Amidinopropane, their use and pharmaceutical composition

 

(57) Abstract:

Amidinopropane General formula I and their salts, pharmaceutically acceptable esters and prodrugs, where X is methylene, n takes values from 1 to 7; R1, R2is hydrogen, alkyl, alkenyl, quinil, amino group, carboxyl group, halogenated, C3-6-alicyclic hydrocarbon, C4-10-aromatic hydrocarbons, and these radicals can be substituted by 1 or more substituents selected from hydroxyl, alkyl, alkoxyl, amino, carboxyl, carbalkoxy, which in turn possibly substituted amino or carboxyl group, or the substituents R1and R2together can optionally form a C3-6-alicyclic hydrocarbon, R3, R4Is H or OH. The compounds of formula I can be used as synthetase inhibitors of nitric oxide. 4 C. and 8 C.p. f-crystals, 2 tab.

The present invention is a partial continuation of patent application U.S. series N 08/141168 aimed for consideration October 21, 1993.

The present invention relates to amidinopropane, pharmaceutical compositions containing amidinopropane, and their use in therapy, in particular to note is the group of vascular voltage, caused by acetylcholine, depends on the presence of endothelium, and this activity is attributed to the labile humoral factor, called the endothelium due to relaxing factor (endotelium - derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator factor known already for 100 years and NO is the active ingredient in amylnitrite, glycerinated and other nitrovasodilators. The recent identification of EDRF with NO coincides 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 a number of biological activities, including cytotoxicity phagocytic cells and transfer from cell to cell in the Central nervous system (see Moncada et al., Biochemical Pharmacology, 38, 1709-1715 (1989) and Moncada et al., Pharmacology Reviews, 43, 109-142 (1991). Now suppose that the production of an excess of NO can occur when the number of States, especially States, in which there is a systemic hypotension, such as toxic shock syndrome and the treatment of certain cytokines.

The synthesis of NO from L-arginine can also be inhibited Ana is toxic shock and other types of systemic hypotension (WO 91/04024 and GB-A-2230041). In applications WO 91/04024 and EP-A-0446699, for the same purposes, in addition to L-NMMA was proposed therapeutic use some other inhibitors of NO-synthase.

Recently it has become evident that there are at least three types of NO-synthase:

(I) a constitutive, Ca++/calmodulin-dependent enzyme, located in the endothelium that releases NO in response to receptor or physical irritation;

(II) a constitutive, Ca++/calmodulin-dependent enzyme, located in the brain that releases NO in response to receptor or physical irritation;

(III) Ca++-dependent enzyme that is induced after the initiation of the vascular smooth muscle, macrophages, endothelial cells and other cells by endotoxin and cytokines; once selected this inducible NO-synthase synthesizes NO for a longer time period.

Release NO constitutive enzymes occurs by the mechanism of traductio, which lies at the basis of a number of physiological reactions. NO produced by induced enzyme, is a cytotoxic molecule for tumor cells and invaginating microorganisms. It is also clear that the negative impact of probbally extent the effect of NO, synthesized by inducible NO-synthase.

Also, a growing number of factors, indicating that NO may be involved in the process of the degeneration of cartilage that occurs in some conditions, such as arthritis, and it is also known that the synthesis of NO is increased in rheumatoid arthritis. Thus, additional conditions that must inhibition of NO synthesis from L-arginine, are autoimmune and/or inflammatory condition affecting the joints, for example arthritis.

The condition in which inhibition of NO synthesis from L-arginine has a positive impact also include systemic hypotension due to septic and/or toxic shock caused by a large number of agents; treatment with cytokines, such as TNF, IL-1 and IL-2, and as an auxiliary state in the short-term immunosuppression in transplant process. Other conditions under which effectively inhibiting the production of NO from L-arginine, are autoimmune diseases and/or inflammatory conditions that affect the joints, such as arthritis or inflammatory diseases of the internal organs, cardiovascular ischemia, Diaby ischemia, secondary to cardiac arrest) and other diseases of the Central nervous system that modulate the synthesis of NO.

Some inhibitors of NO synthase proposed for therapeutic applications, and in particular L-NMMA, are non-selective and inhibit both constitutive and induced synthase nitric oxide. The use of such non-selective NO-synthase requires great care to avoid possible serious consequences of complete inhibition of constitutive NO-synthase, including hypertension, and thrombosis and tissue damage. In particular, in the case of therapeutic use of L-NMMA in the treatment of toxic shock is recommended to monitor blood pressure of the patient during the entire treatment. Therefore, although non-selective inhibitors of NO-synthase find therapeutic application in compliance with the relevant precautions, selective inhibitors of NO-synthase, i.e., those that inhibit induced NO synthase to a much greater extent than the basic NO-synthase, should be more effective and easier to use.

In applications WO 94/12165, WO 94/14780, WO 93/13055, EP 0446699 A1 and in U.S. patent N 5132453 disclosed compounds that inhibit the synthesis of TFR this description as a reference.

A brief description of the drawings.

In Fig. 1 shows the effect of applied oral 2-aminopiperidine (mg/kg) on LPS-induced increase in the concentration of nitrite in the plasma of rats.

Brief description of the invention.

In General, the present invention relates to the inhibition or modulation of the synthesis of nitric oxide in the subject that needs such inhibition or modulation, by introducing compounds which preferably inhibits or modulates the induced synthase isoforms of nitric oxide compared with constitutive synthase isoform of nitric oxide.

The invention also relates to pharmaceutical compositions containing a compound of the formula I

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and its salts, pharmaceutically acceptable esters and prodrugs,

where X is selected from the group comprising methylene, nitrogen atom, oxygen atom, S, SO and SO2where the nitrogen atom and lower alkyl radicals can be optionally substituted hydroxy group, lower alkyl, lower alkoxy group, amino group and halogenation;

n takes values from 0 to about 7;

the substituents R1and R2independently from each other, are selected from the group comprising an atom of water-group, halogen atom, nitro group, amino group, carboxyl group, cyano group, sulfonyloxy group, halogenation, carbalkoxy, barbarians, carbalkoxy group, alicyclic hydrocarbon, a heterocycle, an aromatic hydrocarbon, -CONR5R6, -SO2NR5R6, -COR5, -SO2R5alkylsulfonyl, arylsulfonyl, alkylsulfonyl, arylsulfonyl, alkylsulfate, arylsulfonic and sulfonamide, where all these radicals can be optionally substituted by one or more substituents from: hydroxy groups, lower alkyl, lower alkenyl, lower quinil, lower alkoxy groups, lower dialkoxy group, halogen atom, nitro group, amino group, carboxyl group, cyano group, sulfonyloxy group, carbalkoxy, barbarians, carboxycellulose groups, halogenoalkane, -SO2NR5R6and-SO2R5where all these substituents can be optionally substituted by one or more substituents from among: amino group, carboxyl group, carbalkoxy group, barbarians group, carboxycellulose and lower alkoxy groups; the substituents R1, R2together can optionally form alicyclics is to be optionally substituted by one or more substituents from among: lower alkyl, lowest alkenyl, lower quinil, which may be optionally substituted carboxyl group, carbalkoxy, barbarians, carboxycellulose and lower alkoxy groups; the substituents R3, R4independently from each other, are selected from the group comprising a hydrogen atom, hydroxy group, alkyloxy group; the substituents R5and R6independently from each other, are selected from the group comprising a hydrogen atom, lower alkyl and aryl; provided that when n = 1

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and the substituent R1and/or R2are in position 3 or 4, and any substituent R1or R2are not Allami; in combination with at least one non-toxic pharmaceutically acceptable carrier.

Preferably, when n takes on the values 1, 2, 3, 4, 5, 6 or 7, more preferably when n takes on the values 1 to 5, and more preferably, when n = 1-4, and most preferably, when n = 1-3.

Compounds and compositions, as defined above, are used as inhibitors synthase nitric oxide. These compounds are also predominantly inhibit induced form, but not the constitutive form of NO synthase.

Detailed description of the invention.

Predpochtite is s, includes methylene, nitrogen atom, oxygen and sulfur;

n takes on integer values from 0 to 5;

the substituents R1and R2independently from each other, are selected from the group comprising a hydrogen atom, hydroxy group, lower alkyl, lower alkenyl, lower quinil, halogenated, aromatic hydrocarbon and alicyclic hydrocarbon, where all the abovementioned radicals may be optionally substituted by one or more substituents from: carboxylic groups, carbalkoxy group, amino group, lower alkoxy group, a lower dialkoxy groups and lower alkyl, where these substituents can be optionally substituted by one or more substituents from among: amino group, carboxyl, carbalkoxy groups; and the substituents R1, R2together can optionally form a alicyclic hydrocarbon or aromatic hydrocarbon; and the substituents R3, R4independently from each other selected from the group comprising a hydrogen atom and a hydroxy group;

Another preferred embodiment of the present invention is a compound of the formula:

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and its salts, pharmaceutically acceptable esters and prodrugs,

where X is selected from the group vglisille 7;

the substituents R1and R2independently from each other selected from the group comprising a hydrogen atom, hydroxy group, lower alkyl, lower alkenyl, lower quinil, a lower alkoxy group, a lower dialkoxy group, halogen atom, nitro group, amino group, carboxyl group, cyano group, sulfonyloxy group, halogenation, carbalkoxy, barbarians, carbalkoxy group, alicyclic hydrocarbon, a heterocycle, an aromatic hydrocarbon, -CONR5R6, -COR5, -SO2R5, -SO2NR5R6alkylsulfonyl, arylsulfonyl, alkylsulfonyl, arylsulfonyl, alkylsulfate, arylsulfonic and sulfonamide, where all the abovementioned radicals may be optionally substituted by one or more substituents from: hydroxy groups, lower alkyl, lower alkenyl, lower quinil, a lower alkoxy group, halogen atom, nitro group, amino group, carboxyl group, cyano group, sulfonyloxy group, carbalkoxy, barbarians, carboxycellulose groups, halogenoalkane, -SO2NR5R6and-SO2R5where all these substituents can be optionally substituted by one or more substituents from among: amino-group the group; and the substituents R1, R2together can optionally form a alicyclic hydrocarbon, a heterocycle or aromatic hydrocarbon, and the above-mentioned optionally formed ring may be optionally substituted by one or more substituents from among lower alkyl, lower alkenyl, lower quinil, which may be optionally substituted carboxyl group, carbalkoxy, barbarians, carboxycellulose and a lower alkoxy group; the substituents R3, R4represent a hydrogen atom, hydroxy group, alkyloxy group; the substituents R5and R6independently from each other selected from the group comprising a hydrogen atom, lower alkyl and aryl; provided that when n = 1

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and the substituent R1and/or R2are in position 3 or 4, and any substituent R1nor Deputy R2are not Allami; with the additional condition that, when the Deputy X represents methylene, nitrogen atom, oxygen or sulfur, the substituents R1and R2cannot simultaneously be hydrogen atoms or halogenation, and when n = 3, the substituent R1may not be the stands in position 7.

The present invention includes s are salt, which are formed with organic and inorganic acids. Such acid additive salts are pharmaceutically acceptable, although pharmaceutically unacceptable salts may be used in the process of obtaining and purification of the considered compounds. Therefore, the preferred salts are the salts formed with hydrochloric, Hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, oxalic, fumaric, maleic, salewoman, methansulfonate, econsultancy, p-colorsort, baselslt and italianboy acids. Salts of compounds of formula (I) can be obtained by reaction of the corresponding compound in free base form with a suitable acid.

Although the compound of the formula (I) can be used as individual compounds, it is preferable to produce it in the form of pharmaceutical compositions. In accordance with an additional aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt or solvate in combination with one or more pharmaceutically acceptable carriers and optionally with one who I their compatibility with other ingredients of the formulation and not harmful to the recipient.

Recipes are recipes that are intended for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and local (including dermal, buccal, sublingual and intraocular) administration although the most preferred method may, for example, depend on condition and disease of the recipient. The formulations can be presented in the form of single dosing forms and can be prepared by any of the known pharmaceutical methods. All methods include the stage of mixing the compounds of formula (I) or its pharmaceutically acceptable salt or MES ("active ingredient") with the carrier that contains one or more accessory ingredients. In General the formulations are prepared by thorough and homogeneous mixing of the active ingredient with liquid carriers or finely powdered solid carriers or both, followed, if necessary, giving the product the desired shape.

Tablets can be obtained by extrusion or molding, optionally with one or more accessory ingredients. Molded tablets can be obtained by press the m mixing with the binder, the lubricant, inert diluent, surface active or dispersing agent using the appropriate machines. Molded tablets can be prepared at molding a mixture of the powdered compound moistened with an inert liquid diluent, using appropriate machines. The tablets may optionally be coated or ledge, and can be retseptoriani so as to provide slow or controlled release of the active ingredient of this pill.

Formulations for parenteral administration are aqueous or non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic factors and soluble substances that give the recipe isotonicity with the blood of the patient; aqueous or non-aqueous sterile suspensions, which may contain suspendresume agents and thickeners. Such formulations can be presented in the form of packages at one time or in several doses, for example in the form of sealed ampoules or vials, and may be stored in lyophilized form to add immediately before the introduction of the sterile liquid carrier, napamahal to be prepared from sterile powders, granules and tablets described above.

Formulations for rectal injection are candles on the basis of the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for local administration through the mouth, for example podmecheno or sublingual include pellet, containing the active ingredient in Corrientes basis such as sucrose and the Arabian gum or tragakant, or tablets containing the active ingredient in such manner as gelatin and glycerin or sucrose and Arabian gum.

Preferred formulations with standard dose are formulations containing an effective dose of the active ingredient, which will be shown below, or its appropriate part.

It should be understood that in addition to the ingredients listed above, formulations of the present invention may include other agents conventional in this field based on the type of the considered formulations, such as agents that can be used for oral introduction include agents that alter the taste and smell of the drug.

Compounds of the present invention can be administered orally or by injection in doses of from 0.1 to 500 mg/kg / day. For Usrednenie dose usually can contain a number of compounds of the present invention, which is effective at such dosage or multiple of the dose (for example, tablets containing 5-500 mg, usually 10-100 mg).

The amount of active ingredient that may be mixed with the material of the carrier for receiving standard dosing forms will vary depending on the recipient, and the particular method of administration.

It should be understood that the specific level of dosage for any particular patient will depend on many factors, including the activity of the specific compound, the age, weight, General health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease.

As used in this description, the term "lower alkyl", single or in combination with other terms, refers to an acyclic alkyl, the radical that contains from 1 to about 10, preferably from 1 to about 8 carbon atoms, and most preferably from 1 to about 6 carbon atoms. Examples of such radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, Pew hydrocarbon radical, because it contains at least one double bond. Such radicals contain from about 2 to 10 carbon atoms, preferably from about 2 to 8 carbon atoms, and most preferably from about 2 to 6 carbon atoms. Examples of suitable alkenyl radicals are propylene, butene-1-yl, isobutyl, penten-1-yl, 2-methylbutan-1-yl, 3-methylbutan-1-yl, HEXEN-1-yl, hepten-1-yl, octene-1-yl, etc.

The term "lower quinil" refers to an unsaturated acyclic hydrocarbon radicals, because they contain one or more triple bonds. Such radicals contain from about 2 to 10 carbon atoms, preferably from about 2 to 8 carbon atoms, and most preferably from about 2 to 6 carbon atoms. Examples of suitable etkinlik radicals are ethinyl, PROPYNYL, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutan-1-yl, hexyne-1-yl, - hexyne-2-yl, - hexyne - 3-yl, 3,3-dimethyl-butyn-1-yl, etc.

The term "alicyclic hydrocarbon" means an alicyclic radicals containing in the ring from 3 to about 10 carbon atoms, preferably from 3 to about 6 carbon atoms. Examples of such alicyclic the, cyclohexyl, etc.

The term "aromatic hydrocarbon radical" refers to a radical containing from 4 to about 16 carbon atoms, preferably from 6 to 12 carbon atoms, most preferably from 6 to about 10 carbon atoms. Examples of such aromatic hydrocarbon radicals are phenyl, naphthyl, etc.

The notion of "acyloxy" refers to the Deputy containing from 1 to about 4 carbon atoms. Examples are alkanoyloxy group, benzoyloxy group and the like groups.

The term "heterocyclic radical" refers to saturated or unsaturated cyclic hydrocarbon radical containing from 4 to about 10 carbon atoms, preferably approximately from 5 to 6 carbon atoms, where from 1 to 3 carbon atoms substituted by nitrogen atoms, oxygen or sulfur. "Heterocyclic radical" may be condensed with an aromatic hydrocarbon radical. Examples of the respective radicals are pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolyl, 3-pyrrolyl, pyrrolidinyl, 1,3-DIOXOLANYL, 2-imides is poured, 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 "lower alkoxy group", single or in combination, means the residue Olkiluoto ether, where the term "alkyl" defined above, and most preferably contains from 1 to about 4 carbon atoms. Examples of suitable residues alilovic esters are methoxy, ethoxy-, n-propoxy, isopropoxy, h-butoxy, isobutoxy-, sec.-butoxy-, tert.-butoxy groups, etc.

The term "lower dialkoxy group" means the same as "alkoxy group", except that instead of the oxygen atom is a sulfur atom.

The term "halogen atom" means fluorine atoms, chlorine, bromine and iodine.

The concept of "halogenated" means the lower alkyl defined above, containing 1-5, preferably 1-3 halogen atom associated with the specified lower alkyl chain.

The term "prodrug" means a compound that is more active in vivo.

As used in this description, the term "treating" a patient also includes the prevention of illness is the W as a reference material.

Schemes I-IV reactions illustrate the present invention (see end of text).

Example 1. Hydrochloride of 2-imino-heptamethylnonane

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Into the flask to 50 ml add 5 g (0.04 mol) of 2-oxoethylidene and 15 ml of benzene. The mixture with stirring, boil and added dropwise 4.8 g (0.038 mole) of dimethylsulfate. At the end of the addition the reaction mass is boiled with stirring for 18 hours. The heating is stopped, the reaction mixture was diluted with ethyl acetate (EtOAc) and washed with an aqueous solution of potassium carbonate (K2CO3) (X ml). The organic layer is dried with magnesium sulfate (MgSO4), filtered and concentrated receive 4,2 g aminoether in the form of a yellow oil. In 50 ml of anhydrous ethanol was dissolved 2.2 g (0.016 mole) of aminoether and add 0.85 grams (0.016 mole) of ammonium chloride. The resulting mixture is stirred at a temperature of 25oC for 3 days. The solvent is evaporated in vacuum, obtain 1.7 g (48%) of the hydrochloride of 2-imino - heptamethylnonane in the form of a white solid. So pl. 166 - 175oC. Mass spectrum: MH+=127.

Elemental analysis. Calculated, %: C, 50.30; H, 9.35; N, 16.76; C7H14N2HCl1/4H2O. Found, %: C, 49.95; H, 9.22; N 17.12.

Example 2. Hydrochloride of 2-imino-octamethylene

4filter and concentrate, get 4.4 g of aminoether in the form of a yellow oil. Iminoethyl dissolved in 50 ml of anhydrous ethanol and added 1.5 g (0.028 mole) of ammonium chloride. The mixture is stirred at a temperature of 25oC for 6 days. The solvent is evaporated in vacuum, get 2,75 g (45%) of the hydrochloride of 2-imino-octamethylene in the form of a white solid. So pl. 108-128oC.

Mass spectrum: MH+=141.

Elemental analysis. Calculated, %: C, 52.77; H, 9.74; N, 15.35; C8H16N2HCl 1/3H2O. Found, %: C, 53.05; H, 9.41; N 14.98.

Example 3. Hydrochloride 3,4,5,6,7, 8-hexa - hydro-2[1H]-chinaindia

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The mixture 3,4,5,6,7,8-hexahydro-2[1H] -quinoline (3.0 g, 20 mmol), 2,4-disulfide 2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4 - diphosphate (4.0 g, 10 mmol) and 100 ml of toluene is stirred and refluxed for 3 hours. The dark brown solution is cooled to room temperature and filtered. The filtrate is evaporated on a rotary evaporator. The residue is dissolved in METI thioamides, identified mass spectrometrically, combined and evaporated. The remainder (of 0.38 g, 2.3 mmole) is treated with iodine stands (0.36 g, 2.6 mmole) in acetone at 20oC for 4 hours. After evaporation on a rotary evaporator the residue is washed several times with ether (Et2O). The resulting residue is treated with ethanol saturated with ammonia at 20oC for 12 hours. After evaporation the residue was washed with Et2O and recrystallized from a mixture of EtOH and Et2O. the Product is isolated in the form of a pale yellow solid. The mass spectrum corresponds to the proposed structure.

MH+=to 150.1; so pl. 150-155oC.

Example 4.Hydrochloride of 2-imino-3-methyl-tetramethylaniline

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A named connection receive according to the method of example 3. 3-Methyl-2 - pyrrolidine (5.0 g, 50 mmol) in turn thioamide, which reacts with iodide stands with subsequent treatment with ethyl alcohol saturated with ammonia. The product is isolated in the form of a white amorphous solid, mass spectrum corresponds to the proposed structure.

MH+=98,4; so pl. 73-75oC.

Example 5. Hydrochloride of 2-imino-5-methyl-tetramethylaniline

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For the conversion of 5-methyl-2-pyrrolidone in a named connection, kotoraya. The mass spectrum of the product complies with the proposed structure.

MH+=98,4; so pl. 83-85oC.

Example 6. Acetate 2-imino-4-methylpiperidine

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A mixture of 2-amino-4-methylpyridine (1.56 g, 15 mmol) and 5%on rhodium coal (0.51 g, wet Degussa type G10) in glacial acetic acid (30 ml) was shaken over night in the apparatus Parr hydrogenation at hydrogen pressure of 55 lbs/inch2(3,74 ATM). The catalyst is filtered off, the filtrate is diluted with water to 250 ml and lyophilizers. Get a light yellowish-brown powder, which was recrystallized from a mixture of warm ethanol/ether, to obtain 0.3 g of a white solid substance, so pl. 180 - 182oC, Receive the second portion of the white solid (0.85 grams), so pl. 180-182oC.

Mass spectrum: MH+=113.

Range of TMR (D2O) : 3.32-3.16 (m, 2H), 2.54-2.46 (m, 1H), 2.10-2.00 (m, 1H), 1.80-1.70 (m, 2H), 1.74 (s, 3H), 1.32-1.25 (m, 1H), 0.87 (d, J=6.6 Hz, 3H).

Elemental analysis: C6H12N2CH3COOH

Calculated, %: C, 55.79; H, 9.36;

Found, %: C, 55.85; H, 9.22.

Example 7. Acetate 2-imino-5-methylpiperidine

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For the conversion of 2-amino-5-methylpyridine in a named connection, which is obtained in the form of a white solid, using the method of obtaining the acetate. So pl. 175-178oC.

Mass spectrum: MH+=113.

Range of TMR (D2O) : 3.28-3.21 (m, 1H), 2.79-2.70 (m, 1H), 2.49-2.43 (m, 2H), 1.79-1.67 (m, 2H), 1.73 (c, 3H), 1.30-1.23 (m, 1H), 0.82 (d, J=6.6 Hz, 3H).

Elemental analysis: C6H12N2CH3COOH

Calculated, %: C, 55.79; H, 9.36

Found, %: C, 55.81; H, 9.39

Example 8. Hydrochloride of 2-imino-6-methyl-piperidine

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For the conversion of 2-amino-6-methylpyridine in a named connection, which is obtained in the form of a white solid, using the method of producing acetate 2-imino-4-methylpiperidine, example 6. Data analysis of the product shows its compliance with the proposed structure. So pl. 160-162oC.

Mass spectrum: MH+=113.

Range of TMR (D2O) : 3.58-3.40 (m, 1H), 2.60-2.35 (m, 2H), 1.95-1.70 (m, 2H), 1.68-1.50 (m, 1H), 1.40-1.35 (m, 1H), 1.05 (d, J=6.6 Hz, 3H).

Elemental analysis: C6H12N2HCl

Calculated, %: C, 48.49; H, 8.82; N 18.85;

Found, %: C, 48.32; H, 9.01; N 18.70.

Example 9. Acetate 2-imino-3-methylpiperidine

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For the conversion of 2-amino-6-methylpyridine in a named connection, which is obtained in the form of a white solid, using the method of producing acetate 2-imino-3-methylpiperidine, example 6. Data analysis of the product shows its conformity >) : 3.22-3.15 (m, 2H), 2.67-2.55 (m, 1H), 1.80-1.40 (m, 4H), 1.75 (s, 3H), 1.17 (d, J=7.2 Hz, 3H).

Elemental analysis: C6H12N2CH3COOH 3/4H2O;

Calculated, %: C, 51.73, H 9.50, N 15.08;

Found, %: C, 51.87, H 9.29, N 15.04.

Example 10. Acetate 2-imino-4,6-dimethyl-piperidine

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For the conversion of 2-amino-4,6-dimethylpyridine in a named connection, which is obtained in the form of a white solid, using the method of producing acetate 2-imino-3-methylpiperidine, example 6. Data analysis of the product shows its compliance with the proposed structure. So pl. 163-166oC.

Mass spectrum: MH+=127.

Range of TMR (D2O) : 3.48-3.40 (m, 1H), 2.52-2.40 (m, 1H), 2.07-1.95 (m, 1H), 1.85-1.75 (m, 2H), 1.75 (s, 3H), 1.12 (d, J= 6.3 Hz, 3H), 1.02-0.92 (m, 1H), 0.86 (d, J=6.3 Hz, 3H).

Elemental analysis: C7H14N2CH3COOH;

Calculated, %: C, 58.04, H 9.74, N 15.04;

Found, %: C, 57.86, H 10.09, N 15.01.

