Polyaminosteroid branched derivatives

FIELD: chemistry.

SUBSTANCE: polyaminosteroid branched derivatives of general formula I are described, where R1 is saturated or unsaturated C2-C10alkyl (conjugated or branched) or methyl, R2 is COOH or branched polyamine fragments, R3 is H, OR19, where R19 is H or C1-6acyl, R4 is H, R5 is H, CH3, R6 is H, CH3, R7=R8=R9=H, R10 is H, CH3, R11 is OH,-OSO3, - O-acyl, -(Z)n-(NR-Z)p-N(R)2, Z is linear hydrocarbon diradical, n=0, 1, p=1, R-H, C1-6alkyl, C1-6aminoalkyl, possibly substituted by C1-6alkyl, R12=R13=R15=H, R16 is H, OH, R17 is H, R18 is H, CH3, possible double bond. Compounds possess bactericidal activity and can be used for prevention of bacterial infections.

EFFECT: production of polyaminosteroid derivatives, possessing bactericidal activity which can be used for prevention of bacterial infections.

27 cl, 31 ex, 1 tbl, 2 dwg

 

The invention relates to new compounds possessing a wide spectrum of antibacterial activity, specifically to steroids containing branched polianinova side chains, as well as to the use of such compounds as microbicides for the treatment of various infections.

Resistance to drugs when the use of antibiotics is an increasing problem involving a threat to health. Existing for many years the belief that infectious diseases can be controlled with modern Arsenal of antibacterial drugs, led to the development of a few new and more effective drugs. However, recent data polyresistance pathogenic bacteria revived interest in the development of new antibiotics. Although resistance to many antibiotics, such as beta-lactams, macrolides, tetracyclines and aminoglycosides, and the rapid growth of this stability known for many years, it was assumed that such a backup of the medicinal product, as glycopeptides and fluoroquinolones, able to effectively deal with the majority of infections. However, due to the large number of alarm messages about resistance to vancomycin, multidrug resistance and examples of migration resis entih genes between different species introduced in the late eighties and early nineties, the problem of drug resistance is becoming the focus of health care and pharmaceutical industries. In this regard, an important task is the identification of new compounds with antibacterial activity.

Steroids are a group of compounds found in living organisms, the main examples of which are hormones. All steroids have a common basis or kernel, including three six-membered rings and one five-membered ring, and in this regard may be considered derivatives of cyclopentanoperhydrophenanthrene. Steroids have important biological properties. They have a decisive influence on the catabolism and anabolism of all major biochemical substances, such as proteins, carbohydrates and lipids, and their action is the induction of the synthesis of enzymes that regulate the levels of these biochemical compounds. Hormones can be classified into estrogens, androgens, progestins, mineralocorticoids and glucocorticoids. They regulate the most important aspects of biological activities, such as the growth and functioning of bone and muscle tissue, blood pressure, glucose levels in the blood and the development of sexual characteristics. Performing a multitude of biological the functions, steroids in the form of hormones or their loved ones chemical properties of derivatives themselves are powerful drugs against various diseases. Steroids are used in replacement therapy in the treatment of patients with inadequate secretion of steroids glucocorticoids in high concentrations are applied systemically and locally as an anti-inflammatory and immunosuppressive agents; estrogen and progestin-only steroids used for the treatment of dysfunctions of the reproductive system and, more commonly, as a contraceptive.

Antibiotic action has a limited number of steroids, for example positiva acid. Positiva acid, which is a product of fermentation of Fusidium coccineum, known since the early 1960s (U.S. patent 3072531). Positiva acid (for example, Fucidin®LEO Pharmaceutical Products Ltd, Denmark) used in clinical trials for treatment of infectious diseases such as staph infections, and this drug is used both topically and systemically (Kuchers et al., 1997 and cited in the reference document; Duvold et al., 2001 and cited in the reference document; Christiansen, 1999, and cited in the reference document). Usually this drug is used in conjunction with traditional antibiotics, such as penicillins, eritromicina or clindamycin.

Recently steroid antibiotic was isolated from the same is the RCU shark-dogfish, Squalus acanthias (Moore et al., 1993; Rao et al., 2000). This connection to steroid base containing linear polyamine and sulfate functional group, was named squalamine (squalamine) and it was found that this substance has a broad spectrum of bactericidal properties against gram-positive and gram-negative bacteria, fungi and protozoan organisms. The use of natural squalamine as an antimicrobial agent disclosed in US 5192756. Was carried out chemical synthesis of squalamine, although it used a rather complicated method. A number salamunovich analogs and their use as antibiotics are disclosed in WO 00/09137.

Other squalamine analogues containing polianinova side chains are disclosed in WO 02/14342, and B. Ding et al., J. Med. Chem. 45, 2002, pp. 663-669.

About the antibiotic properties of these branched polyamines is not reported.

The authors of the present invention unexpectedly found that steroid derivatives containing steroid-based, connected with the branched polyamines, are compounds with a broad spectrum of antimicrobial and especially bactericidal activity. Extensive polienovy fragment gives antibacterial activity of steroids, not possessing such activity, and enhances the bactericidal activity of steroids, with its symptom is initial.

Thus, the present invention relates to a compound of formula I

in which condensed rings a, b, C and D, independently of one another, are a saturated or partially or fully unsaturated rings;

the bond between C-17 and C-20 are shown in solid and dashed line to indicate that the indicated bond may be single or double;

R1 represents hydrogen, halogen, a lipophilic group, -(Z)n-(NR-Z)p-N(R)2or C(O)-(Z)n-(NR-Z)p-N(R)2where n is 0 or 1, and p represents an integer from 1 to 5;

each Z, independently from each other, represent a hydrocarbon biradical straight or branched chain, optionally substituted C1-6the alkyl, C1-6alkenyl,1-6the quinil, hydroxy, alkoxy, amino, C1-6aminoethoxy,1-6aminoalkyl,1-6aminoethylaminomethyl,1-6alkyls3-8cycloalkyl or1-6alkylglycerol;

each R, independently of one another, represents hydrogen or C1-6alkyl, C1-6aminoalkyl,1-6aminoalkanoic or1-6aminoethylaminomethyl, and all of these groups optionally substituted with alkyl or C1-6aminoalkyl;

provided that at least one Z is substituted With1-6the alkyl, C1-6alkene the Ohm, With1-6the quinil, hydroxy, alkoxy, C1-6aminoethoxy,1-6aminoalkyl,1-6aminoethylaminomethyl,1-6alkyls3-8cycloalkyl or1-6alkylglycerol, or at least one R is different from hydrogen;

R2 is halogen, C1-4alkyl, optionally substituted by COOH; C1-4alkoxy, -COOH, -(Z)n-(NR-Z)p-N(R)2or C(O)-(Z)n-(NR-Z)p-N(R)2;

R3 represents hydrogen, halogen or O-R19 where R19 is hydrogen, -SO3C1-6alkyl, C1-6acyl, or -(Z)n-(NR-Z)p-N(R)2;

each of R4, R7, R8, R10, R11, R12, R13, R16 and R17, independently of one another, represents hydrogen, halogen, hydroxy, -OSO3, -O-acyl, -(Z)n-(NR-Z)p-N(R)2or C(O)-(Z)n-(NR-Z)p-N(R)2;

each of R5, R6, R9, R14, R15 and R18, independently of one another, represents hydrogen or methyl, or each independently absent in the case when one of the condensed rings a, b, C and D is unsaturated so that all of the valences of the corresponding carbon atom were occupied;

provided that at least one but not more than three of the substituents R1, R2, R4, R7, R8, R10, R11, R12, R13, R16 and R17 are -(Z)n-(NR-Z)p-N(R)2or C(O)-(Z)n-(NR-Z)p-N(R)2;

and its pharmaceutically acceptable salts or esters

The exact mechanism of action of the compounds of the present invention is presently unknown. Not limited to a particular hypothesis, it is assumed that these compounds are able to perforate the cell membrane and result in the formation of pores can be lysis of membranes. It is expected that the compounds of the present invention is able to influence two main mechanisms of drug resistance, affecting some other antibiotics that are related to the degradation of cells under the action of enzymes and export routes (Sadownik et al., 1995; Savage and Li, 2000, and references in this work).

Another aspect of the present invention relates to pharmaceutical compositions containing a compound of formula I together with pharmaceutically acceptable excipient or diluent.

Another aspect of the present invention relates to the use of compounds of formula I in the manufacture of a medicine for the prevention or treatment of infections.

In accordance with another aspect of the present invention relates to a method for preventing or treating infections comprising the administration to a patient in need of treatment an effective amount of the compounds of formula I.

Figure 1 shows the kinetics of changes in the minimum bactericidal concentration (MBC) of compound 102 against S.aureus.

On IG presents the kinetics of changes in the minimum bactericidal concentration (MBC) of compound 102 in respect of these bacteria to antibiotics.

In the context of the present description, the term "hydrocarbon" refers to a compound containing only carbon and hydrogen, in which the carbon atoms form a linear or branched chain.

The term "alkyl" denotes a monovalent radical formed from alkane with a straight or branched chain resulting from the removal of a hydrogen atom from any carbon atom. Such term includes subclasses of primary, secondary and tertiary Akilov, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl.

