Derivatives of arylsulphonylstilbene for treatment of insomnia and associated with it disorders

FIELD: medicine.

SUBSTANCE: invention relates to novel compounds of formula or to its pharmaceutically acceptable salts, where n is 0 or 1; R1 represents H or F; R2 represents C1-4alkyl; R7 represents H or C1-4alkyl; and Z represents hydroxyl C1-6alkyl or C1-6alkoxycarbonyl, or 5- or 6-member heteroaromatic ring, which belongs to aromatic rings which have given number of atoms, of which at least one is N, O or S, the remaining being carbon atoms, and which also optionally has methyl substituting group. Invention also relates to pharmaceutical composition, to application of compounds, as well as to method of obtaining formula I compounds.

EFFECT: obtaining novel biologically active compounds, possessing activity of receptor 5-HT2A antagonists.

9 cl, 25 ex

 

This invention relates to the class of sulfanilic derivatives that act on serotonin (also known as 5-hydroxytryptamine) or 5-HT receptors. More specifically, this invention relates to arylsulfonamides and their derivatives. These compounds are potent and selective antagonists of the receptor 5-HT2Athe human body and are therefore suitable as pharmaceutical agents, especially for the treatment and/or prevention of adverse conditions of the Central nervous system, including sleep disorders such as insomnia, psychotic disorders such as schizophrenia and psychiatric disorders, such as anxiety.

Compounds proposed in this invention usually have a more efficient binding to the receptor 5-HT2Athe human body in comparison with other receptors of the human body, such as the D2, 5HT2Cand IKr. Consequently, it can be expected that they will cause fewer side effects than compounds which are not restricted in their binding affinity for these receptors. In particular, these compounds have a lesser impact on receptors IKr, and the separation of the desired effect from side effects such as cardiac effects.

Group is a rotary also take advantage of connections proposed in this invention that they exhibit strong activity as an antagonist of the human receptor 5-HT2Athese compounds are effective in the treatment of neurological conditions, including sleep disorders such as insomnia, psychotic disorders, such as schizophrenia, depression, anxiety, panic disorder, obsessive-compulsive disorder, pain disorder associated with eating, such as anorexia (anorexia nervosa), and dependence or acute toxic effects caused by drugs, such as LSD or MDMA; they also act in a positive way in the settlement of extrapyramidal symptoms associated with taking neuroleptic funds. They can be also effective in lowering intraocular pressure and may also be effectively used for the relief of symptoms caused by menopause, including hot flushes (see Waldinger et al, Maturitas, 2000, 36, 165-8).

Different classes of compounds containing, inter alia, sulfonyloxy part, described in WO 01/74797, WO 2004/101518, WO 2005/047246, WO 00/43362, WO 96/35666, EP-A-0261688, EP-0304888 and U.S. patents 4218455 and 4128552, DE-A-3901735 and Fletcher et al, J. Med. Chem., 2002, 45, 492-503. None of these publications, however, is not disclosed and is not offered a special class of compounds presented in this invention.

This is the connection according to this invention are potent and selective antagonists of the receptor 5-HT 2Arespectively having affinity for binding to the human receptor 5-HT2A(Ki) of 100 nm or less, typically 50 nm or less, and preferably 10 nm or less. Compounds proposed in this invention can possess at least 10-fold selective affinity, typically at least 20-fold selective affinity, and preferably at least 50-fold selective affinity for the human receptor 5-HT2Ain relation to the human receptor dopamine D2and/or human receptors IKr and/or 5-HT2c. Preferred compounds exhibit at least 100-fold selectivity against human receptor 5-HT2c

The invention includes a compound of the formula I:

or its pharmaceutically acceptable salt or hydrate, where:

n is 0 or 1;

R1denotes H or F;

R2denotes halogen, CN, CONH2C1-4-alkyl or C1-4-alkoxy;

R7denotes H or C1-4-alkyl; and

Z denotes hydraxis1-6alkyl or C1-6alkoxycarbonyl or 5 - or 6-membered heteroaromatic ring which optionally has a substituting methyl group.

Used here, the expression "C1-xalkyl, where x is an integer greater than 1, refers to alkaline the groups with non-branched chain and branched chain, in which the number constituent of carbon atoms is in the range from 1 to x. Typical alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such as "hydraxis1-6alkyl" and "C1-6alkoxy"should be interpreted in the same way.

Used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine, of which the preferred fluorine and chlorine, and fluorine are particularly preferred.

Used herein, the term "heteroaromatic" refers to an aromatic ring having the specified number of atoms, of which at least one is N, O or S and the remaining atoms are carbon. In the case of a 6-membered heteroaromatic rings one, two or three (preferably one or two) atoms of the ring are nitrogen atoms. In the case of 5-membered heteroaromatic rings one, two, three or four atoms of the ring are selected from N, O and S with the proviso that not more than one atom of the ring is O or S.

For use in medicine, the compounds of formula I may be in the form of pharmaceutically acceptable salts. Other salts, however, may be suitable for producing compounds of the formula I or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid additive salts, which can the be formed by mixing a solution of the compounds according to this invention with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, methanesulfonate acid, benzolsulfonat acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Alternatively, in case the connection according to this invention contains an acidic component, salt, suitable for pharmaceutical purposes, can be formed by neutralization of the specified acid component with a suitable base. Examples formed when salts suitable for pharmaceutical purposes, include salts of alkaline metal such as sodium or potassium; ammonium salts; salts of alkaline earth metals such as calcium salt or magnesium; and salts formed with the use of suitable organic bases, such as amine salt (including a salt of pyridinium and Quaternary ammonium salt.

If the compounds in accordance with this invention have one or more asymmetric centers, they may accordingly exist as enantiomers. If the compounds in accordance with this invention have two or more asymmetric center, they may in addition exist in the form of diastereoisomers. You should take into account that all such isomers and mixtures thereof in any the second ratio are included in the scope of this invention.

In the formula I R1denotes H or F. In some embodiments, the implementation of R1denotes H.

In formula I, n is 0 or 1. In some cases, the implementation of n is 0. If the group R2it can be attached in any appropriate position of the ring, but preferably in the ortho - or meta-position relative to the sulfonic component, most preferably in the ortho-position. Groups that are suitable as R2include halogen (particularly fluorine), C1-4alkyl (in particular methyl), or C1-4alkoxy (such as methoxy), CONH CN and2. In a preferred embodiment, R2absent or represents methyl.

In the formula I R7denotes H or C1-4alkyl, and when R7represents C1-4alkyl, the alkyl group may be attached in any possible position of the ring, but in most cases it is bound in the ortho-position relative to the olefinic component. Preferably R7denotes H or methyl, most preferably H.

Olefinic double bond in formula I can be in any of the two geometric configurations, but preferably in the E-configuration.

The group Z may be attached in any appropriate position of the ring, but preferably in the ortho - or meta-position on the reference to sulfonic component, most preferably in the ortho-position.

In one embodiment of the present invention Z represents hydraxis1-6alkyl group. In this embodiment, this alkyl group may be non-branched chain or branched chain and preferably contains up to 4 carbon atoms, inclusive. The hydroxyl group may be attached at any appropriate position of this alkyl group with the formation of primary, secondary, or tertiary alkanol. Examples of suitable hydraxis1-6alkyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 2-hydroxy-2-propyl, which is particularly suitable 1-hydroxyethyl. Specified 1-hydroxyethylene group is very suitable in the S-configuration. Specific examples of compounds in this embodiment of the present invention include:

(1S)-1-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]ethanol;

(1S)-1-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]ethanol;

(1S)-1-[2-({4-[(E)-2-(4-forfinal)vinyl]-3-were}sulfonyl)phenyl]ethanol;

[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]methanol;

[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]methanol;

2-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]propan-2-ol;

2-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]propan-2-ol; and

2-[2-({4-[(E)-2-(4-forfinal)wines is l]phenyl}sulfonyl)phenyl]ethanol.

In the second embodiment of the present invention Z represents C1-6alkoxycarbonyl, in particular, C1-4alkoxycarbonyl, such as CO2Me, CO2Et and CO2iPr. Specific examples of compounds in this second embodiment of the present invention include:

methyl-2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)benzoate;

methyl-2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)benzoate;

methyl-3-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)benzoate; and

methyl-2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)-3-methylbenzoate.