Example 11. Acetate 2-imino-3-hydroxypiperidine

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For the conversion of 2-amino-3-hydroxypyridine in a named connection, which is obtained in the form of a white solid, using the method of producing acetate 2-imino-3-methylpiperidine, example 6. Data analyses show that the product meets the proposed structure. So pl. 128-130o

Elemental analysis; C7H10N20CH3COOH;

Calculated, %: C, 48.27, H 8.10, N 16.08;

Found, %: C 48.04, H 8.48, N 15.96.

Additional compounds of the present invention are:

Example 12. Hydrochloride 2-aminopyrrolidine E. J. Moriconi and A. A. Cevaso, J. Org, Chem., 33, 2109-2111 (1968).

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Example 13. Hydrochloride of 2-aminopiperidine Aldrich Chemical Co.

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Example 14. Polyhydroxylated 2-imino-tetrahydropyrimidine D. J. Brown. and R. F. Evans, J. Chem. Soc., 4039-4045 (1962)

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Example 15. 2-Iminoimidazolidine D. Stefanye and W. C. Howard, J. Amer. Chem. Soc., 77, 761-762 (1955).

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Example 16. Hydrochloride 2-aminothiazoline Aldrich Chemical Co.

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Example 17. Hydrochloride of 2-imino-3-thepipeline D. L. Klayman and T. S. Woods, J. Org. Chem., 39, 1819-1823 (1974).

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Example 18. Hydrochloride of 2-imino-3-oxo-piperidine B. Adcock and A. Lawson, J. Chem. Soc., 474-479 (1965)

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Example 19. 2-Iminoimidazolidine, Transworld Chemical Inc.

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Example 20. 5-Chloromethyl-2-iminoimidazolidine, Janssen Chinica.

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Example 21. 2-Iminobiotin, Sigma Chemical Co.

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Example 22. Ethyl ester of 2-iminobiotin

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Example 23. 1-Methyl-2-aminomethylpyrimidine, GER 765547

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Example 24. The oxime 4-ethylcyclohexane (intermediate compound)

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(Mus) in a mixture of ethanol (EtOH, 35 ml) and water (25 ml). The resulting mixture is boiled for 5 hours in nitrogen atmosphere. After cooling to room temperature, stirred for another 5 days, all solvent is evaporated under reduced pressure. The residue is distributed between ethyl acetate (EtOAc) and water, the organic phase is washed with saturated NaCl solution (brine) (g ml), dried with Na2SO4and vacuum evaporated solvent. Obtain 5.5 g (100%) of the named compound as a yellow mobile oil. This product has a retention time of 9.83 min (100% purity according to the total peak area) with gas chromatography (GC) Shimadzu GC-14A with column 0.25 mm x 25 m, methyl-, 5% penicilian, NMR and IR spectra correspond to the proposed structure.

Elemental analysis: C8H15NO H2O (molecular weight 159.23);

Calculated, %: C, 60.35, H 10.76, N, 8.80;

Found, %; C 60.64, H 9.25, N 8.41.

Example 25. 5-Ethyl-hexahydro-1H-azepin-2-he (intermediate compound)

< / BR>
The compound of example 24 (5,3 g, 37.7 mmole) was placed in an addition funnel containing 6 ml of 80% H2SO4. Obtained after stirring the mixture in the form of a turbid solution is added dropwise (over 10 min) to 5 ml of 80% H2SO4mixed with the magnet which is heat, and the reaction temperature is increased to 160oC, and then decreases again to 120oC. After 10 minutes, the flask is removed from the bath and allowed to cool to room temperature. The resulting mixture was diluted with water (20 ml) and with concentrated NH4OH bring the pH of the mixture to 6. Then the solution was diluted with 75 ml of water and extracted with methylene chloride (CH ml). The combined organic phases are washed with brine (CH ml), dried (Na2SO4), filtered and vacuum the solvent is distilled off completely. The oily residue is purified using HPLC (high performance liquid chromatography) on silica gel, get to 3.73 g (70%) of the named compound in the form of a cream solid color. When H.H. the product has a retention time 13,17 minutes and the peak area 100% under conditions identical to the conditions used for the product of example 24.

Elemental analysis: C8H15NO 0,05 H2O (molecular weight 142,12);

Calculated, %: C, 67.61, H 10.71, N, 9.86;

Found, %: C 67.47, H 10.67, N, 9.90.

Example 26. 4-Ethyl-3,4,5, 6-tetrahydro - 7-methoxy-2H-azepin (intermediate compound)

< / BR>
To a suspension of tetrafluoroborate trimethylhexane (Lancaster, and 0.62 g, 4.2 mmole) in CH2Cl2(15 ml) in an atmosphere of argon (Ar) and under stirring with a magnetic stirrer type connection which should then diluted with 10 ml of CH2Cl2and partitioned between 40 ml of saturated KHCO3and 50 ml EtOAc. The organic phase is separated, dried with Na2SO4filter and vacuum the solvent is distilled off completely, get a named connection in the form of a pale yellow oil. The resulting product is subjected to rapid chromatography on a special column of the firm Merckh silica gel (eluent EtOAc: n-hexane, 1: 1). Named pale yellow liquid product when GC has a retention time of 8.56 minutes (100%). The NMR and IR spectra were consistent with the indicated structure.

Example 27. Monohydrochloride 5-ethyl-hexahydro-1H-azepin-2-imine

< / BR>
The compound of example 26 (0,28 r, 1.80 mmole) and 0.11 g (2.0 mmole) of ammonium chloride (NH4Cl) is boiled in 20 ml of methanol (MeOH) in a nitrogen atmosphere for 3.5 hours. After cooling the reaction mixture to room temperature it is filtered in vacuum, the solvent is distilled off and the resulting residue partitioned between 20 ml of water and 25 ml of EtOAc. The organic and aqueous phases are separated and the aqueous phase is washed with 25 ml EtOAc, then lyophilizer, allocate 0.27 g (80%) of the named compound as a white solid.

The mass spectrum of high resolution (electron impact): calculated m/e= 140.131 (C8H16N2), found m/e=140.131.

Elemental analysis: C8H16N2HCl of 0.1 H2O 0,2 NH4Cl (molecular weight 189,19).

Calculated, %: C, 50.79, H 9.59, N 16.26, Cl 22.49;

Found, %; C 50.71, H 9.48, N 16.30, Cl 22.45.

Example 28. The oxime 4-phenylcyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 4-phenylcyclohexanone (Aldrich, 10.0 g, 57.4 mmole) turns on the named connection using hydroxylamine hydrochloride (6.0 g, 81.1 mmole) and sodium acetate solution (8.5 g, 103.3 mmole) in a mixture of 75 ml of EtOH and 50 ml of water. Obtain 10.2 g (94%) of the claimed compounds in the form of a white solid.

Elemental analysis: C12H15NO (molecular weight 189,26);

Calculated, %: C, 76.16, H 7.99, N 7.40;

Found, %: C, 75.96, H 7.89, N 7.33.

Example 29. Hexahydro-5-phenyl-1H - azepin-2-he (intermediate compound)

< / BR>
To the product of example 28 (9.0 g, 47.6 mmole) in 50 ml of acetone was added 1 n NaOH solution (52,4 ml, 52,4 mmole). The resulting mixture was cooled in an ice bath and with stirring and in a nitrogen atmosphere for 5 minutes is added dropwise benzosulphochloride (8.5 g, 48.0 mmol). The reaction mixture is allowed to warm to room temperature and then stirred for weeks. From the reaction mixture is filtered the white solid is waiting EtOAc and brine. The organic layer is dried (Na2SO4), filtered and vacuum the solvent is distilled off completely. The remaining solid is triturated with a mixture of EtOAc/hexane (1:1) and filtered. Receive an additional 2.9 g (total yield 80%) of these lactam.

Elemental analysis: C12H15NO (molecular weight 189,26);

Calculated, %: C, 76.16, H 7.99, N 7.40;

Found, %: C, 75.95, H 8.16, N, 7.28.

Example 30. 3,4,5,6-Tetrahydro-7-methoxy - 4-phenyl-2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 conduct the reaction between the product of example 26 (2.0 g, 10.5 mmole) and tetrafluoroborate trimethylhexane (2.0 g, 13.6 mmole), gain of 1.9 g (89%) of the named compound.

Elemental analysis: C13H17NO 0.5 H2O (molecular weight 209,23);

Calculated, %: C, 74.63, H 8.51, N 6.69;

Found, %: C At 74.77, H 8.14, N 6.65.

Example 31. Monohydrochloride hexahydro-5-phenyl-1H-azepin-2 - imine

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 30 (1.7 g, 8.6 mmole) in 20 ml MeOH and ammonium chloride (0,43 g, 8.0 mmol), obtain 1.7 g (91%) of the named compound.

The mass spectrum of high resolution (electron impact): calculated m/e= 188,131 (C12H16N2), found m/e=188,133.

Range PMR (CD3OD) : 7. the analysis: C12H16N2HCl 0,33 H2O (molecular weight 230,68)

Calculated, %: C, 62.48, H 7.72, N 12.14, Cl 15.34;

Found, %: C, 62.41, H 7.54, N 12.13, Cl 15.63.

Example 32. The reaction of 3,5-dimethylcyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 3.5 dimethylcyclohexane (Cl, and 22.6 g, 180 mmol) turns on the named connection using hydroxylamine hydrochloride (18.7 g, 270 mmol) and sodium acetate solution (26,6 g, 324 mmol) in a mixture of 200 ml of EtOH and 150 ml of water. Obtain 23.1 g (94%) of the named compound as a white solid.

Elemental analysis: C8H15NO 0,1 H2O (molecular weight 143,02);

Calculated, %: C, 67.19, H 10.71, N 9.79;

Found, %: C 67.37, H 10.52, N 9.79.

Example 33. Hexahydro-4,6-dimethyl-1H - azepin-2-he (intermediate compound)

< / BR>
According to the method of example 25, the product of example 32 (10.0 g, 69.9 mmole) turn to the named compound as a mixture of two diastereoisomeric pairs, using 22 ml of 80% H2SO4. Get 8,4 g (85%) of the named compound as a pale yellow sticky solid.

Elemental analysis: C8H15NO (molecular weight 141,21);

Calculated, %: C, 68.04, H 10.71, N, 9.92;

Found, %: C, 67.92, H 10.04, N 9.83.

Example 34. 3,4,5,6-Tetrahydro-7-MDU product of example 33 (2.0 g, 14.2 mmole) and tetrafluoroborate trimethylhexane (2.7 g, an 18.4 mmole), gain of 1.9 g (73%) of the named compound.

Elemental analysis: C9H17NO 0,125 H2O (molecular weight 157,49);

Calculated, %: C, 68.64, H 11.04, N, 8.89;

Found, %: C, 68.66, H 11.14, N 8.87.

Example 35. Monohydrochloride hexahydro-4,6-dimethyl-1H-azepin-2 - imine

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 34 (1.75 g, 8.6 mmole) in 25 ml MeOH and ammonium chloride (0,48 g, 9.0 mmol), obtain 1.4 g (83%) of the named compound.

The mass spectrum of high resolution (electron impact):

calculated m/e=140,131 (C8H16N2), found m/e=140,130.

Range PMR (CD3OD) : 3.26-3.18 (m, 1H), 2.42 (m, 1H), 1.91 (m, 1H), 1.85-1.62 (m, 2H), 1.09 (d, 3H, J=6.8 Hz), 0.95 (d, 3H, J=6.8 Hz).

Elemental analysis: C8H16N2HCl 0,25 H2O (molecular weight 181,195);

Calculated, %: C, 53.03, H 9.74, 15.46 N, Cl 19.57;

Found, %: C, 53.19, H 9.85, N 15.46, Cl 19.26.

Example 36. The reaction of 2,6-dimethylcyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 turn 2,6-dimethylcyclohexanone (Aldrich, 20,0 g, 158,5 mmole) in a named connection, using hydroxylamine hydrochloride (16.5 g, 237,6 mmole) and sodium acetate (23,4 g, 285,1 mmole) in a mixture of 150 m is SS="ptx2">

Elemental analysis: C8H15NO 0,25 H2O (molecular weight 145,72);

Calculated, %: C, 65.94, H 10.72, N, 9.61;

Found, %: C, 65.74, 10.45 H, N 9.67.

Example 37. Hexahydro-3,7-dimethyl-1H - azepin-2-he (intermediate compound)

Diastereomer pair and diastereomer pair IN

< / BR>
According to the method of example 25 turn the product of example 36 (8,14 g, and 57.6 mmole) of the above mixture of two diastereoisomeric pairs, using 15 ml of 80% H2SO4. Two diastereomeric pair share when chromatographicaliy on silica gel normal phase, eluent 3-10% isopropanol/n-heptane. Gain of 3.3 g (41%) of these diastereomeric pair A, which is washed from the column first, and 1.05 g (13%) diastereomeric pair, which is washed with the second column, the two couples were allocated in the form of white solids.

The enantiomeric pair A:

Elemental analysis: C8H15NO 0,05 H2O (molecular weight 142,12)

Calculated, %: C, 67.61, H 10.71, N, 9.86;

Found, %: C, 67.83, H 10.71, N, 9.87.

The enantiomeric pair IN:

Elemental analysis: C8H15NO (molecular weight 141,214)

Calculated, %: C, 68.04, H 10.71, N, 9.92;

Found, %: C, 68.94, H 10.88, N, 9.43.

Example 38. 3,4,5,6-Tetrahydro-7-methoxy - 2,6-dimethyl-2H-azepin (Intermediate soparo And example 37 (2.0 g, a 14.1 mmole) and tetrafluoroborate trimethylhexane (2.7 g, an 18.4 mmole), gain of 1.9 g (86%) of the titled compound in the form of a transparent volatile liquid.

Example 39. Monohydrochloride hexahydro-3,7 - dimethyl-1H-azepin-2-imine

The enantiomeric pair AND

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 38 (1.24 g, 8.0 mmol) in 25 ml MeOH and ammonium chloride (0,37 g, 6.8 mmole), gain of 1.23 g (91%) of the named compound.

The mass spectrum of high resolution (electron impact):

calculated m/e=140,131 (C8H16N2), found m/e=140 (100%).

Range PMR (CD3OD) 3.89-3.79 (m, 1H), 3.10-3.00 (m, 1H), 1.98-1.90 (m, 1H), 1.87-of 1.75 (m, 3H), 1.54-1.32 (m, 2H), 1.32 (d, J=6,7 Hz, 3H), 1.26 (d, J=7.0 Hz, 3H).

Elemental analysis: C8H16N2HCl 0,125 H2O 0,05 NH4Cl (molecular weight 181,62);

Calculated, %: C, 52.91, H 9.68, N 15.81, Cl 20.50;

Found, %: C, 52.89, H 9.63, N 15.49, Cl 20.76.

Example 40. 3,4,5,6-Tetrahydro-7-methoxy - 2,6-dimethyl-2H-azepin (intermediate compound)

The enantiomeric pair IN

< / BR>
According to the method of example 26 conduct the reaction between the enantiomeric pair In example 37 (510 mg, 3.6 mmole) and tetrafluoroborate trimethylhexane (694 mg, 4.7 mmole), receive 489 mg (86%) of the titled compound in the form of a transparent flying.

The enantiomeric pair IN

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 40 (380 mg, 2.4 mmole) in a mixture of 15 ml of MeOH and 5 ml of CH2Cl2and ammonium chloride (104 mg, 2.0 mmole), receive 368 mg (100%) of the claimed compounds.

Mass spectrum (electron impact): calculated m/e=140,131 (C8H16N2found m/e=140,132 (100%).

Range PMR (CD3OD) : 3.85 (m, 1H), 3.00 (m, 1H), 1.95-1.70 (m, 5H), 1.42 (m, 1H), 1.40 (d, J=7 Hz, 3H), 1.30 (d, J=6 Hz, 3H)

Elemental analysis: C8H16N2HCl of 0.1 H2O 0,1 NH4Cl (molecular weight 183,84);

Calculated, %: C 52.27, H 9.65, 16.00 N, Cl 21.21;

Found, %: C, 52.44, H 10.16, N 15.85, Cl 21.23.

Example 42. The reaction of 2-methylcyclohexanone series (intermediate compound)

< / BR>
According to the method of example 24 turn 3,5-dimethylcyclohexanone (Aldrich, 11.2 g, 100.0 mmol) named in connection with the use of hydroxylamine hydrochloride (13,9 g, 200 mmol) and sodium acetate (17,2 g, 210 mmol) in a mixture of 160 ml of EtOH and 160 ml of water. Get the 10.1 g (79%) of the named compound as a white solid.

Example 43. A mixture of hexahydro-3-methyl-1H-azepine-2-it hexahydro-7-methyl-1H-azepin-2-one (intermediate compound)

< / BR>
Isomer And Isomer IN

According to the method of example 25, the product of example 42 (g (62%) of the claimed compounds. The mixture chromatographic on silica gel (eluent 3-7% isopropanol/n-heptane), get isomer A (525 mg) and isomer B (735 mg).

Example 44. 3,4,5,6-Tetrahydro-7-methoxy - 6-methyl-2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 conduct the reaction between the isomer a of example 43 (511 mg, 4.1 mmole) and tetrafluoroborate trimethylhexane (227 mg, 5.5 mmole). After chromatography was carried out get 505 mg (87%) of the named compound.

Example 45. 3,4,5,6-Tetrahydro-7-methoxy - 2-methyl-2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 conduct the reaction between the isomer In example 43 (762 mg, 6.0 mmol) and tetrafluoroborate trimethylhexane (1,15 g of 7.8 mmole). After chromatography was carried out obtain 780 mg (92%) of the named compound.

Example 46. Monohydrochloride hexahydro-3 - methyl-1H-azepin-2-imine (intermediate compound)

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 44 (294 mg, 2.1 mmole) in 14.5 ml of MeOH and ammonium chloride (103 mg, 2.0 mmole), obtain 260 mg (77%) of the named compound.

Mass spectrum (electron impact): calculated m/e=126,116 (C7H14N2), found m/e=126 (100%).

Range PMR (CD3OD) : 3.51-3.42 (m, 2H), 3.06-3.00 (m, 1H), 1.99-1.93 (m, 1H), 1.82-1.73 (m, 3H), 1.61-1.50 (m, 2H), 1.30 (DCCA 171,62);

Calculated, %: C, 48.99, H 9.28, N 17.14, Cl 22.72;

Found, %: C, 48.95, H 9.60, N 17.29, Cl 22.59.

Example 47. Monohydrochloride hexahydro-7 - methyl-1H-azepin-2-imine (intermediate compound)

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 45 (125 mg, of 0.89 mmole) in 9.0 ml of MeOH and ammonium chloride (to 44.0 mg, or 0.83 mmole), obtain 101 mg (63%) of the named compound.

The mass spectrum of high resolution (electron impact): calculated m/e= 126.116 (C7H14N2), found m/e=126 (100%).

Range PMR (CD3OD) : 3.77 (m, 1H), 2.77 (DDD, 1H), 2.62 (m, 1H), 2.03-1.95 (m, 2H), 1.84 (m, 1H), 1.7 (m, 3H), 1.51-1.35 (m, 2H), 1.32 (d, J= 6,84 Hz, 3H).

Elemental analysis: C7H14N2HCl 0,33 H2O 0,21 NH4Cl (molecular weight 179,84);

Calculated, %: C at 46.75, H 9.25, N 17.21, Cl at 23.85;

Found, %: C 46.53, 9.45 H, N 17.29, Cl 24.25.

Example 48. The oxime 3-(trifluoromethyl)cyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 turn 3-cryptometrics (Aldrich., 3,3 g, 20.0 mmol) in a named connection, using hydroxylamine hydrochloride (2.8 g, 40.0 mmol) and sodium acetate (3.4 g, 42,0 mmole) in a mixture of 30 ml of EtOH and 30 ml of water. Obtain 2.9 g (80%) of the named compound as a white solid.

Example 49. The mixture exag>/BR>< / BR>
According to the method of example 25 turn the product of example 48 (2.3 g, 12.5 mmol) of the above mixture of two isomers position using 4 ml of 80% H2SO4. Receive 795 mg (36%) of the above mentioned compounds. A mixture containing 80% isomer A, is subjected to obremenitve HPLC (eluent acetonitrile/water), only give isomer A (330 mg).

Example 50. A mixture of hexahydro-4-(trifluoromethyl)-1H - azepin-2-he with hexahydro-6- (trifluoromethyl) -1H - azepin-2-one (intermediate compound)

< / BR>
With stirring, added dropwise 3-trifluoromethyl cyclohexanone (Aldrich, 1.7 g, 10.0 mmol) to a mixture of 12 ml of concentrated H2SO4and 4 ml of CH2Cl2. To the obtained mixture at 0 to 10oC in several portions over 1 hour add sodium azide (0.8 g, 0.12 mmole). After heating to room temperature and stirring overnight the reaction was poured into 50 ml ice water and the mixture extracted with CHCl3(50 ml). The organic layer was washed with water, dried with sodium sulfate (Na2SO4), filtered and evaporated. Get called a mixture containing 63% of the isomer C. the resulting product is subjected to obremenitve HPLC (eluent acetonitrile/water), to mention only the isomer In (438 mg).

Example 51. 3,4,5,6-Tetrahydro-7 is tion between the isomer a of example 49 (457 mg, 2.5 mmole) and tetrafluoroborate trimethylhexane (484 mg, 3.3 mmole). After chromatography was carried out obtain 430 mg (87%) of the named compound.

Example 52. 3,4,5,6-Tetrahydro-7-methoxy-3-(trifluoromethyl) - 2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 reaction between the isomer In Primera (350 mg, 1.9 mmole) and tetrafluoroborate trimethylhexane (371 mg, 2.5 mmole). After chromatography was carried out obtain 280 mg (76%) of the named compound.

Example 53. Monohydrochloride hexahydro-4-(trifluoromethyl)-1H - azepin-2-imine

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 51 (240 mg, 1.2 mmole) in 7.0 ml of MeOH and ammonium chloride (66,0 mg, 1.2 mmole), obtain 265 mg (94%) of the named compound.

The mass spectrum of high resolution (electron impact): calculated m/e= 180,087 (C7H11N2F3), found m/e=180,087.

Range PMR (CD3OD) : 1.63 (m, 1H), 1.79 (m, 1H), 1.99 (m, 1H), 2.22 (m, 1H), 2.63 (m, 1H), 2.86 (dt,1H), 2.98 (DD,1H), 3.42 - 3.46 (m, 2H).

Elemental analysis: C7H11N2F3HCl 0,125 H2O 0,2 NH4Cl (molecular weight 229,59);

Calculated, %: C 36.62, H 5.73, N 13.42, Cl at 18.53;

Found, %: C 36.93, H 5.51, N 13.19, Cl 18.41.

Example 54. Monohydrochloride hexahydro-6-(trifluoromethyl)-1H - azepin-2-the chloride of ammonium (21,0 mg, to 0.39 mmole) obtain 83 mg (94%) of the named compound.

The mass spectrum of high resolution (electron impact): calculated m/e= 180,087 (C7H11N2F3), found m/e=180,087.

Range PMR (CD3OD) : 3.7 (m, 1H), 3.57-3.66 (m, 1H), 2.85

(DDD, 1H), 2.75 (DDD, 1H), 2.53 (m, 1H), 2.2 (m, 1H), 2.1 (m, 1H), 1.84 (m, 1H), 1.70 (m, 1H).

Elemental analysis: C7H11N2F3HCl 0,2 H2O + 0,1 NH4Cl (molecular weight 225,59)

Calculated, %: C 37.27, H 5.72, N 13.04, Cl at 17.27;

Found, %; C 37.21, H 5.47, N 12.72, Cl 16.93.

Example 55. The reaction of 2-ethylcyclohexane (intermediate compound)

< / BR>
According to the method of example 24 2-ethylcyclohexane (Pfaltz &Bauer, 9.5 g, 75.0 mmol) turns on the named connection using hydroxylamine hydrochloride (10.4 g, 150 mmol) and sodium acetate (12,6 g 153,7 mmole) in a mixture of EtOH and water (120 ml each. Gain of 9.8 g (93%) of the named compound as a white solid.

Example 56. A mixture of 7-ethyl-hexahydro-1H-azepin-2-one with 3-ethyl - hexahydro-1H-azepin-2-one (intermediate compound)

< / BR>
According to the method of example 25, the product of example 55 (4.9 g, 34.3 mmole) in turn named a mixture of two isomers position, using 11 ml of 80% H2SO4. Obtain 7.2 g (73%) of the above mentioned compounds in ASS="ptx2">

Example 57. 2-Ethyl-3,4,5,6-tetrahydro-7 - methoxy-2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 conduct the reaction between the isomer a of example 56 (938 mg, 6,55 mmole) and tetrafluoroborate trimethylhexane (1.28 g, 8.6 mmole), after chromatography was carried out receive 802 mg (78%) of the named compound.

Example 58. 6-Ethyl-3,4,5,6-tetrahydro-7 - methoxy-2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 conduct the reaction between the isomer In example 56 (700 mg, 5.0 mmol) and tetrafluoroborate trimethylhexane (955 mg, 6.4 mmole), after chromatography was carried out receive 613 mg (89%) of the named compound.

Example 59. Monohydrochloride 7-ethyl-hexahydro-1H-azepin-2-imine

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 57 (802 mg, 5.2 mmole) in 15 ml MeOH and ammonium chloride (225 mg, 4.2 mmole), receive 627 mg (82%) of the named compound.

The mass spectrum of high resolution (electron impact): calculated m/e= 140,131 (C8H16N2), found m/e=140,131.

Range PMR (CD3OD) : 3.57-3.51 (m, 1H), 2.82-2.75 (m, 1H), 2.65-2.60 (m, 1H), 2.03-1.97 (m, 2H), 1.89-1.83 (m, 1H), 1.72-1.62 (m, 3H), 1.54-1.47 (m, 1H), 1.41 to 1.32 (m, 1H), 1.05-1.01 (t, J=7.45 Hz, 3H).