The term "alkenyl" refers to the monovalent radical derived from an alkene with a straight or branched chain resulting from the removal of a hydrogen atom from any carbon atom. The term includes subclasses of primary, secondary and tertiary alkenyl, such as vinyl, 1-propenyl, Isopropenyl, butenyl, tert-butenyl, pentenyl and hexenyl.

The term "quinil" refers to the monovalent radical derived from alkyne with a straight or branched chain resulting from the removal of a hydrogen atom from any carbon atom. This term includes ethinyl, PROPYNYL, isopropanol, tert-butenyl, pentenyl and hexenyl.

The term "alkoxy" is used to denote a radical of the formula OR'where R' is above uglevodorodnyi radical, for example methoxy, ethoxy, propoxy, butoxy etc.

The term "alkoxycarbonyl" is used to denote a radical of the formula-COOR'in which R' represents the above hydrocarbon radical, for example methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl etc.

The term "cycloalkyl" is used to denote saturated cycloalkane radical, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Similarly, the term "cycloalkenyl" is used to denote cycloalkanones radical, for example cyclopropyl, cyclobutyl, cyclopentenyl or cyclohexenyl.

The term "aryl" is used to denote radicals carbocyclic aromatic rings, optionally condensed bicyclic ring, for example phenyl or naphthyl. The term "heteroaryl" is used to denote radicals of heterocyclic aromatic rings, in particular 5 - or 6-membered rings with 1-3 heteroatoms selected from O, S and N, or optionally condensed bicyclic rings with 1-4 heteroatoms, examples of which include pyridyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, isothiazolin, benzimidazolyl and benzofuranyl.

The term "acyl" refers to a radical of the formula-CO-R'in which R' is defined, lenny higher hydrocarbon radical.

The term "aralkyl" is used to denote an aromatic ring with an alkyl side chain, such as benzyl.

The term "halogen" denotes fluorine, chlorine, bromine or iodine.

The term "amino" is used to denote a radical of the formula-NR2in which each R", independently of one another, represents hydrogen or a hydrocarbon radical.

The term "aminoethoxy" refers to a radical of the formula-OR'-NR2in which R' represents a hydrocarbon biradical, and each R", independently of one another, represents hydrogen or a hydrocarbon radical.

The term "aminoalkyl" refers to a radical of the formula-R'-NR2in which R' represents a hydrocarbon biradical, and each R", independently of one another, represents hydrogen or a hydrocarbon radical.

The term "aminoethylaminomethyl" refers to a radical of the formula-C(O)-NR" -, R'-NR2in which R' represents a hydrocarbon biradical, and each R", independently of one another, represents hydrogen or a hydrocarbon radical.

The term "branched polyamine" is used to refer to compounds of General formula other-(Z)n-(NR-Z)p-N(R)2in which n and R, and each R and Z, independently of one another, defined above, and at least one R has a value other than hydrogen and at least one Z is replaced by the 1-6the alkyl, C1-6alkenyl,1-6the quinil, hydroxy, alkoxy, C1-6aminoalkyl,1-6aminoalkanoic,1-6aminoethylaminomethyl,1-6alkyls3-8cycloalkyl or1-6alkylglycerol.

The term "pharmaceutically acceptable salt" is used to denote salts of alkaline and alkaline-earth metals, for example salts of sodium, potassium, magnesium or calcium, and silver salts and salts with bases as ammonia or suitable non-toxic amines, such as lower alkylamines followed, such as triethylamine, hydroxycobalamin lower bonds alkylamines, for example 2-hydroxyethylamino or bis-(2-hydroxyethyl)amine, cyclooctylamine, such as dicyclohexylamine, or benzylamines, such as N,N-dibenziletilendiaminom and dibenzylamine, as well as salts attaching a suitable organic or inorganic acids, such as hydrochloric, Hydrobromic, uudistoodetena, sulphuric, nitric, phosphoric, acetic, lactic, maleic, phthalic, citric, propionic, benzoic, glutaric, gluconic, methansulfonate, salicylic, succinic, tartaric, toluensulfonate, sulfamic or fumaric acid.

The term "pharmaceutically acceptable esters" is used to denote such an easily hydrolyzable esters, as alkanoyloxy, arulkumaran alkalemia, urologically esters, for example acetoxymethyl, pivaloyloxymethyl, benzoyloxymethyl esters and the corresponding 1'-oxyethylene derivatives, or alkoxycarbonylmethyl esters, for example methoxycarbonylmethylene and ethoxycarbonylmethylene esters and the corresponding 1'-oxyethylene derivatives, or lactonase esters, for example palidrome esters, or dialkylaminoalkyl esters, for example dimethylaminoethyl esters. Easily hydrolyzable esters include in vivo hydrolyzable esters of compounds of formula I. Such esters can be obtained by conventional methods known to experts in this field, for example by the method disclosed in GB Patent No. 1490852 included in the present description by reference.

The terms "antibiotic" and "antibacterial (antimicrobial)" are used interchangeably and have the same value.

According to a preferred variant of the invention, R2, R7, R11 and/or R16 represent-(Z)n-(NR-Z)p-N(R)2or C(O)-(Z)n-(NR-Z)p-N(R)2.

Specific examples of R19 are1-6alkyl and C1-6acyl.

A concrete example R7, R11 and R16 is-HE. The compounds of formula I in which R11 is O-SO3or O-acyl, are also particularly suitable. The preferred implementation of the present from which retene relates to the compound of General formula Ia or Ib

in which R1, R2, R3, R4, R7, R8, R10, R11, R12, R13, R16 and R17 have the above values.

Specific examples of the compounds of the present invention are the compounds of formula Ia or Ib, in which R2 represents -(Z)n-(NR-Z)p-N(R)2or C(O)-(Z)n-(NR-Z)p-N(R)2, especially those in which R7 and R11 both represent hydroxy; R11 and R16 both represent hydroxy; or R3 is-OR19 where R19 represents a C1-6alkyl or C1-6acyl.

More typical examples of the compounds of the present invention are the compounds of formula Ia or Ib, in which R11 is -(Z)n-(NR-Z)p-N(R)2or C(O)-(Z)n-(NR-Z)p-N(R)2especially in the case when R2 represents C1-4alkyl, optionally substituted by COOH; C1-4alkoxy or -- COOH; or when R3 is-OR19 where R19 represents a C1-6alkyl or C1-6acyl.

In the compounds of formula I and, more particularly, formula Ia or Ib, R1 preferably represents a lipophilic group, i.e. mainly non-polar group. It is assumed that the non-polar nature of the substituents R1 are responsible for the ability of the compounds of the present invention to be placed in the cell membrane, which also has a lipophilic nature. Examples of such lipophilic groups are the Xia C 1-10alkyl, aryl, C3-8cycloalkyl, aralkyl with 1-10 carbon atoms in the alkyl fragment, With1-10alkylaryl,1-10alkyls3-8cycloalkyl,1-10alkoxy and heteroaryl. Preferably, R1 represents a saturated or unsaturated With1-10a hydrocarbon radical straight or branched chain, for example a fragment of formula II

in which the carbon-carbon bond, indicated by the symbol "*"is a single or double bond.

According to a preferred variant of the invention, R2 and/or R11 represent a fragment of formula VIII, IX, X, XI, XII or XIII below:

In accordance with a preferred embodiment of the invention the compounds of formula I are selected from the group including

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-17R,20S,24,25-tetr hydrofuse-21-amide (compound 101),

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-11-deoxy-17R,20S,24,25-tetrahydrofolic-21-amide (compound 102),

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-16-deacetoxy-17R,20S,24,25-tetrahydrofolic-21-amide (compound 103),

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-13(17)-EN-17,20,24,25-tetrahydrofuran-21-carboxamide (compound 104),

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-3β-deacetoxy-17R,20S,24,25-tetrahydrofolic-21-amide (compound 105),

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-9(11)-ene-17R,20S,24,25-tetrahydrofolic-21-amide (compound 106),

24-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-3α-hydroxy-5β-Holan-24-amide (compound 107),

22-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-23,24-bisnor-5-cholenic-22-amide (compound 108),

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}fusid-21-amide (compound 109),

21-N-{3'-[bis(3'-aminopropyl)amino]propyl}fusid-21-amide (compound 110),

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-3-OSO3-11-deoxy-17,20,24,25-tetrahydrofolic-21-amide (compound 111),

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-11-deoxy-16-deacetoxy-17S,20,24,25-tetrahydrofolic-21-amide (compound 112),

21-N-{3'-[bis(3'-aminopropyl)amino]propyl}-17R,20S,24,25-tetrahydrofolic-21-amide (compound 113),

22-N-{3'-[bis(3'-aminopropyl)amino]propyl}-23,24-bisnor-5-cholenic-22-amide (compound 114),

21-N-{3'-[bis(3'-aminopropyl)amino]propyl}-}-3-SLA-17R,20S,24,25-tetrahydrofolic-21-amide (compound 115),

21-N-{3'-[bis(3'-aminopropyl)amino]propyl}-}-3-OSO3-11-de is hydroxy-17,20,24,25-tetrahydrofolic-21-amide (compound 116),

21-N-{3'-[bis(3'-aminopropyl)amino]propyl}-}-11-deoxy-16-deacetoxy-17S,20,24,25-tetrahydrofolic-21-amide (compound 117),

