Oligosacharides 14-aminosteroid, the method of production thereof, pharmaceutical composition, method of treatment, method of introduction of amino groups

 

(57) Abstract:

Describes the new oligosacharides 14-aminosteroid General formula I, where R1- COOR5where R5lower alkyl with 1-6 carbon atoms, COR, where R is amino group, possibly substituted lower alkyl with 1-6 carbon atoms; R2- NH2group; R3- the rest of the oligosaccharide General formula II, where Rgis hydrogen, hydroxy, acetoxy, benzoyloxy; R10is an oxygen atom, and if next R11Deputy of the terminal monosaccharide residue, R11HE, methyl, acetoxy and R is hydrogen, methyl, methylhydroxylamine, or oligosaccharide residue of General formula III, where R14and R15identical or different, denote a lower alkyl with 1-6 carbon atoms; R17can be hydrogen; hydroxy, acetoxy or benzox; R18and R19means hydroxy, acetoxy or benzox, or oligosaccharide residue of General formula VI, where R14and R15identical or different, denote a lower alkyl with 1-6 carbon atoms; R14ais hydroxy, acetoxy; R4- N. The compounds of formula I are active in the treatment of congestive heart failure, because the increase contractility of the heart muscle. Describes tawadey amino group. 5 C. and 7 C.p. f-crystals.

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The scope of the invention

The invention relates to a new oligosaccharide-containing 14-aminosteroid connections. This invention also relates to pharmaceutical compositions containing these novel compounds and to a method for treatment of congestive heart failure (CHF) with the use of compounds of the present invention. Further, this invention relates to a new process of introducing an amino group at position 14 of the steroid skeleton.

CHF is a progressive disease in which the heart is largely unable to maintain adequate cardiac output (SV), which represents the volume of blood is continuously pumped from the heart to deliver oxygenated blood to peripheral tissues. In the initial period of heart disease the rest of the body compensates for the lack of army and such compensatory mechanisms eventually lead to a syndrome known as CHF. As CHF progresses, there are structural and hemodynamic disturbances. These structural abnormalities are manifested at the macroscopic level in the form of ventricular hypertrophy in mi is th tissue in the wall of the ventricle, decreased density of capillaries of the myocardium and death of myocardial cells. When there is fibrosis of the tissues of the myocardium, it endangers the heart, because the remaining, viable cells have a big load.

Hemodynamically insufficient heart the ability to develop force along the systole phase in the cardiac cycle, during which the ejection of blood from the ventricle) is reduced. So, to perform the same external work requires a greater end-diastolic volume (during a diastolic phase of the cardiac cycle is the filling of the ventricle). In heart failure reduced emissions caused by non-compliance with health and stress, leads to an increase in end-diastolic pressure and the pressure in the pulmonary capillaries. Frequent effects are pulmonary embolism and peripheral edema. As CHF progresses, the patient experiences worsening symptoms of fatigue and shortness of breath.

Effective treatment of CHF requires determination of its etiology, if possible, as some CHF etiology require its special and unique form of treatment. CHF has many causes, including diseases mikee disease cardiac arrhythmia, hypertension and diabetes. For example, if a cause of CHF is myocarditis or fibrillation, the treatment of the patient antibiotics or anti-arrhythmic agent, respectively, can restore a patient's normal cardiac function.

However, if the etiology is not responsive to treatment, designate one or more of the three treatment options: 1) improvement of cardiac activity by the appointment of an agent that alters the contractility of muscle tissue, such as digitalis; 2) reducing the load on the heart due to holidays and/or destination vasodilator drugs, such as captopril; and 3) regulation of sodium and water retaining using salt-free diet or administration of diuretics, such as teased. Treatment of CHF adapted in accordance with the symptoms of the patients and portability of their medicines. For example, some patients have a strong tendency to digitalis poisoning, whereas in other patients with a milder form of the disease can occur improvement on diuretics having great therapeutic breadth. Moreover, common sense suggests that diuretics are suitable as the first tool in the treatment of CHF, and that treatment diurea effective when assigning patients suffering from CHF severe. Cm. General provisions, Braunwald, Heart Disease: A Textbook of Cardiovascular Medicine. Vol. (3rd ed. 1988), Chung, E. K., Quick Reference to Cardiovascular Disease. Chapter 27 (2d ed. 1983), and Fowler, N. O., Caidiac Diagnosis and Treatment. Chapter 12 (2d ed. 1976).

Although digitalis suitable for improving symptoms associated with hemodynamic disturbances, characteristic of severe CHF, in fact its low therapeutic range limits its therapeutic use. Cm. General provisions, Braunwald, Heart Disease: A Textbook of Cardiovascular Medicine, Vol. (3rd ed. 1988), Chung, E. K., Quick Reference to Cardiovascular Disease. Chapter 27 (2d ed. 1983), and Fowler, N. O., Cardiac Diagnosis and Treatment. Chapter 12 (2d ed. 1976) and Goodman and Gilman, The Pharmacological Basis of Therapeutics, Chapter 34 (8th ed. 1990).

Problems of toxicity associated with digitalis, prompted researchers to try to get a more secure active heart funds. Cardioactive compounds containing a steroid skeleton, described in the following patents: application WO 87/04167 (Chiodini et al.), published on July 16, 1987, describes aminoglycoside derivatives of steroids have in position 3 is the remainder of the amino sugar, and in regulation 14 - acetal. In the abstract it is argued that compound suitable for the treatment of hypertension. French patent 2,642,973 (Guina), published August 17, 1990, describes Digi is let, substituted in position 3 on the balance of glucose in position 17 on the rest of the lactone, and the position of the 14 - hydroxyl group. The abstract says that the connection is suitable for prevention of pathological conditions resulting from heart failure, for whom prescribed digitalis, and to prevent pathological conditions arising from hypertension due to obyzvestvleniya artery. Connection Guina, as claimed, is a positive inotrope (modifies airway muscle tissue), peripheral vasodilating agent and antiarrhythmic agent. Application WO 87/04167 (Chiodini et al.), July 16, 1987, describes aminoglycoside steroid with a 3-position residues of alkyl substituted amino sugars, such as 2-amino or 2-alkylamino-2-deoxy-hexopyranosyl, 3-amino or 3-alkylamino-3-deoxy-hexopyranosyl, 3-amino or 3-alkylamino-3,6-dideoxy-hexopyranosyl, 3-amino or 3-alkylamino-2,3,6-trideoxy-hexopyranosyl, 4-amino or 4-alkylamino-2,4,6-trideoxy-hexopyranosyl and cyclic amide (lactam) in position 17. In position 14 Deputy represents N. It is said that the connection can be used as protivogipertonicheskoe tool. Application WO 91/17176 (Kenny, et al. ), publ, the within in position 3 fragment sugar, such as pentose, hexose or their combination, and the lactone cycle in position 17, position 14 Deputy HE, H or F, Cl, Br or NH2; DD 296,502 A5, issued on 5 December 1991, provides for the treatment of heart failure steroid Amin, whose position 3 is sulfonylamino and in position 17 Deputy 5 - or 6-membered lactone ring cycle, in position 14 Deputy is OH. U.S. patent 5,144,017 (LaBella) 1 September 1992 declares steroid compounds, which, as indicated, applicable as cardiac stimulants, and in which position 3 Deputy is a glycoside radical, such as D-glucoside, L-rhamnoside, redigitized and in position 17 deputies are acetoxy or amino group, and in position 14 Deputy is OH-group; U.S. patent 5,175,281 (McCall), December 29, 1992, declares pyrimidinylpiperazine steroid compounds, applicable for the treatment of spinal injuries, head injuries and related cerebral vascular spasm, prevent injuries caused by restoration of the activity of the heart and lungs during heart attack, compounds in which at position 3 are deputies HE, CH3O, COOH or benzox, position in the April 1988, declares a method of obtaining cardioactive steroids, in which 3-position of the steroid molecule is Deputy - morpholinoethoxy residue, the position 17 of the steroid skeleton substituted lactone cycle; and in position 14 are deputies HE, H or olefin. The claimed compounds, allegedly applicable to increase contractility of the heart muscle. The Japan patent 4-290899 (Ichikawa, et al.), issued October 15, 1992, declares cardiotonic steroid compound in which the 3-position of the steroid skeleton is oligosaccharide; specified oligosaccharide consists of three glucopyranosyl fragments in position 14 is OH-group, and the position 17 substituted lactone cycle. Templeton, et al., 36 J. Med. Chem. 42-45 (1993) describes the synthesis of derivatives of 14-hydroxy-21-nor-5 , 14 - pregnane and 5 , 14 pregnan C-3 - L-rhamnoside and Tris - D-digitoxose. It is reported that these compounds are effective cardiotonic agents. These derivatives having a C-17 COCH2HE, CH2OH, COOH, COOMe, CH2NH2or CH2NO2the group affect the other side of the heart muscle, which responds to the digitalis receptor. Templeton, et al., 1 J. Chem. Sci. Trans., 2503-2517 (1992) describes the synthesis of 20 - and 20 - acetamido-, amino-, diegnan together with-20-oxime, the hydrazone and amidinohydrolase. It is argued that these compounds are effective cardiotonic agents.

In addition, inhibitors of angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce mortality among patients with CHF. Cm. Nicklas, J. M. and Pitt, B., et al. (The SOLVD Jnvestigators), "Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure", N. Engl. J. Med. 325(5):293 (1991).

However, four million people still suffer from CHF. The mortality rate five years after diagnosis of CHF is observed for 60% of men and 45% women. This is a clear indication that you need the best therapeutic agents for the treatment of CHF. Cm. Parmley, W. W., "Pathophysiology and Current Therapy of Congestive Heart Failure", J. Am. Col. Cardiol. 13:771-785 (1989); Francis, G. S. et al., "Congestive Heart Failure: Pathophysiology and Therapy", Cardiovascular Pharmacology, 3rd Edition (1990).

14-Aminosteroid compounds have been shown to be active in the treatment of CHF, as the increase contractility of the heart muscle. These compounds give a therapeutic effect by increasing contractility of the heart muscle without the side effects of digitalis. These 14-aminosteroid and methods for their preparation are described in the following three patents together with given references: U.S. patent 4,325,879 (Jarreau, et al.), issued 20 AP is.S. '868); U.S. patent 4,584,289 (Jarreau, et al.), issued April 22, 1986 (U. S. '289) and U.S. patent 4,885,280 (Jarreau, et al.), issued on 5 December 1989 (U. S. '280). These four patents describe a 14-aminosteroid compounds with biological activity, and methods for their preparation. U. S. '879; '868; '289 and '280 - all declare the use of attestations acid to obtain azide derivatives in position 14, which are then restored to amines. Adeoti, S. B., et al., "Introduction Of A 14-Nitrated Function Into The Steroid Ring To Prepare The Cardioactive Molecule, 14-Amino-5 Pregnane-3 , 20-Diol, from Progesterone and Deoxycholic Acid," 45(12) Tetrahedron Letters, 3717-3730 (1989) describes two ways of introducing a 14-amino function in the steroid molecule, including 1) the reaction of cyclization in the presence of N3H, BF3Et2O or ammonia, or 2) treatment of steroid skeleton N3H, BF3Et2O. These methods yield cardioactivity 14 amino-5 pregnan-3 , 20 - diol. Naidoo. C. K. et al., "Cardiotonic Steroids I: Importance of 14b-hydroxy Group in Digitoxigenin," 63 (9) Jnl Pharm Sci., 1391-1394 (1974) describes the experimental attempts to obtain 14 - aminosteroids connection using iodization. However, the researchers failed to introduce the amino group in position 14 steroid skeleton, using chemistry iodization. Applicability chemistry iodization to the synthesis of steroid vitat," Journal f. pract. Chemie, Band 325, Heft 1, 1983, S. 123132; Ponsold, K., et al., "Synthese und Reaktivitat von Estra-1,3,5(10)-trienen mit heterocyclischen Vierringen in 14,15-Stellung", "Journal f. pract. Chemie, Band 328, Heft 5/6, 1986, p. 673-681; and Bohl, M., et al. , "Quantitative structure-activity relationships of estrogenic steroids substituted at C14, C15", Steroid Biochem. Vol. 5, pp. 589-597, 1987.

It was found that 14-aminosteroid compounds of the present invention, in which position 3 Deputy is a fragment of the oligosaccharide, represent a more effective inotropic agents. These oligosacharides 14-aminosteroid more resistant to metabolism and, therefore, provide a greater duration of inotropic activity than previously used in practice 14-aminosteroid. It was also found that the amino group can be introduced at position 14 of the steroid skeleton by way of using iodization, which is safer and more effective than previous methods.