Elemental analysis: C8H16N2HCl of 0.1 H2O 0,01 NH4Cl (mo is for example 60. Monohydrochloride 3-ethyl-hexahydro - 1H-azepin-2-imine

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 58 (600 mg, 3.0 mmole) in 20 ml MeOH and ammonium chloride (165 mg, 3.1 mmole), get 512 mg (93%) of the named compound.

The mass spectrum of high resolution (electron impact): calculated m/e= 140,131 (C8H16N2), found m/e=140,132.

Range PMR (CD3OD) : 3.48-3.30 (m, 2H), 2.76-2.74 (m, 1H), 1.90-1.71 (m, 4H), 1.70-1.64 (m, 4H), 1.05-1.02 (m, 3H).

Elemental analysis: C8H16N2HCl 0,2 H2O 0,01 NH4Cl (molecular weight 180,83)

Calculated, %: C, 53.14, H 9.72, N 15.57, Cl 19.80;

Found, %: C, 52.98, H 10.46, 15.60 N, Cl 20.04.

Example 61. The oxime of 3,3-dimethylcyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 turn 3,3-dimethylcyclohexanone (Wiler, of 18.9 g of 150.0 mmol) in a named connection, using hydroxylamine hydrochloride (20.7 g, 300 mmol) and sodium acetate (25,2 g, 307,5 mmole) in a mixture of 400 ml of EtOH and 400 ml of water. Obtain 16.2 g (77%) of the named compound as a white solid.

Example 62. A mixture of hexahydro-6,6-dimethyl-1H-azepin-2-it hexahydro-4,4-dimethyl-1H-azepin-2-one (intermediate compound)

< / BR>
The product of example 61 (7,1 g, 50.0 mmol) in turn named (87%) of a mixture of the above mentioned compounds in the form of a light brown solid. The mixture is separated using chromatography, obtain 1.4 g of isomer a and 1.8 g of isomer Century

Example 63. 3,4,5,6-Tetrahydro-7-methoxy - 3,3-dimethyl-2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 conduct the reaction between the isomer a of example 62 (985 mg, 7.0 mmol) and tetrafluoroborate trimethylhexane (1.3 g, 9.1 mmole) by the method of example 26. After chromatography was carried out get 525 mg (48%) of the named compound.

Example 64. 3,4,5,6-Tetrahydro-7-methoxy - 5,5-dimethyl-2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 conduct the reaction between the isomer In example 62 (437 mg, 3.1 mmole) and tetrafluoroborate trimethylhexane (573 mg, 3.9 mmole). After chromatography was carried out obtain 265 mg (55%) of the named compound.

Example 65. Monohydrochloride hexahydro-6,6-dimethyl-1H-azepin - 2-imine

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 63 (490 mg, 3.2 mmole) in 18 ml of MeOH and ammonium chloride (125 mg, 2.4 mmole), receive 387 mg (69%) of the named compound.

Mass spectrum (electron impact): calculated m/e=140,131 (C8H16N2), found m/e=140 (100%).

Range PMR (CD3OD) : 5.80 - 5.72 (m, 2H), 5.62-5.58 (m, 2H), 3.2 (s, 2H), 2.68-2.63 (m, 2H), 0.95 (s, 6H).

Elemental analysis: C8H5.17, Cl 19.61.

Example 66. Monohydrochloride hexahydro-4,4-dimethyl-1H-azepin-2 - imine

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 64 (260 mg, 1.7 mmole) in 10 ml EtOH and ammonium chloride (88 mg, 1.7 mmole), obtain 185 mg (55%) of the named compound.

The mass spectrum of high resolution (electron impact): calculated m/e= 140,131 (C8H16N2), found m/e=140,132.

Range PMR (CD3OD) 3.42-3.39 (m, 2H), 2.62 (s, 2H), 1.75-1.65 (m, 4H), 1.07 (s, 6H).

Elemental analysis: C8H16N2HCl 0,2 H2O 0,32 NH4Cl (molecular weight 197,26);

Calculated, %: C, 48.71, H 9.47, N 16.47, Cl at 23.72;

Found, %: C, 48.68, H 9.41, N 16.49, Cl 24.04.

Example 67. The oxime of 4-methylcyclohexanone series (intermediate compound)

< / BR>
According to the method of example 24 4-methylcyclohexanone (Aldrich 5.0 g, 44,6 mmole) turns on the named connection using hydroxylamine hydrochloride (4.6 g, 66,9 mmole) and sodium acetate (6.2 g, 75.8 mmole) in a mixture of 25 ml of EtOH and 25 ml of water. Obtain 4.8 g (84%) of the named compound as a pale yellow oil.

Example 68. Hexahydro-5-methyl-1H-azepin-2-he (intermediate compound)

< / BR>
According to the method of example 25, the product of example 67 (4.0 g, of 31.4 mmole) turn named in connection with ispolzovanie 69. 3,4,5,6-Tetrahydro-7-methoxy - 4-methyl-2H-azepin (intermediate compound)

< / BR>
The product of example 68 (2.5 g, 19.7 mmole), dissolved in 25 ml of benzene, dried by boiling with a nozzle Dean-stark for 30 minutes. To the resulting mixture add dimethylsulfate (1,4 ml, 19.7 mmole) and heated for 17 hours. After cooling to room temperature the reaction mixture was diluted with EtOAc (50 ml) and washed with 50 ml of a saturated solution of NaHCO3. The aqueous layer was extracted with ethyl acetate (CH ml) and the combined organic layers are dried Na2SO4, filtered and the solvent is distilled off completely under reduced pressure to obtain a mixture of two immiscible oils. The upper, lighter phase (1.6 g, 58%) separated, identified as a named connection.

Example 70. Monohydrochloride hexahydro-6 - methyl-1H-azepin-2-imine

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 69 (750 g, 5.3 mmole) in 3 ml of EtOH and ammonium chloride (285 mg, 5.3 mmole) obtain 700 mg (77%) of the named compound.

The mass spectrum of the high-resolution m/z, M+C7H15N2, 127,124.

Range PMR (CD3OD, 400 MHz) : 3.4-3.45 (m, 2H), 2.7-2.8 (m, 1H), 1.6-1.69 (m, 1H), 1.9-2.0 (m, 1H), 1.75-1.89 (m, 2H), 1.14-1.28 (m, 2H), 1.0 (d, J=4.2 Hz, 3H).

H 9.66, N 16.32, Cl 17.56;

Found, %: C, 49.20, H 8.94, N 16.01, Cl 17.24.

Example 71. The oxime 4-cyclohexylcyclohexanes (intermediate compound)

< / BR>
According to the method of example 24 4-cyclohexylcyclohexanes (Bader, 5.0 g, to 27.7 mmole) turns on the named connection using hydroxylamine hydrochloride (2.9 g, to 41.6 mmole) and sodium acetate (3.9 g, 47,1 mmole) in a mixture of 25 ml of EtOH and 25 ml of water. Get 5,3 g (97%) of the named compound as a pale yellow oil.

Example 72. 5-Cyclohexyl-hexahydro-1H - azepin-2-he (intermediate compound)

< / BR>
According to the method of example 25, the product of example 71 (4.5 g, 23,0 mmole) in turn named connection, using 10 ml of 80% H2SO4. After chromatography was carried out obtain 2.1 g (47%) of the named compound as a yellow oil.

Example 73. 4-Cyclohexyl-3,4,5,6-tetrahydro-7-methoxy-2H - azepin (intermediate compound)

< / BR>
According to the method of example 26 conduct the reaction between the product of example 72 and tetrafluoroborate trimethylhexane, get a named connection.

Example 74. Monohydrochloride 5-cyclohexyl-hexahydro-1H-azepin - 2-imine

< / BR>
According to the method of example 27 the product of example 73 in MeOH is treated with ammonium chloride, get a named connection

Example 75. ACS is hexanon (P & In, 3.8 g, 26.9 mmole) turns on the named connection using hydroxylamine hydrochloride (2.8 g, 40,4 mmole) and sodium acetate (3.7 g, 45,7 mmole) in a mixture of 25 ml of EtOH and 25 ml of water. Obtain 4.1 g (100%) of the titled compound as a clear oil.

Example 76. Hexahydro-5-(1-methylethyl)- 1H-azepin-2-he (intermediate compound)

< / BR>
The product of example 75 (3.7 g, and 24.2 mmole) turns on the named compound by the method of example 25 using 10 ml of 80% H2SO4. After chromatography was carried out obtain 2.4 g (63%) of the named compound.

Example 77. 3,4,5,6-Tetrahydro-7-methoxy-4-(1-methylethyl)-2H - azepin (intermediate compound)

< / BR>
According to the method of example 26, the product of example 76 is treated with tetrafluoroborate trimethylhexane, get a named connection.

Example 78. Monohydrochloride hexahydro-5-(1-methylethyl)-1H - azepin-2-imine

< / BR>
According to the method of example 27 the product of example 77 in MeOH is treated with ammonium chloride, get a named connection.

Example 79. The oxime 4-pentylcyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 4-n-pentylcyclohexanone (Cl, 5,2 g, was 31.0 mmol) turns on the named connection using hydroxylamine hydrochloride (3.2 g, 46,7 mmole) and ACET the liquid.

Example 80. Hexahydro-5-pentyl-1H-azepin-2-he (intermediate compound)

< / BR>
According to the method of example 25, the product of example 79 (5.7 g, of 31.4 mmole) in turn named connection, using 20 ml of 80% H2SO4. Obtain 3.7 g (64%) of the named compound as a yellow oil.

Example 81. 3,4,5,6-Tetrahydro-7-methoxy - 4-pentyl-2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 conduct the reaction between the product of example 80 (1.5 mg, 8.2 mmole) and tetrafluoroborate trimethylhexane (1.4 g, 9.8 mmole). After chromatography was carried out obtain 1.1 g (65%) of the named compound.

Example 82. Monohydrochloride hexahydro-5 - pentyl-1H-azepin-2-imine

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 81 (755 mg, 3.8 mmole) in 7.5 ml of EtOH and ammonium chloride (204 mg, 3.8 mmole), receive 643 mg (73%) of the named compound.

The mass spectrum of high resolution (electron impact): calculated m/e= 182,178 (C11H22N2), found m/e=182,179.

Range of TMR (D2O, 400 MHz) : 3.35-3.53 (m, 2H), 2,6-of 2.75 (m, 2H), 1.96-2.04 (m, 1H), 1.85-1.95 (m, 1H), 1.6-1.75 (m, 1H), 1.2-1.4 (m,10H), 0.88 (t, J=4 Hz, 3H).

Elemental analysis: C11H22N21,0HCl0,2H2O0,15NH4Cl (molecular weight 176,69)

Calculated, %: C is-7-methoxy - 2H-azepin (intermediate compound)

< / BR>
According to the method of example 69 carry out the reaction of 4-tert.-butyl caprolactam (Bader, 2.5 g of 14.8 mmole) dimethylsulfate (1,4 ml of 14.8 mmole). After chromatography was carried out obtain 2.7 g of the named compound.

Example 84. Monohydrochloride 5-(1,1-dimethylethyl)-hexahydro-1H - azepin-2-imine

< / BR>
According to the method of example 27 to conduct the reaction between the product of example 83 (2.5 g, of 13.6 mmole) in 50 ml of EtOH and ammonium chloride (730 mg, of 13.6 mmole) obtain 2.2 g (78%) of the named compound.

Range of TMR (D2O, 400 MHz) : 3,5 (DDD, 1H, J=1.87, 6.08, 15.0 Hz), 3.33-3.42 (m, 1H), 2.66-2.71 (m, 2H), 2.13-2.21 (m, 1H), 2.0-2.08 (m, 1H), 1.39 (TT, 1H, J=2.9, 11.9 Hz), 1.15-1.26 (m, 2H), 0.9 (c,9H).

Elemental analysis:C10H20N20,8 HCl 0,125 H2O 0,6 NH4Cl (molecular weight 249,80);

Calculated, %: C, 47.65, H 10.28, 14.45 N, Cl 19.69;

Found, %: C, 47.75, H 9.76, N 14.22, Cl 19.97.

Example 85. The oxime 3R-methylcyclohexanone series (intermediate compound)

< / BR>
According to the method of example 24 R(+)-3-methylcyclohexanone (Aldrich 5.0 g, 44,6 mmole) turns on the named connection using hydroxylamine hydrochloride (4.6 g, 66,9 mmole) and sodium acetate (6.2 g, 75.8 mmole) in a mixture of 25 ml of EtOH and 25 ml of water. Obtain 5.7 g (100%) of the titled compound as a clear oil.

Example 86. A mixture of hexahydro-4R-methyl-1H-asapi the CT of example 85 (5.0 g, 39,3 mmole) in turn named a mixture of two spatial isomers using 10 ml of 80% H2SO4. Obtain 4.3 g of the claimed compounds in the form of a pale yellow oil. The resulting mixture is separated into the individual isomers by chromatography, to obtain 215 mg of isomer a and 318 mg of isomer Century

Example 87. 3,4,5,6-Tetrahydro-7-methoxy - 5R-methyl-2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 the isomer a of example 86 treated with tetrafluoroborate trimethylhexane, get a named connection.

Example 88. 3,4,5,6-Tetrahydro-7-methoxy - 3R-methyl-2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 isomer In example 86 (225 mg, 1.8 mmole) is treated with tetrafluoroborate trimethylhexane (340 mg, 2.3 mmole). After chromatography was carried out get 900 mg of crude titled compound.

Example 89. Monohydrochloride hexahydro-4R,- methyl-1H-azepin-2-imine

< / BR>
According to the method of example 27 the product of example 87 in the Meon treated with ammonium chloride, get a named connection.

Example 90. Monohydrochloride hexahydro-6R - methyl-1H-azepin-2-imine

< / BR>
The product of example 88 (250 ml, 1.8 mmole) in 10 ml of MeOH is treated with ammonium chloride (80 mg, 1.5 mmole) by the method m, 2H), 1.89 - 1.94 (m, 2H), 1.75-1.79 (m, 1H), 1,59-1.66 (m, 1H), 1.44-1.50 (m, 1H), 0.92 (d, J 4.2 Hz, 3H).

Elemental analysis: C7H14N21,0 HCl 0,25 H2O 0,55 NH4Cl (molecular weight 196,60)

Calculated, %: C 42.77, H 9.08, N 18.17, Cl 27.95;

Found, %: C 43.07, H 9.04, N 18.42, Cl 28.37.

Example 91. The reaction of 2-cyclohexylcyclohexanes (intermediate compound)

< / BR>
According to the method of example 24 2-cyclohexylcyclohexanes (Fluka 10.0 g, of 55.5 mmole) turns on the named connection using hydroxylamine hydrochloride (5.8 g, 69,5 mmole) and sodium acetate (7.7 g, 82,0 mmole) in a mixture of 50 ml EtOH and 50 ml of water. Get 11.7 g of crude titled compound as pale yellow oil.

Example 92. A mixture of 3-cyclohexyl-hexahydro-1H-azepin-2-one with 7-cyclohexyl-hexahydro-1H-azepin-2-one (intermediate compound)

< / BR>
According to the method of example 29 the product of example 91 (10.0 g, 51,2 mmole) in turn named a mixture of two spatial isomers using 9,13 g (51,7 mmole) of benzosulfimide. The crude mixture of products triturated with Et2O obtain 4.9 g of the named isomer B. the Filtrate is concentrated and receive a mixture of isomers, predominantly containing isomer A. the Mixture is divided into isomer a and isomer B using chromatography.

Example 93. 6-CEC the EP And example 92 treated with tetrafluoroborate trimethylhexane, get a named connection.

Example 94. 2-Cyclohexyl-3, 4, 5,6-tetrahydro - 7-methoxy-2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 isomer In example 92 (1.50 g, 3.6 mmole) is treated with tetrafluoroborate trimethylhexane (1.48 g, 10.0 mmol), get 0,76 g (48%) of the named compound in the form of a transparent liquid.

Example 95. Monohydrochloride 3-cyclohexyl-hexahydro-1H - azepin-2-imine

< / BR>
The product of example 93 in MeOH is treated with ammonium chloride by the method of example 27, get a named connection.

Example 96. Monohydrochloride 7-cyclohexyl-hexahydro-1H - azepin-2-imine

< / BR>
The product of example 94 (730 mg, 3.45 mmole) in 30 ml of MeOH is treated with ammonium chloride (177 mg, of 3.31 mmole) by the method of example 27, receive 579 mg (75%) of the named compound.

Range PMR (400 MHz, CD3OD) : 3.48-3.41 (DD, J=9.3 Hz,1H), 2.8-2.7 (m, 1H), 2.61-2.54 (m, 1H), 2.0-1.0 (m, 17H).

Elemental analysis: C12H22N21,0 HCl 0,6 H2O 0,01 NH4Cl (molecular weight 241,59)

Calculated, %: C, 59.66, H 10.10, 11.60 N, Cl, 14.67;

Found, %: C, 59.41, H 9.92, N 11.31, Cl 14.83.

Example 97. The reaction of 2-(1,1-dimethylethyl)cyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 2-tert-butylcyclohexanone (cetat sodium (4.5 g, 55,0 mmol) in a mixture of 50 ml EtOH and 50 ml of water. Receive 5.0 g (92%) of the crude titled compound.

Example 98. A mixture of 3-(1,1-Dimethylethyl)-hexahydro-1H-azepin-2 - one with 7-(1,1-dimethylethyl)-hexahydro-1H-azepin-2-one (intermediate compound)

< / BR>
The product of example 97 (4.7 grams of 27.8 mmole) in turn named a mixture of two spatial isomers according to the method of example 25 using 9 ml of 80% H2SO4. Gain of 3.9 g of a mixture of the above mentioned compounds in the form of a yellow solid. The mixture is separated using chromatography, receive 832 mg of isomer And and 2.52 g of isomer Century

Example 99. 6-(1,1-Dimethylethyl)-3,4,5,6-tetrahydro-7-methoxy - 2H-azepin (intermediate compound)

< / BR>
According to the method of example 26 conduct the reaction between the isomer a of example 98 (664 mg, 3.9 mmole) and tetrafluoroborate trimethylhexane (696 mg, 4.7 mmole). After chromatography was carried out receive 654 mg (91%) of the named compound.

Example 100. 2-(1,1-Dimethylethyl)-3,4,5,6-tetrahydro-7-methoxy - 2H-azepin (intermediate compound)

< / BR>
The isomer In example 98 (352 mg, 2.1 mmole) is treated with tetrafluoroborate trimethylhexane (370 mg, 2.5 mmole) by the method of example 26. After chromatography was carried out get a named connection.

Example 101. Monohydrochloride 3-(1,1-delictum ammonia (145 mg, 2.7 mmole) by the method of example 27, obtain 350 mg of the named compound.

Example 102. Monohydrochloride 7-(1,1-dimethylethyl)-hexahydro - 1H-azepin-2-imine

< / BR>
The product of example 100 (174 mg, 1.0 mmole) in 10 ml of EtOH is treated with ammonium chloride (51 mg, 1.0 mmole) by the method of example 27, get a named connection.

Example 103. The reaction of 2-(2-propenyl)cyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 2-allylcyclohexane (Frinton, 2.0 g, 14.5 mmole) turns on the named connection using hydroxylamine hydrochloride (1.5 g, and 21.7 mmole) and sodium acetate (2.0 g, to 24.6 mmole) in a mixture of 25 ml of EtOH and 25 ml of water. Obtain 2.6 g of crude titled compound.

Example 104. A mixture of hexahydro-3-(2-propenyl)-1H-azepin-2-it hexahydro-7-(2-propenyl)-1H-azepin-2-one (intermediate compound)

< / BR>
The product of example 103 (2.0 g, 13.0 mmol) in 15 ml of acetone containing 1 n NaOH solution (to 14.3 ml, 52,4 mmole), treated with benzosulphochloride (2.3 g, 13.1 mmole) by the method of example 29. The crude reaction mixture is divided into isomer a and isomer In using chromatography.

Example 105. 3,4,5,6-Tetrahydro-7-methoxy - 6-(2-propenyl)-2H-azepin (intermediate compound)

< / BR>
The isomer a of example 104 (130 mg, of 0.85 mmole) obrabotca 91 mg (64%) of the named compound.

Example 106. 3,4,5,6-Tetrahydro-7-methoxy - 2-(2-propenyl)-2H-azepin (intermediate compound)

< / BR>
The isomer In example 104 (250 mg, and 1.63 mmole) is treated with tetrafluoroborate trimethylhexane (312 mg, 2,11 mmole) by the method of example 26. After chromatography was carried out obtain 194 mg (71%) of the named compound.

Example 107. Monohydrochloride hexahydro-3-(2-propenyl)-1H - azepin-2-imine

< / BR>
The product of example 105 (90 mg, 0.54 mmole) in 10 ml of MeOH is treated with ammonium chloride (24.5 mg, and 0.46 mmole) by the method of example 27, obtain 68 mg (67%) of the named compound.

Range PMR (300 MHz, CD3OD) : 5.9-5.7 (m, 1H), 5.3-5.1 (m, 2H), 3.6-3.4 (m, 2H), 3.0-2.9 (m, 1H), 2.7-2.5 (m, 1H), 2.45-2.3 (m, 1H), 2.0-1.6 (m, 6H).

Example 108. Monohydrochloride 7-(2-propenyl)-hexahydro-1H - azepin-2-imine

< / BR>
The product of example 106 (70 mg, at 0.42 mmole) in 3 ml MeOH is treated with ammonium chloride (21,4 mg, 0.4 mmole) by the method of example 27, obtain 60 mg (76%) of the named compound.

Range PMR (400 MHz, D2O) : 5.9-5.8 (m, 1H), 5.26-5.19 (m, 2H), 3.79-3.70 (m, 1H), 2.8-2.7 (m, 1H), 2.62-2.56 (m, 1H), 2.42-2.39 (m, 2H), 2.04 - 1.94 (m, 2H), 1.91-1.84 (m, 1H), 1.7-1.6 (m, 1H), 1.56-1.35 (m, 2H).

Elemental analysis: C9H16N21,0 HCl 0,75 H2O 0,05 NH4Cl (molecular weight 204,88).

Calculated, %: C, 52.76, H 9.20, N 14.01, Cl 18.17;

On the BR>< / BR>
According to the method of example 24 2-n-propylcyclohexanone (Farchan, 19,7 g to 140.5 mmole) turns on the named connection using hydroxylamine hydrochloride (14.6 g, 211,0 mmol) and sodium acetate (20,8 g, 252,9 mmole) in a mixture of 150 ml of EtOH and 100 ml of water. Get to 23.4 g of crude titled compound

Example 110. A mixture of hexahydro-3-propyl-IH-azepin-2-it hexahydro-7-propyl-1H-azepin -2-one (intermediate compound)

< / BR>
The product of example 109 (11.5g, 74,1 mmole) in turn named a mixture of two spatial isomers according to the method of example 29, using benzosulphochloride (13,2 g, 74,5 mmole). The crude pale yellow solid mixture of products (6,1 g) is separated into its constituent isomer a and isomer In using chromatography.

Example 111. 3, 4, 5,6-Tetrahydro-7-methoxy-6 - propyl-2H-azepin (intermediate compound)

< / BR>
The isomer a of example 110 (0.5 g, 3.2 mmole) is treated with tetrafluoroborate trimethylhexane (0,62 mg, 1,10 mmole) by the method of example 26. After chromatography was carried out obtain 0.45 g (83%) of the named compound.

Elemental analysis: C10H19NO 0,1 H2O (molecular weight 169,27);

Calculated, %: C, 70.21, H 11.31, N, 8.19;

Found, %: C, 70.35, H 11.32, N, 7.97.

Example 112. 3,4,5,6-Tetrahydro-7-methoxy - 2-propyl-2H-azepin (proxenia (0,81 g, 5.4 mmole) by the method of example 26. After chromatography was carried out get of 0.60 g (84%) of the named compound.

Elemental analysis: C10H19NO 0,125 H2O (molecular weight 171,52)

Calculated, %: C, 70.03, H 11.31, N, 8.47;

Found,%: C, 69.94, H 11.41, N, 7.92.

Example 113. Monohydrochloride hexahydro-3-propyl-1H-azepin-2 - imine

< / BR>
The product of example 111 (415 mg, of 2.45 mmole) in 20 ml of MeOH is treated with ammonium chloride (111 mg, 2.1 mmole) by the method of example 27, obtain 360 mg (76%) of the named compound.

Range PMR (400 MHz, CD3OD) : 3.48 (m, 2H), 2.90-2.81 (m, 1H), 1.96-1.85 (m, 1H), 1.85-1.55 (m,7H), 1.55-1.32 (m, 2H), 1.00 (t, J=7.3 Hz, 3H).

Elemental analysis: C9H18N21,0 HCl 0,15 H2O 0.02 NH4Cl (molecular weight 194,43)

Calculated, %: C, 55.60, H 10.02, N 14.55, Cl 18.60;

Found, %: C, 55.57, H 9.92, N 14.35, Cl 18.62.

Example 114. Monohydrochloride hexahydro - propyl-1H-azepin-2-imine

< / BR>
The product of example 112 (560 mg, 3.3 mmole) in 20 ml of MeOH is treated with ammonium chloride (150 mg, 2.8 mmole) by the method of example 27, receive 514 mg (78%) of the named compound.

Range PMR (400 MHz, CD3OD) : 3.68-3.58 (m, 1H), 2.79 (DDD, J=14.3, 12.2, 1.9 Hz, 1H), 2.61 (DD, J=14.6, 6.6 Hz, 1H), 2.06-1.95 (m, 2H), 1.90-1.81 (m, 1H), 1.75-1.32 (m, 7H), 0.98 (t, J=7.2 Hz, 3H).

Elemental analysis: C9
Found, %: C, 53.95, H 10.15, N 13.96, Cl 18.64.