In the third embodiment of the present invention Z represents a 5 - or 6-membered heteroaromatic ring, which optionally is methyl substitute group. When the group Z is an optionally substituted five-membered heteroaromatic ring, it is preferably a nitrogen-containing ring such as pyrrole, imidazole, pyrazole, oxazole, thiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole or tetrazole; any of these rings may be optionally substituted methyl group. Such rings can be linked via a carbon atom or the chemical feasibility) through the nitrogen atom, however, the connection is through a carbon atom is preferable. Suitable examples include pyrazole-1-yl, imidazol-1-yl, 2-methyl-1,2,4-triazole-3-yl, oxazol-2-yl, thiazol-2-yl, imidazol-2-yl, 1-Mei-2-yl, pyrazole-3-yl, 1,2,3-triazole-4-yl and 1,3,4-oxadiazol-2-yl, which are particularly suitable imidazol-2-yl and 1,3,4-oxadiazol-2-yl.

When the group Z is an optionally substituted six-membered heteroaromatic ring, it is preferably pyridine, pyrazino, pyrimidine, pyridazine or triazine; any of these rings may optionally be substituted by methyl group. Preferably six-membered heteroaromatic ring, which is denoted as Z contains at least 2 nitrogen atom, and most preferably, it was pyridium. Specific examples of six-membered heteroaromatic ring, which is denoted as Z include 2-pyridyl and 3-pyridyl.

Specific examples of compounds in this third embodiment of the present invention include:

2-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]-1H-imidazole;

2-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]-1H-imidazole;

2-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]-1,3,4-oxadiazol;

and

2-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]-1,3,4-oxadiazol.

Compounds proposed in this invention have activity as an antagonist of the human receptor 5-HT2Aand, therefore, ahadiat use for the treatment or prevention of disorders, due to the activity of the receptor 5-HT2A.

This invention also provides pharmaceutical compositions that contain one or more compounds according to this invention and a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol, droplet-liquid sprays, drops, capsules, transdermal patches, autoinjection devices or suppositories, for oral, parenteral, intranasal, sublingual or rectal introduction or for introduction via inhalation or insufflation. The main active ingredient is usually mixed with a pharmaceutical carrier, e.g. conventional components for the manufacture of tablets, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalcium phosphate, or resins, dispersing agents, suspendresume agents or surfactants, such as servicemanuals and polyethylene glycol, and other pharmaceutical diluents, e.g. water, to form a homogeneous pre-composition containing the compound as proposed in the present invention, or its salt, suitable DL is pharmaceutical purposes. When considering these prior compositions as homogeneous " refers to the fact that their active ingredients are distributed evenly throughout the volume of the composition, and this composition can be easily divided into equal dosage forms such as tablets, pills and capsules. This preliminary composition is then divided into dosage forms of the aforementioned types, which contain from 0.1 to about 500 mg of the active component as proposed in the present invention. Typical dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg of the active component. The tablets or pills of this new composition can be coated or combined in any way to get dosage forms that realize the advantage of prolonged action. For example, the tablet or pill may contain components of internal dose and external dose, the second of which is in the form of a shell on top of the first component. These two components can be separated intersolubility layer that resists degradation in the stomach and allow the inner component to pass intact into the duodenum or to be released with a delay. For such Intercollege layer or coating can be used a variety of materials; such materials include a number of polymeric acids and ismeca with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the new compositions according to this invention can be combined for oral administration or by injection include aqueous solutions, capsules filled with liquid or gel, syrup with the appropriate aromatization, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil or coconut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic and natural resins, such as tragacanth gum, Arabia gum, alginate, dextran, carboxymethylcellulose sodium, methylcellulose, poly(ethylene glycol), poly(vinyl pyrrolidone) or gelatin.

This invention also provides a compound of formula I or its pharmaceutically acceptable salt for use in the method of treatment of the human body. Preferably, the treatment is performed in the case of disorders caused by the activity of the receptor 5-HT2A.

This invention also provides the use of compounds of formula I or its pharmaceutically acceptable salt in obtaining drugs for treatment or prevention of disorders caused by the activity of the recipe is RA 5-HT 2A.

Also disclosed is a method of treatment of a subject suffering from disorders caused by the activity of the receptor 5-HT2Aor prone to such disorders, which includes an introduction to this subject an effective amount of a compound according to formula I or its pharmaceutically acceptable salt.

In one aspect of the present invention violation caused by the activity of the receptor 5-HT2Ais sleep disorders, particularly insomnia. In another aspect of this invention, the disturbance caused by the activity of the receptor 5-HT2Aselected from psychotic disorders (such as schizophrenia), depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, disorders associated with eating (such as anorexia (anorexia nervosa)), dependencies or acute toxic effects due to drugs, such as LSD or MDMA, and hot flushes associated with menopause.

In the treatment here, for example, insomnia or schizophrenia suitable dose is from about 0.01 to 250 mg/kg / day, preferably from about 0.05 to 100 mg/kg / day, and particularly preferably from about 0.05 to 5 mg/kg / day. These compounds can be taken 1-4 times a day, but preferably once a day, for example, before ododo is to sleep.

If necessary, the compounds in accordance with this invention can be made in conjunction with other soporific, protivospazmaticheskim or anti-fobia sedative drug. Such co-administration may be desirable if the patient is already adapted to the treatment drugs, protiwaritmicescie or anti-fobia sedatives, including other conventional medicines. In particular, for the treatment of sleeping disorders, compounds according to this invention can be made in conjunction with receptor antagonists GABAAsuch as gaboxadol, or drugs means short and/or fast-acting hypnotics means, such as zolpidem or benzodiazepine, barbiturate, modulator prokineticin, antihistamine, trazodone, or a derivative of trazodone, as disclosed in WO 03/068148.

In accordance with another aspect of the present invention proposed a combination of compounds of formula I or its pharmaceutically acceptable salt or hydrate and gaboxadol for the treatment or prevention of sleep disorders, schizophrenia or depression.

Also in accordance with this invention, a method for treating or preventing sleep disorders, schizophrenia or depression, comprising the administration to a subject in need this, the compounds of formula I or the th pharmaceutically acceptable salt or hydrate in combination with gaboxadol.

Used here, the expression "in combination with" requires that this subject was administered a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt or hydrate and gaboxadol, but it makes no restrictions on the method by which this can be achieved. So, both products can be combined into a single dosage form for simultaneous reception by the patient or can be provided as a separate dosage form for simultaneous or sequential administration. Serial reception can be divided small or long period of time, such as one remedy can be taken in the morning and another in the evening. These separate funds may be accepted with the same frequency or a different frequency, for example, one remedy is taken once a day, and the other twice a day or more often. These individual tools can be the same or different way, for example, one tool is made by ingestion, and the other is injected parenterally, although both tools are preferred, if possible, ingestion.

In accordance with another aspect of the present invention proposed a pharmaceutical composition that contains a pharmaceutically acceptable carrier, the compound of formula I or eg the pharmaceutically acceptable salt or hydrate and gaboxadol.

The invention also includes the use of compounds of formula I or its pharmaceutically acceptable salt or hydrate and gaboxadol for the manufacture of a medicinal product for the treatment or prevention of sleep disorders, schizophrenia or depression.

The invention also includes a kit containing the first drug comprising the compound of formula I or its pharmaceutically acceptable salt or hydrate, and the second drug containing gaboxadol, along with instructions for sequential or simultaneous to the introduction of these drugs to a patient suffering from a sleep disorder, schizophrenia or depression.

Used here, the term "gaboxadol includes 4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine-3-ol in free base form or in zwitter-ionic form, as well as its pharmaceutically acceptable acid additive salts such as hydrochloride. In most cases gaboxadol is in the form of a crystalline monohydrate of zwitter-ionic forms.

The compounds of formula I can be obtained by the reaction of interaction of the compounds of formula (1a) with styrene of the formula (2a):

(1)(a) X=Hal (2)(a) R=H
(b) X=CHO(b) R=B(OH)2

where Hal denotes Cl, Br or I, and all other designations are the same as above. This reaction interaction occurs at an elevated temperature (e.g. 130°C) 1-organic in the presence of palladium acetate and sodium acetate. Hal is preferably Br.

Alternatively, the compound of formula (1a) can interact with the derived Bronevoy acid (2b), typically in a solution of tetrahydrofuran (THF) in the presence (PPh3)4Pd(0) and a base such as sodium carbonate, when heated (for example, up to 150°C by microwave radiation).

