Politechnika Gdanska

Btg International Limited

Blirt S.a.

Instytut Przemyslu Farmaceutycznego

Bs-154 S.p. Zo.o.

Instytut Przemyslu Farmaceutyoznego Majakowskiego

Edward Borowski

Leonard S Falkowski

Barbara J Stefanska

Elzbieta Troka

Malgorzata Wysocka

Jerzy J Golik

Slawomir Milewski

Ryszard Andruszkiewicz

Andrzej B Jarzebski

Pawel Kolodziejczyk

Maria Milewska

Jan Zielinski

Henryk Chmara

Natalia Salewska

Joanna Boros-Majewska

Izabela Chabowska

Wieslaw Szelejewski

Marcin Cybulski

Andrzej Skladanowski

Joanna Wietrzyk

Wladyslawa Wagner

Pawel Punda

Jan Pawlak

Elzbieta Bylec

Danuta Roslik-Kaminska

Emilia Cybulska

Maria Zaremba

Maria Gdulewicz-Gruszecka

Halina Dahlig

Jan Mazerski

Michal Sabisz

Wojciech A Gruszecki

Jerzy J Cieslak

Ewa Sadowska

Andrzej Czerwinski

Teresa Gumiezna

Jerzy Gumieniak

Maria Dzieduszycka

Pawel Sowinski

Adam Treder

Irena M Busko-Oszczopowicz

Jerzy Borowski

Jolanta Grzybowska

Teresa Zieniawa

Janusz Obukowicz

Zuzanna Kowszyk-Gindifer

Zofia Plociennik

Maria Bontemps-Gracz

Ewa Jakobs

The invention provides semisynthetic N-substituted derivatives of the antifungal antibiotic Amphotericin B and water soluble salts and complexes, pharmaceutical compositions and plant and building treatment products comprising the derivatives and their use as antifungal antibiotics. 

N-substituted second generation derivatives of antifungal antibiotic amphotericin B and methods of their preparation and application

The invention provides semisynthetic derivatives of Nystatin A, water soluble salts and complexes, pharmaceutical compositions and plant protection products comprising the derivatives and their use, as antifungal antibiotics (Formula 1a). 

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The invention relates to the new, asymmetrically substituted derivatives of 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione and their use as cytostatics exhibiting activity against tumor cells, especially against cells with multidrug resistance (MDR). In particular, the invention concerns derivatives of 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione represented by the general formula (I). 

Asymmetrically substituted anthrapyridazone derivatives as cytostatics

The invention relates to an N-alkyl-N-glycosyl derivative of antifungal antibiotics of the polyene macrolide group of general formula 1(a), wherein M represents polyene macrolide antibiotics residues, R represents a variable part of sugar residue, R.sup.1 represents a C.sub.1-4 alkyl group and R.sup.2 represents hydrogen or a C.sub.1-4 alkyl group; their salts of general formula 2(a), wherein R, R.sup.1, R.sup.2 and M are as herein defined and A represents an anion of organic or inorganic acid. Compounds of formula 1(b) and 2(b) wherein the N-alkyl and alkyl ester groups are represented by methyl are of particular interest. The invention relates also to processes for preparation of the compounds, to compositions containing these compounds and to their use in therapy and the treatment of external and internal fungal infections in humans and animals. ##STR1##

Antibiotics

Pharmaceutical compositions

The subject of this present invention is tripeptides of N.sup.3 -4-methoxyfumaryl-L-2,3-diaminopropanoic acid of the general formula ##STR1## where R is a hydrogen atom when R.sub.1 is the dipeptide residue containing the residue of alanine, methonine, valine, leucine or norvaline, or R and R.sub.1 have the same meaning and are the residue of monoaminomonocarboxylic aminoacid, such as those of alanine, methionine, valine, leucine, or norvaline, or R is the dipeptide residue containing the residue of alanine, methionine, valine, leucine, norvaline, lysine, ornithine, sarcosine, 2,4-diaminobutanoic acid and 2,3-diaminopropanoic acid, and R.sub.1 is a hydroxide group, and the method of their obtaining. The method of obtaining involves converting N.sup.2 -tetrbutoxycarbonyl, N.sup.3 -4-methoxyfumaroyl-L-2,3-diaminopropanoic acid into an active ester which is used for acylating a dipeptide or N.sup.2 -tetr-butoxycarbonyl, N.sup.3 -4-methoxyfumaryl-L-2,3-diaminopropanoic acid into an active ester which is used for acylating the aminoacid whereafter the protection of the amino group is removed and the latter is acylated with an active ester of the N-protected aminoacid or N.sup.3 -4-methoxyfumaryl-L-2,3-diaminopropanoic acid is acylated with an active ester of the N-protected dipeptide and the protection of the amino group is removed from the obtained N-protected tripeptide in the medium of a non-polar organic solvent or its mixture with water, whereas the final product in the form of a salt is isolated by being crystallized or being converted into a free acid.

Tripeptides of N.sup.3 -4-methoxyfumaryl-L-2,3-diaminopropanoic acid

The present invention relates to new enamine derivatives of daunorubicin and adriamycin of the formula l: ##STR1## and formula 2: ##STR2## wherein R denotes a hydrogen atom or hydroxyl group. The inventive compounds are useful antineoplastic antibiotics utilized in the treatment of cancer, primarily leukemia. The present derivatives demonstrate a reduction in toxicity, in particular cardiotoxicity, over their parent compounds, while retaining chemotherapeutic properties.

