Derivatives of 6-mercaptocyclodextrin: reversing agents for drug- induced neuromuscular blockade

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a derivative of 6-mercaptocyclodextrin of the general formula (I):

wherein n = 0-7; n = 1-8 and m + n = 7 or 8; R represents (C1-C6)-alkylene substituted optionally with 1-3 OH-groups, or (CH2)o-phenylene-(CH2)p wherein o and p = 0-4 independently; X represents COOH, CONHR1, NHCOR2, SO2OH, PO(OH)2, O(CH2-CH2-O)q-H, OH or tetrazole-5-yl; R1 represents hydrogen atom (H) or (C1-C3)-alkyl; R2 represents carboxyphenyl; q = 1-3; or its pharmaceutically acceptable salt in mixture with pharmaceutically acceptable accessory substances. Also, invention describes a set and pharmaceutical composition for reversing drug-induced neuromuscular blocking comprising derivative of 6-mercaptocyclodextrin of the general formula (I), and a method for reversing drug-induced neuromuscular blockade in patient that involves parenteral administration to indicated patient the effective dose of 6-mercaptocyclodextrine derivative of the general formula (I) by cl. 1.

EFFECT: valuable medicinal properties of agents.

11 cl, 1 tbl, 20 ex

 

The invention relates to derivatives of 6-mercaptothiazoline, to their application to obtain drugs for reversal induced drug neuromuscular blockade and to set to achieve neuromuscular blockade and reversal.

Neuromuscular blocking agent (NMBA, also known as muscle relaxant) in the conventional practice to use when assigning anesthesia to facilitate endotracheal intubation and to provide surgical access to a body cavity, especially the abdomen and chest, without obstacles in the result of arbitrary or involuntary muscle movements. NMBA used when caring for patients in critical condition, subjected to intensive care, to facilitate artificial ventilation with automatic breathing apparatus when only the influence of a sedative agent and analgesia is inadequate, and to prevent strong muscular movements that are associated with electroconvulsive therapy.

On the basis of their mechanism of action NMBA are divided into two categories: depolarizing and nedepoljarizatsii. Depolarizing neuromuscular blocking agents associated with nicotinic acetylcholine receptors (nAChR) at the neuromuscular connection method, similar to what procedure endogenous neurotransmitter acetylcholine. They stimulate the initial opening of the ion channel, causing a reduction called fasciculatum. However, because these drugs are destroyed, only relatively slowly, enzymes cholinesterase, compared to the rapid hydrolysis of acetylcholine by acetylcholinesterase, they contacted within a significantly longer period than acetylcholine, causing a persistent depolarization of the end plate and, therefore, neuromuscular blockade. Succinylcholine (suxamethonium) is the most famous example depolarizing NMBA.

Nedepoljarizatsii neuromuscular blocking agents compete with acetylcholine for binding to the muscle nAChR, but unlike depolarizing NMBA, they do not activate the channel. They block the activation of the channel by acetylcholine and, therefore, prevent depolarization of the cell membrane, and as a result, the muscle becomes flaccid. Most clinically used NMBAs belong to nedepoliarizuth category. They include tubocurarine, atracurium, (CIS)-atracurium, mivacurium, pancuronium, vecuronium, rouroni and rapacuronium (Org 9487).

At the end of surgery, or the period of intensive therapy, the patient is often given the reversing agent NMBA to help restore muscle function. The most commonly used reversing agents are inhibi the ora acetylcholinesterase (AChE), such as neostigmine, Adriani and pyridostigmine. Because the mechanism of action of these drugs is to increase the level of acetylcholine at the neuromuscular connections through inhibition of acetylcholine, they are not suitable for reversion depolarizing NMBA, such as succinylcholine. The use of AChE inhibitors as reversing agents leads to problems with selectivity, because neurotransmission all synapses (both somatic and autonomic), including the neurotransmitter acetylcholine, potentiated by these agents. This neselektivno can lead to many side effects due to selective activation of muscarinic and nicotinic acetylcholine receptors, including bradycardia, hypotension, increased salivation, nausea, vomiting, abdominal cramps, diarrhea, and bronchostenosis. Therefore, in practice, these agents can only be used after or together with the introduction of atropine (or glycopyrrolate) to create antagonism of muscarinic effects of acetylcholine at muscarinic acceptors in the joints autonomic parasympathetic neuroeffector (e.g., heart). The use of an antagonist of muscarinic acetylcholine receptor (mAChR), such as atropine, causes a number of side effects, such as tachycardia, xerostomia, blurred vision, difficulty in emptying the bladder and, in addition, it may affect cardiac conduction.

Another problem with anticholinesterase agents is that there must be a residual neuromuscular activity (>10% seizure activity)to allow rapid recovery of neuromuscular function. Occasionally, either because of hypersensitivity patients, either excessive doses, as an accident, the introduction of NMBA can cause a complete and prolonged blockade of neuromuscular function ("deep blockade"). Currently there are no reliable means for the reversal of such "deep blockade". Attempts to overcome the "deep blockade" high doses of AChE inhibitors pose a risk of induction of cholinergic crisis, leading to a wide range of symptoms related to increased stimulation of nicotinic and muscarinic receptors.

In the application for the European patent 99/306411 (AKZO NOBEL N.V.) described the use of chemical chelators or chelating agents) as the reversing agent. Describes the chemical chelators that are capable of forming a complex of guest-host for the manufacture of medicines, reversing induced drug neuromuscular blockade. The use of chemical chelators as Reversi the respective agents for NMBA has the advantage of they are efficient reverse action as depolarizing and non depolarizing NMBA. Their use does not increase the level of acetylcholine and therefore they possess a weaker side effects and are not associated with the stimulation of muscarinic and nicotinic receptors observed for reversing agents AChE. Additionally, there is no need for the combined use of an inhibitor of AChE and mAChR antagonist (e.g., atropine), whereas chemical chelators can be safely used for reversion "deep blockade". Examples of such chemical chelators, as described in European patent 99/306411 were selected from different classes mostly cyclic organic compounds, which are able to form inclusion complexes with various organic compounds in aqueous solution, for example, cyclic oligosaccharides, cyclophane, cyclic peptides, calixarenes, crown ethers, azacrown-esters.

Cyclodextrins,

n=6-9

the class of cyclic molecules containing six or more units α-D-glucopyranose linked by 1,4-positions α-bonds, as in amylose, and their derivatives have been identified in the European patent 99/306411 as particularly useful for reversal of many of the commonly used neuromuscular blocking the hentov or muscle relaxants, such as rouroni, pancuronium, vecuronium, rapacuronium, mivacurium, atracurium, (CIS)atricure, succinylcholine and tubocurarine.

Applicants found that derivatives of 6-mercaptocysteine having a General formula I

where m is 0-7 and n is 1-8 and m+n is equal to 7 or 8;

R represents a (C1-6)alkylene, optionally substituted 1-3 HE-groups, or - (CH2)o-phenylene-(CH2)p-;

o and p, independently, is equal to 0-4;

X is COOH, CONHR1, NHCOR2, SO2OH, RHO(OH)2, O(CH2-CH2-O)q-H, HE or tetrazol-5-yl;

R1represents H or (C1-3)alkyl;

R2is carboxyphenyl;

q is 1-3;

or their pharmaceutically acceptable salts are highly active in vivo reversion of action of neuromuscular blocking agents.

