Antiarrhythmic compound precursors, synthesis processes and methods of application

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula formula (1) formula (2) or to their hydrate, solvate, salt or tautomer form where R₁ independently represents H or halogen; R₂ represents H or --R₁₀-NR₁₁R₁₂ where R₁₀ represents C₁-C₆ alkylene; R₁₁ and R₁₂ independently represent H, C₁-C₄ alkyl; and R₃ independently represents H or halogen. Besides, the invention covers methods of preparing the compounds of the present invention.

EFFECT: new compounds which can find application for preparing the compounds applicable for treatment or prevention of cardiac arrhythmia.

6 cl, 1 tbl, 2 ex

BACKGROUND of the INVENTION

Congestive heart failure (CHF) is a disease that affects approximately 2% of the population of the United States (Sami, M.H. [1991] J.Clin.Pharmacol.31:1081). Despite advances in diagnosis and treatment of CHF prognosis remains poor, with a mortality rate within 5 years from the date of diagnosis is greater than 50% (McFate Smith, W. [1985] Am.J.Cardiol. 55:3A; McKee, P.A., W.P.Castelli, P.M. McNamara, W.B.Kannel [1971] N.Engl.J.Med.285:1441). Among patients with CHF the lowest survival was observed in those patients who have strongly suppressed the function of the left ventricle, as well as in patients with frequent ventricular arrhythmias. In patients with ventricular arrhythmias and ischemic cardiomyopathy there is an increased risk of sudden death. The presence of ventricular tachycardia in patients with severe CHF leads to a threefold increase in the frequency of sudden death compared to patients who do not have tachycardia (Bigger, J.T., Jr. [1987] Circulation 75 (suppl.IV):28). Due to the significant prevalence of sudden unexpected death in patients with CHF, there is a growing interest in the reliability prediction of arrhythmias in these patients.

Several of the compounds used in the treatment of cardiac arrhythmias in patients with congestive heart failure. Unfortunately, antiarrhythmic drug therapy has been disappointing. The effectiveness of antiarrhythmic Leka is the only means significantly decreases left ventricular function, so only a small proportion of patients with CHF respond to antiarrhythmic treatment. Does not exist antiarrhythmic drugs capable of preventing sudden death in patients with CHF, and even had a question about the increased mortality associated with certain antiarrhythmic agents (the CAST investigators [1989] N.Engl.J.Med.321:406).

Scientists determine tachycardia and ventricular fibrillation as a phenomenon of multiple nature. Now was clear and made in the technique that the mechanism underlying the most sustainable types of arrhythmia, is the circulation of excitation. Therefore, revived the interest in increasing the duration of ventricular repolarization as a means of prevention of ventricular fibrillation. This gives grounds to consider drug class-III as the preferred drugs for the treatment of arrhythmias. The funds referred to in this application by means of class-III, are funds that are assigned to this class in the classification of antiarrhythmic drugs Vaughan-Williams. Class-III showing his primary antiarrhythmic effect by increasing the duration of action potential (APD) of the heart muscle and, thereby, the effective refractory period (ERP), without affecting the conductivity. These electrophysiological changes, the reason is which is the blockade of cardiac potassium channels, well known in the art. Because blockade of cardiac potassium channels is not associated with the suppression of myocardial contractility, class-III are particularly interesting for use in patients with CHF. Unfortunately, existing tools class III limited from the point of view of their applicability to additional types of pharmacological activity, lack of bioavailability for oral use or poor toxicity profile. Two means of class-III, which are currently available commercially are bretylium (only intravenously) and amiodarone (intravenous and oral).

Amiodarone is an antiarrhythmic agent with vasodilating properties, which can be useful for patients with severe heart failure. It was shown that amiodarone improves the survival rate of post-infarction patients with asymptomatic life-threatening ventricular arrhythmias, in addition, proved the effectiveness of this tool in patients resistant to other complications, without deterioration of left ventricular function. For use in patients with coronary insufficiency have been described cardiotoxin means and ways in which amiodarone is used in synergistic combination with vasodilator means and beta-blockers (U.S. patent No. 5175187). In addition to the CSO, described the use of amiodarone in combination with antihypertensive agents, such as (S)-1-[6-amino-2-[hydroxy(4-phenylbutyl)phosphinyl]oxyl]-L-Proline (U.S. patent No. 4962095) and zofenoprilat (U.S. patent No. 4931464)to reduce arrhythmia associated with CHF. However, the use of amiodarone as a drug is hampered by numerous side effects, some of which are dangerous.

The reason most dangerous long-term toxicity of amiodarone is the kinetics of distribution and elimination. It is absorbed slowly, with low bioavailability and relatively long half-life. These characteristics have clinically significant consequences, including the need to introduce shock doses, delay achieving the full antiarrhythmic action and a prolonged period of introduction of the drug after withdrawal.

In addition, amiodarone may adversely interact with many drugs, including aprindine, digoxin, flecainide, phenytoin, procainamide, quinidine, and warfarin. He also has a pharmacodynamic interaction with catecholamines, diltiazem, propanolol and quinidine, leading to alpha - and beta antagonism, stop the sinus node and hypotension, bradycardia and stop the sinus node, as well as bi-directional which corresponds ventricular tachycardia and ventricular tachycardia, respectively. In addition, there is evidence that amiodarone inhibits the vitamin K-dependent coagulation factors, thereby improving anticoagulation effect of warfarin.

Numerous side effects limit the clinical applicability of amiodarone. Can have significant side effects, including microclone in the cornea, gipertireoidizmom, hypothyroidism, liver dysfunction, pulmonary alveolitis, photosensitivity dermatitis, bluish in color, and peripheral neuropathy.

Currently on the market there are no drugs-class III, which can be safely applied to patients with CHF. The market for cardiovascular drugs is the largest in the whole area of study drugs, and effective and safe antiarrhythmic agent of class-III, which can be used by patients with CHF is expected to bring significant benefits. Therefore, the drug, which could successfully improve the prognosis in patients with CHF, but with significantly better compared with amiodarone safety profile, it would be extremely useful and desirable. Various analogues of amiodarone have been described previously (U.S. patent№ 6372783; 6362223; 6316487; 6130240; 5849788; 5440054 and 5364880). The present invention adds to the Arsenal of connections.

u> The INVENTION

The invention relates to compounds of formula (1)

formula (1)

and their hydrates, solvate, salts and tautomeric forms, where

R₁represents H or halogen;

R₂represents H or-R₁₀-NR₁₁R₁₂where

R₃represents H or halogen;

R₁₀represents a C₁-C₆alkylen and

R₁₁and R₁₂independently represent H, C₁-C₄alkyl.

Further, the present invention relates to methods for producing compounds of formula (1)and formula (2)to(4)described in the text of this application.

The compounds of formula (1) is applicable in the synthesis of compounds of formula (5), which is applicable in the treatment or prevention of arrhythmia and significantly reduce the adverse effects associated with the introduction of evidence, such as the interaction of drugs with each other, microclone in the cornea, gipertireoidizmom, hypothyroidism, liver dysfunction, pulmonary alveolitis, dermatitis and peripheral neuropathy. For this reason, the present invention further includes methods of making compounds of the formula (5), intended for the treatment or prevention of cardiac arrhythmias, with the use of compounds of formula (1).

In addition, the present invention cover which indicates the method of obtaining (R)-sec-butyl 2-(3-(4-(2-(diethylamino)ethoxy)for 3,5-diadvisor)benzofuran-2-yl)acetate.

DETAILED description of the INVENTION

In addition to the above, the invention relates to compounds of formula 2:

formula (2)

and their hydrates, solvate, salts and tautomeric forms, where

R₁represents H or halogen and

R₃represents H or halogen.

Further, the invention relates to compounds of the formula (3):

formula (3)

and their hydrates, solvate, salts and tautomeric forms.

Further, the invention relates to compounds of the formula (4):

formula (4)

and their hydrates, solvate, salts and tautomeric forms.

Further, the invention relates to compounds of the formula (5):

formula (5)

and their hydrates, solvate, salt, where

R₁represents H or halogen;

R₂represents H or-R₁₀-NR₁₁R₁₂where

R₁₀represents a C₁-C₆alkylen and

R₁₁and R₁₂independently represent H, C₁-C₄alkyl;

R₃represents H or halogen; and

R₄represents a C₁-C₆alkyl, such as methyl, ethyl, n-propyl, ISO-propyl, butyl, sec-butyl, tert-butyl and the like, In particular, consider the Xia alkyl fragments with one or more chiral centers, for example, S-2-butyl.

Further, the invention encompasses methods of producing compounds of the formula(1)-(5).

Another aspect of the present invention relates to methods of using compounds of formula(1)-(5).

In addition, the invention encompasses methods of making compounds included in table 1, and their hydrates, solvate, salt:

Table 1
Structure	Chemical name
	(R)-Deut-butyl 2-(3-(4-(2-(diethylamino)ethoxy)for 3,5-diadvisor)benzofuran-2-yl)acetate
	(R)-Deut-butyl 2-(3-(4-(2-(ethyl(methyl)amino)ethoxy)for 3,5-diadvisor)benzofuran-2-yl)acetate
	(R)-Deut-butyl 2-(3-(4-(2-(ethylamino)ethoxy)for 3,5-diadvisor)benzofuran-2-yl)acetate
	(R)-Deut-butyl 2-(3-(3,5-dead-4-(2-(methylamino)ethoxy) benzoyl)benzofuran-2-yl)acetate
		(R)-Deut-butyl 2(3-(4-(2-(dimethylamino)ethoxy)for 3,5-diadvisor)benzofuran-2-yl)acetate

In the present invention developed ways to produce compounds which are more susceptible to collapse under the action of serum and/or cytosolic esterases in comparison with amiodarone and thus give an opportunity to avoid the unwanted effects associated with metabolism by the action of cytochrome P450.