3-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}positiva acid (compound 118),

21-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}-17R,20S,24,25-tetrahydrofolic-21-amide (compound 119),

21-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}-11-deoxy-17R,20S,24,25-tetrahydrofolic-21-amide (compound 120),

21-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}-16-deacetoxy-17R,20S,24,25-tetrahydrofolic-21-amide (compound 121),

24-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}-3α-hydroxy-5β-Holan-24-amide (compound 122),

21-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}-11-deoxy-16-deacetoxy-17R,20S,24,25-tetrahydrofolic-21-amide (compound 123),

3-N-{3'-[bis(3'-aminopropyl)amino]propyl}positiva acid (compound 124),

3-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}positiva acid (compound 125),

21-N-{3-({4'-[(3'-aminopropyl)methylamino]butyl}methylamino)propyl}-17R,20S,24,25-tetrahydrofolic-21-amide (compound 126),

21-N-{3'-({3'-[(3'-aminopropyl)ethylamino]propyl}ethylamino)propyl}-17R,20S,24,25-tetrahydrofolic-21-amide (compound 127),

21-N-{3'-({4'-[(3'-aminopropyl)ethylamino]butyl}ethylamino)propyl}-17R,20S,24,25-tetrahydrofolic-21-amide (compound 128),

21-N-{3-({3'-[(3'-aminopropyl)ethylamino]propyl}ethylamino)propyl}-11-deoxy-17R,20S,24,25-tetrahydrofolic-21-amide (compound 129),

21-N-{3'-({4'-[(3'-aminopropyl is)cyclopropanemethylamine]butyl}cyclopropanemethylamine)-propyl}-17R,20S,24,25-tetrahydrofolic-21-amide (compound 130),

21-N-{3'-[(3'-aminopropyl)-(3'-dimethylaminopropyl)amino]propyl}-11-deoxy-17R,20S,24,25-tetrahydrofolic-21-amide (compound 131),

and their pharmaceutically acceptable salts and esters.

Names listed above compounds are given in accordance with the IUPAC nomenclature for extensive polyominoes side chain and conventions name fusidin and steroid to steroid fragments. For notation program was used, available at http://www2.acdlabs.com/ilab/.

The compounds of formula I contain chiral centers and the carbon-carbon double bond that provides for the existence of the stereo and geometric isomers. It should be borne in mind that the present invention includes all isomeric and tautomeric forms of the compounds covered by formula I, as in the form of pure compounds and mixtures thereof.

The pharmaceutical composition

Compositions of the present invention contain as an active ingredient at least one compound of formula I (hereinafter referred to as active ingredient), including its pharmaceutically acceptable salts and esters, together with at least one pharmaceutically acceptable carrier and/or diluent.

The ratio of active ingredient to the carrier in a given composition may vary from 0.5% to 100 wt%, mainly from 0.1 to approximately the additional 50% of the mass. Compositions can be prepared in the form of various pharmaceutical formulations such as granules, tablets, pills, pills, suppositories, capsules, tablets, delayed release, suspensions, injectables, and can be placed in vials, tubes or similar containers in accordance with generally accepted principles for the preparation of pharmaceutical formulations, for example as described in Remington: The Science and Practice of Pharmacy, 20thEd., Mack Publishing Company, 2000. For the preparation of compositions containing compounds of the present invention, it is possible to use the following pharmaceutically acceptable organic or inorganic, solid or liquid carriers and/or diluents suitable for oral, enteral, parenteral or topical application: water, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal oils and fats, benzyl alcohol, gum, polyalkyleneglycol, vaseline, cocoa butter, lanolin and other emulsifying agents, as additional agents can be used salts for regulating the osmotic pressure or buffers corresponding pH value.

In addition, the composition may contain other therapeutically active ingredients that can be used together with the compounds of the invention for the treatment of infectious diseases, for example, a friend who e appropriate antibiotics, such antibiotics that are able to increase the activity of the composition and/or to prevent the development of resistance. Such antibiotics include penicillins, cephalosporins, tetracyclines, rifamycins, eritromicina, lincomycin, clindamycin, and fluoroquinolones. Other compounds that can successfully be combined with the compounds of the invention, especially in preparations for topical application include, for example, corticosteroids such as hydrocortisone or triamcinolone. Alternatively, other therapeutically active components can be entered (either simultaneously or sequentially) as a means associated with the use of a composition of the present invention.

In the case of granules, tablets, capsules or pills pharmaceutical composition of the present invention contains from 25 to 98% of the active ingredient of the invention, and in the case of oral suspensions appropriate amount of active ingredient is from 2 to 20%.

When the active ingredient is administered in the form of salts of pharmaceutically acceptable non-toxic acids or bases, it is desirable that the preferred salt lightly or moderately dissolved in water to ensure appropriate uptake rate.

As noted above, the compounds of formula I and their salts may be contained in the pharmaceutical preparations vklyuchyenii, ointments and creams. Pharmaceutical preparation for oral administration may also be in the form of a suspension of the active ingredient as such or in the form of pharmaceutically acceptable salts with moderate solubility in water, and this product contains the carrier in an amount of from 20 to 100 mg/ml Pharmaceutical preparation for topical application may be in the form of ointment or cream, with a content of active ingredient in an amount of from 0.5 to 50% of the quantity of the drug. The topical preparations are particularly suitable due to resistance to sunlight and appropriate lipophilic nature of the compounds of the present invention.

The dosage of the compounds of the present invention can be chosen in such a way as to achieve the desired activity without serious side effects. In systemic therapy of human compounds of the present invention and their salts usually do (for adults) in dosage units containing not less than 50 mg to 1000 mg, preferably from 200 to 750 mg per compound of formula I.

The term "dosage unit" means a single dose that can be administered to the patient and which can be easy in handling and packaging, staying physically and chemically stable unit dose containing either the active ingredient or mixture is one or more solid or liquid pharmaceutical diluents or fillers.

The compound in the form of dosage units, you can enter one or several times a day, at certain intervals of time, but always depending on the patient's condition and in accordance with doctor's orders.

Systemic treatment daily dosage unit is preferably 0.5 to 3 g of the active ingredient.

The term "common unit" in relation to the local application means used, i.e. a single dose which may be introduced locally to a patient in an amount of from 0.1 to 10 mg, preferably from 0.2 to 1 mg of active ingredient per square centimeter infected area.

For use of the composition by injection provides a closed ampoule, vial or similar container containing a parenterally applicable sterile aqueous or oily solution for injection or dispersion of the active ingredient in the form of single dose.

Parenteral preparations are particularly useful for treatment of such conditions under which the desired fast response to treatment. During the continuous treatment of patients suffering from infectious diseases, a suitable form of a pharmaceutical preparation can be tablets or capsules, which is associated with prolonged action of drugs in oral administration, particularly in the form of tablets about ongrowing actions.

In the treatment of infectious diseases preferred tablets containing other active ingredients, as described above.

According to the method of treating patients suffering from infectious diseases, the compound of formula I or an equivalent amount of its salt or ester can be entered to the patients at a dose of 0.03-0.7 g/kg body weight (1-3 times a day, preferably 0.5 to 3 g per day. The active ingredient preferably in the above dosage units.

Patients which can be treated or treated according to the invention, can be animals, including mammals, and especially humans. Animals can also include such animals as horses, cows, pigs, sheep, poultry, fish, cats, dogs and other Zoological animals.

The treatment of infectious diseases often includes establishing resistance specified diseases to the proposed treatment, which is often carried out before the actual start of treatment. For example, the patient may take samples containing infectious microbes, such as samples of blood or urine, after which the sample is subjected to cultivation and the effects of treatment in order to clarify the reaction of the organism to the treatment of the above infections. Accordingly, the present invention also provides a method for identifying compounds with bactericidal action, include the rd contacting the microorganism with a compound of formula I, optionally together with other therapeutically active agents, and the establishment of toxic or static action of the compounds or mixture of compounds on the target microorganism.

Compositions of the present invention are not limited to pharmaceuticals, but also can not be used in a therapeutic context to control microbial growth. For example, the selectivity bactericidal agents makes them useful substances that enhance the growth of specific microorganisms (such as non-pathogenic microorganisms) due to the growth of other microorganisms in multi-species culture.

Further, the present invention is illustrated by the following examples of the preparation of compounds of the invention and examples of their application, does not limit the claimed scope of the invention.

Examples of making and using compounds of the invention

Methods for obtaining compounds of the invention

The original steroid compounds

Source carboxyethylidene steroid analogs can be purchased commercially or obtained by the methods described in the literature. Steroids, related to fuseboy acid, can be obtained through various literary techniques of natural Positano, such as positiva acid, fumigatin, vicidomini acid, and compounds of the family C is floorin P (see, for example, Godtfredsen and Vangedal, 1962; Arigoni et al., 1964; Godtfredsen et al., 1965aand 1965b; Godtfredsen et al., 1966; Diassi et al., 1979; von Daehne and cited in these referenced documents, the contents of which are incorporated into this description by reference), or well known to a person skilled simple chemical modification of the above Positano, including the hydrogenation of double bonds, the reaction of dehydration, sulfonation and oxidation.

