3,7-diazabicyclo[3,3,1]-containing preparations as anti-arrhythmic compounds

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel solid formulation of anti-arrhythmic medicinal agents. Invention describes crystalline formulation of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benznitrile, tert.-butyl-2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-dizabicyclo[3.3.1]non-3-yl}ethylcarbamate, tert.-butyl-2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or tert.-butyl-2-{7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate and their pharmaceutically acceptable salts. Also, invention describes methods for their synthesis, a pharmaceutical preparation based on thereof, a method for prophylaxis or treatment of arrhythmia and their using.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

73 cl, 22 dwg, 22 tbl, 23 ex

 

The scope of the invention

This invention relates to new solid state forms of certain antiarrhythmic drugs, containing their pharmaceutical compositions and to methods for their preparation.

Background of the invention

In the manufacture of pharmaceutical compositions, it is important that the medicinal substance was in the form in which it can conveniently be treated. This is important not only from the point of view of achieving effective industrial mode of production, but also from the point of view of the subsequent production of pharmaceutical preparations containing the active connection.

In addition, in the manufacture of pharmaceutical compositions, it is important that after the injection the patient was provided with reliable, reproducible and constant profile in plasma concentrations of the drug.

Chemical stability, stability in the solid state and "shelf life" of the active ingredients are also very important factors. Drug substance-containing composition preferably should be capable of efficiently storing in the continuation of significant periods of time without significant changes in the physico-chemical characteristics of the active component (e.g., its chemical composition, density, hygroscopicity and solubility).

More t the th, it is also important to be able to manufacture the drug in such a chemically pure form as possible.

In this respect, considerable problems can imagine amorphous materials. For example, such materials are usually difficult processing and production of these drugs cause false solubility and often exhibit instability and chemical heterogeneity.

Professional obviously, if the drug can easily be obtained in a stable crystalline form, the above problems can be resolved.

Thus, in the production of commercially viable and pharmaceutically acceptable pharmaceutical compositions, such as compositions with modified release, it is important, where possible, to obtain the drug essentially crystalline and stable form.

It should be noted, however, that this goal is not always achievable. Indeed, it is usually not possible solely from molecular structure to predict the behavior of the connection during crystallization. In most cases this can only be determined empirically.

Prior art

In the published international application WO 01/28992 revealed a number oxybisethanol compounds, including:

(a) 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile:

where this connection is indicated below as Compound A. Compound a is disclosed, in particular, in WO 01/28992 as in free base form and in the form benzosulfimide salt;

(b) tert-butyl 2-{7-[3-(4-cyanoaniline)propyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}ethylcarbamate:

in free base form, where this connection is indicated below as a link.

C) tert-butyl 2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethylcarbamate:

in free base form, where this connection is denoted below as the Connection; and

g) tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate:

in free base form, where this connection is indicated below as Compound D.

It is shown that the compounds of the publication of the international application WO 01/28992 are useful in the treatment of cardiac arrhythmias.

Methods of synthesis of Compounds a, b, C and D described in Examples 3, 7, 8 and 9 (respectively) WO 01/28992.

Particular pharmaceutically acceptable salts of the Compounds b, C and D are not disclosed in WO 01/28992. In addition, no information is provided regarding the different crystalline forms of any of the Compounds a, b, C or D or is Olya, which can be obtained.

Description of the invention

According to the first aspect of the present invention proposed pharmaceutically acceptable salt of Compound A, Compound B, Compound C or Compound D, provided that this salt is not salt Compounds And benzosulfimide acid.

According to the second aspect of the invention the proposed Compound a, Compound B, Compound C or Compound D or pharmaceutically acceptable salt of any of these compounds in essentially crystalline form.

Compounds a, b, C and D and their salts according to the first and second aspects of the invention set forth in this description as "compounds of the invention".

Despite the fact that the inventors have discovered that it is possible to obtain compounds according to the invention in forms which are more crystalline than 80%, the term "essentially crystalline," the authors include more than 20%, preferably more than 30% and, more preferably, more than 40% crystalline. Degree (%) crystallinity can be determined by the expert by using x-ray diffraction on the powder (XRPD). Additionally, there may be used other techniques, such as NMR for substances in the solid state FT-IR (infrared spectroscopy with Fourier transform)spectroscopy is kombinatsionnogo scattering, differential scanning calorimetry (DSC) and microcalorimetry.

Preferably, when the compound according to the invention is a salt of the Compound, with a pair of toluensulfonate acid, it is proposed in essentially crystalline form.

When the connection according to the invention is proposed in the form of a crystalline form of the salt of the Compound, with benzosulfimide acid, it is preferable that the crystalline form was not a form specifically described below in Example 4 (and/or in item 8 of the claims).

When the connection according to the invention is proposed in the form of a crystalline form of Compound A (free base), preferably, the crystalline form was not a form specifically described in any of Examples: Example 1 (and/or in paragraph 4 of the claims), Example 2 (and/or item 5 claims) or Example 3 (and/or item 6 of the claims).

When the connection according to the invention is proposed in the form of a crystalline form of the Compound And, preferably, this connection has not been offered in free base form or in the form benzosulfimide salt, when it is proposed in the form of a salt.

When the connection according to the invention is proposed in the form of a crystalline form of the Compound (free base), preferably, the crystalline form was not a form, the spiral is outlined below in Example 12 (and/or A.25 claims).

When the connection according to the invention is proposed in the form of a crystalline form of Connection, it is preferable that the connection is not offered in the free base form.

When the connection according to the invention is proposed in the form of a crystalline form of Compound D (free base), preferably, the crystalline form was not a form specifically described below in Example 9 (and/or claim 19 claims).

When the connection according to the invention is proposed in the form of a crystalline form of Compound D, preferably, this connection is not offered in the free base form.

When the connection according to the invention is proposed in the form of a crystalline form of the Compound, it is preferable that the connection is not offered in the free base form.

Compounds according to the invention can be in the form of MES, hydrate or mixtures MES/hydrate. The solvate may be formed with one or more than one organic solvent, such as lower alkalemia (for example, C1-4alkyl) alcohols (e.g. methanol, ethanol or isopropanol), ketones (such as acetone), esters (such as ethyl acetate) or mixtures thereof.

Compounds according to the invention can have improved stability compared with compounds/salts, disclosed in WO 01/28992.

The term "stable is inost", as defined here, includes the chemical stability and the stability of the solid state.

The term "chemical stability", the authors include the ability to store compounds according to the invention in an isolated form or in the form of the drug, in which they proposed in a mixture with pharmaceutically acceptable carriers, diluents or adjuvants (e.g. in an oral dosage form such as tablet, capsule and so on), under normal storage conditions, with an insignificant degree of chemical degradation or destruction.

The term "stability solid state", the authors include the ability to store compounds according to the invention in an isolated solid form or in the form of a solid preparation, in which they proposed in a mixture with pharmaceutically acceptable carriers, diluents or adjuvants (e.g. in an oral dosage form such as tablet, capsule and so on), under normal storage conditions, with an insignificant degree of transformation of the solid state (for example, crystallization, recrystallization, phase transition solid state, hydration, dehydration, solvation or desolvatation).

Examples of "normal storage conditions" are temperatures from minus 80 to plus 50°With (preferably from 0 to 40°more preferred the room is the temperature, such as from 15 to 30° (C), a pressure from 10 to 200 kPa (0.1 to 2 bar) (preferably atmospheric pressure), relative humidity 5% to 95% (preferably from 10 to 75%) and/or UV/visible light up to 460 luxury for long periods of time (i.e. more than six months, or periods equal to six months). It can be found that under these conditions, the compounds according to the invention is less than 15%, more preferably less than 10% and especially less than 5% of chemically degraded/decomposed or have transformed solid state, as appropriate. Specialist it is obvious that the above-mentioned upper and lower limits for temperature, pressure and relative humidity are extreme values of the normal storage conditions, and that some combination of these extreme values will not be tested in the continuation of normal storage (e.g., temperature 50°and a pressure of 10 kPa (0.1 bar)).

Preferred salts of the Compounds a, b, C and D include salts of attaching the base or, preferably, acid, and these salts can be formed by adding the appropriate amount of the appropriate acid or base before allocation (which may include crystallization). For example, in the case of compounds according to the invention in essentially crystalline is the form of the acid or base can be added to the crystallization mixture before crystallization.

Preferred salts of joining include salt accession of inorganic and especially organic acids, preferably salts of carboxylic acids, such as hippuric acid, naphthoic acid and replacement naphthoic acid (for example, 1-hydroxy-2-naphthoic acid), aspartic acid, maleic acid, succinic acid, malonic acid, acetic acid, fumaric acid, benzoic acid, terephthalic acid, pamula acid and hydroxybenzoic acid; salts of hydroxy acids such as salicylic acid, glycolic acid, malic acid, ascorbic acid, citric acid, gluconic acid, lactic acid, and tartaric acid and its derivatives, such as O,O'-dibenzoyltartaric acid (for example, O,O'-Dibenzoyl-D-tartaric acid or O,O'-Dibenzoyl-L-tartaric acid) and O,O'-di-para-toluylene acid (for example, O,O'-di-para-toluoyl-D-tartaric acid or O,O'-di-ParetoLogic-L-tartaric acid); salts other dibasic acids, such as 2,2,3,3-tetramethyl-1,4-dimetanola acid and 1,2-cyclopentanecarbonyl acid; and salts of alkyl-, aryl - and alkylarylsulfonates, for example With1-8alkyl, C6-10aryl-, and C1-4alkyl-C6-10aryl-sulfonic acids and aryl - and alkylarylsulfonates acids may be substituted on the aryl part, for example, one or bol is e than one methyl, methoxy, hydroxy or galactography), including the salt benzosulfimide acid, toluensulfonate acid, the replacement benzosulfimide acid, naphtalenesulfonic acid, naphthalenedisulfonic acid, mesitylenesulfonic acid, methanesulfonic acid, econsultancy acid and 2-hydroxyethanesulfonic acid.

Salt accession acid, in particular, Compounds D, which may also be mentioned include salts, where the acid is a derivative of the hippuric acid, for example the acid of formula I,

where

Ar1represents phenyl or naphthyl, both of which may substituted by one or more than one Deputy, selected from halogeno (e.g., chloro), nitro, C1-6of alkyl, C1-6alkoxy, hydroxy and phenyl; and

R1, R2and R3independently represent N or C1-3alkyl.

Specialist it is obvious that when Ar1represents phenyl, and R1, R2and R3all represent H, then the acid of formula I is the hippuric acid.

Preferred groups Ar1include phenyl and the phenyl group possibly substituted phenyl (e.g., position 4 relative to the point of joining a group S(O)), chloro (e.g., positions 3 and/or 4 from siteline group C(O)), nitro (for example, position 4 relative to group C(O)) and/or C1-4the alkyl, such as methyl (e.g., positions 2 and/or 4 in relation to the group C(O)); and naphthyl. More preferred values Ar1include phenyl, 4-phenylphenyl (diphenyl), 3,4-dichlorophenyl, 2-naphthyl, 4-nitrophenyl and 2,4,6-trimetilfenil.

Preferred groups R1and R2include H and methyl. Preferably, when R1and R2either both represent H, or both represent methyl.

Preferred groups R3include N.

When R1and R2both represent methyl, preferably, Ar1represented phenyl. When R1and R2both represent H, it is preferable that Ar1was a 4-nitrophenyl, 2,4,6-trimetilfenil or, in particular, 3,4-dichlorophenyl, 2-naphthyl or 4-phenylphenyl (diphenyl).

Acids of formula I are commercially available (for example, hippuric acid, 4-nitropiperonyl acid and 2-, 3 - or 4-methylhippuric acid) or can be obtained in accordance with standard techniques.

For example, acids of formula I can be obtained by interaction of the compounds of formula II,

where R1, R2and R3such as defined above, with an acid chloride of the formula III,

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where Ar1such as defined above, for example, in the presence of a base such as aqueous NaOH, in accordance with the classical methods of Schotten's-Bauman (see, for example, J. Med. Chem., 1989, 32, 1033). Neutralization of the acid, for example concentrated hydrochloric acid, can upset the acid of formula I, which can be recrystallized, if necessary, from various solvents such as isopropyl alcohol, methanol, ethanol, acetone and water, or mixtures of these solvents.

Alternatively, the ether derivatives (for example, lower alilovic esters) compounds of the formula II, possibly in the form of a salt, such as hydrochloride salt, can be brought into interaction with the acid chloride of the formula III in the presence of a base, such as triethylamine, in a suitable solvent, for example dichloromethane, to obtain the ester-amide of the formula IV,

where R4represents a lower alkyl (such as1-6alkyl) or lower alkylphenyl (for example, C1-3alkylphenyl), and Ar1, R1, R2and R3such as defined above (see, for example, J. Heterocyclic Chem., 1973, 10, 935; Tetrahedron, 1989, 45, 1691 and J. Org. Chem., 1999, 64, 8929). Ester-amides of the formula IV can be solids at room temperature and therefore can be purified by crystallization after their education, if appropriate. With the unity of formula IV can then be converted into the compounds of formula I by conventional hydrolysis, for example, an aqueous solution of sodium hydroxide, and then adding the acid, for example hydrochloric acid, to precipitate the product. If necessary, can then be carried out recrystallization.

Compounds of formulas I, II and IV, where R3represents a C1-3alkyl, can be obtained by conventional alkylation of the corresponding compounds of formula I, II or IV, where R3represents N.

Compounds of formula II (and ether derivatives), and III are commercially available or can be easily obtained using standard techniques.

According to another aspect of the present invention, a method for obtaining compounds according to the invention, in which:

(a) to the Connection a, b, C or D add appropriate amount of acid or base with the formation of salt accession acid or base; and/or

(b) carry out the crystallization of Compounds a, b, C or D or salts of the Compounds a, b, C or D.

It is possible to carry out crystallization of Compounds a, b, C and D and their pharmaceutically acceptable salts in the presence or in the absence of a solvent (for example, crystallization can be carried out from the melt under supercritical conditions or achieved through sublimation). However, the authors prefer crystallization from an appropriate solvent system.

Crystalline Sol the accession of acid or base Compounds And, B, C, or D can be obtained by adding the appropriate quantity of a suitable acid or base to the crystallization mixture (for example, the solvent system comprising Compound a, b, C or D in the form of free base) before carrying out crystallization. For example, can be added organic acids (possibly in the form of a solution containing a suitable polar solvent (e.g., lower alkilany alcohol, such as methanol or ethanol or acetate, such as ethyl acetate) to Connection a, b, C or D (possibly in the form of a solution, where this free base is in an appropriate solvent for crystallization). (Specialist it is obvious that in this context the term "free base" means "free form" Compounds a, b, C or D (i.e. forms that are not form salts accession acid or base)).

Specialist it is obvious that the acid or base can be combined in this way with Connection a, b, C or D by dissolving the appropriate materials in appropriate solvents as described above, at least partial removal of these solvents, and then re-dissolving the mixture before carrying out crystallization, as described above.

If the compounds according to the invention are in the form of salts join the various acid, suitable stoichiometric ratio of acid to the free base are in the range from 0.25:1.5 to 1.5:1, such as from 0.45:of 1.25 to 1.25:1, including from 0.50:1 to 1:1.

The solvent system may be heterogeneous or homogeneous, and may thus contain one or more than one organic solvent, such as alkyl acetate (e.g., linear or branched C1-6alkyl acetate such as ethyl acetate, isopropylacetate and butyl acetate); lower (for example, linear or branched C1-6) alkilany alcohol, such as hexane-1-ol, 3-methylbutane-1-ol, pentane-1-ol, pentane-2-ol, 4-methyl-2-pentanol and 2-methyl-1-propanol, or1-4alkilany alcohol, such as methanol, ethanol, n-propanol, isopropanol and butanol (for example, n-butanol); aliphatic (for example, C6-12such as7-12aliphatic) hydrocarbons (for example, isohexane, isooctane and n-heptane) and aromatic hydrocarbons (e.g. toluene); chlorinated alkane (e.g., chloroform and dichloromethane); dealkylation (for example, acetone, methyl isobutylketone), acetonitrile, diakidoy ether (e.g. diethyl ether, di-isopropyl ether, di-n-propyl ether, di-n-butyl ether and tert-butyl methyl ether); and/or an aqueous solvent such as water. Can be used any mixture of the above solvents.

Different crystalline forms which may have different solubility in a given solvent at each given temperature. In this regard, the above-mentioned solvents can be used as antibacterial" (i.e. solvents in which the compounds according to the invention poorly soluble) and therefore may contribute to the process of crystallization. So, antibacterial include hydrocarbons and dialkyl ethers listed above.

Thus, suitable solvents include allylacetate (such as ethyl acetate or isopropylacetate), lower alkalemia alcohols (such as methanol, ethanol and isopropanol), chlorinated methanes (such as dichloromethane), alkanes (such as n-heptane), ethers (such as diethyl ether), ketones (such as acetone), water and so on.

Crystallization of the compounds according to the invention from the corresponding system of solvents may be accomplished by achieving swarnakumari in the solvent system that contains the Connection a, b, C or D or its salt (for example, by cooling by evaporation of solvents and/or by adding antibacterial (i.e. a solvent in which the compounds according to the invention poorly soluble (for example, hydrocarbons, such as isooctane, n-heptane or isohexane or dialkylamino ether such as diisopropyl ether, di-n-butyl ether, and so forth))), or by reducing the solubility of the substance by adding salt (such to the to NaCl), or, in the case of compounds according to the invention, which are salt accession acids, by adding an excess of the appropriate acid.

The crystallization temperature and time of crystallization depends on the compounds or salts, which need to crystallize, the concentration of the compound/salt in solution and the solvent system.

In addition, the crystallization may be initiated and/or performed according to standard methods, for example with or without using seed crystals of the corresponding crystalline compounds according to the invention and/or bringing the pH.

The specific process of crystallization, which can be used to obtain the Compounds a, b, C and especially D, and their salts, involves dissolving the compounds according to the invention in the solvent system that contains3-7alkilany alcohol and the corresponding di-C3-5alkilany ether as antibacterial.

Thus, according to another aspect of the present invention, a method for obtaining essentially crystalline form of Compound A, Compound B, Compound C or, in particular, Compounds D, or a pharmaceutically acceptable salt of any of these compounds, which are crystallization relevant compounds from a solvent system containing combination is, s 3-7Olkiluoto alcohol and di-C3-5Olkiluoto ether.

Preferred esters include di-C3-5alkalemia esters, such as di-n-propyl ether, diisopropyl ether and di-n-butyl ether. Preferred alcohols include n-propanol, isopropanol, n-butanol, 4-methyl-2-pentanol, 3-methyl-1-butanol, 2-methyl-1-propanol and pentane-1-ol.

Preferred combinations of solvents include:

n-propanol and di-n-propyl ether;

isopropanol and diisopropyl ether;

n-butanol and di-n-butyl ether;

4-methyl-2-pentanol and di-n-butyl ether;

isopropanol and di-n-butyl ether;

4-methyl-2-pentanol and diisopropyl ether; and

pentane-1-ol and diisopropyl ether.

The compound/salt can be added to the solvent system ethanol/ether, the latter is a pre-mixed form. Alternatively, the compound/salt can be dissolved in the corresponding alcohol and then to the resulting solution may be added to the ether. Salt can also be obtained in situ, as described above.

Preferably the compound/salt dissolved in a combination of solvents by heating at an elevated temperature (for example, from 50 to 100°With, in particular from 65 to 90°With, for example, from 75 to 85° (C) to ensure complete dissolution. Then the resulting solution was left to cool is I for the implementation of crystallization.

This process of crystallization from ethanol/ether is preferably used for obtaining crystalline forms of Compound D and its salts. Preferably it can be used to obtain crystalline Compound D in free base form.

The authors of the present invention found that when the compounds according to the invention (and in particular, the Compound D) are obtained by crystallization from this particular solvent system, you effectively get vysokokritichnyh material, with a high degree of extraction of the crystalline material (good output) and for a predictable period of time.

In addition, the compounds according to the invention can be obtained in the form of MES (in the notion that the authors of the invention include the form of a hydrate, such as the monohydrate), or in another form (for example, in the form of anhydrite).

To provide education anhydrate, solvent, from which the crystallization, it is preferable to dehydrate or before the crystallization process, or during the crystallization process in order to reduce the water content below the critical level, which preferably should not exceed a continuation of crystallization. The solvent can be dehydrated in the continuation of the process of crystallization, for example, by reduction with is the actual content of the water in the mixture of the compound/salt, you want to crystallize, and in the corresponding system of organic solvent/water solvent (for example, by increasing the number present of an organic solvent and/or removal of water by the formation of azeotropic mixtures with subsequent distillation).

To ensure the formation of hydrates (for example, monohydrate), in a solvent from which crystallization is carried out, there should be water. In continuation of crystallization water content preferably should be maintained above a critical level, above.

"Critical level" of water depends on such factors as temperature, concentration in solution connection that you want to crystallize, impurity profile and used the system solvent, but can be defined nasopalatine.

So, crystalline hydrates can be obtained by crystallization of the compounds according to the invention from a solvent system containing water or a combination of water and one or more than one organic solvent, including organic solvents, which are capable of dissolving water (e.g., methanol, ethanol, isopropanol and so on).

Crystalline anhydrate, on the contrary, can be obtained by crystallization of the compounds according to the invention from a suitable system organically the solvent, which may already be dehydrated and/or can be dehydrated in the continuation of the process of crystallization, so that the water content was below the aforementioned critical level. Thus, anhydrate can be formed by crystallization from a solvent system, which is essentially free of water.

The term "essentially free of water", the authors include the water content in the solvent system below this water content, which will lead to the formation of a maximum of 10% hydrate (e.g., monohydrate) for any given solvent system and the set of conditions of crystallization.

Compounds according to the invention, representing anhydrate, contain not more than 3%, preferably 2%, more preferably 1% and more preferably of 0.5% (by weight) of water, whether the water is in a bound state (water of crystallization or other) or not. Hydrates contain not less than 0.5 mole of water per mole of the compounds according to the invention.

Will anhydrate or hydrates to crystallize, is associated with the kinetics and equilibrium of the corresponding forms in specific circumstances.

If the connection according to the invention represented in crystalline salt form of the Compounds And benzosulfimide acid, preferably, this salt was presented in the form of a monohydrate.

In addition, as evide specialist compounds according to the invention, which is in the same chemical form (free base/salt)can also be obtained in different physical forms (e.g., different crystalline forms) under different conditions of crystallization. The obtained crystalline form of the compound according to the invention depends on the kinetics and thermodynamics of the crystallization process. Under certain thermodynamic conditions (solvent system, temperature, pressure and concentration of the compounds according to the invention) one crystalline form may be more stable than the other (or, certainly, any other). However, crystalline form, having a relatively low thermodynamic stability, can have kinetic advantages. Thus, in addition to this, the kinetic factors such as time, impurity profile, mixing, presence or absence of the seed, and so forth, can also influence what shape is formed. Thus, disclosed in this description of the methodology can be adapted by the specialist, as appropriate, to obtain different crystalline forms.