Example 115. The reaction of 2-(1-methylpropyl)cyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 2-sec.-butylamine (Lancaster, 9,9 g, 64,2 mmole) turns on the named connection using hydroxylamine hydrochloride (6.7 g, 96,3 mmole) and sodium acetate (9.5 g, 115,6 mmole) in a mixture of 75 ml of EtOH and 50 ml of water. Obtain 11.3 g of crude titled compound.

Example 116. A mixture of hexahydro-3-(1-methyl-propyl)-1H-azepin-2 - it hexahydro-7-(1-methylpropyl)-1H-azepin-2-one (intermediate compound)

< / BR>
The product of example 115 in turn named a mixture of two spatial isomers according to the method of example 25, using 80% H2SO4. The mixture of products is divided into the isomer a and isomer In using chromatography.

Example 117. 3,4,5,6-Tetrahydro-7-methoxy-6-(1-methylpropyl) - 2H-azepin (intermediate compound)

< / BR>
The isomer a of example 116 treated with tetrafluoroborate trimethylhexane by the method of example 26, get a named connection.

Example 118. 3,4,5,6-Tetrahydro-7-methoxy - 2-(1-propenyl)-2H-azepin (intermediate compound)

< / BR>
The isomer In example 116 treated with tetrafluoroborate trimethylhexane by the method of example 26, receive nazvannomu example 117 in MeOH is treated with ammonium chloride by the method of example 27, get a named connection.

Example 120. Monohydrochloride hexahydro-7-(2-methylbutyl)-1H - azepin-2-imine

< / BR>
The product of example 118 in MeOH is treated with ammonium chloride by the method of example 27, get a named connection.

Example 121. The reaction of 3,4-dimethylcyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 3,4-dimethylcyclohexanone (Cl, 9.0 g, 71,0 mmol) turns on the named connection using hydroxylamine hydrochloride (7.4 g, 107,0 mmol) and sodium acetate (9,9 g, to 121.0 mmol) in a mixture of 50 ml EtOH and 50 ml of water. Obtain 2.6 g of crude titled compound.

Example 122. A mixture of hexahydro-4,5-dimethyl-1H-azepine-2-it hexahydro-5,6-dimethyl-1H-azepin-2-one (intermediate compound)

< / BR>
The product of example 121 (8.0 g, 56.6 mmole) in turn named a mixture of two isomers position according to the method of example 25, using 20 ml of 80% H2SO4. Gain of 7.1 g of a mixture of the above mentioned compounds in the form of amber liquid. The mixture is separated into the isomers by chromatography, get 233 mg of isomer a and 87 mg of isomer Century

Example 123. 3,4,5,6-Tetrahydro-7-methoxy - 4,5-dimethyl-2H-azepin (intermediate compound)

< / BR>
The isomer a of example 122 (205 mg, 1.5 mmole) is treated terraforming connection.

Example 124. 3,4,5,6-Tetrahydro-7-methoxy - 3,4-dimethyl-2H-azepin (intermediate compound)

< / BR>
The isomer In example 122 treated with tetrafluoroborate trimethylhexane by the method of example 26, get a named connection.

Example 125. Monohydrochloride hexahydro-4,5 - dimethyl-1H-azepin-2-imine

< / BR>
The product of example 123 (100 mg, of 0.64 mmole) in 5 ml MeOH is treated with ammonium chloride (29.3 mg, 0,547 mmole) by the method of example 27, obtain 68 mg (66%) of the named compound as a white solid.

Range PMR (300 MHz, D2O) : 3.25-3.45 (m, 2H), 2.85 (d,1H, J=12 Hz), 2.6 (DD, 1H, J=9, 15 Hz), 2.05-2.08 (m, 1H), 1.9-2.0 (m, 1H), 1.4 -1.61 (m, 2H), 0.94 (d, 3H, J=9 Hz), 0.88 (d, 3H, J= 6 Hz).

Elemental analysis: C8H16N21,0 HCl 0,01 H2O 0,2 NH4Cl (molecular weight 187,57).

Calculated, %: C, 51.23, H 9.58, N 16.43, Cl 22.68;

Found, %: C At 50.85, H 9.51, N 16.22, Cl 22.59.

Example 126. Monohydrochloride hexahydro-5,6-dimethyl-1H-azepin - 2-imine

< / BR>
The product of example 124 in methanol is treated with ammonium chloride by the method of example 27, get a named connection.

Example 127. The reaction of 2,5-dimethylcyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 2.5-dimethylcyclohexane (Cl, 9.0 g, 71,0 mmol) is transformed into a mixture of 50 ml EtOH and 50 ml of water. According to the method get of 7.1 g (71%) of the crude titled compound.

Example 128. A mixture of hexahydro-3,6-dimethyl-1H-azepin-2-it hexahydro-4,7-dimethyl-1H-azepin-2-one (intermediate compound)

< / BR>
According to the method of example 25 product of example 127 (6.8 g, 48.5 mmole) in turn named a mixture of two isomers position, using 20 ml of 80% H2SO4. Get a mixture of these compounds. The resulting mixture is separated into the isomers by chromatography was carried out. Obtain 1.3 g of pure isomer and isomer in pure form is almost no selection. After re-chromatography was carried out pure isomer A.

Example 129. 3,4,5,6-Tetrahydro-7-methoxy - 3,6-dimethyl-2H-azepin (intermediate compound)

< / BR>
The isomer a of example 128 treated with tetrafluoroborate trimethylhexane by the method of example 26, get a named connection.

Example 130. 3,4,5,6-Tetrahydro-7-methoxy - 2,5-dimethyl-2H-azepin (intermediate compound)

< / BR>
The isomer In example 128 (1.0 g, 7.1 mmole) is treated with tetrafluoroborate trimethylhexane (1.3 g, 8.5 mmole) by the method of example 26. After chromatography was carried out obtain 700 mg of the compound.

Example 131. Monohydrochloride hexahydro-3,6 - dimethyl-1H-azepin-2-imine

< / BR>
The product is CLASS="ptx2">

Example 132. Monohydrochloride hexahydro-4,7 - dimethyl-1H-azepin-2-imine

< / BR>
The product of example 130 (250 mg, 1.6 mmole) in 2.5 ml of EtOH is treated with ammonium chloride (86,0, 1.6 mmole) by the method of example 27, obtain 220 mg (75%) of the titled compound as a white solid.

Range PMR (400 MHz, CD3O) : 3.7-3.8 (m, 1H), 2.7 (DD, 1H, J=10, 12 Hz), 2.4 (d, 1H, J=15 Hz), 1.9-2.0 (m, 1H), 1.7-1.85 (m, 2H), 1.4-1.55 (m, 2H), 1.3 (d, 6H, J=8 Hz), 1.06 (d, 3H, J= 8 Hz).

Elemental analysis: C8H16N21,06 HCl 0,25 H2O (molecular weight 183,38)

Calculated, %: C, 52.40, H 9.65, N 15.28, Cl 20.49;

Found, %; C 52.10, H 9.82, N 15.94, Cl 20.77.

Example 133. The reaction of (2R-TRANS)-2-(methylethyl) 5-dimethylcyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 (-)-menthone (Aldrich, 10.0 g, 64.8 mmole) turns on the named connection using hydroxylamine hydrochloride (6.8 g, 97,3 mmole) and sodium acetate (9.0 g, 110,2 mmole) in a mixture of 50 ml t and 50 ml of water. Get a named connection.

Example 134. (4R-TRANS)-hexahydro-7-(methylethyl)-4-methyl-1H - azepin-2-he mixture of (3R-TRANS)-hexahydro-3-(methylethyl)-6 - methyl-1H-azepin-2-one (intermediate compound)

< / BR>
According to the method of example 25, the product of example 133 (10.0 g, or 59.0 mmol) make the above mixture of two isomers, espey provisions chromatographytandem, obtain 3.1 g of the named isomer and 1.5 g called pure isomer Century

Example 135. (5R-TRANS)-3,4,5,6-tetrahydro-7 - methoxy-2-(1-methylethyl)-5-methyl-2H-azepin (intermediate compound)

< / BR>
The isomer a of example 134 (1.0 g, 5.9 mmole) is treated with tetrafluoroborate trimethylhexane (1.1 g, 7.1 mmole) by the method of example 26. After chromatography was carried out obtain 740 mg (68%) of the named compound.

Example 136. (6R-TRANS)-3,4,5,6-tetrahydro-7-methoxy-6- (1-methylethyl)-3-methyl-2H-azepin (intermediate compound)

< / BR>
The isomer In example 134 (840 mg, 5.0 mmol) is treated with tetrafluoroborate trimethylhexane (880 mg, 6.0 mmol) by the method of example 26. After chromatography was carried out receive 441 mg (49%) of the named compound.

Example 137. Monohydrochloride (7R-TRANS)-hexahydro-7-(1 - methylethyl)-4-methyl-1H-azepin-2-imine

< / BR>
The product of example 135 (690 mg, 3.8 mmole) in 20 ml of MeOH is treated with ammonium chloride (201 mg, 3.8 mmole) by the method of example 27, obtain 570 mg (73%) of the named compound as a white solid.

The mass spectrum of high resolution (electron impact): calculated m/e= 168,163 (C10H20N2), found m/e=168,163.

Range PMR (400 MHz, D2O) : 3.4-3.5 (m, 1H), 2.7 (DD, 1H, J=12, 15 Hz), 2.4 (user. d, 1H, J=14 >21,0 HCl 0,33 H2O 0,05 NH4Cl (molecular weight 213,36).

Calculated, %: C, 56.29, H 10.33, N 13.46, Cl 17.45;

Found, %: C, 56.28, H 10.81, N 13.57, Cl 17.58.

Example 138. Monohydrochloride (3R-TRANS)-hexahydro-3-(1 - methylethyl)-6-methyl-1H-azepin-2-imine

< / BR>
The product of example 136 (300 mg, 1.6 mmole) in 10 ml of MeOH is treated with ammonium chloride (70 mg, 1.3 mmole) by the method of example 27, obtain 240 mg (86%) of the titled compound as a white solid.

[]D= +33,6o(0,53 CH3OH)

Range PMR (400 MHz, D2O) 3.6 (user.d, 1H, J=14 Hz), 3.2 (DD, 1H, J=4, 16 Hz), 2.35-2.45 (m, 1H), 2.2-2.3 (m, 1H), 1.95 (m, 3H), 1.65-1.75 (m, 1H), 1.42-1.52 (m, 1H), 1.0 (DD, 6H, J= 7 Hz), 0.95 (d, 3H, J=6 Hz).

Elemental analysis: C10H20N21,0 HCl 0,33 H2O 0,05 NH4Cl (molecular weight 213,73).

Calculated, %: C, 56.20, 10.45 H, N 13.11, Cl 15.76;

Found, %: C, 56.58, H 10.24, N 12.70, Cl 15.88.

Example 139. The oxime 3R-methylcyclopentanone (intermediate compound)

< / BR>
According to the method of example 24 (R-(+)-methylcyclopentanone (Aldrich. 5.0 g, 50,9 mmole) turns on the named connection using hydroxylamine hydrochloride (5.3g, 76,4 mmole) and sodium acetate (7,1 g, 86,5 mmole) in a mixture of 25 ml of EtOH and 25 ml of water. Obtain 4.9 g (86%) of the titled compound as a white solid.

Example 141. 2,3,4,5-Tetrahydro-6-methoxy - 4R-methylpyridin (intermediate compound)

< / BR>
The isomer a of example 140 treated with tetrafluoroborate trimethylhexane by the method of example 26, get a named connection.

Example 142. 2,3,4,5-Tetrahydro-6-methoxy - 3R-methylpyridin (intermediate compound)

< / BR>
The isomer In example 140 treated with tetrafluoroborate trimethylhexane by the method of example 26, get a named connection.

Example 143. Monohydrochloride 4R-methylpiperidin-2-imine

< / BR>
The product of example 141 in methanol is treated with ammonium chloride by the method of example 27, get a named connection.

Example 144. Monohydrochloride 5R-methylpiperidin-2-imine

< / BR>
The product of example 142 in methanol is treated with ammonium chloride by the method of example 27, get a named connection.

Example 145. The oxime 3-ethylcyclopentane (intermediate compound)

< / BR>
According to the method of example 24 3-ethylcyclopentane pravr is 146. A mixture of 4-ethylpiperidine-2-one with 5-ethylpiperidine-2 - one (intermediate compound)

< / BR>
According to the method of example 25 product of example 145 to turn in the said mixture of compounds using 80% H2SO4. The resulting mixture was divided into isomer a and isomer In using chromatography.

Example 147. 4-Ethyl-2,3,4,5-tetrahydro - 6-methoxypyridine (intermediate compound)

< / BR>
The isomer a of example 146 treated with tetrafluoroborate trimethylhexane by the method of example 26, get a named connection.

Example 148. 3-Ethyl-2,3,4, 5-tetrahydro - 6-methoxypyridine (intermediate compound)

< / BR>
The isomer In example 146 treated with tetrafluoroborate trimethylhexane by the method of example 26, get a named connection.

Example 149. Monohydrochloride 4-ethylpiperidine-2-imine

< / BR>
The product obtained in example 147, in methanol is treated with ammonium chloride by the method of example 27, get a named connection.

Example 150. Monohydrochloride 5-ethylpiperidine-2-imine

< / BR>
The product obtained in example 148, in methanol is treated with ammonium chloride by the method of example 27, get a named connection.

Example 151. The reaction of 2-ethylcyclopentane (intermediate connection using hydroxylamine hydrochloride (8.5 g, 122,5 mmole) and sodium acetate (12.9 g, 157.5 mmole) in a mixture of 90 ml of EtOH and 90 ml of water. Obtain 12.0 g of the named compound as a yellow oil.

Example 152. A mixture of 6-ethylpiperidine-2-one with 3-ethylpiperidine-2 - one (intermediate compound)

< / BR>
The product of example 151 (2.1 g, a 16.4 mmole) in turn indicated a mixture of two isomers position according to the method of example 29 using benzosulfimide (2.9 g, a 16.4 mmole). The crude product (mixture of 2 isomers) as a yellow solid separated into isomer a and isomer In using chromatography.

Example 153. 2-Ethyl-2,3,4, 5-tetrahydro - 6-methoxypyridine (intermediate compound)

< / BR>
The isomer a of example 152 (280 mg, 2.2 mmole) is treated with tetrafluoroborate trimethylhexane (425 g, 2.9 mmole) by the method of example 25. After chromatography was carried out obtain 300 mg (96%) of the named compound as a crystalline product.

Example 154. 3-Ethyl-3,4,5,6-tetrahydro - 2-methoxypyridine (intermediate compound)

< / BR>
The isomer In example 152 is treated with tetrafluoroborate trimethylhexane by the method of example 26, get a named connection.

Example 155. Monohydrochloride 6-ethylpiperidine-2-imine

< / BR>
The product of example 153 in methanol is treated with chloride am ridin-2-imine

< / BR>
The product of example 154 in methanol is treated with ammonium chloride by the method of example 27, get a named connection.

Example 157. The reaction of 2,2-dimethylcyclopentane (intermediate compound)

< / BR>
According to the method of example 24 2.2-dimethylcyclopentane (Aldrich, 9.0 g, 80,0 mmol) turn named in connection with the use of hydroxylamine hydrochloride (7.8 g, 112,0 mmol) and sodium acetate (11.8 g, 144, 0mm mmol) in a mixture of 90 ml of EtOH and 90 ml of water. Get to 13.1 g of the named product as colorless oil.

Example 158. A mixture of 6,6-dimethylpiperidine-2-she and 3.3 - dimethylpiperidin-2-she (intermediate compound)

< / BR>
The product of example 157 (13.3 g, 104,7 mmole) in turn named a mixture of two isomers position according to the method of example 29 using benzosulfimide (18.5 g, 104,7 mmole). The crude mixture of products in the form of a pale pink solid product is separated into isomer a and isomer In using chromatography.

Example 159. 2,3,4,5-Tetrahydro-6-methoxy - 2,2-dimethylpyridin (intermediate compound)

< / BR>
The isomer a of example 158 (880 mg, 6.9 mmole) is treated with tetrafluoroborate trimethylhexane (1.3 g, 9.0 mmol) by the method of example 26. After chromatography was carried out obtain 502 mg (51%) of these compounds is (intermediate compound)

< / BR>
The isomer In example 158 treated with tetrafluoroborate trimethylhexane by the method of example 26, get a named connection.

Example 161. Monohydrochloride 6,6-dimethylpiperidine-2-imine

< / BR>
The product of example 159 in methanol is treated with ammonium chloride by the method of example 27 to obtain these compounds.

Example 162. Monohydrochloride 3,3-dimethylpiperidin-2-imine

< / BR>
The product of example 160 in methanol is treated with ammonium chloride by the method of example 27, get a named connection.

Example 163. 3,4-dihydro-2-methoxyaniline (intermediate compound)

< / BR>
According to the method of example 26 3,4-dihydroorotase (Apin Chemicals Ltd., 736 mg, 5.0 mmol) is treated with tetrafluoroborate trimethylhexane (924 mg, 6.2 mmole). After chromatography was carried out obtain 130 mg (16%) of the named compound.

Example 164. Monohydrochloride 1,2,3,4-tetrahydroquinolin-2-imine

< / BR>
The product of example 163 (98 mg, and 0.61 mmole) in 10 ml of methanol and 10 ml of methylene chloride is treated with ammonium chloride (27 mg, of 0.52 mmole) by the method of example 27. The output of these compounds is 57 mg (47%).

The mass spectrum of high resolution; m/e M+147,086 (C9H11N2calculated m/e 147,092.

9H11N21,0 HCl 0,2 H2O 1,0 NH4Cl (molecular weight 240,65).

Calculated, %: C, 44.92, H 6.49, N 17.46, Cl 29.46;

Found, %: C, 44.94, H 6.48, H 17.58, Cl 29.60.

Example 165. 2,3,4,5-Tetrahydro-1H-1 - benzazepin-2-he (intermediate compound)

< / BR>
Alpha-tetralone (Aldrich, 36.5 g, 0.25 mmole) turns on the named compound by the method of example 50 using sodium azide (19.5 g, 0.3 mmole) in a mixture of 300 ml of concentrated sulfuric acid and 100 ml of methylene chloride. After recrystallization from ethanol to 12.1 g (30%) of the named compound.

Example 166. 4,5-Dihydro-2-methoxy - 3H-1-benzazepin (intermediate compound)

< / BR>
The compound of example 165 (3.2 g, 20.0 mmol) is treated with tetrafluoroborate trimethylhexane (4.4 g, 30.0 mmol) by the method of example 26. After chromatography was carried out yield the named product is 2.5 g (73%).

Example 167. Monohydrochloride 2,3,4,5-tetrahydro-1H-1 - benzazepin-2-imine

< / BR>
The product of example 166 (1.9 g, 11.1 mmole) in 15 ml of methanol and 10 ml of methylene chloride is treated with ammonium chloride (413 g of 7.8 mmole) by the method of example 27. The output of the above mentioned product is 1.4 g (88%).

The mass spectrum of the high-resolution: m/f M+161,103; (C10H13N2calculated analysis: C10H12N21,0 HCl 0,33 H2O (molecular weight 202,63)

Calculated, %: C, 59.28, H 6.80, N 14.24, Cl 17.50;

Found, %: C, 59.30, H 6.68, N 13.90, Cl 17.41.

Example 168. 4,4-Dimethylpiperidin-2-he (intermediate compound)

< / BR>
A solution of 3,3-dimethylglutaric anhydride (10 g, 70 mmol) in ammonium hydroxide (conc. 30 ml) hydronaut on Pd/Al2O3at a pressure of 1600 pounds per square inch (108,9 ATM) at 250oC for 6 hours. The flask was cooled to room temperature and treated with saturated brine (75 ml) and then extracted with methylene chloride (150 ml), dried with sodium sulfate and evaporated. Get a solid product, which was purified using chromatography. Allocate 1.4 g (16%) of the named compound.

IR-spectrum (KBr): 3260, 2949, 1655, 1626, 1502, 1338.

Range PMR (CDCl3) : 5.98 (ush.s, 1H), 3.38-of 3.32 (m, 2H), 2.13 (s, 2H), 1.59 (t, J=5 Hz, 2H), 1.05 (m, 6H).

Elemental analysis: C7H13NO 0,02 CHCl3(molecular weight 127,19)

Calculated, %: C, 65.07, H 10.13, N, 10.81;

Found, %: C, 65.20, H 9.74, N, 10.78.

Example 169. 2,3,4,5-Tetrahydro-4,4-dimethyl-6-methoxypyridine (intermediate compound)

< / BR>
The compound of example 168 (636 mg, 5 mmol) is treated with tetrafluoroborate trimethylhexane (890 mg, 6 mmol) by the method of example 26. After 4,4-dimethylpiperidin-2-imine

< / BR>
The product of example 169 (550 mg, 3.9 mmole) in 25 ml of methanol is treated with ammonium chloride (178 mg, 3.3 mmole) by the method of example 27. The output of these compounds is 460 mg (86%).

DSC: 167,65oC.

Mass spectrum (electron impact), m/e 126 (100%, M+).

IR-spectrum (KBr): 3294, 3148, 3009, 2945, 1687.

Range PMR (DMSO-d6D2O exchange) : 3.33 (t, J=5 Hz, 2H), 2.34 (s, 2H), 1.60 (t, J=5 Hz, 2H), 1.00 (s, 6H).

Elemental analysis: C7H14N21,0 HCl 0,2 H2O 0,2 NH4Cl (molecular weight 176,97)

Calculated, %: C, 47.51, H 9.23, N 17.41, Cl 24.04;

Found, %: C 47.13, H 9.05, N 17.76, Cl At 24.31.

Example 171. (TRANS)-Octahydro-1H - isoindole-1-he (intermediate compound)

< / BR>
The anhydride solution of TRANS-1,2-cyclohexanedicarboxylic acid (10.0 g, 65 mmol) in concentrated ammonium hydroxide (30 ml) hydronaut by the method of example 168. The output of these compounds is 7.4 g (80%). So pl. 85-88oC.

Range PMR (CDCl3) : 6.47 (ush.s, 1H), 3.42-3.31 (m, 1H), 3.00-2.93 (m, 1H), 2.50-2.35 (m, 1H), 2.07-1.15 (m, 9H).

Example 172. (TRANS)-3A, 4,5,6,7,7-Hexahydro-3-methoxy-1H - isoindole (intermediate compound)

< / BR>
The compound of example 171 (1.39 g, 10 mmol) is treated with tetrafluoroborate trimethylhexane (1.78 g, 12 mmol) Example 173. Monohydrochloride (TRANS)-OCTA - hydro-2H-isoindole-1-imine

< / BR>
The compound of example 172 (1.04 g, 6,79 mmole) in 50 ml of methanol is treated with ammonium chloride (359 mg, 6,70 mmole) in 50 ml of methanol according to the method of example 27. The output of these compounds is 940 mg (75%).

IR-spectrum (KBr): 3400-2700, 1686 cm-1< / BR>
Range PMR (DMSO-d6D2O exchange) : 3.52-3.45 (m, 1H), 3.28-3.22 (m, 1H), 3.04-2.98 (m, 1H), 1.90-1.20 (m, 8H).

Elemental analysis: C8H14N21,0 HCl 0,25 H2O 0,25 NH4Cl (molecular weight 192,55)

Calculated, %: C 49.90, H 8.64, N 16.37, Cl 23.02;

Found, %: C, 50.00, H 8.27, N 16.28, Cl 23.09.

Example 174. The reaction of bicyclo [2.2.1]- heptane-2-she (intermediate compound)

< / BR>
Norcamphor (11 g, 100 mmol) is treated with hydroxylamine hydrochloride (13,2 g) and sodium acetate (13.1 g) by the method of example 173. The output of these compounds is 11.5 g (96%).

Example 175. A mixture of 2-azabicyclo-[3.2.1]-Octan-3-one and 3-azabicyclo[3.2.1] -octane-2-she (intermediate compound)

< / BR>
The product of example 174 (10 g, 80 mmol) make the above mixture of isomers position according to the method of example 25 using 80% sulfuric acid. The mixture of products is distilled chromatographytandem, but do not share the isomer a and isomer Century. Receive the 835 mg is about[3.2.1]octane-2-she (intermediate compound)

< / BR>
The compound of example 175 (650 mg, 5 mmol) is treated with tetrafluoroborate trimethylhexane (890 mg, 6 mmol) by the method of example 26. After chromatography was carried out yield the named compound is 550 mg (80%).

Example 177. A mixture of monohydrochloride 2-azabicyclo[3.2.1] Octan-3-imine and monohydrochloride 3-azabicyclo[3.2.1]octane-2 - imine

< / BR>
The product of example 176 (530 mg, 3.9 mmole) in 25 ml of methanol is treated with ammonium chloride (178 mg, 3.3 mmole) by the method of example 27. The output of these compounds is 400 mg (76%).

Mass spectrum (electron impact): m/e 124 (90%), 83 (100%).

Range PMR (DMSO-d6-D2O exchange) : 3.44-3.47 (m, 1H), 3.19-3.11 (m, 1H), 2.95-2.89 (m, 1H), 2.57-2.50 (m, 2H), 2.07-1.52 (m, 5H).

Elemental analysis: C8H14N21,08 HCl 0,75 H2O TO 0.4 NH4Cl (molecular weight 212,500).

Calculated, %: C 42.36, H 8.22, N 16.94, Cl 26.44;

Found, %: C 42.70, H 8.27, N 17.03, Cl 26.65.

Example 178. 2,2,2-Trichloro-N-(2-propenyl) ndimethylacetamide (intermediate compound)

< / BR>
To a solution of allylamine (5 g, 88 mmol) and triethylamine (9.6 g, 95 mmol) in methylene chloride (200 ml) under stirring and at -10oC add trichloroethylene (16.7 g, 92 mmole). The resulting solution is allowed to gradually warm to room temperature the m sodium. Get 17 g (96%) of the named compound as a white solid.