Therapeutic compounds obtained according to the methods of the present invention, are stable during storage, but have a relatively short half-life in the physiological environment; therefore, the use of compounds of the present invention may be accompanied by a low frequency of side effects and toxicity.

In some aspects of the present invention developed methods for producing therapeutic stereoisomeric compounds, which are applicable in the treatment of cardiac arrhythmia and which contain the ester group, prone to decomposition under the action of esterases, which leads to the collapse of the connections and facilitates its efficient removal from the body evaluation of the proposed treatment of the patient. In a preferred aspect, therapeutic stereoisomeric compounds undergo metabolism during phase I detoxification of drugs. In particular, the methods of obtaining and purification of these stereoisomeric compounds. Ways of introduction into the molecule of such ester fragments, as well as obtaining and purification of stereoisomers are well known to the specialist in the art and can be easily implemented using the guidelines outlined in this application.

DEFINITIONS AND conventions

Below are definitions and explanations of terms used throughout the text of this document, including the description and the claims.

I. legend in formulas and variable definitions

Chemical formulas representing the various compounds or molecular fragments in the description and the claims, in addition to right particular structural fragments can contain variables deputies. These variable substituents are identified by a letter or a letter followed by a numerical subscript or Superscript notation, for example “Z₁”, or “Z¹”, or “R_i”where “i” indicates an integer. These variable substituents are either monovalent or bivalent. I.e. they represent the groups attached to the rest of the molecule one or two chemical bonds. An ordinary person skilled in the art it should be clear from the context, one or two links present in a particular case. For example, the group Z₁could be a divalent Deputy, as, for example, in the structure of CH₃-C(=Z₁)H. In another example, the group R_iand R_jwould represent monovalent variable substituents, as in the structure of CH₃-CH₂-C(R_i)(R_j)H. If the structure is shown in linear form, as in the above cases, variables deputies, placed in parentheses, associated with the atom, which is directly to the left of the bracketed Deputy. If in brackets there are two or more coming one after another substituent, each of the consecutive variable substituents bound to the atom, standing directly (i.e. first) to the left of the brackets. For example, in the above formula, both Deputy R_iand R_jassociated with the preceding carbon atom. In addition, for any molecule with an established system of numbering of carbon atoms, such as steroids, these carbon atoms are marked as C_iwhere “i” is an integer corresponding to the number of carbon atom. For example, C₆means 6 position the tion or the number of carbon atoms in the steroid nucleus according to the traditional designation, adopted from experts in the field of steroid chemistry. “C_i” can refer to the i-th carbon atom or to a fragment containing the “i” of carbon atoms. The meaning of the use of this designation in a particular case should be clear to an ordinary person skilled in the technical field of the context in which used the symbol.

Chemical structures or fragments thereof, shown in a linear form, represent the atoms in a straight chain. The characters “--“ and “-“usually means a bond between two atoms in the chain. So CH₃--O--CH₂--CH(R_i)--CH₃and CH₃-O-CH₂-CH(R_i)-CH₃and combinations “--“ and “-“ in these formulas represent the 2-substituted-1-methoxypropan. In addition, a linear mapping patterns can be cast without character relations “-” and/or “-”. For example, the formula CH₃OCH₂CH(R_i)CH₃also displays the 2-substituted-1-methoxypropan. Similarly, the symbol “=” indicates a double bond, for example CH₂=C(R_i)--O--CH₃and the symbol “≡” displays a triple bond, such as CH≡C-CH(R_i)--CH₂--CH₃. Carbonyl group, usually displayed in one of four ways: CO, C(O)C(=O) or C=O, surrounding communication “--“ can be either shown or not shown, with the first two ways images are preferred in the Lu their simplicity. The numbers that follow immediately after the atoms in chemical formulas or their fragments, displayed either a normal or an inferior font, mean number of previous atoms or groups of atoms, as in the usual practice of chemistry. For example, both refer to a “C1-C8 alkyl” and “C₁-C₈alkyl describe the alkyl fragment comprising from 1 to 8 carbon atoms.

Hard cyclic (ring) structure for all connections in this application determines the orientation of the substituents attached to each of the carbon atoms of such cyclic compounds, relative to the plane of the loop. For saturated compounds in which the carbon atom that is part of a cyclic system, attached two Deputy, ie --C(X₁)(X₂)--these two substituent may be either axial or Equatorial position relative to the cycle, and can also change the position between the axial and Equatorial. However, the position of the two substituents relative to the cycle and relative to each other remains constant. Although any of the deputies from time to time may be in the plane of the loop (Equatorial position), and not above or below this plane (axial position), one of the substituents is always above the other relative to the plane of the loop, depicted in a particular ori is ncacii. In the chemical structural formulas depicting such compounds, a substituent (X₁), which is "below" another substituent (X₂), is defined as the Deputy located in the alpha (α) configuration, and is shown in the text broken, dashed or dotted line going to the carbon atom, i.e. the symbol “- - -“ or “...”. The appropriate Deputy (X₂) "above" the others (X₁), named in the text of the substituent in the beta (β) configuration and is shown as a solid line going to the carbon atom. In the following example, the Deputy X₁is "under" X₂: if X₁is Equatorial, X₂located axially, up from the plane of the loop, leaving the plane of the paper in the direction of view of 2-dimensional patterns. An alternative example is when X₂is Equatorial, X₁located axially down from the plane of the loop in the plane of the paper and in the direction opposite to the direction of view of 2-dimensional patterns.

If AC Deputy is divalent, if a particular variable Deputy these valence can be used together, separately, or both at once. For example, a variable substituent R_iattached to the carbon atom in the fragment-C(=R_i)-could be two alentum and in this case could be defined as oxo or ketogroup (hence, the fragment would be a carbonyl group (-CO-)or could be defined as two separately attached monovalent variable substituent α-R_i-jand β R_i-kwhere “i” identifies a specific group R and “j” and “k” define a specific group R_i. When the bivalent variable substituent R_idefined in such a way that it consists of two monovalent variable substituents, a designation used to refer to two monovalent substituents, has the form “α-R_i-jand β R_i-k” or any of its variants. In this case, both Deputy α-R_i-jand β R_i-kattached to the carbon atom forming the fragment-C(α-R_i-j)(β-R_i-k)-. For example, if it is determined that the bivalent variable substituent R₆in the fragment-C(=R₆)consists of two monovalent variable substituents, the two monovalent variable Deputy represent α-R_6-1: β-R_6-2and form the fragment-C(α-R_6-1)(β-R_6-2)-. Likewise, for the bivalent variable substituent R₁₁in the snippet --C(=R₁₁)-- the designation of two monovalent variable substituents are α-R_11-1: β-R_11-2. In the case of cyclic substituent, in which there is no separate α and β orientations (for example, due to the presence in the cycle double carbon-carbon is due), and for Vice-related carbon atom that is not part of the cycle, still using the above symbol, but letter symbols α and β are omitted.

Just as the bivalent variable Deputy can be defined as two separate monovalent variable Deputy, and two separate monovalent variable substituent can be defined as together forming a divalent AC Deputy. For example, in formula C₁(R_i)H-C₂(R_j)H- (C₁and C₂arbitrarily defined as the first and second carbon atoms, respectively) Ri and Rj can be defined as jointly forming (1) a second bond between C₁and C₂or (2) a bivalent group such as oxa (-O-), and in this case, the above formula describes the epoxides.

The number of carbon atoms in variable substituents are shown as follows: the number of carbon atoms in each component of the definition is shown separately by enclosing them in brackets denote “C_i-C_j” and placing it in front of the part of the General definition of the Deputy, which defines the symbol. According to this first symbol C₂-C₄alkoxycarbonyl describes a group CH₃-(CH₂)_nO-CO-, where n represents one, two or three. Similarly, although both denote C₂-C₆alkoxyalkyl and (C₁-C₃)alkoxy(C₁-C₃)alkyl define CNS group containing from 2 to 6 carbon atoms, the two definitions differ since the first one allows for the presence of 4 or 5 carbon atoms in the alkoxy or alkyl portion Deputy, whereas the second definition limits the number of carbon atoms in any of these groups the number 3.

If the fragment is included mandatory heteroatoms (the inclusion of the term "hetero" without parentheses) or optional heteroatoms (the inclusion of the term "hetero" in parentheses, such as(hetero)"), preferably numbering reflects the replacement of the existing carbon atom in the fragment of the heteroatom. So, although in General the reference to "C₆of alkyl" includes linear, branched or cyclic alkyl radicals with up to six carbon atoms, "C₆heteroalkyl" (or "C₆(hetero)alkyl"), which includes a heteroatom, contains in this example five carbon atoms and a heteroatom, which was replaced by another carbon atom.

It should be understood that the use in the present description of the singular includes both the singular and the plural.

General definitions as used in this application have the following value in R is mcah of the present invention.

