[(benzodioxan, benzofuran or benzopyran)-alkylamino]- alkyl-substituted guanidine as selective vasoconstrictor tools, methods for their preparation, intermediates for them, pharmaceutical composition and method of reception

 

(57) Abstract:

The invention relates to vasoconstrictor /(benzodioxan, benzofuran and benzopyran)-alkylamino/-alkyl-substituted guanidine formula I, their pharmaceutically acceptable salts, or their stereochemical isomers, where X = O, CH2or a direct bond; R1= H, C1-C4alkyl, R2= H, C1-C6alkyl, C3-C6alkenyl, C3-C6quinil, R3= H, C1-C4alkyl; or R2and R1taken together, may form a bivalent radical of the formula/CH2/m-, where m = 4 or 5; or R1and R2taken together may form a bivalent radical of formula-CH=CH -, or the formula/CH2/n-, where n = 2, 3 or 4; or R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH= -, -CH= CH-N= or-CH=N-CH=; where one or two hydrogen atom substituted by a halogen atom, a C1-C6alkoxygroup, C1-C6the alkyl, CN, NH, mono - or di(C1-C6alkyl) amino group, aminocarbonyl, C1-C6alkylaminocarbonyl, R4-H or C1-C6-alkyl; Alk1denotes a divalent C1-C3-alkane is B>4-alkyl, where each R6=H or C1-C4-alkyl, Alk2represents C2-C15-alcander or C5-C7-cycloalkenyl, and each "R" represents 0, 1, 2, R7and R8each independently is H, a halogen atom, a C1-C6by alkyl, hydroxyl, C1-C6allyloxycarbonyl, C1-C6alkoxygroup, cyano, amino, C1-C6the alkyl, carboxyla, nitro or amino group, aminocarbonyl, C1-C6alkylcarboxylic or mono - or di-(C1-C6)alkylamino, provided that excluded /2-/ (2,3-dihydro-1,4-benzodioxin-2-yl)-methyl/-amino/-ethyl-guanidine. Pharmaceutical preparations which are suitable as vasoconstrictor funds. Describes compositions containing the above-mentioned guanidine derivatives as active ingredients, methods of obtaining the above-mentioned derivatives of guanidine and a new P-cyanoguanidine; intermediate;

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9 C. and 5 C.p. f-crystals. 10 table.

The invention relates to new /benzodioxin, benzofuran or benzopyran/-alkyl-substituted guanidine formula I

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their pharmaceutically acceptable salts accession acids and their who appoints hydrogen or C1-C6- alkyl;

R2denotes hydrogen, C1-C6- alkyl, C3-C6alkenyl or C3-C6- quinil;

R3denotes hydrogen or C1-C6- alkyl; or

R2and R3taken together form a bivalent radical of the formula/CH2/m- where m = 4 or 5; or

R1and R2taken together form a bivalent radical of formula-CH=CH -, or the formula /CH2/n-, where n = 2, 3 or 4; or

R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH=, -CH=CH-N= or-CH=N-CH=, where one or two hydrogen atoms may be replaced by halogen, C1-C6-alkyl, C1-C6-alkoxyl, piano, amino group, mono - or di-/C1-C6-alkyl/- amino group, mono or di-/C3-C6-cycloalkyl/- amino group, aminocarbonyl /C1-C6-alkyl>/- aminocarbonylmethyl;

R4denotes hydrogen or C1-C6- alkyl;

Alk1denotes a divalent C1-C3- ascandilwy radical,

A denotes a divalent radical of the formula:

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where each R5denotes hydrogen or C12-C15- alcander or C5-C7- cycloalkenyl; and each p = 0, 1, or 2; and

R7and R8each, independently of one another, denote hydrogen, halogen, C1-C6- alkyl, hydroxyl, C1-C6- alkyloxy, cyano, amino /C1-C6-alkyl, carboxyl, C1-C6- alkyl oxycarbonyl, nitro, amino, aminocarbonyl /C1-C6-alkyl/ - carbylamine; or mono - or di-/C1-C6-alkyl/ - amino group;

provided that excluded [2-[/2,3 - dihydro-1,4-benzodioxin-2-yl/-methyl]-amino]-ethyl-guanidine.

Known /EP N 3387771/ derivatives benzopyran which exhibit inhibitory activity on Maillard reaction and possess anti-oxidant action.

Also known arZneim-Forsch 25 /9/, S. 1404 /1975/ [2-[/2,3-dihydro-1,4-benzodioxin-2-yl/-methyl] -amino] -ethyl - guanidine used to reduce the level of norepinephrine In the WIPO - 83/03607 describes a number of cyanoguanidine with antihypertensive and vasodilator activity.

The present invention is the creation of new compounds with selective vasoconstrictor activity, to form compositions for treating conditions Swede new compounds of General formula I.

The compounds of formula /1/, where R2, R3or R6denote hydrogen, can also exist in their tautomeric forms. Such forms are within the scope of the present invention.

As used in the above definitions, halogen denotes fluorine, chlorine, bromine and iodine; C1-C4-alkyl refers to linear and branched chain saturated hydrocarbon radicals with 1-4 C atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, etc.

C1- C6-alkyl represents C1-C4- alkyl and the higher homologues with 5-6 C atoms, such as, for example, pentyl, hexyl, 1-methylbutyl, etc.; C3-C6alkenyl refers to linear and branched chain hydrocarbon radicals containing one double bond and having 3-6 C-atoms, such as for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, etc. and the carbon atom of the above C3- C6- alkenyl associated with the nitrogen atom preferably is saturated; C3- C6- quinil refers to linear and branched chain hydrocarbon radicals containing one triple bond and having 3-6 C-atoms, such as for example, 2-PROPYNYL, 3-butini linelog radical, linked to the nitrogen atom, preferably saturated, C3- C6- cycloalkyl denotes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

C1- C3alcander denotes a divalent, linear and branched chain saturated hydrocarbon radicals with 1 to 3 C-atoms, such as for example, meander, 1,2-ethandiyl, 1:3-propandiol, 1,2-propandiol, etc.; C2- C15- alcander denotes a divalent, linear and branched chain saturated hydrocarbon radicals with 2 to 15 C atoms, such as, for example, 1,2 - ethandiyl, 1,3 - propandiol, 1,4 - butandiol, 1,5 - pentandiol, 1,6 - hexandiol, 1,7 - heptanediol, 1,8 - octandiol, 1.9 - nonanediol, 1,10 - decanediol, 1,11 - undecanedioic, 1,12 - dodecanediol, 1,13 - tridecanol, 1,14 - tetradecane, 1,15 - pentadecanedioic, and their branched isomers; C5- C7- cycloalkenyl denotes a divalent, cyclic, saturated hydrocarbon radicals, such as, for example, 1,2-cyclopentanediol, 1,3-cyclopentanediol, 1,2-cyclohexanediol, 1,3-cyclohexanediol, 1,4-cyclohexanediol, 1,2-cycloheptadiene, 1,3-cycloheptadiene, 1,4-cycloheptadiene.

Pharmaceutically acceptable salt accession acids include therapeutically active non-toxic forms saleitem processing the main form of compounds 1 appropriate acid, as the inorganic acid, such as halogen acids, for example hydrochloric acid, Hydrobromic acid, etc.; sulfuric acid, nitric acid, phosphoric acid and so on; or organic acids, such as acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, oxalic acid, perpendiculat, butanedioate, /Z/-2-butandikislota, /E/-2-butandikislota, 2-hydroxybutyrate, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylate acid, methanesulfonate, econsultation, benzosulfimide, 4-methyl-benzosulfimide, cyclohexanesulfamic, 2-hydroxybenzoic acid, 4-amino-2-hydroxy-benzoic acid and the like acids. On the contrary, the salt form by treatment with alkali may be converted into the form of a free base.

The term "salt of the accession also includes hydrated forms and the form of the accession of the solvent, which is able to form compounds of the formula /1/. Examples of such forms are, for example, hydrates, alcoholate, etc., a Component may be acyclic, in which case R1preferably represents hydrogen, methyl or ethyl; R2preferably the seat is mentioned component may also be cyclic, in which case you can represent radicals of the formula:

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where

R3in particular represents hydrogen or methyl.

