Amino derivatives, method for the inhibition of the synthesis of nitric oxide, a method of selective inhibition of the synthesis of nitric oxide produced by inducible no-synthase, the method of reducing levels of nitric oxide, a pharmaceutical composition

 

(57) Abstract:

The invention relates to new derivatives of formula (I), where R1- R4- hydrogen atoms; X - alkylene with 1 to 6 carbon atoms; Y is lower alkyl; B is - NR5R11where R5is a hydrogen atom, R11selected from 5 - to 6-membered heterocyclic radical, in which one ring member is a carbon and 1 to 4 members of the heteroatoms nitrogen, or sulfur, or their pharmaceutically acceptable salts, are useful as inhibitors of the synthesis of nitric oxide. Also proposed a method of inhibiting the synthesis of nitric oxide, a method of selective inhibition of the synthesis of nitric oxide produced by inducible NO-synthase, the method of reducing nitrogen oxide and pharmaceutical composition. 5 C.p. f-crystals, 1 PL.

The invention relates to the derivatives of aminotetrazole and their use in therapy, in particular to their use as inhibitors synthase nitric oxide.

Since the 1980-ies it is known that the vascular relaxation induced by acetylcholine, depends on the presence of endothelium, and this activity is attributed to the labile humoral factor, named secreted by the endothelium relaxing factor (EDRF). The activity of nitric oxide (NO) as vazo the other nitrovasodilators. The recent identification of EDRF as NO coincided with the opening of the biochemical pathway by which NO is synthesized from the amino acid L-arginine by the enzyme NO synthase.

NO is an endogenous stimulator of soluble guanylate cyclase and in addition to endothelium-dependent relaxation is involved in many biological activities, including cytotoxicity phagocytic cells and the communication cell - to-cell in the Central nervous system (see Moncada et al. Biochemical Pharmacology, 38, 1709-1715 (1989) and Moncada et al. Pharmacological Reviews, 43, 109-142 (1991). Currently, it is believed that excessive production of NO may affect many States, especially States, which include systemic hypotension, such as toxic shock syndrome and the treatment of certain cytokines.

The synthesis of NO from L-arginine may be Engibarov analogue of L - arginine, L-N-monomethyl-arginine (L-NMMA), and it was suggested that therapeutic use of L-NMMA for the treatment of toxic shock and other types of systemic hypotension (WO 91/04024 and GB-A-2240041). Therapeutic use some other inhibitors of NO synthase, excluding L-NMMA, for the same purpose has also been proposed in WO 91/04024 and EP-A-0446699.

Recently, it has become apparent that there are at m is calitanii in the endothelium and produce NO in response to receptor or physical stimulation.

(ii) a constitutive, Ca++/calmodulin - dependent enzyme that is localized in the brain and produce NO in response to receptor or physical stimulation.

(iii) Ca++- independent enzyme, which is induced after activation of vascular smooth muscle, macrophages, endothelial cells and other cells by endotoxin and cytokines. Once originated, this inducible NO synthase synthesizes NO in for extended periods.

NO, the selected constitutive enzymes, acts as a transduction mechanism, emphasizing different physiological reactions. NO produced induced enzyme, is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that the harmful effects of excessive NO production, in particular pathological vasodilatation and tissue damage, may be largely a result of the effects of NO synthesized induced by NO synthase.

There is increasing evidence that NO may be involved in the degeneration of cartilage, which takes place under certain conditions, such as arthritis, and it is well known that the synthesis of NO is enhanced when revmote is of NO from L-arginine, include autoimmune and/or inflammatory condition affecting the joints, such as arthritis, inflammatory bowel disease, cardiovascular ischemia, diabetes, hyperalgesia (allodynia), cerebral ischemia (local ischemia, thrombotic lesion and extensive ischemia, secondary stopping of the heart), and other disorders of the Central nervous system, mediated by NO, and other disorders mediated by NO.

In addition, the conditions under which it is advisable to inhibit the production of NO from L - arginine include systemic hypotension associated with septic and/or toxic shock caused by a wide variety of agents; therapy with the use of cytokines, such as TNF, IL-1 and IL-2, and used as adjuvant to short term immunosuppression in transplantation.