II. Definitions:

All temperatures are given in degrees centigrade, unless otherwise indicated.

The reduction in TLC (TLC refers to thin layer chromatography.

The reduction of psi refers to the pounds/inch².

Reduction HPLC (HPLC) refers to liquid chromatography high pressure.

The reduction in Ac refers to acetyl (methylcarbamyl).

Reduction of aq (aq.) means "water".

Reduction BFAA refers to benzofuran-2-luxusni acid.

Reduction Bn refers to benzyl.

Reduction of BOC refers to 1,1-dimethylethoxysilane and t-butoxycarbonyl, ie --CO--O--C(CH₃)₃.

The reduction in c refers to the concentration (g/ml unless otherwise specified).

The reduction in CDI refers to 1,1'-carbonyldiimidazole.

The term "chromatography" (column and flash chromatography refers to the purification/separation of compounds with the use of stationary phase and eluent. Assume that the appropriate fractions are collected and concentrated, obtaining the desired compound(I).

Abbreviation conc. means "concentrated". For example, the phrase "conc. hydrochloric acid" or ".HCl" refers to concentrated hydrochloric acid.

Reduction DCM refers to dichloromethane, or methylene chloride, or CH₂Cl₂.

Reduction de refers to diastereomeric excess.

With the reduction DMA refers to the dimethylacetamide.

Reduction DME refers to dimethoxyethane.

The reduction in DMF (DMF refers to N,N-dimethylformamide.

Reduction EA refers to the ethyl acetate (EtOAc).

Reduction of EDTA (EDTU) refers to ethylenediaminetetraacetic acid.

Reducing eq (EQ.) means "equivalent".

The reduction in Et refers to ethyl.

The term "ether" refers to diethyl ether.

The reduction in EtOH refers to ethanol.

The reduction in g refers to grams.

The reduction of h refers to hours.

Reduction IC₅₀refers to the concentration of a compound that reduces (inhibits) the activity of the enzyme in half.

The prefix "ISO" refers to alkyl chain with a terminal 2-methylpropyloxy a group that is --CH(CH₃)₂.

The reduction of l refers to litres.

Reduction min refers to the minutes.

Reducing max refers to the maximum.

Reduction of mg refers to milligrams.

The reduction of ml refers to milliliters.

The reduction in mm refers to millimeters.

The reduction in mm refers to the concentration, expressed in mmol.

Reduction mmol refers to mmol.

Reduction TPL refers to the melting temperature.

Reducing Me refers to the stands.

The prefix n - refers to the normal, i.e. unbranched, fragment, for example n-Pr means --CH₂--CH₂--CH₃if it is not the end the comfort round or square brackets, for example, --(CH)_n--, where n refers to the AC Deputy.

The reduction of H refers to the normality of the solution.

Reduction ng refers to nanograms.

Reduction nm refers to nanometers.

The reduction in the NMR relates to spectroscopy nuclear (proton) magnetic resonance, where the chemical shifts are expressed in ppm (d) in the weak field relative to TMS.

The reduction in OD is the optical density.

Reducing GHG refers to picograms.

Reduction PM means "picomolar".

The abbreviation RT (CT) refers to room temperature.

The prefix t -, or tert - refers to the presence of the tertiary fragment in the alkyl chain, such as t-butyl represents --C(CH₃)₃.

The term "tautomer", "tautomeric form" refers to one of the two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Of several possible types of tautomerism usually, there are two: keto-enol tautomerism and ring-chain tautomerism. When keto-enol tautomerism takes place simultaneous shift of electrons and a hydrogen atom. When ring-chain tautomerism of the aldehyde group in the linear chain sugar molecule interacts with one of the hydroxyl groups of the same molecule with the formation of cyclic (ring) forms the. As an example, if R₂in the formula (1) represents OH, a connection may exist in tautomeric equilibrium:

Reduction TEA refers to triethylamine.

The reduction in TFA (TFU) refers to triperoxonane acid, i.e. CF₃--COOH.

The reduction in THF (THF refers to tetrahydrofuran.

Reduction Tol refers to toluene.

Reduction of UV refers to the ultraviolet radiation.

Reduction μl means microliter.

Reduction μm means micromolar concentration (concentration expressed in micromol/litre).

Unless otherwise noted, all radicals of functional groups (e.g. alkyl, aryl, cycloalkyl etc) are optionally substituted. Substituted radicals of functional groups substituted by one or more substituents, unless otherwise indicated. Suitable substituents of substituted radicals of functional groups include as non-limiting examples of C₁-C₈(hetero)alkyl (i.e. the "alkyl" fragment, including linear, branched and cyclic (hetero)alkali and heteroaromatics analogues), C₁-C₈(hetero)alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₈)(hetero)alkylamino, di(C₁-C₈)(hetero)alkylamino, mono(C₁-C₈)(hetero)arylamino, di(C₁-C₈)(heteros who)arylamino, (C₁-C₈)(hetero)aryl-(C₁-C₈)(hetero) alkylamino, (C₂-C₈)(hetero)alkenyl, (C₂-C₈)(hetero)quinil, C₁-C₈halogenated, C₁-C₈halogenoalkane, amino(C₁-C₈)(hetero)alkyl, mono(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, di(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, =O, thiol, (C₁-C₈)(hetero)alkylthio, (hetero)aryl, (hetero)aryloxy, (hetero)aryl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkyl(hetero)aryl, (hetero -) aryl(C₁-C₈)(hetero)alkoxy, (C₁-C₈)(hetero)alkylsulphonyl, (hetero)arylcarbamoyl, (C₁-C₈)(hetero)allyloxycarbonyl, (hetero)aryloxyalkyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxylic, (C₁-C₈)(hetero)allyloxycarbonyl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)alkyl, (hetero)arylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)aryl, (hetero)arylcarboxylic(hetero)aryl, (C₁-C₈)(hetero)alkylthio, (C₁-C₈)(hetero)alkylsulfonyl, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)aryloxy, aminosulfonyl is l, optionally N-mono - or N,N-disubstituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)arylsulfonyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxamide, urea, optionally substituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, amido, sulfamido, acetylene, amidino, and similar groups, attached at any available atom in the connection.

In addition, unless otherwise indicated, the radicals of all functional groups, including circuit (for example, alkyl, heteroalkyl etc), can be linear, branched or cyclic.

DEFINITIONS of RADICALS

In the present description the term "alkane" or "alkyl", used alone or in combination with other radicals and/or substituents, are saturated hydrocarbon radicals containing from 1 to about 20, preferably from 1 to about 15 carbon atoms (unless specifically defined). The term "alkyl" refers to linear alkyl, branched alkyl or cycloalkyl radicals or substituents in the radicals (i.e. substitutions). Preferably, a linear or branched alkyl group contains from 1 to about 15, more preferably from 1 to about 8, even more predpochtitelno 1 to about 6, even more preferably from 1 to about 4 and more preferably from 1 to about 2 carbon atoms, representing, for example, methyl, ethyl, propyl, isopropyl, butyl, ISO-, sec - and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl etc. Preferably, each of cycloalkyl groups is independently monocyclic, bicyclic or polycyclic system comprising from 3 to about 10, more preferably from 3 to about 6 atoms in the cycle, and represents, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. In the number of Akilov also include linear chain or branched alkyl groups that contain or inside the chain which is cycloalkenyl fragment. Linear or branched (substituted or unsubstituted, as described below) alkyl groups attached to any available atom, if this connection leads to a sustainable connection. Examples of such compounds include, but are not limited to, 4-(isopropyl)-cyclohexylmethyl or 2-methylcyclopropene. In the number of "Akilov" also includes linear alkyl, branched alkyl and/or cycloalkyl groups defined previously, is independently substituted by 1-6 groups or substituents such as C₁-C₈(hetero)alkyl (i.e. the "alkyl" fragment, including linear, branched and cyclic (gets the ro)alkali and analogues, containing a heteroatom), C₁-C₈(hetero)alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₈)(hetero)alkylamino, di(C₁-C₈)(hetero)alkylamino, mono(C₁-C₈)(hetero)arylamino, di(C₁-C₈)(hetero)arylamino, (C₁-C₈)(hetero)aryl-(C₁-C₈)(hetero)alkylamino, (C₂-C₈)(hetero)alkenyl, (C₂-C₈)(hetero)quinil, C₁-C₈halogenated, C₁-C₈halogenoalkane, amino(C₁-C₈)(hetero)alkyl, mono(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, di(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, =O, thiol, (C₁-C₈)(hetero)alkylthio, (hetero)aryl, (hetero)aryloxy, (hetero)aryl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkyl(hetero)aryl, (hetero -) aryl(C₁-C₈)(hetero)alkoxy, (C₁-C₈)(hetero)alkylsulphonyl, (hetero)arylcarbamoyl, (C₁-C₈)(hetero)allyloxycarbonyl, (hetero)aryloxyalkyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxylic, (C₁-C₈)(hetero)allyloxycarbonyl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)alkyl, (hetero)arylcarboxylic(C₁-C₈)(g is Tero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)aryl, (hetero)arylcarboxylic(hetero)aryl, (C₁-C₈)(hetero)alkylthio, (C₁-C₈)(hetero)alkylsulfonyl, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)aryloxy, aminosulfonyl, optionally N-mono - or N,N-disubstituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)arylsulfonyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxamide, urea, optionally substituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, amido, sulfamido, acetylene, amidino and similar groups, attached at any available atom alkyl.