The last cyclical components can be unsubstituted or substituted, preferably by halogen, especially iodine; C1-C6- alkyl, especially stands C1- C6- alkoxyl, especially methoxy group, a cyano; amino; di-/C1- C6-alkyl/-amino group, especially dimethylaminopropoxy; or aminocarbonyl.

Interest compounds are those compounds of formula I, where Alk1denotes - CH2-CH2- or-CH2-, especially - CH2-.

Also of interest such compounds of formula I, where R4denotes hydrogen or C1-C4-alkyl, especially methyl.

Further, of interest such compounds of formula I, where X denotes - CH2and where R7and R8each, independently of one another, denote hydrogen; halogen, preferably fluorine, chlorine or bromine; C1-C6-alkyl, preferably methyl, ethyl, propyl or butyl; C1-C6-alkoxy, preferably a methoxy group; hydroxyl; cyano; amino; amino-/C1-C

Other interest compounds are those compounds of formula I, where X = 0 and where R7and R8each, independently of one another, denote hydrogen, halogen, preferably fluorine, chlorine, bromine;

C1-C6-alkyl, preferably methyl or ethyl; C1-C6-alkoxy, preferably a methoxy group; hydroxyl; cyano - or nitro-group.

Also of interest compounds are such compounds where X denotes a direct bond and R7and R8each, independently of one another, denote hydrogen; halogen, preferably fluorine, chlorine or bromine; or C1-C6-alkyl, preferably methyl or ethyl.

Particular compounds are those compounds of formula I, where A denotes the radical of the formula /a/; Alk2represents C2-C15-alcander, especially C2-C10-alcander, mainly C2-C6-alcander, preferably 1,3-propandiol; R5denotes hydrogen or methyl; and R6denotes hydrogen or methyl.

Hereinafter, the preferred compounds are those compounds of formula I, where A denotes the radical of the formula a /b/ or /c/, p = 0, 1, or 2, especially 0 Il.

Especially interesting are such compounds where the absolute configuration of the carbon atom in position 2 in the formula /I/, indicated with asterisk /x/, such as shown in the formula below:

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Particularly interesting compounds are those which have substituents in the 7 - or 8-position as defined in the formula /I/ benzodioxane, benzofuranol or benzopyranones component.

The preferred compounds are those compounds of formula I, where X denotes-CH2-; R7and R8each, independently of one another, denote hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxyl, hydroxyl, or cyano, especially when substituted in the 7 - or 8-position benzopyrano component and where A denotes the radical of the formula /a/, where Alk2represents C2-C10-alcander PII R5and R6each, independently of one another, denote hydrogen.

The most preferred compounds are N-[/3,4-dihydro-2H-1-benzopyran-2-yl/methyl] N'/1,4,5,6-tetrahydro-2 - pyrimidinyl/-1,3/-propandiamine, its stereochemical isomers, especially the R - isomer, its pharmaceutically acceptable salt accession acids.

Term the formula I /I/. If not specified particularly, the chemical name of the compounds denotes the mixture of all possible stereochemical isomeric forms, with the above mixture include all diastereomers and enantiomers of basic molecular structure. Mainly, stereogenic centers may have the R - or S-configuration; substituents of the divalent saturated cyclic hydrocarbon radicals may have either the CIS-or TRANS-configuration, and C3-C6-alkeline radicals may be E or Z configuration. Stereochemical isomeric forms of the compounds of the form /I/ is also included in the scope of the present invention.

The compounds of formula (I) is produced by the interaction of the diamine of formula (II), where A, R4, R7and R8are specified in the formula /I/ values, with a reagent of formula /III/, where R1, R2and R3are specified in the formula /I/ values, and W1indicates reactive delete the group, such as, for example, halogen, e.g. chlorine, bromine, alkoxy, for example, a methoxy group, ethoxypropan, etc.; alloctype, for example, fenoxaprop etc.; allylthiourea, for example, methylthio-, ethylthiourea etc.; aristocrata, for example, menzilcioglu, etc.

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Above the reaction, such as, an alcohol, e.g. methanol, ethanol, propanol, etc; halogenated hydrocarbons, e.g. dichloromethane, trichloromethane, etc. or a simple ether, e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane and so on ; aromatic hydrocarbons such as benzene, toluene, xylene, etc., For binding the acid, which can be formed in the reaction, optionally you can add a base, such as, for example, a carbonate of an alkali metal, e.g. sodium carbonate or potassium; an acid carbonate of an alkali metal, for example, acidic sodium carbonate or potassium; an appropriate organic base, such as N,N-diethylethanamine, pyridine, N-/1-methylethyl/-2-propanamine, and similar reasons. Increased temperatures can increase the reaction rate. Preferably the reaction is carried out at the boiling temperature of the reaction mixture under reflux.

The compounds of formula I can also be obtained by reductive N-alkylation of amino formula /VI/ using the appropriate aldehyde of the formula /V/, where r=0,1 or 2.

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The above reaction is carried out by mixing the reagents in an appropriate solvent, such as, and so spirt p. ; aromatic solvents such as benzene, toluene, xylene, etc. is Optional, you can use topolitical, to remove the water formed during the reaction. The resulting Imin then can be recovered by catalytic hydrogenation in the presence of an appropriate catalyst, such as, for example, palladium-on-charcoal, palladium-on-barium sulfate, platinum-on-charcoal, Raney Nickel, etc. in a suitable solvent such as an alcohol, e.g. methanol, ethanol and so on ; a simple ether, e.g. tetrahydrofuran, 1,4-dioxane, and so forth; ester carboxylic acids, for example, ethyl acetate, butyl acetate and so on; or a carboxylic acid, e.g. acetic acid, propionic acid, etc., Optionally the reaction can be performed at elevated temperatures and/or pressures.

The intermediate aldehyde of the formula /V/ can be obtained by restoring the acyl derivative of the formula /V/, where r has the above meaning, and V denotes a halogen, for example chlorine, bromine. Allalone can be obtained by reacting the acid of formula IV, where V=OH, with a halogenation reagent such as thionyl chloride, trichloride phosphorus, tribromide phosphorus, oxalicacid etc. Pole, such as, for example, halogenated hydrocarbons such as dichloromethane, chloroform, etc., aromatic hydrocarbons such as benzene, toluene, xylene and so on ; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc., or dipolar aprotic solvents, such as N,N-dimethylformamide, N, N-dimethylacetamide, etc., Mixing and rising temperatures increase the reaction rate.

The above restore acylhomoserine formula /IV/, for example, can be performed by catalytic hydrogenation in the presence of a catalyst such as palladium-on-charcoal, palladium-on-barium sulfate, platinum-on-charcoal, and so on; in appropriate solvents, such as ethers, for example diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.; preferably mixed with a dipolar aprotic solvent, such as, for example, N, N-dimethylformamide, N,N-dimethyl-ndimethylacetamide, etc. is Optional, you can add a catalytic poison, such as thiophene, quinoline-sulfur, etc., the Sequence of reactions on the basis of the intermediate aldehyde of formula /IV/, to obtain compounds of formula (I) can be carried out in the same tank.

Connection fo the uly /VII/, where W2represents a reactive delete the group, such as, for example, halogen, for example chlorine, bromine or iodine, sulfonyloxy, for example, methanesulfonate, benzosulfimide, toluensulfonate, and so on ; in appropriate solvents, such as ketones, e.g. 2-propanone, 2-butanone, etc.; ethers, for example diethyl ether, tetrahydrofuran, 1,4-dioxane and so on; aromatic hydrocarbons such as benzene, toluene, etc.; dipolar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, etc.

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Mixing and heating can increase the reaction rate. Optional, for binding formed during the reaction of the acid can be added a suitable base, such as, for example, a carbonate of an alkali metal, e.g. sodium carbonate, potassium carbonate; acid carbonate of an alkali metal, for example, acid sodium carbonate, acidic potassium carbonate, etc., appropriate organic base, such as N,N-diethylethanamine, pyridine, etc.