No protection per se is not claimed for the following derivatives of 6-mercaptocysteine:

6 perdesi-6-TRANS-(2-hydroxyethylthio)-β-cyclodextrin and

6 perdesi-6-TRANS-(2-hydroxyethylthio)-γ-cyclodextrin,

described Ling, S. and Darcy, R. J. Chem. Soc. Chem Connn. 1993, (2), 203-205); 6 monodeluxe-6-mono-(2-hydroxyethylthio)-β-cyclodextrin, which is described Fujita, K. et al. (Tetr. Letters 21, 1541-1544, 1980); 6 perdesi-6-per-(carboxymethylthio)-β-cyclodextrin, which is described Guillo, E. et al. (Bull. Chem. Soc. Chim. Fr. 132 (8), 87-866, 1995); 6 monodeluxe-6-mono(carboxymethylthio)-β-cyclodextrin, which is described Akiie, T. et al (Chem. Lett. 1994 (6), 1089-1092); 6A,6B, dideoxy-6A,6B-bis[(o-carboxyphenyl)thio]-β-cyclodextrin, 6A,6B, dideoxy-6A,6B-bis(carboxymethylthio)-β-cyclodextrin, which are described Tubashi, I. et al. (J. Am. Chem. Soc. 108, 4514-4518, 1986), and 6-perdesi-6-per-(2,3-dihydroxypropyl)-β-cyclodextrin, which is described Baer, H.H. and Santoyo-Gonzalez, F. (Carb. Res. 280, 315-321, 1996). These derivatives of 6-mercaptocysteine prior art have been described in connection with different applications in each case.

However, the above derivatives of 6-mercaptocysteine prior art actually belong to the principal aspect of the present invention, which relates to the application of the derived 6-mercaptocysteine General formula I for the manufacture of medicines, reversing induced drug neuromuscular blockade.

In one implementation the invention relates to derivatives of 6-mercaptocysteine having a General formula I

where m is 0-7 and n is 1-8 and m+n is equal to 7 or 8;

X is COOH, HE or CONHCH3;

R represents a (C1-6)alkylene or (CH2)about-phenylene-(CH2)p;

o and p, independently, is equal to 0-4; or their pharmaceutically acceptable salts, except

6-bardeux the-6-TRANS-(2-hydroxyethylthio)-β -cyclodextrin;

6 monodeluxe-6-mono-(2-hydroxyethylthio)-β-cyclodextrin;

6 perdesi-6-TRANS-(2-hydroxyethylthio)-γ-cyclodextrin;

6 perdesi-6-per-(carboxymethylthio)-β-cyclodextrin;

6 monodeluxe-6-mono(carboxymethylthio)-β-cyclodextrin;

6A,6B, dideoxy-6A,6B-bis[(o-carboxyphenyl)thio]-β-cyclodextrin, 6A,6B, dideoxy-6A,6B-bis(carboxymethylthio)-β-cyclodextrin.

The term (C1-6)alkylen used in the definition of formula I, means the divalent carbon radical with a straight or branched chain containing 1-6 carbon atoms, such as methylene, ethylene (1,2-ethandiyl), propylene (1-methyl-1,2-ethandiyl), 2-methyl-1,2-ethandiyl, 2,2-dimethyl-1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,5-pentanediol and 1,6-hexandiol. The term phenylene means a bivalent moiety, the free valence of which can be located either in the ortho-, meta-or para-position to each other. The term (C1-3)alkyl means an alkyl group with straight or branched chain containing 1-3 carbon atoms, i.e. methyl, ethyl, propyl and isopropyl. The term carboxyphenyl means a phenyl group which is substituted or ortho-, meta-or para-position by carboxypropyl. It is preferable ortho-carboxyaniline group.

Compounds according to formula I, where n+m is 7, derive β-is Icodextrin, compounds in which n+m is equal to 8, derive γ-cyclodextrin.

Preferred are derivatives of 6-mercapto-cyclodextrin of the formula I, in which X is COOH, or their pharmaceutically acceptable salts. More preferred are derivatives of 6-mercapto-γ-cyclodextrin of the formula I, in which n is equal to 8, R represents a (C1-6)alkylene and X is COOH.

Especially preferred derivatives of 6-mercaptocysteine invention are:

6 perdesi-6-TRANS-(2-carboxyethyl)thio-γ-cyclodextrin;

6 perdesi-6-TRANS-(3-carboxypropyl)thio-γ-cyclodextrin;

6 perdesi-6-TRANS-(4-carboxyphenyl)thio-γ-cyclodextrin;

6 perdesi-6-TRANS-(4-carboxypentyl)thio-γ-cyclodextrin;

6 perdesi-6-TRANS-(2-carboxypropyl)thio-γ-cyclodextrin and

6 perdesi-6-TRANS-(2-sulfoethyl)thio-γ-cyclodextrin.

Derivatives of 6-mercaptocysteine formula I can be obtained by the interaction of C6-activated derivative of cyclodextrin of the formula II with the derived alkylthiol, arylalkyl or arylthiol corresponding to the formula H-S-R-X, where R and X have the above meanings, in the presence of inorganic or organic bases.

Formula II where m is 0-7, n = 1-8, m+n is equal to 7 or 8 and Y represents a leaving group which, which can be a halogen (Cl, Br or I), the functional group of ether sulfuric acids or ether sulfonic acids, such as toluensulfonate, naphthalenesulfonate or triftormetilfullerenov (triplet).

On the other hand, derivatives of 6-mercaptocysteine formula I can also be obtained by the interaction of the derivative of 6-thiol-γ- or -β-cyclodextrin of formula III with an alkylating agent, for example, alkylhalogenide, arylalkylamines, alkylsulfonates, arylalkylamines corresponding to the formula Y-X-R, where Y, X and R have the meanings stated above, or with a reagent containing a double bond, for example, vinylalcohol, acrylate, and so forth, or the epoxide, in the presence of inorganic or organic bases.

Formula III, where m is 0-7, n = 1-8, m+n=7 or 8.

Alternative synthesis for the preparation of derivatives of 6-mercaptocysteine of the invention known to the person skilled in the art. Chemistry of obtaining derivatives of cyclodextrins are well described (see, for example: Comprehensive Supramolecular Chemistry, Volumes 1-11, Atwood, J.L., J.E.D. Davies, D.D. MacNicol, Vogtie F., eds; Elsevier Science Ltd., Oxford, UK, 1996).

Pharmaceutically acceptable salts of derivatives of 6-mercaptocysteine formula I, where X represents a carboxylic acid group COOH, sulfonic acid group SO2OH, a phosphonic acid group PO(OH) 2or tetrazol-5-ilen group, can be obtained by treatment of the acid with an organic base or a mineral base such as sodium hydroxide, potassium or lithium.