In the present description, the term "heteroalkyl", used alone or in combination with other radicals and/or substituents, refers to "alkyl"as defined above in which one or more heteroatoms selected from N, O, S and P, replace one or more atoms "alkyl" fragment. So, for example, "C₈heteroalkyl" can be-C₄-N-C₃-, -C₃-N-C₄-, -C₂-N-C₅- etc. Heteroalkyl groups are unsubstituted or substituted, for example, C₁-C₈(hetero)alkyl (i.e. the "alkyl" fragment including linear, rasvet the military and cyclic (hetero)alkali and analogues, containing a heteroatom), C₁-C₈(hetero)alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₈)(hetero)alkylamino, di(C₁-C₈)(hetero)alkylamino, mono(C₁-C₈)(hetero)arylamino, di(C₁-C₈)(hetero)arylamino, (C₁-C₈)(hetero)aryl-(C₁-C₈)(hetero)alkylamino, C₂-C₈(hetero)alkenyl, (C₂-C₈)(hetero)quinil, C₁-C₈halogenation, C₁-C₈halogenoalkane, amino(C₁-C₈)(hetero)alkyl, mono(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, di(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, =O, thiol, (C₁-C₈)(hetero)alkylthio, (hetero)aryl, (hetero)aryloxy, (hetero)aryl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkyl(hetero)aryl, (hetero -) aryl(C₁-C₈)(hetero)alkoxy, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarbamoyl, (C₁-C₈)(hetero)allyloxycarbonyl, (hetero)aryloxyalkyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxylic, (C₁-C₈)(hetero)allyloxycarbonyl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)alkyl, (heteroarylboronic(C ₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)aryl, (hetero)arylcarboxylic(hetero)aryl, (C₁-C₈)(hetero)alkylthio, (C₁-C₈)(hetero)alkylsulfonyl, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)aryloxy, aminosulfonyl, optionally N-mono - or N,N-disubstituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)arylsulfonyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxamide, urea, optionally substituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, amido, sulfamido, acetylene, amidino and similar groups, attached at any available atom heteroalkyl.

In this application the term "alkene" and "alkenyl", used alone or in combination with other radicals and/or substituents include linear, branched or cyclic (or a combination of linear or branched cyclic) hydrocarbon containing from 2 to about 20, preferably from 2 to about 17, more preferably from 2 to about 10, even more preferably from 2 to about 8, most preferably from 2 to about 4 carbon atoms and at least one, preferably from 1 to about 3, most of the e preferably from 1 to about 2, most preferably one double carbon-carbon bond. If cycloalkenyl group pairing more than one double carbon-carbon connection is not so, which is able to give the cycle aromaticity. Double carbon-carbon links are either cycloalkyl part (thus forming a "cycloalkenyl") except cyclopropyl, either in linear or branched portions. Examples alkenyl groups include ethynyl, propenyl, Isopropenyl, butenyl, chicagokent, cyclohexenylmethyl, etc. the Term "alkene" or "alkenyl" refers to substituted and unsubstituted to alkenyl with a linear chain, branched alkenyl or cycloalkenyl groups defined earlier, is independently substituted from 1 to about 10 groups or substituents, such as, for example, C₁-C₈(hetero)alkyl (i.e. the "alkyl" fragment, including linear, branched and cyclic (hetero)alkali and analogues containing a heteroatom), C₁-C₈(hetero)alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₈)(hetero)alkylamino, di(C₁-C₈)(hetero)alkylamino, mono(C₁-C₈)(hetero)arylamino, di(C₁-C₈)(hetero)arylamino, (C₁-C₈)(hetero)aryl-(C₁-C₈)(hetero)alkylamino, (C₂-C₈)(hetero)alkenyl, (C₂-C₈)(hetero)alkyne is, C₁-C₈halogenated, C₁-C₈halogenoalkane, amino(C₁-C₈)(hetero)alkyl, mono(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, di(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, =O, thiol, (C₁-C₈)(hetero)alkylthio, (hetero)aryl, (hetero)aryloxy, (hetero)aryl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkyl(hetero)aryl, (hetero -) aryl(C₁-C₈)(hetero)alkoxy, (C₁-C₈)(hetero)alkylsulphonyl, (hetero)arylcarbamoyl, (C₁-C₈)(hetero)allyloxycarbonyl, (hetero)aryloxyalkyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxylic, (C₁-C₈)(hetero)allyloxycarbonyl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)alkyl, (hetero)arylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)aryl, (hetero)arylcarboxylic(hetero)aryl, (C₁-C₈)(hetero)alkylthio, (C₁-C₈)(hetero)alkylsulfonyl, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)aryloxy, aminosulfonyl, optionally N-mono - or N,N-disubstituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, (C₁-C₈(geteroarilsulfoksidu, (hetero)arylsulfonyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxamide, urea, optionally substituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, amido, sulfamido, acetylene, amidino and similar groups, attached at any available atom alkenyl.

In this application, the term "heteroalkyl" and "heteroalkyl", used alone or in combination with other radicals and/or substituents, refers to the "alkene" and "alkenyl" groups defined above claims, in which one or more heteroatoms selected from N, O, S, and P, is the Deputy of one or more atoms "alkene" or "alkenylphenol" fragment. So, for example, "C₈heteroalkyl" can be-C₁=C₃-N-C₃--, -C₂=C₂-N-C₄-, -C₂-N-C₂=C₃- etc. Heteroalkyl group and heteroalkyl can be unsubstituted or can be optionally substituted, for example, C₁-C₈(hetero)alkyl (i.e. the "alkyl" fragment including linear, branched and cyclic (hetero)alkali and analogues containing a heteroatom), C₁-C₈(hetero)alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₈)(hetero)alkylamino, di(C₁-C₈)(hetero)alkylamino, mono(C₁-C₈)(g is Tero)arylamino, di(C₁-C₈)(hetero)arylamino, (C₁-C₈)(hetero)aryl-(C₁-C₈)(hetero)alkylamino, C₂-C₈(hetero)alkenyl, (C₂-C₈)(hetero)quinil, C₁-C₈halogenation, C₁-C₈halogenoalkane, amino(C₁-C₈)(hetero)alkyl, mono(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, di(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, =O, thiol, (C₁-C₈)(hetero)alkylthio, (hetero)aryl, (hetero)aryloxy, (hetero)aryl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkyl(hetero)aryl, (hetero -) aryl(C₁-C₈)(hetero)alkoxy, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarbamoyl, (C₁-C₈)(hetero)allyloxycarbonyl, (hetero)aryloxyalkyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxylic, (C₁-C₈)(hetero)allyloxycarbonyl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)alkyl, (hetero)arylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)aryl, (hetero)arylcarboxylic(hetero)aryl, (C₁-C₈)(hetero)alkylthio, (C₁-C₈)(hetero)alkyls what heniam, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)aryloxy, aminosulfonyl, optionally N-mono - or N,N-disubstituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)arylsulfonyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxamide, urea, optionally substituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, amido, sulfamido, acetylene, amidino and similar groups, attached at any available atom heteroalkyl.

In this application the term "alkyne" or "quinil", used alone or in combination with other radicals and/or substituents include linear or branched hydrocarbon containing from 2 to about 20, preferably from 2 to about 17, more preferably from 2 to about 10, even more preferably from 2 to about 8, most preferably from 2 to about 4, carbon atoms, containing at least one and preferably one triple carbon-carbon bond. Examples etkinlik groups include ethinyl, PROPYNYL, butynyl, etc. the Term "substituted quinil" refers to the quinil with a linear chain or branched quinil defined above, independently substituted from 1 to about 10 groups or substituents,such as, for example, C₁-C₈(hetero)alkyl (i.e. the "alkyl" fragment, including linear, branched and cyclic (hetero)alkali and analogues containing a heteroatom), C₁-C₈(hetero)alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₈)(hetero)alkylamino, di(C₁-C₈)(hetero)alkylamino, mono(C₁-C₈)(hetero)arylamino, di(C₁-C₈)(hetero)arylamino, (C₁-C₈)(hetero)aryl-(C₁-C₈)(hetero)alkylamino, (C₂-C₈)(hetero)alkenyl, (C₂-C₈)(hetero)quinil, C₁-C₈halogenated, C₁-C₈halogenoalkane, amino(C₁-C₈)(hetero)alkyl, mono(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, di(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, =O, thiol, (C₁-C₈)(hetero)alkylthio, (hetero)aryl, (hetero)aryloxy, (hetero)aryl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkyl(hetero)aryl, (hetero -) aryl(C₁-C₈)(hetero)alkoxy, (C₁-C₈)(hetero)alkylsulphonyl, (hetero)arylcarbamoyl, (C₁-C₈)(hetero)allyloxycarbonyl, (hetero)aryloxyalkyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxylic, (C₁-C₈)(hetero)allyloxycarbonyl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkitab is iloxi(C ₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)alkyl, (hetero)arylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)aryl, (hetero)arylcarboxylic(hetero)aryl, (C₁-C₈)(hetero)alkylthio, (C₁-C₈)(hetero)alkylsulfonyl, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)aryloxy, aminosulfonyl, optionally N-mono - or N,N-disubstituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)arylsulfonyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxamide, urea, optionally substituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, amido, sulfamido, acetylene, amidino and similar groups, attached at any available atom quinil.