The compounds of formula I, where A denotes a bivalent radical of the formula /a/ and R5denotes hydrogen, and the above connection of the Sabbath.
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The above dibenzylamine can be carried out according itself known methods, such as catalytic hydrogenation using appropriate catalysts, such as platinum-on-charcoal, palladium-on-charcoal, in an appropriate solvent, such as alcohols, e.g. methanol, ethanol, 2-propanol and so on; ethers, for example diethyl ether, tetrahydrofuran, diisopropyl ether, etc., If necessary, can be applied elevated temperature and pressure.

The compounds of formula I, where R1denotes hydrogen, and the above-mentioned compounds represented by the formula /I-b/, can be obtained by hydrolysis of the intermediate cyanoguanidine formula IX-a/:

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The above hydrolysis can be performed by stirring the intermediate of cyanoguanidine formula IX-a/ in the presence of acid, such as, inorganic acid, e.g. hydrochloric acid, bromatologia acid, sulfuric acid and so on; or an organic acid, such as acetic acid, formic acid, etc.; optionally mixed with an appropriate solvent, such as alcohol, e.g. methanol, ethanol, propanol, etc. ; simple ether, for example diethyl ether, diisopropylidene /IX-b/. The above intermediate compound of formula IX-b/ before you can select and then hydrolyze to obtain compounds of the formula /I/.

The compounds of formula I also can be transformed into any other by transformations of functional groups.

For example, the compounds of formula (I) in the where - component denotes pyrimidinyl part, and the above-mentioned compounds denoted by the formula /I-c/, can be turned into a tetrahydro-counterparts /I-d/ by a certain kind of way catalytic hydrogenation:

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This recovery can be accomplished simultaneously with dibenzylammonium mentioned above in the description of the synthesis of compounds of the formula /I-a/.

Further, the compounds of formula (I) with C3-C6-alkenylphenol group or a C3-C6-alkenylphenol group can be converted into the corresponding compounds with C1-C6is an alkyl group according to known kinds of ways hydrogenation. The compounds of formula (I) with cyano can be converted to the corresponding compounds containing aminomethyl Deputy, according to known kinds of ways hydrogenation. Compounds with CNS Deputy can be converted into compounds with a hydroxyl group by obrabotvane acid, for example, bromatologia acid, or tribromide boron, etc., Compounds containing amino Deputy, can N-allievate or N-alkilirovanii according to known kinds of ways N-acylation or N-alkylation.

Some intermediate and starting materials are known compounds which can be obtained in accordance with known methods of obtaining and some intermediate compounds are new.

Intermediate compounds of formula (II), where A denotes the radical of the formula /a/ and R6denotes hydrogen, and the above intermediate compound denoted by formula (II-a/, can be obtained by recovering the nitrile of the formula /X/, where q=1-14, recovery. The above restore, for example, can be accomplished by catalytic hydrogenation using an appropriate catalyst such as, for example, Raney Nickel, palladium-on-charcoal, palladium-on-barium sulphate, etc.,; in an appropriate solvent, such as alcohol, e.g. methanol, ethanol, propanol, etc.; simple ether, for example diethyl ether, tetrahydrofuran, 1,4-dioxane, etc. or a mixture of such solvents.

Preferably voli pressure.

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The above restore can also be done by mixing the nitrile with a reducing agent such as borane, sociallyengaged, etc. in an appropriate solvent, such as a simple ether, for example, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, etc.; or a hydrocarbon, e.g. pentane, hexane and so forth; aromatic solvent, e.g. benzene, toluene, xylene, etc., If necessary, you can use elevated temperatures to increase the rate of reaction.

Intermediate compounds of the formula /X/ can be obtained by reacting an amine of the formula /XI/ with a reagent of formula /XII/, where W2and q have the above significance, in an appropriate solvent, such as a dipolar aprotic solvent, e.g. N,N-dimethylformamide, dimethylsulfoxide, acetonitrile and so on; aromatic solvent, e.g. benzene, toluene, xylene and so on; a ketone, e.g. 2-propanone, 4-methyl-2-pentanon etc.; simple ether, for example diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.

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To bind the acid which is formed during the reaction, you can add the base, as indicated in obtaining the compounds of formula (I) from intermediates Megalochori amine can also denote benzyl. This protective group can then be removed at a later stage of the synthesis.

To obtain the intermediate compounds of the formula /X/, where q=2, and the above intermediate compounds denoted by the formula /X-a/, the alkylation can be carried out by mixing an amine of the formula /XI/ 2-propenenitrile in an appropriate solvent such as an alcohol, e.g. methanol, ethanol, propanol, etc.; simple ether, for example diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.

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Higher temperatures increase the reaction rate. Preferably the reagents are stirred at the boiling temperature under reflux the reaction mixture.

Intermediate compounds of formula /XX-a/, where R4, R7, R8X Alk1have the above meaning and denotes A bivalent radical of the formula /a/, /c/, /d/, /e/, where R2denotes hydrogen, C1-C6- alkyl, C3- C6alkenyl or C3-C6-quinil, and R3denotes hydrogen or C1-C6- alkyl, or R2and R3taken together form a bivalent radical of the formula /CH2/mwhere m is 4 or 5, are new.

Intermediate compounds of formula IX-a/ you can obtain way jonesborobuy remove the group as defined in the formula /III/.

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The above reaction can be performed by stirring the reactants in an appropriate solvent, such as alcohol, e.g. methanol, ethanol and so on; halogenated hydrocarbons, e.g. dichloromethane, chloroform, etc.; an aromatic solvent, e.g. benzene, toluene, xylene and so on; dipolar aprotic solvent, for example n, N-dimethylformamide, n, N-dimethylacetamide, etc., not necessary for binding the acid, which is formed in the process of implementation of the response, you can add a base, as indicated in obtaining compounds of formula (I) from intermediates of formula II, and formula /III/. Preferably the reaction is carried out at room temperature.

Intermediate compounds of formula /XIII/ can be obtained by interaction of cyanamide of the formula /XIV/, where W1is specified in the formula /III/ value, an amine of the formula /XV/.

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The above reaction can be performed by stirring the reactants in an inert solvent such as halogenated hydrocarbon, e.g. dichloromethane, chloroform, and so on; aromatic solvent, e.g. benzene, toluene, etc.; simple ether, for example diethyl ether, Tetra is hawlati basis. Appropriate bases are carbonates and acid carbonates of alkaline or alkaline earth metals.

For example, as sodium carbonate, sodium bicarbonate, potassium carbonate, etc., Increased temperatures can increase the rate of reaction.

Pure stereochemical isomeric forms of the compounds of the present invention can be obtained by known methods.

Diastereoisomer can be divided by physical separation methods such as selective crystallization and chromatographic techniques such as liquid chromatography. Enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. The above pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction proceeds in a stereospecific. Preferably, if desired specific stereoisomer, the above compound can be synthesized by stereospecific methods of obtaining. In these methods, preferably using enantiomerically pure starting materials. Stereochemical is of the formula /I/, their pharmaceutically acceptable salts accession acids and their stereochemical isomeric forms possess interesting pharmacological properties: they exhibit 5 HT1- etc. agonistic activity. Compounds of the present invention have strong and selective vasoconstrictor activity. They are suitable for the treatment of conditions that are associated with the extension (blood) vessels. For example, they are suitable for the treatment of conditions characterized by or associated with headaches, such as migraine, severe headache and headache associated with vascular disorders. These compounds are also suitable for the treatment of venous insufficiency and for treating conditions associated with hypotension.

Vasoconstrictor activity of the compounds of formula (I) can be determined using the test in vitro, as described in "Instantaneous chauges of alpha-adrenoreceptor offinity caused by moderate cooling in cauine cutaneous Veins /Instant changes means to alpha-adrenergic receptors caused a moderate cooling in the skin blood vessels of the dog] in the American Journal of Phusiology, 234/4/, H 330-H, 337, 1978, or in the test described in pharmacological example, where similar serotonin response of the compounds of the present invention experience is similar pharmacological activity.

