Derived dihydrobenzofuran with vasoconstrictive action, intermediate compounds, methods of preparation, pharmaceutical composition and method of reception

 

(57) Abstract:

Derivatives dihydrobenzofuran formula I, where R1, R2, R3each independently hydrogen or C1-6-alkyl; R4is hydrogen, halogen or1-6-alkyl; Q is a radical of the formula (AA) - (nn), the values of other radicals, see p. 1 of the claims. Pharmaceutical composition based on compounds of the formula I has a vasoconstrictive action. 7 C. and 5 C.p. f-crystals, 18 PL.

The present invention relates to new derivatives dihydrobenzofuran, method of production thereof, pharmaceutical compositions containing them and their use as pharmaceuticals, in particular for the prevention or treatment of disorders characterized by excessive expansion of vessels, in particular migraine.

Migraine - non-fatal disease that affects the tenth man. The main symptom is pain; other symptoms include vomiting and photophobia. For many years the most widely used treatment of migraine included the appointment of ergoalkaloidov, which gave unpleasant side effects. Recently as a new drug against migraines began to apply the derivative of tryptamine, i.e., sumatriptan. eticheskuyu activity and can be used in the treatment of disorders, characterized by excessive expansion of vessels, especially migraines.

The present invention relates to compounds of the formula:

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their pharmaceutically acceptable salts of acidic or basic join their stereochemical isomeric forms,

in which R1, R2and R3each independently is hydrogen or C1-6-alkyl;

R4is hydrogen, halogen, C1-6-alkyl, hydroxy, C1-6-alkyloxy, aryloxy or animetake;

R5and R6denote R5aand R6awhere R5aand R6ataken together form a bivalent radical which is linked in the 7 and 8 positions with a fragment dihydrobenzofuran and has the formula:

-CH=CH-CH-CH- (A1),

-(CH2)n- (a2),

-(CH2)m-X- (a3),

-X-(CH2)m-- (a4),

-CH=CH-X- (a5),

-X-CH=CH- (a6)

-O-(CH2)t-Y- (A7),

-Y-(CH2)t-O- (A8)

-(CH2)t-Z- (A9),

-Z-(CH2)t- (a10),

-CH=CH-Z- (a11),

-Z-CH=CH- (A12),

-NH-C(A)=N- (a13),

O-C(A)=N- (a14),

N=C(A)-O- (A15);

in these bivalent radicals one or two hydrogen atoms may be substituted C1-6-alkyl, C1-6-alkylcarboxylic or C1-6-alkyl - S(O)-;

n is 3 or 4;

each X, the independent is-, -S(O)2-, -C(O)-, NR7-;

Z-O-C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NH-; each t is independently 1 or 2;

R7is hydrogen, C1-6-alkyl, C1-6-alkylaryl or C1-6-alkyl - S(O)-,

Each And independently hydroxy, C1-6-alkyl, C1-6-alkyloxy; or R5and R6denote R5aand R6bwhere R5bis hydrogen and R6b-hydroxy C1-6-alkyl, carboxyls1-6-alkyl, C1-6-allyloxycarbonyl C1-6-alkyl, trihalomethyl, C1-6-alkylsulphonyl, C1-6-allyloxycarbonyl C1-6-alkyl-S-, carboxyls1-6-alkyl-S-, C1-6-alkyl-S-, C1-6-alkyl-S(O)-, aryl-S-, aryl-S(O)- or R6brepresents a radical of the formula:

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R8and R9each independently is hydrogen, carboxyl, C1-6allyloxycarbonyl, aminocarbonyl, mono - or di(C1-6alkyl)aminocarbonyl;

R10, R11, R12, R13, R14, R15, R16and R17each independently is hydrogen, halogen or C1-6-alkyl;

