Derivatives of indole, the method of production thereof, and pharmaceutical composition

 

(57) Abstract:

The invention relates to a derived indole of General formula (I)

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or its physiologically acceptable salt, or metabolically labile ether complex, where R is chlorine in positions 4 and 6 of the indole ring, R2represents phenyl, possibly substituted by one or two groups selected from fluorine, trifloromethyl, lower alkyl, alkoxy, hydroxy and nitro group, X represents NH. Methods of obtaining these derivatives include the interaction of the indole, including carboxyamide group CR4O, where R4hydrogen or C1-C4-alkyl, ilida phosphorus formula

(R5)3P=CH-COXR2or (R7O)2OP=CR6-COXR2,

where R5- alkyl or phenyl; R6is hydrogen or C1-C4-alkyl; R7- C4-C4alkyl, and X and R2above. The obtained indole derivatives as active ingredients included in pharmaceutical compositions having the property antagonist amino acid, excitatory NMDA receptor complex. 4 C. and 9 C.p. f-crystals, 2 tab.

The invention relates to new derivatives of indole, to methods p is t, it refers to a derivative of indole, which are the strong and specific antagonists of excitatory amino acids.

U.S. patent N 4960786 reveals that certain well-known 2-carboxy indole derivatives are antagonists of excitatory amino acids EP-A 0396124, also States that certain 2-carboxy indole derivatives have therapeutic efficacy in the treatment of disorders of the Central nervous system (CNS), due to neurotoxic damage or neurodegenerative diseases. In EP-0394905 A2 discloses derivatives of 2-carboximide with similar claimed compounds activity and containing farbkomposition.

Now found a new group of 2-carboxyester derivatives, which have a very strong and specific antagonistic activity against insensitive to strychnine plot (site) binding of glycine, localized on the NMDA receptor complex.

Thus, this invention provides a compound of formula (I)

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or a salt, or metabolically labile ester, where R represents a group selected from: halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, triptoreline, nitro, the l or an integer of 1 or 2.

A represents ethnicgroup or optionally substituted ethinyl, or cyclopropyl group;

X represents-O - or NH;

R2is airgroup and, when X is an oxygen atom, R2may also represent a hydrogen atom or alkyl group.

Compounds represented by formula (I) can exist in more than one isomeric form. Thus, when group A in the compounds of formula (I) is optionally substituted ethynyl or optional substituted cyclopropyl, there may be CIS - and TRANS-isomers and the invention includes all such isomers and mixtures thereof.

When used in medicine, the salts of the compounds of formula (I) should be physiologically acceptable to do this. However, other salts can be used to prepare compounds of formula (I) or their physiologically acceptable salts. Therefore, unless otherwise stated, references to salts include physiologically acceptable salts and physiologically acceptable salts of the compounds of formula (I).

Suitable physiologically acceptable salts of the compounds of the invention include basic salts of accession and where they are appropriate, salts accession acids.

Mall or salt of an alkali metal, such as salts of sodium, potassium, calcium, magnesium and ammonium, derived from amino acids (e.g. lysine or arginine) and organic basic (for example, procaine, phenylendiamin, ethanolamine, diethanolamine and N-methyl glucosamine).

You should take into account that the compound of formula (I) can be obtained in vivo (in a living organism) by the metabolism of a suitable prodrug. Such prodrugs can be, for example, physiologically acceptable metabolities labile esters of compounds of General formula (I). These esters can be obtained by esterification, for example, any carboxylic acid groups in the initial compound of General formula (I) with advanced protection, where appropriate, any other reactive groups present in the molecule, and subsequent removal of the protection, if required. Examples of such metabolities unstable esters include C1-4alkyl esters, e.g. the methyl or ethyl ethers, substituted or unsubstituted aminoacylase esters (for example, aminoacylase, 2-(N, N-diethylamino) ethyl, or 2-(4-morpholino) ethyl esters) or aryloxyalkyl esters, such as acyloxymethyl Il 1-acyloxyacyl, for example: pivaloyloxymethyl, 1-pivaloyloxymethyl, acetoxy the 1-isopropoxycarbonyloxymethyl, cyclohexylcarbodiimide, 1-cyclohexyloxycarbonyloxy ether, cyclohexyloxycarbonyloxy, 1-cyclohexyloxycarbonyloxy, 1-(4-tetrahydropyranyloxy) or 1-(4-tetrahydropyranyloxy).

Preferred metabolities labile esters of compounds of formula (I) include C1-4alkalemia esters, more particularly methyl or ethyl, aminoacylase esters, more specifically 2-(4'-morpholino) ethyl, or acyclically esters, such as acetoxymethyl, evolocity, 1-cyclohexyloxycarbonyloxy or 1-(4-tetrahydropyranyloxy)ethyl.

The compounds of formula (I) and salts and metabolities labile esters may form a solvate, for example hydrates, and the invention includes such a solvate.

In the compounds of formula (I), the group R can be in any of four possible positions on the condensed benzene ring, and when m is 2, the two R groups may be the same or different.

The term alkyl in the sense as it is used here as a group or part of a group refers to an alkyl group with a linear or branched chain containing from 1 to 4 carbon atoms. Examples of such groups include ethicsa to the fluorine atom, chlorine or bromine. The term optionally substituted ethynyl means atenolop optionally substituted by 1 or 2 alkyl groups, such as methylgroup, and includes both CIS-and TRANS-conformation. Examples of such groups include ethynyl, 1 - methylethenyl, 2-methylethenyl and/or 1,2-dimethylethanol.

The term optionally substituted cyclopropyl means cyclopropyl optionally substituted by 1, 2 or 3 accelgroup, such as methylgroup.

For group R2the term aryl means an optionally substituted phenyl group, or a 5 or 6 membered heteroaryl group, in which 5-membered heteroaryl group contains 1 or 2 heteroatoms selected from oxygen, sulfur or nitrogen, and 6-membered heteroaryl group contains 1 or 2 nitrogen atom. Examples of suitable heteroaryl groups include furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl and pyrimidinyl.

The term substituted phenyl refers to a phenyl group containing up to three substituents selected from : halogen, C1-4alkyl, C1-4alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, triptoreline, hydroxy, cyano, nitro, amino, SO2R1or COR1when there is more than one same formula (I) are those compounds where R is chlorine, m is 1 or 2 and R is 4 and/or 6 positions, and especially m is 2.

When A is optionally substituted by atenolop it is preferably in the E conformation.

When the group R2represents a substituted phenyl group, preferably phenyl is used by the component substituted by one or more groups selected from : alkoxy, alkyl, amino, alkylamino, dialkylamino, fluoro, chloro, hydroxy, nitro, trifluromethyl or COR1where R1represents hydroxy or methoxy.

A preferred class of compounds of formula (I) are those compounds where R2represents phenyl or phenyl substituted by one or two groups selected from : fluorine, trifloromethyl, alkyl, for example methyl or isopropyl, hydroxy, alkoxy or nitro, or especially R2is phenyl.

In addition, the preferred class of compounds of formula (I) are compounds where X is NH.

A preferred group of compounds of formula (I) are those compounds in which R is chlorine and m is 1 or more, preferably 2, X is NH or O and R2- optionally substituted phenyl group. Within this group the most FAV is soedinenii formula (I) are those compounds in which A represents optionally substituted by cyclopropyl or in the particular case of ethnicgroup or replaced ethnicgroup, such as 1 - methylethenyl. Within this group, particularly preferred compounds include those compounds in which X is NH, and R2represents optionally substituted phenyl, and especially phenyl.

For compounds of formula (I), where A represents an unsubstituted atenolop, preferred compounds of this invention include those compounds in which X is NH, R2represents optionally substituted phenyl and the group A is TRANS (E) configuration. Within this preferred group of compounds, especially preferred compounds include those compounds in which R2represents a phenyl group substituted by one or two groups selected from: fluorine, trifloromethyl, methyl, isopropyl, hydroxy, alkoxy such as methoxy or ethoxy, or nitro.

Especially preferred compound of the invention, in particular due to its potent and selective effects on the strychnine-insensitive binding site glycine, in combination with a very advantageous bioavailability is (E) -3-[2-(forcarbon the ethers. Preferred salts of the compounds include the salts of potassium and especially sodium. Preferably metabolic labile esters of this compound include ethyl and 2-(4-morpholino) ethyl esters.