Taking into account their useful pharmacological properties, which are the subject of the invention compounds may be formulated into various pharmaceutical forms for administration. To prepare the pharmaceutical compositions of the present invention, an effective amount of individual compounds in base form or in salt form accession acid, as the active ingredient, combined with careful stirring, with a pharmaceutically acceptable carrier, and the carrier depending on desirable for the injection form of the drug. These pharmaceutical compositions are preferably in unitary dosage form suitable, preferably, for administration by the oral, rectal /intestinal/, subcutaneously, or by parenteral injection. For example, when preparing the compositions in oral dosage form, may be used any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja agents and the like, in the case of powders, pills, Capua oral unit dosage form, in case which usually use solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes sterile water, at least for the most part, although, for example, to aid solubility, may be included with other ingredients. For example, it is possible to prepare solutions for injection, in which the carrier is a saline solution, glucose solution or a mixture of saline and glucose solutions. It is also possible to prepare a suspension for injection, use the appropriate liquid carriers, suspendresume agents, etc. In suitable for subcutaneous injection compositions, the carrier optionally includes enhancing the penetration of the agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor quantities, and additives should not cause significant adverse effects on the skin. The above additives can facilitate the introduction into the skin and/or may be useful for the preparation of the desired compositions. These compositions can be entered in different ways, for example, in the form of a transdermal patch, in the form of rubbing, in the form of ointment. Especially, it is preferable to formulate the above pharmaceutical to the full-time form as used herein in the description and the claims refers to physically discrete units suitable as unitary dosages, each unit contains a defined quantity of active ingredient calculated to produce the desired therapeutic effect, in Association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including tablets scored or coated tablet, capsule, pill, packing powders, pills, solutions for injection or suspension for injection, preparations for admission on a full teaspoon or tablespoon, etc. and their individual set.

Therefore, the compounds of the present invention can be used as medicines for the treatment of conditions associated with the expansion of blood vessels, more specifically hypotension, venous insufficiency and especially headaches, including migraines. Compounds of the invention are also suitable for the treatment of warm-blooded animals suffering from conditions associated with vasodilation, such as hypotension, venous insufficiency and especially headache, including migraine, by introducing an effective amount of the compounds of formula (I), e is the GKO to determine the effective amount from the test results, are presented below. It is usually assumed that the effective number should be from 1 μg/kg to 1 mg/kg of body weight, and, in particular, 2-200 µg/kg body weight. May be suitable introduction of necessary doses of two, three, four or more partial doses at appropriate intervals throughout the day. The above partial doses may be formulated as unit dosage forms, for example, containing from 0.005 to 20 mg and in particular 0.1 to 10 mg of the active ingredient in a unit dosage form.

The following examples are intended to illustrate and not limit the framework of the invention in all its aspects.

Experimental part

A. the production of intermediate compounds

Example 1.

a) To a stirred and cooled (0oC) the solution is 32.8 g of 3,4-dihydro-2H-1-benzopyran-2-methanol (71 ml of pyridine and 135 ml of benzene was added dropwise a solution of 41.9 g of 4-methyl-benzosulfimide in 72,5 ml of benzene. At the end of the addition stirring is continued for 25 hours, the Reaction mixture was washed successively with hydrochloric acid (10%), water and sodium carbonate solution (10%) of the organic layer is dried, filtered and evaporated. The residue is purified by number is to 28.3 g {3,4 - dihydro-2H-1-benzopyran-2-methyl} -4-methylbenzenesulfonate /ester/ in the form of a solid residue. So pl. 59,4oC (intermediate compound). Similarly also receive { 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methyl} -4 - methylbenzenesulfonate /ester/ (intermediate compound 2).

b) a Mixture of 7.7 g of the intermediate compound /1/, 5.3g of benzoylmethylene, 5 g of sodium carbonate and 250 ml of 4-methyl-pentanone stirred and refluxed using a water separator. The reaction mixture is cooled and washed with water. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography (silica gel, CHCl3/CH3OH = 90; 10). Eluent target (desired fraction is evaporated and the residue is converted into the oxalate (salt) in ethanol. The salt is filtered off and suspended in 2-propanone. The product is filtered and dried, obtaining of 1.16 g (19,5%) of 3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine-oxalate (1: 1) (intermediate compound 3).

Similarly also receive 2,3-dihydro-N-(phenylmethyl)-1,4-benzodioxin-2-methanamine (intermediate compound 4).

Example 2. In the European patent 0145067 describes the synthesis of (+)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (about what soedineniya /5/ and 244 ml of toluene was added dropwise, within 85 min, 54 ml of thionyl chloride. Upon completion of the addition, stirring is continued for 2 h at 80oC. After cooling to room temperature, the reaction mixture is evaporated. The residue is treated with toluene and the solvent is again evaporated, getting 60.4 g (100%) of (+)-(S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carbonyl-chloride as a residue (intermediate compound 6).

b) a Mixture 46,9 g of intermediate compound /6/ in 60 ml of N,N-dimethylacetamide and 350 ml of diisopropyl ether hydronaut in the presence of 3 g of palladium-on-coal as a catalyst (10%) and 5 ml of a solution of thiophene in methanol (4%). After absorption of the calculated amount of hydrogen the catalyst is filtered off and the filtrate added to a mixture of 25 g of benzoylmethylene, 20 g of potassium acetate and 300 ml of methanol. This mixture again hydronaut in the presence of 3 g of palladium-on-coal as a catalyst (10%) and 3 ml of a solution of thiophene in methanol (4%). After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is poured into water and the solution is alkalinized with NaOH (50% solution).

The product is extracted with dichloromethane and the extract is dried, filtered and evaporated. The residue is purified by column items is to participate in hydrochloride (salt) in 2-propanone by adding saturated HCl in 2-propanol. The salt is filtered off and dried, obtaining 46,9 g (69,3%) of the hydrochloride of (+)-(S)-6-fluoro-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine. So pl. 210,7oC;

()2D0= +92,63(c = 0.1% in methanol), (intermediate compound 7).

Similarly also get:

(S)-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine (intermediate compound 8);

(-) (R)-6-fluoro-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine hydrochloride; so pl. 210,4oC; ()2D0= -79,47(c=0.1% in methanol) (intermediate compound 9);

(R)-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine (intermediate compound 10);

()-3,4-dihydro-2-methyl-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine (intermediate compound II).

C) a Mixture of 28 g of the intermediate /10/ and 300 ml of methanol hydronaut in the presence of 2 g of palladium-on-coal as a catalyst (10%). After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated, receiving of 18.2 g (100%) (-) (R)-3,4-dihydro-2H-1-benzopyran-2-methanamine in the form of the crude residue (intermediate compound 12).

Similarly also get:

(-)-2,3-dihydro-1,4-benzodioxin-2-methanamine (sub -, 4-dihydro-2H-1-benzopyran-2-methanamine (intermediate compound 15);

()-3,4-dihydro-6-methoxy-2H-1-benzopyran-2-methanamine (intermediate compound 16); and

()-3,4-dihydro-2H-1-benzopyran-2-methanamine (intermediate compound 17).

Example 3.

a) a Mixture of 34 g (ethyl)-4-oxo-1-piperidine-carboxylate, 20 g of 2-pyrimidinamine, 8 drops of acetic acid and to 103.5 ml of toluene is stirred for 28 h at the boiling point under reflux using a water separator. The reaction mixture is evaporated, receiving 50 g (ethyl)-4-(2-pyrimidinylidene)-1-piperidinecarboxylate as a residue (intermediate compound 18).

b) To a stirred and cooled (5 to 10oC) a mixture of 50 g of the intermediate compound (18) in 76 ml of methanol portions add 7.5 g of tetrahydroborate sodium. At the end of the addition stirring is continued first for 45 min at room temperature and then for 3 hours at the boiling temperature under reflux. After cooling, the reaction mixture was poured into water and the product extracted twice with benzene. The combined extracts washed with water, dried, filtered and evaporated. The remainder utverjdayut in a mixture of diisopropyl ether with 2-propanone. The product is filtered off and crystallized from benzene, receiving 7 g {ethyl}-4-(2-pyrimidinamine is and 80.5 ml Hydrobromic acid (48%) is stirred for 2 hours at the boiling temperature under reflux. The reaction mixture is evaporated and the residue is treated with water. All alkalinized with dilute sodium hydroxide solution, while cooling in an ice bath. The product is extracted with dichloromethane, and the extract is dried, filtered and evaporated. The residue was stirred in diisopropyl ether. The product is filtered and converted into the hydrochloride (salt) in 2-propanol. The salt is filtered off and crystallized from ethanol, receiving 2 g hemihydrate ()-N-(4-piperidinyl)-2-pyrimidinamine-dihydrochloride. So pl. 268,5oC (intermediate compound 20).