In another alternative embodiment, the aldehyde of formula (1b) is associated with benzylphosphonates, such as (3a), or benzylphosphonates salt, such as (3b):

where R1has the same meaning as described above. This reaction can be carried out in tetrahydrofuran (THF) in the presence of a strong base such as BuLi or a combination of sodium hydride with crown-ether.

In another alternative embodiment, the compound of formula (1a) can be processed tributyl(vinyl)tin with the formation of the alkene (4), which can be associated with brombenzene or yogansonom (5):

where X1denotes Br or I, and all other designations are the same as before. Binding occurs when the conditions analogous to the binding of (1a) with (2a).

The compounds of formula (1a) and (1b) can be obtained by reaction of interaction of the compounds (6) with compound (7) with subsequent oxidation of the educated tiefer (8):

where Y1means I, and Y2denotes SH, or Y1denotes SH, and Y2I, and all other designations are the same as before. The formation of thioethers (8) occurs in the presence of CuI, ethylene glycol and bases, such as sodium carbonate, in a solvent such as isopropanol. Oxidation of thioethers (8) two or more equivalents of oxidizing agent (e.g. m-chloroperoxybenzoic acid or ozone) leads to the formation of sulfones (1a).

Alternatively, sulfones (1a) can be obtained directly by the reaction of interaction between the compound of formula (6) and the compound of the formula (7), in which one of the groups Y1and Y2represents I or Br, preferably I), and the other - SO2-Na+. This reaction can be carried out in a polar aprotic solvent such as dimethylsulfoxide (DMSO), at elevated temperature (e.g. at about 110°C), in the presence of salts of Cu(I), such as iodide or Tr is flat. Preferably use about 3 molar equivalent of a salt of Cu(I).

You can easily notice that it is possible to vary the order in which executed the above stages of the reaction. For example, it is possible binding of the compounds of formula (2a), (2b), (3a) or (3b) with the compound of the formula (7) (X=Hal, or CHO, depending on what is appropriate) and bringing the resulting product into the reaction interaction with the compound of the formula (6) under conditions similar to those described above. Accordingly, the preferred synthesis of compounds of formula I involves the reaction of a derivative of bromo - or odensala (9) with salt silencelevel acid (10):

where X2denotes Br or I, and all other designations are the same as above.

Preferably, X2means I, and the reaction is carried out in dimethyl sulfoxide (DMSO) at about 110°C in the presence of CuI. Derivatives of stilbene (10) can be obtained by linking compounds (2a), (2b), (3a) or (3b) with compounds of the formula (7), in which Y2means SO2-Na+and X denotes Hal or CHO, depending on what is appropriate. During this linking group SO2-Na+preferably protected as an adduct with Acrylonitrile. This can be achieved through the reaction of interaction of the corresponding connection Faure the uly (7) (Y 2=SO2-Na+) with 2 equivalents of Acrylonitrile in a mixture of acetic acid and water at 100°C with the formation of the corresponding arylsulfonamides. After linking the functionality of the group SO2-Na+can be restored by treatment with alcoholate such as sodium methylate, at room temperature in an alcohol solvent, for example a mixture of methanol and tetrahydrofuran (THF).

In case of impossibility of use of commercial products raw materials and reagents described above can be obtained from commercially available precursors by well-known procedures for the synthesis. Suitable methods are disclosed here in the "Examples"section. Accordingly, the compounds of formula (6) or equation (9), in which Z denotes hydraxis1-6alkyl, can be obtained (if necessary) the recovery of the corresponding compounds in which Z denotes a suitable aldehyde or ketone with sodium borohydride or by reaction of the corresponding aldehyde or ketone with the appropriate alkyl Grignard reagent. The compounds of formula (6) or equation (9)in which Z represents a 5-membered heteroaromatic ring linked via N, can be obtained (if necessary) reaction by interaction of the corresponding compounds in which Z denotes F, approach Asim N-heterocycle (for example, by heating in a solution of dimethyl sulfoxide (DMSO)). The compounds of formula (6) or equation (9)in which Z represents a 5 - or 6-membered heteroaromatic ring linked through the C, can be obtained (if necessary) reaction by interaction of the corresponding compounds in which Z denotes Br or I, with a suitable heteroaromatic or derived heteroarylboronic, usually by heating in an aprotic solvent such as dimethylformamide (DMF)in the presence of a catalyst, such as (Ph3P)4Pd(0). Alternatively, 5 - or 6-membered heteroaromatic ring, which is denoted as Z, can be formed using conventional techniques heterocyclic synthesis. For example, methoxycarbonyl or ethoxycarbonyl group, denoted as Z, can be converted to 1,3,4-oxadiazol-2-ilen group by sequential processing of hydrazinehydrate and triethylorthoformate. Similarly, compounds in which Z represents 1,2,3-triazole-4-yl, can be obtained by treating the corresponding compounds in which Z is atenilol, azidotimedinom (for example, in a sealed tube at 150°C during the night). Similarly, compounds in which Z represents 1,2,4-triazole-3-yl, can be obtained by treating the corresponding compounds in which Z is the CN, 4H-1,2,4-triazole-4-amine and sodium ethylate in ethanol under reflux, followed by conducting the reaction of the educated N'-4H-1,2,4-triazole-4-yl-carboximidic with etelcharge.com (for example, in acetonitrile under reflux). Similarly, compounds in which Z represents a thiazole-2-yl, can be obtained by treating the corresponding compounds in which Z is C(S)NH2with bromoacetaldehyde or diethylacetal (for example, in dephlegmation ethanol). Similarly, compounds in which Z represents 2-pyridyl, can be obtained by diazotization of the corresponding compounds in which Z is NH2and processing the obtained salts, page by an excess of pyridine (for example, at 80°C).

You should take into account that the above transformations replacement group Z can be performed as the final step in the synthesis of compounds of formula I, if necessary.

Similarly, the identity of the group R2(if available) in the compounds of the formula I or their precursors can be modified using standard methods of synthesis. For example, compounds in which R2represents CN, can be obtained from corresponding compounds in which R2is Br, by processing ZnCN in the presence of (Ph3P)4Pd(0), and resultyou is the following NITRILES can be converted into the corresponding carboxamide (R 2=CONH2) by acid hydrolysis or treatment with trimethylsilanol sodium (for example, in tetrahydrofuran under reflux).

If the above-described processes for the production of compounds suitable for use in this invention, to provide a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. These compounds can be obtained in racemic form, or may be received individual enantiomers by enantiospecific synthesis or by separation. Connections can be, for example, separated into their component enantiomers by standard techniques such as preparative high performance liquid chromatography (HPLC), or after the formation of diastereomeric couples through the formation of salts with optically active acid, such as di-p-toluoyl-D-tartaric acid and/or di-p-toluoyl-L-tartaric acid, perform fractionated crystallization and recovery of the free base. The compounds can also be separated through education diastereomeric esters or amides, followed by separation and removal of the chiral additives.

When conducting any of the above sequences of synthesis may be necessary and/or desirable to protect the feeling is twitteling or reactive groups on any of the participating molecules. This can be implemented by conventional protective groups such as the groups described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. These protective groups can be removed at a convenient subsequent stage using methods known in this field.

Compounds were tested for their binding to the receptor 5-HT2Aand with other receptors, such as 5-HT2Cand Ikr, when using the techniques described in Fletcher et al, J. Med. Chem., 2002, 45, 492-503.

EXAMPLES

The intermediate product 1

4-[(E)-2-(4-forfinal)vinyl]benzosulfimide sodium

Stage 1

To a suspension dihydrate 4-bromophenylacetate sodium (130 g, of 0.53 mol) in water (600 ml) was added Acrylonitrile (70 ml, 1.07 mol) and acetic acid (62 ml, 1.07 mol). The reaction was conducted under stirring for 1.5 h at 100°C, then cooled to room temperature. A solid component was filtered, thoroughly washed with water and dried over P2O5getting 3-[(4-bromophenyl)sulfonyl]propanenitrile (125 g). δH(400 MHz, CDCl3): 7,27-7,22 (4H, m), 2,85 (2H, t, J=7,6), is 2.30 (2H, t, J=7,6).

