSSKE, FRITZ, SHAN, RUDONG, STADLER, MARC, STERNER, OLOV
Applicants: ANKE HEIDRUN, BOEHRINGER MANNHEIM GMBH, DOERGE LIESEL, HANSSKE FRITZ, SHAN RUDONG, STADLER MARC, STERNER OLOV, ANKE, HEIDRUN, DOERGE, LIESEL, HANSSKE, FRITZ, SHAN, RUDONG, STADLER, MARC, STERNER, OLOV
Application year: 1996
Main classification: C07D493
IPC codes: A61K31, C07D493, C12P17, C12R1