Example 4.

a) 3 ml N. N. N.-trimethylenetrinitramine was added dropwise to a stirred mixture of 60 g ()-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine in 350 ml of 2-propenenitrile. After stirring for 4 days at the boiling point under reflux, the reaction mixture is cooled and poured into diethyl ether. Everything is filtered through diatomaceous earth and the filtrate is evaporated, getting 21 grams(28,6%) ()-3-[(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/(phenylmethyl)-amino] -propanenitrile in the form of the crude residue (intermediate compound 21).

b) a Mixture of 21 g of the intermediate /21/ 250 ml of methanol hydronaut in the presence of 5 g of Nickel Linealuce 20 g (94%) ()-N/(3,4-dihydro-2H-1-benzopyran-2-yl)methyl/-N-(phenylmethyl)-1,3 - propandiamine in the form of the crude residue (intermediate compound 22).

C) a Mixture of 10 g of the intermediate /22/, of 4.2 g of 2-chloropyridine, 6 g of sodium carbonate and 100 ml of ethanol is stirred and heated for 18 hours the Reaction mixture is cooled and the solvent is evaporated. The residue is treated with water and the product extracted with diethyl ether. The extract is dried, ethyltrimethylammonium,polucha(88,5%)()-N/(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/N-(phenylmethyl)-N'- (2-pyrimidinyl)-1,3-propandiamine in the form of the crude residue (intermediate compound 23).

Similarly also receive (see tab.1).

< / BR>
Example 5.

a) To a stirred solution of 6 g of diphenylcarbonate in 50 ml of dichloromethane at room temperature add portions of 2.1 g of piperidine. Stirring is continued for 30 minutes at room temperature. The reaction mixture is evaporated and the residue is crystallized from diisopropyl ether. The crystals are filtered and dried, obtaining 4.6 g (80%) [phenoxy-(1-piperazinyl)-methylene]-cyanamide. So pl. 85,7oC (intermediate compound 32).

Similarly also receive: O-phenyl-N-cyano-N,N-dimethylcarbamate (intermediate compound 33).

b) a Mixture of 4.0 g ()-N/(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/-1,3-propandiamine, 4,2 g between the mixture is evaporated and the residue is dissolved in dichloromethane. The solution was washed with aqueous solution of Na2CO3(15%). The organic layer is separated, dried, filtered and evaporated. The residue is purified twice by column chromatography (silica gel, CH2Cl2/CH3OH = 95:5). Eluent target fraction is evaporated and the residue is converted into the oxalate (salt) in 2-propanol. The salt is filtered off and recrystallized from methanol. The crystals are filtered and dried, obtaining of 1.02 g (12,7%) ()-N-cyano-N-{3-[(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/amino]- propyl}-1-piperidinecarboxylate-oxalate (1:1). So pl. 176,0oC (intermediate compound 34).

Similarly also receive (see tab.2).

Example 6.

A mixture of 3.1 g ()-N'-cyano-N-{-[/(3,4-dihydro-2H - 1-benzopyran-2-yl)-methyl] -amino} -propyl-N'-ethylguanidine in a solution of 10 ml of hydrochloric acid in 2-propanol and 50 ml of methanol is stirred and refluxed for 30 minutes the Solvent is evaporated. The residue is dissolved in water and this mixture is alkalinized with aqueous (10%) NaOH solution. The resulting mixture was extracted with methylene chloride. The organic layer was separated, washed with water, dried over magnesium sulfate, filtered and the solvent is evaporated. The residue is purified by column of chromatogra and the solvent is evaporated. The residue is dissolved in 2-propanol and converted into the hydrochloride (salt) (1: 2) with saturated HCl in 2-propanol. The salt is filtered off and recrystallized from 2-propanol. The crystals are filtered and dried, obtaining 2,95 g dihydrochloride ()-N'-{[/(3- -[/(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/- amino]-propyl/-amino]-(ethylamino)-methylene}-urea.

So pl. of 182.2oC (intermediate compound 51).

Similarly also get dihydrochloride ()-N'-{[/(2-[/(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/- amino]-ethyl/-amino]-(ethylamino)-methylene} -urea.

So pl. 200,2oC (intermediate compound 52).

Example 7.

a) a Mixture of 12.5 g of 3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2 - methanamine, 9 g of 4-bromobutyronitrile, 200 ml of N,N-dimethylformamide and 10 ml of N,N-diethylethanamine stirred for 72 hours at room temperature. The reaction mixture is evaporated and the residue partitioned between diethyl ether and water. The organic layer is separated, dried, filtered and evaporated, receiving 11,(68,7%) ()-4-{ /(-3,4- dihydro-2H-1-benzopyran-2-yl)-methyl/(phenylmethyl)- amino}-butanetriol (Intermediate compound 53).

b) a Mixture of 11 g of the intermediate compound (53) and 250 ml of tetrahydrofuran hydronaut in the presence of 2 g nor the mandate. The residue is partitioned between diethyl ether and water. The organic layer is separated, dried, filtered and evaporated to give 10 g (90,6%) ()-N/(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/N-(phenylmethyl)- 1,4-butanediamine (intermediate compound 54).

C) a Mixture of 10 g of the intermediate compound (54), of 5.4 g of 2-chloropyrimidine, 8 g of sodium carbonate and 250 ml of ethanol is stirred for 18 h at boiling temperature under reflux. The reaction mixture is evaporated and the residue partitioned between diethyl ether and water. The organic layer is separated,dried,ethyltrimethylammonium,polucha,g(83,3%)(

Example 9.

a) To a stirred mixture of 38.6 g N. N-dibenzyl-N-(3,4-dihydro-2H-1-benzopyran-2-yl)-1,2-academia, 1.2 g n-N dimethyl-4-pyridylamine and 300 ml of acetonitrile at room temperature, was added dropwise a solution of 24 g of bis(1,1-dimethylethyl)-dicarbonate in 50 ml of acetonitrile.

After stirring for 3 h, the reaction mixture is evaporated and the residue diluted with water. The product is extracted with diethyl ether and the extract is dried, filtered and evaporated, receiving 50 g (100%) ()-1,1-dimethylethyl-{2-/bis(phenylmethyl)-amino/-ethyl} /(3,4 - dihydro-2H-1-benzopyran-2-yl)-methyl)-carbamate in the form of the crude residue (intermediate niederlage-on-coal (10%) as catalyst. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filter is evaporated. The residue is purified by column chromatography (silica gel; CH2Cl2/CH3OH (NH3) = 95:5).

Eluent target fraction is evaporated, getting 1,22, ()- 1,1-dimethylethyl-(2-amino-ethyl)-/X,4-dihydro-2H-1-benzopyran - 2-yl)-methyl)-carbamate (intermediate compound 75).

C) To a mixture of 7.0 g of the intermediate /75/ 100 ml of chloroform added to 3.3 g (dimethyl) cyanocarbonimidate. After stirring for 48 hours at boiling temperature under reflux, the reaction mixture is evaporated. The residue is purified by column chromatography (silica gel, CH2Cl2/CH3OH=99:1). Eluent target fraction is evaporated, receiving a 9.09 g (96,5%) ()-1,1-dimethylethyl-{ 2-[/(cyanoimino)-(methylthio)-methyl/- amino]-ethyl}-/(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl)-carbamate (intermediate compound 76).

g) To a mixture of 18 g of intermediate compounds /76/ 150 ml ethanol add 40 ml of water (70%) solution of ethanamine. After stirring for 16 hours at boiling temperature under reflux, the reaction mixture is evaporated and the residue is dissolved in dichloromethane. The solution is washed in>/CH3OH = 95:5). Eluent target fraction is evaporated and the residue precipitated from diisopropyl ether, receiving 13,9, (77,2%) ()-1,1-dimethylethyl-{ 2-[/cyanoimino)(ethylamino)-methyl/-amino] ethyl}-/3,4-dihydro-2H-1-benzopyran-2-yl)-methyl)-carbamate. So pl. 115,4oC (intermediate compound 77).

d) a Mixture of 6 g of intermediate compound /77/ 20 ml of saturated HCl in 2-propanol and 200 ml of methanol is stirred for 30 minutes at boiling temperature under reflux. The reaction mixture is evaporated and the residue crystallized from methanol. The product is filtered and washed with methanol and diisopropyl ether, receiving of 4.3 g (73%) dihydrochloride ()-N-{[/(3,4 - 2-dihydro-2H-1-benzopyran-2-yl)-methyl/-amino] -ethyl/- amino] -(ethylamino)-methylene}urea. So pl. 200,2oC (intermediate compound 78).