Some of the inhibitors of NO synthase proposed for therapeutic use long enough, and in particular L-NMMA, are indiscriminate in that they inhibit both constitutive and inducible NO synthase. The use of such a non-selective inhibitor of NO synthase requires great care when taking in order to avoid potentially seriously the thrombosis and tissue damage. In particular, in the case of therapeutic use of L-NMMA for the treatment of toxic shock it is recommended that continuous monitoring of blood pressure of the patient during treatment. Thus, although non-selective inhibitors of NO synthase have therapeutic utility, provided appropriate precautions, inhibitors of NO synthase, which are selective in the sense that they inhibit inducible NO synthase to a much greater extent than constitutive isoforms of NO synthase, would be even more therapeutically useful and more convenient to use.

W094/12165, W094/14780, W093/13055, EP0446699A1 and U.S. patent N 5132453 disclose compounds that inhibit the synthesis of nitric oxide and preferably inhibit the induced synthase isoforms of nitric oxide. Messages, therefore, are by reference in its entirety, as described here.

In a broad aspect, the present invention is directed to the inhibition or modulation of the synthesis of nitric oxide in the body of a subject in need of such inhibition or modulation, by introducing a compound that mainly inhibits or modulates the induced synthase isoforms of nitric oxide compared to constata the subject, in need of such reduction.

Compounds of the present invention represented by the following chemical formula

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and their pharmaceutically acceptable salts;

where R1, R2independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower quinil;

R3, R4independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower quinil, aryl, COR7or SO2R8where R7and R8independently selected from the group consisting of lower alkyl, lower alkenyl, lower quinil and aryl;

X is independently selected from the group consisting of lower alkyl, lower alkenyl and lower quinil, and all of them can be substituted by lower alkyl, lower alkoxygroup, hydroxy, halogen, trifluoromethyl, nitro, cyano, amino;

or X is selected from the group of the formula -(CH2)pQ(CH2)r- where p = 1-3, r=1-3, and Q is oxygen, C= 0, S(0)twhere t = 0-2, or NR12where R12is hydrogen or lower alkyl which may be substituted by lower alkyl, lower alkoxygroup, hydroxy, halogen, trifluoromethyl, nitro, cyano, amino; or

X is selected from the group of the formula -(CH2)
Y is selected from the group consisting of lower alkyl, lower alkenyl and lower quinil, or Y can be NR9R10where R9and R10independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower quinil, nitro, amino, aryl and lower alkaryl:

B-NR5R11where R5selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower quinil and aryl and R11selected from a 3-8 - membered heterocyclic radical, in which at least one member of the ring is hydrogen and in which from 1 to about 4 members are heteroatoms independently selected from oxygen, nitrogen and sulfur, and the heterocyclic radical may be substituted by hydroxyl, lower alkoxygroup, lower alkyl, halogen, nitro, carboxyla, S02R13where R13selected from lower alkyl, lower alkoxygroup, NR1R2, amino, acyloxy, trifloromethyl, phenyl and naphthyl which may be substituted with halogen, nitro, lower alkoxygroup and lower alkyl.

The advantage of the present invention that these compounds are more selective than known compounds.

The purpose of the present invention is to provide compounds that are more selective than known.

Advantage also lies in the fact that the compounds of the present invention have a preferred physical properties in comparison with known compounds. For example, the connection specified in Example 1, is a crystalline product as well as all intermediate compounds. On the contrary, NIL, which is presented in WO 93/13055, in the form of cleaners containing hydrochloride salt can be isolated as a colorless crystal, but it has the property to be liquefied. The connection quickly becomes very viscous sticky oil under the influence of moisture in normal room air, which makes handling them.

The present invention covers compounds of formula (1) in the form of salts, in particular additive salts with an acid. Suitable salts include the salts formed with organic and inorganic acids. Cesky unacceptable salts may be useful for the production and purification of compounds in question. Thus, preferred salts are those derived from hydrochlorite, hydrobromides, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, oxalic, fumaric, malic, salewoman, methansulfonate, econsultancy, p - toluensulfonate, benzosulfimide and italianboy acids. Salts of compounds of formula (1) can be obtained by reaction of the corresponding compound in free base form with an appropriate acid.