In addition, the most preferred compounds include:

3-[2-(phenylcarbamoyl)ethinyl] -4,6-dichlorobenzo-2-carboxylic acid, physiologically acceptable salts and metabolically labeline esters;

3-[2-(phenylcarbamoyl)propenyl]-4,6-dichlorobenzo-2-carboxylic acid, physiologically acceptable salts and metabolities labile esters;

Other most preferred compounds include:

(E)-3-[2-(4-ethoxyphenylurea)ethynyl] -4,6-dichlorobenzo-2 - carboxylic acid;

(E)-3-[2-(2-hydroxy-5-nitrophenylamino)ethynyl)] -4,6 - dichlorobenzo-2-carboxylic acid;

(E)-3-[2-(2-methyl-4-methoxyphenylacetyl)ethynyl)] -4,6-dichlorobenzo - 2-carboxylic acid;

(E)-3-[2-(2-isopropylaminocarbonyl)ethynyl)] -4,6-dichlorobenzo-2 - carboxylic acid;

(E)-3-[2-(2,4-diftorhinolonom)ethynyl)] -4,6-dichlorobenzo-2 - carboxylic acid;

(E)-3-[2-(3,4-dimethoxycinnamoyl)ethynyl)] -4,6-dichlorobenzo-2 - carboxylic acid;

and their physiologically acceptable salts, for example sodium or caioli are antagonists of excitatory amino acids. More specifically, they are potent antagonists against strychnine - insensitive binding site glycine with the NMDA receptor complex. As such, they are powerful antagonists of the NMDA receptor complex. In addition, the compounds of the invention find a favorable activity profile, including a good bioavailability. Therefore, these compounds are useful in the treatment or prevention of neurotoxic damage or neurodegenerative diseases. Thus, the compounds are useful for treatment of neurotoxic injury, followed by cerebral attack, thromboembolitic attack, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, anesia, hypoxia, anoxia, cardiac arrest with perinatal asphyxia. The compounds are useful in the treatment of chronic neurodegenerative diseases such as Huntingdon disease a, ad - presenilny dementia, amyotrophic lateral sclerosis, a type of Glutaric acidemia, dementia, multiple heart attacks, epilepsy, injuries injuries (e.g. spinal cord injury), viral infection causing neurodegeneration (for example, Spiewania irritable bladder, drug dependency, including autism symptoms from alcohol, cocaine, narcotics, nicotine, benzodiazepine.

Potent and selective effects of compounds of the invention on the strychnine-insensitive binding site glycine, located on the NMDA receptor complex can be easily determined by conventional test methods.

Thus, the ability to communicate with a plot of the strychnine-insensitive glycine binding was determined using techniques Kishimoto et al., J. Neurochem. 1981, 37, 1015 - 1024. The selective action of the compounds of the invention on the strychnine-insensitive binding site glycine was confirmed by studies on other known ionotropic excitatory amino acid receptors. Thus, we have found that the compound of the invention finds a small affinity or lack of it to the cocaine receptor acid (cocaine) L-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid (AMPA) receptor or binding site of NMDA.

Using techniques Chiamulera C. et al., Psychopharmacology (1990) 102, 551-552 also found that the compounds of the invention inhibit NMDA-induced convulsions (seizures) in mice.

Neuroprotective activity of the compounds of the invention t is and described Chiamulera C. et al., European Journal of Pharmacology, 216 (1992), 335-336.

The connection was active when introduced in predicamental or postischemic condition.

Therefore, the invention provides the use of compounds of formula (I) and/or physiologically acceptable salts or metabolities labile ester for use in therapy, in particular, used as a drug to counteract the effects of excitatory amino acids on the NMDA receptor complex.

The invention also provides the use of compounds of formula (I) and/or a physiologically acceptable salt, or metabolically labile ester for the production of a drug to counteract the effects of excitatory amino acids on the NMDA receptor complex.

According to further aspect the invention also provides a method of counteracting the effects of excitatory amino acids on the NMDA receptor complex, including an introduction to the needy in this patient antagonistic amount of a compound of formula (I) and/or a physiologically acceptable salt, or metabolically labile ester.

Specialists in the art will understand the fact that the certain diseases or symptoms.

In addition, you should pay attention to the fact that the amount of the compound of the invention required for use in treatment will vary with the nature of the proposed method of drug administration, the age and condition of the patient and will be ultimately at the discretion of the physician.

In General, however, doses used for the treatment of adult humans are usually in the range of from 2 to 800 mg per day, depending on the method of administration.

Thus, the daily dose for parenteral administration is usually in the range of 20 to 100 mg, preferably 60-80 mg per day. For oral administration, the daily dose is normally in the range 200-800 mg, for example 400-600 mg per day. The desired dose can usually be represented by a single dose or divided doses, administered at appropriate intervals, for example as two, three, four or more podos a day.

Although it is possible that, for use in therapy a compound of this invention may be administered as the raw chemical, it is preferable to give the active ingredient in the form of a pharmaceutical composition.

The invention, thus, provides the pharmaceutical composition comprising the compound of formula (I) or its priemlemim media and, optionally, other therapeutic and/or prophylactic ingredients. The carrier (s) must be "acceptable" in the sense that is compatible with the other ingredients and not disruptive to the recipient.

Compositions of the invention include compositions composed mainly in the form for oral, transbukkalno, parenteral, by inhalation or insufflation, implants or rectal administration. Preferably parenteral administration.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, juice, acacia, gelatin, sorbitol, tragakant, mucilage of starch or polyvinylpyrrolidone; fillers, for example lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol; lubricants, for example magnesium stearate, stearic acid, talc, polyethylene glycol or silica, disintegrators, such as potato starch or starch glycolate, sodium, or moisturizing agents, such as sodium lauryl sulfate. Tablets can be coated membrane according to well-known in the art methods. Oral lived elixirs, or can be presented as a dry product for compiled before use with water or other suitable solvent.

Such liquid preparations may contain conventional additives such as suspendresume agents, for example sorbitol syrup, methyl cellulose, glucose/ sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, gel, aluminum stearate or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or juice of acacia; non-aqueous solvents, which can include edible oils, for example almond oil, fractionated coconut oil, olive esters, propylene glycol or ethyl alcohol; and preservatives, for example methyl or propyl p-hydroxybenzoate or ascorbic acid. The composition may be formulated as suppositories, e.g. containing conventional suppozitornoj bases such as cocoa butter or other glycerides.

For transbukkalno the introduction of the composition can be manufactured in the form of tablets or pellets prepared in the usual way.

According to the invention the composition may be formulated for parenteral administration by injection or continuous infusion. Stood the zo with the addition of preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous solvents, and may include forming agents, such as suspendisse, stabilizing and/or dispersing agents. Or otherwise, the active ingredient may be in powder form for composing with a suitable solvent, such as sterile, pyrogen-free water, before use.

For administration by inhalation the compounds according to the invention is usually supplied in the form of packaged under pressure, providing an aerosol spray using a suitable propellant, such as DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable propellant, such as DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a spray bottle. In the case of an aerosol under pressure to leave dosing quantity unit dosage can be determined by allocated volume.

On the contrary, for administration by inhalation or insufflation, the compounds according to the invention can be taken in the form of a dry powder composition, for example a powder mixture is presented in the form of a unit dose, for example, capsules or cartridges, covered with, for example, gelatin or bubble shells, from which the powder may be administered using inhalers or insufflator.

The composition according to the invention can also be prepared as a preparation for deposition. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or be used as sparingly soluble derivatives, for example, as a sparingly soluble salt.

According to the invention the composition may contain between about 0.1-99% of the active ingredient, suitable 30-95% for tablets and capsules and 3-50% for liquid preparations.

Compounds of General formula (I) and their salts can be prepared by conventional methods described in General terms in the future. In the following description, the groups R, R1and R2are as defined for compounds of formula (I), unless otherwise noted.

The compounds of formula (I), in which predstavlenie above values, R3is carboxylato group, and R4is a hydrogen or C1-4altergroup.

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by interacting with the corresponding ridom phosphorus able to turn the group CR4O group ACOXR2where X and R2have the same values as defined above for formula (I), followed where necessary or desirable, removing carboxyl protective group.