B. Obtaining the target product

Example 10. A mixture of 7.4 g of N1-/(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/-1,2-academia, 4.1 g of chloropyrimidine and 4.2 g of sodium carbonate and 50.6 ml of ethanol is stirred for 4 hours at the boiling temperature under reflux. The reaction mixture is evaporated. The residue is purified by column chromatography (silica gel, CHCl3/CH3OH=90:10).

Eluent target fraction is evaporated and the residue PR is the ()-N-/3,4-dihydro-2H-1-benzopyran-2-yl)methyl/-N'-(2 - pyrimidinyl)-1,2-amandemen-dihydrochloride. So pl. 192,7oC (compound 1).

Example 11. A mixture of 8.5 g of 3,4-dihydro-2H-benzopyran-2-carbonyl-chloride, 30 ml of N, N-dimethylacetamide and 100 ml of diisopropyl ether hydronaut in the presence of 2 g of palladium-on-coal (10%) as catalyst and 2 ml (4%) solution of thiophene in methanol. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate added to a mixture of 5 g ()-N1-(2-pyrimidinyl)-1,2-propandiamine and 150 ml of methanol. All hydronaut in the presence of 2 g of palladium-on-coal (10%) as catalyst and 5 g of potassium acetate. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in diethyl ether, washed with aqueous NaOH solution, dried, filtered and evaporated. The residue is converted into the oxalate (salt) (1:2) in 2-propanol. The salt is filtered off and dried in vacuum at 60oC, receiving 8.7 g (55,1%) ()-N1-/3,4-dihydro-2H-1-benzopyran-2-yl)methyl/- N2-(2-pyrimidinyl)-1,2-propandiamine-oxalate (1:2). So pl. 150,2oC (compound 119)

Example 12. A mixture of 4.8 g of 6-bromo-3,4-dihydro-2H-1-benzopyran-2 - carboxaldehyde and 3.1 g of N-2-pyrimidinyl-1,3-propandiamine in 200 ml of methanol hydronaut when using 2 g of platinum on activated axenia absorption of H2the catalyst is filtered off. The filtrate is evaporated. The residue is dissolved in 2-propanol and converted into the salt of oxalic acid (1: 2). The salt is filtered off and recrystallized from ethanol-water. The crystals are filtered and dried, obtaining 2,7, (18,8%) ()-N-/(6-bromo-3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/-N'-(2 - pyrimidinyl)-1,3-propandiamine-oxalate (1:2). So pl. 215,3oC (compound 20).

Example 13. A mixture of 3 g of N-2-pyrimidinyl-1,3-propandiamine in 150 ml of methanol and 10 ml of a solution of hydrogen chloride in 2-propanol hydronaut when using 2 g of palladium on active coal (5%) as catalyst. After cessation of absorption of H2the catalyst is filtered off. To the filtrate is added a solution of 4.8 g of 6-bromo-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde and 100 ml of methanol. Add 10 g of potassium acetate and the resulting mixture hydronaut when using 2 g of platinum on active coal (5%) as catalyst, in the presence of 2 ml of a solution of thiophene in methanol (4%). After cessation of absorption of H2the catalyst is filtered off. The solvent is evaporated and the residue dissolved in a mixture of H2O/CH2Cl2. This solution is alkalinized with NaOH. The organic layer is separated, dried, filtered and the solvent is evaporated. the. The resulting fraction will recrystallized from ethanol-water. The crystals are filtered and dried, obtaining 3.5 g (31,2%) ()-N-/(6-bromo-3,4-dihydro-2H-1-benzopyran-2-yl)-methyl-/N'- (1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propeciaminoxidilua (1: 2). So pl. 204,8oC (compound 56).

Example 14. A mixture of 7.9 g {3,4-dihydro-2H-1-benzopyran-2-methyl}- 4-methylbenzenesulfonate (ester), 4.5 g of N-(4-piperidinyl)-2-pyrimidinamine, with 5.3 g of sodium carbonate and 100 ml of 4-methyl-2-pentanone stirred over night at the boiling point under reflux. The reaction mixture is evaporated and the residue diluted with water. The product is extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue is purified by column chromatography (silica gel, CH2Cl2/100%. Eluent target fraction is evaporated and the residue crystallized from acetonitrile. The product is filtered and dried, obtaining 28 g (98,8%) ()-N - {1-/(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/ -4-piperidinyl}-2-pyrimidinamine. So pl. 141,9oC (compound 128).

Example 15. A mixture of 8.4 g of (-)-(R)-N-(6-fluoro-3,4-dihydro-2H-1 - benzopyran-2-yl)-methyl-N-phenylmethyl-N'-(2-pyrimidinyl)-1,2-academia and 150 m methanol hydronaut in the presence of 2 g of palladium-on-coal (10%) as catalyst. Policyset by column chromatography (silica gel, CH2Cl2/CH3OH = 90:10).

Eluent target fraction is evaporated and the residue is crystallized from diisopropyl ether. The product is filtered and dried, obtaining 3.5 g (55,1%) of (-)-(R)-N-/(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl/- N'- (2-pyrimidinyl)-1,2-academia. So pl. 103,2oC.

()2D0= -76,58o(C = 1% in methanol) (compound 46).

Example 16. A mixture of 3.6 g hemihydrate (-)-(R)-N-/(3,4-dihydro-2H-1-benzopyran-2-yl)methyl/-N'-(2 - pyrimidinyl)-1,3-propandiamine-dihydrochloride in 150 ml of methanol and 20 ml of saturated HCl in 2-propanol hydronaut in the presence of 1.5 g of palladium-on-coal (2%) as catalyst. After absorption of the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated. The product is crystallized from acetonitrile, filtered off and dried, obtaining 2.7 g (74,0%) hemihydrate (-)-(R)-N-/(3,4-dihydro-2H-1-benzopyran-2-yl)methyl/-N'-(1,4,5,6 - tetrahydro-2-pyrimidinyl)-1,3-propandiamine-dihydrochloride. So pl. 200,2oC. ()2D0= -60,97o(C = 1% in methanol) (compound 62).

Example 17. A mixture of 7.8 g of N-(3,4-dihydro-2H-1-benzopyran-2-yl)- methyl-N-phenylmethyl-N'-(2-pyrimidinyl)-1,3-propandiamine, 200 ml of methanol and 10 ml of saturated HCl in 2-propanol hydronaut in the presence of 2 g Yo filtered off and the filtrate is evaporated. The residue is converted into the dihydrochloride (salt) in 2-propanol by adding saturated with hydrogen chloride 2-propanol. The salt is filtered off and dried, obtaining 2.9 g (38,0%) ()-N/ (3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propandiamine-dihydrochloride. So pl. 227,0oC (compound 95).

Example 18. A solution of 6.9 g ()-N/(3,4-dihydro-6-methoxy-2H-1-benzopyran-2-yl)-methyl/ -N'-(2-pyrimidinyl)-1,3-propandiamine in 50 ml of dichloromethane was added dropwise to a mixture of 150 ml of tribromide boron in dichloromethane (1 M) and 250 ml of dichloromethane, stirred under nitrogen atmosphere at 0oC.

The reaction mixture was stirred for 2 h at room temperature. The precipitate is filtered off and stirred in a mixture of 150 g of ice, 42 g of sodium chloride and 175 ml of NH4OH. Add dichloromethane and everything is filtered through diatomaceous earth. The layers are separated and the aqueous layer was extracted with dichloromethane. The combined organic layers dried, filtered and evaporated. The residue is purified by column chromatography (silica gel, CH2Cl2/CH3OH(NH3) = 95:5). Eluent target fraction is evaporated and the residue is converted into the salt of oxalic acid in 2-propanone. The salt is filtered off and dried in vacuum at 60oC (compound 49).