Different crystalline forms of the compounds according to the invention can easily be characterized using the methods of x-ray diffraction on the powder (XRPD), for example, as described ZV is camping next.

To provide a specific crystalline form in the absence of other crystalline forms, the crystallization is preferably carried out by introducing the seed of embryonic and/or seed crystals of the desired crystalline form of the essentially complete absence of germ and/or seed crystals of other crystalline forms. The seed crystals of the corresponding compounds/salts can be obtained, for example, by slow evaporation of solvent from the solution of the corresponding compound/salt.

Compounds according to the invention can be isolated using techniques that are well known to experts in the art, for example, by decantation, filtration or centrifugation.

Connections can be dried using standard techniques. Specialist obvious that the drying temperature and drying time can affect the properties of solid state compounds (or salts)in the form of a solvate such as a hydrate (e.g., at elevated temperatures and/or reduced pressure may be dehydration). For example, after the formation of crystalline hydrate critical humidity can be set, below which the drying should not be performed because of crystallization in the Yes may be lost, and may be the transformation of the solid state, i.e. crystallization water can be lost if the crystals are dried at high temperatures or at very low pressures over a longer period.

The inventors have discovered that through the use of crystallization processes, as they are disclosed in the present description, it is possible to obtain compounds according to the invention with a higher chemical purity than the compounds according to the invention, which is to be allocated first.

Further purification of the compounds according to the invention may be performed using techniques that are well known to specialists in this field of technology. For example, impurities can be removed by recrystallization from appropriate solvents such as ethyl acetate, isopropylacetate, dichloromethane, isopropanol, n-heptane, methanol, ethanol, methyl ethyl ketone, acetonitrile, pentane-2-ol, 3-methylbutane-1-ol, hexane-1-ol, water or combinations of these solvents). Suitable temperature and time of recrystallization depends on concentration of the compound or salt in solution and specific solvents.

When the compounds according to the invention is crystallized or recrystallized, as here described, the resulting compound or salt can be in the form, it is the fact that superior chemical stability and/or stability of the solid state, as referred to here above.

Pharmaceutical and therapeutic applications.

Compounds according to the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.

Thus, according to another aspect of the invention proposed compounds according to the invention for use as pharmaceuticals.

In particular, the compounds according to the invention exhibit myocardial electrophysiological activity, for example, as demonstrated in tests such as the tests described inter alia in the publications of international applications WO 99/31100, WO 00/77000 and WO 01/28992, the relevant descriptions of which are incorporated by reference.

Thus, it is expected that the compounds according to the invention will be useful in the prevention and treatment of arrhythmias, in particular atrial and ventricular arrhythmias. Specific painful conditions that may be mentioned include atrial arrhythmia (e.g. atrial fibrillation).

Thus, the compounds according to the invention is shown in the treatment or prevention of heart disease or testimony related to heart disease, in which, as I believe, adults play a major role, including coronary heart disease, sudden heart attack, infarc the myocardium, heart failure, heart surgery and cases of thromboembolism.

In the treatment of arrhythmias was found that the compounds according to the invention selectively inhibit cardiac repolarization. Although it was found that the compounds according to the invention inhibit cardiac repolarization, in particular, in the treatment of arrhythmias, the method(s) of their action is not necessarily limited to(s) this way.

According to another aspect of the present invention, a method for treating arrhythmia in which the subject suffering from such conditions or subject to such condition, introducing a therapeutically effective amount of the compounds according to the invention.

For the avoidance of doubt, the term "treatment," the authors include therapeutic treatment as well as prevention of the condition.

Compounds according to the invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermal, intranasal, by inhalation, or by any other parenteral routes of administration, in the form of pharmaceutical preparations containing the active ingredient (either in the form of a free base or as a salt), in a pharmaceutically acceptable dosage form. Depending on the disease and the patient being treated, and the method of administration, the compositions can be entered in the ranks of the doses.

In addition, the compounds according to the invention can be combined with any other drugs useful in the treatment of arrhythmias and/or other cardiovascular diseases.

Thus, according to another aspect of this invention offered a pharmaceutical drug comprising the compound according to the invention in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Compounds according to the invention can be subjected to further processing before manufacture of the drug in the form of a suitable pharmaceutical preparation. For example, the crystalline form can chop or grind to particles of smaller size.

Preferred pharmaceutical products include medicines in the form of gelling matrix systems in which the compounds according to the invention is presented in Association with the polymer which swells in an aqueous environment, such as found in the gastrointestinal tract. Such systems are well known to experts in the art (see, e.g., Advanced Drug Delivery Reviews, 11, 37 (1993)).

The number of compounds according to the invention, which is used in such preparation will depend on the condition and the patient being treated, as well as from the use(s) connection(s), but can be defined nasopalatine.

Suitable daily doses of the compounds according to izaberete the Oia at (for example, therapeutic) treatment of people of approximately 0.005 to 25.0 mg/kg body weight by oral administration and approximately 0.005 to 10.0 mg/kg of body weight when administered parenterally, for free base (i.e., in the case of salt, after deduction of any mass, resulting from the presence of the counterion). The preferred spacing of doses of the compounds according to the invention (in free base form, as shown above) when (e.g., therapeutic) treatment of people of approximately 0.005 to 10.0 mg/kg body weight by oral administration and approximately 0.005 to 5.0 mg/kg body weight at parenteral administration.

Compounds according to the invention have the advantage that they are effective against cardiac arrhythmias.

In addition, the compounds according to the invention have the advantage that they can be more effective, less toxic, have a greater range of actions (including the manifestation of any combination of the activity of class I, class II, class III and/or class IV (in particular the activity of class I and/or class IV in addition to the activity of class III)), to have a stronger impact, to have a more lasting effect, to cause fewer side effects (including lower percentage of proirity, such as pointes de pointes), it is easier to absorb than the compounds known in the prior art, or in t is m, they may have other useful pharmacological properties over existing compounds known from the prior art.

Compounds according to the invention have the advantage that they are in a form that provides greater convenience in handling. In addition, the compounds according to the invention have the advantage that they can be made in the form, which has improved chemical stability and the stability of the solid state (including, for example, low hygroscopicity). Thus, these compounds may be stable when stored for a long periods of time.

Compounds according to the invention may also have the advantage that they can crystallize with good outputs, with a higher degree of purity, in less time, more conveniently and at lower cost than the form of compounds a, b, C and D and their salts obtained previously.

The invention is illustrated, but any way that is not limited to, the following further examples with reference to the attached figures, where:

figure 1 shows the diffraction pattern x-ray powder for crystalline form of Compound A (form)obtained by the method of Example 1;

figure 2 shows the diffraction pattern x-ray powder for crystalline form of Soy is inania A (form A), obtained by the method of Example 2;

figure 3 shows the diffraction pattern x-ray powder for crystalline form of Compound A (form C), obtained by the method of Example 3;

figure 4 shows the diffraction pattern x-ray powder for crystalline form of the salt of the Compound, with benzosulfimide acid obtained by the method of Example 4;

figure 5(a) shows the diffraction pattern x-ray powder for crystalline form of the salt Compounds And paratoluenesulfonyl acid (form A)obtained by the method of Example 5;

figure 5(b) shows the diffraction pattern x-ray powder for crystalline form of the salt Compounds And paratoluenesulfonyl acid (form)obtained by the method of Example 5;

figure 6 shows the diffraction pattern x-ray powder for crystalline form of the salt of the Compound, 1-hydroxy-2-naphthoic acid obtained by the method of Example 6;

7 shows the diffraction pattern x-ray powder for crystalline form of the salt of the Compound, with 1.5-naphtalenesulfonic acid obtained by the method of Example 7;

on Fig shows the diffraction pattern x-ray powder for crystalline form of the salt of the Compound, 2-mesitylenesulfonic acid obtained by the method of Example 8;

figure 9 show the and the x-ray diffraction pattern for the powder to crystalline forms of Compound D, obtained by the method of Example 9;

figure 10 shows the diffraction pattern x-ray powder for crystalline form of the salt of Compound D with methanesulfonic acid obtained by the method of Example 10;

figure 11 shows the diffraction pattern x-ray powder for crystalline form of the salt of Compound D with the hippuric acid obtained by the method of Example 11;

on Fig shows the diffraction pattern x-ray powder for crystalline form of the Compound, obtained by the method of Example 12;

on Fig shows the diffraction pattern x-ray powder for crystalline form of the salt Connection with methanesulfonic acid obtained by the method of Example 13;

on Fig shows the diffraction pattern x-ray powder for crystalline form of the salt Connection with paratoluenesulfonyl acid obtained by the method of Example 14;

on Fig shows the diffraction pattern x-ray powder for crystalline form of the salt of Compound D with [(diphenyl-4-carbonyl)-amino]acetic acid obtained by the method of Example 15;

on Fig shows the diffraction pattern x-ray powder for crystalline form of the salt of Compound D with gementera acid obtained by the method of Example 16;

on Fig shows the diffraction pattern of x-rays is a powder of crystalline form of the salt of Compound D (3,4-dichloraniline)-acetic acid, received by way of Example 17;

on Fig shows the diffraction pattern x-ray powder for crystalline form of the salt of Compound D with [(naphthalene-2-carbonyl)-amino]acetic acid obtained by the method of Example 18;

on Fig shows the diffraction pattern x-ray powder for crystalline form of the salt of Compound D with 2,2,3,3-tetramethyl-1,4-debutantes acid obtained by the method of Example 19;

on Fig shows the diffraction pattern x-ray powder for crystalline form of the salt of Compound D with TRANS-D,L-1,2-cyclopentane-dicarboxylic acid obtained by the method of Example 20;

on Fig shows the diffraction pattern x-ray powder for crystalline form of the salt of Compound D (+)-O,O'-Dibenzoyl-D-tartaric acid, obtained by the method of Example 21;

on Fig shows the diffraction pattern x-ray powder for crystalline form of the salt of Compound D (+)-O,O'-di-ParetoLogic-D-tartaric acid, obtained by the method of Example 22.

General methods

Analysis of x-ray diffraction on the powder (XRPD) was performed using a variable slit on samples prepared according to standard methods, for example, as described in Giacovazzo, C. et al (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R.L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; Bunn, C.W. (198), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, LE (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York. X-ray analysis was performed using the Siemens diffractometer D5000.

Differential scanning calorimetry (DSC) was performed using Mettler instrument DSC820 according to standard methods, for example as described in Höhne, G. W. H. et al (1996), Differential Scanning Calorimetry, Springer, Berlin.

Thermogravimetric analysis (TGA) was performed using Mettler Toledo instrument TGA850.

Specialist it is obvious that the crystalline forms of the compounds according to the invention can be obtained similarly to the methods described herein and/or in accordance with the following Examples, and can show essentially the same pattern of diffraction XRPD and/or DSC and/or TGA thermograms as those presented here. The term "essentially the same" pattern diffraction XRPD and/or DSC and/or TGA thermograms authors include cases when relevant pictures and/or images (assuming the error of the experiment) it is clear that formed essentially the same crystal form. If provided, the starting point in the DSC can vary in the range ±5°With (for example, ±2°C), and values XRPD-distance (d) can vary in the range ±the last 2 decimal places. Specialist it is obvious that the intensity of the XRPD may change when the measurement is essentially about the Noah and the same crystalline form for a number of reasons, including, for example, the preferred orientation.

Preparatory example a

Obtaining the connection and its benzosulfimide salt

(1) 4-[(3-Hydroxypropyl)amino]benzonitrile

Option 1. A mixture of 4-perbenzoate (12.0 g; of 99.1 mmol) and 3-amino-1-propanol (59,6 g; 793 mmol) was stirred at 80°C in an atmosphere of inert gas for 3 hours before adding water (150 ml). The mixture was left to cool to room temperature and then was extracted with diethyl ether. The organic layer was separated, dried (Na2SO4), was filtered and was concentrated under vacuum, receiving 17 g (97%) of the compound indicated in the subtitle, in the form of oil, which crystallized upon standing.

Option 2. 4-Perbenzoate (24.6 g; 0,203 mol, Aldrich 99%) was added to 3-amino-1-propanol (122,0 g; 1,625 mol; 8 equiv.; Aldrich 99%) and the mixture was heated up to 80°C for 5 hours in nitrogen atmosphere. The solution was left to cool to 22°and added water (300 ml). A cloudy solution was twice extracted with methylene chloride (300 ml and 200 ml) and the combined methylenechloride extracts were washed with water (300 ml; analysis GC (gas chromatography) of the organic layer showed ˜1% square residual aminopropanol).

Option 3. To 4-perbenzoate (30,29 g; 247,7 mmol; 1.0 EQ.) was added 3-amino-1-propanol (150 ml; 148, 8 persons g; 1981,5 mmol; 8.0 EQ.). The mixture was stirred in an atmosphere of nitrogen is at room temperature (27° (C) until complete dissolution of the solid phase. The solution was heated (oil bath) to 77°C and held at this temperature for 7 hours before stir at ambient temperature overnight (14 hours). Was added water (365 ml) and the resulting cloudy solution was extracted with dichloromethane (365 ml, then 245 ml). The combined organic layers were washed with water (365 ml). A solution of the product in dichloromethane (DHM) was dried by distillation: solvent removed (200 ml) and was replaced by a fresh DHM (200 ml). The excess solvent (250 ml) was removed, bringing the total amount of the solvent to 365 ml.

(2) 3-(4-Cyanoaniline)propyl-4-methylbenzenesulfonate

Option 1. The cooled solution (0° (C) 4-[(3-hydroxypropyl)-amino]benzonitrile (with the above stage (1) (Option 1); 17 g; of 96.5 mmol) in anhydrous MeCN (195 ml) was treated with triethylamine (9.8 g; of 96.5 mmol) and then paratoluenesulfonyl (20,2 g, 106 mmol). The mixture was stirred at 0°C for 90 minutes before concentrating under vacuum. To the residue was added water (200 ml) and the aqueous solution was extracted with DHM. The organic phase was dried (Na2SO4), filtered and concentrated under vacuum. The resulting residue was purified by crystallization from isopropanol to obtain 24.6 g (77%) of the connection specified in the header.

Option 2. A solution of the crude 4-[(3-hydroxy who ropyl)amino]-benzonitrile (with the above stage (1) (Option 2)) was concentrated to a volume of 300 ml by distillation, added an additional 200 ml of methylene chloride and re-distilled to 300 ml (aqueous solution by Karl-Fischer. 0,07%). Was added triethylamine (20,55 g; 0,203 mol) followed by addition of 4-(N,N-dimethylamino)pyridine (248 mg; 2.0 mmol) and cooled the solution to 0°C. solution was Added taillored (38,70 g; 0,203 mol) in methylene chloride (150 ml) over about 30 minutes while cooling and sufficient stirring, allowing the temperature to rise to 5°C. the Reaction mixture was stirred for 23 hours in the temperature range from 3 to 5°C in nitrogen atmosphere. (After 5 hours was the precipitation of triethylamine hydrochloride. TLC (thin layer chromatography) showed very little, if any there were, further transformation of the residual Cyanophyta on 20-23 hours.) Was added water (300 ml) and vigorously stirred layers within 15 minutes. The organic solution was concentrated by distillation at a temperature of from 35 to 40°With up to a volume of about 60 to 70 ml) was Added isopropanol (100 ml) for 5 minutes. (At this stage before adding isopropanol was negligible deposition of the product in the form of granular sludge. Adding isopropanol crystallization occurred quickly). The distillation is continued, using a vacuum to remove any residual methylene chloride. (Even removed ˜30 ml) and the distillate was tested item is means of GC in the absence of methylene chloride). The suspension of crystals was cooled to a temperature in the range from 0 to 5°C for about 1 hour with slow stirring and kept for one hour at 0-5°C. the Crystals were filtered through the filter material and dense moist residue on the filter was carefully washed with cold (0° (C) isopropanol (80 ml). The filter cake was dried under vacuum and in a stream of nitrogen overnight. Output: 52,6 g; 78,4 mol%; HPLC (high performance liquid chromatography): 99,64% of the area.

Microanalysis: found (theoretical): % S: 61,60 (61,67); % N: 5,41 (5,49); % N: 8,44 (Of 8.47); % S: 9,71 (9,70).

(3) N,N-bis(2-Oxiranylmethyl)benzosulfimide

To benzosulfimide (250 g; 1 EQ.) was added water (2.5 l, 10 vol.) with the subsequent addition of epichlorohydrin (500 ml, 4 EQ.). The reagents were heated to 40°C. Aqueous sodium hydroxide (130 g in 275 ml of water) was added so that the temperature of the reaction mixture remained between 40 and 43°C. It took approximately 2 hours. (It is necessary that the speed of adding sodium hydroxide was slower at the beginning add, than at the end, in order to maintain the established temperature limits). After adding sodium hydroxide was complete, the reaction mixture was stirred at 40°C for 2 hours and then at ambient temperature overnight. The excess epichlorohydrin was removed in the form of water is Oh azeotropic mixture by vacuum distillation (about 4000 PA (40 mbar); the internal temperature of 30° (C) to complete the distillation of epichlorohydrin. Added dichloromethane (1 l) and the mixture was rapidly stirred for 15 minutes. The phases were left to delaminate (it took 10 minutes, although absolutely pure phase was obtained after settling in for the night). The phases were separated and the dichloromethane solution was used in the next stage below.

1H NMR (400 MHz, CDCl3): δ 2.55-2.65 (2H, m), 2.79 (2H, t, J4.4), 3.10-3.22 (4H, m), 3.58-3.73 (2H, m), 7.50-7.56 (2H, m), 7.58-7.63 (1H, m), 7.83-7.87 (2H, m).

(4) 5-Benzyl-3,7-dihydroxy-1-phenylsulfonyl-1,5-diazacyclooctadecane

IMS (industrial methylated spirits) (2.5 l; about 10.) was added to the dichloromethane solution obtained in the above stage (3). The solution was distilled until then, until the internal temperature reached 70°C. Collected approximately 1250 ml of solvent. Added an excess of IMS (2.5 l; about 10.) with the subsequent addition of benzylamine (120 ml; 0.7 EQ.) as one portion (heat was not observed) and the reaction mixture is heated under reflux for 6 hours (no changes since test points 2 hours). Added excess benzylamine (15 ml) and the solution was heated for another 2 hours. IMS drove (about 3,25 l) was added in toluene (2.5 l). The excess solvent was distilled (about 2.4 liters) and then added an additional amount of toluene (1 l). The temperature at the top is part of the distiller now was 110° C. were Collected at 250 ml solvent at 110°C. Theoretically, after this one had the product in about 2.4 liters of toluene at 110°. This solution was used in the next stage.

1H NMR (400 MHz, CDCl3): δ 7.83-7.80 (4H, m, ArH), 7.63-7.51 (6N, m, ArH), 7.30-7.21 (10H, ArH), 3.89-3.80 (4H, m, CH(a)+CH(b)), 3.73 (2H, s, CH2Ph(a)), 3.70 (2H, s, CH2Ph(b)), 3.59 (2H, dd, CHHNSO2Ar(a)), 3.54 (2H, dd, CHHNSO2Ar(b)), 3.40 (2H, dd, CHHNSO2Ar(b)), 3.23 (2H, dd, CHHNSCO2Ar(a)), 3.09-2.97 (4H, m, CHHNBn(a) + CHHNBn(b)), 2.83 (2H, dd, CHHNBn(b)), 2.71 (2H, dd, CHHNBn(a)).

(Data obtained on purified material containing a mixture of 1:1 TRANS - and CIS-diol (b)).

(5) 3-Benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonan

The toluene solution from the previous stage (4)above was cooled to 50°C. was Added anhydrous methansulfonate acid (0.2 l). This caused the temperature increase from 50 to 64°C. After 10 minutes was added methanesulfonyl acid (1 l) and the reaction mixture was heated to 110°C for 5 hours. Then drove the toluene from the reaction mixture; gathered 1,23 L. (Note that the internal temperature should not exceed 110°at any stage, otherwise the output will be reduced). The reaction mixture was then cooled to 50°and used the vacuum to remove residual toluene. Heated to 110°under pressure 65000 PA (650 mbar) allowed to remove more of 0.53 l (If the toluene may be-is at a lower temperature and pressure, it is profitable). The reaction mixture is then left to cool to 30°and added deionized water (250 ml). This caused a temperature increase from 30 to 45°C. was Added an excess of water (2,15 l) during the overall period of time of 30 minutes so that the temperature was less than 54°C. the Solution was cooled to 30°and then added dichloromethane (2 l). With external cooling and rapid stirring, the reaction mixture was podslushivaet by adding aqueous sodium hydroxide (10 M, 2 l) with such a rate as to maintain the internal temperature below 38°C. It took 80 minutes. The stirring was stopped and shared phase for 3 minutes. The layers were separated from each other. To a solution of dichloromethane was added IMS (2 l) and started distillation. The solvent (2,44 l) were collected up until the temperature in the upper part of the distiller has not reached the 70°C. Theoretically, after this one had the product at 1.56 l IMS. This solution is then left to cool to ambient temperature overnight with slow stirring. The precipitated solid product was filtered and washed with IMS (0.5 l) to give the product a yellowish-brown color, which, after drying at 50°under vacuum gave up 50.8 g (8,9% in 3 stages). to 20.0 g of this product was dissolved in acetonitrile (100 ml) at the temperature of reflux distilled, obtaining a pale yellow Rast is op. After cooling to ambient temperature the resulting crystals were collected by filtration and washed with acetonitrile (100 ml). The product was dried under vacuum at 40°C for 1 hour to obtain 17.5 g (87%) of the compound indicated in the subtitle.

1H NMR (400 MHz, CDCl3): δ 7.18-7.23 (10H, m), 3.86-a-3.84 (2H, m), 3.67 (2H, d), 3.46 (2H, s), 2.91 (2H, d), 2.85 (2H, dd), 2.56 (2H, dd).