Suitable carboxylate groups include allyl, alkyl, trichloroallyl, trialkylsilyl or arylmethyl such as benzyl, nitrobenzyl or trityl. In one embodiment of this method, the reaction can be carried out using phosphorus ylides of the formula (III)

(R5)3P = CHCOXR2(III)

where R5represents alkyl or panelgroup, and X and R3have the above values.

The reaction is carried out in an aprotic solvent such as acetonitrile, or a simple ether such as 1,4-dioxane, and preferably by heating, for example, to 40-12oC.

In another embodiment of the method, the reaction is carried out using phosphorylate formula (IV).

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where R6represents hydrogen or C1-4alkyl.

R7is C

The compounds of formula (I), where A is optionally substituted by cyclopropyl, can be prepared by treatment of the olefin (V)

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where R, R3, R4, R6are as defined above meanings and R8is a hydrogen or C1-4accelgroup, diazopropane (VI), where the groups X and R2such as defined above, followed, where necessary or desirable, removing carboxylamide group.

The reaction is carried out in a solvent such as 1,2-dimethoxyethane, and in the presence of rhodium (II) catalyst, such as acetate or pivalate rhodium.

The compounds of formula (I), where A represents ethnicgroup, can be prepared by the interaction of the alkyne of formula (VII)

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where R, m, X and R2have the meanings defined in formula (I),

R9represents a group (CH3)3SiCH2CH2OCH2-

with hydrochloric acid in ethanol, followed by interaction with a suitable base, such as lithium hydroxide.

The compounds of formula (I) or are protected derivatives can be converted into other compounds of the invention.

can be prepared from the corresponding compounds of formula (I), where A represents ethinyl, by restoring using hydrogen and palladium on the carrier calcium carbonate/lead oxide as a catalyst.

The compounds of formula (I) in which A represents optionally substituted by cyclopropyl, can be prepared by the coupling of compounds of formula (I), where A is optionally substituted by atenilol, or its protected derivative, for example a simple ester with diazomethane in the presence of palladium acetate, followed where necessary or desirable, removing any protective groups.

The reaction is carried out in an aprotic solvent, such as dichloromethane and/or diethyl ether, preferably at a temperature in the range of 0-20oC.

In any of the above reactions carboxylamide group R3can be removed by conventional methods known for the removal of such groups. Thus, the group R3can be removed by hydrolysis using alkali metal hydroxide such as lithium hydroxide in a solvent such as ethanol, followed by the addition where it is desirable or necessary, a suitable acid, for example hydrochloric acid, to obtain the corresponding SV is otopleni treatment of the corresponding acid base, for example, a hydroxide of alkali or alkaline earth metal in an appropriate solvent, such as alkanol for example methanol.

Metabolically labile esters of compounds of formula (I) can be prepared by esterification of carboxylic acid groups or salts or by transesterification using conventional techniques. For example, aryloxyalkyl esters can be prepared by the interaction of the free carboxylic acid or salt with the appropriate aryloxyalkyl the halide in a suitable solvent, such as dimethylformamide. For the esterification of the free carboxyl groups of the reaction is preferably conducted in the presence of a Quaternary ammonium halide such as tetrabutylammonium chloride or benzyltriethylammonium chloride.

Aminoacylase esters can be prepared by transesterification of the corresponding Olkiluoto ether, for example methyl or ethyl ether, through interaction with the appropriate aminoalcohol at elevated temperature, for example 5-150oC.

The compounds of formula (II) in which R3is carboxyl protective group, R4is hydrogen, can be prepared by treatment sootvetstvuyshee in the solvent, such as 1,2-dichloroethane.

The compounds of formula (II) in which R3is carboxyl protecting group, R4is alkyl and n is zero can be prepared by treatment of indole (VIII) amidon (CH3)2NCOR4and phosphorus oxychloride in a suitable solvent.

The compounds of formula (V) can be prepared by treatment of the corresponding compounds of formula (II) with a reagent capable of introducing the group CR4= CR6R8.

Thus, the interaction of the compounds of formula (II) with triphenylphosphine derivative Ph3P+CH2R6Br-in the presence of a suitable base such as butyl lithium, in an aprotic solvent to give the corresponding compound of formula (V) in which R8is hydrogen.

The compounds of formula (V) in which R4is hydrogen and R6and R8independently represent C1-4alkyl, can be prepared by treating compound of formula (II), where R4represents hydrogen, twice substituted R6R8-C-P+Ph3in a suitable solvent such as N,N-dimethylformamide. Preferably, double-substituted prepared on the spot by processing the trimethylsilyl derivatives of rimacillin derivative can be prepared by Bestmann and Bomhard, Angew. Chem, Int. Ed. Eng. 21 (1982) N 7 pages 545-546.

The compounds of formula (V),where R4, R6and R8each represents altergroup can be prepared from the corresponding compounds of formula (II) by reacting with vinylsulfonate (PhSO2CHR6R8). The reaction can be carried out using conventional reaction techniques described Julia and Paris Tetrahedron Letters No. 49, 4833-4836 1973.

The compounds of formula (VII) can be prepared by interaction bromosilane acid (IX)

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with the appropriate isocyanate R2The NC or chloroformiate R2OCOCl in the presence of a suitable base, such as t-butyl lithium in an aprotic solvent such as tetrahydrofuran, followed by the interaction of the crude reaction product with trimethylsilyldiazomethane ((CH3)3SiCHN2). Bromosilane (IX) acid may be prepared from indole (II), where R4represents hydrogen by the following reaction sequence.

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The compounds of formula (IX) can be prepared by alkaline hydrolysis of the corresponding ester (X). Ether (X) can be prepared from the corresponding dibromophenol (XI) by reacting with a suitable base, such as I) can be prepared from the corresponding aldehyde (XII) interaction with triphenylphosphine and cetarehhloristam carbon in a solvent, such as dichloromethane.

N-protected indole (XII) may be prepared from indole (II, R4=H) interaction with trimethylsilylamodimethicone in the presence of a base such as sodium bis-trimethylsilyl, in a polar aprotic solvent such as dimethylformamide.

The indoles of formula (VIII) are either known compounds or can be prepared by methods analogous to those described for the known compounds.

In order for the invention to be more thoroughly understood only as illustrations the following examples.

For intermediates and examples, unless otherwise stated, the melting temperature (m.p.) defined on the device for determining the melting temperature Gallenkamp and have not been adjusted. All temperature-relatedoC and to the spectrum measured on the instrument FI-IR. Range PMR (1H-NMR) recorded at 300 MHz, chemical shifts are presented in ppm (M. D.) bottom area (d) with respect to Me4Si, used as internal standard and are interpreted as singlets (S), doublets (d), double doublets (dd), triplets (t), quarter (g) or multiplets (m). Column chromatography was performed on silica gel (Merck AG Dar [5.4.0] undec-7-ene. DMF = NM - dimethylformamide THF = tetrahydrofuran, LiOH. H2O = the monohydrate of lithium hydroxide. TlC refers to thin layer chromatography on plates of silica gel. The solution was dried over anhydrous sodium sulfate.

The intermediate product 1

Ethyl 4,6-dichlorobenzo-2-carboxylate

To a solution of ethyl pyruvate (2,05 ml) in absolute ethanol (38 ml) slowly with vigorous stirring was added concentrated sulfuric acid (0.5 ml). The resulting mixture was stirred at 23oC for 10 minutes, then added in portions 3,5-dichloropyridazin hydrochloride (4 g). The mixture was heated to boiling point under reflux for 4 hours, cooled to 23oC, poured into cold water (500 ml) and was extracted with diethyl ether (3 300 ml). Organic salts are separated and dried. The solvent was evaporated under reduced pressure to obtain ethyl ester 2-(3,5-dichloropyridazin) propionic acid as a yellow solid (5 g, tl DCM, Rf= 0,79, 0,47) in E and Z isomeric mixture. The solid product was added under stirring to polyphosphoric acid (20 g) and the mixture was heated to 45oC for 20 minutes to obtain a brown product, which was led from 95% ethanol (300 ml) to obtain the name (CDCl3) Vmax(cm-1) 3440 (NH), 1772-1709 (C=0).

The intermediate product 2

Ethyl 3-formyl-4,6-dichlorobenzo-2-carboxylate

A solution of N-methyl formanilide (5,19 g) and phosphorus oxychloride (5.53 g) was stirred at 23oC for 15 minutes. Added 1,2 - dichloroethane (60 ml) and intermediate 1 (6 g) and the resulting suspension was stirred at 80oC for 6 hours. The reaction mixture was poured into 50% aqueous solution of sodium acetate (300 ml) to obtain by filtering mentioned in the title compound as a yellow solid (4.1 g tlc EA/CH; 4/6; Rf= 0,4).