The invention

The oligosaccharide-containing 14-aminosteroid compounds and pharmaceutically-suitable salts or esters of the acids of General formula

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in which (a) R1means

(i) COOR5where

R5means hydrogen; alkyl with 1-6 carbon atoms; lower alkali with 1-6 carbon atoms, a substituted amino group; Ariel hydrogen or lower alkyl with 1-6 carbon atoms; or

(iii) COR"', where

R"' represents hydrogen; lower alkyl with 1-6 carbon atoms; aminosilane lower alkali with 1-6 carbon atoms; amino or dialkylamino; and

b) R2means-NR7R8where

R7and R8which may be identical or different, denote hydrogen atoms or lower alkali with 1-6 carbon atoms; and

(C) R3means

(i) the oligosaccharide sugar residue having the following structure:

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where R9means hydrogen; methyl; hydroxy; carboxy; acetoxy; Allakaket; heteroaromatic; or benzox; R10means hydrogen; methyl; carboxy; acetoxy; Allakaket; heteroaromatic; benzox or hydroxy; R11mean oxygen; which then, if R11is the Deputy at the end monosaccharide residue, R11means OH; methyl; acetoxy; heteroaromatic; Allakaket; and R12means hydrogen; methyl; methylhydroxylamine; or acetoxymethyl; or

(ii) the oligosaccharide sugar residue having the following structure:

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where R14and R15that may be the same or different, signify hydrogen; lower alkali with 1-6 carbon atoms; arylalkyl; heteroaromatic; heteroaryl or is ataxi or benzox; or

(iii) oligosaccharide residue having the following structure:

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where R14and R15that may be the same or different, signify hydrogen; lower alkali with 1-6 carbon atoms; heteroaromatic; arylalkyl or aryl; R14amean oxygen; where then, if R14adoes the Deputy have a terminal monosaccharide residue, R14amust be hydroxy; methyl; acetoxy; Allakaket or heteroaromatic; and

d) R4means

(i) HE or

(ii) H, or

(iii) OR13where R13means monosaccharide residue; acetoxy; benzoxa; arylalkyl or heteroaromatic; and

e) Z means

(i) -CH-, where a and b denote a single bond, or

(ii) =s, where either a or b means of the double bond.

The present invention also relates to a method of introducing an amino group at position 14 of the steroid skeleton, in which the specified amino group diastereoselective is entered in position 14 steroid nucleus through the accession iodization and which involves the following stages:

a) attaching iodization to the double bond in position 14-15 steroid nucleus; and

b) dehalogenase; and

(C) the conversion of isocyanate to amine in position 14 steroid nucleus.

"Aminosteroid" means a steroid cyclic compound having an amino group in the steroid nucleus.

"Alkyl" means unsubstituted or substituted, unbranched, cyclic or branched, saturated hydrocarbon residue, having from 1 to 8 carbon atoms and, preferably, unless otherwise specified, from 1 to 4 carbon atoms. Preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl and butyl; monovalent radical produced from aliphatic hydrocarbons excluding 1H; as, for example, methyl. The lower alkyl groups contain 1-6 carbon atoms.

"Heteroalkyl" is used below for unsubstituted or substituted saturated 3-8 membered chain and containing carbon atoms and one or two heteroatoms.

"Alkenyl" means unsubstituted or substituted, unbranched or branched hydrocarbon chain having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond.

"Quinil" means unsubstituted or substituted, straight or branched hydrocarbon chain having from 2 to 8 carbon atoms, preferably from 2 to 4 atoms, and the radical.

"Acetoxy": The Atomic Charges. Radical, CH3COO-.

"Acetyl": Acyl radical, CH3WITH-.

"Aglycon": the component of a glycoside, for example, a plant pigment that is not sugar.

"Carbocyclic ring" or "Carbocycle", as used hereinafter, refers to unsubstituted or substituted, saturated, unsaturated or aromatic hydrocarbon cycle, typically containing from 3 to 8 atoms, preferably from 5 to 7 atoms.

"Heterocyclic ring" or "Heterocycle", as used hereinafter, refers to unsubstituted or substituted, saturated or unsaturated or aromatic cycle, which consists of carbon atoms and one or two heteroatoms in the ring. Heterocyclic rings usually contain from 3 to 8, preferably from 5 to 7 atoms. Unless otherwise specified, the heteroatom may be independently selected from nitrogen, sulfur and oxygen.

"Aryl" means an aromatic carbocyclic ring. Aryl groups include, but are not limited to, phenyl, tolyl, xylyl, cumenyl and naphthyl; an organic radical derived from an aromatic hydrocarbon by subtracting one hydrogen atom: for example, phenyl from benzene.

"Heteroaryl" oznachaut this, thronged, furyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiazolyl, chinoline, pyrimidinyl and tetrazolyl.

"Alkoxy" means an oxygen atom, with Deputy hydrocarbon chain, where the hydrocarbon chain means alkyl or alkenyl (for example, -O-alkyl or-O-alkenyl); "Alkoxy" is an alkyl radical attached to the rest of the molecule through an oxygen; as methoxy. Preferred alkoxygroup include, but are not limited to, methoxy, ethoxy, propoxy, allyloxy.

"Hydroxyalkyl" means a substituted hydrocarbon chain, which has Deputy hydroxy (e.g.,- OH), and may have other substituents. Preferred hydroxyalkyl groups include, but are not limited to, hydroxyethyl, hydroxypropyl, phenylhydroxylamine.

"Carboxylic" means a substituted hydrocarbon chain, which has Deputy carboxy (e.g.,- COOH), and may have other substituents. Preferred carboxialkilnuyu group include carboxymethyl, carboxyethyl and their acids and esters.

"Aminoalkyl" means a hydrocarbon chain (e.g., alkyl), substituted on the amine fragment (e.g., NH-alkyl), such as dimethylaminoethyl.

"Alkylamino" means a fragment of the amine, having one or two alkenyl substituent (for example, -N-alkenyl).

"Alkynylamino" means a fragment of an amine having one or two etkinlik substituent (for example, -N-quinil).

"Alkylamino" means the imine fragment having one or two alkyl substituent (for example, N=alkyl).

"Allakaket" means an oxygen atom, with the Deputy arylalkyl, for example, phenylmethoxy; phenylmethylene

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"Heteroaromatics" means an oxygen atom, with the Deputy heteroallyl, for example

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"Arylalkyl" means alkyl fragment with aryl as a substituent. Preferred arylalkyl groups include benzyl and phenylethyl.

"Heteroaromatic" means alkyl fragment with a heteroaryl group as a substituent.

"Arylamino" means the residue of an amine, substituted aryl group (e.g.,- NH-aryl).

"Aryloxy" means an oxygen atom, aryl having a substituent (for example, -O-aryl).

"Acyl" or "carbonyl" means a fragment formed by removal of the hydroxy from a carboxylic acid (e.g., R-C(=O)-). Preferred alkylsilane groups include, but are not limited to, acetyl, propion for example, -O-C(=O)-alkyl.

"Acylamino" means the residue of an amine having the acyl substituent (for example, N-acyl); for example, -NH-(C=O)-alkyl.

"Benzoxa": Benzoyloxymethyl.

"Benzoyl": Aryl radical, WITH6H5CO-produced from benzoic acid.

"Benzoyloxy": Benzox. Radical C6H5COO-, derived from benzoic acid.

"Carbamate": Salt carbamino acid; it contains NCO2radical, also known in practice as urethane or ether of carbamino acid.

"Carboxy": Prefix indicates acidic carboxyl group.

"Ether" (complex): Organic salt formed from the alcohol (base) and organic acids with the allocation of water; functional derivatives of carboxylic acids - means those compounds which are converted to carboxylic acids by simple hydrolysis. The most common of these derivatives are esters in which the hydroxy-group substituted on the alkoxy group, for example

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"Glycoside": a Natural compound sugar with other substances which are hydrolyzed with the formation of sugar plus the primary connection (e.g., coniferin gives glucose plus coniferious alcohol as a base); glucosides give glitch is lo", "halogen" or "halogen" means radicals of chlorine atoms, bromine, fluorine or iodine. The preferred Halogens are chlorine, bromine and fluorine.

"Lactone": Any of a class of internal esters hydroxycarbonic acids, formed by loss of a water molecule of the hydroxy and carboxylic acid groups, characterized by the presence of the carbonyl-oxy group,- OCO - ring and which is classified by the position of the hydroxy-group in the original acid; a cyclic ether.

"Pharmaceutically-acceptable salts means cationic salt formed any acidic (e.g., carboxyl) group, or an anionic salt formed any basic (e.g., amino) group. Many such salts are known in practice, as described in the application WO 87/05297 (Johnston et al.), published September 11, 1987, and are there links. Preferred cationic salts include alkali metal salts (such as sodium and potassium), alkaline earth metals (such as magnesium and calcium). Preferred anionic salts include salts kaleidograph acids (such as hydrochloric acid).

"Salt": Substances resulting from the reaction between acids and bases: connection radicals metal (positive) and nonmetal (negative): Mobidev, combining the sterols, bile acids, cardiac glycosides, saponins and sex pheromones.

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"Deputy": Any atom or group that replaces a hydrogen source compounds.

"Replace": to put the connection in place of one element or radical Deputy.

"Substituted": Refers to a connection that has undergone substitution.

"Substitution": the Reaction in which an atom or group of atoms in a molecule (usually organic) is replaced by another (other).

In the substituents themselves may be the substitution. Such substitution may be performed by one or more substituents. Such substituents include, but are not limited to, those listed in C. Hansh and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979) and in the data there the links. Preferred substituents include, but are not limited to, alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (for example, aminomethyl and so on), cyano, halo, carboxy, alkoxyalkyl (for example, carbethoxy and so on ), thiol, aryl, cycloalkyl, heteroaryl, heteroseksualci (for example, piperidinyl, morpholinyl, piperazinil, pyrrolidinyl and so on), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof.

epoxyhexane and so on, of rhamnose, glucose, arabinose, digitoxose, fructose, galactose, rhamnopyranose, hexopyranosyl, 6-deoxyglucose, 4,6-dimethoxypropionate, mannose, Cimarosa, xylose, lyxose, ribose, digitalose, 4-amino-2,4,6-triazacyclohexane, 4-amino-4,6-dimethoxypropionate, 2,3-dimethoxybenzophenone, 4-methoxy-4,6-dimethoxypropionate.

"Oligosaccharide" means a sugar containing 2-8 monosaccharide residues, mostly 2-3. Last monosaccharide residue of the oligosaccharide is known as "end" ("terminal") monosaccharide residue. Monosaccharide residues constituting the oligosaccharide may be the same and different. These monosaccharide residues can connect glycosidic bond from the OH group of one monosaccharide residue to the anomeric carbon of another monosaccharide residue.

"Monosaccharide or oligosaccharide" the balance can be plotted in the form of a loop or in a configuration of the chair. For example, glucose (monosaccharide) can be represented respectively

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Detailed description of the invention

The present invention encompasses some oligosacharides 14-aminosteroid compounds, methods for their production, pharmds treatment of congestive heart failure in humans and other mammals. Specific compounds and compositions used in the invention must be, respectively, pharmaceutically acceptable. As used below, the terms "pharmaceutically acceptable" component means that it is suitable for human use and/or other mammals without undue adverse side effects (such as toxicity, irritation, allergic reaction) and thus has a significant ratio of benefit/risk.

The active substance

The oligosaccharide-containing 14-aminosteroid compounds and pharmaceutically acceptable salts, acids or esters of General formula

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in which

a) R1means

(i) COOR5where

R5means hydrogen; lower alkyl with 1-6 carbon atoms; lower alkyl with 1-6 carbon atoms, a substituted amino group; arylalkyl or heteroaromatic or carbocyclic ring, or

(ii) CHR6OH, where

R6means hydrogen or lower alkyl with 1-6 carbon atoms, or

(iii) COR"', where

R"' represents hydrogen; lower alkyl with 1-6 carbon atoms; lower alkyl with 1-6 carbon atoms, a substituted amino group; amino or dialkylamino:

b) R2means-NR7R8where

R7and R
(C) R3means

(i) the residue of the oligosaccharide having the following structure:

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where R9means hydrogen; methyl; hydroxy; carboxy; acetoxy; Allakaket; heteroaromatics or benzox; R10means hydrogen; methyl; carboxy; acetoxy; Allakaket; heteroaromatic; benzox or hydroxy; R11mean oxygen; if next R11is Deputy at the terminal monosaccharide residue, R11means HE; methyl; acetoxy; heteroaromatic; Allakaket; and R12means hydrogen; methyl; methylhydroxylamine; or acetoxymethyl; or

(ii) oligosaccharide residue having the following structure:

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where R14and R15that may be the same or different, signify hydrogen; lower alkyl with 1-6 carbon atoms; arylalkyl; heteroaromatic; heteroaryl or aryl; R17can be hydrogen; hydroxy; acetoxy or benzox; R18and R19mean hydroxy; acetoxy, benzoxa; or

(iii) oligosaccharide residue having the following structure:

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where R14and R15that may be the same or different, signify hydrogen; lower alkyl with 1-6 carbon atoms; heteroaromatic; arylalkyl; aryl them the remainder, R14amust be hydroxy; methyl; acetoxy; Allakaket or heteroaromatic; and

d) R4means

(i) HE or

(ii) H, or

(iii) OR13where R13means monosaccharide residue; acetoxy; benzoxa; arylalkyl or heteroaryl; and

e) Z means

(i) -CH, where a and b denote a single bond, or

(ii) =C, where a or b means of the double bond.

The symbol " _ " is used in further indicates that the stereochemistry is not defined and that the substituents in the steroid skeleton may have or configuration. Preferably the substituents in the steroid skeleton are-configuration. Further monosaccharide units comprising the residue of the oligosaccharide can be-and configuration. Professionals with experience in carbohydrate chemistry, understand that the configuration of the substituents in the sugar residue is determined by the specific name of sugar.

The present invention also includes a method of introducing an amino group at position 14 of the steroid skeleton, characterized in that the amino group is introduced diastereoselective in position 14 steroid skeleton by attaching iodization and includes the following stages:

a) attaching iodization to double what Gruppo in position 14 steroid skeleton.