Derivatives of 6-mercaptocysteine or their pharmaceutically acceptable salt or solvate applied in accordance with the invention, is administered parenterally. The path of the injection may be intravenous, subcutaneous, transcutaneous, intramuscular, or intraarterial. The preferred route is intravenous route. Accurate used dose will depend on the needs of the individual subject who is administered a drug, the degree of muscle activity that you want to restore, and evaluation of anesthesist/specialist in the treatment of critical conditions. Also examines the in vitro use of chemical chelators of the invention, for example, by mixing the chemical chelator with blood during dialysis or during plasmapheresis.

The following aspect of the invention relates to a kit for providing neuromuscular blocking and reversal, comprising (a) a neuromuscular blocking agent and (b) the derivative of 6-mercaptocysteine General formula I, are capable of forming a complex of guest-host with neuromuscular blocking agent. Set in accordance with the invention, means are ready preparative forms is, which has a separate pharmaceutical preparations, i.e. neuromuscular blocking agent, and the derivative of 6-mercaptocysteine formula I, i.e. the reversing agent. Components of such a kit should be used consistently, i.e. neuromuscular blocking agent is administered to a subject in need of it, followed, in time, when you want to restore muscle function, the introduction of the reversing agent, i.e. the derivative of 6-mercaptothiazoline in accordance with the present invention.

A preferred kit according to the invention contains a derivative of 6-mercaptocysteine formula I and neuromuscular blocking agent, which is selected from the group consisting of rocuronium, vecuronium, pancuronium, rapacuronium, mevacore, atricure, (CIS)of atricure, tubocurarine and subsumation. Particularly preferred kit of the invention includes rouroni as a neuromuscular blocking agent.

In a mixture with a pharmaceutically acceptable auxiliary agents and pharmaceutically acceptable liquids, for example, as described in the standard reference, Gennaro et al., Remington''s Pharmaceutical Sciences (18thed., Mack Publishing Company, 1990, Part 8: Pharmaceutical preparations and their manufacture; see, especially, section 84 for "Parenteral preparations", pp.1545-1569; and section 85 on "Intravenous mixtures", pp.1570-1580), derivatives of 6-mercapto is codextron can be applied in the form of a solution, for example, for use as an injectable.

In the alternative case, the pharmaceutical composition may be provided in containers with a single dose or multiple doses, for example, in sealed vials and ampoules can be stored in dried by freezing (liofilizirovannom) condition requiring only the addition of sterile liquid carrier, for example water, before use.

The invention further includes pharmaceutical finished formulations form, as described herein above, in combination with packaging material suitable for this composition, with the specified packaging material includes instructions for using the composition as described here above.

The invention is illustrated by the following examples.

Example 1

Sodium salt of 6-monodeluxe-6-mono-(4-carboxyphenyl)thio-γ-cyclodextrin

In a round bottom flask containing pyridine (120 ml), add dry γ-cyclodextrin (2.0 g, 1.54 mmol) under nitrogen atmosphere at room temperature. Once dissolved, add 2-naphthalenesulfonate (1,05 g, with 4.64 mmol) in pyridine (20 ml) and the mixture is stirred for 24 hours by Quenching with water (50 ml) and evaporation to dryness obtain crude 6-mono-O-(2'-naphthalenesulfonyl)-γ-cyclodextrin.

Sodium hydride (0,38 g, 5.83 mmol) suspended in dry dimethylformamide (20 ml). To the suspension were then added 4-mercaptobenzoic acid (0.7 g, 4,55 mmol) and the resulting mixture is stirred for 20 minutes. To the mixture add toilet γ-cyclodextrin (3.2 g, 2,12 mmol) and the reaction mixture is heated to 100°C for 90 minutes. After cooling, add acetone to precipitate a solid substance, which is again precipitated from a mixture of water/acetone. The precipitate is then dissolved in water (20 ml), pH was adjusted to 7.0 by adding 2 N. hydrochloric acid, then chromatographic on a column of DEAE Sephadex A-25. The appropriate fractions are combined dialist, then precipitated twice from a mixture of water/acetone, while getting 400 mg specified in the connection header.

1H-NMR in DMSO: δ 7,4-7,8 (ArH), 5,0-5,2 (8H), 4,13 (1H), 3,7-4,0 (29N), 3,7-3,4 (17H)AT 3.25 (1H) ppm13With NMR in DMSO δ: 129, 9mm and of 127.5 (ArC), 103,3 and 102,9 (C1 and C1'), 85,0 (C4'), 81,6 (C4), 73,8 (C3), 73,5 (C2)72,2 (C5), and 70.8 (C5'), 60,6 (C6), 34,3 (C6') ppm MS elektrorazpredelenie [M+H]+=1455,7 and [M+Na]+=1477,7.

Example 2

Sodium salt of 6-monodeluxe-6-mono-(2-carboxyphenyl)thio-γ-cyclodextrin

Sodium hydride (60%dispersed in oil, 0.18 g, 4.5 mmol) is added in one portion to thiosalicylic acid (0.34 g, 2.2 mmol) in DMF (25 ml) and stirred at room temperature for 30 minutes To the mixture of crude solution of 6-mono-O-(2'-naphthalenesulfonyl)-γ-cyclodextrin is (2.5 g, 1,45 mmol) in DMF (15 ml) and heated to 70°C for 24 hours. The mixture is cooled and quenched with water (20 ml) before evaporation to dryness. To the residue and then water is added and the resulting solution was poured into acetone (250 ml) to precipitate. The formed solid is filtered off and dissolved in water (10 ml) before passing through a column of Sephadex DEAE A-25 with elution with water, then with 0.2 N. NaOH.

The fractions containing the product are combined and evaporated to small volume and cialiswhat (MWCO 1000) replacement of the internal water four times. The internal solution evaporated to small volume and poured into acetone (100 ml). The solid is filtered off and dried in vacuum at 70°With, while getting mentioned in the title compound (235 mg) as a white solid.

1H-NMR (D2O) δ:7,50-7,10 (4H, m, Ar-H), 5,14 (8H, m, CyD 1-N)TO 4.16 (1H, m, CyD 5-H), 3,98-3,85 (N, m, CyD 3,5,2,4-N), 3,70-3,61 (20N, m, CyD 2,3,4,6-N)AND 3.15 (1H, m, CyD 6-H) ppm; MS elektrorazpredelenie m/z 1477,6 for [M+Na]+calculated for C55H83NaO41S M 1455,304.

Example 3

Sodium salt of 6-perdesi-6-TRANS-(3-carboxyphenyl)thio-γ-cyclodextrin

Triphenylphosphine (30.1 g, 15 equiv.) dissolved with stirring in dry DMF (160 ml). The solution for 10 min add iodine (30.5 g, 15,6 equiv.), what causes heat. Then add dry γ-cyclade the Stryn (10 g, 7.7 mmol) and the mixture is heated to 70°C for 24 hours. The mixture is allowed to cool, add sodium methoxide (3.1 g of sodium in 50 ml of methanol) and the mixture stirred for 30 min before pouring into methanol (800 ml) and evaporation to dryness. To the residue add water (500 ml) and the solid is filtered off and washed with water (3×100 ml), then acetone (3×100 ml) and dried in vacuum at 70°With, however, getting a 6-perdesi-6-periodγ-cyclodextrin in the form of a yellow solid (16.2 g), which is used without further purification.