(6) 3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan × 2HCl

Concentrated Hydrobromic acid (1.2 l; 3 Rel. (rel) about.) added to solid 3-benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane (400 g; see above stage (5)) and this mixture was heated to the temperature of reflux distilled in a nitrogen atmosphere. The solid was dissolved in acid at 95°C. After heating the reaction mixture for 8 hours, HPLC analysis showed that the reaction is complete. The contents were cooled to room temperature. Was added toluene (1.2 l; 3 Rel. about.) and this mixture was vigorously stirred for 15 minutes. The stirring was stopped and the phases were separated from each other. Phase toluene with a small amount of material from the interface section is discarded. The acid phase is returned to the original reaction vessel was added sodium hydroxide (10 M; 1.4 l; 3.5 Rel. about.) in one portion. The internal temperature was raised from 30 to 80°C. Controlled pH to ensure that it is with the is > 14. Was added toluene (1.6 l; 4 Rel. about.) and lowered the temperature from 80 to 60°C. After vigorous stirring for 30 minutes, the phases were separated from each other. The aqueous layer together with a small amount of material from the interface section is discarded. Phase toluene returned to the original reaction vessel was added 2-propanol (4 l; 10 Rel. vol.). The temperature was set between 40 and 45°C. was Added concentrated hydrochloric acid (200 ml) over 45 minutes so that the temperature remained between 40 and 45°C. white precipitate was Formed. The mixture was stirred for 30 minutes and then cooled to 7°C. the Product was collected by filtration, washed with 2-propanol (0.8 l; 2 Rel. vol.), dried by sucking and then further dried in a vacuum drying Cabinet at 40°C. Output = 297 g (91%).

1H NMR (CD3OD+4 drops of D2O): δ 2.70 (br d, 2H), 3.09 (d, 2H), 3.47 (br s, 4H), 3.60 (s, 2H), 4.12 (br s, 2H), 7.30-7.45 (m, 5H).

API-MS: m/z=219 [C13H18+N2O+H]+.

(7) 3,3-Dimethyl-1-[9-oxa-7-(phenylmethyl)was 3.7-diazabicyclo[3.3.1]non-3-yl]-2-butanone

The sodium bicarbonate (114,2 g; 4 EQ.) was added water (500 ml, 5 vol.) with the subsequent addition of 1-chlorphenamine (45,8 ml; 1 EQ.). Was slowly added a solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane × 2HCl (100.0 g; see above stage (6)) in water (300 ml, 3 vol., so in order to control the allocation of dio the sid carbon (20 minutes). The reaction mixture was heated at a temperature of from 65 to 70°C for 4 hours. After cooling to ambient temperature was added dichloromethane (400 ml, 4 vol.) and after stirring for 15 minutes, the phases were separated. The aqueous phase was washed with dichloromethane (400 ml, 4 vol., and the organic extracts were combined. The solution was distilled and collected solvent (550 ml). Was added ethanol (1 l) and continued distillation. Continued to collect the solvent (600 ml). Was added ethanol (1 l) and continued distillation. Continued to collect the solvent (500 ml) (temperature at the top of the distiller now 77°). This solution (theoretically containing 1150 ml ethanol) directly used in the next stage.

1H NMR (400 MHz, CDCl3): δ 1.21 (S, s), 2.01-2.59 (2H, m), 2.61-2.65 (2H, m), 2.87-2.98 (4H, m), 3.30 (2H, s), 3.52 (2H, s), 3.87 (2H, br s), 7.26 (2H, d, J 7.6), 7.33 (1H, dd, J 7.6, 7.6), 7.47 (2H, d, J 7.6).

(8) 3,3-Dimethyl-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-butanone

To the ethanol solution from the previous stage (7)above, was added palladium on coal (44 g; 0.4 weight. EQ. 61%wet catalyst; Johnson Matthey Type 440L). The mixture was first made under pressure 400000 PA (4 bar). The reaction was considered complete after 5 hours. The catalyst was removed by filtration and washed with ethanol (200 ml). United ethanol filtrates were used on stage (9)below. Analysis Rast is ora showed the presence of 61,8 g is specified in the header of the product in ethanol (theoretically 1,35 l; in the measurement of 1.65 l). Part of the product was isolated and purified. The analysis was performed on the purified product.

1H NMR (300 MHz, CDCl3): δ 1.17 (S, s), 2.69 (2H, dt, J 11.4, 2.4), 2.93 (2H, d, J 10.8), 3.02 (2H, d, J 13.8), 3.26 (2H, s), 3.32 (2H, dt, J 14.1), 3.61 (2H, br s).

This reaction can also be carried out using a lower mass ratio of the catalyst to benzylurea source material. This can be achieved in several different ways, for example using different catalysts such as Pd/C with metal filling other than that which is present in the catalyst Type 440 L used above, or Rh/C) and/or by improving the characteristics of mass transfer of the reaction mixture (a specialist in the art it will be clear that the improvement in mass transfer can be achieved, for example, by carrying out the hydrogenation in a larger scale than that described in the above reaction). When using such methods, the mass ratio of the catalyst to the source material can be reduced to below 4:10 (for example, between 4:10 and 1:20).

(9) the Monohydrate salt of the Compound, with benzosulfimide acid

Method 1

Potassium carbonate (56,6 g; 1.5 EQ.) and 3-(4-cyanoaniline)propyl-4-methylbenzenesulfonate (see above stage (2); 90,3 g; 1 EQ.) was added to the ethanol solution of 3,3-dimethyl-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-buta is it (see above stage (8); 61,8 g from the analysis of 1.65 l). The reaction mixture was heated at 80°C for 4 hours. The analysis showed that there remains a certain amount of reagent (8,3 g), so I added an excess of 3-(4-cyanoaniline)propyl-4-methylbenzenesulfonate (12.2 g) and heat the resulting mixture at 80°C for 4 hours. The solvent (1.35 l) was distilled, then added isopropylacetate (2.5 liters). The solvent of 2.51 l) were removed. Added isopropylacetate (2.5 liters). The solvent (0,725 l) were removed. The internal temperature now was 88°C. the Solvent (0,825 l) was removed, leaving the product in the form of a solution in isopropylacetate (theoretically in 2.04 l). After cooling to 34°With added water (0.5 l). The mixture contained a black suspension, perhaps palladium. the pH of the aqueous phase was 11. Sodium hydroxide (1 M; 0,31 l) was added so that the temperature was less than 25°C and vigorously stirred the mixture for 5 minutes. the pH of the aqueous phase was 12. The phases were separated and the aqueous phase was discarded. Added an excess of water (0.5 l) and separated phases. The aqueous phase was discarded. The remaining ether solution was filtered to remove suspended particles, and then the volume of the filtrate is brought exactly to 2 L. Then, this solution was divided into portions 2×1 L.

(In order to avoid obtaining specified in the subtitle product with a high palladium content, you can perform the following processing: resin Deloxan® (12.5 g; 25 wt.%) was added to a solution of free base (1 l) and the mixture was heated under reflux with vigorous stirring for 5 hours. Then the solution was cooled to room temperature and was stirred for 2 days. The resin was removed by filtration).

To calculate the required amount of benzosulfimide acid to obtain the salt of benzosulfimide, conducted the analysis.

A solution of benzosulfimide acid (20,04 g; 1 EQ.; assuming that the acid was a pure monohydrate) isopropylacetate (200 ml) was added within 5 minutes (it is better to add more slowly, if possible) with vigorous stirring to a solution of free base (1 l) and formed a pale yellow precipitate. The temperature was increased from 18 to 22°C. After 10 minutes the mixture was cooled to 10°and the product collected by filtration. The product was washed with isopropylacetate (250 ml), then dried on the filter by suction of the liquid under vacuum at 40°C for 2 days, getting 59.0 g (61% from 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane × 2HCl).

(Alternatively, the crude salt bansilalpet was obtained by adding 70% (wt./wt.) aqueous solution of benzosulfimide acid to an ethanolic solution of the free base).

The crude product indicated in the subtitle, is isolated in the form of a monohydrate.

<> To the crude compound (50.0 g), indicated in the subtitle, was added ethanol (500 ml) and water (250 ml). The solution was heated to 75°C. the Material was completely dissolved at 55°C. the Solution was kept at 75°C for 5 minutes, then was cooled to 5°C for 1 hour. The deposition started at 18°C. the Cold solution was filtered and the filtrate was washed with a mixture of ethanol:water (2:1; 150 ml), dried on the filter by sucking and then dried under vacuum at 40°getting a pure product that is specified in the subtitle (41,2 g; 82%).

The recrystallization can be carried out with the use of large amounts of solvent, if necessary, selecting the reaction vessels, for example:

EtOH:water, 2:1, about 45. (let 62%),

EtOH:water, 6:1, about 35. (gave yield 70%)).

The product specified in the subheading, provided in the form of the monohydrate after recrystallization (as determined by x-ray diffraction on single crystal).

Method 2

(a) 3-(4-Cyanoaniline)propylbenzenesulfonyl

To a solution of 4-[(3-hydroxypropyl)amino]benzonitrile (from step (1) above, Option 3; source 43,65 g; 247,7 mmol; 1.0 EQ.) in dichloromethane (360 ml total volume of solution) was sequentially added triethylamine (52 ml; 37,60 g; 371,55 mmol; 1.5 EQ.) and trimethylamine hydrochloride (11,89 g; 123,85 mmol; 0.5 EQ.) in one portion. The yellow solution was cooled is about -20° (Bath using acetone/dry ice or a cooling plate) and treated with a solution of benzosulfimide (32 ml; 43,74 g; 247,7 mmol; 1.0 EQ.) in dichloromethane (220 ml, 5 vol. regarding Cyanophyta) using a dropping funnel for pressure equalization. The solution was added in portions so that the internal temperature did not exceed -14°C. to complete the add, it took 25 minutes. Then the mixture was stirred for 35 minutes at a temperature between -15 and -10°C. was Added water (365 ml), and the temperature rose to 10°C. the Mixture was again cooled to 0°and vigorously stirred for 15 minutes. The organic layer (the volume of 570 ml) was collected and distilled at atmospheric pressure to remove DHM (450 ml; temperature Cuba 40-42°C; the temperature in the upper part of the distillation 38-39°). Added ethanol (250 ml) and the solution was left to cool down to a temperature below 30°With, before you create a vacuum. The excess solvent was removed (40 ml were collected; the pressure of 5.2 kPa (52 mbar); the temperature of the cube and at the top of the distiller was 21-23° (C) and the product gradually precipitated from the solution. At this point the distillation was stopped and added an excess of ethanol (50 ml). This mixture was heated (hot water bath at 50° (C) up to 40°to dissolve all solids and slowly added water (90 ml) via a dropping funnel. Races the thief was slowly stirred at room temperature (20° (C) overnight (15 hours), by this time, some portion of the product was crystallized from solution. The mixture was cooled to -5°With (bath ice/methanol) and stirred at this temperature for 20 minutes before by filtration to collect a pale yellow solid. This solid was washed with a mixture of ethanol/water (42 ml EtOH; 8 ml of N2O) and dried by suction of fluid within 30 minutes before drying to constant weight in a vacuum drying Cabinet (40°s; 72 hours). The mass of the obtained crude product was 47,42 g (149,9 mmol; 60%). To the crude product (20,00 g; 63,22 mmol; 1.0 EQ.) added ethanol (160 ml, 8 vol.). This mixture was stirred in nitrogen atmosphere and was heated to 40°using hot water bath. Upon reaching this temperature, all the solid had dissolved, giving a clear yellow solution. Water (60 ml, 3 vol.) was added dropwise over a period of 10 minutes and at the same time maintained the internal temperature in the range of 38-41°C. Cleaned water bath and the solution was left to cool to 25°C for 40 minutes, by this time began crystallization. The mixture was cooled to -5°C for 10 minutes, then held at this temperature for another 10 minutes. The pale yellow solid was collected by filtration, dried by sucking within 10 m of the nut, then dried to constant weight in a vacuum drying Cabinet (40°S; 15 hours). Weight of the obtained compound indicated in the title, was 18,51 g (58,51 mmol; 93% (crude product)).

(b) the Monohydrate salt of the Compound, with benzosulfimide acid

To an ethanol solution (total volume of 770 ml; approximately 20 rpm. relative to the amine) of 3,3-dimethyl-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-butanone (original 34,97 g (confirmed by analysis); 154,5 mmol; 1.0 EQ.; see above stage (8)) was added 3-(4-cyanoaniline)propyl-bansilalpet (49,05 g; 154,52 mmol; 1.0 EQ.; see above stage (a)) in one portion. The resulting mixture was heated at 74°C for 6 hours, then stirred at room temperature (20°) for 65 hours (over a weekend; the specialist in the art will understand that the reaction will successfully proceed without this prolonged stirring at room temperature). Ethanol (370 ml) was removed and added to water (200 ml) (got a mixture of EtOH:H2Oh, 2:1, total volume 600 ml). Adding water temperature Cuba declined from 80 to 61°C. the Solution was again heated to 70°With, then left to cool naturally to ambient temperature overnight (19 hours)slowly while stirring. At this stage, observed the formation of a solid substance. CME is ü was cooled to 0° C and then stirred at this temperature for 15 minutes before collecting by filtration yellowish solid. This solid was washed with cold mixture of ethanol:water 2:1 (150 ml), dried by sucking in 1.25 hours, then dried in a vacuum drying Cabinet (40°S; 20 hours). The mass of the obtained crude product was 57,91 g (103,3 mmol; 60%).

Found that the crude product has a degree of purity 98,47% (as determined by HPLC analysis), and recrystallized it (using the methodology described in detail below) to obtain the compound indicated in the title, with a purity of 99.75% (yield 84%).

The recrystallization method:

To the crude product obtained above (56,2 g)was added ethanol (562 ml) and water (281 ml). The solution was heated to 75°C. All material was dissolved at 55°C. the Solution was kept at 75°C for 5 minutes before cooling to 5°C for 1.5 hours. The deposition was started at 35°C. the Cold solution was filtered and the collected precipitate was washed with a mixture of ethanol:water (2:1; 168 ml). The solid material was dried on the filter by sucking before drying under vacuum at 40°With receipt of the product (47,1 g; 84%).

(10) Compound (free base)

The way I

Untreated benzosulfimide salt (50,0g; 1.0 EQ., from the stage (9)described above, the Method 1) was added to aqueous sodium hydroxide (1M; 500 ml), washing with dichloromethane (1.0 l; 20 volumes). The combined mixture was stirred for 15 minutes. Then the layers were separated and a small amount of interfacial material was collected together with the upper water layer. To the dichloromethane solution was added ethanol (500 ml, 10 volumes) and then the solvent was removed by distillation (1.25 l). The temperature of the head ring was at that time 78°C. the Solution was left to cool down to a temperature below the temperature of reflux distilled was added in ethanol (250 ml, 5 volumes). The solvent was removed (250 ml). This warm solution was diluted with ethanol to 890 ml, 17.8 volumes (25 volumes per 100%conversion into the free base). After heating to the temperature of reflux distilled solution was slowly cooled. At 5°With added seed specified in the connection header. Started crystallization, and the mixture was stirred at 5°C for 30 minutes. The product was collected by filtration and washed with ethanol (2×50 ml; 2×1 volume). Then the product was dried in a vacuum oven at 40°C for 60 hours to obtain powder whitish color (26,3 g; 74%).

1H NMR (400 MHz; CDCl3): δ 7.86-7.82 (2H, m), 7.39-7.32 (3H, m), 7.30-7.26 (2H, m), 6.47 (2H, m), 4.11-4.07 (4H, m), 3.70 (2H, s), 3.36-3.33 (4H, m), 3.26 (2H, t), 3.12 (2H, d), 2.90 (2H, d), 2.28-2.21 (2H, m), 1.06 (9H, s).

13C the Mr (CDCl 3): δ 24.07, 26.38, 41.52, 43.52, 56.17, 56.47, 63.17, 68.46, 96.61, 111.64, 121.03,133.43.

MS (ES): m/z=385.1 (M+H)+.

Method II

A mixture of 4-{[3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}-benzonitrile (see Preparation example B(l)(6) below; 5.73 g; 0.02 mol), K2CO3(11,05 g; 0.08 mol) in MeCN (300 ml) was treated with 1-chlorphenamine (4.44 g; to 0.032 mol). The mixture was stirred at 50°during the night before to add DCM and filtered mixture. The filter cake was further washed with a mixture of DCM and MeCN before from the filtrate to evaporate the solvent. The obtained residue was purified by chromatography on silica, elwira gradient ethyl acetate/methanol/ammonia methanol (95:5:0 95:0:5) to obtain the specified title compound (5.8 g; 73,9%).

Preparatory example(I)

Getting Connections (Method I)

(1) tert-Butyl-2-bromantically

Sodium bicarbonate (6,15 g; 0,073 mol) and di-tert-butyl-dicarbonate (11,18 g; 0,051 mol) was dissolved in a mixture of N2About (50 ml) and dichloromethane (150 ml), then was cooled to 0°C. was Slowly added solid 2-brometalia hydrobromide (10.0 g; 0,049 mol) and the reaction mixture was stirred overnight at 25°C. the Dichloromethane layer was separated, washed with H2O (200 ml) and washed with a solution of sodium hydrosulphate (150 ml, pH 3.5). The organic layer was dried (Na2SO4) and concentrated under vacuum. Neocidin the e oil was chromatographically on silica gel, elwira dichloromethane, obtaining 7,87 g (72%) indicated in the subtitle compound as a clear colorless oil.

1H NMR (300 MHz; CDCl3): δ 4.98 (bs, 1H), 3.45-3.57 (m, 4H), 1.47 (s, 9H).

API-MS: (M+1-C5H8CO2) 126 m/z.

(2) 3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan × HCl

This method of obtaining alternative is described in Preparatory example(6). Three-neck flask with a capacity of 3 l equipped with a magnetic stirrer, thermometer and a partial condenser. Aqueous Hydrobromic acid (48%; 0,76 l; 4,51 mol) was added to a solid 3-benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane (190 g; of 0.53 mol; see Preparation example(5) above) and the mixture was heated to the temperature of reflux distilled in a nitrogen atmosphere. The solid was dissolved in 90°C. After heating the mixture for 12 hours, GC analysis showed the reaction completed. The contents of the reaction mixture was cooled to room temperature. Was added toluene (0.6 l) and the mixture was stirred for several minutes. The phases were separated. The aqueous phase is returned to the original reaction vessel was added aqueous sodium hydroxide (10 M; 0,85 l; 8.5 mol) in one portion. The internal temperature was increased to 80°and the mixture became strong. When the internal temperature dropped to 55°S, we use the and toluene (0.8 l). After vigorous stirring for 30 minutes the toluene phase is separated and returned to the original reaction vessel. Was added 2-propanol (1.9 l) and the internal temperature was maintained between 40°s and 50°C. was Added concentrated hydrochloric acid (up until the mixture became acidic) with such a rate as to maintain the temperature between 40 and 50°C. the Formed precipitate is white. The mixture was stirred for 30 minutes and then cooled to 7°C. a white Powder was collected by filtration, washed with 2-propanol (0.4 l), dried by passing air through the sample for ten minutes, and then further dried in a vacuum Cabinet at 40°C. Output: 130 g (84%).

(3) tert-Butyl 7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-carboxylate hydrochloride

Three-neck flask with a capacity of 5 l equipped with overhead stirrer, thermometer and nitrogen bubbler. Into the flask were successively loaded water (1.4 l), dichloromethane (1.4 l), sodium bicarbonate (150 g; 1,79 mol) and 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan × 2 HCl (130 g; 0,447 mol; from step (2)above). The mixture was rapidly stirred for ten minutes and then was slowly added di-tert-butyl-dicarbonate (0,113 l; 0,491 mol). The mixture was rapidly stirred for three hours at room temperature. The organic layer was separated, dried with magnesium sulfate, filtrowanie concentrated to obtain 160 g of a solid substance whitish color. Solid whitish color was loaded into the three-neck flask with a capacity of 3 l equipped with overhead stirrer, thermometer and addition funnel. Downloaded ethyl acetate (0.6 l) and the clear solution was cooled to -10°C. was added dropwise a solution of HCl in dioxane (4M) up until the pH drops below 4. The hydrochloride salt precipitated and the mixture was stirred for an additional hour. The product was collected by filtration, washed with ethyl acetate (0.1 l) and dried overnight in a vacuum Cabinet. Mass of white crystalline product was 146 g (92%yield).

(4) tert-Butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-carboxylate hydrochloride

The hydrochloride salt from step (3)described above, (146 g, 0,411 mol) and 20%Pd(OH)2-C (7.5 g) was loaded into the vessel Parra for hydrogenation. Was added methanol (0.5 l) and the vessel was vigorously shaken in a hydrogen atmosphere at 350 kPa (3.5 bar). Over the course of the reaction was monitored by GC-analysis and found that the reaction was complete after one hour. The catalyst was filtered and the filtrate was concentrated to obtain a crystalline product whitish color. The crude product was dissolved in hot acetonitrile (1.2 l) and then filtered in hot condition. The filtrate was diluted with ethyl acetate (1.2 l). The clear solution was left overnight at room temperature. Collected the first batch of crystals and dried under vacuum to obtain 52 g specified in the subtitle compound in a solid white color. The filtrate was concentrated until almost dry, then was dissolved in hot acetonitrile (0.4 l) and was diluted with ethyl acetate (0.4 l). A second batch of crystals (38 g) was obtained after cooling the solution to 10°C. Both parties according to GC-analysis and1H NMR analysis were comparable. Total yield: 90 g (83%).

(5) tert-Butyl 7-[3-(4-cyanoaniline)propyl]-9-oxa-3,7-diazabicyclo-[3.3.1]nonan-3-carboxylate

The hydrochloride salt of tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-carboxylate (see stage (4)described above; 1.1 g; 4,15 mmol) was mixed with MeCN (46 ml), water (2.5 ml) and K2CO3(3.5 g; 25 mmol). The mixture was stirred for 4 h before adding CHCl3and the mixture was filtered through Celite®. The filtrate was concentrated under vacuum to obtain 0,933 g of free base. Then it was mixed with 3-(4-cyanoaniline)propyl-4-methylbenzenesulfonate (see Preparation example(2)described above; 2.1 g; 6.2 mmol) and K2CO3(0,86 g; 6.2 mmol) in MeCN (18 ml). The resulting mixture was stirred over night at 60°before concentrating under vacuum. The residue was treated with DCM (250 ml) and 1M NaOH (50 ml). The layers were separated and the DCM layer was twice washed aqueous NaHCO3before dried (Na2SO4) and concentrate under vacuum. The product was purified flash chromatography, elwira gradient mixture of toluene: etilize is at; the triethylamine (2:1:0 to 1000:1000:1), to obtain 1.47 g (91%) indicated in the subtitle of the connection.

(6) 4-{[3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}-benzonitrile

Specified in the subtitle compound was obtained with 96%yield, using a technique similar to that described below in the Preparation examples(5) and D(3), and using tert-butyl 7-[3-(4-cyanoaniline)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-carboxylate (from step (5)described above).

(7) the Connection

To a solution of tert-butyl 2-bromethylamine (4,21 g; 0.019 mol; see stage (1)above) in DMF (65 ml) was added 4-{[3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}benzonitrile (see stage (6)described above; 4,48 g; to 0.016 mol) and triethylamine (3,27 ml; 0,024 mol). The mixture was stirred overnight at 35°and then concentrated under vacuum. The residue was dissolved in dichloromethane (80 ml) and washed with saturated sodium chloride. The aqueous layer was extracted with dichloromethane (1×150 ml). The combined organic extracts were dried (Na2SO4) and concentrated under vacuum. Crude oil red-brown color was chromatographically (×2) on silica gel, elwira a mixture of chloroform: methanol: concentrated NH4OH (9:1:0,02), with 3.75 g (56%) specified in the connection header.