Stage 2

To a suspension of sodium acetate (54 g, 0.66 mol) and 4-torterolo (90 g, of 0.74 mol) in 1-methyl-2-pyrrolidinone (500 ml) was added 3-[(4-bromophenyl)sulfonyl]propanenitrile (stage 1, 90 g, 0.33 mol) and palladium (II) acetate (1.4 g, 6.2 mmol). A mixture of preparing the Ali in an oil bath at 100°C and was heated to 135°C for 20 minutes. The cooled reaction mixture was diluted with water and EtOAc and filtered through Hyflo®. The organic layer of the filtrate was washed with water (×3), then concentrated in vacuo. The residue was ground into powder with isohexanol, getting 3-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)propanenitrile (73 g). δH(360 MHz, CDCl3): 7,88 (2H, d, J=8.0 a), of 7.69 (2H, d, J=8,3), 7,51 (2H, DD, J=5,6, 8,3), 7,22 (1H, d, J=15,0), 7,10-7,02 (3H, m), 3,39 (2H, t, J=7,7), and 2.83 (2H, t, J=7,7).

Stage 3

To a mixture of 3-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)propanenitrile (phase 2, 75 g, 0.24 mol) in tetrahydrofuran (THF) (1 l) and MeOH (500 ml) was added sodium methylate (13 g, 0.24 mol). The mixture was stirred for 1 h at room temperature, then was diluted with isohexane and Et2O. Solid component was filtered, triturated to powder with isohexane and dried in vacuum, obtaining 4-[(E)-2-(4-forfinal)vinyl]benzosulfimide sodium (66 g). δH(500 MHz, d6DMSO): the 7.65 (2H, t, J=6,8), 7,53 (2H, d, J=7,8), was 7.45 (2H, d, J=7,7), 7,26-to 7.18 (4H, m). m/z (ES-) 261(M-Na)-].

The intermediate product 2

4-[(E)-2-(2,4-differenl)vinyl]benzosulfimide sodium

Was obtained in the same manner as the intermediate product 1, using 2,4-diverticula instead of 4-torterolo on stage 2. δH(400 MHz, d6DMSO): to 7.84 (1H, square, J=8,1), at 7.55 (2H, d, J=8,0), 7,47 (2H, d, J=8,0), 7,32-7,20 (3H, m), 7,15-7,11 (1H, m). m/z (ES-) 279 [(M-Na)-].

Example 1

(1S)-1-[2-({4-[(E)-2-(4-forfinal)Winnie the]phenyl}sulfonyl)phenyl]ethanol

Stage 1

In each of three identical reaction vessels with Emrys microwave heating was added (S)-1-(2-bromophenyl)ethanol (1,67 g, 8.3 mmol), CuI (189 mg, 1.0 mmol), 1,4-dioxane (12,4 ml), N,N'-dimethylethylenediamine (of 0.18 ml, 1.7 mmol) and the dihydrate of sodium iodide (3.1 g, of 16.6 mmol). Each vessel was sealed and heated in a reactor Emrys microwave heated up to 150°C for 2 hours After cooling, the mixture mutually combined and then distributed between water (20 ml) and EtOAc (20 ml). The organic phase was washed with brine (20 ml), dried (MgSO4), filtered and concentrated in vacuum. The obtained crude product was placed in isohexane (50 ml) and kept the solution at -15°C for 16 h, obtaining (S)-1-(2-itfeel)ethanol as a white crystalline solid (4,95 g).

Stage 2

A suspension of (S)-1-(2-itfeel)ethanol (step 1; 4.4 g of 17.7 mmol), intermediate 1 (5,54 g of 19.5 mmol), CuI (10.1 g, to 53.0 mmol) and dimethyl sulfoxide (DMSO) (80 ml) was degirolami repeated evacuation and freed from the N2, and then was heated in an oil bath at 110°C for 75 minutes. The cooled mixture was distributed between a concentrated ammonium hydroxide solution (100 ml) and EtOAc (100 ml), the aqueous phase was extracted with additional EtOAc (50 ml). The organic mixture was washed with water (C ml) and with brine (100 ml), dried (MgSO4), the filter is Wali and concentrated in vacuum. The obtained crude product was purified flash chromatography on silica gel (eluant 25-35-45% EtOAc/isohexane) and then with 5% Et2O/CH2Cl2. Formed foam was stirred with pentane for 1 h, obtaining the pure product as a white amorphous solid (of 3.97 g). This material was recrystallized from a mixture of about 90% MeOH/water, getting colourless crystals; TPL 75°C. δH(500 MHz, d6DMSO): 8,02 (1H, d, J=7,3), 7,81 for 7.78 (5H, m), 7,73-to 7.67 (3H, m), 7,52 (1H, t, J=7,2), the 7.43 (1H, d, J=16.5 in), 7,29 (1H, d, J=16,4), 7,22 (2H, t, J=8,8), 5,44-of 5.40 (1H, m), 5.28 (1H, d, J=4.0)is, of 1.09 (3H, d, J=6,2); m/z (ES+) 365 [(M-OH)+].

Example 2

(1S)-1-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]ethanol

Received as described in example 1, replacing intermediate 1 to intermediate 2. δH(500 MHz, d6DMSO): 8,03 (1H, d, J=7,9), of 7.90-7,80 (6H, m), 7,72 (1H, t, J=7,4), 7,53 (1H, t, J=7,7), 7,40 (2H, square, J=12,7), 7,34-7,28 (1H, m), 7,16 (1H, t, J=8,5), 5,43 of 5.39 (1H, m), and 5.30 (1H, d, J=4.0)is, of 1.09 (3H, d, J=6,2). m/z (ES+) 383 [(M-OH+)].

Example 3

(1S)-1-[2-({4-[(E)-2-(4-forfinal)vinyl]-3-were}sulfonyl)phenyl]ethanol

Stage 1

4-bromo-3-methylbenzenesulfonamide (1,145 g of 4.25 mmol) was added in portions to a solution of sodium sulfite (0,578 g to 2.29 mmol) and sodium bicarbonate (0,749 g, 2.4 mmol) in water (10 ml) at 80°C. the Reaction mixture was heated at 90°C for 3 h the Cooled reaction mixture was evaporated in vacuum topoloveni volume, it was formed precipitate. The precipitate was removed by filtration. The filtrate was further concentrated, then was cooled to 5°C and removed the formed precipitate by filtration. Compound residue was washed with water and dried, obtaining 4-bromo-3-methylbenzenesulfonic sodium (0.54 g).

Stage 2

(1S)-1-[2-({4-bromo-3-were}sulfonyl)phenyl]ethanol was obtained as described in example 1, step 2, using 4-bromo-3-methylbenzenesulfonate sodium instead of intermediate 1.

Stage 3

The reaction vessel with Emrys microwave heating, containing (1S)-1-[2-({4-bromo-3-were}sulfonyl)phenyl]ethanol (71 mg, 0.2 mmol), [(E)-2-(4-forfinal)vinyl]Bronevoy acid (43 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, at 0.020 mmol), tetrahydrofuran (THF) (2 ml) and 2M aqueous sodium carbonate solution (1 ml)was heated in the reactor Emrys with microwave heating at 150°C for 10 minutes. After cooling, the mixture was distributed between EtOAc (15 ml) and water (15 ml), washed the organic phase with brine, dried (MgSO4), filtered and concentrated in vacuum. Formed crude product was purified flash chromatography on silica gel (eluent 30% EtOAc/isohexane), obtaining the target compound as a white solid (45 mg). δH(500 MHz, d6DMSO): 8,01 (1H, d, J=7,9), 7,88 (1H, d, J=8,2), 7,80 (1H, d, J=7,8), 7,73-7,63 (5H, m), 7,52 (1H, t, J=7,6), 7,37 (1H, d, J=16,3), 7,29 (1H, d, J=16,2) 7,22 (2H, t, J=8,7), the 5.45 (1H, s), and 5.30 (1H, s)to 2.46 (3H, s), is 1.11 (3H, d, J=5,9). m/z (ES+) 379 [(M-OH)+].

Example 4

[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]methanol

Stage 1

2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl} sulfonyl)benzaldehyde was obtained in accordance with the method of example 1, step 2, using 2-iodobenzaldehyde instead of (S)-1-(2-itfeel)ethanol and intermediate 2 instead of intermediate 1.