Although it is possible to enter the compounds of formula (1) in the form of the chemical, it is advisable to provide them in the form of pharmaceutical compositions. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (1) or its pharmaceutically acceptable salt or MES together with one or more pharmaceutically acceptable carriers for him and possibly one or more other therapeutic ingredients. The carrier (s) must be "acceptable" in the sense that it must be compatible with other ingredients of the composition and not to be harmful to its recipient.

Compositions include those that are suitable stationary), rectal and local (including skin, cheek, sublingual and intraocular) administration although the most suitable route of administration may depend, for example, the condition and disease of the recipient. The compositions may be presented in a convenient dosage form and may be obtained by any of the methods well known in pharmacy. All methods include the stage of combining the compounds of formula (1) or its pharmaceutically acceptable salt or MES ("active ingredient") with the carrier which constitutes one or more accessory ingredients. Basically, the compositions have a uniform and thorough mixing of the active ingredient with liquid carriers or finely ground solid carriers or both, and then shaping the product into desired formulations form.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets, which contain a specified amount of the active ingredient; as a powder or granules; solutions or suspensions in aqueous liquids or non-aqueous liquid; or in the form of a liquid emulsion of the type oil-in-water or liquid emulsion

The tablet can be obtained by extrusion or molding, possibly with one or more accessory ingredients. Molded tablets can be obtained by sealing in a special machine the active ingredient in free granular form, such as powder or granules, possibly mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets can be obtained by molding in a special machine a mixture of the powdered compound moistened inert liquid diluent. Tablets may be coated or may have a notch and can be designed to provide slow or controlled release of active ingredient from them.

Preparative dosage forms for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic and dissolved substances, which give the composition isotonicity with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspendresume substances and thickeners. Preparative form can be represented in cannom freezing (liofilizirovannom), requiring only the addition of sterile liquid carrier, such as saline solution, water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the previously described species.

Preparative forms for rectal injection can be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.

Preparative form for local injection in the mouth, such as the cheek or under the tongue, include pellet, containing the active ingredient in a flavored basis such as sucrose, gum acacia or tragakant, and tablets containing the active ingredient in a base such as gelatin and glycerol or sucrose and gum acacia.

The preferred dosage preparative forms are those which contain an effective dose as described here below, or the appropriate portion thereof, of the active ingredient.

It should be understood that in addition to the above ingredients the composition of this invention may include other agents conventional in this type of compositions, referred to, when the P> Compounds of the invention can be administered orally or by injection at a dose of from 0.001 to 2500 mg/kg / day. The dose limits for adults mainly from 0.005 mg to 10 g/day. Tablets and other present dosage forms in the form of discrete units usually contain the number of compounds of the invention, which is effective at such dosage or in several doses, for example, in the form of units containing 5 mg to 500 mg, usually around 10 mg to 200 mg

The compounds of formula (1) preferably administered orally or by injection (intravenous or subcutaneous). The exact number of connections, enter the patient must identify the attending physician. However, the applied dose is usually depends on many factors, including the age and gender of the patient, the specifics of the disease, requiring treatment and its severity, and the route of administration may vary depending on the condition and its severity.

As used here, the term "lower alkyl", alone or in combination, means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 6 carbon atoms. Examples of such radicals are methyl, ethyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, Gex is adekale, which contains at least one double bond. Such radicals contain from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms, better still from 2 to about 6 carbon atoms. Examples of suitable alkenyl radicals are propylene, butene-1 - yl, isobutyl, penttinen-1-yl, 2-2-methylbutan-1-yl, 3 - methylbutan-1-yl, HEXEN-1 - yl, hepten-1-yl and octene-1-yl, etc.

The term "lower quinil" refers to an unsaturated acyclic hydrocarbon radical, which contains one or more triple connections, such radicals contain from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms, better still from 2 to about 6 carbon atoms. Examples of suitable etkinlik radicals are ethinyl, PROPYNYL, butyn - 2-yl, pentyn-2-yl, 3-methylbutan-1-yl, hexyne-1-yl, - hexyne-2-yl, - hexyne-3-yl, 3,3-trimethylbutane-1-yl, etc.