Primer. A mixture of 2.6 g ()-N"-cyano-N-{3-[/(3,4-dihydro - 2H-1-benzopyran-2-yl)-methyl/amino]propyl}-N-(1-methylethyl)-guanidine in 20 ml of 6 N. hydrochloric acid is stirred for 2 hours at the boiling temperature under reflux. The reaction mixture is evaporated and the residue is dissolved in 10 ml of methanol. The resulting solution is filtered and the filtrate is evaporated. The oily residue is dissolved in 10 ml of ethanol. The mixture is filtered and the filtrate is evaporated, getting 1,32 g (44,4%) dihydrochloride ()-N-{3-[/(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl/-amino] -propyl}-N-(1-methylethyl - guanidine. So pl. 97,5oC (compound 150).

Example 20. 2.3 g ()-N-/(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl/ -1,3-propandiamine and 1.6 g of monochloride iodine dissolved in 50 ml of acetic acid. The resulting solution was stirred over night while boiling under reflux. The solvent is evaporated. The residue is purified by column chromatography on silica gel (eluting agent: CH2Cl2/CH3OH = 99: 1 to 95:5). Collect all the target fraction and the solvent is evaporated. The remainder (50% purity) is recrystallized from ethanol. The crystals are filtered and dried, obtaining 0,650 g (20,1%) monohydrochloride (+)-N-/ (6-fluoro-3,4-dihydro-2H-1-the EP 21. A mixture of 0.250 g of palladium-on-active charcoal, 10%, 50 ml of methanol is stirred under vacuum and rinsed with hydrogen. Add 5 ml of saturated HCl in 2-propanol. Then was added dropwise a solution of 0.5 g of the dihydrochloride hemihydrate ()-3,4-dihydro-2- {[/3-(2-pyrimidinamine)-propyl-amino]-methyl} -2H-1 - benzopyran-6-carbonitrile in 5 ml of methanol. The reaction mixture hydronaut with stirring for 2 hours After cessation of hydrogen absorption, the mixture is filtered through dicalite. The remaining filtrate is washed with methanol. The filtrate is evaporated and the residue is stirred in 10 ml of CH3OH, filtered over a folded filter paper and washed with 5 ml of methanol. The filtrate is evaporated. The residue is stirred in 10 ml 2-propanol, filtered through a glass filter. The filter residue is dried, receiving 0,427 g (82.2 per cent). So pl. 240,1oC (compound 102).

Example 22. To 4.3 g ()-methyl-8-ethinyl-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate are added 50 ml of toluene and then evaporated. The residue is dissolved in 100 ml of toluene and this solution is cooled to -70oC. was added dropwise a solution of 25 ml of hydro-bis-(2-methyl-propyl)-aluminiumhydride in toluene (20%). The reaction mixture was stirred for 1 h at -70oC. was added dropwise 10 ml of methanol and irout diethyl ether. The separated organic layer is dried, filtered and the solvent is evaporated. The residue is dissolved in methanol and add 1,95 g N-/2-pyrimidinyl/-1,3-propandiamine.

This mixture hydronaut at room temperature using 1 g of palladium-on-active coal (10%) as catalyst in the presence of 4 ml of a solution of thiophene (4%). After cessation of hydrogen absorption, the catalyst is filtered off. The filtrate is evaporated. The residue is purified by column chromatography on silica gel /eluting medium : CH2Cl2/ CH3OH = 95:5 to 90:10/. Pure fractions are collected and the solvent is evaporated. The residue is dissolved in 80 ml of 2-propanol and converted into the salt of oxalic acid /1:1/. The salt is filtered off, washed with 2-propanol and Diisobutyl ether, then dried, obtaining 4.3 g /63,1%/ oxalate /1:2/ // -N-[/8-ethyl-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl/-methyl] -N'-2 - pyrimidinyl-1,3-propandiamine. T. pl. 210,8oC (compound 54).

All are listed in tables 5-10 connections receive as described in the examples 10-22 ways of getting.

B. Pharmacological example.

Example 23. Extracted from pigs, shot through pentobarbital sodium, segments of the main arteries put the thief incubated at 37oC and saturated with a mixture of 95% O2- 5% CO2. Drugs dilate until then, until they reach a stable principal stretch 2,

Drugs are narrowing with serotonin /310-7M/.

Response to adding serotonin measure and then serotonin wash. This procedure is repeated as long as there is a stable reactions.

Then in the tub for body administered the test compound and measuring the narrowing of the drug. This reaction narrowing expressed as a percentage of the response to serotonin, pre-measured.

ED50Value (molar concentration) defined as the concentration at which the test compound causing 50% convergent reactions dealt with serotonin. Above ED50values evaluated from experiments on three different drugs.

In table. 6 presents the ED50values for compounds of the formula /1/.

1. Examples of compositions

"Active ingredient" /A. I./ refers to the connection formula /1/, its pharmaceutically acceptable salt accession acid or its stereochemical isomeric form, namely A. I. represents a connection 62 (alniditan).

Example etilenglikola at 60 - 80oC. After cooling to 30 - 40oC added 35 l of polyethylene glycol and the mixture well stirred. Then add a solution of 1750 g of sodium saccharin in 2.5 l of purified water and while stirring add 2.5 litres giving cocoa flavor and polyethylene glycol to a total volume of 50 l, obtaining a solution for oral administration in the form of droplets containing 10 mg/ml A. I. the resulting solution is poured into suitable containers.

Example 25. Solution for injection oral.

9 g {Methyl}-4-hydroxybenzoate and 1 g {propyl}-4-hydroxybenzoate dissolved in 4 l of boiling purified water. In 3 l of this solution are dissolved first 10 g of 2,3-dihydroxy-succinic acid and then 20 g of A. I. Last solution combine with the rest of the first solution and there add 12 l 1,2,3-propanetriol and 3 l of 70% aqueous solution of sorbitol. 40 g sodium saccharin dissolved in 0.5 l of water and add 2 ml of raspberry and 2 ml of gooseberry family essences. The latter solution is combined with the first solution, add water to a total volume of 20 l, receiving galinovsky solution containing 5 mg of active ingredient on a full teaspoon (5 ml). The resulting solution is poured into suitable containers.

Example 26. The capsule.

20 g A. I., 6, lauryl sodium, 56 E other. Then the resulting mixture was making 1000 suitable hard gelatin capsules, each containing 20 mg of active ingredient.

Example 27. Film-coated tablets.

Preparation of core tablets.

A mixture of 100 g A. I., 570 g lactose and 200 g starch is mixed well and then moisturize with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture is sieved, dried and again sieved. Then add 100 g of microcrystalline cellulose and 15 g hydrogenated vegetable oil. All is well mixed and pressed into tablets, receiving 10,000 tablets, each contains 10 mg of active ingredient.

Floor

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3 - propanetriol. Melt 10 g of polyethylene glycol and dissolved in 75 ml of dichloromethane. The last solution is added to the first and then add 2.5 g of octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of pigment and all homogenized. Core tablets are covered with this mixture in the AP 2 g (propyl)-4-hydroxybenzoate dissolved in about 0.5 l of boiling water for injection. After cooling to approximately the 50oC, all the while stirring, add 4 grams lactic acid, 0.05 grams propylene glycol and 4 g of A. I. the Solution is cooled to room temperature and add additional water for injection to a total volume of 1 l, obtaining a solution containing 4 mg/ml A. I. the Solution is sterilized by filtration (U. S. P. XVII, S. 811) and poured with sterile container.

Example 29. The candles.

3 g A. I. dissolved in a solution of 3 g of 2,3 - dihydroxy-succinic acid in 25 ml of polyethylene glycol 400. 12 g of surfactant (SPAN) and triglyceride /Witepsol 555to a total of 300 g of melted together. The latter mixture is well mixed with the first solution. This resulting mixture is then poured into molds at 37 - 38oC to 100 suppositories, each containing 30 mg/ml A. I.

Example 30. The solution for injection.