Example 179. 3,3-Dichloro-4-(chloromethyl)- pyrrolidin-2-he (intermediate compound)

< / BR>
To a solution of compound of example 178 (15 g, 74 mmole) in xylene (600 ml) under nitrogen atmosphere and with stirring, add RuCl2(PPh3)3(696 mg, of 0.74 mmole) and the resulting solution is boiled for 2 hours. The solvent is then evaporated and the obtained residue chromatographic and recrystallized from ethyl acetate. The output of these compounds in the form of a solid product is 4.5 g (30%).

Range PMR (CDCl3) : 7.40 (ush.s, 1H), 4.00 (DD, J=4, 12 Hz, 1H), 3.76 (DD, J= 9, 12 Hz, 1H), 3.70 (DD, J=6, 8 Hz, 1H), 3.28 (DD, J=8, 9 Hz, 1H), 3.12-3.23 (m, 1H).

Example 180. 4 Methylpyrrolidine-2-he (intermediate compound)

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A mixture of compound of example 179 (3 g, 15 mmol), anti-hydride (14,3 ml) and AlBN (25 mg) was kept at 140oC for 8 hours. The resulting product chromatographic and allocate 900 mg (61%) of the named compound as a solid substance.

Example 181. 3,4-Dihydro-5-methoxy - 3-methyl-2H-pyrrole (intermediate compound)

< / BR>
The product of example 180 (500 mg, 5 mmol) is treated with tetrafluoroborate trimethylhexane (890 mg, 6 mmol) by the method prlja, is 610 mg.

Example 182. Monohydrochloride 4-methyl - pyrrolidin-2-imine

< / BR>
The product of example 181 (610 mg, 5 mmol) in 25 ml of methanol is treated with ammonium chloride (200 mg, 4 mmole) by the method of example 27. The output of these compounds is 500 mg (70%).

The mass spectrum of the high-resolution: m/f M+98,0844; C5H10N2calculated 98,0844.

Elemental analysis: C5H10N2HCl 0,25 H2O 0,75 NH4Cl (molecular weight 179,23)

Calculated, %: C 33.50, H 8.15, N 21.49, Cl 34.62;

Found, %: C At 33.17, H 7.96, N 21.40, Cl At 34.69.

Example 183. The reaction of 2-butylcyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 turn 2-n-butylcyclohexanone (Aldrich, 10.4 g, 67.2 per mmole) named in connection with the use of hydroxylamine hydrochloride (7.0 g, 100,7 mmole) and 9.8 g (120,1 mmole) of sodium acetate in a mixture of 75 ml of ethanol and 50 ml of water. Obtain 11.3 g (99%) of crude product.

Example 184. A mixture of 3-butilhioscina-1H-azepin-2-it 7 - butilhioscina-1H-azepin-2-she (intermediate compound)

< / BR>
The product of example 184 (11.1 g, 65.6 mmole) in turn indicated a mixture of two isomers position according to the method of example 29 using benzosulfimide (12.3 g, 70.0 mmol). Raw is.

Example 185. 6-Butyl-Z,4,5,6-tetrahydro-7 - methoxy-2H-azepin (intermediate compound)

< / BR>
The isomer a of example 184 treated with tetrafluoroborate trimethylhexane by the method of example 26, get a named connection.

Example 186. 2-Butyl-3,4,5,6-tetrahydro-7 - methoxy-2H-azepin (intermediate compound)

< / BR>
The isomer In example 184 (0,63 g, 3.7 mmole) is treated with tetrafluoroborate trimethylhexane (0.71 g, 4.8 mmole) by the method of example 26. After chromatography was carried out get of 0.53 g (84%) of the named compound.

Elemental analysis: C11H21NO 0,125 H2O (molecular weight 185,55)

Calculated, %: C, 71.21, H 11.54, N, 7.55;

Found, %: C, 71.14, H 11.73, N 7.25.

Example 187. Monohydrochloride 3 butilhioscina-1H-azepin-2-imine

< / BR>
The product of example 185 treated in methanol ammonium chloride by the method of example 27, get a named connection.

Example 188. Monohydrochloride 7 butilhioscina-1H-azepin-2-imine

< / BR>
The product of example 186 (500 mg, 2.7 mmole) in 20 ml of methanol is treated with ammonium chloride (124 mg, 2.3 mmole) by the method of example 27. The output of these compounds is 425 mg (74%).

Range PMR (400 MHz, CD3OD) : 3.64-3.55 (m, 1H), 2.79 (DDD, 1H, J= 14.6, 6.7, 1.5 Hz), 2.61 (DDT, 1H, J=14.H20N21,0HCl0,33H2O0,03NH4Cl (molecular weight 212,29).

Calculated, %: C, 56.58, H 10.34, N 13.39, Cl 17.20;

Found, %: C, 56.49, H 10.47, N 12.99, Cl 17.55.

Example 189. The reaction of 2-phenylcyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 2-phenylcyclohexanone (Aldrich, 10.4 g, 60 mmol) turn named in connection with the use of hydroxylamine hydrochloride (7.2 g, 104 mmole) and sodium acetate (8,4 g, 102 mmole) in a mixture of 75 ml of ethanol and 75 ml of water. Get 11,0 g (97%) of the named compound as a white solid product.

Example 190. Hexahydro-7-phenyl-1H - azepin-2-he (intermediate compound)

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To the product of example 189 (10,9 g, 57,7 mmole) in 60 ml of acetone was added 1 n NaOH solution (64 ml, 64 mmole). After cooling the reaction mixture with an ice bath under stirring in nitrogen atmosphere for 5 minutes, added dropwise benzosulphochloride (10.6 g, 60 mmol). The temperature of the reaction mixture was raised to room temperature and stirred overnight, filtered, the filtrate concentrated and distributed between ethyl acetate and brine. The organic layer is dried with sodium sulfate, filtered and evaporated in vacuum to dryness. The obtained white solid product is recrystallized from hot sagita-7-methoxy-2-phenyl-2H-azepin (intermediate compound)

< / BR>
The product of example 29 (1.75 g, 9.3 mmole) is treated with tetrafluoroborate trimethylhexane (1.8 g, 12.0 mmol) according to the method of example 26. Obtain 1.4 g (72%) of the named compound.

Example 192. Monohydrochloride hexahydro-7-phenyl-1H-azepin-2 - imine

< / BR>
The product of example 191 (1.4 g, 6.9 mmole) in 75 ml of methanol is treated with ammonium chloride (0.31 g, 5.9 mmole) by the method of example 27. The output of these compounds is 1.2 g (77%).

Range PMR (CD3OD) : 7.50-7.30 (m,5H), 2.98 (TT, 1H), 2.74 (DD, 1H), 2.12-1.76 (m, 6H), 1.60 (m, 1H).

Elemental analysis: C12H16N2HCl 0.5 H2O 0,03 NH4Cl (molecular weight 233,74)

Calculated, %: C, 61.66, H 7.76, N 11.98, Cl 15.17;

Found, %: C, 61.69, H 8.15, N 11.42, Cl 15.41.

Example 193. The reaction of 2-(2-ethylbutyl)- cyclohexanone (intermediate compound)

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According to the method of example 24 transform 2-(2-ethylbutyl)cyclo hexane (Aldrich, 10,1 g of 55.5 mmole) named in connection with the use of hydroxylamine hydrochloride (5.4 g, 77,7 mmole) and sodium acetate (8.2 g, 99,9 mmole) in a mixture of 90 ml of ethanol and 90 ml of water. Obtain 11.9 g (100%) of crude product.

Example 194. A mixture of 3-(2-ethylbutyl)hexahydro - 1H-azepin-2-it 7-(2-ethylbutyl)hexahydro-1H-azepin - 2-she (intermediate compound)

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Productteam of benzosulfimide (7,1 g, 40.0 mmol). The crude product as a pale yellow solid (7,3 g) share on isomer a and isomer In using chromatography.

Example 195. 6-(2-ethylbutyl)-3,4,5,6-tetrahydro-7-methoxy-2H - azepin (intermediate compound)

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The isomer a of example 194 treated with tetrafluoroborate trimethylhexane by the method of example 26, get a named connection.

Example 196. 2-(2-ethylbutyl)-3,4,5,6-tetrahydro-7-methoxy-2H - azepin (intermediate compound)

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The isomer In example 194 (520 mg, 2.6 mmole) is treated with tetrafluoroborate trimethylhexane (506 mg, 3.4 mmole) by the method of example 26. After chromatography was carried out receive 472 mg (85%) of the named compound.

Example 197. Monohydrochloride 3-(2-ethyl - butyl)hexahydro-1H-azepin-2-imine

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The product of example 195 in methanol is treated with ammonium chloride by the method of example 27, get a named connection.

Example 198. Monohydrochloride 7-(2-ethyl-butyl)hexahydro-1H - azepin-2-imine

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The product of example 196 (470 mg, 2.2 mmole) in 18 ml of methanol is treated with ammonium chloride (98 mg, 1.8 mmole) by the method of example 27. The output of these compounds is 242 mg.

Example 199. Monohydrochloride hexahydro-7-imino-1H-azepin-2 - ethanol
Aut in a mixture of methylene chloride (100 ml) and methanol (50 ml) and cooled to -78oC. After the resulting solution was bubbled ozone until a blue color. The reaction mixture is blown with nitrogen to remove excess ozone. Then the reaction mass is then warmed to room temperature and evaporated in vacuum to dryness. The resulting residue is dissolved in ethanol (100 ml), cooled to 0oC and intensively stirred with the addition of a cold solution of sodium borohydride (0.7 g, 18.5 mmole) in a mixture of ethanol/water, 1:1. The pH value of the reaction mixture 8-9 (pH-indicator paper) support simultaneous addition of 2 M aqueous solution of acetic acid. At the end of the addition the mixture is stirred at room temperature for 10 hours, the reaction mass is acidified to pH 2 using diluted hydrochloric acid and evaporated to dryness in a vacuum before the formation of a resinous residue. The resulting residue is dissolved in a small amount of ethanol, filtered, evaporated in vacuo to a solid product which is dissolved in water and applied on a column of ion exchange resin Dowex 50 (H+). The column is washed with deionized water and wash the named connection using 2 n hydrochloric acid. The eluate evaporated in vacuo, the resulting solid product is dissolved in a small amount of water is 92,69.

Example 200. Monohydrochloride hexahydro - 7-imino-1H-azepin-2-acetic acid

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Monohydrochloride hexahydro-7-(2-propenyl)-1H-azepin-2-imine (product of example 108) (3.0 g, 14.7 mmole) dissolved in methyl ethyl ketone (150 ml) and cooled to -78oC. and Then through a solution bubbled ozone until a blue coloration and at -78oC add 10% solution of hydrogen peroxide (12 ml). Give the reaction mass to warm to room temperature and evaporated in vacuum. Get a solid residue which is triturated with diethyl ether, dried, dissolved in water and lyophilizers. Get a named connection. If treatment is necessary, the resulting product is dissolved in deionized water and passed through a layer of ion exchange resin Dowex 50(H+) The resin is washed with deionized water and the product quickly elute 1 N. solution of ammonium hydroxide. The solution is quickly evaporated in vacuum at room temperature and collect water. The resulting solution was concentrated in vacuo. Get a solid product, C8H14N2O2HCl, mol.m. 206,67.

Example 201. Monohydrochloride methyl ester hexahydro-7 - imino-1H-azepin-2-acetic acid

< / BR>
To dry methanol (150 ml) with stirring and when the're asked at -20oC for 30 minutes. The product of example 200 (3.0 g, a 14.6 mmole) dissolved in minimum amount of dry methanol and treated with molecular sieves 3A. The mixture is filtered, protecting it from moisture, and add a cold solution of HCl in methanol. The reaction mixture was protected from moisture and stirred at room temperature overnight. The reaction mixture was evaporated in vacuum and get a named connection, C9H16N2O2HCl, mol.m. 220,81.

Example 202. The reaction of 2-(2-propenyl)- cycloheptanone (intermediate compound)

< / BR>
In dry DMF (1.25 ml/mmol) is mixed 2-carboethoxy cycloheptanone (1 mmol), finely ground powder of potassium carbonate (2 mmole), allylbromide (1.5 mmole) and tetrabutylammonium iodide (10 mg/mmol), and stirred in nitrogen atmosphere at a temperature of 55 - 60oC for 16-18 hours. Then the reaction mixture at room temperature, poured into water and extracted with ethyl ether and ethyl acetate. The combined organic extracts washed with brine, dried and evaporated in vacuum. Get 2-allyl-2 - carboethoxy-Cycloheptane. The resulting product is mixed with lithium chloride (5 mmol), water (1.05 mmole) and dimethyl sulfoxide (5 ml/mmol) and the mixture boil for about 4 shall indicate the brine, dried and vacuum evaporated solvent. Get 2-allylcyclohexane. Then 2 - allyl-Cycloheptane turn to the named compound by the method of example 24 using hydroxylamine hydrochloride and sodium acetate in a mixture of ethanol and water.

Example 203. A mixture of octahydro-3-(2-propenyl)Asotin-2-it, octahydro-8-(2-propenyl)-Asotin-2-she (intermediate compound)

< / BR>
The product of example 202 in turn named a mixture of position isomers according to the method of example 29 using benzosulfimide. The crude mixture is separated into the isomer a and isomer In using chromatography.

Example 204. 3,4,5,6,7, 8-Hexahydro-2-methoxy-3-(2-propenyl) Asotin

< / BR>
The isomer a of example 203 treated with tetrafluoroborate trimethylhexane by the method of example 26. Get a named connection.

Example 205. 2,3,4,5,6, 7 Hexahydro-8-methoxy-2-(2-propenyl) Asotin

< / BR>
The isomer In example 203 treated with tetrafluoroborate trimethylhexane by the method of example 26. Get a named connection.

Example 206. Monohydrochloride octahydro-3-(2-propenyl)Asotin - 2-imine

< / BR>
The product of example 204 in methanol is treated with ammonium chloride by the method of example 27. Get a named connection.


Example 208. N-(2-butenyl)-2,2,2-trichloroacetamide

< / BR>
A solution of 3-butene-2-ol (8.7 ml, 100 mmol) in tetrahydrofuran (50 ml) is added to potassium hydride (KN, 600 mg, 15 mmol) for 15 minutes. The resulting solution of the alkoxide added under stirring to a solution of trichloroacetonitrile (there is a 10.03 ml, 100 mmol) in ether (100 ml) at -10oC. the Solution was stirred at 0oC for 3 hours and then evaporated in vacuum, the solvent temperature is below the 25oC); add pentane (400 ml) and methanol (1 ml) and the resulting mixture filtered. After evaporation of the solvent receives a yellow oil (17,4 g). The oil is dissolved in xylene (450 ml) and boiled for 2.5 hours. The solvent is evaporated, get to 16.8 g of the above compound in the form of a white solid product.

Example 209. 3,3-Dichloro-4-(1-chloroethyl)- pyrrolidin-2-he (intermediate compound)

< / BR>
A mixture of compound of example 208 process RuCl2(PPh3)3in boiling xylene by the method of example 179. Get a named connection.

Example 210. 4-Ethylpyrrolidin-2-he (intermediate compound)

< / BR>
The compound of example 209 treated with anti-hydride and ALBN by the method of example 180. Get a named connection.

Example 212. Monohydrochloride 4-ethyl - pyrrolidin-2-imine

< / BR>
The product of example 211 in methanol is treated with ammonium chloride by the method of example 27. Get a named connection

Example 213. 2,2,2-Trichloro-N-(2-methylenbis) ndimethylacetamide (intermediate compound)

< / BR>
CIS-2-penten-1-ol is treated with potassium hydride and trichloroacetonitrile, and then treated in boiling xylene by the method of example 208. Get a named connection.

Example 214. 3,3-Dichloro-4-(chloromethyl)- 5-ethylpyrrolidin-2-he (intermediate compound)

< / BR>
A mixture of compound of example 213 process RuCl2(PPh3)3boiling xylene by the method of example 179. Get a named connection.

Example 215. 5-Ethyl-4-methylpyrrolidine-2-he (intermediate compound)

< / BR>
The compound of example 214 is treated with anti-hydride and ALBN by the method of example 180. Get a named connection.

Example 216. 2-Ethyl-3,4-dihydro-5-methoxy-3-methyl-2H-pyrrole (intermediate compound)

< / BR>
The compound of example 215 treated with tetrafluoroborate trimethylhexane by the method of example 26. Get a named connection.

Example 217. Monohydrochloride 5-what about the method of example 27. Get a named connection

Example 218. 3,4-Dihydro-5-methoxy-2S-(methoxymethyl)-2H - pyrrole (intermediate compound)

< / BR>
S-(-)-5-(hydroxymethyl)-2-pyrrolidinone treated with tetrafluoroborate trimethylhexane (2.2 equivalent) according to the method of example 26. Get a named connection.

Example 219. Monohydrochloride 5S-(methoxymethyl)pyrrolidin-2 - imine

< / BR>
The product of example 218 in methanol is treated with ammonium chloride by the method of example 27. Get a named connection.

Example 220. 3,4-Dihydro-5-methoxy-2R-(methoxymethyl)-2H - pyrrole (intermediate compound)

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R-(-)-5-(hydroxymethyl)-2-pyrrolidinone treated with tetrafluoroborate trimethylhexane (2.2 equivalent) according to the method of example 26. Get a named connection.

Example 221. Monohydrochloride 5R-(methoxymethyl)pyrrolidin-2 - imine

< / BR>
The product of example 220 in methanol is treated with ammonium chloride by the method of example 27. Get a named connection

Example 222. Ethyl ester of 3,4-dihydro-5-methoxy-2H-pyrrole-2S-carboxylic acid

< / BR>
Ethyl ester of (S)-(+)-2-pyrrolidine-5-carboxylic acid is treated with tetrafluoroborate trimethylhexane (2.2 equivalent) according to the method of example 26. Get named>/BR>The product of example 222 in methanol is treated with ammonium chloride by the method of example 27. Get a named connection.

Example 224. 5-S-(methyl bromide)pyrrolidin-2-he (intermediate compound)

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A solution of S-(+)-5-(hydroxymethyl)-2-pyrrolidinone (2 g, to 17.4 mmole) in methylene chloride (160 ml) is treated with triphenylphosphine (10.5 g, 40 mmol) and cetarehhloristam carbon (13,35 g, 40 mmol). The resulting solution was stirred for 18 hours and then evaporated and chromatographic (eluent ethyl acetate: hexane, 40:1, silica gel). Get to 1.32 g of the above compound in the form of a white solid product.

Example 225. 3-[[(5-Oxopyrrolidin-2S-yl)methyl]oxy]-2S - [[(phenylmethoxy)carbonyl]amino]propanoic acid

< / BR>
A solution of N-Cbz-serine in DMF is treated with 2 equivalents of NaH at 0oC, and then add the compound of example 224. The resulting solution was stirred at room temperature for 5 hours, water is added and extracted with ethyl acetate. The solution is acidified to pH 3.5 with citric acid and again extracted with ethyl acetate, dried and evaporated. Get a named connection.

Example 226. Methyl ester of 3-[[(5-Oxopyrrolidin-2S - yl)methyl]oxy]-2S-[[(phenylmethoxy)carbonyl]-amino]propanoic KIS is adistem the stands. The resulting mixture is filtered and distributed between ethyl acetate and water. The organic phase is washed with brine, dried and evaporated. Get a named connection.

Example 227. Methyl ester of 3-[[(3,4-dihydro-5-methoxy-2H - pyrrolidin-2S-yl)methyl] oxy] -2S-[[(phenylmethoxy) carbonyl] amino] propanoic acid (intermediate compound)

< / BR>
The product of example 226 treated with tetrafluoroborate trimethylhexane by the method of example 26. Get a named connection.

Example 228. Monohydrochloride methyl ester 3-[[(5 - aminopyrrolidine-2S-yl)methyl]oxy]-2S-[[(phenylmethoxy) carbonyl]amino]propanoic acid

< / BR>
The product of example 227 in methanol is treated with ammonium chloride by the method of example 27. Get a named connection.

Example 229. The methyl ester dihydrochloride 2S-amino[[(5 - aminopyrrolidine-2S-yl)methyl]oxy]propanoic acid

< / BR>
The product of example 228 in a mixture of methanol/hydrochloric acid is treated with hydrogen at 10% Pd/C, get a named connection.

Example 230. Monohydrochloride 3-(7-aminoadipyl-2-yl)-1,2 - PROPANEDIOL

< / BR>
To the product of example 108 in a mixture of acetone and tetrahydrofuran added osmium tetroxide. Then to the reaction mixture add Vodnye add sodium bisulfite and the mixture was evaporated in vacuum to dryness. The obtained solid residue is shaken out three times with methanol and the combined extracts evaporated in vacuum. The resulting solid product is dissolved in water and applied on a column of ion exchange resin Dowex 50 (H+), which was washed with water and then with 0.2 G. hydrochloric acid. Get a named connection.

Example 231. 6-[(Tetrahydropyran-2-yl)- oxy]Gex-2-EN-1-ol (intermediate compound)

< / BR>
The named compound is obtained from tetrahydropyranol ether of 1,4-butanediol according to the method described by V. S. Martin et al., Tet. Lett. Vol. -31, N5, p.p.763-766, 1990.

Example 232. 2,2,2-Trichloro-N-[1-ethynyl-4-[(tetrahydropyran - 2-yl)-oxy] butyl]ndimethylacetamide (intermediate compound)

< / BR>
The product of example 231 treated with NaH and trichloroacetonitrile, and then treated with boiling xylene by the method of example 208, receive a named connection.

Example 233. 3,3-Dichloro-4-(chloromethyl)-5-[3-[(tetrahydropyran - 2-yl)-oxy] propyl]pyrrolidin-2-he (intermediate compound)

< / BR>
The compound of example 232 handle RuCl2(PPh3)3in boiling xylene by the method of example 179. Get a named connection.

Example 234. 4-Methyl-5-[3-[(tetrahydropyran-2-yl)oxy] propyl]pyrrolidin-2-he (intermediate connection is ucaut named connection.

Example 235. 5-(3-Hydroxypropyl)-4-methylpyrrolidine-2-he (intermediate compound)

< / BR>
The compound of example 234 is treated with a mixture of acetic acid, tetrahydrofuran and water (4:2:1) and evaporated. The resulting product was then purified column chromatography, get a named connection.

Example 236. 5-(3-bromopropyl)-4-methyl - pyrrolidin-2-he (intermediate compound)

< / BR>
The compound of example 235 is treated with triphenylphosphine and cetarehhloristam carbon by the method of example 224, get a named connection.

Example 237. Ethyl ester-amino-3-methyl-5-oxopyrrolidin-2 - pentanol acid (intermediate compound)

< / BR>
A solution of ethyl ester of N-(diphenylmethylene) glycine (Aldrich, 37 mmol) in THF (20 ml) is added at -78oC to a solution of bis (trimethylsilylmethyl) sodium (35 mmol, 0.5 M solution in THF), maintaining the solution temperature below -65oC. the resulting mixture was continued to stir at -72oC for 30 minutes, and then through the catheter quickly add the cooled solution (-72oC product of example 236 (24 mmole) in THF. Immediately remove the cooling and allow the mixture to warm to 0oC for 4 hours. The reaction mixture is partitioned between ether and 10% aqueous solution offered by the connection handle of 0.1 N. aqueous hydrochloric acid for 3 hours, and then extracted with ether and lyophilizers aqueous solution. Get a named connection.

Example 238. Ethyl ether -[[(1,1-dimethylmethoxy) carbonyl]amino]-3-methyl-5-oxopyrrolidin-2-pentanol acid (intermediate compound)

< / BR>
A solution of the compound of example 237 treated with di-tert.- BUTYLCARBAMATE in methylene chloride in the presence of triethylamine. The reaction mixture is extracted with water, dried with magnesium sulfate, filtered and evaporated. Get a named connection.

Example 239. Ethyl ether -[[(1,1-di methylethoxy)carbonyl] amino]-3,4-dihydro-5-methoxy-3-methylpyrrolidine-2-pentanol acid (intermediate compound)

< / BR>
The product of example 238 treated with tetrafluoroborate trimethylhexane by the method of example 26. Get a named connection.

Example 240. The dihydrochloride of ethyl ether-amino-5 - imino-3-methylpyrrolidine-2-pentanol acid

< / BR>
The product of example 239 in methanol is treated with ammonium chloride by the method of example 27. The resulting product is then treated with a mixture of 3 M HCl/ethyl acetate and get a named connection.

Example 241. Hexahydro-7-[(oxiran-2-yl)methyl]-1H-azepin-2 - he (intermediate soy is lotay (MJNBK, of 5.05 g, 29.3 mmole) for 3 hours. After stirring at room temperature over night adds extra MJNBK (1.0 g, 5.8 mmole) and the reaction mass is again boiled for 6 hours. The solvent is evaporated, the obtained residue is dissolved in ethyl acetate (150 ml) and washed with saturated sodium bicarbonate solution (g ml). Get the crude product, which was purified using quick column chromatography (silica gel, eluent 100% ethyl acetate), to Obtain 2.25 g (68%) of the named compound.

Example 242. Ethyl ether -[(diphenylmethylene)amino] hexahydro-7-oxo-1H-azepin-2-pentanol acid (intermediate compound)

< / BR>
From isomer In example 241 (1.0 g, 5,91 mmole) in THF (30 ml) receive anion when the processing at -78oC in argon atmosphere bis(trimethylsilyl)amidon lithium (5,91 mmole) in THF. The temperature of the resulting solution was raised to -60oC, and then again lowered to -78oC and add the anion of ethyl ester of N-(diphenylmethylene) glycine (obtained by reaction with bis(trimethylsilyl)amidon lithium in THF (5,91 mmole) at -78oC). The resulting solution was allowed to warm to room temperature over night. Add a saturated solution of ammonium chloride and then extrarodinary allocate a named connection.