To a solution of 3-mercaptobenzoic acid (1.0 g, 10 EQ.) in DMF (30 ml) is added portions of 60% sodium hydride dispersed in oil (476 mg, 22 equiv.) for 30 minutes the Mixture cool and add 6 perdesi-6-periodγ-cyclodextrin (1.4 g) in DMF (30 ml). The mixture was then stirred at 70°C for 24 hours. The mixture is allowed to cool to room temperature and quenched by addition of water (20 ml) before evaporation to a small volume. The solution was poured into acetone (500 ml) and the precipitate is filtered off, dissolved in water (20 ml) and cialiswhat (MWCO 1000) replacement of the internal water four times. The internal solution evaporated to small volume and poured into acetone (250 ml). The solid precipitate is filtered off and dried in vacuum at 70°With, while getting mentioned in the title compound (1.45 g) as a white solid.

<> 1H-NMR (D2O) δ: to 7.77 (8H, Sirs, Ar-H), 7,55 (8H, d, J=6.0 Hz, Ar-H), 7,71 (N, m, Ar-H), 5,16 (8H, s, CyD 1-H), 4,00-3,94 (N, m, CyD, 3,5-H), TO 3.58-3,53 (N, m, CyD 4,2-N), 3,43 IS 3.40 (8H, m, CyD 6-H), 3,24-3,20 (8H, m, CyD 6-H); MS elektrorazpredelenie: m/z 1190,6 for [M-8Na+6H]2-calculated for C104H104Na8O48S8M 2562,39.

Example 4

Sodium salt of 6-perdesi-6-TRANS-(2-carboxyethyl)thio-γ-cyclodextrin

3-Mercaptopropionic acid (1,22 ml, 14.0 mmol) was dissolved in dry DMF (45 ml) in an atmosphere of N2at room temperature. To this solution was added in three portions sodium hydride (1.23 g, 30,8 mmol, 60%) and the mixture is stirred for an additional 30 minutes To this mixture is then added dropwise a solution of 6-perdesi-6-periodγ-cyclodextrin (3.12 g, of 1.40 mmol) in 45 ml of dry DMF. After the addition the reaction mixture is heated at 70°C for 12 hours. After cooling, to the mixture is added water (10 ml) and the volume reduced to 40 ml in vacuo, to the residue is added ethanol (250 ml), resulting in precipitation. The solid precipitate is filtered off and cialiswhat within 36 hours. The volume is then reduced to 20 ml under vacuum. To the residue is added ethanol and the precipitate is filtered off and dried, thus obtaining specified in the title compound as a white solid (1.3 g, 43%).

1H-NMR (D2O) δ: 2,47 is 2.51 (m, N); 2,84-is 2.88 (m, N); 3,00-3,02 (t, 8 is); 3,11-3,14 (t, 8H); 3,62-3,68 (m, N); 3,92-of 3.97 (m, 8H); 4,04-4,06 (m, 8H); 5,19 (m, 8H) ppm MS FIA+ion at 2024,9 m/z.

Example 5

Sodium salt of 6-perdesi-6-per-(5-carboxypentyl)thio-γ-cyclodextrin

Specified in the header of the connection receives the same way as described in example 4, the interaction of 6-mercaptohexanol acid (1,34 g, 0/90 mmol) with 6-perdesi-6-periodγ-cyclodextrin.

1H-NMR (D2O): δ of 1.40 (s, N); 1,57-of 1.64 (m, N); 2,17-of 2.21 (m, N); 2,67-3,00 (m, N); 2,85-2,90 (m, 8H); 3,15-3,20 (m, 8H); 3,52-3,59 (m, 8H); 3,60-3,63 (m, 8H); a 3.87-3,93 (m, N); 5,16 (s, 8H) ppm MS FIA+ions when 2362,2, 2213, 2065 and 1919 m/z.

Example 6

Sodium salt of 6-perdesi-6-TRANS-(3-carboxypropyl)thio-γ-cyclodextrin

Specified in the header of the connection receives the same way as described in example 4, the interaction of the 4-mercaptoethanol acid (1.10 g, 0,009 mol) of 6 perdesi-6-periodγ-cyclodextrin.

1H-NMR (D2O): δ 1,87-of 1.88 (m, N); 2,27-2,30 (m, N); 2,67-a 2.71 (m, N); 2,98-3,00 (m, 8H); 3,13-and 3.16 (m, 8H); 3,61-3,63 (m, N); 3,94-a 4.03 (m, N); to 5.21 (s, 8H) ppm MS FIA+ion at 2138,8 m/z.

Example 7

Sodium salt of 6-perdesi-6-percarboxylic-γ-cyclodextrin

Sodium hydride (60% dispersion, 0.34 g, 8.60 mmol) is added to a mixed solution of ethyl-2-mercaptoacetate (0,92 AM to 8.40 mmol) in DMF (20 ml) under nitrogen atmosphere pikantnoi temperature. After the termination of the allocation of vials (15 min) to the system add per-6-dioxide-6-iodine-γ-cyclodextrin (2.17 g, 1.00 mmol). After 5 min the temperature was raised to 70°and the reaction mixture is left under stirring for 17 hours. After cooling, the DMF is removed under vacuum. Add methanol (50 ml), and a creamy white solid slowly crystallizes from solution. It is filtered with suction, washed with methanol and dried, thus obtaining 6-perdesi-6-percarboxylic-γ-cyclodextrin in the form of solids (1,74 g, 82%). δH(d6-DMSO) 4,95-4,85 (8H, m, 8 × anomericCH), 4,05 (N, kV, 8×CH2CH3), 3,85 of 3.75 (8H, m), 3,60-3,50 (8H, m), 3,40-3,20 (N, Shir. with, 8×CH2SCH2), 3,20-3,10 (8H, m), 2.95 and-to 2.85 (8H, m), 1,20 (24N, t, 8×CH2CH3).

1 M sodium hydroxide solution (7 ml) is added 6-perdesi-6-percarboxylic-γ-cyclodextrin (1,00 g, 0.47 mmol) and the reaction mixture left to stir at room temperature. After 18 hours the clear solution cialiswhat within 8 hours, and water (2 l) replace every 2 hours. After this time the contents of the dialysis tube was poured into the flask and the water is evaporated in vacuum, thus obtaining specified in the title compound as a white solid (0,62 g, 64%). δN(D2O) to 5.21 (8H, d, 8 × anomericCH) 4,18-of 4.05 (8H, m)4,00 (8H, DD), of 3.78 (8H, DD), 3,70 (8H, DD), 3,40 (N, DD), 3,20 (8H, d), to 3.02 (8H, DD). δc(D2O) 178,1, 101,6, 82,8, 73,0, 72,7, 71,8, 39,0, 34,1 LC/MS TOF 1889 m/z.

Example 8

Sodium salt of 6-perdesi-6-lane(4-carboxyphenyl)thio-γ-cyclodextrin

To a solution of 4-mercaptobenzoic acid (856 mg) in DMF (30 ml) is added portions of 60% sodium hydride dispersed in oil (372 mg) for 30 minutes the Mixture is cooled and one portion add per-6-dioxide-6-bromo-γ-cyclodextrin (1.0 g) and the mixture was stirred at 70°C for 24 hours. The mixture is allowed to cool to room temperature and quenched by addition of water (20 ml) before evaporation to a small volume. The solution was poured into ethanol (250 ml) and the precipitate is filtered off, dissolved in water (20 ml) and cialiswhat (MWCO 1000) replacement of the internal water four times. The internal solution evaporated to small volume and poured into acetone (250 ml). The solid precipitate is filtered off and dried in vacuum at 70°With, while getting mentioned in the title compound (1.2 g) as a white solid.