The intermediate product 3

Ethyl-3-formyl-1-(2-(trimethylsilyl)-ethoxymethyl)-4,6-dichlorobenzo - 2-carboxyla acid

To a chilled solution of intermediate (2) (700 mg) in dry DMF (20 ml) at 0oC was added lithium bis-trimethylsilyl (3,7 ml), 1M solution in THF.

The mixture was stirred for 15 minutes at 0oC, then added a three-methylsiliconate chloride (0,817 g). After one hour the mixture was poured into water (25 ml) and was extracted with ethyl acetate (3 20 ml). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to obtain R>
The intermediate product 4

Ethyl 3-(2,2-dibromovinyl)-1-(trimethylsilyl-ethoxy-methyl)-4,6 - dichlorobenzo-2-carboxylate

Intermediate 3 (300 mg) was dissolved in dry dichloromethane (7 ml) and the solution was cooled to -15oC in a bath of ice/salt. Then added triphenylphosphine (1,14 g) and chetyrehhloristy carbon (719 ml) and the resulting solution was stirred for 1.5 hours while the temperature was gradually raised to 0oC. Then added saturated NH4Cl (20 ml), divided in two phases and the aqueous phase was extracted twice with dichloromethane. The combined organic phase was dried, concentrated and the resulting residue is missed through a layer of silica gel (CH/EA : 9/1) to obtain named the title compound (390 mg) as a yellow oil. Rf= 0,62 CH/EA : 9/1

The intermediate product 5

Ethyl-3-bromoethyl-1-(2-trimethylsilylethynyl)-4,6 - dichloride-2-carboxylate

Intermediate 4 was dissolved in dry (50 ml) and the solution was cooled to 0oC in a bath of ice/water. Of the syringe slowly added lithium bis-trimethylsilyl (7,6 ml, 1.0 M solution in THF), and the mixture was stirred at 0oC for 30 minutes and then stopped the reaction by mixing with cold saturated NH4Cl (20 ml). Added ethyl acetate, the two phases razdelnoe product was purified column chromatography to obtain named the title compound (2.9 g) as a yellow oil.

Rf= 0,35 CH/EA : 95/5.

The intermediate product 6

3-Bromoethyl-1-(2-trimethylsilylethynyl)-4,6-dichlorobenzo-2 - carboxylic acid

Intermediate 5(2.9 g) was dissolved in 95% ethanol (40 ml), then added LiOH H2O and the solution was stirred over night at 80oC. the Reaction mixture was then concentrated to dryness and the resulting residue was washed for 1H. HCl. After filtration, the obtained solid product was washed with water and dried over P2O5to get named in the title compound (2.6 g) as a white solid product.

IR (Nujol) Vmax(cm-1) 1676 (C = 0), 1600 (C=C)

1H-NMR (DMSO) 14,00 (S) of 7.90 (d), 7,38 (d) of 5.92 (S) to 3.41 (t) 0,76 (t) -0,13 (S).

The intermediate product 7

Methyl-3-phenylcarbamoyl-1-(2-trimethylsilyloxy - methyl)-4,6-dichlorobenzo-2-carboxylate

The intermediate product 6 (454 g) was dissolved in dry THF (15 ml) and the solution was cooled to -78oC. is Slowly added a solution of t-butyl lithium (1.3 ml) and 1.7 M in hexane) and the reaction mixture was stirred for 2 hours. Then added phenylisocyanate (0,12 ml) and the mixture was gradually heated to room temperature and stirred 3 hours. The reaction was stopped by addition of cold saturated NH4Cl and extracted atylosia. The crude product was solubilisate then in dichloromethane (8 ml) and methanol (2 ml) and treated at room temperature Me3SiCHN2(1,2 ml, 1.0 M solution in hexane). After stirring for 30 min the solution was concentrated to dryness and the crude product was purified instant chromatography (CH/EA : 85/5) to get named in the title compound (230 mg) as a yellow solid product.

The intermediate product 8

(E)-Ethyl 3-[2-(phenylcarbamoyl)ethynyl]-1-(2-trimethyl ciliatoxic)-4,6-dichlorobenzo-2-carboxylate

To a cooled (0oC) a solution of (E)-ethyl-3-2-(phenylcarbamoyl) ethynyl-4,6-dichlorobenzo-2-carboxylate (300 mg) in dry DMF (25 ml) was added dropwise a solution of sodium bis(trimethylsilyl) amide (1M; 0,0814 ml). The resulting mixture was stirred at room temperature for 30 minutes and then cooled to 0oC. was Added trimethylsilylamodimethicone (185 mg) and the reaction mixture was stirred for one hour at room temperature.

The resulting solution was poured into H2O (20 ml) and was extracted with diethyl ether (15 MLH). The organic layers were dried, concentrated under reduced pressure and the product was isolated by chromatography on silica gel (CH/EA : 83/15) having nazvannoj)-propenyl] -1-(2-trimethylsilylethynyl)-4,6-dichlorobenzoyl-2-carboxylate

P, P-Diethyl-2-phosphono-propanamine (644 mg) was dissolved in anhydrous DMF (10 ml) and the resulting solution was cooled to 0oC and processed Lin(Me3Si)2(2,3 ml of 1.0 M solution in THF) for 1.5 hours. To this mixture was added intermediate 3 (784 mg), separately dissolved in dry DMF (8 ml) and stirring was continued throughout the night. The reaction was stopped by pouring the reaction mixture into 50 ml of chilled saturated NH4Cl:

the aqueous phase was then extracted with ethyl acetate and the organic layer was washed 1 N. hydrochloric acid, water and saline, dried, filtered, and concentrated. Final purification column chromatography gave named the title compound (660 mg) in the form of not quite white solid product. Rf= 0,35 CH/EA 8,5/1,5.

Example 1A.

(E) Ethyl-3-[2-(phenylcarbamoyl)ethynyl]-4,6-dichloride-2-carboxylate

DBU (319 mg) was added to a stirred suspension of phenylcarbamoylmethyliminodiacetic (1 g) in acetonitrile (100 ml) under nitrogen atmosphere. Stirring is continued at 0oC for 15 minutes, then added intermediate 2 (680 mg) and the mixture was heated to boiling under reflux for 6 hours. After dilution Rf= 0,5), in the form of a white solid product.

IR (Nujol) Vmax(cm-1) 3305 - 3288 (NH), 1678 - 1662 (C = O), 1627 - 1601 (C = C)1H -

NMR(DMSO) was 12.61 (S), And 10.20 (S), 8,27 (d), 7,73 (d), 7,52 (d) of 7.36 - 7,30 (m), 7,06 (m), 6,77 (d), 4,39 (q) 1,36 (t).

Example 1B

(E) Ethyl 3-[2-(4-cryptomaterial)ethynyl]-4,6-dichlorobenzo-2-carboxylate

To a stirred suspension of 4-(trifluoromethyl) phenyl - carbamoyltransferase chloride (0,99 g) in acetonitrile (10 ml) at 0oC in nitrogen atmosphere, was added DWI (0.3 g), Stirring was continued at 0oC for 25 minutes, then added intermediate 2 (0.56 g) and the mixture was heated to boiling under reflux for 8 hours After dilution with dichloromethane (20 ml), the precipitate was collected by filtration, having named the title compound (0.6 g).

EA/CH : 4/6 Rf= 0,49) in the form of a white solid product.

IR (Nujol) Vmaxcv-133100 (NH), 1676 (C = O), 1632, 1612 (C=C)

Example 1C

(E) Ethyl 3-[2-(2-2-isopropylphenyl)carbamoylethyl]-4,6-dichlorobenzo-2-carboxylate

To a stirred suspension of (2-isopropylphenyl) carbamoyltransferase chloride (0,83 g) in acetonitrile (10 ml) at 0oC in an atmosphere of nitrogen was added DWI. Stirring is continued Priam refrigerator for 4 hours After dilution with dichloromethane (20 ml) the resulting precipitate was collected by filtration, having named the title compound (340 mg, tlc EA/CH : 4/6 Rf= 0,53) in the form of a white solid product. IR (nujol) Vmax(cm-1) 3304 (NH), 1676, 1659 (C=O).