The term "heterocyclic radical" denotes an unsaturated heterocyclic hydrocarbon radical of 3-6 carbon atoms, where from 1 to about 4 carbon atoms may be replaced by nitrogen, oxygen or sulfur. "Heterocyclic radical" may be condensed with an aromatic hydrocarbon radical. Padmasali, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolyl, 3-pyrrolyl, pyrrolidinyl, 1,3-DIOXOLANYL, 2-imidazolyl, imidazolidinyl, 2 - pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3 - oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxane, morpholine, 1,4-ditional, thiomorpholine, pyrazinyl, piperazinil, 1,3,5-triazinyl, 1,3,5 - tritional, benzo(b)thiophenyl, benzimidazolyl, chinoline etc.

The term "aryl" denotes an aromatic hydrocarbon radical of 4 to about 16 carbon atoms, preferably from 6 to about 12 carbon atoms, still preferably from 6 to about 10 carbon atoms. Examples of suitable aromatic hydrocarbon radicals are phenyl, naphthyl, etc.

The term "cycloalkyl" or "cycloalkenyl" means alicyclic radical of 3 to about 10 carbon atoms in the ring, and preferably from 3 to about 6 carbon atoms. Examples of suitable alicyclic radicals are cyclopropyl, cyclopropylethyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1-eleniel, cyclohexenyl etc.

The term "alkoxy", alone or in combination, denotes a radical simple Olkiluoto ether, in which the term alkyl yavlyaetsya radicals simple Olkiluoto ether are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.

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

The term "prodrug" refers to a connection that is more active in vivo.

In the sense used here, reference to "treatment" of the patient implies and prevention.

All references, patents or pending patent applications, U.S. or foreign, cited in the application are given for information as if they are described here.

Following the main sequence of synthesis used in the implementation of the present invention.

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It seems that specialist in this area may, without further elaboration, using the preceding description, utilize the present invention to its fullest extent. Therefore, the following preferred specific embodiments should be considered only as illustrative and not limiting of the rest of the announced any way.

All experiments are conducted in an atmosphere of dry nitrogen or argon. All solvents and reagents used without further purification unless otherwise stated. Accepted in practice the implementation of the reactions on the one solvent. The aqueous layer was extracted with n (x) specified organic solvent. The combined organic extracts washed with n times (x) the specified aqueous solutions, dried over anhydrous Na2SO4, filtered, concentrated in vacuo and purified as indicated. Separation by column chromatography carried out under the conditions described Still. (Still, W. C.: Kahn, M.; Mitra, A. Rapid Chromatographic Technique for Prerarative Separation with Moderate Resolution. J. Org. Chem., 1978, 43, 2923-2925). Cleaners containing hydrochloride salt is obtained from 1N HCl, HCl in ethanol (EtOH), 2N in MeOH or 6N HCl in dioxane. Thin-layer chromatogram carried out on 0.25 mm plates of silica gel 60 F254 pre-coated EAT. Liquid chromatogram high resolution (IHVR) get on C-8 or C-18 columns for chromatography with reversed phase, which receive from various suppliers. Analytical samples are dried in an Abderhalden apparatus at 56oC or 78oC.1H Yarm range get spectrometer General Electric QE-300 or Varian VXR 400 MHz with tetramethylsilane was as an internal standard.13With Yarm range get spectrometer Varian when for 125.8 MHz with tetramethylsilane was as an internal standard.

Example 1

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2S-amino-6-[(1-iminoethyl)amino]-N-(1H-tetrazol-5-yl) hexanamide, hydrate, N,N - diisopropylethylamine (DIPEA) (5,1 g, 6.9 ml, 39,54 mmol) in 20 ml of dimethylformamide (DMF) at ambient temperature add hexaphosphate benzotriazol-1-yl-oxy-Tris(dimethylamino)phosphonium (THIEF) (6.4 g, 14,49 mmol).