Example 243. Ethyl ether -[(diphenylmethylene]amino]-3,4,5,6-tetrahydro- -dimethoxy-2H-azepin-2-pentanol acid (intermediate compound)

< / BR>
The product of example 242 treated with tetrafluoroborate trimethylhexane (2 equivalent) in methylene chloride according to the method of example 26. Get a named connection.

Example 244. The dihydrochloride of ethyl ether-amino-7 - imino- -methoxy-1H-azepin-2-pentanol acid

< / BR>
The product of example 243 in methanol is treated with ammonium chloride by the method of example 27. After lyophilization from aqueous hydrochloric acid will receive a named connection.

Example 245. Monohydrochloride ethyl ester 2-amino-5- (hexahydro-7-oxo-1H-azepin-2-yl)-3-pentanol acid (intermediate compound)

< / BR>
The product of example 242 stirred with aqueous hydrochloric acid and get a named connection.

Example 246. Monohydrochloride ethyl ester-aminohexyl-7-oxo-1H-azepin-2-pentanol acid

< / BR>
The product of example 245 restore by hydrogenation using a catalyst of palladium-on-charcoal grill. Get a named connection.

Example 247. Ethyl ester of hexahydro-7-oxo - a -[[(phenylmethoxy)-carbonyl]amino]-1H-azepin-2-pentane andartes technique. Get a named connection.

Example 248. Ethyl ester 3,4,5,6-tetrahydro-7 - methoxy - a -[[(phenylmethoxy)-carbonyl]amino]-2H-azepin-2 - pentanol acid (intermediate compound)

< / BR>
The product of example 247 treated with tetrafluoroborate trimethylhexane in methylene chloride according to the method of example 26. Get a named connection.

Example 249. Monohydrochloride ethyl ester hexahydro-7 - imino- -[[(phenylmethoxy)carbonyl]amino]-1H-azepin-2 - pentanol acid

< / BR>
The product of example 248 in methanol is treated with ammonium chloride by the method of example 27. Get a named connection.

Example 250. The dihydrochloride of ethyl ether-aminohexyl - 7-imino-1H-azepin-2-pentanol acid

< / BR>
The product of example 249 restore when the hydrogenation with hydrogen using a catalyst of palladium-on-charcoal grill. After lyophilization from aqueous hydrochloric acid will receive a named connection.

Example 251. The reaction of 2-(cyclohexen-1-yl)- cyclohexanone (intermediate compound)

< / BR>
According to the method of example 24 using hydroxylamine hydrochloride and sodium acetate in a mixture of ethanol and water transform 2-(1-cyclohexenyl)cyclohexanone in a named connection.

Example 253. 2-(Cyclohexen-1-yl)-3,4,5,6-tetrahydro-7 - methoxy-2H-azepin

< / BR>
The product of example 252 treated with tetrafluoroborate trimethylhexane in methylene chloride according to the method of example 26. Get a named connection.

Example 254. Monohydrochloride 7-(cyclohexen-1-yl)hexahydro - 1H-azepin-2-Amin (intermediate compound)

< / BR>
The product of example 253 in methanol is treated with ammonium chloride by the method of example 27. Get a named connection.

Example 255. The reaction of 2-(2-butenyl)cyclohexanone (intermediate compound)

< / BR>
According to the method of example 202 using potassium carbonate in DMF at 60oC 2-carbomethoxyamino treated with 1-bromo-2 - Butina with subsequent descarboethoxyloratadine in a boiling mixture of DMSO, lithium chloride and water and the subsequent conversion of the oxime using a mixture of hydroxylamine hydrochloride, sodium acetate, ethanol and water.

Example 256. 7-(2-butynyl)hexahydro - 1H-azepin-2-he (intermediate compound)

< / BR>
The product of example 255 turn to the named compound by the procedure of example 29 using benzosulfimide.

Example 257. 2-(2-butynyl)-3,4,5,6-Tetra-hydro-7-methoxy-2H - azepin (intermediate compound)
advanoe connection.

Example 258. Monohydrochloride 7-(2-butynyl)-hexahydro-1H - azepin-2-imine

< / BR>
The product of example 257 in methanol is treated with ammonium chloride by the method of example 27. Get a named connection.

Example 259. 1,1-Dimethylethyl-N-[1-ethynyl-4-(3-methyl-5 - oxopyrrolidin-2-yl)butyl]carbamate (intermediate compound)

< / BR>
To a solution of the product of example 238 (20 mmol) in dry toluene cooled to -78oC, with stirring, added dropwise a 1 M solution of diisobutylaluminium in toluene (40 ml, 40 mmol). The resulting solution was stirred for further 20 minutes and the methanol to stop the reaction. After removing the ice bath to the reaction mixture is added 150 ml of a saturated solution of Rochelle salt (potassium tartrate sodium). After stirring for 1 hour, the layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts washed with water, dried, filtered, evaporated. The resulting residue is purified using chromatography, receive aldehyde, which is directly used in the next stage. To a suspension of methyltriphenylphosphonium (2,18 g, 6.1 mmole) in ethyl ether with stirring, added dropwise a 0.5 M solution hexamethyldisilazide potassium in toluene (12,2 ml, 6.1 mmole) of the Ira. After 16 hours the white precipitate is filtered off and the filtrate evaporated. The resulting residue is purified using chromatography and get a named connection.

Example 260. 1,1-(Dimethylethyl)-N-[1-(1,2-dihydroxyethyl)-4-(3 - methyl-5-oxopyrrolidin-2-yl)butyl]carbamate (intermediate compound)

< / BR>
To a solution of compound of example 259 (3.3 mmole) in 80 ml of a mixture of acetone:water (3: 1) was added with stirring N-oxide N-methylmorpholine (0.64 g, 4.8 mmole) and 2.5% solution of osmium tetroxide in tert.-butanol (3.4 ml, 3.4 mmole). After 18 hours the reaction mixture are added 120 ml of water, 8 g of celite and 1.6 g of Na2S3O4. The mixture is then filtered through a layer of wet celite and to the filtrate add 200 ml of 1 M solution of KHSO4. The filtrate is extracted with ethyl acetate (CH ml). The combined organic layers dried, filtered and evaporated. The resulting residue is purified using chromatography. Get a named connection.

Example 261. 1,1-(Dimethylethyl)-N-[4-(3-methyl-2-oxopyrrolidin - 2-yl)-1-(2-oxo-1,3-dioxolane-4-yl)butyl]carbamate (intermediate compound)

< / BR>
The product of example 260 in pyridine is treated with phosgene in toluene for 1 hour. Get a named connection.

Example 262. 1,1-(Dimethylethyl)-N-[4-(3,4-dihydro-5-IU the product of example 261 treated with tetrafluoroborate trimethylhexane in methylene chloride according to the method of example 26. Get a named connection.

Example 263. The dihydrochloride of 4-(1-amino-4-(5-imino-3 - methylpyrrolidine-2-yl)butyl]-1,3-dioxolane-2-it

< / BR>
The product of example 262 in methanol is treated with ammonium chloride by the method of example 27. Then treated with a mixture of 3 M HCl/EtAc and get a named connection.

Example 264. 3-Amino-6-(5-aminopyridin-2-yl)-1,2 - hexanediol

< / BR>
The product of example 263 treated with an aqueous barium hydroxide at 70oC and get a named connection.

Example 265. 4-Methyl-5-(2-propenyl - pyrrolidin-2-he (intermediate compound)

< / BR>
The product of example 235 treated with p-toluensulfonate in boiling toluene using nozzles Dean-stark removal of water. The solvent is evaporated and get a named connection.

Example 266. 3,4-Dihydro-5-methoxy-3-methyl-2-(2-propenyl)-2H - pyrrole (intermediate compound)

< / BR>
The product of example 265 treated with tetrafluoroborate trimethylhexane in methylene chloride according to the method of example 26. Get a named connection.

Example 267. Monohydrochloride 4-methyl-5-(2-propenyl)pyrrolidin - 2-imine

< / BR>
The product of example 266 in methanol is treated with ammonium chloride by the method of example 27 and receive] carbamate intermediate connection)

< / BR>
The product of example 246 treated with di-tert.-BUTYLCARBAMATE by the method of example 238. The resulting product, containing protective Treatment group, treated with diisobutylaluminium (DIBAL), and then methyltriphenylphosphonium by the method of example 260. Get a named connection.

Example 269. 1,1-Dimethylethyl-N-[1-(1,2-dihydroxyethyl)-4- (hexahydro-7-oxo-1H-azepin-2-yl)butyl]carbamate (intermediate compound)

< / BR>
To the product of example 268 in a mixture of acetone and tetrahydrofuran added osmium tetroxide. Then add an aqueous solution of N-oxide of the research and the resulting mixture was stirred at room temperature overnight. Add sodium bisulfite and the mixture was diluted with ethyl acetate and washed with brine, dried, filtered and evaporated in vacuum the entire solvent. The resulting residue is purified by column chromatography and get a named connection.

Example 270. 1,1-Dimethylethyl-N-[4-(hexahydro-7-oxo-1H - azepin-2-yl)-1-(2-oxo-1,3-dioxolane-4-yl)-butyl]carbamate (intermediate compound)

< / BR>
The product of example 269 treated with phosgene by the method of example 261 and get a named connection.

Example 271. 1,1-Dimethylethyl-N-[1-(2-oxo-1,3-dioxolane-4-emer 270 treated with tetrafluoroborate trimethylhexane by the method of example 26. Get a named connection.

Example 272. The dihydrochloride of 4-[1-amino-4-(hexahydro-7-imino-1H - azepin-2-yl)butyl]-1,3-dioxolane-2-she (intermediate compound)

< / BR>
The product of example 271 in methanol is treated with ammonium chloride by the method of example 27. Then treated with a mixture of 3 M HCl/EtAc and get a named connection.

Example 273. 3-Amino-6-(hexahydro-7-imino-1H-azepin-2-yl) - 1,2-hexanediol

< / BR>
The product of example 272 treated with an aqueous barium hydroxide at 70oC and get a named connection.

Example 274. The dihydrochloride 2S-amino-3-[[(5-aminopyrrolidine-2S-yl)-methyl] oxy]propanoic acid

< / BR>
The product of example 229 2 N. hydrochloric acid is boiled for 1 hour. After lyophilization get a named connection.

Example 275. The oxime of hexahydro-7-(2-propenyl)- 1H-azepin-2-it

< / BR>
In a round bottom flask of 50 ml in the atmosphere of argon is added hydroxylamine hydrochloride (0.14 g, 2,02 mmole) and sodium methoxide (0,107 g, 1.99 mmole) in methanol (15 ml). To the resulting mixture is added the product of example 106 (0.29 grams, of 1.73 mmole). The reaction mixture is boiled for 12.5 hours, cooled to room temperature and vacuum evaporated solvent. The resulting product was then purified using the="ptx2">

Range PMR (400 MHz, D2O) : 5.9-5.8 (m, 1H), 5.3-5.15 (m, 2H), 3.8-3.7 (m, 1H), 2.75-2.65 (m, 1H), 2.6-2.4 (m, 3H), 2.0-1.85 (m, 3H), 1.75-1.6 (m, 1H), 1.55-1.4 (m, 2H).

Elemental analysis: C9H16N2O 1,3 HCl 1,1 H2O (molecular weight 235,46)

Calculated, %: C, 45.91, H 8.35, N 11.90, Cl 19.57;

Found, %: C, 45.96, H 8.17, N 11.65, Cl 19.67.

Example 276. The oxime of hexahydro-2-(2-propenyl)-1H-azepin-2-it

< / BR>
According to the method of example 275 from the compound of example 105 receive a named connection.

Range PMR (300 MHz, D2O) : 5.9-5.7 (m, 1H), 5.3-5.1 (m, 2H), 3.6-3.5 (m, 2H), 2.85-2.75 (m, 1H), 2.65-2.55 (m, 1H), 2.45-2.35 (m, 1H), 1.9-1.5 (m, 7H).

Elemental analysis: C9H16N2O1,05HCl0,5H2O (molecular weight 217,33)

Calculated, %: C 49.74, H 8.46, N 12.89, Cl 17.13;

Found, %: C, 49.73, H 8.11, At 12.82 N, Cl 17.30.

Example 277. Acetate 3-hydroxy-2-imino - 6-methylpiperidine

< / BR>
For the conversion of 3-hydroxy-6-methyl-2-nitropyridine in a named connection use the method of obtaining acetate 2-imino-4 - methylpiperidine, except that the reaction is carried out at a temperature of 55oC. give the product as a dark solid, which is recrystallized from a mixture of ethanol/ethyl acetate. Get a light amber crystals, so pl. 158-160oC.

Mass spectrum: M>/P>Elemental analysis: C8H16N2O30,15 H2O.

Calculated, %: C, 50.33, H 8.61, N 14.67;

Found, %: C, 50.33, H 8.54, N At 14.66.

Example 278. Hydrochloride 3-ethoxy-2-imino-6-methylpiperidine

< / BR>
For the conversion of 3-ethoxy-2-nitropyridine in a named connection use the method of obtaining acetate 2-imino-4 - methylpiperidine, except that the reaction is carried out at a temperature of 44oC. the Product is obtained as a dark oil and purified using C-18-obremenitve chromatography, eluent water/acetonitrile. The fraction containing the target product, lyophilizers, re-dissolved in 1 N. hydrochloric acid, receive the product as a pale yellow oil. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 143.

Range of TMR (D2O), 4.35-4.20 (m, 1H), 3.80-3.50 (m, 2H), 3.30 - 3.10 (m, 2H), 2.25-2.10 (m, 1H), 2.00-1.5 (m, 3H), 1.07 (d, J=7 Hz, 3H).

Example 279. Acetate 2-imino-decahydro-isoquinoline

< / BR>
In methanol (0.5 g) under stirring suspended 2-iminoisoindolin (1 g), palladium black (0.5 g) and ammonium formate (1 g). The reaction mass is stirred for 2 days (weekends) at 40oC and the catalyst is filtered off. The filtrate is evaporated to dryness, Gcta. Mass spectrum (ES-MS): MH+=147.

For the conversion of 3,4-benzo-2-aminopiperidine in a named connection use the method of obtaining acetate 2-imino-4 - methylpiperidine, except that as the catalyst using platinum oxide. The resulting product is recrystallized from a mixture of ethyl acetate with ethanol and receive a reddish-brown solid product. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+=153.

Range of TMR (D2O) : 3.40-3.10 (m, 3H), 2.60-2.40 (m, 1H), 2.20-1.00 (m, 10H), 1.75 (s, 3H).

Example 280. Acetate 2-amino-5,6,7,8-tetrahydroisoquinoline

< / BR>
For the conversion of 2-aminoisoquinoline in a named connection use the method of obtaining acetate 2-imino-4-methylpiperidine, except that as the catalyst using platinum oxide. The resulting product is triturated with ethanol, to obtain a white solid product. Data analyses confirm the structure of the obtained compounds.

Range of TMR (D2O) : 7.35 (d, J=6 Hz, 1H), 6.55 (d, J=6 Hz, 1H), 2.60-2.50 (m, 2H), 2.20-2.10 (m, 2H), 1.75 (s, 3H), 1.70-1.50 (m, 4H)

Elemental analysis: C11H16N2O20,15 H2O

Calculated, %: C, 63.44, H 7.74, N 13.45

Found, %: C, 63.22, H 7.89, N, 13.47.

Mass spectrum: MH+= 114.

Range of TMR (D2O) : 3.80-3.60 (m, 2H), 3.40-3.25 (m, 1H), 2.75 - 2.65 (m, 2H), 2.25-2.15 (m, 1H), 2.15-1.85 (m, 1H).

Elemental analysis: C5H13Cl2N3,

Calculated, %: C 32.27, H 7.04, N 22.58;

Found, %: C At 32.43, H 7.00, N 22.48.

Example 282. Hydrochloride of 2-imino-4-piperidinecarboxylic acid

< / BR>
For the conversion of 2-aminopyridine-4-carboxylic acid in a named connection use the method of obtaining acetate 2-imino - 4-methylpiperidine, except that as the catalyst using platinum oxide. The obtained product is dissolved in 3 N. hydrochloric acid and lyophilizers. Get white solid product, which is recrystallized from ethanol and receive a white solid. Data analyses confirm the line is 0 (m, 2H), 2.80-2.70 (m, 2H), 2.20-2.00 (m, 1H), 2.00-1.80 (m, 1H).

Elemental analysis: C6H11ClN2O2.

Calculated, %: C 40.35, H 6.21, N 15.68;

Found, %: C 40.43, H 6.20, N 15.29.

Example 283. The dihydrochloride of 5-amino-2-imino-4-methylpiperidine (CIS - and TRANS-isomers)

< / BR>
< / BR>
For the conversion of 2-amino-5-methyl-5-nitropyridine in a named connection use the technique to obtain hydrochloride 5-amino-2 - aminopiperidine. Get the product as white solids, which according to PMR spectrum contains two isomers. After recrystallization from a mixture of ethanol/ water get white solid product, which according to PMR spectrum contains a single isomer, which is pre-assigned the TRANS configuration. The mother liquor is concentrated under vacuum and dissolved in warm ethanol. After cooling to produce the first product that contains more of isomer A. the Second dropped the residue contains a mixture of isomers a and B. the Third residue is a pure isomer, which is attributed to the configuration of the CIS isomer. Data analysis confirmed the proposed structure of the obtained compounds.

Range PMR for isomer A (D2O) : 3.80-3.70 (m, 1H), 3.68-3.58 (m, 1H), 3.50-3.40 (m, 1H), 2.90-2.75 (m, 1H), 2.45-2.35 (m, 2H), 1.00 (d, J=7 Hz, 3H).

Elemental analysis.

Isomer A: C5H15Cl2N3(H2O) is Calculated, %: C 33.04, H 7.86, N 19.26;

Found, %: C 33.01, H 7.39, N 19.20.

Isomer B: C6H15Cl2N3(0,4 H2O) is Calculated, %: C 34.76, H 7.68, N 20.27;

Found, %: C 34.53, H 7.54, N 20.67.

Example 284. Hydrochloride ethyl ester (2'-imino)-2-(3' -piperidinyloxy)-acetic acid

< / BR>
In anhydrous DMF (75 ml) for 15 minutes mix 3-hydroxy-2-nitropyridine (5 g) and anhydrous potassium carbonate (5 g). Then add ethylbromoacetate, the resulting reaction mass is stirred overnight, poured into ice water and extracted with ethyl acetate (CH ml). An ethyl acetate extracts are combined, dried with magnesium sulfate, evaporated in vacuum and get 2'-nitro-2-(3'-pyridyloxy)acetate as a light yellow solid product (6.6 g).

For the conversion of 2'-nitro-2-(3'-pyridyloxy)acetate in a named connection use the technique to obtain hydrochloride 5-amino-2-aminopiperidine. After cleaning with the help of 18-To-obremenitve chromatography and recrystallization from a mixture of ethanol/ethyl acetate to give the product as a white solid.

Data analyses confirm the structure obtained is>
0,25 H2O

Calculated, %: C 44.82, H 7.31, N, 11.61;

Found, %: C, 44.92, H 7.62, N, 11.75.

Example 285. Acetate 2-imino-5-(n-butyl)- piperidine

< / BR>
During the night boil the mixture husarova acid (2 g), diphenylphosphinite (2.4 ml) and triethylamine (1.6 ml) in tert.- butanol (70 ml), the Reaction mass is then evaporated in vacuo and treated with 25% aqueous HBr (20 ml) for 24 hours. After neutralization with 50% NaOH solution, the reaction mass is extracted with methylene chloride, dried with magnesium sulfate and evaporated in vacuum. Get 2-amino-5-(n-butyl) pyridine as an oil (1.1 g).

For the conversion of 2-amino-5-(n-butyl) pyridine in a named connection use the technique of 2-imino-4-methylpiperidine, except that as the catalyst using platinum oxide. The resulting product is triturated with ether and get a solid white product. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 155.

Range of TMR (D2O) : 3.35-3.25 (m, 1H), 2.85-2.75 (m, 1H), 2.60 - 2.35 (m, 2H), 1.85-1.55 (m, 2H), 1.75 (s, 3H), 1.35-1.05 (m, 7H), 0.75 - 0.65 (m, 3H).

Example 286. Hydrochloride of 2-imino-5-(trifluoromethyl)piperidine

< / BR>
For the conversion of 2-amino-3-chloro-5-(trifluoromethyl)pyridine in a named connection is allsouth oxide of platinum. The resulting product is triturated with ether and emit a white solid. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 167.

Range of TMR (D2O) : 3.65-3.50 (m, 1H), 3.40-3.20 (m, 1H), 2.85 - 2.45 (m, 3H), 2.15-2.00 (m, 1H), 1.80-1.60 (m, 1H).

Elemental analysis: C6H10Cl2F3N2(0,1 H2O).

Calculated, %: C 35.26, H 5.03, N 13.70;

Found, %: C 34.91, H 4.97, N, 13.64.

Example 287. O-[3-(2-aminopiperidine)]-4-amino-1-butanol

< / BR>
In anhydrous DMF (75 ml) for 15 minutes mix 3-hydroxy-2-nitropyridine (5 g) and anhydrous potassium carbonate (5 g). Then add 4-bromobutyronitrile (3.6 ml), the resulting reaction mass is stirred overnight, poured into ice water and filtered 4-[2'-nitro-(3'-pyridyloxy)]-butyronitrile in the form of a white solid product.

For the conversion of 4-[2'-nitro-(3'-pyridyloxy)]butyronitrile in a named connection use the method of obtaining acetate 2-imino - 4-methylpiperidine, except that as the catalyst using platinum oxide. After cleaning with the help of 18-To-obremenitve chromatography and recrystallization from a mixture of ethanol/ethyl acetate to give the product as a white firm is = 185.

Range of TMR (D2O) : 3.75-3.65 (m, 1H), 3.50-3.40 (m, 2H), 3.30-2.85 (m, 6H), 1.80-1.45 (m, 8H).

Elemental analysis: C9H21ClN3O.

Calculated, %: C 41.88, H 8.20, N 16.28;

Found, %: C 41.83, H 8.33, N 15.98.

Example 288. Dihydrobromide 4-amino-2-aminopiperidine

< / BR>
A mixture of 4-amino-3,5,6-trichloropicolinic acid (1.0 g), diphenylphosphinite (1.0 ml) and triethylamine (0.6 ml) in tert.- butanol (35 ml) is boiled during the night. The reaction mass is evaporated in vacuum, get a solid residue, which is treated with 25% aqueous HBr (20 ml) for 24 hours. Filter out dihydrobromide 2,4-diamino-3,5,6-trichloropyridine in the form of a light yellow solid product (1.2 g).

In the hydrogenation apparatus Parra for 48 hours under hydrogen pressure of 55 pounds per square inch (3,74 ATM) shake dihydrobromide 2,4-diamino-3,5,6-trichloropyridine (1.1 g) and platinum oxide (520 mg) in ethanol (50 ml). The reaction mass is filtered and the filtrate evaporated in vacuum, get a waxy solid product, which was triturated in a mixture of ether and ethyl acetate. Get dihydrobromide 4-amino-2-aminopiperidine in the form of a white solid product. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 114.

Range Plored 5-aminomethyl-2-imino-4,6 - dimethylpiperidine

< / BR>
For the conversion of 2-amino-5-cyano-4,6-dimethylpyridine in a named connection use the method of obtaining acetate 2-imino - 4-methylpyridine, except that as the catalyst using platinum oxide. The product is treated with ethanol and receive a white solid. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 156.

Range of TMR (D2O) : 3.63-3.40 (m, 2H), 3.20-3.05 (m, 1H), 2.70-2.58 (m, 1H), 2.40-2.20 (m, 1H), 2.05-1.80 (m, 2H), 1.22 (d, J= 7 Hz, 3H), 0.95 (d, J=7 Hz, 3H).

Example 290. Hydrochloride of 2-imino-6-methyl-4-(trifluoromethyl) piperidine

< / BR>
In a steel reactor, equipped with a mechanical stirrer, overnight at a temperature of 180oC withstand a mixture of 2-chloro-6-methyl-4-(trifluoromethyl) pyridine (5.0 g) and conc. ammonium hydroxide (150 ml). The reaction mass is then cooled and distributed between methylene chloride and water. Methylenchloride layer is dried with magnesium sulfate and evaporated in vacuum. Get 2-amino-6 - methyl-4-(trifluoromethyl)pyridine in the form of a white solid.

For the conversion of 2-amino-6-methyl-4-(trifluoromethyl)pyridine in a named connection use the method of obtaining acetate 2-imino - 4-methylpiperidine. The resulting product is triturated with what about the connection.

Mass spectrum: MH+= 181.

Range of TMR (D2O) : 3.60-3.40 (m, 1H), 2.80-2.50 (m, 3H), 2.20-2.05 (m, 1H), 1.42-1.25 (m, 1H), 1.15 J=7 Hz, 3H).

Elemental analysis: C7H12ClF3N20,25 H2O

Calculated, %: C 38.02, H 5.70, N AT 12.67;

Found, %: C At 37.98, H 5.54, N, 12.84.

Example 291. Hydrochloride of 2-imino-4-(trifluoromethyl)piperidine

< / BR>
For the conversion of 2-chloro-4-(trifluoromethyl)pyridine 2-amino-4- (trifluoromethyl) pyridine using the method of obtaining 2-amino-6 - methyl-4-(trifluoromethyl)pyridine.

For the conversion of 2-amino-4-(trifluoromethyl) pyridine in a named connection use the method of obtaining acetate 2-imino-4 - methylpiperidine. The resulting product is triturated with ethyl acetate and receive a white solid product. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 167.

Range of TMR (D2O) : 3.45-3.35 (m, 1H), 3.30-3.20 (m, 1H), 2.85-2.55 (m, 3H), 2.10-2.00 (m, 1H), 1.80-1.60 (m, 1H).