1H NMR (300 MHz; CDI3OD): δ 7.37-7.40 (d, J=8.8 Hz, 2H), 6.64-6.67 (d, J=8.8 Hz, H). 3.94 (bs, 2H), 3.21-3.31 (m, 4H), 3.01 (bs, 4H), 2.47-2.59 (m, 8H), 1.90 (bs, 2H), 1.39(s, 9H).

13C NMR (75 MHz, CD3OD): δ 158.5, 134.7, 121.9, 113.2, 97.7, 80.3, 69.2, 58.8, 58.1, 57.5, 57.3, 41.9, 38.3, 28.9, 26.2.

API-MS:(M+1)=430 m/z.

Preparation example B (II)

Getting connections (Method II)

(1) tert-Butyl ether [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)ethyl]carbamino acid

Option 1

(a) 2-tert-Butyloxycarbonyl)tilcotil

The solution paratoluenesulfonyl (28,40 g, 148 mmol) in dichloromethane (100 ml) was added dropwise within 30 minutes at 0°to a mixture of tert-butyl N-(2-hydroxyethyl)carbamate (20 g, 120 mmol), triethylamine (18,80 g, 186 mmol) and trimethylammonium chloride (1.18 g; 12.4 mmol) in dichloromethane (120 ml). The mixture was stirred at 0°C for 1 hour, then filtered, washed with dichloromethane (100 ml). The filtrate was washed with 10%citric acid (3×100 ml) and with brine (100 ml). The organic layer was dried with magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain oil. The oil was dissolved in ethyl acetate (40 ml) and then slowly added isohexane (160 ml). The resulting suspension was stirred at room temperature for 17 hours and then filtered. The collected solid material was washed with isohexane (240 ml) to obtain specified in the subtitle compound as a colourless powder (25 is; 64%).

TPL 64-66°C.

1H NMR (300 MHz; CDCl3): δ 1.40 (S, s), 2.45 (3H, s), 3.38 (2H, q), 4.07 (2H, t), 4.83 (1H, bs), 7.34 (2H, d), 7.87 (2H, d).

MS: m/z=216 (MN+(316)-Sun).

(b) tert-Butyl ether [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)ethyl]carbamino acid

A solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (see Preparation example(6)above; 10 g; 34 mmol) in water (25 ml) was slowly added to a solution of sodium bicarbonate (10 g, 119 mmol) in water (10 ml). Added additional amount of water (5 ml) and the mixture was stirred at room temperature for 10 minutes. Solution was added 2-(tert-butyloxycarbonyl)tiltability (see stage (a)described above; 11,92 g; 37 mmol) in toluene (40 ml). This mixture then was heated at 65-70°C for 7 hours before you left under stirring overnight at room temperature. The reaction mixture was re-heated to 50°and produced the separation of the phases. The aqueous layer was extracted with toluene (40 ml) at 50°C. the combined organic layers were washed with saturated sodium bicarbonate (25 ml). The solvents are evaporated under reduced pressure, obtaining the mixture of oil and solid (13 g; >100%). Part oily solid (5 g, 138 mmol) was added ethyl acetate (50 ml) and citric acid (10%; 25 ml). The aqueous layer was separated and the organic layer it is again washed with citric acid (10%; 20 ml). The aqueous layers were combined and treated with solid sodium bicarbonate until neutral. The aqueous phase was extracted with ethyl acetate (2×50 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated until dry under reduced pressure to obtain specified in the subtitle compound as a colourless semi-solid substance, which completely solidify when stored in the fridge (a 4.86 g; 93%).

TPL 58-60°C.

1H NMR (300 MHz; CDCl3): δ 1.46 (S, s), 2.38-2.57 (4H, m), 2.6-2.68 (2H, m), 2.75-2.85 (4H, m), 3.22 (2H, q), 3.26 (2H, s), 3.83 (2H, bs), 6.17 (1H, bs), 7.2-7.4 (5H, m).

MS: m/z=362 (MH+).

Option 2

(a) 3-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]propionamide

The triethylamine (of 3.60 g; 35,7 mmol) was slowly added to a solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (see Preparation example(6)above; 5 g; 17 mmol) in ethanol (50 ml). To this mixture was added acrylamide (1,34 g; 18 mmol) and this mixture then was heated at the temperature of reflux distilled for 7 hours. The reaction mixture was then concentrated under reduced pressure. To the residue was added water (50 ml) and sodium hydroxide (1M; 150 ml) and the mixture was extracted with ethyl acetate (2×200 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure, obtaining a colorless TV is Joe substance. It was recrystallized from ethyl acetate (50 ml) to obtain specified in the subtitle compound (3.80 g; 76%).

TPL 157-159°C.

1H NMR (300 MHz; CDCl3): δ 2.39 (2H, t), 2.42-2.61 (6N, m), 2.82-2.95 (4H, m), 3.39 (2H, s), 3.91 (2H, bs), 5.07 (1H, bs), 7.18-7.21 (2H, m), 7.25-7.39 (3H, m), 9.5(1H, bs).

MS: m/z=290 (MH+).

(6) tert-Butyl ether [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)ethyl]carbamino acid

N-Bromosuccinimide (6.0 g; 33 mmol) in portions over 1 minute was added to a solution of 3-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-propionamide (see stage (a), above; 5 g; 12 mmol) in tert-butyl potassium tert-butanol (1M; 81 ml) and tert-butanol (20 ml). The mixture was then heated at 60-65°C for 30 minutes. The reaction mixture was left to cool to room temperature and then added water (100 ml). The mixture was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered (washing the filter cake with ethyl acetate (50 ml)and then the filtrate was concentrated under reduced pressure to obtain specified in the subtitle compound as a brown oil (6.5 g; >100%).

1H NMR (300 MHz; CDCl3): δ 1.46 (S, s), 2.4-2.58 (4H, m), 2.58-2.7 (2H, m), 2.75-2.91 (4H, m), 3.22 (2H, q), 3.28 (2H, s), 3.83 (2H, bs), 6.19 (1H, bs), 7.2-7.42 (5H, m).

MS: m/z=316 (MH+).

Option 3

(a) 3-Benzyl-9-oxa-3.7-d is azabicyclo[3.3.1]nonan

The magnitudes of all volumes and equivalents are measured relative to the number of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (see Preparation example(6)above). The dihydrochloride of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane (60,07 g; 206,03 mmol; 1 EQ.; see Preparatory example(6)above) was added toluene (420 ml; 7 volumes) and aqueous sodium hydroxide solution (2M; 420 ml; 7 volumes; 4 EQ.). The mixture was stirred in nitrogen atmosphere, was heated to 60°C and kept at this temperature for 30 minutes, during which formed two transparent layer. The lower aqueous layer was removed and the toluene solution is indicated in the subtitle compound (free base) azeotrope dried at atmospheric pressure (total volume remote solvent = 430 ml; total volume of added toluene = 430 ml), then concentrated to a volume of 240 ml (4 volume). Analysis by Karl Fischer (Karl Fischer) at this stage showed the presence of 0.06% of the water in the solution. The dried solution is indicated in the subtitle compound (theoretically 44,98 g; 206,03 mmol; 1.0 EQ.) directly used in the next stage.

(b) 2-(tert-Butyloxycarbonyl)ethyl-2,4 .6-trimethylbenzene-sulfonate

The triethylamine (65 ml; 465,3 mmol; 1.5 EQ.) was added in one portion to a solution of tert-butyl N-(2-hydroxyethyl)carbamate (5,11 g; 310,2 mmol; 1.0 EQ.) in dichloromethane (250 ml, 5 volumes). The solution was cooled to -10°and was added as one portion of trimethylamine hydrochloride (14,84 g; 155, 1mm mmol; 0.5 EQ.). The mixture was then cooled to -15°C, stirred for 5 minutes, then treated with a solution of mesitylenesulfonyl (74,74 g; 341,2 mmol; 1.1 EQ.) in dichloromethane (250 ml, 5 volumes) in the sequel to 28 minutes, so that the internal temperature remained below -10°C. Upon completion of adding the formed precipitate, and the mixture was stirred at -10°in the next 30 minutes. Was added water (400 ml; 8 volumes) and all the precipitate was dissolved. The mixture was rapidly stirred for 5 minutes, and then the mixture was separated into two layers. Carried out the replacement of the solvent dichloromethane in isopropanol by distillation under reduced pressure. The solvent was removed (450 ml) and was replaced by isopropanol (450 ml) (initial pressure of 45 kPa (450 mbar), BP. 24°; final pressure of 11 kPa (110 mbar), BP. 36°). At the end of the distillation the solvent (150 ml) was removed, which resulted in a volume reduction of up to 350 ml (7 volumes in relation to the use of tert-butyl N-(2-hydroxyethyl)carbamate). The solution was cooled to 25°With, then slowly with stirring was added water (175 ml), the resulting solution was gradually Motel. At this stage, has not formed any solid precipitate. D is balali additional amount of water (125 ml) and after you add about 75 ml began the formation of a solid precipitate. The internal temperature rose from 25 to 31°C. the Mixture is slowly stirred and cooled to 7°C. the Solid is collected by filtration, washed with a mixture of isopropanol: water (1:1, 150 ml) and dried under vacuum at 40°C for 21 hours to obtain specified in the subtitle compound as a crystalline substance of white color (92,54 g; 87%).

TPL 73,5°C.

1H NMR (300 MHz; CDCl3): δ 1.42 (9H, s), 2.31 (3H, s), 2.62 (6H, s), 3.40 (2H, q), 4.01 (2H, t), 4.83 (1H, bs), 6.98 (2H, s).

(C) Salt of tert-butyl methyl ether [2-(7-benzyl-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl)ethyl]carbamino acid with 2,4,6-trimethyl-benzosulfimide acid

Warm (28° (C) a solution of 2-tert-butyloxycarbonyl)ethyl-2,4,6-trimethylbenzenesulfonyl (70,93 g; 206,03 mmol; 1.0 EQ.; see stage (b)above) in toluene (240 ml, 4 volume) was added to a solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane (44,98 g; 206,03 mmol; 1.0 EQ.) in toluene (240 ml, 4 volume) (see stage (a), above). The resulting solution was slowly stirred in nitrogen atmosphere with heating at 68°C for 8 hours. The reaction mixture was allowed to mix at ambient temperature for 84 hours. In the pale yellow solution was formed solid precipitate white. The mixture was cooled to +9� With those indicated in the subtitle compound was collected by filtration. The reaction vessel was rinsed with toluene (100 ml) and was added to the filter. The filter cake was washed with toluene (150 ml). The solid white product was dried by suction for 15 minutes, then dried to constant weight under vacuum at 40°C for 23 hours. The output specified in the subtitle compound was 79,61 g; 141,7 mmol; 69%. The combined filtrate and washings (670 ml) was washed with an aqueous solution of sodium hydroxide (2M; 200 ml; 3.3 volume). The mixture was heated to 60°C and kept at this temperature for 20 minutes with rapid stirring. Then the two layers were separated. Toluene solution was concentrated to 200 ml by vacuum distillation (BP. 50-54°s at 65 to 70 kPa (650 to 700 mbar); BP. 46°With 12 kPa (120 mbar) at the end). As the distillation of the solution became turbid due to the formation specified in the subtitle compound. It was assumed that 20% of the initial amount of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane remains in the filtrate, and therefore, in addition in one portion was added 2-(tert-butyloxycarbonyl)ethyl-2,4,6-trimethylbenzene-sulfonate (14,20 g; 41,21 mmol; 0.2 EQ.) (the download should be performed in a solid than in the form of a solution in toluene). The turbid solution was heated at 67°C for 8 h, the owls with rapid stirring and then allowed to mix at ambient temperature for 11 hours. The mixture was cooled to +8°and specified in the subtitle compound was collected by filtration. The reaction vessel is again washed with toluene (2×30 ml) and was added to the filter. The solid white product was dried by suction for 15 minutes, then dried to constant weight under vacuum at 40°C for 7 hours. The output specified in the subtitle compound was 23,25 g; 41,39 mmol; 20%. The total yield specified in the subtitle compound (solid white color) was 102,86 g; 183,11 mmol; 89%.

TPL 190-190,5°C.

1H NMR (300 MHz; CDCl3): δ 1.43 (S, s), 2.17 (3H, s), 2.51 (6H, s), 2.73-2.80 (2H, m), 2.90-2.94 (4H, m), 3.14-3.22 (4H, m), 3.37 (2H, bm), 3.89 (2H, bs), 4.13 (2H, bs), 6.74 (2H, s), 7.12 (1H, bt), 7.42-7.46 (5H, m).

(2) tert-Butyl ether [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]carbamino acid

Method 1. Sodium bicarbonate (0,058 g; 0,069 mmol) and 5%Pd/C (0,250 g, pasta Johnson Mattey Type 440) was added to a solution of tert-butyl methyl ether [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamino acid (see stage (1), Option 1, described above; 1 g, 2.77 mmol) in ethanol (10 ml). Then the mixture was first made at 500 kPa (5 bar) for 18 hours. The reaction mixture was filtered through Celite® and then washed with ethanol (20 ml). The solution was concentrated under reduced pressure to obtain oil. It was dissolved in dichloromethane (20 ml) and washed what ydroxide sodium (1M; 10 ml). The organic phase was separated, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain specified in the subtitle compound in a solid yellow color (0,67 g; 87%).

TPL-93°C.

1H NMR (300 MHz; CDCl3): δ 1.46 (S, s), 2.25 (2H, t), 2.58-2.65 (2H, m), 2.95-3.06 (4H, m), 3.2-3.38 (4H, m), 3.64 (2H, bs), 4.65 (1H, bs).

MS: m/z=272 (MH+).

Method 2. Salt tert-butyl ester [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamino acid with 2,4,6-trimethylbenzenesulfonamide acid (320 g; 1.0 mol-EQ.; 1.0 Rel. about./mass; see stage (1), Option 3, above), toluene (640 ml; 2,0 about.) and aqueous sodium hydroxide (1M, 1.6 l; 5.0 volumes) were stirred together for 15 minutes and then the layers were separated. The organic layer containing tert-butyl ether [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamino acid, was diluted with ethanol (690 ml; 2.16 volume) and water (130 ml; 0.4 volume). Added citric acid (32,83 g; 0.3 mol-EQ.) and 5%Pd/C (20,8 g; 0,065 wt.-EQ. catalyst Johnson Mattey Type 440L with 61%moisture content). The combined mixture then was first made within 24 hours under hydrogen pressure of 400 kPa (4 bar). The course of the reaction was controlled by TLC, using a plate of silicon dioxide with mobile phase X:DCM (1:1 (vol./vol.); X is a mixture of chloroform: methanol: koncentrira the config ammonia 80:18:2 (about./vol.)). Visualization was accomplished with UV light (254 nm) and by staining the water with potassium permanganate. Demonstrated complete disappearance of the starting material and the presence specified in the subtitle compound. The reaction mixture was filtered through diatomaceous earth and washed with ethanol (590 ml, 1.84 volume). The resulting solution indicated in the subtitle compound (presumably 154,85 g; 100%) was used directly in subsequent reactions.

Method 3. Salt mpem-butyl ether [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamino acid with 2,4,6-trimethylbenzenesulfonamide acid (50 g; 1.0 mol-EQ.; 1.0 Rel. about./wt.; see stage (1), Option 3, above), toluene (100 ml; 2.0 volume) and aqueous sodium hydroxide (1M, 100 ml; 2.0 volume) was stirred together for 20 minutes, then at 30°C for 10 minutes, then the layers were separated. The organic layer containing tert-butyl ether [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamino acid, was diluted with ethanol (100 ml; 2.0 volume). To it was added a solution of citric acid (5,14 g; 0.3 mol-EQ.) in water (5 ml; 0.1 volume) and then adding 5%Pd/C (1.50 g; 0.03 wt.-EQ. catalyst Johnson Mattey Type 440L with 61%moisture content). The combined mixture then was first made within 24 hours under hydrogen pressure of 400 kPa (4 bar). The course of the reaction was controlled by T Is X, using a plate of silicon dioxide with mobile phase X:DCM (1:1 (vol./vol.); X was a mixture of chloroform: methanol: concentrated ammonia 80:18:2 (about./vol.)). Visualization was accomplished with UV light (254 nm) and by staining the water with potassium permanganate. Demonstrated complete disappearance of the starting material and the presence specified in the subtitle compound. The reaction mixture was podslushivaet aqueous sodium hydroxide (10M; 8 ml, 0.9 mol-EQ.), then filtered through diatomaceous earth. The filter cake was washed with ethanol (100 ml; 2.0 volume). The resulting solution indicated in the subtitle compound (presumably 24,15 g; 100%) was used directly in subsequent reactions.

(3) the Connection

The way I

3-(4-Cyanoaniline)propyl-4-methylbenzenesulfonate (see Preparation example(2)described above; 0,30 g; to 0.92 mmol) and potassium carbonate (0.2 g; 1.38 mmol) was added to a solution of tert-butyl methyl ether [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamino acid (see stage (2), Method 1, described above; 0,250 g; to 0.92 mmol) in ethanol (5 ml). The reaction mixture was heated to 70°C for 10 hours before concentrating the mixture under reduced pressure. The residue was distributed between ethyl acetate (20 ml) and sodium hydroxide (1M, 10 ml). The aqueous phase is re-extracted with ethyl acetate (20 ml). The combined organic is the cue phase was concentrated under reduced pressure to obtain solid yellow (0,290 g). The solid was dissolved in ethyl acetate (10 ml) and this solution was washed with citric acid solution (0,250 g) in water (10 ml). The aqueous phase was separated, podslushivaet sodium hydroxide (1M, 10 ml) and was extracted with ethyl acetate (2×10 ml). Combined organic phase was dried over magnesium sulfate and then filtered (washing the filtered solids with ethyl acetate (10 ml)). The filtrate was concentrated under reduced pressure to obtain solid yellow (0,160 g). His suspended in ethyl acetate (0.2 ml) and then filtered to obtain specified in the connection header (0,050 g; 12%).

TPL 113-115°C.

1H NMR (400 MHz; DMSO-D6): δ 1.32 (S, s), 1.7 (2H, qt), 2.20 (2H, t), 2.22-2.3 (4H, m), 2.38-3.1 (2H, m), 2.8-2.85 (4H, m), 3.05 (2H, q), 3.19 (2H, q), 3.79 (2H, bs), 6.47 (1H, t), 6.66 (2H, d), 6.69 (1H, t), 7.41 (2H, d).

MS: m/z=430 (MH+).

Method II

To a solution of tert-butyl methyl ether [2-(9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl)ethyl]carbamino acid obtained in stage (2) (3)described above (presumably 24,15 g; 1.0 mol-EQ.; 1,0 wt./about.) in a mixture of toluene (approximately 100 ml), ethanol (approximately 200 ml) and water (approximately 14 ml), was added anhydrous potassium carbonate (18,58 g; 1.5 mol-EQ.). Added solid 3-(4-cyanoaniline)propylbenzenesulfonyl (28,17 g; 1.0 mol-EQ.; see Preparatory example A(9), Method 2, stage (a), above), and the joint is United the mixture was heated to 70° With over six hours. Over the course of the reaction was monitored by TLC, using a plate with silicon dioxide with mobile phase X:DCM (1:1 (vol./vol.); where X was a mixture of chloroform: methanol: concentrated ammonia in the ratio of 80:18:2 (about./vol.)). Visualization was carried out in UV light (254 nm) and by staining the water with potassium permanganate. This analysis showed complete disappearance of starting material and the presence specified in the connection header. The reaction mixture was cooled and the solvent concentrated under vacuum. The residue was distributed between toluene (200 ml) and water (200 ml). The layers were separated and the organic phase was concentrated under vacuum to obtain solid yellow (38,6 g).

Preparatory example

Getting Connection

(1) 4-(4-Cyanophenyl)but-3-in-1-ol

Potassium carbonate (376,7 g; 2.5 mol-EQ.) was dissolved in a mixture of 1,2-dimethoxyethane (DME; 1.2 l; 6 volumes) and water (1.2 l; 6 volumes). Added palladium on coal (20 g; 0.01 mol-EQ.; 10%Johnson Matthey Type 87L; 60% water), triphenylphosphine (11,5 g; 0.04 mol-EQ.) and copper iodide(1) (4,2 g; 0.02 mol-EQ.). Then were added 4-bromobenzonitrile (200 g; 1 mol-EQ.), washed with a mixture of DME (200 ml, 1 vol) and water (200 ml; 1 volume). This mixture was rapidly stirred in nitrogen atmosphere for at least thirty minutes. Dropwise within five minutes was added a solution of but-3-in-1-ol (to 92.1 ml; 1.1 mol-EQ.) DME (200 ml; 1 vol.) and water (200 ml; 1 volume). The combined mixture was then heated to 80°C for three hours. Over the course of the reaction was monitored by HPLC for the disappearance of arilbred and education specified in the subtitle compound. When the source material has slashdowns, the reaction mixture was cooled to 25°and filtered through diatomaceous earth. The filter cake was separately washed with toluene (1.6 l; 8 volumes). A mixture of DME: water was partially concentrated under vacuum to remove the main part of the DME. Further, it is distributed using a toluene rinse. Toluene layer was concentrated under vacuum, obtaining specified in subheading alkyne in a solid yellow color, which was dried in a vacuum Cabinet over night at 40°C. Output 182,88 g; 97%.

1H NMR (300 MHz, CDCl3): δ 7.599-7.575 (d, J=7.2 Hz, 2H, CH), 7.501-7.476 (d, J=7.5 Hz, 2H, CH), 3.880-3.813 (q, 2H, CH2), 2.751-2.705 (t, 2H, CH2), 1.791-1.746(t, 1H, OH).

TPL of 79.6-80,5°C.

(2) 4-(4-Hydroxybutyl)benzonitrile

4-(4-Cyanophenyl)but-3-in-1-ol (40 g; 1 wt.-EQ.; see stage (1)described above) in ethanol (200 ml, 5 volumes) and palladium on coal (20 g; 0.5 wt.-EQ.; 10%Johnson Matthey Type 487; 60% water) was rapidly stirred under hydrogen pressure of 500 kPa (five bars) for five hours. Over the course of the reaction was monitored by HPLC for disappearance of starting material and formation specified in subheading connect the Oia. The reaction mixture was filtered through diatomaceous earth and washed with ethanol (80 ml, 2 volumes). The ethanol solution was concentrated under vacuum to obtain specified in the subtitle of alcohol in the form of butter yellow-brown color. The output of 36.2 g; 88,5%.