Example 1D

(E) Ethyl 3-[2-(2-nitrophenylamino)ethynyl] -4,6-dichlorobenzo-2-carboxylate

To a stirred suspension of (2 - nitrophenyl) carbamoyltransferase chloride (0.75 g) in acetone (10 ml) at 0oC in nitrogen atmosphere, was added DWI (238 mg). Stirring is continued at 0oC for 20 minutes, then added intermediate 2 (0.45 g) and the mixture was heated to boiling under reflux for 4 m After dilution with dichloromethane (20 ml) the resulting precipitate was collected by filtration, having named the title compound (420 mg, tlc EA/CH : 4/6 Rf= 0,55) in the form of a yellow solid product.

IR (nujol) Vmax(cm-1) 3348 - 3308 (NH), 1672 (C = O), 1607 - 1590 (C= C), 1556 - 1346 (NO2).

Example 1E

(E) Ethyl 3-[2-(2-methyl-4-methoxyphenylalanine)ethynyl]-4,6-dichlorobenzo-2-carboxylate

To a suspension of (2-methyl-4-methoxyphenyl)aminocarbonylmethyl chloride (is 0.998 g) in acetonitrile (15 ml) at 0oC in nitrogen atmosphere, was added DB the mixture was heated to boiling under reflux for 3 hours. After dilution with dichloromethane (20 ml) the resulting precipitate was collected by filtration, having named the title compound (0,57 g tlc EA/CH : 4 : 6 Rf= 0,34) not quite white solid product.

IR (nujol) Vmax(cm-1) 3302 - 3246 (NH), 1678 - 1659 (C = O), 1624 (C= C).

Example 1F

(E) Ethyl 3-[2-(2-hydroxyphenylarsonic)ethynyl] -4,6-dichlorobenzo e-2-carboxylate

To a suspension of (2-hydroxyphenyl) aminocarbonylmethyl chloride (0,94 g) in acetonitrile (15 ml) at 0oC in an atmosphere of nitrogen was added DWI (0.32 g). Stirring is continued at 0oC for 25 minutes, then added the intermediate compound 2 (0.6 g) and the mixture was stirred for 24 h at room temperature. The suspension was evaporated to dryness and the residue was purified instant chromatography (EA/CH : 3/7, then 4/6), having named the title compound (0,37 g tlc EA/CH: 4/6 Rf= 0,39) solid beige color.

IR (nujol) Vmax(cm-1) 3317 - 3290 (NH), 1678 - 1655 (C = O), 1618 (C= C).

Example 1G

(E) Ethyl 3-[2-(3,4-dimethoxyphenylacetone)ethynyl]-4,6-dichlorobenzo-2-carboxylate

To a suspension of (3,4-acid) aminocarbonylmethyl chloride (0,69 g) in acetonitrile (10 ml) at 0oC atmosphere connection 2 (0.4 g) and the mixture was stirred over night at room temperature, then, they were heated to boiling under reflux for 3 hours. After dilution with dichloromethane (20 ml) the resulting precipitate was collected by filtration, having named the title compound (0,457 g tlc EA/CH: 4/6 Rf= 0,20) as a yellow solid product.

IR (nujol) Vmax(cm-1) 3317 - 3254 (NH), 1678 (C = O), 1620 - 1600 (C= C).

Example 1H

(E) Ethyl 3-[2-(4-ethoxybenzylidene)ethynyl]-4,6-dichlorobenzo-2-carboxylate

To a suspension of (4-ethoxyphenyl) aminocarbonylmethyl chloride (0,67 g) in acetonitrile (10 ml) at 0oC in nitrogen atmosphere, was added DWI (0.21 g) DWI. Stirring is continued at 0oC for 25 minutes, then added intermediate 2 (0.6 g) and the mixture was heated to boiling under reflux for 28 hours. After dilution with dichloromethane (20 ml) the resulting precipitate was collected by filtration, having named the title compound (0,265 g tlc EA/CH : 4/6 Rf= 0,41) as light-yellow solid product.

IR (Nujol) (cm-1) 3321-3260 (NH), 1676 (C=O), 1622 (C=C)

Example 1I

(E) Ethyl 3-[2-(2,4-differetialoperatoren)ethynyl]-4,6 - dichloride-2-carboxylate

To a suspension of (2,4-defloriani)aminocarbonylmethyl chloride (0,655 g) in acetone is their 25 minutes then, they were heated to boiling under reflux for 26 hours. After dilution with dichloromethane (20 ml) the resulting precipitate was collected by filtration, having named the title compound (0,42 g tlc EA/CH : 4/6 Rf= 0,54) as light-yellow solid product.

IR (Nujol) Vmax(cm-1) 3298 (NH), 1678-1661 (C=O), 1624 (C=C)

Example 1J

(E) Ethyl 3-[2-(2-fluorescent-5-nitrophenylamino)ethynyl]-4,6 - dichlorobenzo-2-carboxylate

To a suspension of (2-fluorescent-4-nitrophenyl)aminocarbonylmethyl chloride (0.52 g) in acetonitrile (10 ml) at 0oC in nitrogen atmosphere, was added DBU (0.16 g). Stirring is continued at 0oC for 25 minutes, then added intermediate 2 (0.3 g) and the mixture was heated to boiling under reflux for 18 hours. After dilution with dichloromethane (20 ml) the resulting precipitate was collected by filtration, having named the title compound (0.34 g tlc EA/CH : 4/6 Rf= 0,41) solid beige color.

IR (Nujol) nmax(cm-1) 3300 (NH), 1680-1666 (C=O), 1545-1377 (NO2)

Example 2A

(E) 3-[2-(phenylcarbamoyl)ethynyl]-4,6-dichlorobenzo-2-carboxylic acid

To a solution of example 1A (250 mg) in ethanol (2.5 ml) was added at 23oC hydroxide l is OK, dissolved in water (5 ml). The aqueous layer was acidified using 1 N. hydrochloric acid until precipitation of a white solid precipitate. The latter was collected by filtration and dried, having named the title compound as a white solid (230 mg).

IR (Nujol) Vmax(cm-1) 3402-3281-3192 (OH, NH), 1661 (C=O), 1607-1579 (C=C).

1H-NMR (DMSO) 12,4 (s), 10,1 (s), and 8.50 (d), 7,74 (d) of 7.48 (s), 7,27 (t) 7,16 (s), 7,11 (d), 6,99 (t)

Based on the same General technique were prepared the following compounds:

Example 2B

(E) 3-[2-(Cryptanalytically)ethynyl] -4,6-dichlorobenzo - 2-carboxylic acid

On the basis of example 1B (585 mg), has been named the title compound as a pale brown solid product (520 mg).

IR (Nujol) Vmax(cm-1) 3430-3000 (NH, OH), 1700-1678 (C=O), 1636-1614 (C=C).

1H-NMR (DMSO) 14-13,5 (s), 12,55 (s), 10,54 (s) of 8.37 (d), to $ 7.91 (d), to 7.67 (d) of 7.48 (d), 7,30 (d) 6,86 (d).

Example 2C

(E) 3-[2-(2-Isopropylaminocarbonyl)ethynyl]-4,6-dichlorobenzo - 2-carboxylic acid, delitala salt

On the basis of example 1C (317 mg) obtained named the title compound as a pale brown solid (288 mg).

IR (Nujol) (DMSO) (cm-1) 3661 (NH, OH), 1610 (C=O).

1H-NMR (DMSO) 12,1 (s), 9,39 (s), to 8.57 (d), EUR 7.57 (s), 7,38-7,28 (m), 7,28-7,10 (m), 3,25 (m) and 1.15 (d).

1D (440 mg), received named the title compound as a white solid product (290 mg)

IR (Nujol) Vmax(cm-1) 3234 (NH, OH), 1684-1636 (C=O), 1639 (C=C).

1H-NMR (DMSO) 12,2 (s), 10,51 (s) 8,59 (d), 7,95 (dd), 7,81 (dd), 7,69 (m) of 7.48 (d), 7,38-7,28 (m), 7,20 (d)

Example 2E

(E) 3-[2-(2-Methyl-4-methoxyphenylalanine)ethynyl] -4,6 - dichlorobenzo-2-carboxylic acid

Proceeding from example 1E (0.54 g) obtained named the title compound as a yellow solid (0.39 g).