In this application, the term "heteroalkyl" or "heteroalkyl", used alone or in combination with other radicals and/or substituents, refers to "Alcina" or "alkynylaryl" groups defined above claims, in which one or more heteroatoms selected from N, O, S and P, replace one or more atoms "alkyne" or "akinrinola" fragment. So, for example, "C₈heteroalkyl can serve as an --C≡C₃-N-C₃ --, --C₂≡C₂-N-C₄--, --C₂-N-C₂≡C₃-- etc. Heteroalkyl or heteroalkyl groups can be unsubstituted or optionally substituted, for example, C₁-C₈(hetero)alkyl (i.e. the "alkyl" fragment including linear, branched and cyclic (hetero)alkali and analogues containing a heteroatom), C₁-C₈(hetero)alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₈)(hetero)alkylamino, di(C₁-C₈)(hetero)alkylamino, mono(C₁-C₈)(hetero)arylamino, di(C₁-C₈)(hetero)arylamino, (C₁-C₈)(hetero)aryl-(C₁-C₈)(hetero)alkylamino, C₂-C₈(hetero)alkenyl, (C₂-C₈)(hetero)quinil, C₁-C₈halogenation, C₁-C₈halogenoalkane, amino(C₁-C₈)(hetero)alkyl, mono(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, di(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, =O, thiol, (C₁-C₈)(hetero)alkylthio, (hetero)aryl, (hetero)aryloxy, (hetero)aryl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkyl(hetero)aryl, (hetero -) aryl(C₁-C₈)(hetero)alkoxy, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarbamoyl, (C₁-C₈)(hetero)allyloxycarbonyl, (heteros who)aryloxyalkyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxylic, (C₁-C₈)(hetero)allyloxycarbonyl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)alkyl, (hetero)arylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)aryl, (hetero)arylcarboxylic(hetero)aryl, (C₁-C₈)(hetero)alkylthio, (C₁-C₈)(hetero)alkylsulfonyl, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)aryloxy, aminosulfonyl, optionally N-mono - or N,N-disubstituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)arylsulfonyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxamide, urea, optionally substituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, amido, sulfamido, acetylene, amidino and similar groups, attached at any available atom heteroalkyl.

In this application, the term "alkoxy"used alone or in combination with other radicals and/or substituents, refers to an alkyl group with the specified number of carbon atoms attached to Stalin the second part of the molecule through an oxygen bridge. Examples of alkoxygroup include, for example, methoxy, ethoxy, propoxy, isopropoxy.

In this application, the term "halogenoalkane", used alone or in combination with other radicals and/or substituents, refers to alkoxygroup, substituted with at least one halogen atom and optionally further substituted with at least one additional halogen atom, where each of the halogen atoms independently represents F, Cl, Br or I. Preferred Halogens are F or Cl. Preferred halogenlampe contain 1-6 carbon atoms, more preferably 1-4 carbon atoms and even more preferably 1-2 carbon atoms. The term "halogenoalkane" covers perhalogenated, such as OCF₃or OCF₂CF₃.

In this application, the term "aryl" used alone or in combination with other radicals and/or substituents, refers to an aromatic carbocyclic group containing one cycle (e.g. phenyl)which is optionally condensed or otherwise attached to other aromatic hydrocarbon cycles or non-aromatic hydrocarbon cycles. In the number of "allow" includes substituents that include multiple condensed cycles, at least one of which is aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), where cardys cycles is not necessarily mono-, di - and trisemester the following groups. Preferred aryl groups of the present invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphtho, fluorenyl, tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. More preferred are phenyl, biphenyl and naphthyl. Most preferred is phenyl. In the present invention aryl group optionally substituted by various groups according to one or more provisions which may implement the replacement. Aryl group optionally substituted, for example, C₁-C₈(hetero)alkyl (i.e. the "alkyl" fragment including linear, branched and cyclic (hetero)alkali and analogues containing a heteroatom), C₁-C₈(hetero)alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₈)(hetero)alkylamino, di(C₁-C₈)(hetero)alkylamino, mono(C₁-C₈)(hetero)arylamino, di(C₁-C₈)(hetero)arylamino, (C₁-C₈)(hetero)aryl-(C₁-C₈)(hetero)alkylamino, C₂-C₈(hetero)alkenyl, (C₂-C₈)(hetero)quinil, C₁-C₈halogenation, C₁-C₈halogenoalkane, amino(C₁-C₈)(hetero)alkyl, mono(C₁-C₈)(hetero)alkylamino(C₁-C₈)(hetero)alkyl, di(C₁-C₈(heteroalkyl(C ₁-C₈)(hetero)alkyl, =O, thiol, (C₁-C₈)(hetero)alkylthio, (hetero)aryl, (hetero)aryloxy, (hetero)aryl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkyl(hetero)aryl, (hetero -) aryl(C₁-C₈)(hetero)alkoxy, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarbamoyl, (C₁-C₈)(hetero)allyloxycarbonyl, (hetero)aryloxyalkyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxylic, (C₁-C₈)(hetero)allyloxycarbonyl(C₁-C₈)(hetero)alkyl, (C₁-C₈)(hetero)alkylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)alkyl, (hetero)arylcarboxylic(C₁-C₈)(hetero)alkyl, (hetero)aryloxyalkyl(C₁-C₈)(hetero)aryl, (hetero)arylcarboxylic(hetero)aryl, (C₁-C₈)(hetero)alkylthio, (C₁-C₈)(hetero)alkylsulfonyl, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)aryloxy, aminosulfonyl, optionally N-mono - or N,N-disubstituted (C₁-C₈)(hetero)alkyl and/or (hetero)aryl groups, (C₁-C₈)(hetero)alkylsulfonyl, (hetero)arylsulfonyl, (C₁-C₈)(hetero)alkylcarboxylic, (hetero)arylcarboxamide, urea, optionally substituted (C₁-C₈(hetero)alkyl and/or (hetero)aryl groups, amido, sulfamido, acetylene, amidino and similar groups, attached at any available atom of the aryl.

In this application, the term "halogen"as used alone or in combination with other radicals and/or substituents, applies to all Halogens are chlorine (Cl), fluorine (F), bromine (Br), iodine (I).

In this application, the term "hydroxyl"as used alone or in combination with other radicals and/or substituents, refers to the group-OH.

In this application, the terms "thiol", "thio or mercapto, used alone or in combination with other radicals and/or substituents, belong to the group-SH.

In this application, the term "alkylthio", used alone or in combination with other radicals or substituents, refers to the group-SR, as well as the group-S(O)_n=1-2-R (i.e. sulfanilic and sulfonyloxy groups), where R represents, for example, alkyl, (hetero)aryl and (hetero)aralkyl according to the above definitions.

In this application, the term "amino"as used alone or in combination with other radicals and/or substituents, refers to the group-NRR'where R and R' independently can represent, for example, hydrogen, (hetero)alkyl, (hetero)alkenyl, (hetero)quinil and acyl corresponding to the above definitions, all of these Zam is stitely (except H) are optionally substituted.

In this application, the term "carboxyl", used alone or in combination with other radicals and/or substituents, refers to the group --C(O)OR, where R can represent, for example, hydrogen, (hetero)alkyl, (hetero)cycloalkyl, (hetero)alkenyl, (hetero)quinil, (hetero)aryl, and acyl, corresponding to the above definitions, all of the above substituents (except H) are optionally substituted.

In this application, the term "acyl"as used alone or in combination with other radicals and/or substituents, refers to the group --C(O)R, where R can represent, for example, hydrogen, (hetero)alkyl, (hetero)cycloalkyl, (hetero)alkenyl, (hetero)quinil and (hetero)aryl, appropriate given in this application connections, and all of the above substituents (except H) are optionally substituted.

In this application, the term "pharmaceutically acceptable salts or their pharmaceutically acceptable salts" refers to salts derived from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Since the compounds of the present invention are bases, salts can be derived from pharmaceutically acceptable non-toxic acids. Suitable in pharmaceutical preparations is automatic acceptable acid additive salts of the compounds of the present invention include the salts of such acids, as acetic, benzolsulfonat (besylate), benzoic, camphorsulfonic, lemon, Tinsulanonda, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, setinova, lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, Panova, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate, etc. in Addition, in this application, the term "salt" includes coordination complexes formed ionic compounds of the present invention and one or more counterions. In the most preferred aspect of compounds of formula (5) is administered in free base form or in the form of tartrate or mono - or dihydrochloride.

In this application, the term "treatment" includes prophylactic administration of the compounds or pharmaceutical compositions containing the compound (prevention)and treatment introduction to reduce, suppress or eliminate the disease or disorder mentioned in this application. Prophylactic use is aimed at preventing the disease in the subject, which is threatened by the possibility of getting sick one or more of those mentioned in this application disorders. Thus, in the present description, the term "treatment" or its derivatives involve the partial or total suppression pointed to by the th morbid state if the active ingredient of the present invention is administered prophylactically or following the onset of painful conditions, to combat which impose such active ingredient. The term "prevention" refers to the introduction of active ingredient (ingredients) to a mammal to protect the latter from any of the above in this application, as well as other disorders.

The term "therapeutically effective amount" refers to the amount necessary to achieve the derived therapeutic effect, such as reduction or elimination of arrhythmic events or reduce their severity or duration.