1H-NMR (D2O, 343K): δ 7,70 (N, d, J=8.1 Hz, Ar-H), 7.23 PERCENT (N, d, J=7,3 Hz, Ar-H), 5,15 (8H, s, CyD 1-H), 4,00-3,96 (N, m, CyD 3,5-H), 3,55-3,53 (24N, m, CyD 6',4,2-N)AND 3.15 (8H, m, CyD 6-H); MALDI-TOF, m/z 2383,7 for [M-Na8+H6]calculated for C104H104Na8O48S8M 2562,39.

Example 9

Sodium salt of 6-Perd the hydroxy-6-TRANS-(4-carboxymethyl)thio-γ -cyclodextrin

To a solution of 4-mercaptophenylacetic acid (10 EQ.) in DMF (50 ml) is added portions of 60% sodium hydride in oil (22 EQ.) for 30 minutes the Mixture is cooled and one portion add per-6-dioxide-6-bromo-γ-cyclodextrin (1.0 g) and the mixture was stirred at 70°C for 24 hours. The mixture is allowed to cool to room temperature and quenched by addition of water (20 ml) before evaporation to a small volume. The solution is then poured into acetone (250 ml) and the precipitate is filtered off, suspended in water (20 ml) and cialiswhat (MWCO 1000) replacement of the internal water four times. The internal solution evaporated to small volume and poured into acetone (250 ml). The solid precipitate is filtered off and dried in vacuum at 70°With, while getting mentioned in the title compound (1.44 g) as a white solid.

1H-NMR (D2O, 343K): δ 7,15 (N, d, J=8.0 Hz, Ar-H), 6,99 (N, d, J-8.0 Hz, Ar-H), 4,98 (8H, s, CyD 1-H), 3,90-3,72 (N, m, CyD 3,5-H), 3,51-3,43 (N, m, CyD 4,2-N), 3,28 (24N, m, CH2-Ar, CyD 6'-H), 3,15-3,10 (1H, m, CyD 6-H); MALDI-TOF, m/z 2495,8 for [M-Na8+H6]calculated for C112H120Na8O48S8M 2674,6.

Example 10

6 Perdesi-6-TRANS-(3-aminopropyl) thio-γ-cyclodextrin

To a mixture of 6-perdesi-6-partio-γ-cyclodextrin (500 mg; obtained as described in example 17) and iodide feces is I (5 mg) in DMF (10 ml) is added 4-chlorobutane (673 mg; Fries et al. Biochemistry 1975, 14, 5233). Add cesium carbonate (1.8 g) and the reaction mixture heated to 60°With during the night. The resulting mixture was poured into acetone, filtered, washed with ethanol and water and then dried in vacuum (118 mg; 16,2%).

1H-NMR(DMSO/D2O): δ and 4.9 (1H, s), and 3.8 (1H, m), and 3.6 (1H, m), 3,4 (2H, m), 3,05 (1H, m), 2,85 (1H, m)and 2.2 (2H, m)of 1.75 (2H, m). The mass spectrum with elektrorazpredelenie: M-H (m/z) 2105.

Example 11

6 Perdesi-6-per-(5-hydroxy-3-occupancy)thio-γ-cyclodextrin

2-(2-Mercaptoethane)ethanol (1.4 g, 11.6 mmol) was dissolved in DMF (20 ml) and begin stirring at room temperature in a nitrogen atmosphere. Then add per-6-bromo-γ-cyclodextrin (2 g, 1.12 mmol) and cesium carbonate (3.2 g, 9,86 mmol) and the resulting suspension stirred at 60°C overnight under nitrogen atmosphere. After cooling to room temperature, the suspension was poured into acetone (200 ml) and the insoluble matter is filtered off, washed with acetone (×3) and dried in vacuum. The crude product is dissolved in deionized water (20 ml) and cialiswhat (10 hours). The contents of the dialysis membrane then was concentrated in vacuo, while receiving 1 g of the target product in the form of a cream solid.

1H-NMR (D2O, 400 MHz): δ 2,81-3,00 (m, 24N), 3,21-of 3.31 (d, 8H), 3,49 (t, 8H), 3,55 of 3.75 (m, N), 3,82 (t, 8H), to 3.89 (t, 8H), 5,11 (d, 8H), ESI-MS: 2175 (M-N)-.

the example 12

Sodium salt of 6-perdesi-6-TRANS-[2-(2-carboxybenzoyl) amino) ethyl]thio-γ-cyclodextrin

TRANS-6-mercapto-γ-cyclodextrin (1 g, 0.7 mmol; see example 17) dissolved in DMF (10 ml) and stirring is continued at room temperature under nitrogen atmosphere. Add N-(2-bromacil)phthalimide (1,57 g of 6.17 mmol) and cesium carbonate (2 g, of 6.17 mmol) and the resulting suspension stirred at 60°C overnight under nitrogen atmosphere. After cooling to room temperature, DMF is removed under vacuum and with vigorous stirring, water (100 ml). The precipitate is filtered off, washed with water (x 3) and dried in vacuum, while getting 1,67 g cream solid color. To the crude product (600 mg) were then added an aqueous solution of sodium hydroxide (1M, 20 ml) and the resulting solution stirred at room temperature overnight under nitrogen atmosphere. The solution is then cialiswhat with deionized water until, until it reaches a constant value of pH and the contents of the dialysis membrane is dried in vacuum, while getting 500 mg of the target product as a glassy solid.

1H-NMR (D2O, 400 MHz): δ was 2.76-2,96 (m, 24N), 3,10-3,30 (m, 8H), 3,35-3,62 (m, N), 3,78-3,95 (m, N), 5,02 (d, 8H), 7,30 to 7.62 (m, N); ESI-MS: 1477 (M-2N)2-.

Example 13

6 Perdesi-6-TRANS-(2-oxyethyl)thio-γ-cyclogest is in

To a stirred solution of 2-mercaptoethanol (10,85 g, 10 equiv.) in DMF (500 ml) under nitrogen atmosphere add portions of 60% sodium hydride dispersed in oil (11.7 g, 21 equiv.), for 30 minutes the Mixture is stirred at room temperature for 90 minutes. Add per-6-deoxy-6-Barbra-γ-cyclodextrin (25,0 g) and the mixture is heated to 70°C for 24 hours. The mixture is allowed to cool to room temperature and quenched by addition of water (50 ml) before evaporation to a small volume. The residue is dissolved in water (100 ml) and poured into a mixture of 1:1 methanol/acetone (500 ml). The obtained solid is filtered off, dissolved in water (500 ml) and cialiswhat (MWCO 1000), changing the water four times. The internal solution evaporated to small volume and then the substance is recrystallized from hot water, while getting mentioned in the title compound (8.5 g) as a white cross-shaped crystals.