Sulfonation of hydroxyl groups:

According to available literature data (Kinney et al., 2000) all compounds of the present invention containing one or more free hydroxyl groups, may be subjected to selective sulfonation or by one hydroxyl group, or several hydroxyl groups, using a stoichiometric amount or an excess of a complex of a sulfur trioxide-pyridine. Sulfonation is conducted before the reaction of a combination of a, b and C.

The acylation of hydroxyl groups

The acylation of the free hydroxyl groups of the steroid derivatives carried out using an excess of acetic anhydride in pyridine at room temperature in anhydrous conditions.

Restoration of double bonds

Restoration of double bonds steroid derivatives carried out by catalytic hydrogenation using palladium on coal as a cat is of Isadora and acetic acid, Meon, EtOH or ethyl acetate as solvent. Reactions carried out with shaking for 6-20 hours at room temperature.

Dehydration of hydroxyl groups

Dehydration 11-HE derived fuseboy acid carried out by treatment with excess amount of thionyl chloride in pyridine and dichloromethane at 0°C in anhydrous conditions.

Remove 16-acetoxyl

16-Acetoxygroup derivatives of fuseboy acid can be removed in anhydrous conditions, at the reflux of the corresponding methyl ester in anhydrous methanol in the presence of excess magnesium turnings. Methyl ether is then removed by heating under reflux for 1 hour in an aqueous solution of sodium hydroxide.

The oxidation of hydroxyl groups

Steroids containing keto - or aldehyde functional group can be obtained from the corresponding alcohols of different oxidation methods, which are well known specialist in this field.

Source materials on the basis of extensive polyamine

Extensive polyamine usually chosen from commercially available substances, for example, available in the database, the Available Chemicals Directory (ACD), however, such agents can also be synthesized by known literature methods (selected the e links: Goodnow et al., 1990; Bergeron et al., 1994; Stromgaard et al., 1999; Gaell and Blagbrough, 2000; Kuksa et al., 2000 and references cited in these works; Karigiannis and Papaioannou, 2000 and references cited in this work, all of these works are included in the present description by reference).

The synthesis of steroids branched poliaminom fragment attached through amide linkages (Method A, Scheme 1)

Compounds of the invention, in which the branched polienovy fragment attached to the steroid nuclei via amide bond, can be obtained from various steroids containing the carboxyl group, for example from tetrahydropyrido acid according to scheme 1, and various branched poliamidowych compounds. Carboxyl group of a steroid derivative is subjected to esterification with obtaining reactive complex ester, for example succinimido of ester, by reacting the carboxyl group with N-hydroxysuccinimide in anhydrous THF in the presence of disclocated (DCC). Succinimidyl ester can then be subjected to interaction with the branched polyamines by dissolving excess branched polyamine in anhydrous chloroform in an argon atmosphere and subsequent slow addition of a solution of the activated ester in chloroform. The reaction is carried out at room temperature and complete cher the C 6-24 hours. Then, the reaction mixture can be concentrated without additional washing stages and directly clear by HPLC c reversed phase, using as eluent a mixture of acetonitrile and water, buffered triperoxonane acid, or by column chromatography on silica gel, using as eluent a mixture of dichloromethane, methanol and aqueous ammonia. This method is illustrated by the example shown in figure 1, where the steroid nucleus presents tetrahydropyrido acid. Tetrahydropyrido acid is first converted into the corresponding N-Succinimidyl ether interaction with N-hydroxysuccinimide in anhydrous THF in the presence of disclosability. Then ester tetrahydropyrido acid interacts with N,N-bis(2-amino-ethyl)ethane-1,2-diamine as a result of dissolution of excess (3 equivalents) of N,N-bis(2-amino-ethyl)ethane-1,2-diamine in anhydrous chloroform in an argon atmosphere and subsequent slow (within 30 minutes) adding a solution of the activated complex ether in chloroform. The solvent is evaporated under reduced pressure and the crude oil purified on silica gel, using as eluent a mixture of dichloromethane, methanol and 25% aqueous ammonia solution. After freeze-drying of the pure product is obtained white powder, compound 101.

Method And

Scheme 1

The synthesis of steroids branched poliaminom fragment attached through amide linkages (Method B, Scheme 2)

The alternate connection of the present invention of the formula V can be obtained by the interaction of anhydrous steroid acid such as the anhydride fuseboy acid in scheme 2, abundantly branched polyamine, for example N,N-bis(2-amino-ethyl)ethane-1,2-diamine using the same reaction conditions as specified for method A, and Succinimidyl ester as a starting material (Scheme 2)

Scheme 2

Restoration of amide bonds

Amide bond formed by the interaction of branched polyamine and succinimido of ester or anhydride of carboxylic acid indicated in figure 1 and 2, respectively (for example, the compounds of formula IV and V), can be restored to the corresponding amine by reacting the amide with a 10-fold excess of DIBORANE at boiling under reflux in THF for 5-10 hours. The reaction mixture was then acidified with 4N aqueous hydrochloric acid solution to pH 1 and intensively stirred for 2-4 hours. Next, the reaction mixture was dried by lyophilization and the resulting white powder purified on silica gel using kachestvenna a mixture of dichloromethane, methanol and 25% aqueous ammonia solution. After lyophilization of the pure product is obtained white powder.

Scheme 3. Getting S-21 polyamidoamine analogues of fuseboy acid of the formula IV, in which W represents a radical of the formula -(Z)n-(NR-Z)p-NR2.

The introduction of branched polyamines by reductive amination of ketones (Method C, Scheme 4)

Compounds of the present invention, in which the branched polienovy fragment attached to various parts of steroid nuclei can be obtained from steroid analogues containing keto - or aldehyde functional groups, which it is desirable to replace the branched polyamines. The corresponding steroid can be obtained from commercial sources or can be synthesized by various methods known to the expert (for example, various methods of oxidation, recovery of esters of carboxylic acids and the like). Steroid with a carbonyl group may be subjected to interact directly with unprotected poliaminom block by reductive amination using the methods described for the production of synthetic squalamine (Pechulis et al., 1995; Weis et al., 1999; Kinney at al., 2000). Alternatively, the steroid that contains the amino group may be subjected to interaction with compliance is adequate, the BOC-protected polyaminoamide fragments, containing aldehyde group by reductive amination, as described in the literature to obtain salamunovich equivalents substituted for the atom C-3 spermidine circuit (Hon-Seok Kim et al., 2000). Finally, the BOC-protective group can be split triperoxonane acid and cleaned as described above.

The considered method is illustrated by the example in figure 4, in which the core of fuseboy acid 3 presents etoposide acid. To a solution of 3-etoposido acid (1 equivalent) in methanol was sequentially added N,N-bis(2-amino-ethyl)ethane-1,2-diamine (3 equivalents), acetic acid and NaBH(OAc)3(3 equivalents), the reaction mixture was stirred for 6 to 16 hours after which the methanol is evaporated under reduced pressure with the formation of a pale yellow oil. A pure compound 118 was obtained after chromatography on silica gel using a mixture of dichloromethane, methanol and 25% aqueous ammonia solution as eluent. The connection 118 in the form of a white powder was obtained after lyophilization of the pure product with the release of 70-85%.

Way

Scheme 4. Representative examples of the introduction of an extensive poliamidowych fragments in the steroid nucleus containing carbonyl group by reductive amination using NaBH(OAc)3as the recovery agent (Abdel-Magid, 1996).

Purification of the compounds of the present invention

Compounds of the present invention can be purified using column chromatography on silica gel 60 (E. Merck), 230-400 mesh mesh, using mixtures of dichloromethane, methanol and aqueous ammonia as eluent. The alternate connection of the present invention can be purified preparative high-performance liquid chromatography with reversed phase (HPLC) using triperoxonane or acetic acid as eluent.

Examples of compounds of the present invention obtained in accordance with the General methods a, b and C