The oligosaccharide-containing 14-aminosteroid compounds of the present invention

Steroid skeleton

New oligosaccharide-containing 14-aminosteroid compounds of the present invention consist of a steroid skeleton, wherein said steroid skeleton is different substituents.

The substituents in the steroid skeleton

The substituents R1< / BR>
The substituents R1are in position 17 of the steroid skeleton. There are three (3) possible substituent R1. R1can be ether carboxylic acids, COOR5where R5means hydrogen, lower alkyl with 1-6 carbon atoms, lower alkyl with 1-6 carbon atoms, a substituted amino group, arylalkyl, heteroaromatic or carbocyclic ring. Preferred substituents R5are lower alkyl with 1-6 carbon atoms, arylalkyl or carbocycle, more preferred R5is lower alkyl with 1-6 carbon atoms, and most preferred R5is methyl; R1means COOCH3(carboxymethoxy ether).

R1can also be CHR6OH, where R6means a hydrogen atom or a lower alkyl group containing 1-6 carbon atoms; preferably B>1can be COR"', where R"' is hydrogen, lower alkyl with 1-6 carbon atoms, methylamino, amino or dialkylamino. Preferably R"' represents amino or methylamino. The most preferred R' is amino; R1means CONH2.

The most preferred substituent R1in the steroid skeleton is ether carboxylic acids, COOR5where R5means methyl (COOCH3).

Deputy R2< / BR>
Deputy R2is in position 14 of the steroid skeleton. There is one (1) Deputy R2. R2means-NR7R8where R7and R8which may be identical or different, denote hydrogen atoms or lower alkali with 1-6 atoms C. Preferably R7and R8denote H; then R2mean NH2.

The substituents R3< / BR>
The substituents R3located in the 3-position of the steroid skeleton. There are three (3) possible substituent R3. R3may be the oligosaccharide-containing residue having the following structure:

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where R9means hydrogen; methyl; hydroxy; carboxy; acetoxy; Allakaket or benzox; R10means hydrogen; methyl; carboxy; asaeda Deputy at the terminal monosaccharide residue, R11IT means, methyl; acetoxy; Allakaket; heteroaromatic; a R12means hydrogen, methyl, methylhydroxylamine or acetoxymethyl. In the compounds of the present invention, when R11means oxygen, this oxygen is used for communicating monosaccharide residues via a glycosidic bond.

Oligosaccharide residue may consist of two or three monosaccharide residues, preferably three monosaccharide residues. These monosaccharide residues may be the same or different. The preferred monosaccharide residues are dimethoxybenzophenone and rhamnopyranose.

Preferred substituents R9are hydrogen, methyl and hydroxy. The most preferred R9means hydrogen. Preferred substituents R10are hydrogen, methyl and hydroxy. The most preferred substituent R10is hydroxy. R11means oxygen, except in those cases where R11Deputy of the terminal monosaccharide residue oligosaccharide residue. The preferred substituent R11the terminal monosaccharide residue is hydroxy.

The preferred cover is to, having the following structure:

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where R14and R15that may be the same or different, signify hydrogen; lower alkyl with 1-6 carbon atoms; arylalkyl; heteroaromatic; heteroaryl or aryl; R17can be hydrogen, hydroxy, acetoxy or benzox; R18and R19means hydroxy, acetoxy, benzoxa.

The residue of the oligosaccharide may consist of two or three monosaccharide residues, preferably three monosaccharide residues. These monosaccharide residues may be the same or different. The preferred monosaccharide residues are dimethoxybenzophenone and rhamnopyranose.

Preferred substituents R14are hydrogen and lower alkyl with 1-6 carbon atoms. The preferred substituent R14is lower alkyl with 1-6 carbon atoms. The most preferred substituent R14is methyl. Preferred substituents R15are hydrogen and lower alkyl with 1-6 carbon atoms. The preferred substituent R15is lower alkyl with 1-6 carbon atoms. The most preferred substituent R15is methyl. Preferred substituents R1718are hydroxy and acetoxy. The most preferred substituent R18is hydroxy. Preferred substituents R19are hydroxy and acetoxy. The most preferred substituent R19is hydroxy.

Finally, R3means oligosaccharide residue having the following structure:

< / BR>
where R14and R15that may be the same or different, signify hydrogen; lower alkyl with 1-6 carbon atoms, arylalkyl; heteroallyl, heteroaryl or aryl; R14amean oxygen; if R14ais the Deputy at the end monosaccharide residue, R14amust be hydroxy, methyl, acetoxy, Allakaket or heteroarylboronic. In the compounds of the present invention, when R14ameans oxygen, this oxygen is used for communicating monosaccharide residue through a glycosidic bond.

Oligosaccharide residue may consist of two or three monosaccharide residues, preferably three monosaccharide residues. These monosaccharide residues may be the same or different. The preferred monosaccharide residues are dimethoxybenzophenone and rhamnopyranose.

Prepact/SUB> and R15is methyl. When R14ais the Deputy at the end monosaccharide residue, the preferred R14ais hydroxy.

The substituents R4< / BR>
The substituents R4is a 12-position of the steroid skeleton. R4maybe HE, H or or13where R13means monosaccharide residue; acetoxy; benzoxa; arylalkyl; or heteroaromatic. Preferred substituents R4are H or or13where R13means monosaccharide residue. This monosaccharide residue is selected from hexose, 2-deoxyglucose, 6-deoxyhexose, 2,6-dideoxyhexose, ramnose, glucose and arabinose, digitoxose, fructose, galactose, rhamnopyranose, hexopyranosyl, 6-deoxyglucose, 4,6-dimethoxypropionate, mannose, Cimarosa, xylose, lyxose, ribose, digitalose, glucosamine, 4-amino-2,4,6-triazacyclohexane, 4-amino - 4,6-dimethoxypropionate, 2,3-dimethoxybenzophenone, 4-methoxy-4,6-dimethoxypropionate it is preferably-D or-L anomer.

The most preferred substituent R4is N.

Z

Z denotes-CH-, where a and b denote a single bond or a =C, where a or b means of the double bond. Preferred Z aerodom of the present invention is

< / BR>
(3,5,14,17)-14-Amino-3[(O-2,6-dideoxy--D-RIBO-hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D - RIBO-hexopyranosyl-(1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]-N-methylandrostan-17-carboxamide

< / BR>
Methyl ether (3,5,14,17) -14-amino-3[(O-2,6-di-deoxy- - D - RIBO-hexopyranosyl-(1--->4)-6-deoxy-2,3-O-(1-methyl - ethylidene)- -L-mannopyranosyl]-oxy]-androstane-17-carboxylic acid

< / BR>
(3,5,14,17) -14-Amino-3[(O-2,6-dideoxy- -D-RIBO - hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D - RIBO-hexopyranosyl-(1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]androstane-17-carboxamide

< / BR>
Methyl ether (3,5,14,17)-14-amino-3[(O-2,6-dideoxy- -D - RIBO-hexopyranosyl-(1--->4)-2,6-di-deoxy- -D-RIBO - hexopyranosyl)oxy] androstane-17-carboxylic acid

< / BR>
Methyl ether (3,5,14,17)-14-amino-3[(O-2,6-dideoxy- -D - RIBO-hexopyranosyl-(1--->4)-O-2,6-di-deoxy- -D-RIBO-hexopyranosyl(1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy] androstane-17-carboxylic acid

< / BR>
Methyl ester of 14-amino-3 -[ -(L)-rhamnopyranose-hydroxy- (1--->4)- -(L)-rhamnopyranoside]-5-androstane-17 - carboxylic acid

< / BR>
Methyl ester of 14-amino-3-[- -(L)-rhamnopyranose-hydroxy- (1--->4)-2', 3'-O-isopropylidene- -(L)-frame-pyranosyl-oxy]-5-androstane-17-carboxylic acid

< / BR>
Metalowy] -5-androstane-17-carboxylic acid

< / BR>
Methyl ester of 14-amino-3 -[2",3",4"-tri-O-acetyl -(L)-rhamnopyranose-hydroxy-(1--->4)-2', 3'-O-isopropylidene- -(L)- rhamnopyranose-oxy]-5-androstane-17 - carboxylic acid

< / BR>
Methyl ester of 14-amino-3 -[4"-O-acetyl-2",3"-O - isopropylidene- -(L)-rhamnopyranose-hydroxy-(1--->4)-2',3'-O - isopropylidene- -(L)-rhamnopyranose-oxy]-5-androstane-17-carboxylic acid

< / BR>
Methyl ether (3,5,14,17) -14-amino-3[(2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-6-deoxy - a-L-RIBO-mannopyranosyl)-oxy]-androstane-17-carboxylic acid.

Synthesis of oligosaccharide-containing 14-aminosteroid compounds of the present invention

The present invention also includes a method of introducing an amino group at position 14 of the steroid skeleton. Earlier in chemical practice, according to the U.S. patent 4,325,879; 4,552,868; 4,552,868; 4,552,289; 4,885,250 and links in them, used attestation acid for the introduction of azide fragment in position 14 of the steroid skeleton. Azide fragment was then restored to the amino group in position 14 of the steroid skeleton. This method, which involves applying iodization, is the improvement of modern experiment, as the latter uses explosive idiscovered to the aqueous composition; and it gives the possibility to introduce the amino group at position 14 in the presence of others sensitive to the acid functional groups of the steroid nucleus. Oligosaccharide residue at position 3 of the steroid skeleton is sensitive to acid and extremely easily cleaved attestations acid. Thus, the use of iodization eliminates the problem of removal of oligosaccharide residue from the steroid skeleton.

The method of the present invention allows diastereoselective to introduce the amino group in position 14 steroid skeleton by attaching iodization double bond in position 14-15 steroid skeleton with subsequent dehalogenans and conversion of the isocyanate to the amino group in position 14.

Specifically, the method of the present invention includes:

a) generating in situ iodization, using preferably, but not limited to, silver cyanate and iodine in suitable solvents, which include, but are not limited to, esters of acids, such as ethyl acetate, isopropylacetate or propyl, NITRILES, such as acetonitrile or propionitrile, galoidovodorodami, such as methylene chloride, chloroform or dichloroethane, ethers, such as tetrahydroquinoxaline acetonitrile, with simple or complex esters, more preferably, ethyl acetate or tert.-butylmethylamine ether. The reaction temperature joining may be in the range of from -30 to 100oC, preferably from -10 to 5oC. the reaction time of the accession of the isocyanate may be in the range of from 1 to 6 hours, preferably from 1 to 3 hours. Reagents can be added together in any order and at any rate, the most preferred such arrangement, when iodine is added in a solvent to the mixture of steroid and silver cyanate for 30-60 minutes;

b) dehalogenase preferably processed by organoaluminium, including, but not limited to, alkylhalogenide, such as tri-n-butylaldehyde or allolobophora, such as diphenylacetamide or triphenylphosphite, and a radical initiator, including, but not limited to, 2,2'-azobisisobutyronitrile (AIBN) or peroxides, such as benzoyl peroxide or peroxide of tertiary Laurila, in a suitable solvent, including, but not limited to, esters, such as ethyl acetate, isopropylacetate or propyl, NITRILES, such as acetonitrile or propionitrile, galoidovodorodami, such as methylene chloride, chloroform or dihl, such as hexane or heptane, aromatic, such as benzene or toluene, or mixtures thereof. Preferred solvents include aromatic, more preferable are toluene, and halogenated hydrocarbons, the most preferred is methylene chloride. The reaction temperature of haloiding may be in the range from 0 to 100oC, most preferably from 15 to 30oC. the reaction Time may be from 1 to 6 hours, most preferably from 2 to 4 hours; and

c) water hydrolysis of isocyanate groups to amine using strong acids, including, but not limited to, hydrochloric acid, sulfuric acid, Hydrobromic acid or triperoxonane acid, or bases, including, but not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, or other bases, capable of generating hydroxide in the aqueous medium, such as triethylamine or pyridine. Suitable co-solvents for the hydrolysis reaction include, but are not limited to, miscible with water, NITRILES, such as acetonitrile or propionitrile, miscible with water, ethers such as tetrahydrofuran, dimethoxyethane or dioxane, or friends who occhialini solvents include miscible with water, NITRILES, preferably acetonitrile, and miscible with water, ethers, most preferably tetrahydrofuran, dimethoxyethane and dioxane. The temperature of the hydrolysis reaction may be in the range from 0 to 60oC, for the acid catalyzed hydrolysis most preferably from 15 to 30oC; and in the interval from room temperature to 100oC for base catalyzed hydrolysis, most preferably from 80 to 100oC. the Time of reaction catalyzed by acid hydrolysis may be in the range of from 4 to 72 hours, most preferably from 12 to 36 hours; and can be from 2 to 48 hours for catalyzed by bases, hydrolysis, most preferably from 2 to 12 hours. Following, but not limited to, the examples are illustrated iodittyarteda how the introduction of an amino group in position 14 steroid skeleton.

Example 1

Methyl ether (3,5,14,17) -14-amino-3[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-2,6-di-deoxy- -D-RIBO - hexopyranosyl-(1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]androstane-17-carboxylic acid.

Diagram for example 1 (see the end of the description).