Antineoplastic enamine derivatives of daunorubicin and adriamycin

The invention relates to amides of polyene macrolide antibiotics and their derivatives characterized by the general formula I, ##STR1## where R is the polyene macrolide, R.sub.1 is an alkyl or isoalkyl chain of from one to eighteen carbons, unsubstituted or substituted with a primary or secondary amine; where R.sub.2 is an hydrogen or R.sub.1 or R.sub.1 and R.sub.2 are joined through the nitrogen to form a heterocyclic ring. The method of preparation of these substances according to our invention depends upon the reaction of the polyene macrolide or its derivative in which the carboxylic group is activated; in the environment of an organic solvent or mixture of solvents and in the presence of a substance neutralizing the acid; with a compound containing an amino group; leaving upon completion of the reaction; and precipitation of the product from the reaction mixture, by addition of ethyl ether or a mixture of ethyl ether with hydrocarbons; isolation and purification of the product by means of known methods.

Amides of amphoteric polyene macrolide antibiotics

The acetylmethyl ester of hetacyllin and/or its salts of an organic or inorganic acid are described and methods for their synthesis wherein a tertiary amine and chloroacetone are introduced to hetacyllin in an organic solvent or chloroacetone is introduced to hetacyllin in the form of a salt with an alkali metal in an organic solvent, and then from the reaction mixture, the acetylmethyl ester of hetacyllin is isolated in free form and, if desired, a salt of the ester is obtained by reaction with an organic or inorganic acid in an organic solvent. As tertiary amines, trialkylamine, N-methylpiperidine, N-ethylpiperidine or N-methylmorpholine are used; as organic solvents in obtaining the ester, dimethylformamide, dimethylacetamide or dimethylsulfoxide are used. In obtaining salts of the ester the organic solvents used are aliphatic alcohols of a chain length C.sub.2 -C.sub.5 ; ketones, preferably acetone; ethers, such as diethyl, dipropyl, diisopropyl, dibutyl ethers, or their mixtures. The obtained compounds show an antibacterial action like ampicillin but after administration per os they show a considerably higher level of the antibiotic than that after administration of free ampicillin or its esters.

Acetylmethyl ester of hetacyllin and/or salts of this ester

A process for production of esters of antibiotics from the group of polyene macrolides and of N-substituted derivatives thereof, having the general Formula 1, wherein R denotes the radical of antibiotic or of its R-COOR, I N-substituted derivative, and R.sub.1 denotes an alkyl with the chain length of C.sub.1 through C.sub.5, or an aryl, consisting therein that an antibiotic from the group of polyene macrolides or its N-substituted derivative is dissolved or suspended in alcohol and/or neutral organic solvent, or in a mixture of organic solvents, in presence of dicyclohexylcarbodiimide and/or hydrocybenzotriazole, the whole is allowed to stand at room temperature, or at temperature elevated to 40.degree. C., and then the obtained product is isolated from the reaction medium after known methods.

Method of preparation of esters of antibiotics selected from the group

The invention relates to the method of preparation of N-glycosyl compounds of anthracyclin antibiotics of formula I ##STR1## where R.sub.1 is the hydrogen atom or hydroxylic group, whereas R.sub.2 is the residue of a mono- or oligosaccharide of a series of aldeses and ketoses or the derivatives reacted with the amine group of the antibiotic. The invention depends upon the reaction of the antibiotic, which is converted into the form of base, in an organic solvent by treatment with molar excess of the saccharide or its derivative at temperature from 20.degree. up to 60.degree. C., for several hours, in the presence of a catalyst, under continuous stirring. The product is precipitated from the reaction mixture upon the addition of a nonpolar solvent and subsequently is purified by known methods.

N-Glycosyl derivatives of anthracycline antibiotics and the method of

Inorganic salts of trimethylammonium derivatives of polyene macrolides, particularly the inorganic salts of methyl esters of these derivatives having the general formula: ##STR1## wherein R is the residue of a polyene macrolide and X is an anion of a salt selected from the group consisting of methylsulphate, sulphate, chloride, phosphate and acetate. The preparation of salts of formula (I) or formula (II) is also disclosed.

Water-soluble salts of trimethylammonium derivatives of polyene

The new compounds, N-methylglucamine salts of N-glycosyl derivatives of polyene macrolides particularly N-methylglucamine salts of N-glycosyl derivatives of amphotericin B, polifungin and nystatin are described herein. These compounds exhibit high pharamacological activity in some topical and sistemic fungal infections. The product is prepared by reaction of an amino group containing polyene macrolide with an aldose or ketose mono- or oligosaccharide, in an organic solvent medium or in the mixture of solvents characterized in that the formed N-glycosyl derivatives is precipitated from the reaction medium by water or with an aqueous solution of inorganic salt, preferably ammonium sulphate, and after crystallization from a higher alkanol of C.sub.3-6 atoms, preferably n-butanol transformed into a salt, preferably an N-methylglucamine salt and then crystallized from higher alkanol, preferably n-butanol.

Salts of N-glycosyl derivatives of polyene macrolides, especially

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Edward Borowski