1H NMR (300 MHz, CDCl3): δ 7.550-7.578 (d, J=8.4 Hz, 2H), 7.271-7.298 (d, J=8.1 Hz, 2H), 3.646-3.688 (t, 2H), 2.683-2.733 (t, 2H), 1.553-1.752 (m, 4H).

13With NMR (300 MHz, CDCl3): δ 148.04 (C), 132.16 (C), 119.1 (C), 109.64 (C)62.46 (C)35.77 (C), at 32.08 (C), 27.12 (C).

(3) 4-(4-Cyanophenyl)butylcellosolve

Specified in the subtitle compound was obtained by adding toluensulfonate to 4-(4-hydroxybutyl)benzonitrile (see stage (2)described above).

(4) tert-Butyl 7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo-[3.3.1]nonan-3-carboxylate

Three-neck flask with a capacity of 2 l, equipped with a magnetic stirrer, thermometer and a partial condenser. Into the flask was loaded a solution of 4-(4-cyanophenyl)butylmalonate (72 g; 0,218 mol; see stage (3)described above) in dimethylformamide (0,55 l). Added tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-carboxylate hydrochloride (48,2 g; of 0.182 mol; see Preparation example B(I)(4)described above) followed by the addition of potassium carbonate (62,9 g; 0,455 mol). The heterogeneous mixture was stirred for 22 hours at 85°C. TLC analysis showed complete consumption of starting material. The reactions is nnow the mixture was cooled to room temperature and was diluted with water (0.5 l). The mixture was extracted with ethyl acetate (3×0.4 l) and the organic fractions were combined. After washing with water (2×200 ml) and with brine (200 ml) the organic layer was dried with magnesium sulfate, filtered and concentrated under vacuum. The crude brown oil was purified by chromatography on silica gel, elwira a mixture hexane/ethyl acetate (3:2), with 34 g (48%yield) specified in the subtitle compound as a solid substance whitish color.

(5) 4-[4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile

Three-neck flask with a capacity of 2 l, equipped with a magnetic stirrer, thermometer and addition funnel. Into the flask was loaded tert-butyl-7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-carboxylate (34 g; 88 mmol; from step (4)described above) and dichloromethane (440 ml). Slowly at room temperature was added triperoxonane acid (132 ml). The solution was stirred for three hours, after which TLC analysis showed complete consumption of starting material. The content was transferred into odnogolosy flask and concentrated under vacuum. The residue was dissolved in dichloromethane (500 ml) and washed with saturated sodium bicarbonate solution. The aqueous layer was separated and was extracted with dichloromethane (2×200 ml). The combined organic layers were washed with brine (200 ml), dried over su is hatom magnesium and concentrated under vacuum obtaining of 25.8 g (100%yield) specified in the subtitle compound as a solid substance whitish color. The crude material was used in the next stage without further purification.

(6) Connection With

Three-neck flask with a capacity of 3 l equipped with a magnetic stirrer, thermometer and a partial condenser. Into the flask was loaded crude 4-[4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile (25,8 g; 88 mmol; from step (5)described above), dichloromethane (0,88 l) and tert-butyl-2-bromantically (see Preparation example(I)(1)above; to 27.7 g, 123 mmol). Then was added triethylamine (0,0197 l; 0,141 mol). A clear solution was boiled under reflux for 12 hours under nitrogen atmosphere and then cooled to room temperature. For the development of the reaction was monitored by TLC analysis and found that by the time time the reaction is completed. The reaction mixture was transferred into a separating funnel and then washed with water (200 ml), 15%aqueous sodium hydroxide (200 ml), water (200 ml) and with brine (200 ml). The organic layer was dried over magnesium sulfate and concentrated under vacuum. The resulting viscous yellow oil was chromatographically on silica gel, elwira first with a mixture of dichloromethane/methanol (9:1), then a mixture of dichloromethane/methanol/28%aqueous ammonium hydroxide (9:1:0,02), obtaining specified in the connection header (25,1 g; 66%yield) as a solid whitish color. B is lo detected, that earlier fractions (5,1 g) chromatography contained a small amount of less polar impurities (according to TLC analysis), which was lirowaus a mixture of dichloromethane/methanol/28%aqueous ammonium hydroxide (9:1:0.05), and while the later fraction (20 g) was one spot according to TLC analysis. Earlier fractions (5,1 g) was combined with another party specified in the connection header (7,1 g, containing a small amount of impurities) and chromatographically on silica gel, elwira first with a mixture of dichloromethane/methanol (19:1), then a mixture of dichloromethane/methanol (9:1), obtaining powder pale yellow (5.5 g). The powder was dissolved in dichloromethane (200 ml). The resulting solution was sequentially washed with 25%aqueous sodium hydroxide (50 ml), water (50 ml) and with brine (40 ml). Then the material was dried over magnesium sulfate and concentrated under vacuum to obtain specified in the connection header in the form of a whitish powder colouring (5 g). A fraction weighing 20 g was dissolved in dichloromethane (500 ml). The organic layer is successively washed with 25%aqueous sodium hydroxide (100 ml), water (100 ml) and with brine (100 ml). Then the material was dried over magnesium sulfate and concentrated under vacuum to obtain specified in the connection header in the form of a whitish powder colouring (19 g). Party powder smesi is whether together.

Preparation example D

The connection D

(1) 4-[(2S)-Oxiranylmethyl]benzonitrile

Potassium carbonate (414 g) and (R)-(-)-epichlorohydrin (800 ml) was added to a stirred solution of partenopea (238 g) in 2.0 l of MeCN and the reaction mixture is boiled under reflux in an atmosphere of inert gas for 2 hours the Solution was filtered while hot and the filtrate was concentrated, obtaining a clear oil, which crystallized from diisopropyl ether to obtain the product with 90%yield.

(2) tert-Butyl 7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-carboxylate

In a three-neck flask with a capacity of 3 l equipped with a magnetic stirrer and a thermometer, was loaded tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-carboxylate in the form of the free base (of 53.7 g; 0,235 mol, obtained from the hydrochloride salt in Preparation example B(I)(4)above), 4-[(2S)-oxiranylmethyl]benzonitrile (41,2 g; 0,235 mol; see stage (1)described above) and a solution of 2-propanol/water (0,94 l; 10:1 (vol./vol.)). The mixture was stirred at 60°C for 20 hours, during which the source material is gradually consumed (according to TLC analysis). The mixture was cooled and concentrated under vacuum to obtain 100 g (yield >100%) specified in the subtitle compound in a solid white color. Neojidanni the material used in the next stage.

(3) 4-{[(2S)-2-Hydroxy-3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]-oxy}benzonitrile

In a three-neck flask with a capacity of 3 l equipped with a magnetic stirrer, thermometer and addition funnel, was loaded crude tert-butyl-7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo-[3.3.1]nonan-3-carboxylate (100 g; from step (2)described above) and dichloromethane (1,15 l). Slowly at room temperature was added triperoxonane acid (0,352 l) and the resulting solution was stirred for three hours, after which TLC analysis showed complete reaction. The content was transferred into odnogolosy flask and concentrated under vacuum. The residue was dissolved in dichloromethane (1.2 l) and washed with saturated sodium bicarbonate solution. The aqueous layer was separated and was extracted with dichloromethane (2×0.2 l). The combined organic layers were washed with brine (0.25 l), dried over magnesium sulfate and concentrated under vacuum to obtain 73 g (yield >100%) specified in the subtitle compound as a solid substance whitish color. The crude material was used in the next stage.

(4) Connection D

Method I. Three-neck flask with a capacity of 2 l equipped with a magnetic stirrer, thermometer and a partial condenser. Into the flask was loaded crude 4-{[(2S)-2-hydroxy-3-(9-oxa-3,7-diazabicyclo[3.3.1]non-yl)-propyl]oxy}benzonitrile (73 g; from step (3)described above), dichloromethane (0.7 l) and tert-butyl-2-bromantically (see Preparation example(I)(1)above); 74 g; 0,330 mol). Then was added triethylamine (52 ml; 0,359 mol). A clear solution was boiled under reflux for 16 hours, then cooled to room temperature. The reaction mixture was transferred into a separating funnel and then washed with water (100 ml) and with brine (100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. The resulting viscous yellow oil was purified by chromatography on silica gel, elwira first with a mixture of dichloromethane/methanol (9:1), then a mixture of dichloromethane/methanol/28%aqueous ammonium hydroxide (9:1:0,02) to obtain the foaming solids whitish color (40 g). The solid was dissolved in dichloromethane (200 ml) and successively washed with 20%aqueous sodium hydroxide (100 ml) and water (100 ml). The organic layer was dried over magnesium sulfate and concentrated under vacuum to obtain specified in the connection header in the form of a solid whitish color (35.4 g; 67%yield for three steps).

Method II. Isopropanol (5 ml) and water (0.5 ml) was added to tert-butyl ether [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-carbamino acid (see Preparation example(II)(2), SP is the way I described above; 0,43 g; 1.6 mmol) was added 4-[(2S)-oxiranylmethyl]benzonitrile (0,280 g; 1.6 mmol; see stage (1)above). The mixture was heated at 66°C for 19 hours (the reaction was completed in 2 hours). The solvent is evaporated until dry under reduced pressure, obtaining mentioned in the title compound in the form of a solid whitish color (0.71 g; 100%).

1H NMR (300 MHz; CDCl3): δ 1.41 (S, s), 2.3-2.75 (6H, m), 2.75-3.0 (5H, m), 3.1-3.38 (3H, m), 3.88 (2H, s), 3.95-4.19 (3H, m), 5.85 (1H, bs), 6.99 (2H, d), 7.6 (2H, d).

1H NMR (300 MHz; DMSO-D6): δ 1.35 (S, s), 2.12-2.59 (7H, m), 2.63-2.78 (1H, m), 2.78-2.9 (4H. m), 3.2 (2H, q), 3.78 (2H, m), 4-4 .1 (2H, m), 4.12-4.19 (1H, m), 5.3 (1H, bs), 6.61 (1H, t), 7.15 (2H, d), 7.76 (2H, d).

MS: m/z=447 (MH+).

Method III. A solution of tert-butyl methyl ether [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamino acid obtained above in preparative example In(II)(2), mode 2 (presumably 154,85 g; 1.0 mol-EQ.; 1,0 wt./vol.), in a mixture of toluene (approximately 640 ml), ethanol (approximately 1280 ml) and water (approximately 130 ml) was podslushivaet aqueous sodium hydroxide (10 M; 51 ml; 0.9 mol-EQ.). Was added solid 4-[(2S)-oxiranylmethyl]benzonitrile (99,80 g; 1.0 mol-EQ.; see stage (1)above) and the combined mixture was heated to 70°C for four hours. The course of the reaction was controlled by TLC, using a plate with silicon dioxide with mobile phase X: DCM (1:1 (vol./about.) where X was a mixture of chloroform: methanol: concentrated ammonia 80:18:2 (about./vol.)). Visualization was accomplished with UV light (254 nm) and by staining the water with potassium permanganate. Demonstrated complete disappearance of the starting material and the presence specified in the connection header. The reaction mixture was cooled, filtered through diatomaceous earth and washed with ethanol (620 ml; 4.0 volume). This gave the solution specified in the connection header (presumably 254,38 g; 100% (theoretically); 2.4 l; 1.0 wt./about. for complete reaction). This solution was loaded into a flask, prepared to conduct the distillation under reduced pressure. On the side surface of the flask did the calibration mark. The solvent (1250 ml) was removed at a temperature of from 50 to 35°C, a pressure of 32 kPa (320 mbar) and 10 kPa (100 mbar). Then were added 4-methylpentan-2-ol (1500 ml) to the calibration mark. The solvent (1250 ml) was removed at a temperature of from 35 to 80°C, a pressure of 22 kPa (220 mbar) and 40 kPa (400 mbar). Added additional amount of 4-methylpentan-2-ol (1500 ml) to the calibration mark. The solvent (1250 ml) was removed at a temperature of from 62 to 76°C, a pressure of 10 kPa (100 mbar) and 9 kPa (90 mbar). The combined mixture was cooled to a temperature below 25°and was added aqueous sodium hydroxide (2M; 1,27 l; 5.0 volumes). Separated the layers and the organic layer was filtered through diatomaceous earth, obtaining a clear solution (1.2 l). This solution was loaded into a clean number is, prepared for carrying out distillation under reduced pressure. The solvent (450 ml) was removed at a temperature of from 52 to 55°C, a pressure of 9 kPa (90 mbar) and 3.5 kPa (35 mbar). Theoretically at this point, the product remained in 2 volumes 4-methylpentan-2-ol. Was added di-n-butyl ether (1,27 l; 5 volumes) and the solution was left to slowly cool to room temperature, which caused the formation of a precipitate. The mixture was cooled from room temperature to approximately 10°C. the Product was collected by filtration and washed pre-mixed solution of di-n-butyl ether (320 ml; 1.25 volumes) and 4-methylpentan-2-ol (130 ml; 0.50 volume). The wet product was dried under vacuum at 55°C to constant weight, getting mentioned in the title compound in the form of a solid white color (193,6 g; 76%).

TPL-101°C.

1H NMR (300 MHz; CDCl3): δ 1.41 (S, s), 2.3-2.75 (6N, m), 2.75-3.0 (5H, m), 3.1-3.38 (3H, m), 3.88 (2H, s), 3.95-4.19 (3H, m), 5.85 (1H, bs), 6.99 (2H, d), 7.6 (2H, d).

Example 1

Crystallisation of Compound A (Method (I): form)

Connection And (246,58 g; obtained analogously to the methods described above in preparative example A, although in this case the material was re-United with the mother solution, washed with lye NaOH and then was evaporated, getting solid) suspended in ethyl acetate (500 ml) and then heated to dissolve the solids settled. Received a clear solution. Ethyl acetate (80 ml) was removed by distillation for azeotropic drying the connection (leaving 1.7 volume of ethyl acetate). This solution is then transferred hot preheated flask with a capacity of 1 l with flange (temperature when the transfer was 68°). Then the solution was left to cool naturally (completely remove the source of heat) in the atmosphere of nitrogen with stirring air. After 40 minutes of cooling began crystallization (the internal temperature was 38°). The temperature of the solution in the next 1.5 hours were 38-40°C. Then the solution was cooled to 20°using bath water/ice and left for 1 hour. The product was filtered off, washed with cold (0° (C) ethyl acetate (330 ml) and then dried under vacuum overnight at 40°obtaining 126,83 g (51%yield, assuming that the source material is dry).

The crystals were analyzed using XRPD and the results are presented in the table below (table 1) and shown in figure 1.

Table 1
The value of d (Å)Intensity (%)
11,081
8,32
7,85
7,024
6,72
5,93
the 5.716
5,54
of 5.48
5,144
4,947
4,714
to 4.625
4,5433
of 4.44100
4,3412
4,207
4,122
3,925
the 3.6515
3,519
3,472
3,414
3,345
3,310,8
3,262
3.04 from2
2,894
2,823
2,772
2,702
2,582
2,441
2,344
2,183
to 2.063

Unit cell determined according to x-ray diffraction on a single crystal. It is orthorhombic, with p Strastnoi group P2 12121and the following dimensions: a=9,096 Åb=11,077 Å,=22,136 Å, α=β=γ=90°and V=2230,3 Å3.

DSC analysis showed two endotherm with an extrapolated point beginning approximately 121 and 126°C. TGA analysis showed a decrease in weight of about 0.1% (by weight) between 110 and 130°C.

Example 2

Crystallisation of Compound A (Method (II); shape)

Ethyl acetate (250 ml) was added to Compound a (188,10 g; obtained analogously to the methods described above in preparative example a) and the mixture was heated. Received a hot solution (no precipitate) was filtered. In continuation of the filtering of the filtered solution was dropped a number of sediment. It was re-dissolved in ethyl acetate (50 ml) and filtered. The combined filtrates were concentrated by removal of ethyl acetate (120 ml). The remaining solution was left to cool to room temperature (crystallization began at 40°). Then the suspension was cooled to 10°C for 1 hour. The solid product was filtered off, washed with cold ethyl acetate (100 ml) and then dried under vacuum at 40°obtaining a 126.7 g (68%).

The crystals were analyzed using XRPD. The results are presented in the table below (table 2) and shown in figure 2.

That the face 2
The value of d (Å)Intensity (%)
10,965
8,354
7,89
7,53
7,03
6,96
6,82
6,712
6,42
5,92
5,6 (5,64)26
5,6 (5,56)8
5,57
of 5.420
5,33
5,127
5,014
4,903
4,848
4,788
4,7016
4,4964
of 4.45100
4,3626
4,254
4,156
4,1015
4,039
3,976
3,9011
3,805
to 3.7315
3,602
3,524
3,478
3,443
3,392
3,352
3,316
3,231
3,132
3,011
2,955
2,933
2,895
2,855
2,806
2,743
2,692
2,632
2,562

DSC analysis showed the endotherm with an extrapolated point beginning approximately 125°C. TGA analysis showed a decrease in weight of about 0.1% (by weight) between 120 and 130°C.

Example 3

Crystallisation of Compound A (Method (III): form C)

Monohydrate salt of the Compound, with benzosulfimide acid (4.5 kg; obtained analogously to the methods described above in preparative example A) was added to dichloromethane (89,7 kg). Was added aqueous sodium hydroxide (1M; 46,9 kg) and the reaction mixture was stirred for 45 minutes. The final temperature of the content was 16.9°C. the Two phases were left to separate for 68 minutes and the aqueous layer (48,8 kg) Ambras the Wali. The organic layer was transferred into a clean vessel and filtered. Added ethanol (72 kg). The solvent (101,1 kg) drove 3 hours 20 min). The final temperature of the contents was 76,0°C. was Added ethanol (25,4 kg) and drove an additional 11.6 kg of solvent (1 hour 30 min), the final temperature of the contents was 79,3°C. the Solution was cooled to -17°during the night, but no crystallization was observed. Drove another 32,7 kg of solvent and the reaction mixture was cooled to 15°during the night, in the course of which the product crystallized. The reaction mixture was cooled to 0°and was stirred for 30 minutes. The product was filtered and washed with ethanol (7.3 kg) to obtain a wet solid (2.7 kg). The product was dried at room temperature for 2 hours 16 min (4,4 kPa (33 mm Hg)), then at 40-45°C for 15 hours 24 minutes (a 3.87 kPa (29 mm Hg)to obtain 2,18 kg product 99,76%purity (by area)containing 0.3% wt./wt. of ethanol.

The crystals were analyzed using XRPD. The results are presented in the table below (table 3) and shown in Figure 3.

Table 3
The value of d (Å)Intensity (%)
10,44
9,6100
8,5 0,6
7,00,9
the 5.79
5,36
5,220
a 4.8322
4,716
4,556
4,390,6
3,960,5
3,831
to 3.582
3,501
3,430,4
3,291
3,226
3,192
3,120,3
is 3.080,5
2,990,3
2,860,3
2,660,6
2,630,8
2,550,9
2,370,7
2,310,4
2,190,6
2,130,4
2,100,3

Unit cell determined according to x-ray diffraction on a single crystal. It is orthorhombic, with space group C2cb and the following dimensions: a=10,685 Åb=19,391 Å,=21,071 Å, α=β=γ=90°and V=365,8 Å 3.

DSC analysis showed the endotherm with an extrapolated point beginning approximately 122°C. TGA analysis showed a reduction in weight of approximately 0.3% (by weight) between 25 and 140°C.

Example 4

Crystallization of the monohydrate salt of the Compound, with benzosulfimide acid

1.88 g (4.9 mmol) of the Compound As obtained analogously to the methods described in Preparatory example A) was dissolved in 23 ml of ethyl acetate. 0,807 g (5.1 mmol) of benzosulfimide acid was dissolved in 4.5 ml of methanol. A solution of benzosulfimide acid was added to a stirred solution of Compound A. Benzolsulfonate salt precipitated after about 10 minutes. The precipitate was kept at 4°With during the night. The crystals were filtered off, washed with ethyl acetate and dried under vacuum over night. Yield 1.6 g (60%). The product was recrystallized from a mixture of EtOH:H2O (1:1).

The crystals were analyzed using XRPD. The results are presented in the table below (table 4) and shown in Figure 4.

Table 4
The value of d (Å)Intensity (%)
18,7100
9,413
7,50,3
6,60,2
6,40,2
6,32
5,10,3
4,850,3
4,770,3
4,6937
4,630,7
4,481
4,400,2
4,190,6
4,130,2
4,050,3
3,920,2
3,890,3
3,7628
3,610,2
3,351
3,310,3
3,210,2
3,1314
of 3.070,2
3,000,4
2,682
2,351
2,310,3
2,090,6
2,000,4
1,881

Unit cell determined according to x-ray diffraction on a single crystal. It is monoclinic, with space group P21/c and the following dimensions: a=18,833 Åb=9,293 Å,=16,271 Å, α=90°, β =94,94°, γ=90°and V=2837,1 Å3.

the product is a monohydrate without a clearly defined melting point. DSC analysis showed the endotherm with an extrapolated point in the range of approximately 85-110°C. TGA analysis showed a reduction in weight of approximately 3% (by weight) between 60 and 160°C.

Example 5

Crystallization of salt Compounds And paratoluenesulfonyl acid (Forms a and b)

Connection And (1,14 g; 2,96 mmol; obtained analogously to the methods described in Preparatory example A (for example, before adding benzosulfimide acid in the procedure described here for the formation of salts of the Compounds And benzosulfimide acid)) was dissolved in ethyl acetate (20 ml). Was added dropwise a solution of paratoluenesulfonyl acid (PTSA) (0,57 g; 2,99 mmol) in methanol (0.3 ml). Spent wash PTSA in 0.1 ml of methanol was added 5 ml of ethyl acetate. After a few minutes formed a white suspension. It was stirred for 1 h, the Solid was filtered and washed with 5 ml of ethyl acetate. Yield 1.4 g (84,8%). Solid salt toluensulfonate acid (1.40 g) was mixed with 15 ml of ethyl acetate and heated to the temperature of reflux distilled. To the suspension was added to 0.85 ml of methanol. Within a few seconds all the solid went into solution. It was left to cool, and after a few minutes was observed crystallization. Soon he was fully hardened. To it was added ethyl acetate (10 ml) and methanol (0.15 ml). Ustuu the suspension is then stirred at 0° C for 30 minutes. The solids were filtered off and washed with ethyl acetate (5 ml). They were left to be dried on the vacuum suction. Yield 1.10 g (66,6%). A portion (500 mg) was dried at 50°With under reduced pressure, getting 0,440,

Part of the salt toluensulfonate acid was recrystallized from acetone. Crystals (form A) was analyzed using XRPD. The results are presented in the table below (table 5(a)) and shown in Figure 5(a). Part of the salt toluensulfonate acid suspended in phosphate buffer (ionic strength of 0.1 m at pH 3), followed by decantation. Crystals (form C) was analyzed using XRPD. The results are presented in the table below (table 5(b)) and is shown in Figure 5(b).