No. Conn.MethodThe original steroid compoundThe source of the branched polyamineThe structure of connections
101AN-Succinimidyl ether of tetrahydropyrido acidN,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 177,5; 172,6; 80,2; 72,4; 68,9; 57,6; 54,9; 51,3; 50,3; 50,2; 41,5; 41,4; 41,1; 40,1; 40,1; 38,5; 38,3; 38,0; 37,1; 36,4; 33,1; 31,7, 31,1; 29,1; 26,4; 23,9, 23,3; 23,1; 23,0; 22,6; 21,4; 17,1; 16,5
102AN-Succinimidyl ester of 11-deoxy-tetrahydropyrido acid,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 177,4; 172,6; 80,4; 72,5; 57,7; 55,0; 51,7; 50,9; 50,5; 46,4; 45,9; 41,0; 40,4; 40,2; 40,1; 39,0; 38,5; 37,4; 36,4; 34,5; 32,0; 31,1; 29,9; 29,1; 26,8; 26,4; 24,4; 23,1; 22,9; 21,6; 21,4; 21,3; 20,7; 17,8; 16,5
103AN-Succinimidyl ether 16 deacetoxy-tetrahydropyrido acidN,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 178,6; 72,5; 69,3; 57,2; 54,7; 53,9; 51,8; 51,7; 43,8; 42,4; 41,5; 40,2; 40,0; 38,3; 38,3; 38,0; 37,1; 36,8; 33,1; 32,6; 31,7; 31,2; 31,1; 29,1; 28,7; 26,5; 23,8; 23,2; 23,2; 22,9; 22,7; 16,6; 16,4
104AN-Succinimidyl ether 13(17)-EN-16-deacetoxy-tetrahydropyrido acidN,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 175,9; 143,4; 133,9; 72,5; 70,2; 58,6; 57,6; 56,1; 52,8; 45,3; 44,3; 40,0; 39,9; 39,1; 38,6; 37,9; 36,4; 35,6; 31,9; 31,8; 30,9; 30,7; 30,6; 29,2; 29,0; 25,9; 24,9; 24,1; 23,2; 23,1; 22,9; 22,9; 16,5
105AN-Succinimidyl ether 3β-tetrahydropyrido acidN,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 177,5; 172,6; 80,2; 77,3; 68,8; 57,1; 54,8; 51,3; 51,0; 50,3; 50,2; 44,3; 41,5; 41,3;41,2; 41,1; 40,1; 40,0; 38,4; 37,8; 36,6; 35,3; 33,7; 32,7; 31,7; 29,1; 26,4; 24,5; 23,6; 23,2; 23,0; 22,7; 21,4; 17,1; 16,0
106AN-Succinimidyl ether 9(11)-EN-tetrahydropyrido acidN,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 177,2; 172,6; 153,4; 118,6; 81,2; 71,9; 57,5; 55,0; 52,1; 42,9; 42,4; 40,7; 40,0; 39,3; 39,1; 38,5; 35,1; 34,4; 32,5; 30,8; 29,9; 29,1; 26,4; 26,3; 24,5; 23,1; 22,9; 22,5; 22,4; 21,3; 18,2; 16,1
107AN-Succinimidyl ester of deoxycholic acidN,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 177,0; 74,0; 72,6; 57,6; 57,1; 55,2; 48,1; 47,6; 43,7; 40,5; 40,0; 38,7; 37,5; 37,3; 36,9; 36,5; 35,3; 34,9; 34,2; 33,4; 31,1; 30,0; 28,7; 28,4; 27,5; 24,9; 23,7; 17,7; 13,2
108AN-Succinimidyl ether 23,24-bisnor-5-helenowo acid-3β-OlaN,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 179,8; 142,3; 122,4; 72,4; 57,9; 57,7; 57,4; 55,1; 54,1; 51,7; 45,1; 43,5; 43,1; 41,0; 40,1; 38,6; 38,3; 37,7; 33,3; 33,0; 32,3; 28,5; 25,4; 22,2; 19,9; 18,0; 12,6
109Banhydride fuseboy acidN,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 171,4; 171,1; 140,8; 135,6; 132,1; 123,5; 73,6; 71,4; 68,3; 56,5; 53,1; 49,3; 48,7; 43,1; 39,6; 39,5; 39,3; 37,7; 37,1; 36,3; 36,2; 35,6; 32,4; 30,3; 30,0; 29,4; 28,0; 25,7; 24,2; 22,8; 21,2; 20,8; 17,9; 17,6; 16,0
110Banhydride fuseboy acidN,N-bis(3-amino-propyl)propane-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 174,3; 172,4; 143,4; 135,8; 133,3; 124,6; 75,3; 72,5; 68,6; 52,8; 50,7; 44,6; 40,9; 40,7; 40,3; 39,1; 38,2; 37,9; 37,4; 36,9; 32,9; 31,1; 31,0; 30,5; 29,7; 28,8; 27,5; 25,9; 23,9; 23,8; 22,4; 21,3; 18,0; 17,9; 16,5
111AN-Succinimidyl ester of 11-deoxy-3-OSO3H-tetrahydropyrido acidN,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 177,6; 172,6; 81,6; 80,7; 54,8; 52,0; 50,9; 50,6; 46,5; 46,0; 41,0; 40,5; 40,1; 39,7; 39,4; 38,2; 37,1; 36,1; 34,1; 32,3; 30,3; 29,1; 28,4; 26,9; 26,4; 24,5; 23,1; 23,0; 21,7; 21,4; 21,2; 21,0; 17,8; 16,4
112AN-Succinimidyl ester of 11-deoxy-16-deacetoxy-17S,20,24,25-tetrahydropyrido acidN,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 178,6; 72,5; 57,4; 55,0; 54,3; 52,0; 47,4; 46,4; 44,5; 40,6; 40,1; 40,1; 39,0; 38,4; 37,5; 36,3; 34,6; 32,7; 31,7; 31,1; 30,0; 29,1; 28,7; 27,3; 26,5 24,7; 23,2; 22,9; 21,5; 21,4; 20,7; 17,2; 16,6
113AN-Succinimidyl ether of tetrahydropyrido acidN,N-bis(3-amino-propyl)propane-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 177,4; 172,6; 80,1; 72,5; 68,9; 53,0; 52,9; 51,5; 51,3; 50,3; 50,1; 41,5; 41,4; 41,1; 41,0; 40,1; 38,9; 38,3; 37,9; 37,0; 36,4; 33,1; 31,8; 31,1; 30,0; 29,2; 27,7; 26,4; 23,9; 23,3; 23,2; 23,0; 22,6; 21,4; 17,1; 16,5
114AN-Succinimidyl ether 23,24-bisnor-5-helenowo acid-3β-OlaN,N-bis(3-amino-propyl)propane-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 179,6; 142,3; 122,3; 72,4; 57,9; 54,1; 52,9; 52,7; 51,7; 45,1; 43,5; 43,0; 41,0; 40,9; 38,6; 38,5; 37,7; 33,3; 33,0; 32,3; 29,8; 28,5; 27,7; 25,4; 22,2; 19,9; 18,0; 12,5
115AN-Succinimidyl ether 3-OAc-tetrahydropyrido acidN,N-bis(3-amino-propyl)propane-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 177,3; 172,9; 172,6; 80,1; 76,2; 68,6; 52,9; 51,4; 51,1; 50,3; 50,2; 41,5; 41,3; 41,1; 40,9; 40,1; 38,9; 38,0; 36,6; 33,5; 31,7; 30,0; 29,1; 28,3; 27,7; 26,4; 23,7; 23,4; 23,2; 23,0; 22,3; 21,4; 21,2; 17,2; 16,1
116AN-Succinimidyl ether 3-OSO3H-11-deoxy-tetrahydropyrido acidN,N-bis(3-amino-ol is drank)propane-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 177,1; 172,6; 81,7; 81,4; 52,9; 52,5; 52,3; 51,1; 50,7; 46,5; 46,2; 40,9; 40,6; 40,3; 40,0; 39,3; 38,7; 38,6; 37,0; 36,2; 33,5; 32,7; 30,5; 29,1; 28,3; 27,8; 27,5; 27,0; 26,4; 24,8; 23,1; 22,9; 21,6; 21,3; 21,3; 21,2; 17,9; 16,4
117AN-Succinimidyl ester of 11-deoxy-16-deacetoxy-17S,20,24,25-tetrahydropyrido acidN,N-bis(3-amino-propyl)propane-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 178,4; 72,5; 54,5; 52,9; 52,0; 47,4; 46,4; 44,5; 41,0; 40,6; 40,1; 38,9; 38,8; 37,5; 36,3; 34,6; 32,9; 31,7; 31,2; 30,2; 30,1; 29,1; 28,8; 27,7; 27,3; 26,5; 24,7; 23,2; 22,9; 21,5; 21,4; 20,7; 17,2; 16,6
118C3-etoposido acidN,N-bis(2-amino-ethyl)ethane-1,2-diamine
13C-NMR (CD3OD), δ/ppm: 178,8; 173,2; 139,4; 138,5; 132,6; 125,3; 75,8; 69,0; 61,8; 52,6; 51,6; 50,0; 50,7; 45,9; 43,9; 40,9; 40,2; 38,2; 37,5; 37,4; 37,0; 31,3; 30,9; 30,5; 29,3; 25,9; 24,9; 24,8; 23,3; 22,8; 21,1; 18,0; 17,5; 16,0
119AN-Succinimidyl ether of tetrahydropyrido acidN-(3-aminopropyl)-N-methylpropan-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 177,4; 172,6; 80,2; 72,5; 68,9; 56,6; 56,5; 51,6; 51,3; 50,4; 50,2; 42,3; 41,6; 41,4; 41,1; 40,9; 0,1; 38,7; 38,3; 38,0; 37,1; 36,4; 33,1; 31,8; 31,1; 29,9; 29,2; 27,8; 26,4; 23,9; 23,3; 23,2; 23,0; 22,6; 21,4; 17,1; 16,5
120AN-Succinimidyl ester of 11-deoxy-tetrahydropyrido acidN-(3-aminopropyl)-N-methylpropan-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 177,4; 172,6; 80,5; 72,4; 56,6; 56,6; 52,0; 50,9; 50,5; 46,6; 45,9; 42,3; 41,0; 40,4; 40,0; 39,0; 38,7; 37,4; 36,3; 34,5; 32,1; 31,1; 30,3; 30,0; 29,1; 27,7; 26,8; 26,4; 24,5; 23,1; 22,9; 21,6; 21,3; 21,3; 20,7; 17,8; 16,5
121AN-Succinimidyl ether 16 deacetoxy-17S,20,24,25-tetrahydropyrido acidN-(3-aminopropyl)-N-methylpropan-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 178,5; 72,5; 69,2; 56,6; 56,5; 54,1; 51,8; 51,6; 43,8; 42,4; 42,3; 41,5; 40,9; 40,1; 38,7; 38,3; 37,9; 37,1; 36,8; 33,1; 32,6; 31,6; 31,1; 31,1; 30,0; 29,1; 28,6; 27,7; 26,5; 23,8; 23,2; 22,9; 22,7; 16,6; 16,4
122AN-Succinimidyl ester of deoxycholic acidN-(3-aminopropyl)-N-methylpropan-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 176,8; 74,0; 72,6; 56,5; 56,3; 47,6; 43,7; 42,3; 40,9; 38,7; 37,5; 37,2; 36,9; 36,5; 35,3; 34,9; 34,2; 33,4; 31,1; 30,0; 30,0; 28,7; 28,4; 27,8; 27,5; 24,9; 23,7; 17,7; 13,3
123AN-Succinimidyl ester of 11-deoxy-16-DEZ is ataxi-17S,20,24,25-tetrahydropyrido acid N-(3-aminopropyl)-N-methylpropan-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 178,5; 72,5; 56,7; 56,6; 54,6; 52,0; 47,5; 46,4; 44,5; 42,3; 41,0; 40,6; 40,1; 39,0; 38,7; 37,5; 36,3; 34,6; 32,9; 31,7; 31,2; 30,0; 29,1; 28,9; 27,7; 27,3; 26,6; 24,7; 23,2; 22,9; 21,5; 21,4; 20,7; 17,2; 16,6
124C3-etoposido acidN,N-bis(3-aminopropyl)-N-methylpropan-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 179,6; 173,3; 139,7; 137,8; 132,4; 125,5; 75,9; 69,0; 60,8; 53,1; 52,5; 50,9; 50,0; 49,9; 47,9; 43,7; 40,8; 40,2; 37,6; 37,3; 31,8; 31,1; 30,6; 29,3; 27,7; 26,4; 25,9; 25,6; 24,8; 23,4; 22,7; 21,2; 18,0; 17,6; 16,5
125C3-etoposido acidN-(3-aminopropyl)-N-methylpropan-1,3-diamine
13C-NMR (CD3OD), δ/ppm: 179,6; 173,3; 139,7; 137,5; 132,3; 125,6; 76,0; 69,0; 61,3; 57,3; 56,2; 50,8; 50,0; 43,6; 42,2; 40,8; 40,3; 37,5; 37,4; 37,0; 31,7; 31,1; 30,5;29,2; 27,6; 25,9; 25,4; 25,0; 24,7; 23,3; 22,7; 21,2; 18,0; 17,6; 16,4
126AN-Succinimidyl ether of tetrahydropyrido acidN,N-bis(3-aminopropyl)-N,N'-Dimethylbutane-1,4-diamine
127AN-Succinimidyl ether of tetrahydropyrido acid N'1'-{3-[(3-aminopropyl)ethylamino]propyl}-N'1'-ethylpropane-1,3-diamine
128AN-Succinimidyl ether of tetrahydropyrido acidN,N'-bis(3-aminopropyl)-N,N'-diethylbutyl-1,4-diamine
129AN-Succinimidyl ester of 11-deoxy-tetrahydropyrido acidN'1'-{3-[(3-aminopropyl)ethylamino]propyl}-N'1'-ethylpropane-1,3-diamine
130AN-Succinimidyl ether of tetrahydropyrido acidN,N'-bis(3-aminopropyl)-N,N'-bicyclopentyl-methylbutane-1,4-diamine
131AN-Succinimidyl ester of 11-deoxy-tetrahydropyrido acidN'1'-(3-aminopropyl)-N'1'-(3-dimethylamino-propyl)propane-1,3-diamine