Elemental analysis: C6H10ClF3N2.

Calculated, %: C 35.57, H 4.98, N 13.83;

Found, %: C 35.17, H 4.76, N 13.70.

Example 292. Triptorelin 2-imino-3-(trifluoromethyl)piperidine

< / BR>
For the conversion of 2-chloro-3-(trifluoromethyl) pyridine 2-amino-3- (trifluoromethyl) amino-3-(trifluoromethyl) pyridine in a named connection use the method of obtaining acetate 2-imino-4 - methylpiperidine. The resulting product is crystallized with a mixture of ethyl acetate/hexane and receive a white solid product. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 167.

Range of TMR (D2O) : 3.70-3.50 (m, 1H), 3.35-3.20 (m, 2H), 2.10-1.60 (m, 4H).

Elemental analysis: C8H10F6N2O2.

Calculated, %: C 34.30, H 3.60, N 10.00,

Found, %: C 34.55, H 3.65, N 10.01.

Example 293. Acetate 2-imino-6-(trifluoromethyl)piperidine

< / BR>
For the conversion of 2-chloro-6-(trifluoromethyl)pyridine 2-amino-6- (trifluoromethyl) pyridine using the method of obtaining 2-amino-6 - methyl-4- (trifluoromethyl) pyridine.

For the conversion of 2-amino-6-(trifluoromethyl) pyridine in a named connection use the method of obtaining acetate 2-imino-4 - methylpiperidine. The resulting product is crystallized from ethyl acetate and receive a white solid product. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 167.

Range of TMR (D2O) : 4.20-4.00 (m, 1H), 2.60-2.50 (m, 2H), 2.05-1.50 (m, 4H), 1.80 (c, 3H).

Example 294. Acetate 2-imino-4-(n-propyl)- piperidine

< / BR>
For the conversion of 2-amino-4-(n-propyl)pyridine in a named connection using the technique of the d platinum. The resulting product is triturated with ethyl acetate and receive a white solid. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 141.

Range of TMR (D2O) : 3.35-3.05 (m, 2H), 2.60-2.40 (m, 1H), 2.15 - 2.00 (m, 1H), 1.80-1.60 (m, 2H), 1.78 (c, 3H), 1.35-1.05 (m, 5H), 0.75 - 0.65 (m, 3H).

Example 295. Acetate 2-imino-4-(ethyl)-piperidine

< / BR>
For the conversion of 2-amino-4-(n-ethyl)pyridine in a named connection use the method of obtaining acetate 2-imino-4 - methylpiperidine, except that as the catalyst using platinum oxide. The resulting product is crystallized from cold ethyl acetate and receive a white solid. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 127.

Range of TMR (D2O) : 3.40-3.25 (m, 1H), 3.22-3.10 (m, 1H), 2.60 - 2.50 (m, 1H), 2.15-2.00 (m, 1H), 1.85-1.75 (m, 1H), 1.78 (s, 3H), 1.70 - 1.60 (m, 1H), 1.35-1.15 (m, 3H), 0.75 (t, J=7 Hz, 3H).

Example 296. Hydrochloride 2-aminodimethylaniline

< / BR>
To a solution of tetrafluoroborate trimethylhexane (1 g, 0,0067 mol) in 10 ml of anhydrous chloroform is added 2-azocyclotin-decane (1,33 g, 0,0067 mol). The resulting mixture is boiled under stirring for 4 hours and 18 hours at 25oC. Then , altroot and evaporated. Obtain 1.3 g of rose oil. The oil obtained is dissolved in 25 ml of methanol and added 0.33 g (0,0067 mole) of ammonium chloride and stirred at 25oC for 72 hours, then the mixture is evaporated and obtain 0.6 g of a white solid. The resulting material is treated with water, filtered and the filtrate lyophilizer. Receive hydrochloride 2-aminodimethylaniline in the form of a fluffy solid product.

Mass spectrum: M+H = 197.

Range of TMR (D2O) : 1.10-1.30 (m, 14H), 1.45-1.65 (m, 4H), 2.35 (m, 2H), 3.2 (m, 2H).

Elemental analysis: C12H25ClN22/3NH4Cl.

Calculated, %: C, 53.65, H 10.39, at 13.92 N,

Found, %: C, 53.42, H 10.32, N 13.58.

Example 297. Triptorelin 2-imino-6-cyclopentenopyridine

< / BR>
To a solution of tetrafluoroborate trimethylhexane (1 g, 0,0067 mol) in 20 ml of anhydrous chloroform add 6-cyclopentylphenol (0.5 g, of 0.003 mol). The resulting mixture is boiled under stirring for 3 hours. Then the reaction mass is cooled to 25oC, washed with diluted sodium bicarbonate, dried with magnesium sulfate, filtered and evaporated. Receives a yellow oil. The oil obtained is dissolved in 25 ml of methanol and added 0.16 g of ammonium chloride and stirred prasowania (C-18) was isolated pure trifenatate salt of 2-imino-6 - cyclopentenopyridine in the form of a white solid product.

Mass spectrum: M+H = 167.

Range of TMR (D2O) : 1.05-1.20 (m, 2H), 1.35-1.95 (m, 11H), 2.3-2.55 (m, 2H), 3.15-3.25 (m, 1H).

Example 298. Acetate (2 ethylimino)-4 - methylpiperidine

< / BR>
Hydrobromic acid (48%, to 39.5 ml) cooled to 0oC and add 2-amino-4-picoline (Aldrich., 8.6 g, 0.08 mol). Then slowly dropwise at 0oC add bromine (12 ml, 0,234 mol), and then also at 0oC add a solution of sodium nitrite (14.0 g) in water (20 ml). The resulting reaction mass is stirred for 1-1/2 hours at 0oC and add 50% aqueous sodium hydroxide solution (60 g), while maintaining the temperature of the mixture is not more than 20oC. the Reaction mass is stirred for 1 hour and extracted with ether (CH ml). The ether layers are combined and dried pellets of potassium hydroxide for 1 hour, filtered and evaporated in vacuum. Get orange oil (12.4 g). The oil obtained is distilled on the device using a diffusion pump (Kugelrohr-device) at 40oC (0.25 mm), get 2-bromo-4-methylpyridin in the form of a yellow oil (10.3 g).

In a steel reactor at a temperature of 150oC during the night stand mixture of 2-bromo-4-methylpyridine (1.5 g, of 0.02 mol) and aqueous ethylamine (70%, 100 ml). The reaction mass is then cooled and evaporated in HAC is Trat evaporated in vacuum, receive oil (950 mg). The oil obtained is distilled using a diffusion pump (kugelrohr device) at the 90o(0.35 mm), get 2-(ethylamino)-4-methylpyridin in the form of a white solid connection (670 mg).

For the conversion of 2-(ethylamino)-4-methylpyridine in a named connection use the method of obtaining acetate 2-imino-4 - methylpiperidine, except that as the catalyst added platinum oxide. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 141.

Range of TMR (D2O) : 3.40-3.10 (m, 2H), 3.00 (sq J=6 Hz, 2H), 2.50-2.40 (m, 1H), 2.10-1.90 (m, 1H), 1.83 (s, 3H), 1.80-1.65 (m, 4H), 1.40-1.20 (m, 1H), 1.02 (t, J=6 Hz, 3H), 0.83 (d, J=6 Hz, 3H).

Example 299. Hydrochloride of 2-(N, N-dimethylamino)-4-methyl - 3,4,5,6-tetrahydropyridine (intermediate compound)

< / BR>
For the conversion of 2-bromo-4-methylpyridine 2-(N,N-dimethylamino)- 4-methylpyridin use the technique to obtain 2-(ethylamino)-4-methylpyridine.

For the conversion of 2-(N, N-dimethylamino)-4-methylpyridine in a named connection use the method of obtaining acetate 2-imino - 4-methylpiperidine, except that as the catalyst added platinum oxide. Get the product in the form of a colorless transparent by weight of the aqueous colorless solid. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 141.

Range of TMR (D2O) : 3.44-3.32 (m, 1H), 3.23-3.16 (m, 1H), 3.00 (s, 3H), 2.90 (s, 3H), 2.76-2.64 (m, 1H), 2.08-1.94 (m, 1H), 1.88 - 1.68 (m, 2H), 1.35-1.18 (m, 1H), 0.52 (d, J=6 Hz, 3H).

Example 300. The dihydrochloride of 2'-(2-amino-ethylamino)-5'- (trifluoromethyl) piperidine (intermediate compound)

< / BR>
For the conversion of 2'-(2-aminoethylamino)-3'-chloro-5'- (trifluoromethyl) pyridine in a named connection use the method of obtaining acetate 2-imino-4-methylpiperidine. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 210.

Range of TMR (D2O) : 3.70-3.35 (m, 4H), 3.18 (q, J=6 Hz, 2H), 2.95-2.60 (m, 3H), 2.20-2.00 (m, 1H), 1.90-1.70 (m, 1H).

Example 301. The hydrochloride of 6-benzyl-2 - aminopiperidin

< / BR>
A mixture of 2-benzylpyridine (Aldrich, 2.5 g, 0,015 mol), sodium amide (780 mg, of 0.02 mol) and N,N-dimethylaniline (25 ml) is boiled during the night. The reaction mass is then cooled and partitioned between ether and water. The ether layer is dried with magnesium sulfate and evaporated in vacuum. The resulting oil purified by chromatography and then dissolved in 1 N. hydrochloric acid, lyophilizers and triturated with ethyl acetate. Get 2-amino-6 - benzylpyridine as white is the odik obtain 2-imino-4-methylpiperidine. Get the oil, which is purified using C-18-obremenitve chromatography. Get white solid product, which was dissolved in 1 N. hydrochloric acid, lyophilizers and recrystallized from a mixture of ethanol/ethyl acetate. Get a named connection in the form of a white solid. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 189.

Range of TMR (D2O) : 9.85 (s, 1H), 8.95 (s, 1H), at 8.62 (s, 1H), 7.40-7.10 (m, 5H), 3.80-3.60 (m, 1H), 3.20-3.00 (m, 1H), 2.90-2.70 (m, 2H), 2.65-2.45 (m, 1H), 2.42-2.25 (m, 2H), 1.92 (m, 2H), 1.75 (m, 1H), 1.50-1.35 (m, 1H).

Example 302. Hydrochloride of 2-(cyclohexylmethyl)-6 - aminopiperidine

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For the conversion of 2-amino-6-benzylpiperidine in a named connection use the method of obtaining acetate 2-imino-4 - methylpiperidine, except that as the catalyst added platinum oxide. Obtained in the form of oil product was dissolved in 1 N. hydrochloric acid and lyophilizers. Get white solid product, which is recrystallized from ethyl acetate and get a named connection in the form of a white crystalline substance. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 195.

Range PMR (CDCl3) : 9 303. Hydrochloride of 2-cyclohexyl-6-aminopiperidine

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For the conversion of 2-vinylpyridine (Aldrich) in 2-amino-6 - phenylpyridine use the technique to obtain 2-amino-6-benzylpyridine.

For the conversion of 2-amino-6-phenylpyridine in a named connection use the method of producing acetate 2-imino-4-methylpiperidine, except that the reaction is carried out at 55oC. Receive the product in the form of oil, which is crystallized from a mixture of ethanol/ethyl acetate. Allocate a named connection in the form of a white solid.

Mass spectrum: MH+= 181.

Range PMR (CDCl3) : 3.30-3.15 (m, 1H), 2.50-2.30 (m, 2H), 1.85-1.68 (m, 2H), 1.65-1.20 (m, 8H), 1.20-0.80 (m, 5H).

Example 304. Acetate 4 methylpiperidin-2-hydrazone

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For the conversion of 2-hydrazinopyridazine (Aldrich) in a named connection use the method of obtaining acetate 2-imino-4-methylpiperidine, except that the reaction is carried out in a mixture of glacial acetic acid/water (2: 1) to ensure the solubility of the reagents and the catalyst using platinum oxide. Get the product in the form of a colorless oil, which crystallized with ethyl acetate and recrystallized from ethanol. Get a named connection in the form of white S="ptx2">

Range PMR (CDCl3) : 3.15-1.10 (m, 2H), 2.60-2.50 (m, 2H), 1.98 (s, 3H), 1.80-1.60 (m, 4H).

Example 305. The hydrochloride of 4-methyl-2-(propylimino) piperidine

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For the conversion of the hydrochloride of 4-methyl-2-(propylamino) piperidine in a named connection use a method of obtaining acetate 2-(ethylamino)-4-methylpiperidine. Get the product in the form of a colorless oil, which crystallized with ethyl acetate. Data analyses confirm the structure of the obtained compounds.

Mass spectrum: MH+= 155.

Range of TMR (D2O) : 3.45-3.20 (m, 2H), 3.05 (t, J=6 Hz, 2H), 2.60-2.45 (m, 1H), 2.20-2.00 (m ), 1.95-1.70 (m, 2H), 1.60 - 1.40 (m, 2H), 1.40-1.25 (m, 1H), 0.90 (d, J =6 Hz, 3H), 0.80 (t, J=6 Hz, 3H).

Example 306. Itestosterone salt of 2-aminohexanoate J. Med. Chem 21(10), 1044-1054 (1978)

< / BR>
To a solution of timeproperty (5 g, 0,039 mol) in 100 ml of acetone add iodine methane (6.4 g, 0,045 mol). The resulting mixture was stirred for 2 days at 25oC. Filtered 9.5 g idiscovered salt tominoufiya in the form of a white solid substance, so pl. 177-181oC. the resulting aminoester (3 g) is dissolved in 80 ml of ethanol saturated with anhydrous ammonia. The resulting mixture was sealed and stirred at 25oC for 3 days, evaporated to reduce the volume, and then when the LASS="ptx2">

Mass spectrum, M+N = 113.

Range of TMR (D2O) : 1.45-1.55 (m, 2H), 1.55-1.7 (m, 4H), 2.5 (m, 2H), 3.28 (m, 2H).

Elemental analysis: C6H13N2I.

Calculated, %; C 30.02, H 5.46, N 11,67,

Found, %: C 29.99, H 5.49, N, 11.61.

Example 307. Itestosterone salt of 2-(methylimino)hexamethylenimine

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To a solution of tominoufiya example 306 (1 g, 0,0037 mole) add 40 ml of ethanol saturated with anhydrous methylamine. The resulting mixture was sealed and stirred at 25oC for 3 days, evaporated to reduce the volume, and then when rubbing with ether to obtain 0.9 g of the named compound as a white solid, so pl. 169 -171oC.

Mass spectrum: M+H = 127.

Range of TMR (D2O) : 1.45-1.65 (m,6N), 2.48 (m, 2H), 2,68 (s, 3H), 3.3 (m, 2H).

Elemental analysis: C7H15N2I.

Calculated, %: C 33.09, H 5.95, N 11.02,

Found, %: C At 33.31, H 5.94, N 10.97.

Example 308. Itestosterone salt of 1-methyl-2 - aminopentanedioic

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To a solution of N-methyldiethanolamine (2 g, 0,0155 mol) in 40 ml of acetone add iodine methane (2.4 g, is 0.017 mol).

The resulting mixture was stirred for 3 days at 25oC, filtered and triturated with ether. Get 4 g idiscoveri dissolved in 50 ml of ethanol, saturated with anhydrous ammonia. The resulting mixture was sealed and stirred at 25oC for 18 hours, evaporated to reduce the volume and then triturated with ether. Allocate 0.8 g of the named compound as a white solid, so pl. 157 - 158oC.

Mass spectrum: M+H = 113.

Range of TMR (D2O) : to 1.60-1.70 (m, 2H), 1.70-1.8 (m, 2H), 2,5 (t, 2H), 2.95 (s, 3H), 3.38 (t, 2H).

Elemental analysis: C6H13N2I.

Calculated, %: C 30.02, H 5.46, N 11,67,

Found, %: C 30.16, H 5.49, N, 11.63.

Example 309. Itestosterone salt of 1-methyl-2 - aminohexanoate

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To a solution of N-methylthiocarbamate (2 g, of 0.014 mmole) in 40 ml of acetone add iodine methane (2,18 g, 0,0154 mol). The resulting mixture was stirred for 3 days at 25oC, filtered and triturated with ether. Obtain 3.8 g idiscovered salt tominoufiya in the form of a white solid substance, so square 138-142oC. One gram of the obtained aminoether dissolved in 50 ml of ethanol saturated with anhydrous ammonia. The resulting mixture was sealed and stirred at 25oC for 18 hours, evaporated to reduce the volume and then triturated with ether. Allocate 0.8 g of the named compound as a white solid, so pl. 137-12H).

Elemental analysis: C7H15N2I.

Calculated, %: C 33.09, H 5.95, N 11.02,

Found, %: C 33.12, H 6.01, N 11.07.

Example 310. Itestosterone salt of 2-(triptorelin) pentamethylenebis

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A mixture of P4S10(100 g to 0.23 mol) and Na2CO3(24 g to 0.23 mol) in anhydrous THF (1.5 l) intensively stirred with a mechanical stirrer for 30 minutes. To the resulting mixture while stirring valerolactam (19 g, to 0.19 mol). After stirring for 3 hours the solution was diluted with 1 l of 10% aqueous solution of Na3PO4, 750 ml of ethyl acetate and 750 ml of hexane. The organic layer is separated and the aqueous layer was extracted with ethyl acetate (500 ml). The organic extracts are combined, dried with magnesium sulfate, filtered through silica gel and evaporated. Get a white semi-solid connection. When rubbing in a mixture of hexane-ether to obtain 9.7 g of chivalrously in the form of a white solid substance, so pl. 85-88oC. To a solution of towleroad.com (9 g, 0,078 mol) in 100 ml of acetone add itmean (11.8 g, 0,083 mol). The resulting mixture is stirred for 18 hours at 25oC, filtered and triturated with ether. Get 18,5 g idiscovered salt tominoufiya in the form of a white solid. To restoration close and stirred at 25oC for 18 hours, evaporated the solvent, allocate a named connection in the form of a white solid.

Mass spectrum: M+N = 181.

Range of TMR (D2O) : 1.65-1.70 (m, 4H), 2.58 (m, 2H), 3.32 (m, 2H), 3.95 (q, 2H).

Example 311. Itestosterone salt of 2-(cyclohexylamino) pentamethylenebis

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To a solution of tominoufiya (0.2 g, 0,00077 mol) of example RKW-E in 3 ml ethanol add cyclohexylamine (0.08 g, 0,0008 mol). The resulting mixture was sealed and stirred at 25oC for 18 hours. After evaporation of the solvent receive a named connection in the form of a white solid.

Mass spectrum: M+N = 181.

Range of TMR (D2O) : 1.10-1.30 (m, 6H), 1.45-1.9 (m,10H), 2.42 (t, 2H), 3.25 (t, 3H), 3.95 (q, 2H).

Example 312. Itestosterone salt of 2-(dimethylaminopropylamine) pentamethylenebis

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To a solution of tominoufiya (0.2 g, 0,00077 mol) of example RKW-E in 3 ml of ethanol is added N, N-dimethylaminopropylamine (0.08 g, 0,0008 mol). The resulting mixture was sealed and stirred at 25oC for 18 hours. After evaporation of the solvent receive a named connection in the form of a white solid.

Mass spectrum: M+N = 184.

Range of TMR (D2O) : 1.60-1.75 (m, 6H), 2.1 (s, 6 is in

< / BR>
To a solution of tominoufiya (0.2 g, 0,00077 mol) of example RKW-E in 3 ml of ethanol is added 2 ml of ethanol saturated with anhydrous methylamine. The resulting mixture was sealed and stirred at 25oC for 18 hours. After evaporation of the solvent receive a named connection in the form of a white solid.

Mass spectrum: M+H = 113.

Range of TMR (D2O) : 1.60-1.70 (m, 4H), 2.45 (t, 2H), 2.7 (s, 3H), 3.30 (t, 2H).

Example 314. Itestosterone salt of 2-(benzylamino) pentamethylenebis

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To a solution of tominoufiya (0.2 g, 0,00077 mol) of example RKW-E in 3 ml ethanol add benzylamine (0.08 g, 0,0008 mol). The resulting mixture was sealed and stirred at 25oC for 19 hours. After evaporation of the solvent receive a named connection in the form of a white solid.

Mass spectrum: M+H =189.

Example 315. Itestosterone salt of 2-(ventilationprofile) pentamethylenebis

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To a solution of tominoufiya (0.2 g, 0,00077 mol) of example RKW-E in 3 ml ethanol add phenethylamine (0.09 g, 0,0008 mol). The resulting mixture was sealed and stirred at 25oC for 18 hours. After evaporation of the solvent receive a named connection in the form of a white solid, .4 (t, 2H), 7.18-7.3 (m,5H).

Example 316. Itestosterone salt of 2-(p-methoxyphenethylamine) pentamethylenebis

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To a solution of tominoufiya (0.2 g, 0,00077 mol) of example RKW-E in 3 ml of ethanol is added p-methoxyphenethylamine (0.12 g, 0,0008 mol). The resulting mixture was sealed and stirred at 25oC for 18 hours. After evaporation of the solvent receive a named connection in the form of a white solid.

Mass spectrum: M+H = 233.

Range of TMR (D2O) : 1.6 (m, 4H), 2.18 (m, 2H), 2.75 (t, 2H), 3.05 (m, 2H), 3.25 (t, 2H), 3.7 (s, 3H), 6.85 (d, 2H), 7.1 (d, 2H).

Example 317. Itestosterone salt of 2-(3-hydroxypropylamino) pentamethylenebis

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To a solution of tominoufiya (0.2 g, 0,00077 mol) of example RKW-E in 3 ml of ethanol is added 3-hydroxypropylamino (0.06 g, 0,0008 mol). The resulting mixture was sealed and stirred at 25oC for 18 hours. After evaporation of the solvent receive a named connection in the form of a white solid.

Mass spectrum: M+H = 157.

Range of TMR (D2O) : 1.6-1.8 (m,6N), 2.45 (t, 2H), 3.15 (t, 2H), 3.28 (t, 2H), 3.55 (t, 2H).

Example 318. Hydrochloride of 2-imino-6-paxilphentermine: hydrochloride of 2-imino-3-paxilphentermine, 5 : 3

< / BR>
To a solution of 2-vexillata sodium (9 g, of 0.11 mol). The resulting mixture is stirred at boiling for 4 hours and at 25oC for 18 hours. The reaction mass is evaporated to reduce the volume, diluted with ethyl acetate, washed with aqueous solution of sodium chloride (g ml), dried with magnesium sulfate, filtered and evaporated. Obtain 10.2 g of 2-exercitationem in the form of a colorless oil. A solution of oxime (8 g, 0,044 mol) in acetone (50 ml) at 0oC handle 1 N. a solution of sodium hydroxide (48,4 ml, 0,0484 mol). To the obtained mixture under stirring is added dropwise benzosulphochloride (8.1 g, 0.046 mol) and stirred at 25oC for 18 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with an aqueous solution of sodium chloride, dried with magnesium sulfate, filtered and evaporated. Get 8 g of yellow oil. After chromatography was carried out (C-18, eluent: 10% acetonitrile/water to 70% acetonitrile/water) to 2 g of the obtained oil allocate 1.5 g of a mixture of 6-exillerating and 3-exillerating in the ratio 2: 1. To a solution of thriftimart trimethylhexane (1.5 g, of 0.01 mole) in methylene chloride (35 ml) add the specified mixture of valerolactam (1.5 g, 0,0082 mol) and stirred for 18 hours at 25oC. Then Rea is Agnes, filtered through a layer of silica gel and evaporated. Obtain 0.6 g of aminoether in the form of a yellow oil. The oil obtained is dissolved in 40 ml of methanol and add ammonium chloride (0.18 g, 0,0034 mol). After stirring at the boiling temperature for 4 hours, the reaction mass is stirred for a further 18 hours at 25oC, then the solvent is distilled off. The resulting residue is dissolved in water and extracted with ethyl acetate. The aqueous layer was lyophilizer and obtain 0.16 g of the mixture of the hydrochloride of 2-imino-6-paxilphentermine hydrochloride and 2-imino-3-paxilphentermine in the ratio 5:3 in the form of a white solid.

Mass spectrum: M+H = 183.

Range of TMR (D2O) : 0.72 (t, 3H), 1.1-1.9 (m, 14N), 2.3-2.62 (m, 2H), 3.2 (t,3-isomer), 3.38 (t,6-isomer).

Elemental analysis: C11H23ClN23NH4Cl3/4H2O.

Calculated, %: C 33.64, N 9.34, N 17.83,

Found, %: C 33.82, H 9.20, N 17.97.

Example 319. Hydrochloride of 2-imino-6-heptylaniline: hydrochloride of 2-imino-3-heptylaniline, 3:1

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To a solution of 2-heptylcyclopentanone (10 g, by 0.055 mole) in ethanol (75 ml) and water (50 ml) is added hydroxylamine hydrochloride (5.8 g, 0,083 mol) and sodium acetate (8,3 g of 0.1 mol). The resulting mixture is stirred at the boiling those who with ethyl acetate, washed with aqueous solution of sodium chloride (g ml), dried with magnesium sulfate, filtered and evaporated. Get 10 g of 2-heptylcyclopentanone in the form of a colorless oil. A solution of oxime (8 g of 0.04 mol) in acetone (50 ml) at 0oC handle 1 N. a solution of sodium hydroxide (48,4 ml, 0,0484 mol). To the obtained mixture under stirring is added dropwise benzosulphochloride (7,4 g 0,042 mol) and stirred at 25oC for 18 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with an aqueous solution of sodium chloride, dried with magnesium sulfate, filtered and evaporated. Get 8 g of yellow oil. After chromatography was carried out (C-18, eluent 10% acetonitrile/water to 70% acetonitrile/water) to 2 g of the obtained oils emit 1.1 g of a mixture of 6-heptylaniline and 3-heptylaniline. To a solution of thriftimart trimethylhexane (1 g, to 0.007 mol) in methylene chloride (25 ml) add the specified mixture of valerolactam (1.1 g, 0,0056 mol) and stirred for 18 hours at 25oC. Then the reaction mass is diluted with ethyl acetate, washed with dilute potassium carbonate solution, dried with magnesium sulfate, filtered through a layer of silica gel and evaporated. Obtain 0.6 g of aminoether in the form of a yellow Ivania at boiling point for 4 hours, the reaction mass is stirred for a further 18 hours at 25oC, then the solvent is distilled off. The resulting residue is dissolved in water and extracted with ethyl acetate. The aqueous layer was lyophilizer and obtain 0.31 g of a mixture of the hydrochloride of 2-imino-6 - heptylaniline hydrochloride and 2-imino-3 - heptylaniline in the ratio of 3:1 in the form of a white solid.