60 g A. I. and 12 g of benzyl alcohol mix well and add sesame oil to a total volume of 1 l, obtaining a solution containing 60 mg/ml A. I. the Solution is sterilized and poured into sterile containers.

1. //Benzodioxan, benzofuran or benzopyran/-alkylamino/-alkyl-substituted guanidine General formula I

< / BR>
where X Is O, CH or a direct link;
R3- H or C1-6alkyl; or

R2and R3- put together a bivalent radical (-CH2-)mwhere m = 4 or 5; or

R1and R2- put together a bivalent radical-CH=CH -(CH2)n-, where n = 2, 3, 4; or R3can be a link, when R1and R2taken together form a bivalent radical-CH= CH-CH= , -CH=CH-N=, -CH=N-CH=, where one or two hydrogen atom substituted by a halogen atom, a C1-6alkoxygroup, C1-6the alkyl, CN, MH, mono - or di(C1-6alkyl) amino group, aminocarbonyl, C1-6alkylaminocarbonyl;

R4- H or C1-6alkyl;

Alk1- bivalent C1-3alcander;

A is a bivalent radical of the formula:

< / BR>
< / BR>
< / BR>
< / BR>
or

< / BR>
where R5each H or C1-4alkyl;

R6each H or C1-4alkyl;

Alk2- C2-C15alcander or C5-C7cycloalkenyl;

p each = 0, 1, 2;

R7and R8each independently is H, a halogen atom, a C1-6-alkyl, hydroxyl, C1-6-alkoxygroup, cyano, amino, C1-6-alkyl, carboxyla, C1-C6allyloxycarbonyl, nitro or amino group, aminocarbonyl, C1-C< excluded /2-/(2,3-dihydro-1,4-benzodioxin-2-yl) methyl-(amino)ethylguanidine, or their pharmaceutically acceptable salts, or stereochemical isomers.

2. Connection on p. 1, where Alk1denotes CH2.

3. Connection on p. 1, where X denotes CH2and where R7and R8each, independently of one another, denotes hydrogen or halogen, C1-C6-alkyl, C1-C6-alkyloxy, hydroxyl, cyano - or nitro-group, amino-/C1-C6/-alkyl, amino group, /C1-C6-alkyl/-carbonylation.

4. Connection on p. 2 or 3, where A denotes a bivalent radical of formula (a), where R6denotes hydrogen.

5. Connection on p. 4, where the compound is N-//3,4-dihydro-2H-1-benzopyran-2-yl/methyl/-N-/ 1,4,5,6-tetrahydro-2-pyrimidinyl/-1,3-propandiamine, its stereochemical isomeric form or its pharmaceutically acceptable salt accession acid.

6. The method of obtaining compounds on p. 1, characterized in that the diamine of the formula II

< / BR>
where X, R4, R7, R8A and Alk1have the above values,

subjected to N-alkylation by the action of the reagent of formula III

< / BR>
where R1, R2, R3is mentioned in paragraph (1 value;

W1- reactive delete group

hydronaut with obtaining the compounds of formula I-a

< / BR>
where X, R4, R7, R8A and Alk1are specified in paragraph 1 values

and if necessary, the compound of formula I translate in pharmaceutically acceptable salt, or, on the contrary, the salt is transferred to the ground by the action of alkali and/or get it stereochemical isomeric form.

7. The method of obtaining compounds on p. 1, characterized in that the amino derivatives of formula VI

< / BR>
where A, R1, R2and R3are specified in paragraph 1 values

reductive N-alkylate using the appropriate aldehyde of the formula V

< / BR>
where X, R4, R7and R8are specified in paragraph 1 values;

r is an integer of 0, 1 or 2.

8. The method of obtaining compounds on p. 1, characterized in that the amino derivatives of formula VI

< / BR>
where R1, R2, R3and A are specified in paragraph 1 values

N - alkylate using the compounds of formula VII

< / BR>
where X, R4, R7, R8and Alk1are specified in paragraph 1 values;

W2- reactive the group to delete.

9. The method of obtaining the compounds of formula Ia under item 1

< / BR>
where X, R1, R2, R3, R4, R6
< / BR>
where X, R1, R2, R3, R4, R6, Alk1and Alk2are specified in paragraph 1.

10. A method of obtaining a connection on p. 1 of formula I-b:

< / BR>
where X, R2, R3, R4, R7, R8, Alk1and A are specified in paragraph 1, the hydrolysis of compounds of formula IX-a:

< / BR>
where X, R2, R3, R4, R7, R8and Alk1are specified in paragraph 1.

11. Compounds according to any one of paragraphs.1 to 5, with selective vasoconstrictor activity.

12. The compounds of formula IX-a

< / BR>
or its pharmaceutically acceptable salt, or its stereochemical isomeric forms,

where X Is O, CH2or a direct link;

R2is hydrogen, C1-C6-alkyl, C3-C6alkenyl or C3-C6-quinil;

R3is hydrogen or C1-C6-alkyl; or

R2and R3together may form a bivalent radical of the formula -(CH2)m-, where m = 4 or 5;

R4is hydrogen or C1-C6-alkyl;

Alk1- bivalent C1-C3-ascandilwy radical;

A is a bivalent radical of the formula

< / BR>
< / BR>
where R5each hydrogen or C1-C4- diyl or C5-C7-cycloalkenyl;

p each = 0, 1, or 2;

R7and R8each, independently of one another, hydrogen or halogen, C1-C6-alkyl, hydroxy-group, C1-C6-alkyloxy-, cyano, amino-(C1-C6)alkyl, carboxyl, (C1-C6-alkyl)-oxycarbonyl, nitro-, amino group, aminocarbonyl, (C1-C6-alkyl)-carbonylation or mono - or di-(C1-C6-alkyl)-amino group,

as an intermediate product for producing compounds of formula I-b.

13. Pharmaceutical composition having vasoconstrictor activity, comprising an effective amount of the active ingredient and pharmaceutically acceptable additives target, wherein the active ingredient contains a compound of formula I under item 1.

14. A method of obtaining a pharmaceutical composition having vasoconstrictor activity comprising mixing a therapeutically effective amount of the active ingredient and pharmaceutically acceptable target additives, characterized in that the active ingredient is used as a compound of the formula I on p. 1.

 

Same patents:

The invention relates to 2,3-dihydro-1,4-benzodioxin-5-yl-piperazinyl derivative of the formula I, where R1denotes halogen, lower alkyl or alkoxyl, or cyano; m = 1 or 2, n = 0 or 1, And - Allenova chain with 2 to 6 carbon atoms which may be substituted by one or two lower alkyl groups or one phenyl group; B is methylene, ethylene, carbonyl, sulfinil, sulfonyl or sulfur, or their salts with 5-HTIA-antagonistic activity

The invention relates to new 2,2-dialkyl - 2,2-dialkyl-3,4-dihydro-3 - hydroxy-2H-1-benzopyranyl and their salts, esters and N-oxides and to methods for their preparation, their use as pharmaceuticals and to the containing pharmaceutical compositions

The invention relates to new chemical compounds with valuable properties, in particular to piperidinylmethyl derived chromane General formula (I)

< / BR>
where A is hydrogen or lower alkoxy,

E is hydrogen, hydroxyl, phenyl or piperidyl,

G phenyl not substituted or substituted with halogen and/or trifluoromethyl, fenoxaprop substituted by trifluoromethyl, benzyl, substituted phenylcarbinol, aminocarbonyl,

provided that E does not mean hydrogen or hydroxide, when G is phenyl, and their salts with inorganic acids

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to new derivatives of hinoklidilkarbinola General formula where n is an integer 1, 2, 3, R1-halogen or trihalomethyl, R2is hydrogen, R3-furanyl, tetrahydrofuranyl, DIOXOLANYL, pyranyl, tetrahydropyranyl, optionally substituted by 1, 2 or 3 substituents selected from the group comprising oxoprop and C1-C3-alkyl

The invention relates to new derivatives of N-(3-hydroxy-4-piperidinyl) (dihydro-2H-benzopyran or dihydrobenzoic) carboxamide, having valuable pharmaceutical properties, namely activity to stimulate gastrointestinal peristalsis

The invention relates to new substituted benzopyranones that have antiatherosclerotic and antithrombotic action
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