Bactericidal activity

As a result of in vitro studies it was found that the compounds of the invention have significant activity against a large number of bacteria, including gram-positive and gram-negative strains (Susceptible, Streptococci, Corynebacteriae, Mycobacteriae, Proteus, Propionibacterium, Pseudoonas, Neisseriae, E. coli) and fungal strains (Candida and Aspergillus). Biological tests showed that the activity of the compounds of the invention is superior to known activity of some natural analogues squalamine (WO 00/09137). Antibacterial activity of the compounds of the present invention is also comparable with the activity of related compounds described in the literature (Moore et al., 1993; Kikuchi et al., 1997; Rao et al., 2000) and with a wide range of activity such well-known antibiotics as ampicillin (Kikuchi et al., 1997). Moreover, studies of post-antibiotic action has allowed to establish that the compounds of the invention possess strong bactericidal effect. The Table below shows the MIC values (minimum inhibitory concentration) of compounds of the present invention against several bacterial and fungal strains. The minimum inhibiting concentration was determined using analysis on plates with agar. Bacterial strains were obtained from American Type Culture Collection, or taken from the collection of clinical isolates belonging to the authors of the invention. Colonies from a fresh overnight culture resuspendable in salted water to a value of 0.5 MacFarland, the 108CFU/ml 200 ml of Mueller Hinton agar (Oxoid) for 48°C inoculable at a concentration of 106CFU/ml and poured into square Petri dishes (h mm). In inoculated cups made holes and each hole is participation was placed in 200 µl of the tested compounds. A dilution series of the compounds contained six dilutions in the range of 0.25 to 125 mcg/ml When using a Streptococci agar Mueller Hinton was supplemented with 5% sheep blood. Plates were incubated and the diameters of the zones of inhibition of growth was measured using electronic calipers. The MIC was determined using curve linear regression, built in the coordinates of the diameter of zone of inhibition of growth-log2the concentration of the sample. Parameters microbiological analysis meet the European Pharmacopoeia 3rdedition (1997). Zones of growth inhibition is functionally dependent on the concentration of the used compounds. As reference compounds used well-known antibiotics, including fuseboy acid (FA), mupirocin and linezolid.

td align="left"> E.coli HA 165
Compounds of the invention and their in vitro activity MIC (mg/l)
Microorganism/

strain
101102103104105106107114117112111115116FALinezolidMupirocin
S.aureus CJ2474411616 4161611------0,0210,5
S.aureus CJ2004411616--16161116440,0241
S.aureus CJ234R4411616416161116440,02161
S.aureus CJ234F4411616416161116--41610,5
S.aureus N644116164161611------16----
S.epidermis CK5441 161641616114440,020,250,04
Propionibacterium acnesFN33441161641616----44160,21--
Corynebacterium xerosis FF4411616416640,250,25166440,1----
Streptococcus pyogenes EC8816164166441664----164161641
Streptococcus faeclum ES161616>64641616------------------
16164>6464161616----161664>64----
Pseudomonas aeruginosa BA17641616>64161616>125---->12516125>64----
Saccaromyces cervisiae ZZ74164166416464----641616>64----
Candida albicans ZA164116161616>125----1251664>64----
Aspergillus niger ZM3544>125>64646316------64 12564>64----

Notes to table:

Very clear zones of inhibition for all the compounds listed in the table indicate a bactericidal effect.

FA = positiva acid

-- = missing value MIC

Strains:

FF = Corynebacterium xerosisBA17 = Pseudomonas
EC88 = Streptococcus pyrogenesHJ = Proteus
CJ234(F) = Staphylococcus aureus (MRSA#, Fus. stable)EI119(P)=Streptococcus faecium (penicillin-resistant)
CJ(N6) = Staphylococcus aureus (Fus. stable)ZA= Candida albicans
CJ247 = Staphylococcus aureusHA165 = E.coli
CJ234(R) = Staphylococcus aureus (MRSA#, rifampicin-resistant)ZZ7 = Saccharomyces cerevisiae
CJ1200 = Staphylococcus aureusFN33 = Propionibacterium
CK5 = Staphylococcus epidermidisZM6 = Aspergillus flavus
#MRSA: methicillin-resistant S.aureusZM35 = Aspergillus niger

The minimum bactericidal concentration (MBC) for connection 102

106bacteria were inoculable in 3 ml of growth medium (S.aureus - LB broth, these bacteria to antibiotics - HS broth)containing compound 102 in concentrations HMS, 1xMIC, 0,5xMIC and 0xMIC (MIC relative to the tested strain). The S.aureus strains were grown in aerobic conditions, and these bacteria to antibiotics - the anaerobic conditions in the atmosphere of the incubator, enriched with carbon dioxide. The samples were diluted and were sown on LA plates (S.aureus) or on a plate with blood agar (these bacteria to antibiotics), then before counting the resulting colonies were incubated at 37°C within 24 hours.

Connection 102 has a strong bactericidal effect on susceptible varieties and streptococci, destroying bacteria at a concentration equal to twice the value of the MIC, as shown in figures 1 and 2.

The data presented in the Table show that the compounds of the present invention are typically characterized by a wide spectrum of activity against the tested microorganisms. Moreover, they are active against strains resistant to standard antibiotics, as fucicola acid, rifampicin and penicillin. The absence of cross-resistance suggests that the mechanism of bactericidal action of the compounds of the present invention and known antibiotics is different. To overcome the immediate problem of resistance to antibiotics is vital to develop new antibiotics with new mechanisms of action.