Stage 2

Sodium borohydride (89 mg, 1.8 mmol) was added to a solution of 2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)benzaldehyde (step 1; 233 mg, 0.61 mmol) in MeOH (7 ml) and CH2Cl2(3 ml). After 2 h the mixture was distributed between CH2Cl2(10 ml) and water (10 ml), the phases were separated and was extracted with water part of the additional amount of CH2Cl2(10 ml). The combined organic mixture was then dried (MgSO4), filtered and concentrated in vacuum. By purification with flash chromatography (eluent 40% EtOAc/isohexane) received target compound as a white solid (208 mg). δH(500 MHz, d6DMSO): 8,08 (1H, d, J=7,7), 7,89-7,83 (5H, m), to 7.77 (1H, d, J=7,6), 7,72 (1H, t, J=7,4), at 7.55 (1H, t, J=7,5), 7,42-7,34 (2H, m), 7,33-7,27 (1H, m), to 7.15 (1H, TD., J=2,1, 8,4), of 5.39 (1H, t, J=5,7), 4,69 (2H, d, J= 5,7). m/z (ES+) 369 [(M-OH)+].

Example 5

[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]methanol

Received in accordance with the method Primera when using intermediate 1 instead of intermediate 2. δH(400 MHz, d6DMSO): 8,10 (1H, DD, J=1,0, 7,8), 7,86-7,68 (8H, m), EUR 7.57-of 7.55 (1H, m), 7,44 (1H, d, J=16.5 in), 7,32-7,22 (3H, m), 5,41 (1H, t, J=5,7), 4,72 (2H, d, J=5,7). m/z (ES+) 351 [(M-OH)+].

Example 6

2-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]propan-2-ol

Stage 1

(1S)-1-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]ethanol (example 1; 100 mg, 0.26 mmol), N-methylmorpholin-N-oxide (46 mg, 0,39 mmol), activated molecular sieves with pore size 4Å (100 mg) and CH2Cl2(2.6 ml) were combined under nitrogen atmosphere and was stirred for 20 minutes, then added perruthenate Tetra(n-propyl)ammonium (4.6 mg, of 0.013 mmol). After additional exposure for 20 minutes, the mixture was purified flash chromatography (eluent 40% EtOAc/isohexane)to give 1-[2-({4-[(E)-2-(4 - forfinal)vinyl]phenyl}sulfonyl)phenyl]Etalon in the form of a white solid (84 mg). δH(400 MHz, d6DMSO): 8,10 (1H, d, J=7,8), 7,88 (2H, d, J=8,5), 7,80 (3H, DD, J=0,0, 8,7), 7,72-7,68 (3H, m), a 7.62 (1H, d, J=6,6), 7,46 (1H, d, J=16.5 in), 7,32-7,22 (3H, m), 2,61 (3H, s). m/z (ES+) 380 [MH+].

Stage 2

The stirred solution of 1-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]ethanone (phase 1; 65 mg, 0,17 mmol) in tetrahydrofuran (THF) (1 ml) was treated with methylmagnesium (3 N Et2O; 0.17 ml, 0.51 mmol) at ambient temperature. After 75 minutes, the mixture was distributed between water (20 ml) and EtOAc (20 ml). These phases were separated and the organic phase was dried (MgSO4)shown is ovale and concentrated in vacuum. Formed crude product was purified flash chromatography on silica gel (eluant 35% EtOAc/isohexane). Then the obtained product was washed with hexane, obtaining the target compound as a white solid (53 mg). δH(500 MHz, d6DMSO): of 8.25 (1H, d, J=8,1), 7,71-TO 7.64 (8H, m), 7,53 (1H, t, J=6,1), 7,40 (1H, d, J=16,4), 7,30-7,22 (3H, m), to 4.98 (1H, s), and 1.56 (6H, s). m/z (ES+) 419 [(M+Na)+].

Example 7

2-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]ethanol

Stage 1

In each of the two identical vessels were heated mixture of 2-(2-bromophenyl)ethanol (750 mg, 3.7 mmol), dihydrate sodium iodide (1.39 g, 7.5 mmol), CuI (71,0 mg of 0.37 mmol) and N,N'-dimethylethylenediamine (79,4 μl, 65.8 mg, 0.75 mmol) in 1,4-dioxane (8 ml) to 150°C in the reactor with microwave heating for 4 hours Then two of the reaction mixture are mutually combined and diluted with water (90 ml) and concentrated ammonium hydroxide (20 ml), then was extracted with EtOAc (3×50 ml). The combined organic layers were washed with water (50 ml), then with brine (50 ml), dried (MgSO4) and concentrated in vacuum. It was found that the formed pale yellow oil (1,62 g) is a mixture of 2-(2-itfeel)ethanol and 2-(2-bromophenyl)ethanol in a ratio of 3:1, and it was used further without additional purification. The data for the main components: δH(360 MHz, CDCl3): to 7.84 (1H, d, J=8,2), 7,32-7,24 (2H, m), 6,94-6,86 (1H, m), a 3.87 (2H, ush. C)a 3.0 (2H, t, J=7,0), USD 1.43 (1H, s).

Stage 2

A mixture of 2-(2-itfeel)ethanol and 2-(2-bromophenyl)ethanol (step 1; 200 mg) in a ratio of 3:1 was brought into reactive engagement with the intermediate product 1 (275 mg, 0.97 mmol) and CuI (461 mg, 2.4 mmol) in dimethyl sulfoxide (DMSO) (5 ml) by the procedure of example 1, step 2. Formed crude product was purified flash chromatography on silica gel (eluant 25%, then 40% EtOAc/isohexane), obtaining the target compound as a white solid (65 mg): δH(400 MHz, CDCl3): 8,16 (1H, d, J=8,0), to 7.84 (2H, d, J=8,4), to 7.61-7,37 (7H, m), 7,17 (1H, d, J=16,3), 7,07 (2H, t, J=8,6), 7,00 (1H, d, J=16,3), 3,83 (2H, q, J=6,2), 3,14 (2H, t, J=6,5), 1,99 (1H, t, J=5,7). m/z (ES+) 365 [(M-OH)+].

Example 8

Methyl-2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)benzoate

Stage 1

Methyl-2-[(4-bromophenyl)sulfonyl]benzoate was obtained in accordance with the method of example 1, step 2, using methyl-2-bromobenzoate (2.8 ml, 20 mmol) instead of (S)-1-(2-itfeel)ethanol and dihydrate 4-bromophenylacetate sodium (5.6 g, 20 mmol), instead of intermediate 1, together with CuI (19 g, 100 mmol) and dimethylsulfoxide (DMSO) (40 ml)to give product as a white solid (3.8 g).

Stage 2

1-ethinyl-2,4-differental (9.6 g, 69,5 mmol) was heated to 40°C and was added catecholborane (8,3 g of 69.2 mmol). The dark reaction mixture was stirred at 40°C for 3 h, then stirred at 80°C for 24 h Then the mixture of the OHL who was waiting to room temperature and kept for 2 days. After this was added water and was separated educated dark solid is filtered. This solid was washed on the filter with toluene, receiving the solid residue beige color, which was identified as [(E)-2-(2,4-differenl)vinyl]baronova acid and a mixture of anhydrides (3.8 g).

Stage 3

The target compound was obtained in accordance with the method described in example 3, step 3, using methyl-2-[(4-bromophenyl)sulfonyl]benzoate (step 1) instead of (1S)-1-[2-({4-bromo-3-were}sulfonyl)phenyl]ethanol and [(E)-2-(2,4-differenl)vinyl]Bronevoy acid (step 2) instead of [(E)-2-(4-forfinal)vinyl]Bronevoy acid. δH(500 MHz, d6DMSO): by 8.22-to 8.20 (1H, m), 7,94-7,80 (7H, m), 7,69-7,63 (1H, m), 7,44 (1H, d, J=16,4), 7,39 (1H, d, J=16,4), 7,35-7,30 (1H, m), 7,19-to 7.15 (1H, m), a 3.87 (3H, s). m/z (ES+) 383(M-MeO)+].