"Mammal" can be, for example, mouse, rat, pig, horse, rabbit, goat, cow, cat, dog or man. In a preferred aspect, the mammal is a human.

The term "individual" ("individuals") is defined as an individual mammal, which is administered compounds of the present invention. The mammal can be, for example, mouse, rat, pig, horse, rabbit, goat, cow, cat, dog or man. In a preferred aspect, the individual is human.

Radical and its variant, replaced by a heteroatom (for example, aryl and heteroaryl; and "hetero" Deputy includes one or more heteroatoms, t is such as, for example, N, O, S and P), can be mentioned together with the aid of the bracketed prefix (hetero). For example, the term "(hetero)aryl" refers to aryl and the heteroaryl radical corresponding to the above definitions. Further, because the definition of each radical are also optional substituents and, where necessary, specify a linear, branched and/or cyclic in nature (for example, (hetero)alkyl and (hetero)alkanniny and other radicals can be linear, branched or cycloalkyl/cycloalkenyl), references (hetero)radicals (e.g., "(hetero)aryl and(hetero)alkyl") refers to radicals which optionally contain one or more heteroatoms, and in appropriate cases, may have a linear, branched and/or cyclic the character (and their combinations described in the text). Similarly, descriptions of the chemical groups comprising combinations of (hetero)radicals (e.g., "(hetero)alkyl(hetero)aryloxyalkyl")may indicate a combination of any of the typical characteristics of each radical, which were described earlier. Thus, a fragment of(hetero)alkyl(hetero)aryloxyalkyl" may refer to, for example, optionally substituted, linear, branched and/or cyclic (hetero)alkyl substituted, optionally substituted (hetero)aryloxy arborina fragment. Since (hetero)aryl radicals are optionally substituted as specified in their definition, may be present one or more additional substitutions in addition to specifically specified substitution (substitution) (hetero)alkyl. As an additional example, mention serial combinations of the same radical (for example, (hetero)alkyl(hetero)alkyloxy) also apply to all combinations of each of the radicals. For example, the name of the (hetero)alkyl(hetero)alkyloxy radical can be treated as one of many examples, branched, alkyl substituted, heterocyclic, alkyloxy the radical. However, the name of the (hetero)alkyl(hetero)alkyloxy radical may also include, as one of many examples of the linear alkyl substituted heterocyclic, alkyloxy the radical. For example, each of "(hetero)alkyl" radicals in the group "(hetero)alkyl(hetero)alkyloxy" may have different characteristics from one or more heteroatoms or absence of heteroatoms to alkyl chains of different lengths, and linear, branched or cyclic character, etc. similarly, using the previous example, each of the (hetero)alkyl radicals may have the same General characteristics. For example, the name of the (hetero)alkyl(hetero)alkyloxy radical may refer to heterocyclic alkyl substituted heterocyclic, alkyloxy the radical. However, the term "heterocyclic alkyl substituted heterocyclic, alkyloxy radicals" covers more than one type (for example, C₆compared to C₈heterocyclic alkyl Deputy). Thus, although the General characteristics of consecutive radicals with the same names can be the same as in example going prior to this, specific chemical identify each of the radicals need not be the same.

In addition, for functional groups of radicals can be used combinations of these terms. Typically, the last term in the name refers to the radical, which is linked to the rest of the chemical structure. For example, the term "halogenated" refers to the alkyl radical, substituted with halogen, the term "cycloalkenyl" refers to the alkyl radical, substituted by cycloalkyl, and the term "alkylsilanes" refers to cycloalkyl the radical, substituted by alkyl.

For simplicity, the chemical fragments define and mention mainly as a univalent chemical fragments (e.g., alkyl, aryl etc). However, under certain circumstances, a clear to a person skilled in the field of technology, these terms are used to indicate corresponding multivalent particles. For example the EP, while the name "alkyl" fragment, usually refers to a monovalent group (for example, CH₃-CH₂-), in certain circumstances, the bivalent binding fragment can be "alkyl", and in this case, the specialist in the art will understand that the alkyl is a divalent group (for example, -CH₂-CH₂-), which corresponds to the term "alkylene". (Similarly, in those situations where the presence of divalent fragment and confirmed that this fragment is the "aryl", the specialist in the art will understand that the term "aryl" relates to the corresponding bivalent fragment, i.e arylene). Have in mind that all atoms are normal for them the number of valences for the formation of ties (i.e. 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).

EXAMPLES

It is considered that a person skilled in the art using the preceding description, without additional testing methods implements the present invention in practice, in its entirety. In the following detailed examples describe how to get a variety of compounds (i.e. compounds covered by formula (1)to(4), and compounds covered by formula (5), which are derived from compounds of the formulas (1)to(4)and/or implement various techniques for infusion is he to the invention, and these examples should be interpreted only as illustrative and in nowise limiting the foregoing disclosure of the invention. Specialist in the art will quickly find the appropriate changes described methods both in terms of reagents and the conditions and methods of conducting reactions.

Obtaining new compounds of the present invention is shown in the following example, which, however, is not intended to serve as a limitation for these new connections.

In the example in the text descriptions of the reactions can be referred to specific amounts of reactants or "mass parts" and "molar fractions". Mention "mass parts" and "molar fractions" describe, for example, the mass and the stoichiometric ratio between the applied reaction reagents based on arbitrarily prescribed standard. For example, in the reaction, which requires the use of 36 g (approximately 2 moles) of water, water can be selected as the basic reagent. Because the amount of water taken as a starting point, the amount introduced into the reaction water in grams and moles can be defined as, for example, 1 mass part or 1× molar fraction. Thus, in the example of this paragraph 36 g of water are defined as one mass part and 2 mol of water is defined as 1× molar fraction. The selection of a basic reagent to separate reacts and or scheme of the reaction is completely arbitrary, as the selection of base quantities mass parts and molar fractions, and in this application for each of these options is selected the number "1".

Hereinafter amounts of reactants can be specified with respect to water or any other selected basic reagent. For example, the application of 400 g (4,55 mol) of ethyl acetate (mol. weight=88 g) can be described as 400/36 g or 11.1 mass parts and 4,55 mol/2 mol or of 2.27× molar fractions.

Example 1

A typical synthesis of 4-(4-hydroxy-3,5-goodfeel)-3,9-dioxalane-2-it ("enol-lactone")

A typical synthesis:

methyl ether BFAA molmasse: 190,2	dimethylacetal molmasse: 324,3
dimethylacetal molmasse: 324,3	fenilmetilovy ether molmasse: 310,3
fenilmetilovy ether molmasse: 310,3	penaltyshot molmasse: 296,3
diodinamika molmasse: 548,1
diodinamika molmasse: 548,1	enol-lactone molmasse: 530,1

Model stage 1: synthesis of methyl ether benzofuran-2-luxusni acid ("methyl ester BFAA")

Benzofuran-2-luksusowe acid (BFAA defined as 1 mass part; 1× mole fraction) was mixed with toluene (about 4.3 mass parts) was added methanol (approximately 1,96 mass parts) to form a solution. Added concentrated (conc.) hydrochloric acid (approximately 0,28 mass parts of 0.5× mole fraction), keeping the temperature below about 25°C, and stirred the reaction mixture for several hours. The reaction mixture was extinguished by an excess of aqueous sodium bicarbonate solution. Separating the aqueous layer and the organic layer was washed with an aqueous solution of sodium chloride. Separated aqueous layer was concentrated in vacuum, the organic layer containing the product. In this particular example, to the residue was added heptane and concentrated in vacuum to obtain the product methyl ester BFAA.

Typical stage 2: synthesis of methyl ester [3-(4-methoxybenzoyl)benzofur the EN-2-yl]acetic acid ("dimethylsilicone")

methyl ether BFAA molmasse: 190,2	dimethylacetal molmasse: 324,3

To methyl ether BFAA, obtained in stage 1 (the mole fraction taken as 1×)was added p-antillarum (approximately 1,08 mass parts; 1,1× mole fraction) and then methylene chloride (approximately 3,11 mass part). This mixture was stirred and cooled to about 0-5°C. was Added tin chloride (IV) (approximate mass of 1.46 parts), maintaining the temperature of the reaction mixture below about 10°C. the Reaction mixture was stirred at about 0-10°C for about 3 hours, and then gave it to warm up and stirred for several hours at about 20-25°C. was Added methylene chloride, the reaction mixture was cooled and extinguished 4% aqueous solution of hydrochloric acid, keeping the temperature below about 10°C. the Organic layer was separated and washed with water. The organic layer was concentrated in vacuum and dried by distillation of the additional amount of methylene chloride. The obtained product was dissolved in methylene chloride and transferred to a clean vessel.