A. (3,5) -3[(O-3,4-Di-O-acetyl-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-3-O-acetyl-2,6-dideoxy
Digitoxin (2.0 g, 0,0026 mole) is dissolved in anhydrous pyridine (50 ml). Add anhydrous acetic anhydride (25 ml) and the solution heated to 80oC 3 hours. Upon cooling to room temperature the reaction mixture was poured into ice water (500 ml), forming a solid connection amber color. The mixture is extracted with methylene chloride (2 x 100 ml). The organic extracts are combined, washed with saturated aqueous sodium bicarbonate solution (2 x 100 ml), saturated aqueous sodium chloride (1 x 100 ml), dried (magnesium sulfate), treated with darco and filtered. The filtrate is evaporated in vacuum to dryness. Traces of pyridine are removed by azeotropic distillation with toluene (2 x 20 ml) and then with methanol (2 x 20 ml). The result is 1.8 g (74%) of compound 1 as a white solid.

B. (3,5,14,17) -3-[(O-3,4-Di-O-acetyl-2,6-dideoxy- -D-RIBO - hexopyranosyl-(1--->4)-O-3-O-acetyl-2,6-dideoxy- -D-RIBO - hexopyranosyl(1--->4)-3-O-acetyl-2,6-dideoxy- -D-RIBO - hexopyranosyl)oxy] -14,21-dihydroxy-pregnan-20-he

Connection 1 (0,93 g of 0.001 mol) dissolved in methylene chloride (100 ml) and cooled to -78oC. the Cooled solution is treated with ozone 8 minutes until you get a steady blue color. At this point, ozonation stop and reenie 15 minutes and then nitrogen to the disappearance of blue color. The reaction mixture is brought to room temperature, add saturated aqueous potassium carbonate solution (50 ml) and the resulting mixture is stirred for 20 hours. Separate the two layers and the organic layer washed with water (1 x 50 ml), saturated aqueous sodium chloride (1 x 50 ml), dried (magnesium sulfate) and filtered. The filtrate is evaporated in vacuum, get a white foam, which chromatographic on silica gel (230-400 mesh mesh), using as eluent a mixture of methylene chloride:methanol (97:3). The fractions containing pure product are pooled, evaporated and dried in vacuum for 24 hours, obtain 0.6 g (62%) of compound 2 as a white solid. The NMR and mass spectra consistent with the structure. This connection is used in the next stage.

C. (3,5,14,17) -3[(O-3,4-Di-O-acetyl-2,6-dideoxy- -D - RIBO-hexopyranosyl-(1--->4)-O-3-O-acetyl-2,6-dideoxy- -D - RIBO-hexopyranosyl(1--->4)-3-O-acetyl-2,6-dideoxy- - D-RIBO-hexopyranosyl)oxy]-14-hydroxyandrost-17-carboxylic acid

To a solution of compound 2 (17 g, 0,187 mol) in acetone (200 ml) add a solution of potassium carbonate (3.88 g, 0,028 mol) in water (25 ml), and then the solution periodate sodium (12 g, 0,056 mol) in water (50 ml). The resulting mixture is stirred for Palotai. After acidification of the solution is quickly extracted with methylene chloride (2 x 300 ml). The combined organic extracts washed with 5% hydrochloric acid (1 x 200 ml), water (1 x 200 ml), dried (magnesium sulfate) and filtered. The filtrate is evaporated in vacuo to a white solid. Solid chromatographic on silica gel, using as eluent a mixture of methylene chloride : methanol (97,5:2,5). The fractions containing pure product are combined and concentrated in vacuo; obtain 16.2 g (97%) of compound 3 as a white solid. This connection is used in the next stage.

D. Methyl ether (3,5,14,17)-3-[(O-3,4-di-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-3-O - acetyl-2,6-dideoxy - D-RIBO-hexopyranosyl(1--->4)-3-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl)oxy] -14-hydroxyandrost - 17-carboxylic acid

To a solution of compound 3 (15 g, of 0.017 mol) in anhydrous acetonitrile added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.4 ml, 2,89 g 0,019 mol), and then methyl iodide (1,18 ml, 2.7 g, 0,019 mol). The resulting solution was stirred at room temperature for 20 hours. The reaction mixture was diluted with water (1 l) and extracted with methylene chloride (5 x 200 ml). The combined extracts washed with saturated aqueous chloric chromatographic on silica gel (230-400 mesh mesh), using as elution solvent a mixture of methylene chloride : methanol (99:1). The fractions containing pure product, evaporated in vacuum to dryness and dried in vacuum; get 13,68 g (90%) of compound 4 as a white solid, this compound is used in the next stage.

E. Methyl ether (3,5,14,17) -3-[(O-3,4-di-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-3-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl(1--->4)-3-O-acetyl-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]androst-14-ene-17-carboxylic acid

Compound 4 (as 4.02 g, 0,0044 mole) is dissolved in anhydrous pyridine (20 ml) and the solution is cooled to -5oC in a bath of ice/methanol. Add dropwise a solution of chloride of tonila (5 ml) in pyridine (5 ml) for 25 minutes, then the reaction mixture was poured into ice water (400 ml) and stirred until the ice melts (10 min). The resulting mixture is extracted with ethyl acetate (3 x 150 ml). The combined extracts are washed with 1N hydrochloric acid (1 x 100 ml), water (2 x 100 ml), saturated sodium bicarbonate solution (2 x 100 ml), saturated aqueous sodium chloride (1 x 100 ml), dried (magnesium sulfate) and filtered. The filtrate is evaporated in vacuo to a foamy state. This foam chromatographic on silica gel (230-400 mesh mesh), using as albume, get 3,26 g (83%) of compound 5 as a white solid. This connection is used in the next stage.

F. Methyl ether (3,5,14,17) -3-[(O-3,4-di-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl] -1-(1--->4)-O-3-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl(1--->4)-3-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl)oxy]-15-iodo-14-isocyanatoacetate - 17-carboxylic acid

Compound 5 (0.27 g, 0.3 mmole) was dissolved in ethyl acetate (1.35 ml) and acetonitrile (2.7 ml) and the solution is cooled to 1oC (bath ice/ethanol). Added silver cyanate (0,054 g of 0.36 mmole), and then dropwise iodine (of 0.081 g of 0.32 mmole) in ethyl acetate (4 ml). After the accession of iodine (20 min) the reaction mixture is stirred while cooling another 1.5 hours. The reaction mixture was then diluted with ethyl acetate (20 ml) and filtered through celite. The filtrate is washed with 1% aqueous solution of sodium sulfite (1 x 100 ml) and the organic layer evaporated under vacuum. Obtain 0.32 g (99%) of compound 6 in the form of foam. This connection is used in the next stage.

G. Methyl ether (3,5,14,17) -3-[(O-3,4-di-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-3-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl(1--->4)-3-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl)oxy]-14-isocyanatoacetate - 17-carbonvision the methylene (10 ml). To this solution was added a catalytic amount of 2,2'-azobisisobutyronitrile (AIBN, 0.003 g), and then the anti-hydride (of 0.085 ml, 0.091 g, 0.31 in mmole). The resulting solution was stirred at room temperature for 1 hour and then evaporated in vacuum. The resulting oil RUB clean with hexane to solid, which is collected by filtration and dried in air. Obtain 0.25 g (89%) of compound 7. This connection is used in the next stage.

N. Methyl ether (3,5,14,17) -3-[(O-3,4-di-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O - 3-O-acetyl-2,6-dideoxy- -D-RIBO-hexopyranosyl(1--->4)-3-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl)oxy]-14-amino-androstane-17-carboxylic acid

To a solution of compound 7 (0.3 g, of 0.32 mmole) in acetonitrile (15 ml) add a solution of potassium carbonate (0.66 g, 4.8 mmole, 15 EQ) in water (10 ml). The reaction mixture is boiled under stirring for 4 hours. Upon cooling to room temperature the reaction mixture is evaporated in vacuum, removing the acetonitrile. To the remaining aqueous residue add water (20 ml) and the mixture is acidified with 1N hydrochloric acid to pH 1, and then quickly alkalinized (pH 9) with concentrated ammonia solution. The aqueous mixture is extracted with methylene chloride (2 x 30 ml), the combined draw is the cosmology vacuum get 0,23 g (79%) of crude 8. This compound is used directly in the next stage.

I. Methyl ether (3,5,14,17) -14-amino-3-[(O-2,6-di - deoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl(1--->4)-2,6-dideoxy- -D-RIBO - hexopyranosyl)oxy] androstane-17-carboxylic acid

In a flame dried apparatus under nitrogen atmosphere and dissolved compound 8 (0,23 g, 0.3 mmole) in anhydrous methanol (9 ml). Add a solution of sodium alcoholate (0,063 g, 1.2 mmole, 4 EQ) in anhydrous methanol (2 ml) and the mixture is stirred at room temperature for 3 hours. The reaction mixture is evaporated in vacuo, and the residue is white matter. The residue is dissolved in water (30 ml) and cooled (ice/water). The solution is acidified with 1N hydrochloric acid to pH 1 and then quickly alkalinized (pH 9) a concentrated aqueous solution of ammonia. The aqueous mixture is extracted with methylene chloride (2 x 30 ml). The combined extracts dried (magnesium sulfate) and filtered. The filtrate is evaporated in vacuum to dryness. Solid chromatographic on silica gel (230-400 mesh mesh), using as eluent a mixture of methylene chloride : methanol (9:1) containing 0.5% concentrated aqueous ammonia solution. The fractions containing pure product are combined and upakservis-(1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl(1---4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]androstane-17-carboxylic acid, the end product.

Example 2

Methyl ether (3,5,14,17) -14-amino-3-[(O-2,6-di-deoxy- -D-RIBO - hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]androstane-17-carboxylic acid

Diagram for example 2 (see the end of the description).

A. Methyl ether (3,5,17) -3-[(O-2,6-dideoxy- -D-RIBO - hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO - hexopyranosyl(1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]androst-14-ene-17-carboxylic acid

Obtaining methyl ester (3,5,17) -3-[(O-3,4-di-O-acetyl-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-3-O-acetyl-2,6-dideoxy- -D-RIBO-hexopyranosyl(1--->4)-3-O-acetyl-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]androst-14-ene-17-carboxylic acid described previously in example 1.

In dried Plamen device in nitrogen atmosphere was dissolved methyl ether (3,5,17) -3-[(O-3,4-di-O-acetyl-2,6-dideoxy- -D - RIBO-hexopyranosyl-(1--->4)-O-3-O-acetyl-2,6-dideoxy- -D-RIBO - hexopyranosyl(1--->4)-3-O-acetyl-2,6-dideoxy- -D-RIBO - hexopyranosyl)oxy]androst-14-ene-17-carboxylic acid (to 2.29 g, 0,0025 mol) in anhydrous methanol (50 ml). Add a solution of sodium methylate (0,72 g of 0.014 mol) in anhydrous methanol (10 ml) and stirred at room temperature for 3 hours. The reaction mixture is evaporated in vacuum to dryness, the OST is terouanne aqueous solution of ammonia. The resulting mixture is extracted with methylene chloride (2 x 50 ml). The combined extracts are dried (magnesium sulfate) and filtered. The filtrate is evaporated in vacuum to dryness and dried in vacuum; gain of 1.9 g (100%) 1. The NMR and mass spectra consistent with the structure. This connection is used in the next stage.

B. Methyl ether (3,5,17) -3-[(O-2,6-dideoxy-4-O-[1-(1 - methyl-2-oksidoksi)-3-oxopropyl]- -D-RIBO-hexopyranosyl- (1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]androst-14-ene - 17-carboxylic acid

To a solution of compound 1 (1.9 grams, 0,0012 mole) in a mixture of ethanol : water (95: 5) (100 ml) add a solution of periodate sodium (1.9 grams, 0,009 mol) in water (20 ml). The reaction mixture is stirred for 20 hours at room temperature. Filtered and the filtrate evaporated in vacuum to dryness. The residue is dissolved in water (100 ml) and extracted with methylene chloride (3 x 50 ml). The combined extracts washed with 1% aqueous solution of sodium bisulfate (1 x 50 ml), water (2 x 50 ml), dried (magnesium sulfate) and filtered. The filtrate is evaporated in vacuum, get 2 in the form of a white foam of 1.81 g (96%). This connection is used in the next stage.

C. Methyl ether (3,5,17) -3-[(O-2,6-dideoxy-4-O-[3 - hydroxypropyl-1-(2-hydroxy-1-methylethoxy)] - -D-RIBO - hexopyranosyl-(1--->4)-2,6-dideoxy- -D : water (95:5) add detribalized (0,94 g, 0,025 mol) and the solution stirred for 1 hour at room temperature. Added dropwise to the reaction mixture with acetic acid to pH 7. The reaction mixture is evaporated in vacuum to dryness. The residue is dissolved in water (30 ml) and extracted with methylene chloride (3 x 25 ml), dried (magnesium sulfate) and filtered. The filtrate is evaporated in vacuum to dryness, dried in vacuum and get 1,31 g (72%) 3. This connection is used in the next stage.

D. Methyl ether (3,5,17) -3-[(O-2,6-dideoxy- -D-RIBO - hexopyranosyl-(1--->4)- 2,6-dideoxy- -D-RIBO - hexopyranosyl)oxy]androst-14-ene-17-carboxylic acid

To a solution of compound 3 (1.3 g, 0,0018 mol) in methanol (100 ml) is added to 0.05 N hydrochloric acid (22.1 ml). The reaction mixture was stirred at room temperature for 3 hours, neutralized with saturated aqueous sodium bicarbonate solution and evaporated in vacuum to dryness. The residue is dissolved in water (50 ml) and extracted with methylene chloride (3 x 25 ml). The combined extracts are dried (magnesium sulfate) and filtered. The filtrate is evaporated in vacuum, get foamy substance. After drying it in vacuum to obtain 1.0 g (94%) 4. This connection is used in the next stage.