Table 5 (a)
The value of d (Å)Intensity (%)
to 19.9100
10,030
8,70,5
7,61
7,00,9
6,60,7
6,41
6,04
the 5.71
5,50,8
5,21
4,9933
4,864
4,492
of 4.384
4,368
4,195
3,995
3,931
of 3.771
3,592
3,401
3,335
3,291
3,190,7
is 3.081
2,860,7
2,220,7
2,110,6
2,090,7
2,001

For forms And DSC analysis showed endotherm with an extrapolated point beginning approximately 145°C. TGA analysis showed a reduction in weight of approximately 3.3% (by weight) between 20 and 120°C.

Table 5 (b)
The value of d (Å)Intensity(%)
18,6100
the 9.70,6
9,343
7,60,4
6,28
5,00,9
of 4.6620
4,492
to 3.738
3,114
2,330,6

For the form In the DSC analysis showed the endotherm with an extrapolated point beginning approximately 153°C. TGA analysis showed a reduction in weight of approximately 4.4 percent (by weight) between 25 and 120°C.

Example 6

Crystallization of the salt of the Compound, 1-hydroxy-2-naphthoic acid

Connection And (0,60 g; 1.56 mmol; obtained analogously to the methods described in Preparatory example A (for example, before adding benzosulfimide acid in the procedure described here for the formation of salts of the Compounds And benzosulfimide acid)) in ethyl acetate (10 ml) was added 1-hydroxy-2-naphthoic acid (0,323 g; 1.7 mmol) in methanol (1 ml). The solution is not formed. The mixture was stirred at room temperature for 30 minutes. Not mentioned no crystallization. Then the solution was cooled for 30 minutes. Observed the formation of small amounts of crystals. The solvents are evaporated to the dry state, the solids were transferred to the ethyl acetate (5 ml) and was heated to the temperature of reflux distilled. Part of the solution was added methanol (0.2 ml). The resulting suspension was cooled with a mixture of ice/water, filtered and washed with ethyl acetate (2 ml). The solid is then dried in a drying Cabinet at 50°when bonigen the m pressure within 24 hours Output 0,510 g (57%).

The crystals were analyzed using XRPD. The results are presented in the table below (table 6) and is shown in Fig.6.

Table 6
The value of d (Å)Intensity(%)
17,6100
12,416
8,844
7,94
7,55
6,62
6,42
6,25
the 5.75
5,629
5,24
5,16
4,957
4,889
4,4720
4,404
4,214
4,168
4,086
3,955
3,845
3,808
of 3.643
3,553
3,336
3,037
2,962
2,63

Example 7

Crystallization of the salt of the Compound, with 1.5-naphtalenesulfonic acid

Connection And (0,490 g; of 1.27 mmol; obtained analogously to the methods described in Preparatory example A (for example, before adding benzosulfimide acid in the procedure described here for the formation of salts of the Compounds And benzosulfimide acid)) was dissolved in ethyl acetate (10 ml). Solution was added 1,5-naphthalenesulfonate acid in methanol (0.5 ml). After a few minutes came a white solid. All was stirred at room temperature for 30 minutes and then cooled with a mixture of ice/water. The suspension was noted a number of large lumps of white solid. The solids were filtered off to obtain 0.34 g of a solid substance of white color. It's been translated in methanol (50 ml) and water (100 ml) and was heated to the temperature of reflux distilled until then, until we got completely transparent solution. The solution was left to reach room temperature and then cooled with a mixture of ice/water for 30 minutes. The solids were filtered off to obtain a white powder (0,150 g). The solid was dried in a drying Cabinet at 50°and reduced pressure for 5 hours

1H NMR showed the ratio of acid to base is 1:2. The crystals were analyzed using XRPD. Result is you are presented in the table below (table 7) and shown in Fig.7.

Example 8

Crystallization of the salt of the Compound, 2-mesitylenesulfonic acid

A solution of 2-mesitylenesulfonic acid (0,276 g) in methanol (0.3 ml) was added to a stirred solution of Compound A (0.45 g; obtained analogously to the methods described in Preparatory example A (for example, before adding benzosulfimide acid in the procedure described here for the formation of salts of the Compounds And benzosulfimide acid)) in ethyl acetate (10 ml). Precipitate formation occurred immediately. The suspension was stirred at room temperature for 30 minutes and then cooled with a mixture of ice/water. The product was filtered and washed with ethyl acetate (3 ml) to obtain specified in the connection header (0,60 g; 88%). The obtained salt was dissolved in ethyl acetate (10 ml) and was heated to the temperature of reflux distilled. Was added methanol (3 ml) with formation of a transparent solution. The solution was left to cool to room temperature and then was stirred at 0-5°C for 1 h, the Suspension was filtered to obtain a colorless solid matter (0,370 g; 54% in two stages).

The crystals were analyzed using XRPD. The results are presented in the table below (table 8) and shown in Fig.

Table 7
The value of d (Å)Intensity(%)
16,1100
8,64
8,119
7,82
7,17
6,83
6,310
6,06
5,53
5,4 (5,43)3
5,4 (5,39)4
5,32
4,9617
4,8822
to 4.6818
to 4.624
4,499
4,348
4,1012
4,046
3,9413
3,552
3,445
3,4015
3,2311
3,205
3,154
2,872
2,723
2,193
2,183
Table 8
The value of d (Å)Online is newest(%)
18,9100
9,525
8,81
7,81
6,3 (6,33)10
6,3 (6,26)9
the 5.73
5,32
5,13
to 4.982
4,7520
to 4.622
4,504
4,465
to 4.412
4,291
4,241
4,132
3,925
3,8012
3,691
3,542
3,361
3,176
3.04 from1
2,382
2,111

Example 9

Crystallization of Compound D

Method I. the Compound D (obtained analogously to the methods described herein previously) was first purified column chromatography on silica gel using a mixture of dichloromethane/methanol/28%aqueous ammonia (9:1:0,5) as eluent. The resulting powder was light the lo-yellow (203 g) was dissolved in dichloromethane (400 ml) and then the yellow solution was diluted with n-heptane (2 l) as long until the mixture became turbid. The mixture is vigorously stirred at room temperature and added seed crystals of Compound D (obtained by slow evaporation of solvent from a small portion of the solution indicated in the title compound, obtained similar to this method by the way). A large part of the product precipitated after stirring for two hours. The resulting suspension was filtered and then dried under vacuum at 40°obtaining 179 g specified in the connection header in the form of a whitish powder coating. The second part (44 g) is purified on a column of material gave an additional 25 g specified in the connection header after such recrystallization.

Method II. A mixture of Compound D (obtained analogously to methods described previously (mainly see Preparation example D(4), Method III described above); 14,29 g), isopropanol (28 ml) and diisopropyl ether (140 ml) was heated to 80°C. the Solution was filtered hot to transparent state and then re-heated to 80°C. Then the solution was left to cool to room temperature, and then began to precipitate. After stirring for two hours the precipitate was collected by filtration, washed with a mixture of isopropanol: diisopropyl ether (1:6, 70 ml) and then dried by suction on the filter is. The wet product was dried under vacuum at 70°during the night with obtaining specified in the connection header in the form of a solid white color (10.1 g; 70%).

1H NMR (300 MHz, CDCl3) δ 1.41 (S, s), 2.3-2.75 (6N, m), 2.75-3.0 (5H, m), 3.1-3.38 (3H, m), 3.88 (2H, s), 3.95-4.19 (3H, m), 5.85 (1H, bs), 6.99 (2H, d), 7.6 (2H, d).

Method III. Compound D (obtained analogously to the methods described here previously; 1.0 g) was dissolved in a hot mixture (10 ml). Added isohexane (30 ml) and the solution was separated from a small amount of undissolved material by decantation into a clean flask. The solution was cooled overnight in the refrigerator, which led to the formation of granular sludge. The solution was left to warm to room temperature and then the solid was collected by filtration. The solid was dried by suction on the filter, then dried under vacuum at 40°obtaining solid whitish color (0.73 g).

Method IV. Compound D (obtained analogously to the methods described here previously; 1.0 g) was dissolved in hot isopropylacetate (10 ml). Added isooctane (20 ml) and the solution was separated from a small amount of undissolved material by decantation into a clean flask. The solution was cooled overnight in the refrigerator, which led to the formation of granular sludge. The solution was left to warm up to on the th temperature and then the solid was collected by filtration. The solid was dried by suction on the filter, then dried under vacuum at 40°obtaining solid whitish color (0,82 g).

Way V. Compound D (obtained analogously to the methods described here previously; 1.0 g) was dissolved in hot aqueous ethanol (50%, 20 ml). The solution was cooled during the weekend days in the refrigerator, which led to the formation of needle-like crystals form. The crystals were collected by filtration and dried by suction on the filter. Drying under vacuum at 40°gave a colorless solid (0,48 g).

Method VI. Compound D (obtained analogously to the methods described here previously; 100 mg) was dissolved in toluene (1 ml). Added isooctane (2 ml) and the cloudy solution was cooled during the weekend days in the refrigerator, which led to the formation of a precipitate in the form of small pellets. The solution was left to warm to room temperature and then the solid was collected by filtration. The solid was dried by suction on the filter, then dried under vacuum at 40°obtaining solid whitish colour (62 mg).

Crystals (of Methods I-VI) were analyzed using XRPD. The results are presented in the table below (table 9) and shown in Fig.9.

Table 9
C is Uchenie d (Å )Intensity (%)
22,345
11,216
8,441
7,55
7,114
6,417
5,860
5,513
5,27
4,9131
4,8128
4,694
to 4.6210
to 4.52100
4,3277
4,2214
4,1235
4,067
3,919
3,817
3,724
3,535
3,509
3,425
3,3412
3,158
3,035
2,983
2,923
2,834
2,774
2,755
to 2.676
2,373
2,115

Unit cell determined according to x-ray diffraction on a single crystal. It is orthorhombic, with space group P212121and the following dimensions: a=5,870 Åb=9,098 Å,=45,101 Å, α=β=γ=90°and V=2408,6 Å3.

DSC analysis showed the endotherm with an extrapolated point beginning approximately 100-102°C. TGA analysis showed a decrease in weight of about 0.4% (by weight) between 90 and 110°C.

Example 10

Crystallization of the salt of Compound D with methanesulfonic acid

Method I. the Compound D (250 mg; obtained analogously to the methods described above in Preparation example D) was dissolved in methanol (10 ml). To the solution was added methanesulfonyl acid (56 mg; 38 μl). The methanol was removed under reduced pressure and the remaining resin was again dissolved in the minimum possible amount of hot ethyl acetate. The solution was made of the seed prior to salt crystals (obtained by slow evaporation of solvent from small portions of a solution of the compounds obtained is similar to this method by the way) and left in the fridge for a few days for crystallization. The resulting crystals were collected by filtration and washed with a small amount of cold ethyl acetate (with you what Odom 280 mg, 98%).

Method II. Compound D (4,00 g obtained analogously to the methods described above in Preparation example D) was dissolved in ethyl acetate (40 ml). Solution was added methanesulfonic acid (0.87 g) in ethyl acetate (40 ml). After 3 minutes, the solution was made of the seed crystals previously obtained salt (14 mg, from the Way I described above), which caused the immediate formation of a precipitate. After 5 minutes, the solid was collected by filtration and washed with ethyl acetate before drying by suction on the filter. Drying under vacuum at 40°C for 3.5 hours gave a solid crystalline substance of white color (4.71 g; 97%).

TPL 170-2°C (decomp.).

Method III. Sol Connection D with methanesulfonic acid (0.8 g; obtained analogously to the method described above in Method (II) was heated in acetonitrile (8 ml, 10 volumes). A solution was formed at 70°C. It was left to cool to ambient temperature. The product was collected by filtration and washed with a small amount of cold acetonitrile. At first it was dried under vacuum. at 40°From (the melting point (decomposition) from 169,4 to 169.9°s; content of residual solvent of acetonitrile and 0.08 wt.% (GC)). Then it was dried under vacuum at 80°s; content of residual solvent of acetonitrile is less than 0.02 wt.% (GC). Purity 99,92% by HPLC area and (maximum).

Method IV. The mixture of salt of Compound D with methanesulfonic acid (2.0 g; 1.0 mol-EQ., is obtained analogously to the method described above in Method (II) and acetonitrile (20 ml, 10 Rel. about.) was heated up to 80°C. At this temperature, the formed solution. The solution was left to cool to 25°±5°and then cooled before 5°±5°C. the Product was collected by filtration and washed with cold acetonitrile (4 ml, 2 Rel. vol.). The wet solid was dried under vacuum at 80°C. This gave specified in the title compound (0.15 g; 7,5%) in the form of a solid whitish color. 99.97% of the HPLC-area. The content of residual solvent of acetonitrile is less than 0.02 wt.% (GC).

Way V. the Mixture of salt of Compound D with methanesulfonic acid (10.0 g; 1.0 mol-EQ., is obtained analogously to the method described above in Method II, except that in this case, instead of ethyl acetate as a solvent used butyl acetate)and pentane-2-ol (100 ml, 10 Rel. about.) was heated to 85°receiving solution. The solution was left to cool to 25°±5°and then cooled before 5°±5°C. the Product was collected by filtration and washed with cold pentane-2-I (20 ml, 2 Rel. vol.). The wet solid was dried under vacuum at 40°within twenty hours. This gave specified in the header connection (6,72 g; 67,2%) in VI is e solid whitish color. 99,47% HPLC-area.

Method VI. The mixture of salt of Compound D with methanesulfonic acid (3.0 g; 1.0 mol-EQ., is obtained analogously to the method described above in Method V) and 3-methylbutane-1-ol (15 ml, 5 Rel. about.) was heated to 90°receiving solution. The solution was left to cool to 25°±5°and then cooled before 5°±5°C. the Product was collected by filtration and washed with cold 3-methylbutane-1-I (6 ml, 2 Rel. vol.). The wet solid was dried under vacuum at 40°C. This gave specified in the title compound in the form of solids whitish color (2,43 g; 81%).

Method VII. The mixture of salt of Compound D with methanesulfonic acid (2.0 g; 1.0 mol-EQ., is obtained analogously to the method described above in Method V) and hexane-1-ol (15 ml, 5 Rel. about.) was heated up to 80°receiving solution. The solution was left to cool to 25°±5°and then cooled before 5°±5°C. the Product was collected by filtration and washed with cold hexane-1-I (6 ml, 2 Rel. vol.). The wet solid was dried under vacuum at 40°C. This gave specified in the title compound in the form of solids whitish color (2,43 g; 81%).

Crystals (Methods I-VII) were analyzed using XRPD. The results are presented in the table below (table 10) and shown in Figure 10.

Table 10
The value of d (Å)Intensity(%)
a 12.7100
9,46
7,320
7,111
6,83
6,611
6,43
6,017
of 5.418
5,121
4,9238
a 4.8322
4,745
of 4.664
of 4.454
4,2711
4,1414
4,0530
3,9938
a 3.8733
to 3.739
the 3.657
3,4219
3,376
3,313
3,225
3,124
3,006
2,965
2,925
2,894
2,813
2,712
2,635
to 2.572
2,503
2,413

Unit cell determined according to x-ray diffraction on a single crystal. It is orthorhombic, with space group P212121and the following dimensions: a=7,772 Åb=14,250 Å,=25,750 Å, α=β=γ=90°and V=1717,2 Å3.

DSC analysis showed the endotherm with an extrapolated point beginning approximately 167°C. TGA analysis showed a reduction in weight of approximately 1.2% (by weight) between 25 and 100°C.

Example 11

Crystallization of the salt of Compound D with the hippuric acid

A solution of hippuric acid (0.8 g) in methanol (20 ml) was added to a solution of Compound D (2.00 g, obtained analogously to the methods described above in Example 9) in methanol (5 ml). Then the solution was concentrated under vacuum to obtain oil. Added diethyl ether (20 ml) and the mixture was re-concentrated to obtain foam. Stirring in ether (100 ml) overnight and filtering gave 2,22 g specified in the title compound (79%). Salt was dried under vacuum at 34°receiving 2,19 g (78%).

The presence of salt the hippuric acid is confirmed by NMR.

The crystals were analyzed using XRPD. The results are presented in the following table (Table is 11) and shown in 11.

Table 11
The value of d (Å)Intensity(%)
16,4100
13,83
6,98
6,26
6,125
5,65
5,57
5,217
5,115
is 4.9313
4,824
br4.6118
4,5026
4,2830
4,206
4,118
3,688
3,545
with 3.275

Example 12

Crystallization Connection

(1) the Connection is obtained analogously to the procedure described above in Preparation example except that performed following the final stage of the method: three-neck flask with a capacity of 3 l equipped with a magnetic stirrer, thermometer and a partial condenser. Into the flask was loaded crude 4-[4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]-benzonitrile (see Preparation example(5), op the sled above; 25,8 g; 88 mmol), dichloromethane (0,88 l) and tert-butyl-2-bromantically (see Preparation example(I)(1)above; to 27.7 g, 123 mmol). Then was added triethylamine (0,0197 l; 0,141 mol). A clear solution was boiled under reflux for 12 hours under nitrogen atmosphere and then cooled to room temperature. The course of the reaction was controlled by TLC-analysis and found that it was finished by this time.

(2) the Reaction mixture was transferred into a separating funnel and washed successively with water (200 ml), 15%aqueous sodium hydroxide (200 ml), water (200 ml) and with brine (200 ml). The organic layer was dried over magnesium sulfate and concentrated under vacuum. The resulting yellow viscous oil was chromatographically on silica gel, elwira first with a mixture of dichloromethane/methanol (9:1), then a mixture of dichloromethane/methanol/28%aqueous ammonium hydroxide (9:1:0,02), to obtain the crude Compound (25.1 g; 66%yield) as a solid whitish color. Found that earlier chromatographic fractions (5,1 g) contained a small amount of less polar impurities (TLC analysis with elution with a mixture of dichloromethane/methanol/28%aqueous ammonium hydroxide (9:1:0.05 to)), while the later fraction (20 g) gave a single spot according to TLC analysis. Earlier fractions (5,1 g) by Denali to the prior party Connection (7,1 g, contains minor impurities) and chromatographically on silica gel, elwira first with a mixture of dichloromethane/methanol (19:1), then a mixture of dichloromethane/methanol (9:1), obtaining powder pale yellow (5.5 g). The powder was dissolved in dichloromethane (200 ml). The resulting solution was washed successively 25%aqueous sodium hydroxide (50 ml), water (50 ml) and with brine (40 ml). Then the material was dried over magnesium sulfate and concentrated under vacuum to obtain the crude specified in the connection header in the form of a whitish powder colouring (5 g). Fraction of 20 g was dissolved in dichloromethane (500 ml). The organic layer was washed successively 25%aqueous sodium hydroxide (100 ml), water (100 ml) and with brine (100 ml). Then the material was dried over magnesium sulfate and concentrated under vacuum to obtain powder whitish color (19 g). Party mixed together.

The crystals were analyzed using XRPD. The results are presented in the table below (table 12) and shown in Fig.

Table 12
The value of d (Å)Intensity(%)
19,424
10,016
9,164
8,1100
6,5 84
5,519
5,241
5,121
4,9920
4,9021
4,609
4,4630
4,3225
4,0678
4,0033
3,8515
3,8023
3,6610
of 3.565
3,4417
3,334
3,165
2,948
2,824
2,694
2,445

DSC analysis showed an endothermic peak with an extrapolated point beginning approximately 97°C. TGA analysis showed a reduction in weight of approximately 0.6% (by mass) between 25 and 120°C.

Example 13

Crystallization of salts Connection with methanesulfonic acid

Connection With (250 mg; obtained analogously to the method described above in Example 12) was dissolved in methanol (10 ml). To the solution was added methanesulfonyl acid (56 mg; 38 μl). The methanol was removed under reduced pressure and the remaining resin again restore and at a minimum, as far as possible, the amount of hot isopropanol. The solution was made of the seed prior salt (obtained by slow evaporation of solvent from a small portion of the solution indicated in the title compound, obtained similar to this method by the way) and left in the fridge for a few days for crystallization. The resulting crystals were collected by filtration and washed with a small amount of cold isopropanol (220 mg, 72%).

The crystals were analyzed using XRPD. The results are presented in the table below (table 13) and shown in Fig.

Table 13
The value of d (Å)Intensity (%)
13,3100
12,35
9,65
7,56
6,96
6,83
6,712
6,42
6,22
6,02
5,512
5,32
5,113
5,05
4,895
4,81 4
4,344
4,234
4,206
4,085
3,992
3,898
3,855
3,804
3,682
3,522
3,492
3,432
3,392
3,332
3,253
3,012
2,942
2,901
2,801
2,491
2,402

DSC analysis showed endothermic peaks with an extrapolated point beginning approximately 145°With (minor) and 170° (main). TGA analysis showed a decrease in the mass of ~ 0.9% (by weight) between 25 and 105°C.

Example 14 the Crystallization of salts Connection with paratoluenesulfonyl acid

Connection With (250 mg; obtained analogously to the method described above in Example 12) was dissolved in methanol (10 ml). To the solution was added toluensulfonate acid (110 mg). The methanol was removed under reduced pressure and and the remaining resin was again dissolved in the minimum, as far as possible, the amount of hot ethyl acetate. The solution was made of the seed prior salt (obtained by slow evaporation of solvent from a small portion of the solution indicated in the title compound, obtained similar to this method by the way) and left in the fridge for a few days for crystallization. The resulting crystals were collected by filtration and washed with a small amount of cold ethyl acetate (280 mg, 78%).

The crystals were analyzed using XRPD. The results are presented in the table below (table 14) and shown in Fig.

Table 14
The value of d (Å)Intensity(%)
13,2100
8,10,5
7,50,7
7,13
6,60,7
6,40,9
6,30,7
6,00,8
5,61
of 5.42
5,23
5,04
equal to 4.972
4,860,8
4,672
,42 0,7
4,283
4,247
4,192
4,121
4,082
4,032
4,011
3,921
3,820,7
3,780,8
3,660,8
3,570,5
of 3.461
3,362
3,321
3,122

DSC analysis showed an endothermic peak with an extrapolated point beginning approximately 138°C. TGA analysis showed a decrease in weight of about 0.2% (by weight) between 25 and 150°C.

Example 15

Sol Connection D with [(diphenyl-4-carbonyl)amino]acetic acid

(a) Methyl ester [(diphenyl-4-carbonyl)amino]acetic acid

Dichloromethane (50 ml) and then triethylamine (11.2 ml; of 79.6 mmol, 2.0 EQ.) was added to the methyl ester hydrochloride of glycine (5.0 g; 39.8 mmol; 1.0 EQ.) The mixture was stirred and cooled to -5°using a bath of ice/methanol. In continuation of 22 minutes was added a suspension of diphenyl-4-carbonylchloride (compared to 8.26 g, 39.8 mmol; 1.0 EQ.) in dichloromethane (25 ml). The mixture was stirred for 3 h p and -5° And then it was allowed to mix at room temperature overnight (16 hours). Was added water (75 ml) and the mixture was rapidly stirred for 30 minutes at room temperature. The layers were separated. The organic layer was washed with water (75 ml) and then evaporated until dry using a rotary evaporator to obtain a solid substance whitish color (6,58 g; 62%).