Example 9

Methyl-2-({4-[(E)-2-(4-forfinal)vinyl] phenyl}sulfonyl)benzoate

A suspension of methyl 2-iodobenzoate (8,8 ml, 60 mmol), intermediate 1 (20.4 g, 72 mmol) and CuI (17.1 g, 90 mmol) in dimethyl sulfoxide (DMSO) (300 ml) was degirolami repeated evacuation and freed from the N2, and then was heated in an oil bath at 100°C for 4 hours, the Cooled mixture was distributed between water (1 l) and EtOAc (600 ml) and the thick suspension was stirred for 10 minutes, then filtered through Hyflo filter®. The residue was extracted with EtOAc (400 ml), the filtrate was moved the separating funnel, containing an aqueous solution of ammonium hydroxide (200 ml). Educated, the phases were separated and the aqueous phase is extracted with EtOAc (twice). The combined organic fractions were washed with water, then with brine, dried (MgSO4), filtered and concentrated in vacuum. Formed crude product was placed on silica gel and purified flash chromatography (eluant 1% Et2O/CH2Cl2), after which the resulting material was recrystallized from 50% EtOAc/hexane, obtaining the target compound as colorless crystals (13,9 g); so pl. 125°C. δH(500 MHz, d6DMSO): by 8.22-to 8.20 (1H, m), to 7.93 (2H, d, J=8,5), 7,84 for 7.78 (4H, m), 7,72-7,66 (3H, m), 7,46 (1H, d, J=16,4), 7,30 (1H, d, J=16,4) 7,27-7,21 (2H, m), 3,86 (3H, s). m/z (ES+) 365 [(M-MeO)+].

Example 10

Methyl-3-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)benzoate

Received in accordance with the method of example 8, step 1, using methyl-3-bromobenzoate instead methyl-2-bromobenzoate and intermediate 1 instead dihydrate 4-bromophenylacetate sodium. δH(500 MHz, d6DMSO): 8,42 (1H, s), of 8.25 (2H, DD, J=8,0, 12,9), 7,98 (2H, t, J=8,0), 7,83-7,79 (3H, m), of 7.70 (2H, DD, J=5,7, 8,7), was 7.45 (1H, d, J=16,4), 7,31-of 7.23 (3H, m), 3,90 (3H, s). m/z (ES+) 397 [MH+].

Example 11

Methyl-2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)-3-methylbenzoate

Received in accordance with the method of example 9 using methyl-2-iodine-3-methylbenzoate instead methyl-2-IO is benzoate. δH(400 MHz, d6DMSO): to 7.95 (2H, d, J=8,5), a 7.85 (2H, d, J=8,6), 7,71-to 7.67 (3H, m), of 7.48 (3H, DD, J=6,7, 12,9), 7,31 (1H, d, J=16.5 in), 7,25 (2H, t, J=8,9), the 3.89 (3H, s), 2,43 (3H, s). m/z (ES+) 433 [(M+Na)+].

Example 12

2-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]-1H-imidazol

Stage 1

2-(2-bromophenyl)-1H-imidazole (WO 9407486; 1.0 g, 4,48 mmol) was dissolved in tetrahydrofuran (THF) (11 ml) and dimethylformamide (DMF) (11 ml) and cooled to 0°C. Then was added sodium hydride (60%dispersion in mineral oil, 197 mg, is 4.93 mol) and the reaction was performed under stirring for 20 minutes. Then added 2-(trimethylsilyl)ethoxymethylene (0,79 ml, is 4.93 mmol) and the reaction was performed under stirring over night at room temperature. The reaction was suppressed by the addition of MeOH, after which the mixture is distributed between water and Et2O. the Organic layer was dried (MgSO4) and concentrated in vacuo, the residue was purified column flash chromatography, obtaining 2-(2-bromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole in the form of a white with a yellowish or grayish tint solid (1.5 g).

Stage 2

2-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole was obtained in accordance with the method of example 1 using 2-(2-bromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (step 1) instead of (S)-1-(2-itfeel)ethanol and intermediate product 2 instead of the intermediate product 1.

Stage 3

A solution of 2-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (step 2, 110 mg) in CH2C12(5 ml) was treated triperoxonane acid (5 ml) and stirred the solution for 16 h, then concentrated in vacuo and was distributed between saturated aqueous NaHCO3(20 ml) and EtOAc (20 ml). The resulting phases were separated and the organic phase was dried (MgSO4), filtered and concentrated in vacuum. The residue was purified flash chromatography on silica gel (eluant 75% EtOAc/isohexane)to give a colorless oil, which was utverjdali processing Et2O. the Solid was washed with 50% EtOAc/isohexane and dried, obtaining the target compound as a white solid (47 mg). δH(500 MHz, d6DMSO): 12,11 (1H, s), of 8.25 (1H, t, J=4,6), a 7.85 (1H, square, J=8,1), to 7.77-7,71 (2H, m), of 7.69 (2H, d, J=8,4), 7,58 (2H, d, J=8,4), 7,51 (1H, t, J=4,4), 7,39-7,29 (3H, m), 7.23 percent (1H, s), to 7.15 (1H, MD, J=2,5, 8,5), 6,94 (1H, t); m/z (ES+) 422 [MH+].

Example 13

2-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]-1H-imidazol

Received in accordance with the method of example 9 using 2-(2-bromophenyl)-1H-imidazole (WO 9407486; 1.0 g, 4,48 mmol) instead of methyl-2-iodobenzoate. δH(500 MHz, CDCl3): 11,08 (1H, s), 8,35 (1H, d, J=8,0), 8,02 (1H, d, J=7,7), 7,69-to 7.67 (1H, m), 7,60 (1H, t, J=7,7), 7,46-7,38 (6H, m), 7,18 (1H, s), 7,10-7,03 (4H, m), 6.89 in (1H, d, J=16,3). m/z (ES+) 405 [MH+].

Example 14

2-[2-({4-[(E)-2-2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]-1,3,4-oxadiazol

Stage 1

Methyl-2-[(4-bromophenyl)sulfonyl]benzoate (example 8, step 1; 150 mg, 0.46 mmol) and hydrazinehydrate (0.06 ml, 2.32 mmol) was stirred together at room temperature for 1.5 h, then at 90°C for 2 hours, the Excess hydrazine was removed under vacuum and the residue was dissolved in triethylorthoformate (4.6 ml) with a catalytic camphorsulfonic acid and the mixture was heated at 90°C during the night. The cooled reaction mixture was distributed between EtOAc and water, washed the organic layer with brine and evaporated in vacuum. The residue was purified column flash chromatography on silica gel (eluent 50% EtOAc/isohexane)to give 2-{2-[(4-bromophenyl)sulfonyl]phenyl}-1,3,4-oxadiazole (60 mg, 35%). δH(400 MHz, d6DMSO): 9,42 (1H, s), 8,35-of 8.33 (1H, m), 7,97-to $ 7.91 (2H, m), 7,86-to 7.84 (3H, m), 7,80 for 7.78 (2H, m).

Stage 2

The target compound was obtained in accordance with the method of obtaining intermediate 1, step 2, using 2-{2-[(4-bromophenyl)sulfonyl]phenyl}-1,3,4-oxadiazole (step 1) instead of 3-[(4-bromophenyl)sulfonyl]propanenitrile and 2,4-diverticula instead of 4-torterolo. δH(500 MHz, d6DMSO): to 9.45 (1H, s), 8,35 (1H, d, J=7,8), 7,97-A 7.85 (8H, m), 7,47-7,31 (3H, m), 7,17 (1H, t, J=8,6). m/z (ES+) 425 [MH+].

Example 15

2-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]-1,3,4-oxadiazol

Was obtained from methyl 2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)benzoate (example 9) in accordance with the laws the AI with the method of example 14, step 1. δH(400 MHz, d6DMSO): 9,48 (1H, s), at 8.36 (1H, DD, J=1.3, 8,0), 8,00-of 7.82 (7H, m), 7,74-of 7.70 (2H, m), 7,49 (1H, d, J=16.5 in), 7/34-7,24 (3H, m); m/z (ES+) 407 [MH+].

Examples 16-25

The following compounds were obtained by methods which are similar to the methods used in examples 12 and 13:

ExampleR1Zm/z (ES+) [MH+]
16Hthe thiazole-2-yl422
17H1-Me-imidazol-2-yl437
18Hpyrazole-3-yl405
19Fpyrazole-3-yl423
20F1,2,4-triazole-3-yl424
21H1,2,4-triazole-3-yl406
22 oxazol-2-yl424
23F1,2,3-triazole-4-yl424
24F2-pyridyl434
25H3-pyridyl416

1. The compound of the formula I

or its pharmaceutically acceptable salt, where
n is 0 or 1;
R1denotes H or F;
R2stands With1-4alkyl;
R7denotes N or C1-4alkyl; and
Z denotes hydraxis1-6alkyl or C1-6alkoxycarbonyl, or 5 - or 6-membered heteroaromatic ring, which refers to aromatic ring having the specified number of atoms, of which at least one is N, O or S, and the remainder are carbon atoms, and which optionally is methyl substitute group.