E. Methyl ether (3,5,17) -3-[(O-3,4-di-O-acetyl - 2,6-di-deoxy- -D-RIBO-hexopyranosyl-(1--->4)-O- -O-17 mol) dissolved in anhydrous pyridine (15 ml). Add anhydrous acetic anhydride (15 ml) and stirred for 3 hours at 80oC. the Reaction mixture was gradually cooled to room temperature and stirred for 18 hours. Poured into water (200 ml) and stirred for 10 min. Aqueous mixture is extracted with methylene chloride (2 x 75 ml). The combined extracts washed with saturated aqueous sodium bicarbonate (3 x 100 ml), water (1 x 100 ml), dried (magnesium sulfate) and filtered. The filtrate is evaporated in vacuo, the resulting foam is dried in vacuum, get 0,78 g (64%) of compound 5. This connection is used in the next stage.

F. Methyl ether (3,5,14,15,17) -3-[(O-3,4-di-O-acetyl-2,6-dideoxy- -D-RIBO-hexopyranosyl- (1--->4)-O-3-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl)oxy] -15-iodo-14 - isocyanatoacetate-17-carboxylic acid

Compound 5 (0,76 g, about 0.001 mole) is dissolved in ethyl acetate (4.5 ml) and acetonitrile (9 ml) and the solution is cooled to 1oC (ice/methanol). Add dropwise a silver cyanate (0,19 g, 0,0013 mol), and then dropwise iodine (0,30 g, 0,0012 mol) in ethyl acetate (13.5 ml). After the accession of iodine (20 min) the reaction mixture is stirred in the cold for 1 hour. The reaction mixture was diluted with ethyl acetate (50 ml) and filtered through celite. The filtrate is washed with 1% aqueous solution of the bisulphite NAT. is the connection used in the next stage.

G. Methyl ether (3,5,14,17) -3-[(O-3,4-di-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-3-O-acetyl-2,6 - di-deoxy- -D-RIBO-hexopyranosyl)oxy]-14-isocyanato-androstane-17 - carboxylic acid

In dried Plamen device in nitrogen atmosphere dissolve 6 (0.9 g, about 0.001 mol) in anhydrous methylene chloride (18 ml). To this solution was added a catalytic amount of 2,2'-azobisisobutyronitrile (AIBN, 0.001 g), and then the anti-hydride (0.3 ml, 0.32 g, about 0.001 mol). The resulting solution was stirred at room temperature for 3 hours, then evaporated in vacuum. The resulting oil RUB clean with hexane, receive a white solid, which was collected by filtration and dried in air. Obtain 0.65 g (84%) of compound 7. This connection is used in the next stage.

N. Methyl ether (3,5,14,17) -3-[(O-3,4-di-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-3-O-acetyl-2,6 - dideoxy- -D-RIBO-hexopyranosyl)oxy]-14-amino-androstane-17 - carboxylic acid

To a suspension of compound 7 (0.65 g, 0,00085 mol) in acetonitrile (25 ml) add a solution of potassium carbonate (1.8 g, 0,013 mol, 15 EQ) in water (10 ml). The reaction mixture is stirred at the boil for 3 hours. Upon cooling to room temperature the t 1N hydrochloric acid to pH 1, then quickly alkalinized (pH 9) a concentrated aqueous solution of ammonia. The aqueous mixture is extracted with methylene chloride (2 x 50 ml) and the combined extracts dried (magnesium sulfate) and filtered. The filtrate is evaporated in vacuum to dryness, dried in vacuum, to obtain 0.6 g (96%) of crude 8. This compound is used directly in the next stage.

I. Methyl ether (3,5,14,17) -14-amino-3-[(O-2,6-di-deoxy- -D - RIBO-hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO - hexopyranosyl)oxy]androstane-17-carboxylic acid

In a flame dried apparatus under nitrogen atmosphere and dissolved compound 8 (0,60 g, 0,0082 mol) in anhydrous methanol (25 ml). Add a solution of sodium methylate (0.35 g, to 0.007 mol) in anhydrous methanol (10 ml) and the reaction mixture is stirred for 1 hour at room temperature, then evaporated in vacuum, get a white residue which is dissolved in water (50 ml) and cooled (ice/water). The solution is acidified with 1N hydrochloric acid to pH 1, and then quickly alkalinized (pH 9) a concentrated aqueous solution of ammonia. The aqueous mixture is extracted with methylene chloride (3 x 25 ml). The combined extracts are dried (magnesium sulfate) and filtered. The filtrate is evaporated in vacuum to dryness and chromatographic on silica gel (230-400 mesh mesh), using as the functions, containing pure product are combined and evaporated under vacuum; the residue is dried in a vacuum; it is produced methyl ester (3,5,14,17) -14-amino-3-[(O-2,6-di-deoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy] androstane-17-carboxylic acid is the end product.

Example 3

Methyl ether (3,5,14,17) -14-amino-3-hydroxy-androstane-17-carboxylic acid

Diagram for example 3 (see end of description).

A. Methyl ether (3,5,14,17) -3-atomic charges-15-iodo-14-isocyanato-androstane-17-carboxylic acid

Obtaining methyl ester (3,5,17) -3-atomic charges-androst-14 - ene-17-carboxylic acid is described in U.S. patent 4,855,280; 4,584,289; 4,325,879, and in the data there links.

Methyl ether (3,5,17) -3-atomic charges-androst-14-ene-17 - carboxylic acid (50 g, 0,134 mole) is dissolved in ethyl acetate (160 ml) and acetonitrile (320 ml) and the solution is cooled to 1oC (ice/methanol). Added silver cyanate (23.7 g, 0,158 mol), and then dropwise iodine (37,2 g, 0,147 mol) in ethyl acetate (480 ml). After the accession of iodine (20 min) the reaction mixture is stirred in the cold for 1 hour, then filtered and the filtrate washed with 1% aqueous solution of sodium bisulfite (1 x 500 ml). The organic layer is then evaporated in vacuum, receive 70 g (96%) 1 in the form of oil. androstane-17-carboxylic acid

Compound 2 (65 g, 0,121 mole) is dissolved in methylene chloride (325 ml). To this solution was added 2,2'-azobisisobutyronitrile (AIBN, 0.005 g), and then the anti-hydride (33.3 ml, 36 g, 0,126 mol). The resulting solution was stirred at 29oC for 2.5 hours, then evaporated in vacuum. The resulting oil RUB clean with a mixture of hexanol (350 ml), the resulting solid is collected by filtration and dried in air. Get to 38.3 g (77%) 2. This connection is used in the next stage.

C. Methyl ether (3,5,14,17) -14-amino-3-hydroxy-androstane-17-carboxylic acid

Compound 2 is mixed with acetonitrile (247 ml) and concentrated hydrochloric acid (133 ml) and stirred. After 3 hours, add water (133 ml) and the reaction mixture was stirred 48 hours at room temperature. Cooled in a bath of ice/water and maintaining the temperature below 25oC, are added dropwise concentrated aqueous ammonia solution and adjusted the pH to 9. The resulting mixture is extracted with methylene chloride (4 x 200 ml), the combined extracts washed with water (1 x 250 ml), dried (magnesium sulfate) and evaporated in vacuo, Get methyl ether (3,5,14,17) -14-amino-3-hydroxy-androstane-17-carboxylic acid, the final product.

Next is 1, 2 and 3, above, can be converted into amides 17-carboxylic acids, as illustrated by examples 5, 6 and 7.

Example 4

(3,5,14,17) -14-Amino-3-[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]-N-methyl-androstane-17-carboxamide

The scheme is for example 4 (see end of description).

In an autoclave of stainless steel is placed A, methyl ester (3,5,14,17) -14-amino-3-[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy] androstane-17-carboxylic acid (0,61 g of 0.001 mol) in methanol (15 ml) and the solution is cooled in a bath of ice/water. Passed through a solution of gaseous methylamine before saturation (15 min), the autoclave is closed and incubated for 10 days at 90oC. Upon cooling to room temperature the reaction vessel is opened and the contents evaporated in vacuum to dryness. The formed solid product was then purified by chromatography on silica gel, using as eluent a mixture of methylene chloride : methanol (80:20) containing 1% concentrated aqueous ammonia solution. The fractions containing pure product are pooled, evaporated and dried in vacuum, obtaining a pure product.

Example 5

(3,5,14,17) -14-Amino-3-((O-2,6-dideoxy- -D-RIBO - hexopyranoside).

In an autoclave of stainless steel is placed A, methyl ester (3,5,14,17) -14-amino-3-[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl(1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy] androstane-17-carboxylic acid (0,61 g of 0.001 mol) in methanol (15 ml) and the solution is cooled in a bath of ice/water. Flow of gaseous ammonia until saturation (15 min), the reaction vessel is closed and incubated for 10 days at 90oC. Upon cooling to room temperature, the reactor was opened and the contents evaporated in vacuum to dryness. The solid is purified by chromatography on silica gel, using as eluent a mixture of methylene chloride : methanol (75:25) containing 1% concentrated solution of ammonia in water. The fractions containing pure product are pooled, evaporated and dried in vacuum, obtaining the pure final product.

Example 6

(3,5,14,17) -14-Amino-3-[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO - hexopyranosyl(1--->4)-2,6-dideoxy- -D-RIBO - hexopyranosyl)oxy]androstane-17-carboxamide

Diagram for example 6 (see the end of the description).

In an autoclave of stainless steel is placed 289 mg (of 0.0004 mole) of 1 methyl ester (3,5,14,17) -14-amino-3-[(O-2,6-dideoxy- -D - RIBO-hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO - hexopyranosyl- (1--->4)-2,6-didet the Daya bath ice/water, before saturation (15 min). A clear solution close in an autoclave and heated for 10 days at 90oC. Upon completion of reaction (monitored by TLC) light yellow reaction mixture is evaporated on a rotary evaporator to yield a solid whitish color that clean flash chromatography, using as mobile phase of 25% MeOH/CH2Cl2+NH4OH. Faction collect and monitor TLC. Its results for the combined fractions (43-81), with the chromatogram single spot with Rf of 0.23, evaporated on a rotary evaporator to yield a whitish solid, which is dried in vacuum at 55oC during the night; get a clean end product.

Example 7

(3,5,14,17) -14-Amino-3-[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl(1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]-N-methyl-androstane-17-carboxamide

Scheme to example 7 (see the end of the description).

In an autoclave of stainless steel is placed 289 mg (of 0.0004 mole) of 1 methyl ester (3,5,14,17) -14-amino-3-[(O-2,6-dideoxy- -D-RIBO-hexo-pyranosyl-(1--->4)-O-2,6-dideoxy- -D - RIBO-hexopyranosyl(1--->4)-2,6-dideoxy- -D-RIBO - hexopyranosyl)oxy]androstane-17-carboxylic acid and 10 ml of MeOH, pass by cooling (ice/water) Mei>/P>The autoclave was removed from the furnace, cooled, opened and chromatographic (TLC). If the chromatogram shows the absence of the original substance, light yellow reaction mixture is evaporated on a rotary evaporator and receive a semisolid residue, which was purified flash chromatography, using as mobile phase 20% MeOH/CH2Cl2+NH4OH. (Initial value: 20/80/0,9; end ratio 20/80/1,8. Based on the results of TLC combined fractions 22-98, with a single spot with Rf Of 0.43 (20% MeOH/CH2Cl2+NH4OH) evaporated on a rotary evaporator. Get a whitish solid. His RUB clean with cold ether and collected by filtration the final product whitish color, which is dried in vacuum at 55oC 48 hours and get a clean end product.

The new compounds of the present invention obtained by the methods of experimental chemistry previously described in U.S. patent 4,325,879; 4,552,868; 4,552,868; 4,584,289 and 4,885,280 and found in them the links. Following, but not limited to, the examples illustrate how the compounds of the present invention can be obtained previously known methods.

Example 8

Methyl ether (3,5,14,17) -14-amino-3[(O-2,6-dideoxy- -D - RIBO-exoponent example 8 (see at the end of the description).

To the mixture 1,125 g (2.1 mmole) of A methyl ester (3,5,14,17) -amino-3-[[6-deoxy-2,3-O-(1-methylethylidene)- - L-manno-pyranosyl]-oxy]-androstane-17-carboxylic acid, obtained according to the method described in U.S. Patent 4,885,280 and references therein, and 1,250 g (2.1 mmole) of 2,6-dimethoxy-1,3,4-D-(4 - nitrobenzoyl)-D-Ibogaine-pyranoside in 60 ml of CH2Cl2add 3.0 g of molecular sieves 4 8-12 mesh. The mixture is stirred at room temperature for 15 minutes, then cooled (ice bath/acetone), and then added dropwise 2.0 ml trimethylsilyltrifluoromethane (Lancaster) in 10.0 ml of CH2Cl2. After the mixture was stirred at -80oC for 6 hours, to the cold mixture was added to 8.0 ml of triethylamine and continue stirring for 10 minutes the Mixture is gradually heated in the refrigerator over night.