IR (Nujol) Vmax(cm-1) 3279 (NH, OH), 1703-1661 (C=O), 1630 (C=C).

1H-NMR (DMSO) 12,41 (s), 9,39 (s), compared to 8.26 (d) of 7.48 (d) of 7.36 (d), 7,27 (d), 6.90 to (d), 6,80 (d) of 6.75 (dd), to 3.73 (s), 2,19 (s).

Example 2F

(E) 3-[2-(2-Hydroxyphenylarsonic)ethynyl]-4,6-dichlorobenzo - 2-carboxylic acid

On the basis of example 1F (0.34 g) obtained named the title compound as a yellow-brown solid product (0.33 g).

IR (Nujol) Vmax(cm-1) 3150 (NH, OH), 1736-1656 (C=O), 1630 (C=C).

1H-NMR (DMSO) 12,56 (s), becomes 9.97 (s), 9,76 (s), 8,24 (s), and 7.8 (d), 7,49 (d), 7,30 (d) of 6.96 (d) of 6.96 (td), to 6.88 (dd), 6,79 (td).

Example 2G

(E) 3-[2-(3,4-Dimethoxyphenylacetone)ethynyl]-4,6 - dichlorobenzo-2-carboxylic acid

On the basis of example 1G (0,41 g) obtained named the title compound as a pale yellow tverdogo (DMSO) 13,8-13,6 (s), of 12.53 (s), 10,08 (s) 8,23 (d), 7,47 (m), 7,29 (d), 7,20 (dd), 6.89 in (d), 6,74 (d) 3,37 (s), 3,70 (s).

Example 2H

(E) 3-[2-(4-Ethoxybenzylidene)ethynyl] -4,6-dichlorobenzo - 2-carboxylic acid IV

Proceeding from example 1H (0.25 g) obtained named the title compound as a light yellow solid product (0,22 g).

IR (Nujol) nmax(cm-1) 3248 (NH, OH), 1663 (C=O), 1632-1610 (C=C)

1H-NMR (DMSO) 13,7 (s), 12,50 (s), 10,04 (s), by 8.22 (d), to 7.61 (d), 7,47 (d), 7,29 (d) 6,86 (d), 6,74 (d) of 3.97 (q) of 1.29 (t).

Example 2I

(E) 3-[2-(2,4-Differetialoperatoren)ethynyl] -4,6-dalinda - 2-carboxylic acid

On the basis of example 1I (0,41 g) obtained named the title compound as a light yellow solid product (0,37 g)

IR (nujol) nmax(cm-1) 3431-3233 (NH, OH),

1707 - 1678 (C=O), 1612 (O=C).

1H-NMR (DMSO) 14,0 - 13,6 (S), 12,54 (S), 9,99 (S), 8,29 (d), 7,97 (m) of 7.48 (d), 7,30 (m), 7,29 (d), 7,07 (m), 6.90 to (d)

Example 3

Methyl-3-[2-(phenylcarbamoyl)ethinyl]-4,6-dichlorobenzo-2 - carboxylate

The intermediate product 7 was dissolved in ethanol 95% (18 ml), then added dropwise HCl (18 ml, 5 BC) and the solution was heated to boiling under reflux for 3 hours. After adding ethyl acetate (50 ml) two phases were separated and the organic layer was washed with water (2 x 40 ml), dried and purified chromatogr the temperature for 10 minutes. After cooling to 8oC, was added LiOH H2O (42 mg), the mixture was stirred for 1 hour, then poured into a solution of 0.01 N. HCl and was extracted with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure, obtaining a residue, which is triturated in ether and has been named the title compound (100 mg) as a white solid.

Rf= 0,18 CE/EA: 70/30

IR (nujol) Vmax(cm-1) 3273 (NH), 2220 (C=C),

1686 (C=C), 1636 (C=O).

1H-NMR (DMSO) 13,5 (s), 10,71 (s), 7,68 (m), 7,52 (m), 7,40 (d), 7,35 (m), 7,11 (m) 3,96 (s)

Example 4

3-[2-Phenylcarbamoyl)ethinyl]-4,6-dichlorobenzo-2 - carboxylic acid

The mixture of example 3 (100 mg), tetrahydrofuran (4 ml), water (2 ml) and LiOH H2O (39 mg) was stirred at 45oCC within 12 hours. Then it was poured into water (15 ml) and HCl (0.05 M, 5 ml) was added dropwise with stirring. The precipitate was collected by filtration to obtain named the title compound as a yellow solid (63 mg) t.m. = 207oC.

IR (nujol) Vmax(cm-1) 3169 (NH-OH), 2240 (C=C), 1745 (C=O), 1661 (C=O).

1H-NMR (DMSO) of 13.05 (s) 14,0 (s), 10,88 (s) 10,7 (s), to 7.67 (d), 7,51 (d), 7,35 (d), 7,33 (m), 7,10 (m)

Example 5

(D. L. )-TRANS-ethyl-3-[2-phenylcarbamoyl)cyclopropyl]-imethyl)-4,6-dichlorobenzo-2-carboxylate

To a mixture of intermediate 8 (0.1 g) and palladium acetate (P) (4 mg) in dichloromethane (10 ml) under nitrogen atmosphere at 0oC, was added with stirring a solution of diazomethane in diethyl ether (8 ml, 0.125 M). Got a black solid product with the rapid evolution of gas. The reaction mixture was stirred for 15 hours at room temperature, then the solvent and some of the remaining diazomethane was evaporated under reduced pressure in a stream of nitrogen. To the resulting residue were added dichloromethane, filtered through celite and evaporated under reduced pressure.

Cleaning an instant chromatography gave a mixture of starting material, named in the title compounds in the ratio of 0.3 : 1 (86 mg) as a pale yellow solid.

b) (D. L.)-TRANS-ethyl-3-[2-(2-phenylcarbamoyl)cyclopropyl]-4,6 - dichlorobenzo-2-carboxylate

HCl (2 ml of 5 M) was added to the product of example 5a (66 mg) in ethanol (2 ml; 95%) and stirred under heating to boiling point for 2 hours. After cooling the mixture is poured into cold water (50 ml) and was extracted with ethyl acetate (3 x 100 ml). Organic salts were combined, dried and the solvent was evaporated under reduced pressure, having named the title compound (tic C>H-NMR (CDCl3) 12,1 (s), 10,2 (s), 7,60 (d), 7,40 (d), 7,28 (t) 7,01 (m), and 4.40 (m), 4,25 (m) to 2.55 (m), to 1.98 (m), 1,49 (m), 1.27mm (t) 1,22 (m)

Example 6

(D. L. )-TRANS-3-[2-phenylcarbamoyl)cyclopropyl]-4,6 - dichlorobenzo-2-carboxylic acid

Based on Example 5 b (40 mg) and LiOH and using the General method of Example 2a, has been named the title compound as a white solid (23 mg)

IR (nujol) Vmax(cm-1) 3271 (NH), 1663 - 1653 (C=O), 1599 (C=C).

1H-NMR (DMSO) 13,4 (s), 11,98 (s), 10,11 (s), 7,60 (s), 7,37 (d), 7,27 (t), 7,17 (d) 7,00 (t) of 1.97 (m), 1,50 (m), 1,47 (m), 1,2 (m)

Example 7

Ethyl-3-[(2-phenylcarbamoyl)-propenyl]-4,6-dichlorobenzo-2 - carboxylate

The intermediate product 9 (660 mg) was dissolved in 95% EtOH (6 ml) and treated at the boiling temperature of 5h. hydrochloric acid (6 ml) overnight. Then the solution was absorbed in ethyl acetate, washed with 1N hydrochloric acid, water and saline, dried, filtered and concentrated. Purification of column chromatography gave named the title compound (-20 ml) in the form of a white solid product.

Rf= 0,30 CH/EA 7,5/2,5

1H-NMR (DMSO) 12,48 (s, 1H), to 9.70 (s, 1H), 7,80 - 7,72 (m, 3H), of 7.48 (d, 1H), 7,33 (t, 2H), 7,26 (d, 1H), was 7.08 (m, 1H), 4,32 (q, 2H), 1,79 (d, 3H), of 1.30 (t, 3H) ppm,

IR (nujol) (Vmax= cm-1) 3317 - 3288 (NH str), 1678 (str CO)

Example 8

3-[(2-habotai LiOH H2O (32 mg) at 30oC for 1.5 days and then for 2.5 days at room temperature. Then the solution was concentrated to dryness and processed within 2 hours 1H. the hydrochloric acid. The resulting white precipitate was filtered, dried in high vacuum and then recrystallize from diethyl ether, having named the title compound (135 mg) as a white solid product.