2. The compound according to claim 1, in which Z denotes hydraxis1-6alkyl.

3. The compound according to claim 1, in which Z represents C1-6alkoxycarbonyl.

4. The compound according to claim 1, in which Z denotes a 5 - or 6-membered heteroaromatic ring, which refers to the aromatic is alzam, having the specified number of atoms, of which at least one is N, O or S, and the remainder are carbon atoms, and which optionally has a metal replacement group.

5. The compound according to any one of the preceding paragraphs, in which Z is in the ortho-position relative to the sulfonic component in the formula I.

6. The compound according to claim 1, selected from
(1S)-1-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]ethanol;
(1S)-1-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]ethanol;
(1S)-1-[2-({4-[(E)-2-(4-forfinal)vinyl]-3-were}sulfonyl)phenyl]ethanol;
[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]methanol;
[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]methanol;
2-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]propan-2-ol;
2-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]ethanol;
methyl-2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)benzoate;
methyl-2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)benzoate;
methyl 3-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)benzoate;
methyl-2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)-3-methylbenzoate;
2-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]-1H-imidazole;
2-[2-({4-[(E)-2-(4-forfinal)vinyl]phenyl}sulfonyl)phenyl]-1H-imidazole;
2-[2-({4-[(E)-2-(2,4-differenl)vinyl]phenyl}sulfonyl)phenyl]-1,3,4-oxadiazole;
and
2-[2-({4-[(E)-2-(4-torfin the l)vinyl]phenyl}sulfonyl)phenyl]-1,3,4-oxadiazole;
and its pharmaceutically acceptable salts.

7. Pharmaceutical composition for treating or preventing disorders caused by the activity of the receptor 5-HT2Acontaining the compound according to any one of the preceding paragraphs and a pharmaceutically acceptable carrier.

8. The use of compounds according to any one of claims 1 to 6 for the manufacture of a medicinal product for the treatment of disorders caused by the activity of the receptor 5-HT2A.

9. The method of obtaining the compounds of formula I according to claim 1, comprising the reaction of a derivative of bromo - or odensala (9) with salt silencelevel acid (10):

where X2denotes Br or I, a R1, R2, R7n and Z are defined in claim 1.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-aminocyclohexanol of the general formula (I) being optionally as their physiologically acceptable salts and first of all physiologically compatible acids. In compound of the general formula (I) R1 and R2 mean independently of one another hydrogen atom (H) or (C1-C8)-alkyl that can be saturated or unsaturated but both R1 and R2 can't mean simultaneously H, or residues R1 and R form a ring in common and mean (CH2)3-6; R2 means unsubstituted phenyl or phenyl substituted with halogen atom that is added through saturated or unsaturated, branched or linear (C1-C4)-alkyl group; R4 means heteroaryl chosen from 5-membered heteroaryl wherein heteroatoms are chosen from nitrogen, oxygen or sulfur atoms and each of these atoms is condensed with benzene ring and means unsubstituted or monosubstituted (C1-C8)-alkyl; -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7 wherein R6 represents H; R7 represents phenyl that can be unsubstituted or mono- either multi-substituted with halogen atoms. Also, invention relates to a method for synthesis of compounds of the formula (I) and a medicinal agent based on thereof. Synthesized compounds can be sued for preparing a medicinal agent designated for treatment of pain being first of all acute, visceral, neuropathic or chronic pain, and to a medicinal agent designated for treatment of diseases mediated by function of ORL1-receptor, for example, such as fear state, epilepsy, cardiovascular diseases.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and drug.

10 cl, 1 tbl, 21 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to arylsulfonyl derivatives of the formula (I): , wherein Ar means naphthyl or phenyl substituted optionally with halogen atom or (C1-C6)-alkoxy-group; R1 means (C1-C6)-alkyl; R2 means hydrogen atom or (C1-C6)-alkyl, or their pharmaceutically acceptable salts or solvates. Proposed compounds show affinity to HT6 receptors. Also, the claim describes pharmaceutical compositions comprising indicated compounds, their using as therapeutic agents and a method for their preparing. Compounds can be useful in treatment of some disturbances in the central nervous system (CNS).

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

12 cl, 1 tbl, 12 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

The invention relates to omega-Amida N-arylsulfonamides formula I

and/or stereoisomeric forms of the compounds I and/or physiologically acceptable salts of the compounds I where R1means phenyl, phenyl, substituted once with halogen, the rest of the heterocycle of the following groups: morpholine, pyrrolidine; R2means N; R3means -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen to which they are bound, form a residue of formula IIa, IIe

moreover, in formula IIa, IIe q indicates an integer of zero or 1, Z denotes the carbon atom or a covalent bond, and R8means a hydrogen atom or halogen, or R3means -(C1-C4)-alkyl-C(O)-Y, where Y means the remainder of the formula IIC or IId

moreover, in formulas IIc and IId, R8means H or halogen, R9means H, or R3means -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)about-N(R4)-R5and R9has the above values, means the integer 2 and R is substituted by-O-, And means covalent bond, B means -(CH2)m- where m is zero, X is-CH=CH-

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: organic chemistry, chemistry of heterocyclic compounds.

SUBSTANCE: invention relates to heterocyclic compounds possessing the potential biological activity, in particular, to a method for synthesis of 2-methyl-5-substituted 1,3,4-oxadiazoles. Invention describes a method for synthesis of 2-methyl-5R-substituted 1,3,4-oxadizoles wherein R means aryl, hetaryl or alkyl by the cyclization reaction of tributylstannyl derivatives of tetrazole in the presence of aliphatic acid anhydrides by the following scheme: . Method provides preparing 2-methyl-1,3,4-oxadiazoles substituted with bulky substitutes at position 5 by simplified technology.

EFFECT: improved and simplified method of synthesis.

8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 5-amidino-2-hydroxybenzenesulfonamide of the general formula (I): wherein R2 means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (A): wherein (A) means -COORA, -CONRBRC, 3-7-membered monocyclic heterocycloalkyl group comprising one or two heteroatom in ring chosen from atoms N, O, S that can comprise oxo-group and 5-6-membered monocyclic aromatic heterocyclic group comprising one-three heteroatoms in ring chosen from atoms N, O, S that can comprise oxo-group or lower alkyl wherein RA means hydrogen atom (H), 3-7-membered monocyclic aliphatic alkyl group, lower alkyl that can comprises a substitute chosen from the group (i) wherein (i) means -COORA1 wherein RA1 means hydrogen atom (H), -OCORA2 wherein RA2 means lower alkyl group, -OCOORA3 wherein RA3 means lower alkyl, -ORA4 wherein RA4 means hydrogen atom (H), lower alkyl -CONRA5RA6 wherein RA5 and RA6 mean independently hydrogen atom (H), lower alkyl, or -NRA5RA6 forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; wherein RB and RC mean independently hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (ii), or -NRBRC forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; (ii) means -COORB1 wherein RB1 means hydrogen atom (H), lower alkyl; T means oxygen atom (O), sulfonyl group; or TR1 means -SO2NRB3RC3 wherein RB3 and RC3 means independently hydrogen atom (H), lower alkyl; R2 means lower alkyl, phenyl that can comprise one-three substitutes chosen from the group (B) wherein (B) means halogen atom, -COORE, sulfamoyl, lower alkylsulfonyl wherein RE means lower alkyl; Q means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (D) wherein (D) means 5-6-membered monocyclic aromatic heterocyclic group that can comprise one-three heteroatom chosen from atoms N, O, S that can comprise a substitute chosen from the group (iv) wherein (iv) means oxo-group, lower alkyl; Z means hydrogen atom (H), hydroxyl group (OH), -COORN wherein RN means lower alkyl that can comprise a substitute chosen from the group (viii) wherein (viii) means -OCOR5 wherein RN5 means lower alkyl that can comprise -OCORN51 wherein RN51 means lower alkyl; or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit activated factor X in blood coagulation system that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and compositions.

12 cl, 5 tbl

The invention relates to new substituted phenyl derivatives, which are strong blockers chlorine ion channels and as such are useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and to reduce the intraocular pressure for the treatment of disorders such as glaucoma

The invention relates to a new above-mentioned compounds, method of their production and the means of containing this compound, useful for combating fungi and insect pests

FIELD: chemistry.