The solvent is removed in vacuo and the residue chromatographic on silica gel. Impurity delete CH2Cl2, then the desired fraction wash EtOAc/CH2Cl2(1:4) number of 1.98 g

To a solution of 400 mg (0,415 mmole) of the above-described p-nitrobenzophenone disaccharide in 1.0 ml dry methanol (Aldrich, anhydrous) is added by syringe to 7.2 ml 0,1217 mm NaOCH3in dry methanol (Aldrich). The mixture was stirred at 0o

Example 9

Methyl ester of 14-amino - 3-[ -(L)-rhamnopyranoside-(1--->4)-2', 3'-O-isopropylidene- -(L)-rhamnopyranoside]-5-androstane-17-carboxylic acid

< / BR>
260 mg of methyl ester of 14-azido-3 -[2',3'-O-isopropylidene- -(L)-rhamnopyranoside]-5-androstane-17-carboxylic acid, obtained according to the methods described in U.S. Patent 4,895,280 and 4,325,879 and data links, dissolved in 12 ml of acetonitrile and the solution is stirred for 15 minutes in the presence of molecular sieves (130 mg, 3 and 325 mg of tri-O-acetyl-remotivated. Add 232 mg of cyanide of mercury and the reaction mixture is stirred 3 hours at room temperature.

After adding saturated sodium bicarbonate solution, filtration, extraction with toluene and purified by chromatography under pressure (500 mb) on a column of silica gel (eluent ethyl acetate/hexane 1:2), received 252 mg of the methyl ester of 14-azido-3 -[three- 2",3", 4"-O-acetate -(L)- rhamnopyranoside-(1--->4)- 2', 3'-O-isopropylidene- -(L)-rhamnopyranoside]-5-androstane-17-carboxylic acid.

This di-rhamnosyl-14-atidepressant can be recrystallized from a mixture of ethyl ether/petroleum ether.

A mixture of 8.5 ml of absolute ethyl alcohol, obeskislorozhennaja by blowing argon, 99,5 mg powder is stirred for 24 hours at room temperature.

After filtration through celite, evaporation, extraction with ethyl acetate and washing with water, the residue is purified by chromatography under pressure on a column of silica gel, elwira a mixture of chloroform/ethanol/aqueous ammonia (89:10: 1), and receive the methyl ester of 14-amino - 3-[- -(L)-rhamnopyranose-hydroxy- (1--->4)-2', 3'-O-isopropylidene- -(L)-rhamnopyranoside] - 5-androstane-17-carboxylic acid.

Example 10

Methyl ester of 14-amino-3 -[three-2",3",4"-O-acetyl -(L)-rhamnopyranose-hydroxy-(1--->4)-2', 3'-O-isopropylidene- -(L)-rhamnopyranoside] -5-androstane-17-carboxylic acid

< / BR>
5.0 g of the three-hydroxy-derivative, obtained as described in Example 8, was dissolved in 3.7 ml of methylene chloride and the solution cooled in an ice bath. Add acetic anhydride (2.4 ml) and dimethylaminopyridine (313 mg) and the reaction mixture was stirred over night at room temperature.

In the reaction mixture was poured an aqueous solution of caustic soda, and then extracted with methylene chloride.

The organic layer was washed with H2O+NH4OH, dried Na2SO4and evaporated to dryness. Raw triacetate, thus obtained, purified flash chromatography on silica gel, elwira a mixture of methylene chloride/methanol/water which is hydroxy-(1--->4)-2',3'-O-isopropylidene- -(L) rhamnopyranoside]-5-androstane-17 - carboxylic acids.

Example 11

Methyl ester of 14-amino-3 -[2",3"-O-isopropylidene- -(L)-rhamnopyranose-hydroxy-(1--->4)-2', 3'-O-isopropylidene- -(L)- rhamnopyranoside]-5 androstane-17 carboxylic acid

< / BR>
To a solution of 11.2 g of tri-hydroxy-derivative, obtained as described in Example 8, in 77 ml of acetone add 97 ml of dimethoxypropane and 3.5 g of p-toluensulfonate2O. the Reaction mixture was stirred at room temperature for 1 hour and added an aqueous solution of caustic soda under stirring for several minutes, and then extracted with a mixture of methylene chloride/methanol.

The organic extract was washed with H2O+NH4OH, dried Na2SO4and evaporated to dryness. Thus obtained crude product is purified by recrystallization from isopropyl ether and receive the methyl ester of 14-amino-3 -[2",3"-O - isopropylidene- -(L)-rhamnopyranose-hydroxy-(1--->4)-2', 3'- O-isopropylidene- -(L)-rhamnopyranoside]-5 - androstane - 17 - carboxylic acid.

Example 12

Methyl ester of 14-amino-3 -[ -(L)-rhamnopyranoside-(1--->4)- -(L)-rhamnopyranoside]-5-androstane-17-carboxylic acid

< / BR>
Three-hydroxy-derivative (103 mg), obtained as described in Example 8, dissolved in 2 ml chlorate 1 hour.

After extraction with a mixture of methylene chloride/methanol (85:15), washing with a saturated solution of bicarbonate, water, evaporation to dryness the residue is purified by chromatography on a column of silica gel under pressure; eluent a mixture of methylene chloride/methanol/aqueous ammonia (84:15:1). Get the methyl ester of 14-amino - 3-[ -(L)-rhamnopyranoside-(1--->4)- -(L)- rhamnopyranoside)-5-androstane-17-carboxylic acid.

Test pharmacological activity

It is believed that the positive inotropic effect of cardiotonic steroid compounds caused by its effect on the Na+and K+the pump in the sarcolemma of the cells of the heart muscle. In particular cardiotonic steroids inhibit Na+TO+-activated adenosinetriphosphatase that, in turn, leads to increased intracellular calcium. Thus, you need more calcium in order to start the mechanism of contraction. Cm. in General, Goodman and Gilman. The pharmacological Basis of Therapeutics. Chapter 34 (8th ed., 1990).

Positive inotropic activity of new chemical entities were controlled as in isolated cardiac tissues and in experimental animals. Isolated tissue allow direct measurement intrapulmonic interventions, which may affect the reaction of the tissue. In vivo studies allow the assessment, which takes into account the physiological parameters that are missing from the experience with isolated cloth.

In experiments on inotropic activity was used strips of papillary muscles of Guinea pigs. Although papillary muscle is affected by the activities of the valve, the main reduction, exercise this muscle, like the reduction in ventricular muscle. To experience the segment of the papillary muscles, carved from the heart of the Guinea pig is placed in the tissue fluid that allows you to control the temperature of the tissue, while for the functioning of cells required liquid medium containing the substrate. Attaching the sensor to the free end of the strip of muscle so that the muscle was located between the fixed base and the sensor, and feeding electrical impulses, it is possible to measure the contraction, or shortening in response to changes in the concentration of the test compounds. In the typical conditions of positive inotropy defined as the increase in force of contraction, caused by an unknown agent, and the data are usually published as the concentration of drug required to cause an increase in the force of contraction by 50% compared is. the first method is very similar to the method described for the determination of reducing the surgical joining of the tensiometer to the surface of the heart. The second method of the power sensor is placed inside the left ventricle for determining the pressure change. The contractile force of the myocardium correlates with the rate of increase of pressure in the left ventricle and is expressed as +dP/dt. In any case, the data is reported in terms of the amount of medication required to achieve the level of activity, equal to the increase in contractility of 30% or +dP/dt (i.e. the ED30) and are expressed as mg of drug/kg of body weight of the animal.

Pharmaceutical compositions

New oligosaccharide-containing 14-aminosteroid compounds of the present invention may be introduced into the organism of humans and other mammals in several ways, including, but not limited to, the dosage for oral administration and injections (intravenous, intramuscular, intraperitoneal - intraperitoneally, subcutaneous). Numerous other forms, containing oligosaccharide-containing 14-aminosteroid compounds of the present invention, can easily be created by experienced specialists using pharmaceutical carriers, the Ermin "pharmaceutical composition", used in the future, means the combination of a safe and effective amount of the oligosaccharide-containing 14-aminosteroid compounds as the active ingredient, step mixtures thereof, and pharmaceutically-acceptable carriers.

The phrase "safe and effective amount", as used hereinafter, means the number of compounds or compositions that are large enough to significantly modify the symptoms and/or conditions of treatment, yet small enough to avoid serious side effects (with a reasonable ratio of benefit/risk) with common medical point of view. Safe and effective amount of the active ingredient for use in the pharmaceutical compositions used in the treatment according to the method of the invention further may vary depending on the specific conditions of treatment, the age and physical condition, length of treatment, nature carried out simultaneously (together) treatment, the specific active ingredient, the characteristics of the applied pharmaceutically-acceptable carrier, as well as knowledge and experience of the treating physician.

The term "pharmaceutically-acceptable carriers used in the future, definition characteristics of a specific oligosaccharide-containing 14-aminosteroid connection selected for use as the active ingredient. Pharmaceutically-acceptable carriers include, but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, agents that promote ingestion, leavening agents, solvents, co-solvents, buffer systems, surfactants, preservatives, sweeteners, pharmaceutical dyes or pigments and agents viscosity.

The term "form for oral administration", as used below, refers to any pharmaceutical composition that is prescribed for systematic individual human use through the introduction of specified composition in the gastrointestinal tract through the mouth of this man. For the purposes of the present invention, the insertion can be in the form of tablets, coated or not coated; solution; suspension; or capsules, coated or not coated.

The term "injection" used hereinafter, refers to any pharmaceutical composition that is prescribed for regular admission to a person or other mammal by introducing a solution or emulsion containing the active ingredient through the puncture in the skin of this in pity specialist can satisfactorily control, changing one or more of the following factors:

(a) suitable active ingredient;

(b) a pharmaceutically-acceptable carriers; the condition is that the different ways they did not affect the activity of this active ingredient;

(C) the media type associated with the desired texture and permeability (the ability to swell) specified media;

(d) the stability in time of the media itself and/or with other media;

(e) the particle size of the granulated active ingredient; and

(f) dependence of the medium from pH.

As stated above, pharmaceutically-acceptable carriers include, but are not limited to, resins, fillers, binders, lubricants, substances that promote ingestion, solvents, leavening agents, co-solvents, surfactants, preservatives, substances, which impart a sweet taste and aroma, buffer systems, pharmaceutical dyes and pigments.

The preferred solvent is water.

Flavouring substances used in the future, are selected from those described in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, 1990, pp. 1288-1300, and links on tiirough substances.

The dyes and pigments used below, include those described in Handbook of Pharmaceutical Excipients. pp.81-90, 1986, by the American Pharmaceutical Association &the Pharmaceutical Society of Great Britain, and in the data there the links. Pharmaceutical compositions below contain 0-2% dyes or pigments.

Preferred co-solvents include, but are not limited to, ethanol, glycerin, propylene glycol, polyethylene glycol. The pharmaceutical compositions of the present invention contain 0-50% co-solvents.

Preferred buffer systems include, but are not limited to, acetic, boric, carbonic, phosphoric, succinic, malonic, tartaric, citric, acetic, benzoic, lactic, gluconic, glutaric, and glutamic acid and their sodium, potassium and ammonium salts. The pharmaceutical compositions of the present invention typically contain 0-5% buffer system.

Preferred surfactants include, but are not limited to, esters of polyoxyethylenesorbitan and fatty acids, polyoxyethylene-monoalkyl esters, monetary sucrose, esters and ethers of lanolin, alkyl sulphates, sodium, potassium and ammonium salts of fatty acids. Pharmaceutical compositions vkluchaut, but not limited to, phenol, alkalemia esters of p-hydroxybenzoic acid, o-phenylphenolate acids and their salts, boric acid and its salts, sorbic acid and its salts, chlorbutanol, benzyl alcohol, thimerosal, acetate and nitrate of finalstate, nitromersol, benzalconi-chloride, pyridinium-chloride, methylparaben and propylparaben. Most preferred are salts of benzoic acid, pyridinium-chloride, methylparaben and propylparaben. Compositions of the present invention typically contain 0-2% preservatives.

Preferred sweeteners include, but are not limited to, sucrose, glucose, saccharin, sorbitol, mannitol and aspartame. Most preferred are sucrose and saccharin. The pharmaceutical compositions of the present invention contain 0-5% sweeteners.

Preferred agents viscosity include, but are not limited to, methylcellulose, sodium carboxymethyl cellulose, hypromellose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, gum Arabic, gum guar gum xanthan gum and tragakant. The most preferred methyl cellulose, carbomer, resin guar gum xanthan gum, povidone, sodium carboxymethyl predpochtitelnye fillers include, but not limited to, lactose, mannitol, sorbitol, rejonowy calcium phosphate, dibasic calcium phosphate, presswise sugar, starch, calcium sulfate, dextro - and microcrystalline cellulose. Compositions of the present invention contain 0-75% fillers.

Preferred lubricants include, but are not limited to, magnesium stearate, stearic acid and talc. The pharmaceutical compositions of the present invention contain 0.5-2% lubricants.

Preferred agents that promote ingestion, include, but are not limited to, talc and colloidal silicon dioxide. Compositions of the present invention contain 0-5% of such substances.

The preferred leavening agents include, but are not limited to, starch, sodium-glycolate starch, crospovidon, croscarmelose and microcrystalline cellulose. Compositions of the present invention include 4-15% baking powder.