1H-NMR of 13.5 (s, 1H), 12,37 (s, 1H), to 9.70 (s, 1H), 7,76 (d, 2H), of 7.75 (s, 1H), 7,45 (d, 1H), 7,31 (t, 2H), 7.23 percent (d, 1H), 7,06 (t, 1H), 1,78 (d, 3H) ppm:

IR (nujol) (Vmax= cm-1) 3209 (str, NH), 1664 (str, CO)

Example 9

(E) 3-[2-(phenylcarbamoyl)ethynyl] -4,6-dichlorobenzo-2-carboxylic acid sodium salt

Methanol was added dropwise to a suspension of (E) 3-[2- (phenylcarbamoyl)ethynyl] -4,6-dichlorobenzo-2-carboxylic acid 200 mg in 0.5 M of sodium hydroxide (1,01 ml) to obtain a clear solution. After stirring for 15 minutes, the solution was evaporated to dryness and the residue was dried at 50oC for 12 hours to obtain named the title compound as a white solid (150 mg).

IR (nujol) Vmax(cm-1) 3404-3126 (NH), 1624 (C=O), 1600 (C=C)

1H-NMR (DMSO) 11,9 (S) 10,06 (S), 8,59 (d) 7,75 (d), 7,44 (d), 7,27 (t), 7,21 (d), 7,10 (d), 6,98 (t).

Example 10

(E)-2-[-2-(N, N-diethynyl] -4,6-dichlorobenzo-2 - carboxylate (0.3 g) and N,N-diethylethanolamine (1.3 g) was stirred for 20 minutes before adding sodium carbonate (0,073 g) and the mixture was heated at 70oC for 24 hours. The solution was concentrated under reduced pressure and the residue was left to stand over night prior to the formation of a white precipitate. Filtration and crystallization from ethyl acetate gave named the title compound (0,13 g Rf= 0,65 = DS/MeOH 8,2) in the form of a white solid product.

IR (nujol) Vmax(cm-1) 3300 (NH), 1676 (C=O), 1624 (C=C).

1H-NMR (DMSO) to 12.52 (S), 10,18 (S), by 8.22 (d), of 7.70 (d), 7,50 (d), 7,32 (d), 7,31 (t),? 7.04 baby mortality (t), 6.73 x (d) 4,36 (t) 2,75 (t) 2,49 (q) 0,90 (t).

Example 11

(E) 2-[4-(-2N-morpholino)ethyl] -3-[2-(phenylenecarbonyl)-ethynyl]- 4,6-dichlorobenzo-2-carboxylate

A mixture of (E) Ethyl-3-[2-(phenylcarbamoyl)ethynyl] -4,6 - dichlorobenzo-2-carboxylate (400 mg), 4-(2-hydroxyethyl)-research (7 ml) and p-toluensulfonate acid (15 mg) was stirred at 130oC for 120 hours. The mixture was diluted with water and was extracted with ethyl acetate (CH ml). The organic extracts were dried, concentrated and collected precipitate, having named the title compound as a white solid product.

1H-NMR (DMSO) of 10.21 (S) 8,28 (d) 7,75 (d), 7,56 - to 7.35 (d,d), 7,35 (t), was 7.08 (t) 6,74 (d), 4,46 (t) 3,54 (m), 2,43 (m), 2,70 (t).

Example 12

(a) (E)-2-(T-Butylcarbamoyl)-3-[2-(phenylenecarbonyl)ethynyl]-4,6 - dichlorobenzo-2-carboxylate

Example 2. (who or dropwise chloromethylene (118 mg) and the reaction mixture was stirred at room temperature for 48 hours. The mixture was diluted with water and was extracted with ethyl acetate (CH ml). The organic layer was washed with water, dried and evaporated to obtain crude product, which was purified instant chromatography to obtain named the title compound as a yellow solid (190 mg) toCPF 205oC.

IR (nujol) Vmax(cm-1) 3383-3308 (H), 1747 (C=O), 1688 (C=O), 1634 - 1603 (C=C).

1H-NMR (DMSO) was 12.75 (S), 10,22 (S), by 8.22 (d), 7,73 (d), 7,54 (d) of 7.36 (d), 7,33 (t), 7,07 (t), 6,79 (d), 6,02 (S) And 1.15 (S).

Using the same General methodology, has prepared the following link:

(b) (E)-2-[1-(Tetrahydro-4-Piran-4-4-elextronics) ethyl] 3-[2-(phenylenecarbonyl)ethynyl]-4,6-dichlorobenzo-2 - carboxylate

Example 2 (200 mg) in dry DMF (11 ml), benzyltriethylammonium chloride (178 mg) and 1-(tetrahydro-4-H-Piran-4-elextronics) ethyl chloride (244 mg), after 4 days of stirring at room temperature obtained named the title compound as a yellow solid (209 mg) toCPF = 209oCC

IR (nujol) Vmax(cm-1) 3300 (NH), 1749 (C=O), 1730 (C=O).

1H-NMR (DMSO) of 12.73 (S), 10,22 (S), 8,21 (d), 7,72 (d), 7,53 (d), 7,34 (d), 7,32 (t), 7,05 (t), 6,90 (q) 6,76 (d), was 4.76 (m), and 3.72 (m), 1,87 - 1,53 (m), 1,61 (d).

(c) (E)-2-[1-(Cyclohexyloxycarbonyloxy(ethyl]3-[2- (Fe is money chloride (178 mg) and 1-(cyclohexyloxycarbonyloxy) ethyl chloride (242 mg), after 0.5 hour of stirring at room temperature, has been named the title compound as a yellow solid (170 mg) toCPF = 125oC

IR (nujol) Vmax(cm-1) 3300 (NH), 1730 (C=O),

1H-NMR (DMSO) 12,71 (SO, 10, 21 (S), 8,21 (d), 7,71 (d), 7,51 (d) of 7.36 - 7,26 (m), 7,05 (t), 6,85 (q) 6,76 (d) 4,54 (m) 1,79 (m) and 1.51 - 1,1 (m), and 1.6 (d).

(d) (E)-2-[(Methoxycarbonylmethyl)3-2-(phenylenecarbonyl) -ethynyl] -4,6-dichlorobenzo-2-carboxylate

Example 2 (200 mg) in dry DMF (4 ml), tetrabutylammonium chloride (168 mg) and methyl CHLOROACETATE (85 mg), after 48 hours of stirring at room temperature, obtained named in the title compound in the form of not-quite-white solid product (210 mg).

toCPF = 241 - 242oC

IR (nujol) Vmax(cm-1) 3348 (NH), 1749 (C=O), 1672 (C=O), 1634 - 1610 (C=C).

1H-NMR (DMSO) 12,8 (S) Of 10.21 (S) 8,28 (d), 7,72 (d), 7,54 (d), 7,38 - 7,28 (m), 7,06 (t), 6.48 in (d), 7,54 (d), 7,38 - 7,28 (m), 7,06 (t), 6.48 in (d), 5,02 (S) Of 3.73 (S).

Pharmaceutical examples A. Capsules/Tablets

Active ingredient - 200.0 mg

Starch 1500 - 32,5 mg

Microcrystalline cellulose - 60,0 mg

Crosscarmellose sodium - 6.0 mg

Magnesium stearate 1.5 mg

The active ingredient is mixed with other fillers. The mixture can be used for supporterof.

Tablets can be coated membranes using conventional techniques and coatings.

Century Tablet

Active ingredient - 200.0 mg

Lactose - 100.0 mg

Microcrystalline cellulose - 28.5 mg

Povidone - 25.0 mg

Crosscarmellose sodium - 6.0 mg

Magnesium stearate 1.5 mg

The active ingredient is mixed with lactose, microcrystalline cellulose and part of croscarmellose sodium.

The mixture granularit with povidone after dispersion in a suitable solvent (for example water). The pellets, after drying and grinding, are blended with the remaining excipients. The mixture can be extruded using appropriate drills and tablets can be coated membranes using conventional techniques and coatings.