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1. Steroid compound of the formula I

in whichindicates the possibility of a double bond;

R1 represents a saturated or unsaturated With2-10alkyl straight or branched chain or methyl;

R2 represents COOH or fragments of formulas VIII, IX, X, XI, XII, XIII, XVI, XVII, XVIII, XIX, XX, XXI, XXII or XXIII

R3 represents hydrogen or O-R19 where R19 is hydrogen or C1-6acyl;

R4 represents hydrogen; R5 represents hydrogen or methyl; R6 represents hydrogen or methyl; R7 represents hydrogen; R8 represents hydrogen; R9 represents hydrogen; R10 represents hydrogen or methyl; R11 represents a hydroxy, OSO3, -O-acyl, -(Z)n-(NR-Z)p-N(R)2where Z represents a linear hydrocarbon diradical, n is 0 or 1, p is 1, R represents hydrogen, C1-6alkyl or C1-6aminoalkyl, each of which is optionally substituted C1-6by alkyl;

R12 represents hydrogen; R13 represents hydrogen; R15 represents hydrogen; R16 represents hydrogen or hydroxy; R17 represents hydrogen; R18 represents hydrogen or methyl;

each of R9, R15 and R18 are independently absent when one of the condensed rings b, C and D is unsaturated so that all of the valences of the corresponding carbon atom were occupied;

provided that at least one of R2 and R11 are -(Z)n-(NR-Z)p-N(R)2or C(O)-(Z)n-(NR-Z)p-N(R)2,

and its pharmaceutically acceptable salts and esters.

Caetanina according to claim 1, in which R11 represents a - (Z)n-(NR-Z)p-N(R)2.

3. The compound according to claim 1, in which R1 represents methyl.

4. The compound according to claim 1, in which R1 represents a fragment of formula II

where the carbon-carbon bond indicated by the symbol "*" represents a single or double bond.

5. The compound according to any one of claims 1 to 4, in which R19 represents a C1-6acyl.

6. The compound according to any one of claims 1 to 4, in which R11 and/or R16 represents IT.

7. The compound according to claim 5, in which R11 and/or R16 represents IT.

8. The compound according to any one of claims 1 to 4, in which R11 represents a group-OSO3.

9. The compound according to any one of claims 1 to 4, in which R11 represents a group-O-acyl.

10. The compound according to claim 1, which represents a compound of General formula Ia

11. The compound according to claim 1, which represents a compound of General formula Ib

12. The compound of claim 10 or 11, in which R11 and R16 both represent a hydroxy-group.

13. The compound of claim 10 or 11, in which R3 represents a-OR19 where R19 represents a C1-6acyl.

14. The compound of claim 10 or 11, in which R1 represents methyl.

15. The compound of claim 10 or 11, in which R1 represents a saturated or unsaturated With2-10alkyl straight or rasvet the military chain.

16. The compound of claim 10 or 11, in which R1 represents a fragment of formula II

in which the carbon-carbon bond, indicated by the symbol "*" represents a single or double bond.

17. The compound of claim 10 or 11, in which R11 represents a -(Z)n-(NR-Z)p-N(R)2.

18. The connection 17 in which R2 represents COOH.

19. The connection 17, in which R3 represents a-OR19 where R19 represents a C1-6acyl.

20. The connection 17 in which R1 represents methyl.

21. The connection 17 in which R1 represents a saturated or unsaturated With2-10alkyl straight or branched chain.

22. The connection 17 in which R1 represents a fragment of formula II

in which the carbon-carbon bond, indicated by the symbol "*" represents a single or double bond.

23. The compound according to any one of claims 1, 10 or 11, in which R2 and/or R11 represent a fragment of formula XI, XIII,XVI, XVIII, XX or XXII

24. The compound according to claim 1, selected from the GRU is dust, including

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-17R,20S,24,25-tetrahydrofolic-21-amide,

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-11-deoxy-17R,20S,24,25-tetrahydrofolic-21-amide,

21-N-{2'-[bis[2'-amino-ethyl)amino]ethyl}-16-deacetoxy-17R,20S,24,25-tetrahydrofolic-21-amide,

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-13(17)-EN-17,20,24,25-tetrahydrofuran-21-carboxamid,

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-3β-deacetoxy-17R,20S,24,25-tetrahydrofolic-21-amide,

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-9(11)-ene-17R,20S,24,25-tetrahydrofolic-21-amide,

24-N-[2'-[bis(2'-amino-ethyl)amino]ethyl}-3α-hydroxy-5β-Holan-24-amide,

22-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-23,24-bisnor-5-cholenic-22-amide,

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}fusid-21-amide,

21-N-{3'-[bis(3'-aminopropyl)amino]propyl}fusid-21-amide,

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-3-OSO3-11-deoxy-17,20,24,25-tetrahydrofolic-21-amide,

21-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}-11-deoxy-16-deacetoxy-17S,20,24,25-tetrahydrofolic-21-amide,

21-N-{3'-[bis(3'-aminopropyl)amino]propyl}-17R,20S,24,25-tetrahydrofolic-21-amide,

22-N-{3'-[bis(3'-aminopropyl)amino]propyl}-23,24-bisnor-5-cholenic-22-amide,

21-N-{3'-[bis(3'-aminopropyl)amino]propyl}-}-3-SLA-17R,20S,24,25-tetrahydrofolic-21-amide,

21-N-{3'-[bis(3'-aminopropyl)amino]propyl}-}-3-OSO3-11-deoxy-17,20,24,25-tetrahydrofolic-21-amide,

21-N-{3'-[bis(3'-aminopropyl)amino]propyl}-}-11-deoxy-16-deacetoxy-17R,20,24,25-tetrahydrofolic-21-amide,

3-N-{2'-[bis(2'-amino-ethyl)amino]ethyl}positiva acid,

21-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}-17R,20S,24,25-tetrahydrofolic-21-amide,

21-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}-11-deoxy-17R,20S,24,25-tetrahydrofolic-21-amide,

21-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}-16-deacetoxy-17R,20S,24,25-tetrahydrofolic-21-amide,

24-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}-3α-hydroxy-5β-Holan-24-amide,

21-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}-11-deoxy-16-deacetoxy-17R,20S,24,25-tetrahydrofolic-21-amide,

3-N-{3'-[bis(3'-aminopropyl)amino]propyl}-}-positiva acid,

3-N-{3'-[(3'-aminopropyl)(methyl)amino]propyl}positiva acid,

21-N-{3-({4'-[(3'-aminopropyl)methylamino]butyl}methylamino)propyl}-17R,20S,24,25-tetrahydrofolic-21-amide,

21-N-{3'-({3'-[(3'-aminopropyl)ethylamino]propyl}ethylamino)propyl}-17R,20S,24,25-tetrahydrofolic-21-amide,

21-N-{3'-({4'-[(3'-aminopropyl)ethylamino]butyl}ethylamino)propyl}-17R,20S,24,25-tetrahydrofolic-21-amide,

21-N-{3-({3'-[(3'-aminopropyl)ethylamino]propyl}ethylamino)propyl}-11-deoxy-17R,20S,24,25-tetrahydrofolic-21-amide,

21-N-{3'-({4'-[(3'-aminopropyl)cyclopropanemethylamine]butyl}cyclopropylamino)propyl}-17R,20S,24,25-tetrahydrofolic-21-amide, and

21-N-{3'-({3'-[('-aminopropyl)-(3'-dimethylaminopropyl)amino]propyl}11-deoxy-17R,20S,24,25-tetrahydrofolic-21-amide.

25. Antibacterial pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 24 in an effective amount, optionally together with pharmaceutically acceptable excipient or carrier, and optionally other therapeutically active agents.

26. The use of compounds according to any one of claims 1 to 24 for the manufacture of a medicinal product intended for the treatment or prevention of bacterial infections.

27. A method of preventing or treating bacterial infectious diseases, comprising the administration to a patient in need of treatment an effective amount of a compound according to any one of claims 1 to 24.



 

Same patents:

FIELD: medicinal industry, sterols.

SUBSTANCE: invention relates, in particular, to the improved method for producing sterols - lanosterol and cholesterol from wooly fat that can be used in preparing medicinal and cosmetic preparations. Method is carried out by alkaline hydrolysis of raw, extraction of unsaponifiable substances, removal of solvent and successive isolation of lanosterol and cholesterol. Alkaline hydrolysis of raw is carried out with a mixture of ethanol, sodium hydroxide, pyrogallol and water at temperature 70°C for 4 h at stirring in the following ratio of components: raw : ethanol : sodium hydroxide : pyrogallol : water = 100.0:(300.0-350.0):(30.0-35.0):(0.01-0.05):(7.5-12.0), respectively, with the indicated mixture with addition of toluene in the following ratio: raw : ethanol : sodium hydroxide : pyrogallol : toluene : water = 100.0:(220.0-255.0):(30.0-38.0):(0.05-0.12):(100.0-137.0):(2.5-7.0), respectively, and lanosterol is isolated by precipitation from mixture of methylene chloride and ethanol in the ratio = 1:1. Before removal of solvent unsaponifiable substances are extracted at temperature 50°C for 2-3 h at stirring. Invention provides increasing yield of the end product, enhancing qualitative indices and reducing cost of production.