1H-NMR (400 MHz; DMSO): δ 5,91 (N, Shir. with, 2,3-HE), 4,92 (8H, s, 1-H), 4,71 (8H, t, J 4.4 Hz, SCH2CH2OH), 3,75 [8H, t, J=8.0 Hz, 3-H or 5-H)], 3,60-3,50 [24N, m, 5-H (or 3-H), SCH2CH2OH], 3,40-3,30 (N, m, 4-H, 2-H), IS 3.08 (8H, d, J=13,6 Hz, 6-H), 2,82 (8H, DD, J=of 13.6, 6.8 Hz, 6-H), 2,66 (N, t, J=6,8 Hz, SCH2CH2OH); m/z (elektrorazpredelenie) 1775,4 for [M-H]-; calculated for C64H112S8O40M 1776,45.

This connection is of a similar method has been published previously: J. Chem. Soc., Chem. Commun., 203 (1993).

Example 14

6 Perdesi-6-per-(N-methylaminomethyl)thio-γ-cyclodextrin

To a stirred solution of N-methylmercaptopurine (0,58 g, 10 equiv.) in DMF (30 ml) under nitrogen atmosphere add portions of 60% sodium hydride dispersed in oil (0,22 g, 10 equiv.), for 30 minutes the Mixture is stirred at room temperature for 30 minutes. Add per-6-deoxy-6-Barbra-γ-cyclodextrin (1.0 g) and the mixture is heated to 60-70°C for 48 hours. The mixture is allowed to cool to room temperature and quenched by addition of water (20 ml) before evaporation to a small volume. The residual solution was poured into ethanol (100 ml). The obtained solid is filtered off, dissolved in water (200 ml) and cialiswhat (MWCO 1000), replacing the domestic water four times. The internal solution evaporated to small volume and poured into ethanol (100 ml). The precipitate is filtered off and dried in vacuum, while getting mentioned in the title compound (0.55 g) as a white solid.

1H-NMR (400 MHz; D2O): δ from 5.29 (8H, d, J=4.0 Hz, 1 H), 4,10 (8H, Shir. t, J=9.6 Hz, 5-H), OF 4.05 (8H, t, J=9.8 Hz, 3-H), 3,83 (8H, DD, J=10,0, 3,6 Hz, 2-H), 3,74 (8H, t, J=9,2 Hz, 4-H), TO 3.58-3.49 POINTS [N, AV system, SCH2C(O)NHCH3], 3,36 (8H, Shir. d, J=12,8 Hz, 6-H)3,07 (8H, DD, J=14,0, and 8.4 Hz, 6-H), 2,94 (24N, s, SCH2C(O)NHCH3); m/z (elektrorazpredelenie) 1991,7 for [M-H]-; vicis is prohibited for C 72H120N8S8About40M 1992,54.

Example 15

Sodium salt of 6-perdesi-6-TRANS-(2-carboxypropyl)thio-γ-cyclodextrin

Sodium hydride (60% in oil) (0,44 g) is added to methyl-3-mercapto-2-methylpropionate (1,474 g; J. Med. Chem., 1994, 1159) in dimethylformamide (25 ml). After 30 minutes add per-6-dioxide-6-bromo-γ-cyclodextrin (2.25 g)dissolved in dimethylformamide (25 ml). Add a crystal of sodium iodide and the mixture is heated at 75°With during the night. The solvent is distilled off and the residue crystallized from methanol to obtain methyl ether complex (1.3 g). Mass spectrum (M-N) 2224;

1H-NMR (DMSO-d6) δ: of 1.41 (d, 24N), 2,68 (m, N), 2,80 (m, N), to 3.00 (m, 8H), 3,61 (3, 24N), with 3.79 (m, 8H), of 4.95 (s, 8H).

This product is then stirred overnight in a solution of sodium hydroxide (M, 13 ml). The resulting mixture is filtered, dialist until neutral and evaporated to dryness, thus obtaining specified in the title compound (1.13 g). Mass spectrum (M-N) 2112;

1H-NMR (D2O): δ to 1.15 (d, 24N), 2,5 (m, 8H), to 2.65 (m, 8H), 2,8-3,1 (m, 24N), the 3.65 (m, N), 4,0 (m, N), and 5.2 (s, 8H).

Example 16

Sodium salt of 6-perdesi-6-TRANS-(3-carboxypropyl)thio-β-cyclodextrin

TRANS-6-dioxide-6-bromo-γ-cyclodextrin (2.25 g), methyl-4-mercaptopurine (1.7 g; Tetrahedron 1998, 2652), cesium carbonate (4,24 g) and Dima is informed (25 ml) is stirred and heated together for three days. The mixture is cooled, poured into water and filtered. The solid is washed with methanol and dried (2.1 g). The substance is stirred overnight in a solution of sodium hydroxide (M, 21 ml), filtered and the filtrate cialiswhat to neutrality. The filtrate is evaporated to dryness, thus obtaining specified in the title compound (1.7 g). Mass spectrum (M-N) 1848,8.

1H-NMR (D2O): δ to 1.75 (m, N), of 2.15 (m, N), and 2.6 (m, N), 2,85 (m, 8H), 3,05 (m, 8H), 3,55 (m, N), a 3.87 (m, N), 5,07 (s, 8H).

Example 17

Sodium salt of 6-perdesi-6-TRANS-(2-sulfoethyl)thio-γ-cyclodextrin

And: TRANS-6-dioxide-6-thio-γ-cyclodextrin

TRANS-6-dioxide-6-bromo-γ-cyclodextrin (20 g), thiourea (13.5 g) and dimethylformamide (100 ml) are heated together for three days at 65°and then added ethanolamine (20 ml) and heating continued for two hours. The mixture is cooled, diluted with ice water and the product is separated by centrifugation. The solid is washed twice with water and dried in vacuum at 65°With, while getting a thiol (7,34 g). Mass spectrum (M-N) 1424.

1H-NMR (DMSO-d6): δ 2,82 (m, 8H), 3,20 (d, 8H), to 3.35 (m, N), 6,65 (t, 8H), to 7.75 (m, 8H), 5,0 (s, 8H).

In: the Sodium salt of 6-perdesi-6-TRANS-(2-sulfoethyl)thio-γ-cyclodextrin

The above partial (1 g), sodium salt of 2-bromo-econsultancy acid (1.42 g), cesium carbonate (2.2 g) and dimethylformamid the d (10 ml) is stirred and heated overnight at 64° C. the Greater part of the solvent is evaporated in vacuum and the residue is dissolved in water. Add a solution of sodium bicarbonate (5% mass/mass, 5 ml) and the solution cialiswhat three times with water. This solution is evaporated to dryness and the residue is dissolved in sodium bicarbonate solution (10 ml), dialist and evaporated as described above. The process is repeated, the resulting solid is dissolved in a small volume of water and the product precipitated with methanol. The precipitate is dissolved in water and evaporated to dryness, thus obtaining specified in the title compound (1.18 g).

1H-NMR (D2O): δ to 3.9 (m, 24N), 3,2 (m, 24N), 3,55-the 3.65 (m, N), a 3.9 (m, 8H), of 4.05 (m, 8H), 5,15 (s, 8H).