C. Compositions for injection

The active ingredient is 0.1 - 7,00 mg/ml

Sodium phosphate - 1,0 - 50,00 mg/ml

with NaOH to a specified pH (range 3-10) water for injection q.s. up to a volume of 1 ml

The composition may be packaged in a flask (ml) with a rubber stopper (vials, syringes and plastic/metal insulating layer (vials).

Dry powder for preparation with a suitable carrier

Active ingredient: - 0,1 - 100,00 mg

Man is like bottles) plastic-metal insulating layer.

E. Sleeves for inhalation mg/pocket

Active ingredient (micronized) - 5,00

Lactose to - 25,00

The active ingredient in pre-microreserves in powerful grinding to dust the mill to the size of the smallest particles for mixing with used to prepare tablets with lactose normal quality mixer high power. A powder mixture is filled in an appropriate capacity for a single dose in the form of strips or capsule suitable for use by:inhalation or insufflation.

The activity of compounds of the invention in relation to impaired strychnine binding sites glycine was determined by using method H. Kishimoto T. et al Neurochem 1981, 37, 1015 - 1024.

The pKi values obtained are represented by the compounds of the invention are given in table 1.

The ability of compounds of the invention inhibit the N involved convulsions in mice was determined using techniques Chiamulera C. et al. Psychopharmacology 1990, 102, 551 - 552. In this test the ability of compounds to inhibit common epileptic seizures caused intracerebroventricular injection of NMDA in mice were studied at several dose levels. From these results was calculated dose, trebujena.

The results obtained for compounds of the invention administered intravenously or by mouth, are shown in table 2.

Compounds of the invention generally not toxic in therapeutic use hollow doses. For example, the compound of Example 9 does not cause adverse side effects when administered to rats or mice at doses of 3 and 30 mg/kg intravenously or 30 - 300 mg/kg orally.

1. Derived indole of General formula (I)

< / BR>
or its physiologically acceptable salt, or metabolically labile ester,

where R is chlorine in positions 4 and 6 of indole cycle

A represents ethinyl, 1-methylethenyl, ethynyl or cyclopropyl group;

X represents NH;

R2represents phenyl, possibly substituted by one or two groups selected from fluorine, CF3, lower alkyl, alkoxy, hydroxy and nitro groups.

2. A derivative of indole under item 1, where R2represents phenyl.

3. A derivative of indole under item 1 or 2, where a represents ethinyl or 1-methylethenyl in the TRANS configuration.

4. A derivative of indole under item 1 or 2, where a represents unsubstituted atenolol group.

5. A derivative of indole under item 4, where resumes one or two groups selected from fluorine, trifloromethyl, methyl, isopropyl, hydroxyl, methoxy, ethoxy or nitro group.

6. (E)-3-[2-(phenylcarbamoyl)ethynyl] -4,6-dichloride-2-carboxylic acid, physiologically acceptable salt, or metabolically labile esters.

7. Connection on p. 6 in the form of its sodium salt.

8. A derivative of indole under item 1, which is (E)-3-[2-phenylcarbamoyl] -4,6-dichloride-2-carboxylic acid, physiologically acceptable salt, or metabolically labile esters.

9. A derivative of indole under item 1, which is (E)-3-[2-(phenylcarbamoyl)ethinyl] -4,6-dichloride-2-carboxylic acid or its physiologically acceptable salts and metabolically labile esters.

10. Derivatives of indole under item 1, which are compounds selected from the group:

(E)-3-[2-(4-ethoxyphenylurea)ethynyl] -4,6-dichloride-2-carboxylic acid,

(E)-3-[2-(2-hydroxy-5-nitrophenylamino)ethynyl] -4,6-dichloride-2-carboxylic acid,

(E)-3-[2-(2-methyl-4-methoxyphenylacetyl)ethynyl] -4,6-dichloride-2-carboxylic acid,

(E)-3-[2-(2-isopropylaminocarbonyl)ethynyl]-4,6-dichloride-2-carboxylic acid,

(E)-3-[2-(2,4-differencemaker)ethynyl] th acid,

or their physiologically acceptable salt, or metabolically labile esters.

11. Derivatives of indole according to any one of paragraphs.1 - 10 for therapeutic use as agents for combating the effects of excitatory amino acids on the NMDA receptor complex.

12. Pharmaceutical composition having the antagonist properties of amino acids, excitatory NMDA receptor complex, characterized in that it contains a compound of the formula I according to any one of paragraphs.1 - 10 2 - 800 mg and a pharmaceutically acceptable carrier or excipient.

13. The method of obtaining derivatives of indole of General formula (I) as defined in paragraph 1, where a is a lower alkenyl, which includes the interaction of indole (II)

< / BR>
in which R and m have the meanings given in paragraph 1;

R4is hydrogen or C1-C4alkyl and

R3- carboxyamide group,

with ridom phosphorus formula III

(R5)3P=CH-COXR2,

where R5represents alkyl or phenyl;

X and R2have the meanings given in paragraph 1,

or ridom phosphorus formula IV

(R7O)2OP=CR6-COXR2,

where R6is hydrogen or C1-C4alkyl;

R7- C1

 

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Anti-inflammatory // 2086239
The invention relates to medicine, namely to the use of new anti-inflammatory drugs from the class alkanolammonium salts hetarylthioacyl acids, specifically to indolyl-3-diacetate Tris/2-hydroxyethyl/ammonium

The invention relates to medicine, namely to the use of Tris(2-hydroxyethyl) ammonium salt of 3-IntelliTouch acid having the following formula

< / BR>
as a highly effective protective means in cardiogenic shock and toxic stress

FIELD: medicine.

SUBSTANCE: it is suggested to apply tris-(2-hydroxyethyl)ammonium salt of 1-benzylindolyl-3-thioacetic acid earlier known as a stabilizer of cell membrane as preparation to treat autoimmune diseases. The property of the above-mentioned salt to inhibit T-dependent activation of B-lymphocytes, under conditions of decreased medullary function and body leukopenia should enable to develop new pharmacological preparation for treating autoimmune diseases, such as, for example, systemic lupus, rheumatoid polyarthritis, transplant's detachment at transplanting either organs or bony marrow.

EFFECT: higher efficiency of application.

4 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: medicine, arthrology, pharmacy.

SUBSTANCE: agent comprises glucosamine salt as saccharide, dimethylsulfoxide, ointment base and ibuprofen or nimesulide, or piroxicam, or meloxicam, or diclofenac salt, or indometacin, or ketoprofen as a nonsteroid anti-inflammatory agent. Glucosamine hydrochloride, glucosamine sulfate sodium, potassium or calcium salt is used as glucosamine, and diclofenac potassium or sodium salt is used as diclofenac salt. New ointment shows high perfusion rate of active substances to the articulation zone and enhanced effectiveness. Invention expands assortment of agents used in treatment of articulations.

EFFECT: improved, enhanced and valuable medicinal properties of agent.

2 cl, 14 ex

FIELD: medicine, arthrology, pharmacy.

SUBSTANCE: invention relates to agents of topical applying used in treatment of articulation diseases. Proposed agent comprises mixture of chondroitin sulfate and glucosamine salts as a saccharide, the compound taken among the group nonsteroid anti-inflammatory agents, in particular, ibuprofen or nimesulid, or piroxicam, or meloxicam, or diclofenac salt, or indometacin, or ketoprofen, dimethylsulfoxide and an ointment base taken in the definite ratio of components. Invention provides enhancing effectiveness due to the content a mixture of low-molecular and high-molecular saccharides in it that results to increasing diffusion rate of active component to the articulation zone and also the compound taken among the group of nonsteroid anti-inflammatory agents. The combined using these agents provides the curative synergetic effect.

EFFECT: improved and valuable medicinal properties of agent.

2 cl, 14 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to manufacturing solid medicinal formulations of preparations. Invention proposes a medicinal formulation consisting of a core comprising the following components: indometacin, lactose, calcium phosphate, hydroxypropylcellulose, magnesium stearate, sodium croscarmellose and envelope comprising collicute MAE 100P, propylene glycol, pigment titanium dioxide, talc, collidon-30, brown sycovite-70. Also, invention discloses a method for preparing the formulation. Invention provides enhancing stability of envelope to effect of stomach juice, rapid and complete release of active substance, simultaneous simplifying the process of applying the envelope for a single step.

EFFECT: improved and valuable pharmaceutical properties of formulation.

3 cl, 1 tbl

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