Preferred binders include, but are not limited to, gum Arabic, tragakant, hydroxypropylcellulose, pre-gelatinizing starch, gelatin, povidone, hydroxypropylcellulose, hypromellose, methylcellulose, solutions of sugars, such as sucrose and sorbeo of the invention can range from 0.1 to about 99.9 percent by weight of the pharmaceutical compositions of the present invention. Preferably the compounds of the present invention comprise from 20 to 80% by weight of the pharmaceutical compositions of the present invention.

Accordingly, the pharmaceutical compositions of the present invention include from 15-95% of the oligosaccharide-containing 14-aminosteroid compounds as the active ingredient, or mixtures thereof; 0-2% flavoring agents; 0-50% co-solvents; 0-5% buffer system; 0-2% surfactants; 0-2% preservatives; 0-5% sweeteners; 0-5% agents viscosity; 0-75% fillers; 0.5 to 2% lubricants; 1-5% of agents that promote ingestion; 4-15% baking powder and 1-10% of binders.

Applied pharmaceutical compositions described herein. An experienced specialist can infinitely vary the following examples and get a wide range of pharmaceutical compositions.

The choice of a pharmaceutically-acceptable carrier depends on which way you enter the oligosaccharide-containing 14-aminosteroid connection. If the connection is introduced in the form of injection, it is preferred pharmaceutical carrier is a saline solution, pH of which is brought to 7.4. Convenient pharmaceutically-acceptable carriers for topical PrimeTel way of introducing the oligosaccharide-containing 14-aminosteroid compounds of the present invention is the administration through the mouth. Therefore, the preferred form of a single dose are tablets, capsules, etc., containing a safe and effective amount of the oligosaccharide-containing 14-aminosteroid compounds of the present invention. Pharmaceutically-acceptable carriers suitable for the preparation of a single dose for oral administration are well known in practice. Their choice will depend on additional factors, such as taste, cost, stability during storage, which are beyond the purposes of the present invention, and this choice can easily be done by an experienced technician.

For oral administration can be used in a variety of one-forms, including such solid forms as tablets, capsules, granules and powders. These one-forms for oral administration contain a safe and effective amount, mainly from 0.25 to 5.0 mg of oligosaccharide-containing 14-aminosteroid. More preferably, these doses for oral administration contains 0.5 - 1.0 mg of oligosaccharide-containing 14-aminosteroid. Tablets can be compressed, powdered, coated intersolubility shell, sugar, film or repeatedly pressed with appropriate binders, lubricants, rasplavlennoy. Liquid forms for oral administration include aqueous solutions, emulsions, suspensions, solutions and/or suspensions obtained from nishiuchi granules and effervescent preparations obtained from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspendiruemye agents, diluents, sweeteners, agents, contributing to the melting and giving odor. Preferred carriers for oral administration contain gelatin, propylene glycol, cottonseed oil and sesame oil.

The compositions of this invention can be administered for local reception by the subject, i.e. direct laying or applying the composition to the tissue of the epidermis or epithelium of the subject. Such compositions include, for example, lotions, creams, solutions, gels and solids. These compositions for local reception contain a safe and effective amount, preferably from about 0.5 to 2.0 mg of oligosaccharide-containing 14-aminosteroid. More preferred local composition contains 1.0 mg of oligosaccharide-containing 14-aminosteroid. Suitable carriers for topical application preferably remain on the skin long-lasting film and are removed with sweat or water. Typically, the carrier is one who Rashi 14-aminosteroid. The media may contain pharmaceutically-acceptable emollient agents, emulsifiers, thickeners and solvents.

Compositions of the present invention can also be administered by inhalation. Such compositions are prepared using the framework, consisting of a solvent, such as water or glycol, preservatives such as methyl or propyl paraben and propellants, such as nitrogen or carbon dioxide.

In addition, the compositions of this invention can be administered in the form of rolling implant formed of silicone rubber, copolymers of ethylene and vinyl acetate or dairy-glycol copolymers.

To illustrate how to prepare the pharmaceutical compositions containing the new compounds of the present invention, the following, but not limited to, examples of pharmaceutical compositions.

Examples of pharmaceutical compositions

Example 1

Form for emergency oral administration (tablets) containing (3,5,14,17)- 14-amino-3[(O-2,6-dideoxy- -D-RIBO - hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO - hexopyranosyl(1--->-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy] -N-methylandrostan-17-carboxamide, has the following composition:
Media

Microcrystalline cellulose - 28.5 mg

Lactose, water is 67.2 mg

Crosspovidone - 3.0 mg

Magnesium stearate - 0.3 mg

Guidance for the preparation of (for 10,000 tablets)

1) 10.0 g of the drug, 285,0 microcrystalline cellulose, 672,0 g of lactose and 30.0 g of crosspovidone mixed in the mixer Paterson-Kelly (PC) or any other suitable mixer,

2) the above mixture was mixed with 3.0 g of magnesium stearate in a PC or other convenient mixer

3) above the final mixture is pressed into tablets in any suitable machine for tableting.

Example 2

Form for parenteral administration, containing methyl ester (3,5,14,17) -14-amino-3-[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-6-deoxy-2,3-O-(1-methylethylidene)- -L-mannopyranosyl]-oxy]-androstane-17-carboxylic acid; for intravenous injection (VI) apply the following composition:

Active ingredient - Number

Methyl ether (3,5,14,17) -14-amino-3-[[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1---4>)-6-deoxy-2,3-O-(1-methylethylidene)- -L-mannopyranosyl]-oxy]-androstane-17-carboxylic acid - 1.0 mg

Media

Mannitol - 200.0 mg

Citric acid/sodium citrate - a Quantity sufficient to bring the pH of the number of sodium citrate and citric acid dissolved in 2200,0 ml of sterile demonizirovannyj water for injection,

2) the above solution is filtered through a sterile membrane filter of 0.22 micron,

3) 2.2 ml of the above sterile solution is placed in a glass ampoule Type 1 and lyophilized in a suitable liofilizadora,

4) capsules after drying and processing stopper (methyl-bootrom or similar) sealed. Liofilizovannye product is mixed with 2.0 ml of sterile water for injection immediately before use.

Example 3

Release form for long-term oral administration (tablets) containing (3,5,14,17) -14-amino-3-[(O-2,6-dideoxy- -D-RIBO - hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl (1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy] androstane-17 - carboxamide, has the following composition:

Active ingredient - Number

(3,5,14,17) -14-Amino-3-[(O-2,6-dideoxy- -D-RIBO - hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl- (1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy]androstane-17 - carboxamide - 5.0 mg

Media

The hypromellose - 120,0 mg

Lactose, water - 120,0 mg

Magnesium stearate - 12.0 mg

Colloidal silicon dioxide 4.0 mg

Guidance for the preparation of (for 10,000 tablets)

1) 50.0 g drugs, 1.2 kg of hydroxypropylmethylcellulose,

2) to this mixture is added 120 g of magnesium stearate and 40 g of colloidal silicon dioxide and gently mixed in a suitable mixer,

3) the resulting mixture is pressed into tablets weighing 261,0 mg in a suitable press to tablets.

Additional examples

In addition to the above three examples, the active ingredient of the medicine is applied in several different forms:

1) pharmaceutical aerosol containing solvent (for example, water, glycol), preservatives (methyl or propylparaben) and gaseous displacers (nitrogen, carbon dioxide or other suitable media,

2) candles for introduction into the rectum containing cocoa butter or polyethylene glycol,

3) subcutaneous implants containing silicone rubbers, ethylene-vinyl acetate copolymer, lacto-glycol copolymers and hydrogels other suitable polymers,

4) industrial-available devices for implantation

5) transdermal system containing silicone fluid in the membrane of a copolymer of ethylene-vinyl acetate or of other suitable ingredients for submission with or without iontophoresis,

6) is attached to the mucous membrane of the mouth plaster containing hydrocolloid polymers (hydroxyethylcellulose, hydroxagen failure (CHF), as here used, means a progressive disease in which hemodynamic ability, due to malfunction of the heart muscle, dramatically and irreversibly changed. Character CHF, depending on the patient's symptoms, can be divided into 4 classes according to the classification of new York heart Association (NYHA).

New York heart Association

Functional classification

Class

I. Patients with cardiac disease but without limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, anginal pain.

II. Patients with cardiac disease resulting in slight limitation of physical activity. Them brings relief to the rest. Ordinary physical activity causes fatigue, palpitations, shortness of breath and angina pain.

III. Patients with heart disease, which leads to a significant limitation of physical activity. They feel relieved during rest. Activity lower than normal, causes fatigue, palpitation, dyspnea, anginal pain.

IV. Patients with heart disease, which leads to tamanoi toads can be observed even during the holidays. Any physical activity increases the discomfort.

Classes III and IV according to the new York classification, as well as related open congestive heart failure are often treated by assigning compounds that increase the contractility of the heart, causing a positive inotropic effect. The reference compound for increasing the contractility of the heart is digoxin (oral intake). Treating the symptoms of an open CHF purpose of inotropes to increase CO to cover the metabolic needs of the body, it can ease the life of the patient, the patient CHF, as the heart provides better metabolism in the body. Common sense, however, indicates that inotrope, such as digitalis, may hasten death, as inotropic action increases the workload of the heart. Moreover, digitalis has a narrow therapeutic relationship dose : toxic dose, and the use of digitalis in stages earlier than class III of the new York classification is not, apparently, the wise.

In addition, bipyridinyl inotropy, Milrinone been shown to worsen ventricular arrhythmias and may increase mortality. Cm. DiBianco, R. , et al. "A Comparison of Oral Milrinone, Digoxin, and Their Combination in the Treatment of P mechanical ability of the heart. The initial hemodynamic effects of heart failure is a decrease in stroke volume, which is a measure of the amount of blood delivered by the heart in one stroke. Therefore, the heart compensates by increasing CO to maintain current flow to vital organs. As the exacerbation of signs of heart failure, intracardiac pressure rises, as well as pulmonary and venous pressure. Heart largely incapable of providing the desired CO content.

The term "structural damage", as used here, refers to the microscopic and macroscopic changes in the heart of a person suffering from CHF. Structurally, on a microscopic level, the following changes occur. The early stage of hypertrophy of the heart is characterized morphologically by increasing the size of muscle fibers and mitochondria, as well as enlargement of mitochondria and nuclei. Muscle cells more than normal, but the organization of cells mostly preserved. At a later stage of hypertrophy, predominantly larger number of specific organelles, such as mitochondria, as well as irregular accession of new contractile elements on the local surface cells leads and increase.

Cells subjected to prolonged hypertrophy, discover more obvious violations in the organization of cells, such as significantly increased lobed nucleus with a membrane which displace neighboring muscle fibers and cause disruption of the normal registration Z strips. Earlier preferential increase of mitochondria is replaced by a predominance by volume of muscle fibers. The last stage of hypertrophy is characterized by cell death and loss of contractile elements with a noticeable gap Z stripes, sharp disruption of the normal parallel arrangement of sarcomeres, expansion and significant curvature of the T-tubules and replacement of contractile elements fibrous tissue. Cm. Braunwald, Heart Disease: A Textbook of Cardiovascular Medicine. Vol. 1 (3rd ed. 1988). These microscopic changes occur at the macroscopic level of cardiac hypertrophy or enlargement of the heart. Hypertrophied heart becomes less efficient due to microscopic changes that cause loss of contractile elements and fibrous deposits, and clinical patient's symptoms become more serious as it progresses through the new York classification.

Compounds of the present invention HC is accordance with the method of treatment, the severity of CHF and duration of treatment.

To illustrate a specific application of such new oligosaccharide-containing 14-aminosteroid compounds for the treatment of CHF, presents the following, but not limited to, examples of clinical trials.

Clinical trials

Example 1

Woman 65 years old, white, suffering from obesity, 20 years ill non-insulin-dependent diabetes mellitus and hypertension, 2 years previously suffered a myocardial infarction. Hospitalized in the cardiology Department within 12 hours after the onset of myocardial infarction. The disease in the hospital is complicated by pulmonary edema, which manifests itself in severe shortness of breath at rest, orthopnea, the jugular veins, bilateral rales in the interscapular area, increasing the size of the heart and revealed by chest x-ray infiltrates. The pressure in the pulmonary capillary wedge is 35 mm Hg. Treatment: morphine, oxygen, intravenous nitroglycerin, loop diuretic and 0.25 mg (3,5,14,17)-14-amino-3[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO - hexopyranosyl-(1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy] -N-methyl-androstane-17-carboxamide intravenous is dideoxy- -D - RIBO-hexopyranosyl(1--->4)-2,6-dideoxy- -D-RIBO - hexopyranosyl)oxy]-N-methyl-androstane-17-carboxamide orally once daily. In this mode, there is some improvement and will be discharged after 10 days with less shortness of breath (congestive heart failure, class II, new York classification) and continue treatment on an outpatient basis, assigning a diuretic, ACE inhibitor, nitroglycerin and oral 0.25 mg (3,5,14,17) -14-amino-3[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl(1--->4)-2,6-dideoxy- -D-RIBO - hexopyranosyl)oxy]-N-methyl-androstane-17-carboxamide daily.