Example 18

6 Perdesi-6-TRANS-(2,2-di(hydroxymethyl)-3-hydroxypropyl)thio-γ-cyclodextrin

TRANS-6-dioxide-6-thio-γ-cyclodextrin (500 mg; example 17), 3-bromo-2,2-dihydroxyphenylethanol (670 mg), cesium carbonate (550 mg) and dimethylformamide (10 ml) is heated and stirred for 35 days at 65°With, before, until the analysis of LC-MS to confirm the transformation to the target product. The mixture is evaporated to dryness, dissolved in water, dialist from water, evaporated to small volume and precipitated with acetone. Drying in vacuo gives specified in the title compound (550 mg). The mass spectrum of the FIA (M-N) 2369.

1H-NMR (D2O): δ 2,84 (m, N)and 3.15 (m, 8H), 3,24 (m, 8H), of 3.69 (s, N), 3,85-4,19 (m, N in), 5.25 (s, 8H).

Note the R 19

Sodium salt of 6-pardesi-6-TRANS-(3-(tetrazol-5-yl) propyl)thio-γ-cyclodextrin

TRANS-6-dioxide-6-thio-γ-cyclodextrin (1 g), 4-bromobutyronitrile (1 g), cesium carbonate (1 g) and dimethylformamide (10 ml) is stirred together at 60°from Saturday until Monday. The mixture is cooled, water is added and the precipitate was separated by centrifugation. After washing and drying receive barbuttonitem (1.4 g). The product (1 g), sodium azide (1.3 g), triethylamine hydrochloride (2.8 g) and dimethylformamide (13 ml) is stirred and heated together for 7 days at 100°C. the Mixture is cooled, diluted with water, acidified and the precipitate filtered off. The precipitate is washed with water, treated with ultrasound in methanol, separated by centrifugation, dried, and dissolved in sodium hydroxide solution (M, 10 ml), filtered and cialiswhat to neutrality. This solution is evaporated to dryness, thus obtaining specified in the title compound (600 mg). Mass spectrum (M-2N) 1152,8.

1H-NMR (D2O): δ 1,95 (m, N), to 2.55 (m, N), 2,85 (m, 24N), 3,05 (d, 8M), and 3.5 (m, 8H), 3,6 (m, 8H), 3,9 (m, N), is 5.06 (s, 8H).

Example 20

Reversal of neuromuscular blockade at the shot of Guinea pigs in vivo

Male Guinea pigs Dunkin-Hartley (body mass 600-900 g) was anestesiologi by intraperitoneal injection of 10 mg/kg pentobarbitone and 1000 mg/kg of urethane. After tracheotomy animals claim Steno was ventolinbuy with small breathing apparatus Harvard for animals. The catheter was placed in the carotid artery for continuous monitoring of arterial blood pressure and screening of blood samples for analysis of the composition of gases in the blood. Heart rate was obtained from a blood pressure signal. The sciatic nerve is stimulated (rectangular pulses with a duration of 0.5 MS with intervals of 10 s (0.1 Hz) at supramaximal voltage, with the use of stimulant Grass S88), and the force of contractions of the gastrocnemius muscle was measured using sensor power shift. Reduction, blood pressure and heart rate were recorded on a multichannel recorder Grass 7D. Catheters were placed in both the jugular vein. One catheter was used for continuous infusion of neuromuscular blocking agent. Speed infusion of neuromuscular blocking agent was increased to reach a steady-state blocking 85-90%. Another catheter was used for administration of increasing doses of the reversing agent. During continuous infusion of neuromuscular blocking agent was given a single dose of increasing concentrations of the reversing agent. At the end of the experiment measured the force of muscle contraction inflicted on the chart depending on the concentration of the reversing agent, and using regression analysis was calculated concentration 50% reversibility reversal of neuromuscular block, induced muscle relaxant, bromide, rocuronium (Roc)derivatives of 6-mercaptocysteine examples 1-19 are presented in table I. For comparison, also included reversing activity of the parent compounds, β-cyclodextrin and γ-cyclodextrin.

Example parenteral pharmaceutical composition

Prepare a solution containing 100 mg/ml of sodium salt of 6-perdesi-6-lane(2-carboxyethyl)thio-γ-cyclodextrin (compound of Example 4). the pH of the solution was adjusted to 7.5 (valid value in the range of 7.3 to 7.7) by adding 0.1 M HCl or 0.1 M NaOH. The solution is sterilized by filtration through a membrane filter with a pore diameter of 0.2 μm, fill them with standard sterile ampoules 5,3±0.2 ml/vial, and finally sterilized sealed ampoule at 121±2°within 32,5±2.5 minutes.

The toxicity of compounds

Compounds of the present invention, selected as candidates for clinical trials have been tested for biological activity and toxicity in various animal models (Guinea pig, cat, monkey). In all animal models of effective dosage levels, specific for each connection, there were no changes in heart rate and blood pressure, and other signs of toxic de the aftermath of the compounds, obvious on observed changes in the behavior of animals.

Sodium salt of 6-perdesi-6-lane(2-carboxyethyl)-γ-cyclodextrin disclosed in Example 4 (internal index Org 25969), is the preferred compound of the present invention. For her dose of 10 mg/kg, ten times higher than the dose effective for the treatment of blockade induced by rocuronium bromide, does not reach the threshold for toxicity in accordance with the criteria and on the models listed above.

1. The derivative of 6-mercaptocysteine having a General formula I

where m is 0-7 and n is 1-8 and m+n is equal to 7 or 8;

R represents a (C1-6)alkylene, optionally substituted 1-3 HE-groups, or - (CH2)about-phenylene-(CH2)p-;

o and p are independently equal to 0 to 4;

X is COOH, CONHR1, NHCOR2, SO2OH, PO(OH)2, O(CH2-CH2-O)q-H, HE or tetrazol-5-yl;

R1represents H or (C1-3)alkyl;

R2is carboxyphenyl;

q is 1-3;

or its pharmaceutically acceptable salt;

except

6 perdesi-6-TRANS-(2-hydroxyethylthio)-β-cyclodextrin;

6 monodeluxe-6-mono-(2-hydroxyethylthio)-β-cyclodextrin;

6 perdesi-6-TRANS-(2-hydroxyethylthio)-γ-cyclodextrin

6 perdesi-6-per-(carboxymethylthio)-β-cyclodextrin;

6 monodeluxe-6-mono(carboxymethylthio)-β-cyclodextrin;

6A,6B, dideoxy-6A,6B-bis[(o-carboxyphenyl)thio]-β-cyclodextrin;

6A,6B, dideoxy-6A,6B-bis(carboxymethylthio)-β-cyclodextrin and

6 perdesi-6-per-(2,3-dihydroxypropyl)-β-cyclodextrin.

2. The derivative of 6-mercaptocysteine according to claim 1, where R, m and n have the meanings indicated in claim 1, and X is COOH or SO2OH, or its pharmaceutically acceptable salt.

3. The derivative of 6-mercaptocysteine according to claim 1, where m is 0; n is equal to 8; R is (C1-6)alkylene or (CH2)about-phenylene-(CH2)p; and p is independently equal to 0 to 4 and X is COOH or SO2OH, or its pharmaceutically acceptable salt.