Mass spectrum: M+H = 197.

Range of TMR (D2O) 0.7 (t, 3H), 1.05-1.9 (m, N), 2.3-2.6 (m, 2H), 3.2 (t, 3-isomer), 3.35 (t, 6-isomer).

Elemental analysis: C12H25ClN20,6 NH4Cl 1/3H2O.

Calculated, %: C, 53.22, H 10.44, N 13.45,

Found, %: C, 53.29, H 10.53, N 13.26.

Example 319-A. Triptorelin 2-imino-4-methyl-6-butyl - pentamethylenebis

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A named connection receive according to the method of example 319 of 3.4 g of 2-butyl-4-methylcyclopentanone. After purification by HPLC (C-18, eluent: 0-40% acetonitrile/water, 30 minutes) to obtain 0.2 g of the named compound as an oily solid.

Mass spectrum: M+H = 169.

Range of TMR (D2O) : 0.68-0.76 (m, 3H), 0.86 (d, J=Hz, 6N), 1.12-1.24 (m, 4H), 1.28-1.76 (m, 4H), 1.92-2.16 (m, 2H), 2.46 - 2.58 (m, 1H), 3.40-3.50 (m, 1H).

Example 319-B. Triptorelin 2-imino-4-methyl - 6-allyl-pentamethylenebis

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Called with the, eluent: 0-40% acetonitrile/water, 30 minutes) to obtain 1.2 g of the named compound as an oily solid.

Mass spectrum: M+H = 153.

Range of TMR (D2O) : 0.80-0.92 (m, 3H), 1.40-2.88 (m, 7H), 3.20-3.65 (m, 1H), 4.96-5.16 (m, 2H), 5.60-5.78 (m, 1H).

Example 320. Methyl ester of 2-(1-propyl)Cyclopentanone-2 - carboxylic acid (intermediate compound)

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In 100 ml of N, N-dimethylformamide (DMF) under nitrogen atmosphere at 50oC for 16 hours mix methyl ether, Cyclopentanone - 2-carboxylic acid (Fluka, 14.2 g, 0,1 mole), 1-iodopropane (Aldrich, 17 g of 0.1 mol) and potassium carbonate (10 g). Distilled DMF on a rotary evaporator under reduced pressure. The residue is suspended in 500 ml of ethyl acetate and water (mixture 1:1). The ethyl acetate layer was separated, washed with water and then saturated sodium chloride solution, dried with MgSO4. After evaporation obtain 14.6 g (78%) of crude product.

Mass spectrum: M+H = 185.

The crude product was used in subsequent reactions without further purification.

Example 321. 2-(1-Propyl)Cyclopentanone (intermediate compound)

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Methyl ester of 2-(1-propyl) Cyclopentanone-2-carboxylic acid (10 g, 0,054 mol), sodium cyanide (2.9 g, is 0.06 mole) and dimethyl sulfoxide (100 ml) is stirred paragraph is extracted with 300 ml of a mixture of ethyl ether/hexane (1:1). The layer of ethyl ether/hexane is separated, washed twice with saturated NaCl solution, dried with MgSO4and the solvent is distilled off on a rotary evaporator. The crude product is purified by chromatographytandem on a column of silica gel (eluent: hexane: ethyl acetate, 7:3). Obtain 5.5 g (83%) of product. Mass spectrum: M+H = 123.

Example 322. Triptorelin 2-imino-6-(1-propyl) - pentamethylenebis

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2-Imino-6-(1-propyl)-pentamethylenebis receive according to the method of example 322 2-propylcyclohexanone. After purification using obremenitve HPLC (C18, eluent: 0-50% acetonitrile/water, 30 minutes), obtain 0.3 g of the named compound as a white semi-solid substances.

Mass spectrum: M+H = 255.

Range of TMR (D2O) : 0.70-0.78 (t, 3H), 1.15-1.88 (m, 8H), 2.38-2.50 (m, 2H), 3.3-3.4 (m, 1H).

Example 323. 2-(1-Butenyl)-2-carbomethoxyamino (intermediate compound)

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Sodium hydride (60% in mineral oil, 8,3 g, 200 mmol) was washed with 2 portions of hexane and then dried with a stream of N2. The resulting product is suspended in dimethylformamide and in nitrogen atmosphere slowly cooling water bath with a temperature of 25oC add 2-cyclohexanecarboxylate (34,1 g, 200 mmol) (observed foaming and heat). In the eye of mesheau mixture is maintained at 50oC for 18 hours (overnight). The reaction mixture is cooled to room temperature, poured into water, neutralized with diluted HCl and extracted with two portions of a mixture of ether: hexane (1:1). The combined organic layers are washed with two portions of water, saturated brine, dried with MgSO4, filtered and evaporated, get a mixture of products. After purification by chromatography on silica gel (eluent: 5% methyl-tert.-butyl ether/90% hexane) to obtain 28.4 g of the named compound.

Example 324. 2-(1-Butenyl)cyclohexanone (intermediate compound)

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In an atmosphere of N2mix (1-butenyl)-2-carbomethoxyamino (11.2 g, 50 mmol), lithium chloride (10.6 g, 250 mmol), water (0,99 g, 55 mol) and dimethyl sulfoxide (250 ml) and boiled for 2 hours. Then the reaction mixture is cooled to 25oC and poured into water, extracted with two portions of a mixture of ether: hexane (1:1). The organic layers are combined and washed with two portions of water, saturated brine, dried with MgSO4.

After filtration and evaporation the product was then purified by fractional distillation at 1.5 mm RT.article (the product boils at a temperature of from 65 to 79oC at a pressure of from 1 to 2 mm RT.cent.), obtain 5.5 g of the aforementioned ketone.

Example 3 clohexane (example 324, of 7.70 g, 51 mmol) turns on the named connection using hydroxylamine hydrochloride (5.3 g, 76 mmol) and sodium acetate (7.0 g, 85 mmol) in a mixture of 70 ml of EtOH and 70 ml of water. Get 8,48 g of the named compound as a white solid.

Example 326. Hexahydro-7-(1-butenyl)- 1H-azepin-2-he (intermediate compound)

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The compound of example 325 turn to the named compound by the method of example 29.

Example 327. 4,5,6,7-Tetrahydro-2-methoxy - 7-(1-butenyl)-3H-azepin (intermediate compound)

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The product of example 326 (1,34 g, 8 mmol) is treated with tetrafluoroborate trimethylhexane (1.63 g, 11 mmol) by the method of example 26, obtain 1.5 g (100%) of the named compound.

Example 328. Monohydrochloride hexahydro-7-(1-butenyl)-1H - azepin-2-imine

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The product of example 327 (1.5 g, 8 mmol) in 85 ml of MeOH is treated with ammonium chloride (0.36 g, 6.8 mmole) by the method of example 27, obtain 1.4 g (83%) of the named compound.

Range of TMR (D2O) : 5.75-5.95 (m, 1H), 5.1 (m, 2H), 3.65 (TT, 1H), 2.75-2.5 (m, 2H), 2.3 (m, 2H), 2.05-1.3 (m, 8H).

Elemental analysis: C10H17N2HCl 0,45 H2O (molecular weight 210,83).

Calculated, %: C, 56.97, H 9.51, N 13.39, Cl 16.82,

Found, %: C, 57.02, H 9.34, N 13.16, Cl At 16.86.

The result is the basics of nitric oxide shown in the following tests.

Citrullinemia assessment synthase nitric oxide (PL. 1).

Synthase activity of nitric oxide (NOS) is measured by monitoring the conversion of L-[2,3-H] -arginine to L-[2,3-H]-citrulline (1,2). Mouse induced NOS (mi NOS) isolated from an extract of cells of mouse RAW 264.7 treated with LPS and constitutive NOS (rnc NOC) of rat brain isolated from the extract of rat brain. Both drugs are carefully cleaned using chromatography DEAE-Sepharose (2). cDNA for human induced NOS (hi NOS) isolated from a cDNA library made from RNA extracted from a sample of the rectum of a person with ulcerative colitis, human endothelial constitutive NO synthase (hec NOS) isolated from a cDNA library made from RNA extracted from endothelial cells of the umbilical vein of a person (HUVEC). Recombinant enzymes Express in insect cells using a baculovirus vector. From cell extracts produce active enzyme and carefully cleaned using chromatography DEAE - Sepharose (2). Add the enzyme and the inhibitors to a final volume of 50 μl in 50 mm Tris buffer (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, album.cue L-[2,3-3H]-arginine. In the case of constitutive NOS also include calmodulin at a final concentration of 40-100 nm. After incubation at 37oC for 15 minutes 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. Using chromatography on a cation-exchange resin Dowex 50 W X 8 separate [3H]-citrulline and determine the radioactivity using a liquid scintillation counter.

1. Bredt D. S., Snyder, S. H. (1990), Proc. Natl. Acad. USA 87, R. 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., Currie, M. G. (1993). Eur J. Pharm. 233, p.119-125.

Nitrite test RAW cells

RAW 264.7 cells were seeded in 96-hole plate with tissue culture grown overnight (17 hours) in the presence of LPS with the intention of inducing NOS. A series of 3-6 holes left untreated and used as a control to account for the influence of non-specific environment. From each well to extract the environment and the cells washed twice with a solution of Krebs-Ringers-Hepes (25 mm, pH 7.4) containing 2 mg/ml glucose. The cells are then placed on ice and incubated for 1 hour with 50 ml of buffer containing L-arginine (30 mm) +/-inhibitors. The sample is initiated by heating to 37oC in a water bath for 1 hour. Producerof the ice, and nitidulinae buffer is removed and examined for the content of nitrite using previously published methods fluorescent determination of nitrite (Misko et al. , Analytical Biochemistry, 214, 11-16, 1993). All these values are the average of three repeated experiments and compared with the values obtained for control cells.

In vivo evaluation.

Rats do intraperitoneal injection of 10 mg/kg of endotoxin (LPS) with oral introduction or without the introduction synthase inhibitors of nitric oxide. The content of nitrite in plasma was measured 5 hours after treatment. The results show that the introduction of the inhibitor synthase nitric oxide reduces the increase of the content of nitrite in the plasma, which is a reliable indicator of the production of nitric oxide induced by endotoxin (table. 2).

IP - 2-aminopiperidin

LPS - endotoxin

From the above description, a qualified technician can easily identify the essential features of the present invention and without deviating from the essence and scope of the invention can make various changes and implement a number of modifications that allow you to adapt the invention for different applications and the difference is completely, including an active ingredient and at least one non-toxic pharmaceutically acceptable carrier, wherein the active ingredient is used as a compound of the formula I

< / BR>
where X is methylene, nitrogen atom, oxygen atom or S, where the nitrogen atom and methylene radicals can be optionally substituted lower alkyl;

n takes values from 1 to 7;

the substituents R1and R2independently from each other selected from the group comprising a hydrogen atom, a C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, amino group, carboxyl group, halogen-C1-C3-alkyl, C3-C6-alicyclic hydrocarbon, C4-C10aromatic hydrocarbon, where all these radicals can be optionally substituted by one or more substituents from among the hydroxy-group, C1-C6-alkyl, C1-C4-alkoxygroup, amino group, carboxyl group, carbalkoxy, where all these substituents can be optionally substituted by one or more substituents from among: amino group, carboxyl group, and the substituents R1and R2together may not necessarily obrazovanie-3,4-diyl, and this is not necessarily formed by the ring is substituted by one Deputy from among C1-C10-alkyl, which is substituted by a carboxyl group;

the substituents R3and R4represent a hydrogen atom, a hydroxy-group, provided that when n = 1 and the substituents R1and/or R2are in position 3 or 4, neither the substituent R1or R2are not Allami;

and its salts, pharmaceutically acceptable esters in an effective amount.

2. The pharmaceutical composition under item 1, characterized in that the active ingredient is used as a compound of the formula I on p. 1, where X is selected from the group comprising methylene, nitrogen atom, oxygen and sulfur, n takes values from 1 to 5, the substituents R1and R2independently from each other selected from the group comprising a hydrogen atom, a C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, halogen-C1-C3-alkyl, C4-C10aromatic hydrocarbon, C3-C6-alicyclic hydrocarbon, where all these radicals can be optionally substituted by one or more substituents from among carboxyl group, carbalkoxy, amino, C1-C4< one or more substituents of the amino group, carboxyl group, and the substituents R1and R2together can optionally form a C3-C6-alicyclic hydrocarbon, C4-C10-aromatic hydrocarbon, and the substituents R3and R4independently from each other selected from the group comprising a hydrogen atom and a hydroxy-group.

3. The pharmaceutical composition under item 1, characterized in that the active ingredient is used as a compound of the formula I on p. 1, where X is selected from the group comprising methylene, nitrogen atom, oxygen atom, sulfur atom, n takes values from 1 to 5, the substituents R1and R2independently from each other selected from the group comprising a hydrogen atom, a C1-C6-alkyl, amino group, carboxyl group, halogen -(C1-C3)-alkyl group, where all these radicals can be optionally substituted by substituents from among the hydroxy-group, C1-C6-alkyl, C1-C4-alkoxygroup, amino group, carboxyl group, and the substituents R1and R2together may form a C3-C6-alicyclic radical, C4-C10-aromatic radical or tetrahydrothiophene-3,4-diyl.

4. The pharmaceutical composition according to p. 1, ex is a methylene, the nitrogen atom, oxygen atom or sulfur atom, where the nitrogen atom or a methylene radical may be optionally substituted lower alkyl, n takes on integer values from 1 to 4 substituents R1and R2independently from each other selected from the group comprising a hydrogen atom, alkyl containing from 1 to 6 carbon atoms, alkenyl containing from 2 to 6 carbon atoms, quinil containing from 2 to 6 carbon atoms, amino group, carboxyl group, halogen-(C1-C3)-alkyl group, where each of these radicals may be optionally substituted by substituents from among the hydroxy-group, alkyl containing from 1 to 6 carbon atoms, alkoxygroup containing from 1 to 4 carbon atoms, amino group, carboxyl group, and the substituents R1and R2together can optionally form a alicyclic radical containing from 3 to 6 carbon atoms, an aromatic radical or tetrahydrothiophene-3,4-diyl.

5. The pharmaceutical composition under item 1, characterized in that the active ingredient is used as a compound of the formula I on p. 1, where X represents methylene, nitrogen atom, oxygen atom or sulfur atom, n takes on integer values from 1 to 4, and the substituents R1and R2nasaa, the amino group, carboxyl group, where all these radicals can be optionally substituted by substituents from among the hydroxy-group, alkyl containing from 1 to 3 carbon atoms, alkoxygroup containing from 1 to 3 carbon atoms, amino group, carboxyl group, and the substituents R1and R2together can optionally form a alicyclic radical containing from 3 to 6 carbon atoms, or tetrahydrothiophene-3,4-diyl, or aromatic ring.

6. The pharmaceutical composition under item 1, characterized in that the active ingredient is used as a compound of the formula I on p. 1, where X represents methylene, nitrogen atom, oxygen atom or sulfur atom, n takes on integer values from 1 to 4; and the substituents R1and R2independently from each other selected from the group comprising a hydrogen atom, alkyl containing from 1 to 3 carbon atoms, amino group, carboxyl group, where all these radicals can be optionally substituted by substituents from among the hydroxy-group, alkyl containing from 1 to 3 carbon atoms, alkoxygroup containing from 1 to 3 carbon atoms, amino groups, carboxyl groups.

7. The pharmaceutical composition under item 1, characterized in that no-heptamethylnonane, 2-imino-3-methyltyramine, 2-imino-5-methyltyramine, 2-aminopyrrolidine, 2-aminopiperidine, 2-aminomethylpyrimidine, 2-iminoimidazolidine, 2-aminothiazole, 2-imino-3-tubiporidae, 2-imino-3-oxopiperidin, 2-iminoimidazolidine, 5-chloromethyl-2-iminoimidazolidine, 2-imino-Biotin, ethyl ester 2-imino-Biotin or 1-methyl-2-aminomethylpyrimidine, 3,4,5,6,7,8-hexahydro-2[1H]-chinoline, 2-imino-4-methylpiperidine, 2-imino-5-methylpiperidine, 2-imino-6-methylpiperidine, 2-imino-3-methylpiperidine, 2-imino-4,6-dimethyl-piperidine, 2-imino-3-hydroxypiperidine, monohydrochloride hexahydro-3,7-dimethyl-1H-azepin-2-imine, monohydrochloride hexahydro-4-(trifluoromethyl)-1H-azepin-2-imine, monohydrochloride hexahydro-6-(trifluoromethyl)-1H-azepin-2-imine, monohydrochloride 7-ethyl-hexahydro-1H-azepin-2-imine, monohydrochloride 3-ethyl-hexahydro-1H-azepin-2-imine, monohydrochloride hexahydro-6,6-dimethyl-1H-azepin-2-imine, monohydrochloride hexahydro-4,4-dimethyl-1H-azepin-2-imine, monohydrochloride hexahydro-5-methyl-1H-azepin-2-imine, monohydrochloride 5-cyclohexyl-hexahydro-1H-azepin-2-imine, monohydrochloride hexahydro-5-(1-methylethyl)-1H-azepin-2-imine, monohydrochloride hexahydro-5-pentyl-1H-azepin-2-imine, monohydrochloride 5-(1,1-dimethylethyl)-Hexal-1H-azepin-2-imine, monohydrochloride 3-cyclohexyl-hexahydro-1H-azepin-2-imine, monohydrochloride 7-cyclohexyl-hexahydro-1H-azepin-2-imine, monohydrochloride 3-(1,1-dimethylethyl)-hexahydro-1H-azepin-2-imine, monohydrochloride 7-(1,1-dimethylethyl)-hexahydro-1H-azepin-2-imine, monohydrochloride hexahydro-3-(2-propenyl)-1H-azepin-2-imine, monohydrochloride hexahydro-7-(2-propenyl)-1H-azepin-2-imine, monohydrochloride hexahydro-3-propyl-1H-azepin-2-imine, monohydrochloride hexahydro-7-propyl-1H-azepin-2-imine, monohydrochloride hexahydro-3-(1-methylpropyl)-1H-azepin-2-imine, monohydrochloride hexahydro-7-(1-methylpropyl)-1H-azepin-2-imine, monohydrochloride hexahydro-3,6-dimethyl-1H-azepin-2-imine, monohydrochloride (7S-TRANS)-hexahydro-7-(1-methyl-ethyl)-4-methyl-1H-azepin-2-imine, monohydrochloride (3S-TRANS)-hexahydro-3-(1-methylethyl)-6-methyl-1H-azepin-2-imine, monohydrochloride 4R-methylpiperidin-2-imine, monohydrochloride 5R-methylpiperidin-2-imine, monohydrochloride 4-ethylpiperidine-2-imine, monohydrochloride 5-ethylpiperidine-2-imine, monohydrochloride 6-ethylpiperidine-2-imine, monohydrochloride 3-ethylpiperidine-2-imine, monohydrochloride 6,6-dimethylpiperidine-2-imine, monohydrochloride 3,3-dimethylpiperidin-2-imine, monohydrochloride 1,2,3,4-tetrahydroquinolin-2-imine, monohydrochloride 2,3,4,5-tet-1H-isoindole-1-imine, a mixture of monohydrochloride 2-azabicyclo [3.2.1] Octan-3-imine and monohydrochloride 3-azabicyclo [3.2.1] octane-2-imine, monohydrochloride 4 methylpyrrolidine-2-imine, monohydrochloride 7 butilhioscina-1H-azepin-2-imine, monohydrochloride 3 butilhioscina-1H-azepin-2-imine, monohydrochloride hexahydro-7-phenyl-1H-azepin-2-imine, monohydrochloride 3-(2-ethylbutyl)hexahydro-1H-azepin-2-imine, monohydrochloride 7-(2-ethylbutyl) hexahydro-1H-azepin-2-imine, monohydrochloride hexahydro-7-imino-1H-azepin-2-ethanol, monohydrochloride hexahydro-7-imino-1H-azepin-2-acetic acid, monohydrochloride methyl ester hexahydro-7-imino-1H-azepin-2-acetic acid, monohydrochloride octahydro-3-(2-propenyl)Asotin-2-imine, monohydrochloride 4-ethylpyrrolidin-2-imine, monohydrochloride 5-utilityperson-2-imine, monohydrochloride 5S-(methoxymethyl)-pyrrolidin-2-imine, monohydrochloride 5R-(methoxymethyl)-pyrrolidin-2-imine, monohydrochloride ethyl ester 5-aminopyrrolidine-2-S-acetic acid, monohydrochloride methyl ester 3-[[(5-aminopyrrolidine-2S-yl)methyl]oxy]-2S-[[(phenylmethoxy)-carbonyl] amino]propionic acid, the methyl ester dihydrochloride 2S-amino-3[[(5-aminopyrrolidine-2S-yl)methyl] oxy]-propionic acid, monohydrochloride 3-(7-aminoadipyl-2-yl)-orig ethyl ether amino-7-imino--methoxy-1H-azepin-2-pentanol acid, monohydrochloride ethyl ester hexahydro-7-imino--[[(phenylmethoxy)carbonyl] amino]-1H-azepin-2-pentanol acid, ethyl ester dihydrochloride-amino-hexahydro-7-imino-1H-azepin-2-pentanol acid, monohydrochloride 7-(cyclohexen-1-yl)hexahydro-1H-azepin-2-imine, monohydrochloride 7-(2-butynyl)hexahydro-1H-azepin-2-imine, the dihydrochloride of 4-[1-amino-4-(5-imino-3-methylpyrrolidine-2-yl)butyl]-1,3-dioxolane-2-it, monohydrochloride 4-methyl-5-(2-propenyl)-pyrrolidin-2-imine, the dihydrochloride of 4-[1-amino-4-(hexahydro-7-imino-1H-azepin-2-yl)butyl-1,3-dioxolane-2-it, the dihydrochloride 2S-amino-3-[[(5-aminopyrrolidine-2S-yl)methyl]oxy]-propionic acid hydrochloride 3-ethoxy-2-imino-6-methylpiperidine, hydrochloride 5-amino-2-aminopiperidine, hydrochloride 2-imino-4-piperidinecarboxylic acid, dihydrochloride 5-amino-2-imino-4-methylpiperidine(CIS - and TRANS-isomers), ethyl ester hydrochloride (2'-imino)-2-(3'-piperidine) acetic acid, hydrochloride of 2-imino-5-(trifluoromethyl) piperidine, dihydrochloride 5-aminomethyl-2-imino-4,6-dimethylpiperidine, hydrochloride 2-imino-6-methyl-4-(trifluoromethyl)piperidine hydrochloride-2-imino-4-(trifluoromethyl)piperidine hydrochloride of 6-benzyl-2-aminopiperidine, hydrochlori is pilipino)piperidine.

8. The use of 2-imino-3-methylmethanamine, 2-imino-5-methylmethanamine, 2-aminopyrrolidine, 2-aminopiperidine, 2-aminomethylpyrimidine, 2-imino-imidazolidine, 2-aminothiazoline, 2-imino-3-thepipeline, 2-imino-3-oxopiperidine, 2-iminoimidazolidine, 5-chloromethyl-2-iminoimidazolidine, 2-iminobiotin, ethyl ester 2-iminobiotin and 1-methyl-2-aminomethylpyrimidine for the preparation of a pharmaceutical composition having inhibitory synthase nitric oxide activity.

9. Amidinopropane General formula I

< / BR>
and also their salts, pharmaceutically acceptable esters and prodrugs,

where X is methylene;

n takes values from 1 to 7;

the substituents R1and R2independently from each other selected from the group comprising a hydrogen atom, a C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, amino group, carboxyl group, halogen-C1-C3is an alkyl group, a C3-C6-alicyclic hydrocarbon, C4-C10aromatic hydrocarbon, where these radicals may be optionally substituted by one or more substituents from among the hydroxy-group, C1-C6-alkyl, C1-C4-alkoxy is Ino substituted by one or more substituents of the amino group, carboxyl group, and the substituents R1and R2together can optionally form a C3-C6-alicyclic hydrocarbon or C4-C10aromatic hydrocarbon;

the substituents R3and R4represent a hydrogen atom, a hydroxy-group;

provided that when n = 1 and the substituents R1and/or R2are in position 3 and 4, neither the substituent R1or R2are not Allami, hydrogen atoms and halogenation, and when n = 3, the substituent R1may not be the stands in position 7, provided that when n = 1, the substituents R1and/or R2are in position 3 or 4, and either R1and neither R2are not Allami; b) when n = 1, X is methylene, the substituents R1and R2cannot be both hydrogen atoms or halogenation; C) when n = 2, X is methylene, the substituents R1and R2cannot be both hydrogen atoms; g) when n = 3, the substituent R1may not be the stands in position 7.

10. Pharmaceutical composition having inhibitory synthase nitric oxide activity, including an active ingredient and at least one non-toxic pharmaceutically acceptable carrier, wherein the active and the soup of the formula I on p. 9, possessing inhibitory synthase nitric oxide activity.

12. Amidinopropane General formula I according to p. 9 for the reduction of nitric oxide.

 

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