After stirring for 1 h the reaction mixture was concentrated under vacuum. The residue is partitioned between 60 ml of ethyl acetate (EtOAc) and 50 ml of water. The layers are separated. The organic layer is washed with 50 ml of 1 M solution of KHSO4and 2 times 50 ml of water. The product begins to precipitate, and the suspension was concentrated in vacuo, receiving 9 g of crude compound. After drying the product was then purified by boiling in methylene chloride, followed by filtration, gaining 3.7 g 1A (62,7%). Connection characterize1H YARM.

1B 1A (2 g, 4.5 mmol) restore under conditions of catalytic hydrogenation using Pd mobiles when 0,352 kg/cm250% solution of EtOH/AcOH within 12 hours, getting 1,55 r (100%) 1B. Connection characterize1H YARM.

1C To a stirred solution of 1B (1.55 g, 4,15 mmol) and hydrochloride of methylacetamide (0,91 g, 8,31 mmol) in 25 ml DMF added triethylamine (tea) (1.26 g, of 1.74 ml, 12,45 mmol). After stirring for 16 h at ambient temperature the reaction mixture is filtered off from triethylamine hydrochloride and the filtrate kontsentriruemoy by phase C-18 column, obtaining 0.9 g (52,3%) 1C. The product is characterized1H YARM.

1 1C (0.9 g, 2,17 mmol) dissolved in 30 ml of acetic acid and add 3 ml of 4 N HCL/dioxane. The reaction mixture was stirred for 20 min at ambient temperature, then add 150 ml simple ethyl ester. After 2 h the precipitate is filtered off, washed simple with ethyl ether and dried, obtaining 0,78 g 1 (96%). Anal. Rasch. for C9H18N8O, 2HCl, 1,25 H2O: C, 30,91; H, 6,48; N, 32,04; Cl, 20,27. Found: C, 31,64; H, To 6.43; N, 32,19; Cl, 20,19. DSC so pl. 144,9oC.

The compound of example 1 is also more selective than NIL. The compound of example 1 is finely crystalline product as well as all intermediate compounds. On the contrary, NIL is glass, which makes handling them.

Example 2

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2S-amino-5-[[amino(nitramino)methyl]amino]-N-(1H-tetrazol-5 - yl)pentanone, hydrochloride

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2A Sample t-Boc of nitroarginine (5.0 g, 15.6 mmol) and N - methylmorpholine (1.6 g, 15.6 mmol) dissolved in a mixture of methylene chloride (CH2Cl2, 25 ml) and DMF (25 ml) cooled to -78oC. To this stirred reaction mixture in the atmosphere of nitrogen (N2) add isobutylparaben (Aldrich, 2.2 g, of 16.6 mmol). Then allow the reaction cm is t to -78oC. Sample monohydrate 5-aminotetrazole (Aldrich, of 1.62 g, 15.8 mmol) is added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 48 hours All the solvent is removed under reduced pressure and the residue distributed between ethyl acetate (EtOAc) and water. The aqueous layer was free from all water and specified in the header of the material isolated from the crude residual product (9.3 g) by chromatography.

2 Specified in the title material was obtained from 2A in the manner described in Example 1.

Example 3

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2S-amino-6-[(1-iminoethyl)amino] -N-(1H-imidazol-2 - yl)-hexanamide, dihydrochloride

3 Specified in the title material was obtained in the same way as 1, based on 2-aminoimidazole.

Example 4

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2S-amino-6-[(1-iminoethyl)amino] -N-(1H-1,2,4-triazole-3 - yl)-hexanamide, dihydrochloride

4 is Listed in the title material was obtained in the same way as 1, based on 3-aminotriazole.

Example 5

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2S-amino-6-[(1-iminoethyl)amino] -N-(5 - pyrimidinyl)hexanamide, hydrate, dihydrochloride

5 is Listed in the title material was obtained in the same way as 1, starting from 5-aminopyrimidine.

Example 6

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2S-amino-6-[(1-iminoethyl)amino the way that and 1, based on 3-aminopyrazole.

Example 7

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2S-amino-6-[(1-iminoethyl)amino] -N-(thiazol-2 - yl)hexanamide, dihydrochloride

7 is Listed in the title material was obtained in the same way as 1, based on 2-aminothiazole.