Model stage 3: synthesis of methyl ester [3-(4-hydroxybenzoyl)benzofuran-2-yl]acetic acid (phenol is amylovora ether")

dimethylacetal molmasse: 324,3	fenilmetilovy ether molmasse: 310,3

Aluminium chloride (approximately 2,08 mass parts; 2,77× mole fraction) was mixed with methylene chloride (approximately 8,88 mass parts) with formation of a suspension. Solution was added tetrabutylphosphonium (approximately 1,69 mass parts; 0,88× mole fraction) in methylene chloride (approximately 3,35 mass parts), keeping the temperature no higher than about 30°C. In the reaction vessel was added to half of the solution dimethylsilicone obtained in stage 2 (approximately 4.04 the mass part of the solution, presumably of 0.5× mole fraction), keeping the temperature not above 35°C. the Reaction mixture was stirred at a temperature of about 30°C for several hours. The reaction mixture was cooled to a temperature below about 10°C and then transferred into a cold 14% aqueous solution of hydrochloric acid (approximately 18,08 mass parts), keeping the temperature below about 20°C. the Organic layer was separated and repeatedly washed with water. The organic layer was concentrated in vacuum. The residue was re-dissolved in, for example, ethyl acetate and washed with water and 10% aqueous p is the target of sodium chloride. The washed solution fenilmetilsul ether in ethyl acetate was dried in a clean vessel. The second half of the original substance, i.e. dimethylsilicone, was turned into fenilmetilovy ether, using the same method and the processing method. In total, according to the results of the implementation of the two above-described typical syntheses received about 19,96 mass parts of a solution fenilmetilsul ether in ethyl acetate. The joint portion of the solution was concentrated in vacuo and added, for example, n-heptane to precipitate the product. The product was collected at a temperature of about 0°C and dried on the filter with nitrogen. The output of crude phenol methyl ester was approximately 1,96 mass part.

Model stage 4: synthesis of [3-(4-hydroxybenzoyl)benzofuran-2-yl]acetic acid ("finalcolor")

fenilmetilovy ether molmasse: 310,3	penaltyshot molmasse: 296,3

Fenilmetilovy ester obtained in stage 3 (approximately 1,96 mass parts, presumably about 0,80× mole fraction) in the reaction vessel, suspended in water (about 8,46 mass parts). Added a 9% aqueous solution of sodium hydroxide (approximately 180 kg 6,92 mass parts, 2,70× molar fractions), support the live temperature below about 40°C. After about 4 hours at a temperature of about 10-30°C, the reaction mixture was washed with methylene chloride. The aqueous layer containing the product was cooled and acidified with concentrated hydrochloric acid (approximately 1.5 mass parts of 2.64× mole fraction), keeping the temperature below about 10°C, causing thereby the precipitation of the product. The product was extracted with organic solvent, for example ethyl acetate, and the separated water layer. The organic layer containing the product was washed with water. The solution finalcolor in ethyl acetate (approximately 8,54 mass parts) were retained for use in the sample stage 5. Estimated yield, identified by the concentration of the sample to dryness, was 76%.

Typical stage 5: synthesis of [3-(4-hydroxy-3,5-diadvisor)benzofuran-2-yl]acetic acid (dioperasikan)

penaltyshot molmasse: 296,3	diodinamika molmasse: 548,1

To a solution of potassium carbonate (approximately 1,08 mass parts of 1.39 mole fraction) in water (approximately 13,08 mass parts) was added to approximately half of the solution finalcolor in ethyl acetate, obtained in stage 4 (or 4.31 mass part, when listello 0,30× mole fraction). Separated aqueous layer and discard the organic layer. To the aqueous layer was added sodium iodide (approximately 0,017 mass parts 0,020× mole fraction). Three servings for about 3.5 hours at a temperature of 20-25°C was added iodine (1,27 mass parts of 0.89 mole fraction). The reaction mixture was stirred for approximately another 3 hours after the addition of iodine. The reaction mixture is washed, for example, ethyl acetate, and separated the contained product water layer. The aqueous layer was cooled and acidified using conc. hydrochloric acid (approximately 1,08 mass parts, 1,89× mole fraction) to precipitate the product. A suspension of the product was kept at a temperature of about 35-40°C for 1 hour, after which the collected product on the filter. The solid is washed with water and then re-suspended in water, collected on a filter and washed with water. Wet sludge cake again suspended in toluene and dried solid distillation of the azeotrope of water and toluene in vacuum at a temperature not above about 45°C. and Then separated solid is filtered and washed, for example, toluene. This technique was repeated for the remaining half of the original finalcolor.

Typical step 6: synthesis of 4-(4-hydroxy-3,5-goodfeel)-3,9-dioxalane-2-it ("enol-lactone")

diodinamika molmasse: 548,1	enol-lactone molmasse: 530,1

All portions of wet sediment of finalcolor obtained at stage 5 (approximately 10,7 mass parts in the wet state, approximately 1,92 mass of the active substance, and 0.61× mole fraction)was mixed with THF (4,5 mass fraction) and the mixture was heated to about 35°C. To a solution of the original substance was added to a suspension of 1,1'-carbonyldiimidazole (CDI; approximately 0.88 mass parts, 0,97× mole fraction) in THF (about 2,19 mass parts), maintaining a temperature of about 32-40°C. to complete the transfer of the suspension, washed vessel THF (approximately 0,46 mass parts). The reaction mixture was stirred at a temperature of about 35°C for about 1 hour and then cooled. The reaction mixture was extinguished with water (about 3,65 mass parts), maintaining a temperature of about 25-40°C. the Reaction mixture was further cooled and acidified using conc. hydrochloric acid (approximately 1,64× mole fraction), maintaining a temperature of about 10-20°C, until reaching a pH of about 3. The resulting slurry product was stirred at a temperature of about 0-5°C for about 7 hours, and then collecting the product by filtration and washed with cold mixture of THF/water. The product was dried in vacuum the device, getting about 1,60 mass of the dry enol-lactone (approximately 0,53× mole fraction, 87%, without taking into account adjustments for data analysis). Typical physical data enol-lactone:

GHMC (M⁺:531,03);

¹H-NMR: (400 MHz NMR):: 6,22 (S., 1H); 7,25 (m, 1H); 7,46 (m, 3H); 8,11 (S., 1H); 10,46 (users,-OH);

¹³C-NMR: 86,54; 88,14; 108,88; 111,74; 119,31; 120,81; 124,43; 126,18; 129,73; 138,51; 153,57; 156,84; 158,54; 161,79; 168,80.

Enol-lactone, obtained in the result of implementation of the above model stages (i.e. enol-lactone of the formula (3) and its tautomer formula (4)can be used to obtain a large number of compounds that can be used to reduce arrhythmias in patients with the need to achieve such a result. Described below is a typical stage in combination with the above-described stages are a way of synthesis of one of the members of the class of compounds described by the General formula, namely formula (5), which is a (R)-Deut-butyl 2-(3-(4-(2-(diethylamino)ethoxy)for 3,5-diadvisor)benzofuran-2-yl)acetate. However, it is important to note that the methodology is applicable to a wide range of compounds belonging to the class of compounds described by formula (5). Other compounds corresponding to General formula (5)can be obtained, for example, replacement of the reagent on stage 5 (e.g., Cl₂or Br₂instead of I₂or with the exception of stage 5, stabilimenti hydrogen atoms in the structure "finalcolor", both the above synthesis pathway leads to the formation of compounds described by formula (1), and their tautomers, corresponding to the formula (2). Additional sequential or separate changes can be made in other stages described methods, for example the use of other alcohols on stage 7 and/or other amines on stage 8, as described hereinafter. Thus, the method of example 1 and the methods described elsewhere in the text, can be used as a guide to a person skilled in the art to obtain compounds of the formulas (1)to(4) and, in turn, use of these compounds for preparing compounds of the formula (5).

Model step 7: synthesis of (S)-sec-butyl ester of [3-(4-hydroxy-3,5-diadvisor)benzofuran-2-yl]acetic acid ("butyl ether of phenol")

enol-lactone molmasse: 530,1	butyl ether phenol molmasse: 604,2

Enol-lactone (about 0,80 mass parts of 0.26× mole fraction) suspended in THF (about or 4.31 mass parts) and cooled suspension to about -5°C. In a separate reaction vessel was added (S)-2-butanol (about 0,32 mass parts of 0.77× mole fraction) to 19% (wt./wt.) to a solution of tert-BU the oxide of lithium (about 1,50 mass part of the solution, 0,63× mole fraction) to obtain a solution of (S)-2-butoxide lithium. The resulting solution (S)-2-butoxide was added to the cooled suspension enol-lactone, keeping the temperature below about 10°C. To complete the transfer of the suspension was carried out by washing THF (approximately 1,85 mass part). The reaction mixture was stirred for about 6 hours at a temperature of about 0±5°C. the Reaction mixture was extinguished diluted aqueous solution of hydrochloric acid at a temperature below about 10°C. the Separated aqueous layer and the organic layer was washed with 25% aqueous solution of sodium chloride. The organic layer was concentrated in vacuum. Added ethyl acetate, concentrated in vacuo and filtered concentrate to remove all insoluble substances. Was added methanol and the resulting solution was concentrated in vacuum. Added another portion of methanol and concentrated solution again. The concentrate was cooled to about -6°C, separating the product by filtration and washed with cold methanol. The product was dried in vacuum at a temperature of about 60°C. the Yield of dry butyl ether of phenol was about 0,71 mass parts (in this case approximately 78%).