Example 2

Male, black, 44 years old, has many years of uncontrolled hypertension and congestive heart failure moderate (class II new York classification) within one year, for the last 2 weeks was observed several fainting. He also complains of fatigue and shortness of breath during dressing. Treatments include digoxin (0.25 mg/day), lasix and ACE inhibitor. Fixed S3 gallop rhythm, swelling of the legs, left ventricular hypertrophy and ventricular premature beats in the ECG. Additional tests show that polymorphic ventricular extrasystoles, episodes of ventricular tachycardia (Holter monitoring), the ejection fraction of 30% on radionuclide ventriculography and the level of digoxin in the serum is rutili to give. Methyl ether (3,5,14,17) -14-amino-3[(O-2,6-dideoxy- -D - RIBO-hexopyranosyl-(1--->4)-6-deoxy-2,3-O-(1-methylethylidene)- -L-mannopyranosyl] -oxy] -androstane-17-carboxylic acid is prescribed for oral administration of 0.25 mg per day. As fatigue and shortness of breath do not disappear, increase the dose over 6 weeks to 1 mg daily, new cases of fainting is not observed during repeated Holter monitoring are observed decrease in ventricular arrythmia, the absence of ventricular tachycardia and an increase in ejection fraction to 38%. Dyspnea at rest disappeared, and he can work in the garden with a weak and occasional bouts of breathlessness (grade II according to the new York classification). During the year, monitoring its status has changed.

Example 3

Woman, Chinese woman, 24 years old, previously healthy, complaints of shortness of breath while excessive force in the course of two months. In the family there were no patients with cardiac disease; she does not smoke and does not take alcohol. Physical indicators are normal except for tachycardia and offset to the side of the point of maximum impulse. Pulse 105 and the ECG nonspecific flattening of the T wave, and the radiograph shows enlargement of the heart. Echocardiogram shows an increase of both ventricles with global Hypo is emii. Diagnosis: idiopathic expansion cardiomyopathy (class I new York classification). Initially assigned to treatment with ACE inhibitor causes intolerable cough, and therefore discontinued. Assign (3,5,14,17) -14-amino-3[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl- (1--->4)-O-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy] androstane-17-carboxamide oral 1 mg twice a day, and the next month her stress tolerance increases. Increases the ejection fraction (echocardiogram) to 55%, and the testing time on the treadmill came to 200 seconds.

Example 4

Male, white, 55, 2 myocardial infarction; father died unexpectedly at the age of 50 years, angina supported in a stable state within two years, isosorbide dinitrate treatment and beta blockers. For the previous month, however, he had shortness of breath when walking and climbing stairs, swelling of the legs and periodic bouts of breathlessness at night.

Heart rate at rest, 90, 1+ edema of the legs, S3 gallop rhythm, enlarged heart and Kerly B lines on the radiograph. Diagnosis: congestive heart failure in mild (class II NYHA) due to ischemic heart disease. Beta blockers the failure. Prescribe oral methyl ether (3,5,14,17) -14-amino-3[(O-2,6-dideoxy- -D - RIBO-hexopyranosyl- (1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl)oxy] -androstane-17-carboxylic acid 4 mg once a day. Shortness of breath and swelling of the pass (class I NYHA), pulse rate drops to 75, S3 gallop rhythm disappears, the heart size decreases. Signs of congestion of the lungs on x-ray disappear. When tested with the load treadmill test time 1 month increased to 170 seconds. In the next two years, the deterioration is not observed.

Example 5

Female, black, 60 years old, had suffered three heart attacks, and in severe (class IV according to NYHA) congestive heart failure hospitalized. Despite treatment with maximum tolerated doses of lazica, isosorbide dinitrate, digoxin and ACE inhibitor in the previous six weeks was observed four times of acute decompensation. Its symptoms include swelling, shortness of breath at rest, orthopnea, sleeping on 3 pillows, significant fatigue and confusion. Decided to stop giving digoxin and prescribe treatment methyl ether (3,5,14,17) -14-amino-3[(O-2,6-dideoxy- -D-RIBO-hexopyranosyl-(1--->4)- O-2,6-dideoxy- -D-RIBO-hexopyranosyl(1--->4)-2,6-dideoxy- -D-RIBO-hexopyranosyl-hexopyranosyl-(1--->4)-O-2,6-dideoxy- - D-RIBO-hexopyranosyl(1--->4)-2,6-dideoxy- - D-RIBO-hexopyranosyl)oxy] -androstane-17-carboxylic acid is 0.5 mg orally once a day, but on the testimony titration conducted for adequate control of the symptoms, after 2 months is brought to 2 mg three times a day. At the end of two months of treatment her orthopnea, confusion, and swelling disappeared; it increases the ability for daily activities; she can dress without shortness of breath (NYHA class III in, congestive heart failure moderate). The ejection fraction increased from 20 to 35%. Her condition remains stable over the next three months.

Example 6

Recently (2 months) man, 60 years old, white, moderate alcoholic, smokes cigarettes 30 years, hospitalized after three months of progressively worsening dyspnea on exertion, fatigue, orthopnea, edema, and seizures shortness of breath at night. He is short of breath at small strains (while brushing teeth). Physical data: weight is significantly reduced, respiratory rate 30 / minute, pulse 90/50, S3 gallop rhythm, 2+ swelling above the legs, swelling of neck veins, increased liver, ascites, crackles at the lung, increased heart. Careful examination allows astina heart failure due to toxic (alcohol) cardiomyopathy. Treatment started hydrochlor-thiazides, ACE inhibitor and methyl ester of 14-amino - 3-[-(L)- frame-paranoiacs-(1--->4)- (L)-rhamnopyranoside] -5-androstane-17 - carboxylic acid oral 0.25 mg per day. He quickly recovers and is discharged through the week. After losing 20 pounds of weight he can walk to the mailbox with a weak shortness of breath (class II NYHA). Respiratory rate 20, pulse 90, S3 gallop rhythm is no longer bugged, swelling and wheezing disappear. The liver remains unchanged, but the ascites slightly reduced. The ejection fraction increased from 32 to 45% and the size of the heart is reduced.

Example 7

Woman, 70 years old, white, sedentary lifestyle, radiograph, made for the surgeon cataract showed an enlarged heart. Denies that they were ever chest pain, shortness of breath, hypertension, diabetes, or heart disease. On ECG nonspecific changes of the ST segment and the T wave; standard clinical laboratory tests were normal. A load test on the treadmill aborted due to General fatigue. On the echocardiogram - an increase of left and right ventricular, valvular apparatus intact and ejection fraction of 30%. She has a preventive course of the methyl ester of 14-amino - 3-[ (L)-rhamnopyranoside-(1 share) emission increases to 40% and by the time of hospitalization surgeon cataract after 5 years, all symptoms are absent.

1. Oligosacharides 14-aminosteroid General formula

< / BR>
where R1- COOR5where R5lower alkyl with 1 to 6 carbon atoms, COR111where R111- aminosilanes lower alkyl with 1 to 6 carbon atoms, amino or dialkylamino; R2- NH2-group;

R3- the rest of the oligosaccharide General formula

< / BR>
where R9means hydrogen, hydroxy, acetoxy, benzoyloxy;

R10- acetoxy, hydroxy, 4-nitrobenzyloxy;

R11is an oxygen atom, and if next R11is Deputy at the terminal monosaccharide residue, R11means OH, methyl, acetoxy;

R12means hydrogen, methyl, methylhydroxylamine or oligosaccharide residue of General formula

< / BR>
where R14and R15identical or different, denote a lower alkyl with 1 to 6 carbon atoms;

R17can be hydrogen, hydroxy, acetoxy or benzox;

R18and R19is hydroxy, acetoxy or benzox or oligosaccharide residue of General formula

< / BR>
where R14and R15identical or different, denote a lower alkyl with 1 to 6 carbon atoms;

R14ameans hydroxy, acetoxy;

R4- H.

2. Connected to the/SUB>; R3- the rest of the oligosaccharide,

< / BR>
in which R9means hydrogen, hydroxy, acetoxy, or benzox;

R10- acetoxy, hydroxy, 4-nitrobenzoic;

R11is an oxygen atom, and when R11is Deputy at the terminal monosaccharide residue, R12means hydrogen, methyl, methylhydroxylamine.

3. The compound according to any one of paragraphs.1 and 2, in which R1means COOR5and R5lower alkyl with 1 to 6 carbon atoms; R2- NH2and R3- the rest of the oligosaccharide

< / BR>
where R14and R15identical or different, denote a lower alkyl with 1 to 6 carbon atoms;

R17can be hydrogen, hydroxy, acetoxy or benzox;

R18and R19is hydroxy, acetoxy or benzox.

4. The compound according to any one of paragraphs.1 to 3, in which R1means COOR5and R5lower alkyl with 1 to 6 carbon atoms; R2- NH2and R3- the rest of the oligosaccharide

< / BR>
where R14and R15identical or different, denote a lower alkyl with 1 to 6 carbon atoms, and R14ais hydroxy, acetoxy.

5. The compound according to any one of paragraphs.1 to 4, in which R1means COR111and R111- methylamino, amino or (3,5,14,17)-14-amino-3-[(0-2,6-dideoxy--D-abovecaptionskip-(1 -> 4)-0-2,6-dideoxy--D-RIBO-hexopyranosyl-(1->4)-2,6-dideoxy-,5,14,17)-14-amino-3-[(0-2,6-dideoxy--D-RIBO-hexopyranosyl-(1 -> 4)-6-deoxy-2,3-0-(1-methylethylidene)--L-mannopyranosyl] oxy] -androstane-17-carboxylic acid; (3,5,14,17)-14-amino-3-[(0-2,6-dideoxy--D-RIBO-hexopyranosyl-(1 -> 4)-0-2,6-dideoxy--D-RIBO-hexopyranosyl-(1 -> 4)-2,6-dideoxy--D-RIBO-hexopyranosyl)oxy] -androstane-17-carboxamide; methyl ether (3,5,14,17)-14-amino-3-[(0-2,6 dideoxy--D-RIBO-hexopyranosyl-(1 -> 4)-2,6-dideoxy--D-RIBO-hexopyranosyl)oxy] -androstane-17-carboxylic acid; methyl ester (3,5,14,17)-14-amino-3-[(0-2,6-dideoxy--D-RIBO-hexopyranosyl-(1 -> 4)-0-2,6-dideoxy--D-RIBO-hexopyranosyl-(1 -> 4)-2,6-dideoxy--D-RIBO-hexopyranosyl)oxy]-androstane-17-carboxylic acid; methyl ester of 14-[-(L)-frame-paranoiacs(1 -> 4)--(L)-rhamnopyranoside] -5-androstane-17-carboxylic acid; methyl ester of 14-amino-3-[-(L)-frame-paranoiacs-(1 -> 4)-2', 3'-0-isopropylidene--(L)-frame-paranoiacs] -5-androstane-17-carboxylic acid; methyl ester of 14-amino-3-/2", 3"-0-isopropylidene-(L)-rhamnopyranoside-(1 -> 4)-2', 3'-0-isopropylidene--(L)-rhamnopyranoside] -5-androstane-17-carboxylic acid; methyl ester of 14-amino-3-[2", 3", 4"-tri-0-acetyl-(L)-rhamnopyranoside-(1 -> 4)-2', 3'-0-isopropylidene--(L)-rhamnopyranoside-(1 -> 4)-2', 3'-0-isopropylidene--(L)-rhamnopyranoside]-5-androstane-17-carboxylic acid.

7. Pharmaceutical composition having cardiotonic activity and containing a safe and effective amount of from 15 to 95% of the compound according to any one of the preceding paragraphs or mixtures thereof and from 5 to 85% pharmaceutically-acceptable carriers, where the pharmaceutically-acceptable carriers are selected from the group comprising polymers, fillers, binders, lubricants, substances that promote ingestion, leavening agents, solvents, co-solvents, buffer mixtures, surfactants, preservatives, agents, giving a sweet taste and smell, agents, giving the viscosity.

8. The pharmaceutical composition according to p. 7, containing 15 - 95% of the compound according to any preceding item (or their mixtures); 0 - 2% of agents, giving the smell; 0 - 50% co-solvents; 0 - 5% buffer mixture; 0 - 2% surfactant; 0 to 2% preservatives; 0 - 5% sweeteners; 0 to 5% of agents viscosity; 0 - 75% fillers; 0.5 to 2% lubricants; 1 - 5% of substances that contribute to ingestion; 4 - 15% of leavening agents; 1 - 10% binder.

9. The method of treatment of humans and other mammals suffering from congestive heart failure, characterizes whitesky songs on PP.7 and 8, containing compound or mixture of compounds according to any preceding paragraph.

10. The method of introducing an amino group at position 14 of the steroid skeleton, characterized in that the specified amino group diastereoselective is entered in position 14 steroid skeleton by attaching iodization through the following steps: a) attaching iodization to the double bond in position 14 and 15 of the steroid skeleton, with the above connection is preferably performed by means of silver cyanate and iodine; b) dehalogenase, which is preferably carried out in the presence of hydride alkalolu, preferably tri-n-butylaldehyde, and a radical initiator; (C) the conversion of isocyanate to amine fragment in position 14 steroid skeleton, preferably by hydrolysis with water, most preferably in the presence of hydrochloric acid or potassium carbonate.

11. The method of obtaining oligosaccharide-containing 14-aminosteroid compounds on p. 1, characterized in that the amino group in position 14 of the steroid skeleton is administered by joining iodization through the following steps: a) attaching iodization to the double bond in position 14 - 15 steroid skeleton; b) Megalodon is on p. 11, characterized in that the conversion of isocyanate to amine fragment is carried out by hydrolysis with water, preferably in the presence of hydrochloric acid or potassium carbonate, followed by removal of the protection from the protected hydroxy groups.

 

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