1H NMR (300 MHz, CDCl3) δ 3.82 (s, 3H), 4.29 (d, J=5.1 Hz, 2H), 6.68 (s, 1H), 7.3-7.5 (m, 3H), 7.62 (d, J=4.8 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H).

TPL 127-128°C.

(b) [(Diphenyl-4-carbonyl)amino]acetic acid

Methyl ester [(diphenyl-4-carbonyl)amino]acetic acid (6,58 g; 25 mmol; 1.0 EQ.; from step (a)described above) was added to the flask followed by the addition of aqueous sodium hydroxide (1M, 84 ml, 50 mmol; 2.0 EQ.). The mixture was heated to 50°C for 5 hours using an oil bath. Then the solution was stirred overnight (16 hours) at room temperature. As cooling of the formed white precipitate. The mixture was cooled before 5°using a bath of ice/water. To the cooled solution was slowly added concentrated hydrochloric acid (8 ml), making sure the temperature did not rise above 10°C. the Mixture was stirred for 15 minutes and then filtered. Solid white color was dried in air for 30 minutes is then dried under vacuum at 40° C for 16 hours to obtain a solid substance whitish color (5.75 g; 93%).

1H NMR (300 MHz, DMSO-d6) δ 3.95 (d, J=5.7 Hz, 2H), 7.35-7.5 (m, 3H), 7.7-7.8 (m, 4H), 7.97 (d, J=6.9 Hz, 2H), 8.89 (t, J=6.0 Hz, 1H), 12.58 (s, 1H).

TPL 217-217,5°C.

(C) Recrystallization [(diphenyl-4-carbonyl)amino]acetic acid

To [(diphenyl-4-carbonyl)amino]acetic acid (5.0 g; from step (b)described above) was added methanol (100 ml, 20 volumes). The mixture was heated to 62°using an oil bath, with constant stirring. The resulting pale orange solution was kept at this temperature for 10 minutes. The solution was left to cool to room temperature and then cooled before 5°using a bath of ice/water. Crystallization began at about 30°C. the Precipitate was collected by filtration, dried in air for 15 minutes, then dried under vacuum at 40°C for 26 hours to obtain colorless crystals (2.9 g; 58%).

1H NMR (300 MHz, DMSO-d6) δ 3.95 (d, J=5.7 Hz, 2H), 7.35-7.5 (m, 3H), 7.7-7.8 (m, 4H), 7.97 (d, J=6.9 Hz, 2H), 8.89 (t, J=6.0 Hz, 2H), 12.58 (s, 1H).

(g) Salt of Compound D with [(diphenyl-4-carbonyl)amino]acetic acid

[(Diphenyl-4-carbonyl)amino]acetic acid (1,14 g; see stage (b) or (C)above) and Compound D (2 g; obtained analogously to the methods described here previously) was dissolved in hot isopropanol (40 ml)By least cooling to room temperature the formed crystalline precipitate, which was filtered, washed with isopropanol (2×20 ml) and dried by suction on the filter. Drying for 6 hours under vacuum at 40°gave the salt as a colourless crystalline solid (2.50 g; 80%).

1H NMR (300 MHz, DMSO-d6+) δ 1.34 (S, s), 2.25 (2H, t), 2.3-2.5 (4H, m), 2.6-2.7 (1H, m), 2.7-2.8 (1H, m), 2.85-3.0 (4H, m), 3.0-3.1 (2H, m), 3.82 (2H, s), 3.88 (2H, d), 3.95-4.05 (2H, m), 4.1-4.2 (1H, m), 6.65 (1H, t), 7.14 (2H, d), 7.35-7.55 (3H, m), 7.7-7.85 (6H, m), 7.96 (2H, d), 8.75 (1H, t).

TPL 143-143,5°C.

The crystals were analyzed using XRPD. The results are presented in the table below (table 15) and shown in Fig.

4,89
Table 15
The value of d (Å)Intensity (%)
20,445
15,3100
11,524
10,34
10,06
9,411
7,734
7,223
6,25
5,949
the 5.715
5,66
of 5.411
5,313
5,214
5,06
8
4,819
4,706
4,6057
4,5489
4,369
4,227
4,1318
4,068
3,8513
3,7927
of 3.6412
3,6111
3,4011
3,316
2,986
2,9412
2,886

Example 16

Sol Connection D with gementera acid

In a hot solution of Compound D (5.35 g; obtained analogously to the methods described herein previously) and succinic acid (0.71 g) in isopropanol (20 ml) were introduced seed salt of Compound D with gementera acid (obtained by slow evaporation of solvent from a small portion of the solution indicated in the title compound, obtained similar to this method by the way) and then left to stand in the refrigerator. The next day the solid precipitate was collected by filtration and washed with isopropanol (20 ml). The solid was dried by suction on the filter and then dried under vacuum Ave is 40° C for 2 hours to obtain specified in the connection header in the form of a solid white color. The filtrate was left for the complete evaporation by keeping the open air. This gave a solid which was suspended in isopropanol (20 ml) and then filtered, washing the filter with isopropanol (70 ml). The solid was dried by suction on the filter and then dried under vacuum at 40°C for 90 minutes with obtaining specified in the connection header in the form of a solid white color (2.8 g).

TPL 112-114°C.

The crystals were analyzed using XRPD. The results are presented in the table below (table 16) and shown in Fig.

Table 16
The value of d (Å)Intensity (%)
35,45
18,0100
12,12
8,37
8,012
7,515
7,35
6,810
6,112
5,89
of 5.49
4,8941
4,797
to 4.6828
4,595
4,5426
4,4337
4,3510
4,1816
4,0410
3,994
3,905
3,834
to 3.674
to 3.588
3,132
of 3.076
3,033
2,474
2,443

Example 17

The salt of the Compound D (3,4-dichloraniline)acetic acid

(a) Methyl ester (3.4-dichloraniline)acetic acid

Dichloromethane (150 ml) and then triethylamine (33,0 ml, 234 mmol, 2.0 EQ.) was added to the methyl ester hydrochloride of glycine (14,7 g, 117 mmol; 1.0 EQ.) The mixture was stirred and cooled to 2°using a bath of ice/water. In the continuation of the 7 minute solution was added 3,4-dichlorobenzotrifluoride (RUB 24.55 g, 117 mmol; 1.0 EQ.) in dichloromethane (75 ml). The mixture was stirred for 1 h at 2°and then it was allowed to mix at room temperature overnight (16 hours). Was added water (225 ml) and the mixture was rapidly stirred for 30 minutes at room temperature is. The layers were separated. The organic layers were washed with water (225 ml) and then evaporated until dry using a rotary evaporator to obtain a solid substance whitish color. Selected solid (26,18 g; 85%) was added to dichloromethane (300 ml, 10 volumes) with 1M sodium hydroxide solution (300 ml, 10 volumes). The lower organic layer was concentrated until dry under vacuum (25,91 g; 84%).

TPL 133,2-134,3°C.

δN(300 MHz, CDCl3) 3.66 (1H, s, CH3), 4.03 (2H, d, J=6 Hz, CH2), 7.78-7.87 (2H, m, CH), 8.100 (1H, s, CH), 9.18 (1H, t, J=5.7 Hz, NH).

(b) (3,4-Dichloraniline)acetic acid

Methyl ether (3,3-dichlorobenzidine)acetic acid (25,91 g; 100 mmol; 1.0 EQ.; see stage (a), described above) was added to the flask followed by the addition of aqueous sodium hydroxide (1M, 198 ml, 200 mmol; 2.0 EQ.). The mixture was heated to 50°C for 2 hours using an oil bath. As cooling of the formed white precipitate. The mixture was further cooled to 5°using a bath of ice/water. To the cooled solution was slowly added concentrated hydrochloric acid (60 ml), ensuring that the temperature did not exceed 10°C. the Mixture was stirred for 10 minutes and then filtered. Solid white color was dried in air for 15 minutes and then dried under vacuum at 40°t is an increase of 16 hours, getting a solid whitish color (19,15 g; 78%).

TPL 140,0-140,3°C.

δN(300 MHz, DMSO-D6) 3.94 (2H, d, J=6 Hz, CH2), 7.77-7.87 (2H, m, CH), 8.10 (1H, s, CH), 9.06 (1H, t, J=6 Hz), 12.66 (1H, bs, OH).

(C) the Salt of the Compound D (3,4-dichloraniline)acetic acid

(3,4-Dichloraniline)acetic acid (0.56 g; see stage (b)above) and Compound D (1,02 g; obtained as described here earlier methods) was dissolved in hot ethyl acetate (4 ml). When cooled to room temperature formed a crystalline precipitate, which was filtered, washed with ethyl acetate (15 ml) and dried by suction on the filter. Drying overnight under vacuum at 40°gave specified in the title salt as a colourless crystalline solid (0,92 g; 58%).

TPL 128,5-130,5°C.

1H NMR (400 MHz, DMSO-D6) δ 1.34 (S, s), 2.26 (2H, t), 2.3-2.5 (3H, m), 2.5-2.6 (1H, m), 2.6-2.7 (1H, m), 2.7-2.8 (1H, m), 2.85-3.0 (4H, m), 3.0-3.1 (2H, m), 3.8-3.9 (4H, m), 4.01 (2H, d), 4.1-4.2 (1H, m), 6.69 (1H, t), 7.12 (2H, d), 7.7-7.8 (3H, m), 7.84 (1H, dd), 8.09 (1H, dd), 8.92 (1H, t).

The crystals were analyzed using XRPD. The results are presented in the table below (table 17) and shown in Fig.

Table 17
The value of d (Å)Intensity(%)
16,6100
4
10,910
10,33
6,36
6,215
5,531
5,330
5,114
5,012
4,6038
4,3320
4,3011
4,2211
4,113
3,858
3,7013
3,506
3,3010
3,167
3,066
2,995
2,953

Example 18

Sol Connection D with [(naphthalene-2-carbonyl)amino]acetic acid

(a) Methyl ester [naphthalene-2-carbonyl)amino]acetic acid

Dichloromethane (66 ml) and then triethylamine (14.6 ml; 105 mmol, 2.0 EQ.) was added to the methyl ester hydrochloride of glycine (6,61 g; 52,5 mmol; 1.0 EQ.) As you add triethylamine appeared white precipitate, and the solution became thicker. The mixture was stirred and cooled to 2°using a bath of ice/water. In continuation of 15 minutes was added a solution of 2-naphthoyl the reed (10,07 g; 52,5 mmol; 1.0 EQ.) in dichloromethane (33 ml). The mixture is pale brown color was stirred for 25 hours at 5°C. was Added water (100 ml) and the mixture was rapidly stirred for 30 minutes at room temperature. The layers were separated. The organic layer was washed with sodium hydroxide (1M; 100 ml) and then evaporated until dry using a rotary evaporator to obtain a solid substance whitish color (12,21 g; 96%).

TPL 117,7-118,1°C.

δN(400 MHz, DMSO-D6) 3.68 (3H, s, CH3), 4.08 (2H, d, J=4.5 Hz, CH2), 7.59-7.66 (2H, m, CH), 7.935-8.015 (4H, m, CH), 8.491 (1H, s, CH), 9.124 (1H, t, J=45,6 Hz, NH).

(b) [(Naphthalene-2-carbonyl)amino]acetic acid

Methyl ester [(naphthalene-2-carbonyl)amino]acetic acid (there is a 10.03 g; 41 mmol; 1.0 EQ.; see stage (a), described above) was added to the flask followed by the addition of aqueous sodium hydroxide (1M, 120 ml, 123 mmol; 3.0 EQ.). The mixture was heated to 55°C for 2 hours using an oil bath. The mixture was cooled to 5°using a bath of ice/water. To the cooled solution was slowly added concentrated hydrochloric acid (50 ml), ensuring that the temperature did not exceed 10°C. Formed a dense yellow precipitate. The mixture was stirred for 10 minutes and then filtered. Solid yellow dried in air for 15 minutes and then dried under Vacu the IOM at 40° C for 16 hours (8,73 g; 93%). For parts specified in the subtitle compound (5.0 g; 22 mmol) was added methanol (50 ml, 10 volumes) and water (100 ml; 20 volumes). The mixture was heated to 70°using an oil bath, with stirring. The solution was kept at this temperature for 10 minutes and then left to cool before 5°using a bath of ice/water. Crystallization began at about 30°C. the Precipitate was collected by filtration, dried in air for 15 minutes, then dried under vacuum at 40°C for 2 hours (3.2 g; 64%). Selected specified in the subtitle compound (3.2 g; 0.014 mol; 64%) was added to water (100 ml; 20 volumes) and methanol (50 ml, 10 volumes). The mixture was heated to 70°to dissolve the solids. The solution was left to cool to room temperature, as the cooling crystallization occurred. The mixture was cooled up to 2°and then filtered using a ceramic funnel. The solid was dried in air for 10 minutes, then dried under vacuum at 40°C for 16 hours (2,21 g; 44%).

TPL 167,1-167,4°C.

δN(400 MHz, DMSO-D6) 3.98 (2H, d, J=5.6 Hz, CH2), 7.58-7.65 (2H, m, CH), 7.95-8.05 (4H, m, CH), 8.49 (1H, s, CH), 8.99 (1H, t, J=5.6 Hz, NH), 12.63 (1H, bs, OH).

(C) Salt of Compound D with [(naphthalene-2-carbonyl)amino]acetic acid

[(Naphthalene-2-carbonyl)amino]acetic acid is (0.51 g; see stage (b)above) and Compound D (1.01 g; obtained as described here earlier methods) was dissolved in isobutyl ketone (30 ml) at 100°C. when cooled to room temperature formed a crystalline precipitate, which was filtered, washed with acetone (25 ml) and dried by suction on the filter. Drying during the weekend days under vacuum at 40°gave specified in the title salt as a colourless crystalline solid (1,17 g; 77%).

TPL on 138.5-140°C.

1H NMR (300 MHz, DMSO-D6) δ 1.34 (S, s), 2.25 (2H, t), 2.3-2.5 (4H, m), 2.6-2.7 (1H, m), 2.7-2.8 (1H, m), 2.85-3.0 (4H, m), 3.0-3.1 (2H, m), 3.81 (2H, s), 3.92 (2H, d), 3.95-4.05 (2H, m), 4.1-4.2 (1H, m), 6.68 (1H, t), 7.11 (2H, d), 7.5-7.7 (2H, m), 7.7-7.8 (2H, m), 7.9-8.1 (4H, m), 8.47 (1H, d), 8.85 (1H, t).

The crystals were analyzed using XRPD. The results are presented in the table below (table 18) and shown in Fig.

Table 18
The value of d (Å)Intensity (%)
16,8100
6,215
5,811
5,615
5,26
5,115
4,9010
4,7614
of 4.66 4
4,5331
4,377
or 4.3115
4,237
4,0810
3,703
3,519
3,257
3,125

Example 19

Sol Connection D C2,2,3,3-tetramethyl-1.4-debutantes acid

Compound D (200 mg; obtained in the same manner as the earlier methods) was dissolved in ethyl acetate (10 ml). 2,2,3,3-Tetramethyl-1,4-debutando acid (38,3 mg; 0.5 EQ.) was dissolved in 1 ml of methanol and added to a solution of Compound D. the Solvents evaporated, added ethyl acetate, and then the solvent is slowly evaporated by keeping the mixture in an open flask at room temperature for several days. The formed crystals were filtered off. NMR analysis showed the formation of salt in the ratio of 1:1 (˜100 mg, 42%).

The crystals were analyzed using XRPD. The results are presented in the table below (table 19) and shown in Fig.

Table 19
The value of d (Å)Intensity (%)
14,2100
10,312
7,118
6,411
6,05
5,610
of 5.441
5,122
4,8412
4,776
4,7313
of 4.667
4,504
4,293
4,225
a 3.873
3,784
3,625
3,494
3,354
3,096
2,753

Example 20

Sol Connection D TRANS-D,L-1,2-cyclopentanecarbonyl acid

Compound D (100 mg; obtained in the same manner as the earlier methods) was dissolved in ethyl acetate (5 ml). TRANS-D,L-1,2-Cyclopentane-dicarboxylic acid (17,4 mg; 0.5 EQ.) was dissolved in methanol and then added to a solution of Compound D. the Solvents are evaporated and then dissolved in ethyl acetate. After a certain period of time formed a white precipitate. Formed crystals were filtered off. NMR analysis showed the formation of salt in the ratio of 1:1 (˜60 mg).

The crystals were analyzed using XRPD. The results are presented in the table below (table 20) and shown in Fig.

Table 20
The value of d (Å)Intensity (%)
12,9100
11,114
10,735
9,010
7,714
7,015
6,518
6,310
6,114
6,021
5,617
of 5.455
5,337
5,255
4,7329
to 4.6832
or 4.3129
4.26 deaths26
as 4.0213
3,8612
3,6122
3,5019
3,2416
2,9015

Example 21

Sol Connection D (+)-O,O'-Dibenzoyl-D-tartaric acid

Compound D (100 mg; obtained in the same manner as the earlier methods) and 0.5 equivalent of (+)-O,O'-Dibenzoyl--tartaric acid was mixed according to the method described above in Example 20. Salt crystallized from ethyl acetate. NMR showed that the formed salt with a ratio of drug: acid = 2:1, and ˜70%yield.

The crystals were analyzed using XRPD. The results are presented in the table below (table 21) and shown in Fig.

Table 21
The value of d (Å)Intensity(%)
15,1100
13,55
8,72
7,73
7,14
6,64
the 5.73
5,53
5,39
5,27
4,799
4,509
of 4.3810
4,2510
3,533
3,494
2,924

Example 22

Sol Connection D (+)-O,O'-di-ParetoLogic-D-tartaric acid

Compound D (1.0 g; obtained as described here earlier methods) was dissolved in ethyl acetate (15 ml). (+)-O,O'-Di-ParetoLogic-D-tartaric acid (0,43 is) was dissolved in ethyl acetate (20 ml). The solutions were mixed. After a few minutes formed a white precipitate. The mixture was stirred at 4°With during the night. The crystals were filtered and dried under vacuum, obtaining 1.1 g (76%) salt with a ratio of 2:1 (confirmed by NMR).

The crystals were analyzed using XRPD. The results are presented in the table below (table 22) and shown in Fig.

Table 22
The value of d (Å)Intensity (%)
15,8100
14.4V2
13,12
6,87
6,22
the 5.77
5,65
5,3 (5,32)3
5,3 (5,25)5
4,845
4,809
4,759
4,593
4,3913
4,3712
4.26 deaths2
4,102
3,985
3,822
3,323
3,051

Example 23

To italisize Connection

The crude material from Preparatory example, Option II, stage (3), Method II, was dissolved at 60°in isopropanol (190 ml, 5.0 Rel. about.) and the hot solution was filtered. The filtrate was stirred and left to cool to room temperature. Crystallized solid white. The mixture was cooled from room temperature to about 8°C. the Product was collected by filtration and washed with isopropanol (50 ml, and 2.0 vol.). The wet product was dried under vacuum at 40°C to constant weight to obtain specified in the connection header in the form of a solid white color (30,96 g; 81%).

TPL 113,5°C.

1H NMR (400 MHz, CD3OD) δ 1.40 (S, s), 1.81-1.90 (2H, m), 2.35-2.54 (8H, m), 2.93 (4H, t), 3.18-3.27 (4H, m), 3.87 (2H, bs), 6.66 (2H, d), 7.39 (2H, d).

MS: m/z=(MH+, 430).

Reduction

API - ionization at atmospheric pressure (relative to mass spectroscopy (MS)

br - extended (relative to NMR)

d - doublet (relatively NMR)

DCM - dichloromethane

DMF - N,N-dimethylformamide

DMSO - dimethyl sulfoxide

dd - doublet of doublets (relatively NMR)

Et - ethyl

EQ. equivalent(s)

GC - gas chromatography

h - hour(s)

HCl - hydrochloric acid

HPLC - high performance liquid chromatography

IMS industrial methylated spirit

IPA - isopropyl alcohol

KF - Carl-Fischer

m - multiplet (about the relative NMR)

Me - methyl

MeCN is acetonitrile

min - minute(s)

TPL - melting point

MS - mass spectroscopy

Pd/C is palladium on coal

q - Quartet (relatively NMR)

kg - room temperature

s - singlet (relatively NMR)

t - triplet (relative NMR)

TLC - thin layer chromatography

UV - ultraviolet

The prefixes n-, sec-, ISO - and tert - have their usual meanings:

normal, secondary, ISO-and tertiary.

1. Pharmaceutically acceptable salt of one of the following connections:

4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl} amino)benzonitrile;

tert-butyl 2-{7-[3-(4-cyanoaniline)propyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethylcarbamate;

tert-butyl 2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethylcarbamate; or

tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate,

provided that this salt is not salt of 4-({3-(7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benzonitrile with benzosulfimide acid.

2. 4-({3-[7-(3,3-Dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]propyl}amino)benzonitrile;

tert-butyl 2-{7-[3-(4-cyanoaniline)propyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethylcarbamate;

tert-butyl 2-{7-[4-(4-cyanophenyl)b is Teal]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethylcarbamate; or

tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate

or a pharmaceutically acceptable salt of any of these compounds in essentially crystalline form.

3. The compound according to claim 2, which is 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benzonitrile.

4. The compound according to claim 3, characterized by the curve of differential scanning calorimetry at a heating rate of 10°C/min in a closed Cup with point hole injecting nitrogen demonstrating endotherm with an extrapolated point beginning approximately 121°and 126°C; and/or picture of the x-ray diffraction on the powder, characterized by peaks with d values when 11,0; 7,8; 7,0; 5,7; 5,4; 5,1; 4,94; 4,71; 4,62; 4,54; 4,44; 4,34; 4,20; 3,92; 3,65; 3,51; 3,41; 3,34 and 2,89Åand/or essentially as defined in table 1 and/or figure 1.

5. The compound according to claim 3, characterized by the curve of differential scanning calorimetry at a heating rate of 10°C/min in a closed Cup with point hole injecting nitrogen, demonstrating the endotherm with an extrapolated point beginning approximately 125°C; and/or picture of the x-ray diffraction on the powder, characterized by peaks with d values when 10,9; 8,3; 7,8; 6,9; 6,7; 5,6 (5,64); 5,6 (5,56); 5,5; 5,4; 5,1; 5,0; 4,84; 4,78; 4,70; 4,49; 4,45; 4,36; 4,15; 4,1; 4,03; 3,97; 3,90; 3,80; 3,73; 3,47; 3,31; 2,95; 2,89; 2,85 and 2,80Åand/or essentially as defined in table 2 and/or figure 2.