SUBSTANCE: there is described a single-step method for synthesis of 1-(β-phenylethyl)-4-(para-dimethylaminobenzylidenamino)-1,2,4-triazole bromide with high output without release of intermediate products using one solvent. In accordance with the described method, 4-amino-1,2,4-triazole is dissolved in butanol, a solution of β-bromoethylbenzene is added to the butanol, the mixture is boiled for 6-8 hours, cooled to 50-60°C, a solution of para-dimethylaminobenzaldehyde is added, as well as a catalytic amount of concentrated hydrobromic acid, the mixture is kept at 50-60°C for 3-5 hours with subsequent cooling to room temperature; the precipitate is filtered, washed with diethyl ether or butanol and dried in air.

EFFECT: design of an efficient method of producing heterocyclic compounds.

2 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel malononitryl derivatives of formula (I), which can be applied to fight pest insects. In formula (I) R1 represents hydrogen atom; R2 represents hydrogen atom; R represents hydrogen atom; R4 represents C1-C5-alkyl group substituted with at least one halogen atom, C2-C5-alkenyl group; R5 represents hydrogen atom, halogen atom, C1-C5-alkyl group; at least one of X1, X2 and X3 values represents CR6, the other represent nitrogen atoms; R represents hydrogen atom, halogen atom, cyanogroup, nitrogroup, formyl group, C1-C5-alkyl group optionally substituted with at least one halogen atom, C1-C5-alkyltiogroup, substituted with at least one halogen atom, C2-C6-alkylcarbonyl group substituted with at east one halogen atom, C2-C5-alkoxycarbonyl group or group (CH2)mQ, where m = 0, and Q stands for phenyl; and in case when one of R5 and R6 is bonded with two atoms in adjacent positions or two R6 are bonded with two atoms in adjacent positions, they can be bonded to each other in end positions with formation of C2-C6-alkandiyl group, or C4-C6-alkenediyl group. Invention also relates to composition and method used to fight pest-insects.

EFFECT: obtaining novel malononitryl derivatives of formula (I), which can be applied to fight pest-insects.

11 cl, 90 ex

FIELD: pharmacology.

SUBSTANCE: described are novel derivatives of triazole of general formulas (I) or (II) or their pharmaceutically acceptable salts, where R1 represents H, C1-C6-alkyl, or group CONRaRb, Ra represents hydrogen or C1-C6-alkyl; R2 represents H or C1-C6-alkyl; R3 represents H or F, CI, Br or I; R4 represents H; R5 represents CF3 or O-(C1-C4)alkyl, three times substituted with F; R6 and R7 each independently represents H, F or CF3, on condition that one of R6 and R7 always represents H.

EFFECT: application of said compounds for preparing medication for treatment and prevention of pain or pain-induced disturbances; pharmaceutical composition containing novel compounds, and method of their obtaining.

9 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention claims substituted O-[ω-(azol-1-yl)alkyl]-N-phenylthiocarbamates of formula I: where Z=CH, N, R=H, Alk, AlkO, Hal etc., m=1, 2, 3, n=0-5, obtained by acylation of ω-(azol-1-yl)alkanols of formula II by substituted phenylisothiocyanates in polar aprotonic solvents in the presence if tertiary amines. Invention allows for more efficient suppression of phytopathogenic fungi in vitro than by such reference material as triadimefon, due to application of fungicide composition including substituted O-[ω-(azol-1-yl)alkyl]-phenylthiocarbamates I, such as O-(imidazole-1-ylmethyl)-N-(2-methyl-phenyl)thiocarbamates.

EFFECT: efficient suppression of phytopatogenic fungi growth.

4 cl, 5 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: in substituted N-[ω-azol-1-yl)alkyl]benzolsulfamides , X and Y represent CH-group, n stands for 2 or 4, R - similar or different stand for alkyl group with number of carbon atoms from 1 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, n stands for 3, R - similar or different stand for alkyl group with number of carbon atoms from 2 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 2 to 4, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, where X stands for CH-group, Y stands for nitrogen atom, n stands for 2, R - similar or different stand for alkyl group with number of carbon atoms from 2 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, n stands for 3 or 4, R - similar or different stand for alkyl group with number of carbon atoms from 1 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, where X and Y simultaneously are chain C-CH=CH-CH=CH-C constituting together annelated with heterocycle ring, n stands for whole number from 2 to 4, R - similar or different stand for alkyl group with number of carbon atoms from 1 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, methods of their obtaining and application as anti-aggregation preparations. Anti-aggregation activity of N-[ω -azol-1-yl)alkyl]benzolsulfamides, of general formula I, for instance, hydrochloride of N-[4-(1H-triasol-1-yl)butyl]-n-methylbenzolsulfumide (35) is higher than of etalon dazoxyben.

EFFECT: increase of anti-aggregation activity.

4 cl, 5 tbl, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to substituted ω-azolylalkane anilides. Invention describes substituted ω-(1H-azol-1-yl)-N-phenylalkaneamides of the general formula (I): wherein Z and Y mean nitrogen atom of CH-group, or they represent the chain -C-CH=CH-CH=CH-C- simultaneously and forming in common an anellated ring; n means a whole number from 1 to 3; Rm are similar or different and mean hydrogen, halogen atom, alkyl group with number of carbon atoms from 1 to 4, alkoxy group, alkylenedioxy group, benzyloxy group, perfluoroalkyl group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group, carboxyl group, halogenphenylthio group, halogenbenzoyl group; m means a whole number from 0 to 5, their salts with acids. Also, invention describes methods for synthesis of compounds of the formula (I) and their using as anti-aggregative preparations. Invention provides synthesis of novel compounds possessing the useful biological properties.

EFFECT: valuable properties of compounds, improved method of synthesis.

8 tbl, 11 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-(azol-1-yl)ethaneamines that are used as the parent compounds in preparing biologically active compounds of medicinal and agriculture designation. Method for synthesis of 2-(azol-1-yl)ethaneamines of the general formula (I): wherein R1 means hydrogen atom or alkyl group comprising from 1 to 6 carbon atoms; each Z and X means independently -CH or nitrogen atom (N); or Z and X mean in common group -C-CH=CH-CH=CH-C that forms a system anellated with azole cycle involves the alkylation reaction of azole compounds wherein R1, Z and Y have the same values as in the formula (I) with oxazolines of the formula (II): wherein R2 means alkyl group comprising from 1 to 6 carbon atoms, phenyl, halogenphenyl group in the presence of Lewis acid or protonic acid to yield N-[2-(azol-1-yl)ethyl]alkaneamides of the formula (III): wherein R1, R2, Z and X have above given values followed by their hydrolysis in the presence of acids or bases in polar solvent medium at temperature 60-120°C.

EFFECT: improved method of synthesis.

5 cl, 17 ex

FIELD: organic chemistry, fungicides.

SUBSTANCE: invention describes substituted 1-(pyridinyl-2)-2-azolylethanols of the general formula (I): wherein R means hydrogen atom, direct or branched alkyl with 1 to 8 carbon atoms, cycloalkyl with from 3 to 8 carbon atoms; X means nitrogen atom or CH-group. Also, invention relates to a method for synthesis of these compounds and a fungicide composition that contains compound of the formula (I). Invention provides expanding assortment of fungicides for carrying out the effective control of harmful fungi.

EFFECT: valuable fungicide properties of compounds and composition.

5 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel triazole derivative of the general formula (I): wherein R1 represents phenyl group optionally substituted with one or two groups chosen from (C1-C6)-alkyl group, (C1-C6)-halogenalkyl group, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkoxy-group, halogen atom, nitro-group or cyano-group, styrenyl group, (C1-C6)-alkoxystyrenyl-group or pyridyl group; R2 represents methyl or amino-group; A and B are carbon atoms; C and D represent independently carbon or nitrogen atom, and its nontoxic salt and pharmaceutical composition based on thereof. Also, invention relates to methods for synthesis of novel compounds, novel intermediate substances of the formula: wherein R2, A, B, C and D have above given values; n means a whole number from 0 to 2, and to a method for their synthesis. Compounds of the formula (I) possess anti-inflammatory activity and can be used potentially in treatment of fever, pain and inflammation.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 2 tbl, 50 ex

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