Biological data

The activity of the above compounds as inhibitors of NO synthase define the following tests:

Citrullinemia analysis synthase nitric oxide

Synthase activity of nitric oxide measured by monitoring the conversion of L-[2,3-3H] -arginine to L-[2,3-3H]-citrulline (1,2). Inducible NOS man (hiNOS), endothelial constitutive NOS man (hecNOS) and neuronal constitutive NOS man (hncNOS), each clone from RNA extracted from human tissues. Recombinant enzymes Express in insect cells using a baculovirus vector. The active enzyme is extracted from cell extracts and partially purified by DEAE chromatography-Sepharose (2). The enzyme and inhibitors added to a volume of 50 μl in 50 mm Tris (pH 7.6) and initiate the reaction by adding 50 µl of a solution containing 50 mm Tris (pH 7,6), 2.0 mg/ml bovine serum albumin, 2.0 mm DTT, 4.0 mm CaCl2, 20 μm FAD, 100 μm tetrahydrobiopterin, 0.4 to 2.0 mm NADPH and 60 μm L-arginine, soderzhashchaya at 37oC for 15 min the reaction is stopped by adding 300 ál of cold buffer containing 10 mm EGTA, 100 mm HEPES (pH 5.5) and 1.0 mm L-citrulline. [3H]-Citrulline was separated by chromatography on a cation-exchange resin Dowex 50W X-8 and quantify the radioactivity in a liquid scintillation counter.

1. Bredt, D. S. and Snyder, S. H. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 682-685.

2. Misko, T. P., Moore, W. M., Kasten, T. P., Nickols, G. A., Corbett, J. A. , Tilton, R. G., McDaniel, M. L, Williamson, J. R. and Currie, M. G. (1993) Eur. J. Pharm. 233, 119-125.

Compounds according to the invention are non-toxic, as evidenced by tests, for example, the compounds of example I in vivo for 0.1, 0.3, 1.0, 3.0, 10.0, and 600.0 mpk, showed the following results:

Analysis: MTOL po for example 1.

5/5 0.1 mpk 5/5 0.3 mpk 5/5 1.0 mpk

Portable = 0.1 mpk Portable = 0.3 mpk Portable = 1.0 mpk

5/5 3.0 mpk 5/5 10.0 mpk 5/5 600 mpk

Portable = 3.0 mpk-Tolerance = 10.0 mpk Portable = 600 mpk

From the preceding description specialist in this field can easily set the essential characteristics of this invention and, without departing from the scope of its content and scope, can make various changes and modifications of the invention to adapt it to different needs and conditions.

1. Aminophosphonate;

Y is lower alkyl;

B - NR5R11where R5is a hydrogen atom, R11selected from 5 - to 6-membered heterocyclic radical, in which at least one ring member is a carbon and 1 to 4 member heteroatoms independently selected from nitrogen and sulfur,

or their pharmaceutically acceptable salts.

2. Amino derivatives of formula (I) under item 1, where the specified connection selected from the group of 2S-amino-6-[(1-iminoethyl)amino]-N-(1H-tetrazol-5-yl)hexanamide, hydrate, dihydrochloride; 2S-amino-6-[(1-iminoethyl)amino]-N-(1H-imidazol-2-yl)hexanamide, dihydrochloride; 2S-amino-6-[(1-iminoethyl)amino]-N-(thiazol-2-yl)hexanamide, dihydrochloride.

3. The method of inhibition of the synthesis of nitric oxide from the subject in need of such inhibition, by introducing the inhibitor, characterized in that as an inhibitor use a connection on p. 1 or 2 in an effective amount.

4. The method of selective inhibition of the synthesis of nitric oxide produced by inducible NO-synthase, relative to the nitric oxide produced by the constitutive forms of NO synthase, the subject in need of such selective inhibition by injection of the inhibitor, characterized in that as an inhibitor opolska, in need thereof, by introducing a therapeutic ingredient, characterized in that the quality of therapeutic ingredient is used as a compound under item 1 or 2 in an effective amount.

6. Pharmaceutical composition having inhibitory effect on the synthase nitric oxide in the subject in need of such inhibition, containing therapeutic ingredient together with one or more pharmaceutically acceptable carriers, characterized in that as the quality of therapeutic ingredient it contains a connection on p. 1 or 2 in an effective amount.

 

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1 ex

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

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