6. The compound according to claim 3, characterized by the curve of differential scanning calorimetry at a heating rate of 10°C/min in a closed Cup with point hole injecting nitrogen, demonstrating the endotherm with an extrapolated point beginning approximately 122°C; and/or picture of the x-ray diffraction on the powder, characterized by peaks with d values when 10,4; 9,6; 5,7; 5,3; 5,2; 4,83; 4,71; 4,55; 3,83; 3,58; 3,50; 3,29; 3,22 and 3.19Åand/or essentially as defined in table 3 and/or 3.

7. Salt according to claim 2, which is a salt of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benzonitrile with benzosulfimide acid.

8. Salt according to claim 7, characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 18,7; 9,4; 6,3; 4,69; 4,48; 3,76; 3,35; 3,13; 2,68; 2,35 and 1,88Åand/or essentially as defined in table 4 and/or 4.

9. Salt according to claim 1 or 2, which is a salt of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile with toluensulfonate acid.

10. Sol according to claim 9, characterized by the curve of differential scanning calorimetry at a heating rate of 10°C/min in a closed Cup with point hole cont is the so called nitrogen, demonstrating the endotherm with an extrapolated point beginning approximately 145°C; and/or picture of the x-ray diffraction on the powder, characterized by peaks with d values when 19,9; 10,0; 6,0; 4,99; 4,86; 4,38; 4,36; 4,19; 3,99 and 3.33Åand/or essentially as defined in table 5(a) and/or figure 5(a).

11. Sol according to claim 9, characterized by the curve of differential scanning calorimetry at a heating rate of 10°C/min in a closed Cup with point hole injecting nitrogen, demonstrating the endotherm with an extrapolated point beginning approximately 153°C; and/or picture of the x-ray diffraction on the powder, characterized by peaks with d values when 18,6; 9,3; 6,2; 4,66; 4,49; 3,73 and 3,11Åand/or essentially as defined in table 5(b) and/or figure 5(b).

12. Salt according to claim 1 or 2, which is a salt of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile with hydroxynaphthoic acid.

13. Salt 12, characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 17,6; 12,4; 8,8; 5,7; 5,6; 5,1; 4,95; 4,88; 4,47; 4,16; 4,08; 3,84; 3,80; 3,33 and 3,03Åand/or essentially as defined in table 6 and/or 6.

14. Salt according to claim 1 or 2, which is a salt of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile with naphthalenol is about acid.

15. Salt 14, characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 16,1; 8,1; 7,1; 6,3; 6,0; 5,4 (5,39); 4,96; 4,88; 4,68; 4,49; 4,34; 4,10; 4,04; 3,94; 3,44; 3,40; 3,23; 3,20 and 3.15Åand/or essentially as defined in table 7 and/or 7.

16. Salt according to claim 1 or 2, which is a salt of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile with mesitylenesulfonic acid.

17. Salt according to item 16, characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 18,8; 9,5; 6,3 (6,33); 6,3 (6,26); 4,75; 4,50; 4,46; 3,92; 3,80 and 3,17Åand/or essentially as defined in table 8 and/or Fig.

18. The compound according to claim 2, which represents tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate.

19. Connection p characterized curve of differential scanning calorimetry at a heating rate of 10°C/min in a closed Cup with point hole injecting nitrogen, demonstrating the endotherm with an extrapolated point beginning approximately from 100 to 102°C; and/or picture of the x-ray diffraction on the powder, characterized by peaks with d values when 22,3; 11,2; 8,4; 7,1; 6,4; 5,8; 5,5; 5,2; 4,91; 4,81; 4,62; 4,52; 4,32; 4,22; 4,12; 4,06; 3,91; 3,81; 3,50; 3.34 and 3.15Åand/or essentially as defined in table and/or the figure 9.

20. Salt according to claim 1 or 2, which is a salt of tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate with methanesulfonic acid.

21. Salt according to claim 20, characterized by the curve of differential scanning calorimetry at a heating rate of 10°C/min in a closed Cup with point hole injecting nitrogen, demonstrating the endotherm with an extrapolated point beginning approximately 167°C; and/or picture of the x-ray diffraction on the powder, characterized by peaks with d values when 12,7; 9,4; 7,3; 7,1; 6,6; 6,0; 5,4; 5,1; 4,92; 4,83; 4,27; 4,14; 4,05; 3,99; 3,87; 3,73; 3,65; 3,42; 3,37 and 3,00Åand/or essentially as defined in table 10 and/or figure 10.

22. Salt according to claim 1 or 2, which is a salt of tert-butyl-247-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate with the hippuric acid.

23. Salt p.22, characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 16,4; 6,9; 6,2; 6,1; 5,5; 5,2; 5,1; 4,93; 4,61; 4,50; 4,28; 4,20; 4,11 and 3,68Åand/or essentially as defined in table and/or 11.

24. The compound according to claim 2, which represents tert-butyl 2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl-carbamate.

25. The connection point 24, characterized by the curve of differential scanning calorim the tree at a heating rate of 10° C/min in a closed Cup with point hole injecting nitrogen, demonstrating the endotherm with an extrapolated point beginning approximately 97°C; and/or picture of the x-ray diffraction on the powder, characterized by peaks with d values when 19,4; 10,0; 9,1; 8,1; 6,5; 5,5; 5,2; 5,1; 4,99; 4,90; 4,46; 4,32; 4,06; 4,00; 3,85 and 3,80Åand/or essentially as defined in table and/or Fig.

26. Salt according to claim 1 or 2, which is a salt of tert-butyl 2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate with methanesulfonic acid.

27. Salt p characterized curve of differential scanning calorimetry at a heating rate of 10°C/min in a closed Cup with point hole injecting nitrogen demonstrating endotherm with an extrapolated point beginning approximately 145°and 170°C; and/or picture of the x-ray diffraction on the powder, characterized by peaks with d values when 13,3; 12,3; 9,6; 7,5; 6,9; 6,7; 5,5; 5,1; 5,0; 4,89; 4,81; 4,34; 4,23; 4,20; 4,08; 3,89; 3,85 and 3,80Åand/or essentially as defined in table 13 and/or Fig.

28. Salt according to claim 1 or 2, which is a salt of tert-butyl 2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl} ethylcarbamate with toluensulfonate acid.

29. Salt p characterized curve of differential scanning calorimetry at a speed of heating is 10° C/min in a closed Cup with point hole injecting nitrogen, demonstrating the endotherm with an extrapolated point beginning approximately 138°C; and/or picture of the x-ray diffraction on the powder, characterized by peaks with d values when 13,2; 7,1; 5,2; 5,0; 4,67; 4,28; 4,24; 4,19; 4,08; 3,36 and 3.12Åand/or essentially as defined in table 14 and/or Fig.

30. Salt according to claim 1 or 2, which is a salt of tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate with [(biphenyl-4-carbonyl) - amino]-acetic acid.

31. Salt according to item 30, characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 20,4; 15,3; 11,5; 9,4; 7,7; 7,2; 5,9; 5,7; 5,4; 5,3; 5,2; 4,60; 4,54; 4,13; 3,85; 3,79; 3,64; 3,61; 3,40 and 2.94Åand/or essentially as defined in table and/or Fig.

32. Salt according to claim 1 or 2, which is a salt of tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate with gementera acid.

33. Salt p characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 18,0; 8,3; 8,0; 7,5; 7,3; 6,8; 6,1; 5,8; 5,4; 4,89; 4,79; 4,68; 4,59; 4,54; 4,43; 4,35; 4,18; 4,04; 3,99 3,90; 3,83; 3,67; 3,58; 3,07 and 2,47Åand/or essentially as defined in table 16 and/or Fig.

34. Salt according to claim 1 or 2, which is a Sol is tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate (3,4-dichloraniline)acetic acid.

35. Salt 34, characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 16,6; 13,8; 10,9; 6,3; 6.2; 5,5; 5,3; 5,1; 5,0; 4,60; 4,33; 4,30; 4,22; 3,85; 3,70; 3,50; 3,30; 3,16 3,06 and 2,99Åand/or essentially as defined in table 17 and/or Fig.

36. Salt according to claim 1 or 2, which is a salt of tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate with [(naphthalene-2-carbonyl)amino]acetic acid.

37. Salt p characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 16,8; 6,2; 5,8 5,6; 5,2; 5,1; 4,90; 4,76; 4,66; 4,53; 4,37; 4,31; 4,23; 4,08; 3,51; 3,25 and 3.12Åand/or essentially as defined in table and/or Fig.

38. Salt according to claim 1 or 2, which is a salt of tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate with 2,2,3,3-tetramethyl-1,4-debutantes acid.

39. Salt § 38, characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 14,2; 10,3; 7,1 6,4; 6,0; 5,6; 5,4; 5,1; 4,84; 4,77; 4,73; 4,66; 4,50; 4,22; 3,78; 3,62; 3,49; 3,35 and 3,09Åand/or essentially as defined in table 19 and/or Fig.

40. Salt according to claim 1 or 2, which is a salt of tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate with 1,2-Cyclops is candyarbone acid.

41. Salt p characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 12,9; 11,1 10,7; 9,0; 7,7; 7,0; 6,5; 6,3; 6,1; 6,0; 5,6; 5,4; 5,3; 5,2; 4,73; 4,68; 4,31; 4,26; 4,02 3,86; 3,61; 3,50; 3,24 and 2,90Åand/or essentially as defined in table and/or Fig.

42. Salt according to claim 1 or 2, which is a salt of tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate with O,O'-dibenzoyltartaric acid.

43. Salt § 42, characterized pattern of x-ray diffraction on the powder, characterized by peaks with d values when 15,1; 13,5; 7,1 6,6; 5,3; 5,2; 4,79; 4,50; 4,38; 4.25; 3.49 and 2,92Åand/or essentially as defined in table 21 and/or Fig.

44. Salt according to claim 1 or 2, which is a salt of tert-butyl 2-{7-((2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate with O,O'-di-para-toluylene acid.

45. Salt according to item 44, characterized by a pattern of x-ray diffraction on the powder, characterized by peaks with d values when 15,8; 6,8; 5,7 5,6; 5,3 (5,25); 4,84; 4,80; 4,75; 4,39; 4,37 and 3,98Åand/or essentially as defined in table 22 and/or Fig.

46. The method of obtaining salt according to any one of claims 1,2, 7-17,20-23 or 26-45, in which the corresponding compound according to claim 1 in free base form add acid or base (as appropriate),

47. The method according to item 46, in which the ω to the corresponding compound in free base form add acid.

48. A method of obtaining a compound according to any one of claims 1 to 45, in which the crystallization of the corresponding compounds according to claim 1 in free base form or its corresponding pharmaceutically acceptable salt.

49. The method according to p at which carry out the crystallization of the compound or salt from the solvent.

50. The method according to § 49, where the solvent is selected from the group of acetates, lower alkalemia alcohols, aliphatic and aromatic hydrocarbons, dialkyl ethers, dealkylation, acetonitrile, chlorinated alkanes, aqueous solvents or mixtures thereof.

51. The method according to item 50, where the solvent is selected from the group of C1-6allylacetate, linear or branched C1-6alkalemia alcohols6-12aliphatic hydrocarbon, C6-10aromatic hydrocarbons, di-C1-6alkalemia esters, di-C1-6alkylene, chlorinated methanes or atani, acetonitrile, water or mixtures thereof.

52. The method according to § 51, where the solvent is selected from the group of ethyl acetate isopropylacetate, methanol, ethanol, isopropanol, n-heptane, diethyl ether, acetone, dichloromethane, water or mixtures thereof.

53. The method of obtaining salt according to any one of claims 1, 2, 7-17, 20-23 or 26-45, which shall add, as it is stated in item 46 or p, with subsequent crystallization, as she claimed in any of PP-52.

54. A method of obtaining a crystalline form of 4-({3-[7-(33-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile; tert-butyl 2-{7-[3-(4-cyanoaniline)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate; tert-butyl 2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate; or tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or pharmaceutically acceptable salt of any of these compounds, which carry out the crystallization of the relevant compound or salt from a solvent system containing a combination of C3-7Olkiluoto alcohol and di-C3-5Olkiluoto ether.

55. The method according to item 54, where the ester is a di-n-propyl ether, diisopropyl ether or di-n-butyl ether.

56. The method according to item 54 or 55, where the alcohol is n-propanol, isopropanol, n-butanol, 4-methyl-2-pentanol, 3-methyl-1-butanol, 2-methyl-1-propanol or pentane-1-ol.

57. The method according to item 54, where the combination of solvent is n-propanol and di-n-propyl ether; isopropanol and diisopropyl ether; n-butanol and di-n-butyl ester; 4-methyl-2-pentanol and di-n-butyl ether; isopropanol and di-n-butyl ester; 4-methyl-2-pentanol and diisopropyl ether; or pentane-1-ol and diisopropyl ether.

58. The method according to § 57, where a combination of solvents is an isopropanol and diisopropyl ether.

59. The method according to item 54, wherein the compound is heated in combination, rastvoritelya temperature in the range from 50 to 100° C.

60. The method according to item 54, where kristalltherme connection represents tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or its pharmaceutically acceptable salt.

61. The method according to p, where connection is a tert-butyl 2-{7-[(2S)-3-(4-cianfrocca)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate.

62. The compound obtained by the method according to any of PP-61.

63. The compound according to claim 1 for use as drugs for the prevention or treatment of arrhythmia.

64. Pharmaceutical drug with myocardial electrophysiological activity, comprising a compound according to any one of claims 1 to 45 or 62 in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

65. The compound according to claim 1 for use in the prevention or treatment of arrhythmia.

66. The use of compounds according to any one of claims 1 to 45 or 62 as the active ingredient for the production of medicines for use in the prevention or treatment of arrhythmia.

67. Use p where arrhythmia is an atrial or ventricular fibrillation.

68. Use p where arrhythmia is an atrial fibrillation.

69. Use p where arrhythmia is an atrial flutter.

70. The method of prevention or treatment of arrhythmia, to the m to the subject, suffering from this condition or subject to such condition, enter the compound according to any one of claims 1 to 45, or 62.

71. The method according to item 70, where the arrhythmia is an atrial or ventricular fibrillation.

72. The method according to item 70, where the arrhythmia is an atrial fibrillation.

73. The method according to item 70, where the arrhythmia is an atrial flutter.



 

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EFFECT: improved method for preparing.

2 cl, 2 tbl, 20 ex

FIELD: organic chemistry, chemical technology, antibiotics.

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EFFECT: improved preparing method.

1 tbl, 13 ex

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EFFECT: improved preparing method.

1 tbl, 4 ex

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< / BR>
A new connection can be used as an antibacterial and antituberculosis drug

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2 cl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bis-aryl compounds of the formula (I): wherein one among A1-A4 means nitrogen atom and others mean -CH or -CR5; A5-A8 mean -CH or -CR5; R5 means halogen atom or (C1-C)-alkyl; R(1) means -C(O)OR(9), -COR(11); R(9) and R(11) mean CxH2x-R(14); x means 0, 1,2, 3 or 4 and x can't mean 0 if R(14) means -OR(15); R(14) means (C1-C6)-alkyl or phenyl; R(15) means (C1-C5)-alkyl; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y means 0, 1, 2, 3 or 4 and y can't mean 0 if R(16) means -OR(17); R(16) means (C1-C6)-alkyl, phenyl or pyridyl; R(17) means hydrogen atom, (C1-C5)-alkyl, phenyl or pyridyl, or R(3) means -CHR(18)R(19); R(18) means hydrogen atom or CzH2z-R(16) wherein R(16) means abovementioned values; z means 0, 1, 2 or 3; R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and to their pharmaceutically acceptable salts also. Compounds of the formula (I) possess anti-arrhythmic activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

11 cl, 30 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to arylated amides of furan and thiophene carboxylic acids of the formulae (Ia) and (Ib) wherein W means oxygen or sulfur atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x means 0, 1, 2 or 3; R(14) means phenyl, and to their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition and using proposed compounds a medicinal agents. Compounds can be used as anti-arrhythmic biologically active substances and especially in treatment and prophylaxis of atrium arrhythmia.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 29 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 8 tbl, 35 ex

FIELD: medicine, pharmacology.

SUBSTANCE: the suggested preparation contains ethacyzine, interpolymeric complex of polymetacrylic or polyacrylic acid and polyethylene glycol, lactose and/or microcrystalline cellulose and a slipper, and, also, method to obtain the mentioned preparation has been suggested due to mixing the components followed by dry granulation. The preparation provides prolonged maintenance of concentration of active substance at therapeutically efficient level.

EFFECT: higher efficiency of application.

7 cl, 5 ex, 2 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: the suggested preparation contains ethmozine, interpolymeric complex of polymetacrylic or polyacrylic acid and polyethylene glycol, lactose and/or microcrystalline cellulose and a slipper, and, also, method to obtain the mentioned preparation has been suggested due to mixing the components followed by dry granulation. The preparation provides prolonged maintenance of concentration of active substance at therapeutically efficient level.

EFFECT: higher efficiency of application.

7 cl, 1 dwg, 7 ex, 2 tbl

FIELD: medicine, cardiology.

SUBSTANCE: the present innovation deals with introducing nitrates, heparin, beta-blocking agents, calcium antagonists, aspirin. Additionally, one should intravenously inject dalargin once daily at the rate of about 5-7 mcg/kg/h at the dosage of 25-30 mcg/kg daily per 100 ml sodium chloride physiological solution for about 5-6 d against the onset of hospitalization period. The innovation provides favorable impact upon diastolic function of left ventricle by decreasing the risk of dangerous arrhythmias and coronary lethality.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, chemistry of peptides.

SUBSTANCE: invention proposes a new anti-arrhythmic agent that represents a peptide ligand of opioid receptors deltorphine D - compound of the formula (I): Tyr-D-Leu-Phe-Ala-Asp-Val-Ala-Ser-Thr-Ile-Gly-Asp-Phe-His-Ser-Ile-NH2 (I). The effect of this agent is associated with stimulation of opioid receptors and results to reducing frequency in arising multiple ventricular extrasystoles and episodes of ventricular tachycardia.

EFFECT: valuable medicinal properties of agent.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: method involves applying the remedy comprising taurine, an ingredient containing magnesium, an ingredient having tartaric acid as base, an ingredient having L-glutamic acid as base, an ingredient having fumaric acid as base, an ingredient having succinic acid as base, an ingredient having L-aspartic acid as base. An ingredient serving as magnesium source has at least one magnesium compound with succinic, fumaric, glutamic, aspartic, malic, citric or isocitric acid and/or any compound of general formula (I): (R1)n-Mg-(R2)m, where R1 and R2 are succinic, fumaric, glutamic, aspartic, malic, citric or isocitric acid radicals, n=1-50, m=1-50. The remedy is supposed to have at least one potassium salt and at least one ammonium salt.

EFFECT: enhanced effectiveness of treatment.

8 cl, 8 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel solid formulation of anti-arrhythmic medicinal agents. Invention describes crystalline formulation of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benznitrile, tert.-butyl-2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-dizabicyclo[3.3.1]non-3-yl}ethylcarbamate, tert.-butyl-2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or tert.-butyl-2-{7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate and their pharmaceutically acceptable salts. Also, invention describes methods for their synthesis, a pharmaceutical preparation based on thereof, a method for prophylaxis or treatment of arrhythmia and their using.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

73 cl, 22 dwg, 22 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: invention relate to oxabispidinic compounds of formula I, ,where R1 is C1-12alkyl (where the given alky group is substituted with a group selected from phenyl, Het1, N(R5a)R6, -OR5c, -S(O)2N(R9b)R9c and -N(R9b)S(O)2R9d); R5a is H; R5c is C1-6alkyl (which is substituted with phenol) or phenyl; R6 is H or -C(O)OR10b; R10b is C1-6alkyl; R9b in each case where it is used in the given description of the invention represents H or C1-6alkyl; R9c and R9d in each case it is used in the given description of the invention independently presents C1-6alkyl (possibly substituted with one or more substitutes, selected from halogen or phenyl), phenyl or Het7, or R9c is H; R2 is H or OR13; R3 is H; R13 is H; Het1 and Het7 independently represent 5-12-member heterocyclic groups containing one or more heteroatoms, selected from oxygen and nitrogen, where these groups are possibly substituted with one or more substitutes selected from halogen and C1-6alkyl; A is a direct bond, -J-, J-S(O)2N(R19b)- or -J-N(R19c)S(O)2- (where in the last two groups -J is bonded to the nitrogen of an oxabispidinic ring); B is Z-{[C(O)]aC(H)(R20a)}b-, -Z-[C(O)]cN(R20b)-, -Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -Z-S(O)n-, -Z-O- (where in the last six groups Z is bonded to a carbon atom, carrying R2 and R3), -N(R20e)-Z-, -N(R20f)S(O)2-Z-, -S(O)2N(R20g)-Z- or -N(R20h)C(O)O-Z- (where in the last four groups Z is bonded to a phenyl group which is possibly substituted with a R4 group); J is C1-6alkylene, possibly broken by a -S(O)2N(R19d)- or -N(R19e)S(O)2- group and/or possibly substituted with a substitute selected form -OH; Z is a direct bond or C1-4alkylene, possibly broken by a -N(R20i)S(O)2- or -S(O)2N(R20j)- group; a, b and c possibly represent 0 or 1; n is 0, 1 or 2; R19b-R19e in each case where used in the given description of the invention independently represents H or C1-6alkyl; R20a is H or together with the only substitute R4 on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, represents C2-4alkylene, possibly broken or ending with O, N(H) or N(C1-6alkyl) group; R20b is H or C1-6alkyl; R20c-R20j in each case when used in the given description of the invention independently represents H or C1-6alkyl; or R20g and R20i independently represent C1-6alkyl, substituted with 3,5-dimethylisoxazolyl; G is CH; R4 is one or more possible substitutes selected from cyano, halogen, C1-4alkyl and C1-6alkoxy, possibly substituted with one or more hanogen and a R4 substitute on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, together with R20a can represent C2-4alkylene; broken or ending with O or N(H) or a N(C1-6alkyl) group; R41-R46 independently represent H; where each phenyl group is possibly substituted with one or more substitutes selected from halogen, cyano, C1-6alkyl and C1-6alkoxy (where the last two groups are possibly substituted with one or more halogen atoms); or to their pharmaceutically acceptable salts. The invention also relates to methods of producing said compounds, as well as to a pharmaceutical composition based on said compounds, with HERG-channel blocking activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for preventing and treating arrhythmia, particularly cardiac and ventricular arrhythmia.

32 cl, 1 tbl, 15 ex

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