4. The derivative of 6-mercaptocysteine according to any one of claims 1 to 3, selected from

6 perdesi-6-TRANS-(2-carboxyethyl)thio-γ-cyclodextrin;

6 perdesi-6-TRANS-(3-carboxypropyl)thio-γ-cyclodextrin;

6 perdesi-6-TRANS-(4-carboxyphenyl)thio-γ-cyclodextrin;

6 perdesi-6-TRANS-(4-carboxypentyl)thio-γ-cyclodextrin;

6 perdesi-6-TRANS-(2-carboxypropyl)thio-γ-cyclodextrin and

6 perdesi-6-TRANS-(2-sulfoethyl)thio-γ-cyclodextrin or its pharmaceutically acceptable with the l.

5. The derivative of 6-mercaptocysteine General formula I according to claim 1 for use in therapy.

6. The use of the derivative of 6-mercaptocysteine General formula I according to claim 1 for the manufacture of drugs for reversal of neuromuscular blockade induced by a drug.

7. Set to achieve neuromuscular blockade and reversal, comprising (a) a neuromuscular blocking agent and (b) the derivative of 6-mercaptocysteine General formula I according to claim 1.

8. The kit according to claim 6, where neuromuscular blocking agent selected from the group consisting of rocuronium, vecuronium, pancuronium, rapacuronium, mivacron, (CIS)of atricure, tubocurarine and suksametonia.

9. The kit according to claim 7, where neuromuscular blocking agent is rouroni.

10. Pharmaceutical composition for reversing induced drug neuromuscular blocking, including derivative of 6-mercaptocysteine having a General formula I

where m is 0-7 and n is 1-8 and m+n is equal to 7 or 8;

R represents a (C1-6)alkylene, optionally substituted 1-3 HE-groups, or - (CH2)about-phenylene(CH2)p;

o and p are independently equal to 0 to 4;

X is COOH, CONHR1, NHCOR2, SO2OH, PO(OH)2, O(CH2-CH2 -O)q-H, HE or tetrazol-5-yl;

R1represents H or (C1-3)alkyl;

R2is carboxyphenyl;

q is 1-3;

or its pharmaceutically acceptable salt in a mixture with pharmaceutically acceptable excipients.

11. The way reversing induced drug neuromuscular blockade in a patient, which comprises parenteral administration to a specified patient an effective amount of a derivative of 6-mercaptocysteine General formula I according to claim 1.



 

Same patents:

The invention relates to a linear cyclodextrin copolymers and oxidized cyclodextrin, which can be used as a carrier for the delivery of various therapeutic agents

The invention relates to a new complex platinum compound, which is useful in medical practice for the treatment of cancer

- cyclodextrin and method of suppressing tumor growth" target="_blank">

The invention relates to organic chemistry, and medicine, and it applies to substances used in combination with ascorbic acid for the treatment of malignant neoplasms (binary catalytic "dark" therapy of malignant tumors) and method of suppressing tumor growth

The invention relates to new crystalline complex compound of-,and/or-cyclodextrin hydrochloride ranitidine when the molar ratio of these components is from 1:1 to 2:1

The invention relates to physiologically active agents that produce nitric oxide, process for their preparation, containing compositions, and methods of use thereof

The invention relates to the field of pharmaceutical and organic chemistry and relates to new inclusion complexes and pharmaceutical compositions based on them, which are used for treatment of certain medical conditions in mammals

FIELD: medicine, microbiology, pharmacology.

SUBSTANCE: invention proposes a medicinal preparation for treatment of muscular dystonia that comprises botulinic toxin isolated from culture Clostridium botulinum as a liquid substance dissolved mainly in 0.87% physiological solution with albumin. Method for preparing the preparation involves preparing botulinic toxin from culture Clostridium botulinum by culturing its strain at temperature 29-33°C for 3-6 days in nutrient medium. Then dry ammonium sulfate is added to cultural fluid slowly for formation of precipitate. Prepared suspension is centrifuged for preparing precipitate and isolated liquid phase is extracted and subjected for purification. Process for purifying the liquid substance of medicinal preparation is carried out for two stages using metal sorbent at the first stage and gel-filtration at pH 5.5-6.0 - at the second stage. Sterilization of the purified substance is carried out by membrane filtration. Invention provides preparing the preparation with reduced risk for arising intolerance and with high stability in storage.

EFFECT: improved method for preparing, valuable medicinal properties of preparation.

6 cl, 7 ex

FIELD: medicine.

SUBSTANCE: method involves administering selective modulator of steroid sex hormones being in particular compounds of general formula(I) and some quantity of steroid sex hormones precursor selected from a group composed from dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-en-3β,17β-diol and compounds in vivo transformable into one of cited precursors. Bisphosphonates combined with selective estrogen receptor modulators and/or steroid sex hormones precursor are additionally introduced for medically treating and/or inhibiting osteoporosis progress.

EFFECT: enhanced effectiveness of treatment; excluded adverse side effects.

41 cl, 13 dwg, 4 tbl

FIELD: medicine, gastroenterology, phytotherapy, pharmacy.

SUBSTANCE: invention relates to solid medicinal formulations, namely capsules "Gastrobiol-TSD". Gelatin capsule contain the natural pharmacologically active component - sea-buckthorn oil concentrate, cyclodextrin, vitamin U and magnesium oxide taken in the definite ratio of components given in the invention description. Invention provides preparing a medicinal formulation eliciting an anti-ulcer, analgetic and protective effect on mucosa effect being with minimal risk for development of adverse effect.

EFFECT: valuable medicinal properties of preparation.

1 tbl, 1 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of heteroarylalkylpiperazine of the general formula (I):

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to organic chemistry and can find application in medicine

The invention relates to the field of pharmacy and medicine and relates to solid dosage forms such as tablets "Apolar" anabolic and act-protective action based on the nature of the pharmacologically active component of the drone brood

The invention relates to pharmacy and medicine and relates to the development of new medicines

The invention relates to substituted cyclic aminoven compounds of formula (I)

< / BR>
where Ar represents thienyl, substituted pyridine, phenyl unsubstituted or substituted with halogen, hydroxy, alkoxy, C1-C4the alkyl, phenyloxy, NO2or phenyl; R1is NHOR2where R2is hydrogen; W is one or more hydrogen atoms; Y is independently one or more members of the group consisting of hydroxy, SR3, alkoxy, NR6R7where R6and R7independently selected from hydrogen, alkyl, pyridylethyl, SO2R8, COR9or R6and R7can be combined with the formation of the ring containing the nitrogen to which they relate, formulas

< / BR>
where Y' is CH2OH , SO2; R3represents hydrogen, alkyl, aryl, benzothiazolyl, pyrazinyl, N-methylimidazole; R8represents C1-C4alkyl, phenyl; R9represents hydrogen, alkyl, phenyl; Z is hydrogen; n = 1, and its optical isomer, diastereoisomer, or enantiomer, or its pharmaceutically acceptable salt

The invention relates to the pharmaceutical industry and relates to improved pharmaceutical preparations containing dehydroepiandrosterone (DHEA), enriched to polymorphic forms I or II, for therapeutic purposes
Up!