As mentioned above, used in the method (S)-2-butanol can be replaced with different alcohols. For example, methanol, ethanol, n-propanol, isopropanol, n-butanol is, sec-butanol, tert-butanol and the like, Hereinafter described and is provided by the use of alcohols with one or more chiral centers, for example, (S)-2-butanol, (R)-2-butanol, (S)-3-pentanol and (R)-3-pentanol. In addition, can be used halogenated alcohols, such as (S)-4,4,4-triptorelin-2-ol, (S)-4,4,4-Cryptor-3-(trifluoromethyl)butane-2-ol, (2S)-4,4,4-Cryptor-3-methylbutane-2-ol, (R)-4,4,4-triptorelin-2-ol, 4,4,4-triptorelin-2-ol, (S)-4,4,4-trichlorobutene-2-ol and the like, Alcohols can be, for example, alcohols corresponding to the formula HO-(C₁-C₆)alkyl and preferably HO-(C₃-C₄)alkyl, where "alkyl" is appropriate in the application definition, and therefore includes, for example, linear and branched alkyl fragments. In addition, the alcohols can have one or more chiral centers and can be optionally substituted as described in this application. Preferred substitutions include one or more of halogen atoms.

Typical step 8: synthesis of (L)hydrotartrate {(2S)butane-2-yl 2-[3-(4-{2-(diethylamino)ethoxy}is 3.5-diadvisor)benzofuran-2-yl]acetate} (tartrate ATI-2042)

butyl ether phenol molmasse: 604,2	the basis of ATI-2042 molmasse: 703,3

p>

L-tartaric acid molmasse: to 150.1	tartrate ATI-2042 molmasse: 853,4

Butyl ether phenol (approximately 0,71 mass parts of 0.21× mole fraction), potassium bicarbonate (around 0.35 mass parts of 0.62× mole fraction), toluene (approximately is 3.08 mass parts) and water purified according to USP (U.S. Pharmacopoeia) (around 0.35 mass parts)were mixed in a reaction vessel. Was added a solution of the hydrochloride of 2-(diethylamino)ethylchloride (about 0,23 mass parts, 0,23× mole fraction) in water according to USP (about 0,29 mass parts), maintaining the temperature at 25-30°C. an Additional portion of water (about 0,19 mass parts) were added for a more complete transfer of substances. The reaction mixture was heated and stirred for several hours at a temperature of about 50°C. the Reaction mixture was cooled to about 35°C and filtered to remove insoluble substances. Separating the aqueous layer and washed the organic layer with an aqueous solution of sodium chloride. The organic layer was concentrated in vacuum, obtaining a residue, which was again dissolved in isopropanol.

Solution was added L-tartaric acid (about 0,19 mass parts, 0,2× mole fraction) in water, purified according to USP. After heating to about 45°C was added another portion of water purified according to USP, obtaining a solution which was filtered to separate from the suspension. A solution of tartrate of ATI-2042 was cooled and was led from a mixture of isopropanol/water, collecting the solid on the filter and drying in vacuum at a temperature of about 20-35°C, receiving approximately 15 kg of product. Product re-suspended in a mixture of isopropanol/water and collected on the filter.

As mentioned above, used in the described method hydrochloride 2-(diethylamino)ethylchloride (2-chloro-N,Ndiethylethanamine) can be replaced with different halogenated amines and salts of amines. For example, for other aminecontaining fragments can be applied hydrochloride or hydrobromide of 2-chloro-N-ethyl-Nmethylethanamine, hydrochloride or hydrobromide of 2-chloro-N,Ndimethylethanamine, hydrochloride or hydrobromide of 2-chloro-Nmethylethanamine, hydrochloride or hydrobromide of 2-chloro-Ntiletamine, hydrochloride or hydrobromide of 2-chloro-N-ethyl-Nmethylethanamine, 2-chloro-N,N-dimethylethanamine, 2-chloro-N-methylethanamine, 2-chloro-N-tiletamine etc. Amines can be, for example, amines corresponding to the formula X-R₁₀-NR₁₁R₁₂; where X is a halogen; R₁₀represents a C₁-C₆alkyl (coz the ACLs definition given above, i.e. including, for example, linear and branched alkali); and R₁₁and R₁₂independently represent H, C₁-C₄alkyl corresponding to the above definitions.

Example 2

A typical synthesis of 4-(4-hydroxyphenyl)-3,9-dioxalane-2-it ("enol-lactone")

A typical synthesis:

methyl ether BFAA molmasse: 190,2	dimethylacetal molmasse: 324,3
dimethylacetal molmasse: 324,3	fenilmetilovy ether molmasse: 310,3

Typical stages 1-3 of example 2 can, for example, be consistent with those described in example 1.

Model stage 4: synthesis of [3-(4-hydroxybenzoyl)benzofuran-2-yl]acetic acid ("finalcolor")

fenilmetilovy ether molmasse: 310,3	penaltyshot molmasse: 296,3

Fenilmetilovy ester obtained in stage 3 (approximately 1,96 mass part, suppose itelna about 0,80× mole fraction), suspended in water (approximately 8,46 mass parts) in the reaction vessel. Added a 9% aqueous solution of sodium hydroxide (approximately 180 kg, 6,92 mass parts, 2,70× mole fraction), keeping the temperature below about 40°C. after About 4 hours at a temperature of approximately 10-30°C, the reaction mixture was washed with methylene chloride. Containing the product the aqueous layer was cooled and acidified with concentrated hydrochloric acid (approximately 1.5 mass parts of 2.64× mole fraction), keeping the temperature below about 10°C, which caused precipitation of the product in the sediment. The product collected on the filter. The solid is washed with water and then suspended in water, collected on a filter and washed with water. The wet cake of sediment suspended in, for example, toluene and the solid residue was dried by distillation of the azeotrope of water and toluene in vacuum at a temperature not more than about 45°C. Then the solid was separated by filtration and washed, for example, toluene.

Typical stage 5: synthesis of 4-(4-hydroxyphenyl)-3,9-dioxalane-2-it

penaltyshot molmasse: 296,3	diodinamika molmasse: 548,1

All cakes sediment phenol is islote, obtained in stage 4 (about 11 mass parts wet, about 2 mass parts of active substance, of 0.6× mole fraction)was mixed with THF (about 4.5 mass parts) and the mixture was heated to about 35°C. To a solution of the original substance was added to a suspension of 1,1'-carbonyldiimidazole (CDI; approximately 0,88 mass parts, 0,97× mole fraction) in THF (approximately 2.2 mass parts), maintaining a temperature of about 32-40°C. For a full migration of the suspension in the reaction vessel was carried out by washing THF (approximately 0.5 mass part). The reaction mixture was stirred at a temperature of about 35°C for about 1 hour and then cooled. The reaction mixture was extinguished with water (approximately 3.7 mass parts), maintaining a temperature of about 25-40°C. the Reaction mixture was further cooled and acidified using conc. hydrochloric acid (about 1.7× mole fraction), maintaining a temperature of about 10-20°C, until reaching a pH of about 3. The resulting slurry product was stirred at about 0-5°C for about 7 hours and then the product was collected by filtration and washed with cold mixture of THF/water. The product was dried in a vacuum device, receiving approximately 1.7 mass parts of dry enol-lactone (approximately 0.6× mole fraction).

1. The compound of formula (1) or (2)

or its hydrate, MES, salt or tautomeric form, where
R₁independently represents H or halogen;
R₂represents H or --R₁₀-NR₁₁R₁₂where
R₁₀represents a C₁-C₆alkylen;
R₁₁and R₁₂independently represent H, C₁-C₄alkyl; and
R₃independently represents H or halogen.

2. The compound according to claim 1, where R₁and R₃independently represent a halogen, and R₂represents N.

3. The compound according to claim 1, where R₁and R₃represent the atoms of iodine, and R₂represents N.

4. The method of obtaining the compounds of formulas (1)to(4)




or their hydrate, solvate, salt or tautomeric forms, where
R₁represents H or halogen;
R₂represents H or --R₁₀-NR₁₁R₁₂where R₁₀represents a C₁-C₆alkylen;
R₁₁and R₁₂independently represent H, C₁-C₄alkyl; and
R₃represents H or halogen;
including:
(a) interaction benzofuran-2-yl-acetic acid (BFAA) alkanols obtaining ether BFAA;
(b) interaction of ether BFAA with p-antillarum (4-methoxybenzo what inflorida) to produce dealkylation;
(C) dealkylation anisole fragment () dealkylation obtaining finalsilence option () alkylation;
(d) the conversion of ester to the corresponding carboxylic acid;
(e) the optional halogenoalkane; and
(f) the conversion of compounds containing fragment carboxylic acid, enol-lactone.

5. The method of obtaining compounds of formula (5):

where R₁represents H or halogen;
R₂represents H or --R₁₀-NR₁₁R₁₂where
R₁₀represents a C₁-C₆alkylen;
R₁₁and R₁₂independently represent H, C₁-C₄alkyl;
R₃represents H or halogen;
R₄represents a C₁-C₆alkyl; and their hydrates, solvate, salts and tautomeric forms, including
(a) interaction of the compounds according to claim 1 with (C₁-C₆) ultilateral alcohol to ether complex; and
(b) the interaction of the compounds with halogenated amine of the formula X-R₁₀-NR₁₁R₁₂where
X represents halogen;
R₁₀represents a C₁-C₆alkylen; and
R₁₁and R₁₂independently represent H, C₁-C₄alkyl.

6. The method according to claim 5, in which (C_{1 -C6) ultilateral alcohol is a (S)-2-butanol or (R)-2-butanol and the amine of the formula X-R10-NR11R12is a hydrochloride 2-(diethylamino)ethylchloride (also referred to as the hydrochloride of 2-chloro-N,N-diethylethanamine) or hydrochloride 2-(ethylamino)ethylchloride (also referred to as the hydrochloride of 2-chloro-N-tiletamine).}