EFFECT: improved producing method.

2 cl, 3 ex

FIELD: organic chemistry, chemistry of steroids.

SUBSTANCE: invention relates to a new method for synthesis of 6β-formyl-B-norcholestane-3β,5β-diol of the formula (I): by constricting six-membered B-ring of cholesterol. Method involves photooxidation of cholesterol with air oxygen at irradiation by visible light in the presence of porphyrine photosensibilizing agent immobilized on low-molecular fraction of copolymer of tetrafluoroethylene and perfluoro-3,6-dioxo-5-methyl-6-sulfonylfluoride octene-1 in the mass ratio porphyrine photosensibilizing agent : cholesterol = 1:(12-15). As porphyrine photosensibilizing agent 5,10,15,20-tetraphenylporphyrine can be used. Method shows technological simplicity, it doesn't require rigid conditions and provides the high yield of the end product.

EFFECT: improved preparing method.

2 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention represents new derivatives of 17,20-dihydrofusidic acid of the formula (Ia)

wherein Q1 and Q2 are similar or different and mean -CO-, -CHOH-, -CHRO- wherein R means (C1-C4)-alkyl; Q3 means -CH2-; Y means hydrogen atom (H); A means -O- or -S-; R1 means (C1-C4)-alkyl, (C2-C4)-olefin, (C1-C6)-acyl, (C3-C7)-cycloalkylcarbonyl, benzoyl. These derivatives are used in pharmaceutical compositions for treatment of infectious diseases, in particular, in composition for topical applying for treatment of infectious diseases of skin and eyes.

EFFECT: valuable medicinal properties of compounds.

22 cl, 7 tbl, 41 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):

wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

38 cl, 1 tbl, 18 ex

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

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The invention relates to an improved method of direct esterification of Stanlow/sterols interaction of stanol/sterols and acid taken in stoichiometric ratio, in the presence of a sufficient amount of catalyst, which can be acidic or basic, and in the presence of a sufficient amount of decolorizing agent, preferably activated carbon

The invention relates to the field of biologically active substances from plant material, in particular to a method of simultaneously receiving 20-hydroxyecdysone but also of inokosterone, ecdysone, magisteria And having the following structural formula:

20-hydroxyecdysone - R1=OH, R2=H, R3=OH, R4=H

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EFFECT: valuable medicinal properties of drugs.

8 cl, 11 dwg, 38 ex

FIELD: steroids, pharmacy.

SUBSTANCE: invention describes a method for preparing crystals showing the mean coarseness index in the required limits from 3 to 25 mcm and maximal size 100 mcm, not above. Method involves the crystallization process of supersaturated solution of compound representing 11β-benzaldoximestra-4,9-diene wherein it is subjected for wetted grinding by using the correspondence device designated for such wetted grinding to obtain suspension of primary grains. Also, invention crystals prepared by the proposed method and a pharmaceutical agent containing these crystals.

EFFECT: improved preparing method.

14 cl, 8 tbl, 4 dwg, 4 ex

FIELD: organic chemistry, steroids, medicine.

SUBSTANCE: invention describes compounds or their salts of the general formula (I): wherein values C are disclosed in the invention description. These compounds can be used in preparing medicinal agents used in treatment of acute disorders in portal and hepatic venous circulation.

EFFECT: valuable medicinal properties of compounds.

4 cl, 1 tbl, 2 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) , their pharmaceutically acceptable salts, solvates, stereoisomers wherein in each case R1 and R2 mean independently hydrogen atom, possibly substituted alkyl, aryl, heteroalkyl wherein heteroatom means nitrogen atom, heteroaryl wherein a heteroatom means nitrogen, oxygen or sulfur atom; or R1 and R2 in common with N-atom to which they are bound can form a heterocyclic structure as a moiety of organic group comprising 6-12 carbon atoms and comprising optionally 1-6 heteroatoms chosen from nitrogen and oxygen atoms; R3 and R4 mean hydrogen atom or a protective group under condition that R and/or R4 represents part of the hydroxyl protective group; № from 1 to 17 mean carbon atoms wherein C-atoms at № 1, 2, 4, 11, 12, 15 and 16 can be substituted with two from R5 groups; C17-atom can be substituted with one of the following groups: =C(R5)(R5), =C=C(R5)(R5) or two from groups - R5 and -OR6; C-atoms at № 5, 8, 9, 10, 13 and 14 can be substituted with group R5 wherein R means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-halogenalkyl; R6 means H, protective group, such as -OR6-protected OH-group wherein the group -OR6 can form cyclic protective structure for vicinal -OH groups. Proposed compounds can be components of pharmaceutical composition and useful in treatment and/or prophylaxis of different states including inflammation, asthma, allergic disease, chronic obstructive pulmonary disease, allergic dermatitis, solid neoplasms, ischemia and cardiac arrhythmia.

EFFECT: improved treatment method, valuable medicinal properties of substances and pharmaceutical composition.

53 cl, 10 tbl, 24 ex

FIELD: organic chemistry, steroids, biology.

SUBSTANCE: invention relates to steroid compounds of the general formula (X):

wherein in fragment of the formula XA:

each bond between C6 and C7, between C7 and C8, between C8 and C9, between C8 and C14 and between C14 and C15 is a single or double bond under condition that each atom C6, C7, C8, C9, C14 and C15 is bound with adjacent C-atom by a single bond or one double bond; CR3 means -CHOH; A means methylene or ethylene group; R4 and R4' mean (C1-C4)-alkyl, hydrogen atom (H); R20 means (C1-C4)-alkyl; R23 and R23' mean in common piperidine-1-yl, morpholine-4-yl, pyrrolidine-1-yl, piperazinyl possibly substituted with -OH, benzene, pyridine, pyrimidine, phenyl, alkoxycarbonyl group, or R23 means H and R23' means substituted alkyl. These compounds can be used for stimulation of meiosis in human oocytes. In proposed compounds steroid differs specifically as nitrogen atom of amino-group is bound with C17-atom of steroid skeleton by spacer A.

EFFECT: improved methods of synthesis, valuable biological properties of compounds.

16 cl, 8 dwg, 2 tbl, 30 ex

FIELD: organic chemistry, steroids.

SUBSTANCE: invention describes 17α-alkyl-17β-hydroxyestra-1,3,5(10)-trienes possessing anti-estrogenic properties of the general formula (I): wherein Hal means fluorine (F), chlorine (Cl) atoms; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkanoyl, simple cyclic (C3-C7)-ether comprising O-atom; R17' means H, (C1-C4)-alkyl, (C1-C4)-alkanoyl; R17'' means (C1-C4)-alkyl, (C1-C4)-alkynyl; SK means: U-V-W-X-Y-Z-E wherein U means (C1-C13)-alkylene; V means -CH2; W means -N(R6) wherein R means H, (C1-C4)-alkyl; X means (C1-C12)-alkylene; Y means a direct bond between X and Z; Z means possibly fluorinated (C1-C9)-alkylene; E means -CF3. Also, invention describes 17-oxoestra-1,3,5(10)-trienes and 17β-hydroxyestra-1,3,5(10)-trienes as intermediate substances used in synthesis of estratrienes proposed by the invention. Also, invention describes using 17α-alkyl-17β-hydroxyestratrienes for preparing corresponding medicinal agents and pharmaceutical preparations comprising at least one 17α-alkyl-17β-hydroxyestratriene and at least one pharmaceutically acceptable carrier.

EFFECT: valuable medicinal properties of steroids.

5 tbl, 7 dwg

FIELD: organic chemistry, steroids, chemical technology.

SUBSTANCE: invention describes a method for preparing 3-keto-7α-alkoxycarbonyl-substituted ▵4,5-steroid of the formula (I): wherein is taken among or R3 means hydrogen atom (H), lower alkyl, lower alkoxy-group or cyano-group (CN); R21 means hydrogen atom (H) or alkyl; R26 means (C1-C4)-alkyl; R8 and R9 form in common heterocyclic ring system. Method involves interaction of an alkylating agent with 4,5-dihydro-5,7-lactone steroid of the formula (II): wherein R18 means (C1-C4)-alkyl or R18O-group taken in common form O,O-oxyalkylene bridge or keto-group and R3, R8 and R9 have above given values in the presence of a base. Compounds of the formula (I) are used as intermediate compounds in improved methods for synthesis of epoxymexerone.

EFFECT: improved preparing method.

56 cl, 42 tbl, 30 sch, 5 dwg, 89 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):

wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

38 cl, 1 tbl, 18 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to improved method for production of 4,17(20)-E-pregnadiene-3,16-dione (E-guggulsterone) of formula III and 4,17(20)-Z-pregnadiene-3,16-dione (Z-guggulsterone) of formula IV including oxidation of compound of formula II , wherein C-OH or =O; ----- is optional double bond with pyridinium chlorochromate, pyridinium dichromate etc to produce 4,17(20)-E-pregnadiene-3,16-dione of formula III followed by conversion thereof by photochemical, thermochemical reaction or reaction in presence of acidic catalyst. Compounds of formulae III and IV effectively decrease increased low density lipoprotein levels and high cholesterol levels.

EFFECT: improved method for production of 4,17(20)-Z-pregnadiene-3,16-dione.

8 cl, 46 ex, 9 dwg

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