R18, R19, R20, R21, R22, R23, R24and R25each independently is hydrogen or C1-6-alkyl;

or R5and R6denote R5cand R6cand in this case, R4can only mean motorini, hydroxy, C1-6-alkyloxy, cyano, amino1-6-alkyl, carboxyl, C1-6-allyloxycarbonyl, nitro, amino, aminocarbonyl, C1-6-acylcarnitine, or mono - or di(C1-6-alkyl)amino;

Alk1- C1-5-alcander;

Alk2- C2-15-alcander;

Q is a radical of the formula;

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in which R26is hydrogen, cyano, aminocarbonyl or C1-6;-alkyl;

R27is hydrogen, C1-6-alkyl, C3-6alkenyl, C3-6-quinil, C3-6-cycloalkyl or arils1-6-alkyl;

R28is hydrogen or C1-6alkyl; or

R27and R28taken together form a bivalent radical of the formula -(CH2)4-, -(CH2)5- or piperazine, which optionally may be substituted C1-6-alkyl;

R29, R30, R31, R36, R37, R38, R39, R40, R41, R42, R43,

R44, R45, R46, R53, R54and R55each independently is hydrogen, hydroxy, halogen, C1-6-alkyl, C1-6-alkoxy, aryloxy, arils1-6-alkyl, C1-6-alkylthio, cyano, amino, mono - or di-(C1-6alkyl)amino, mono - or di(C3-6-cycloalkyl)amino, aminocarbonyl, C1-6-allyloxycarbonyl,dependent - hydrogen, C1-6-alkyl, C1-6-alkylsulphonyl, or arils1-6-alkyl;

q is 1, 2 or 3;

R33and R34each hydrogen or taken together with the carbon atom to which they are attached form C(O);

r - 1, 2 or 3;

R47and R48each hydrogen or taken together with the carbon atom to which they are attached, may form O(O);

R49is hydrogen, halogen or C1-6-alkyl;

R50- hydrogen and

R51is hydroxy;

or R50and R51taken together may form a bivalent radical of the formula (CH2)3or (CH2)4which may optionally substituted C1-6-alkyl;

aryl represents phenyl, with the possibility of substitution of hydroxy, halogen, C1-6-alkyl, C1-6-alkyloxy; provided that, if R4is hydrogen and R5and R6denote R5cand R6cthen Q must be a radical of the formula (qq), (hh), (ii), (jj), (kk), (ll), (mm), (nn); a radical of formula (aa), where R27- C3-6-cycloalkyl or arils1-6-alkyl; a radical of formula (aa), where R27and R28taken together with the nitrogen atom to which they are attached, form a piperazine which is optionally substituted C1-6-al is rmula (dd), where R35is hydrogen and R33and R34taken together with the carbon atom to which they are attached form C(O); a radical of formula (ee), where R55- arils1-6-alkyl.

Some of the compounds of formula (I) may exist in their tautomeric forms. Such forms are also included in the scope of the present invention, although it is not specifically indicated in the above formula.

Here in definitions and further halogen means fluorine, chlorine, bromine and iodine;

C1-6-alkyl defines radicals of saturated hydrocarbons with straight and branched chain with 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, and others;

C3-6alkenyl determines the hydrocarbon radicals with straight and branched chain, containing one double bond and having 3-6 carbon atoms, such as, for example, 2-propenal, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and others; and the carbon atom of the specified C3-6-alkenyl associated with the nitrogen atom preferably is saturated, C3-6-quinil determines the hydrocarbon radicals with straight and branched chain, containing one triple bond and having from 3 to 6 carbon atoms, such as, for example, 2-the-quinil radical, associated with the nitrogen atom preferably is saturated; C3-6-cycloalkyl is a General concept for cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C1-5-alcander defines bivalent radicals of saturated hydrocarbons with straight or branched chain, having from 1 to 5 carbon atoms, such as, for example, methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butanediyl or 1,4-pentandiol and their isomers with branched chain; C2-15-alcander defines bivalent radicals of saturated hydrocarbons with straight and branched chain, having from 2 to 15 carbon 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-octanediol, 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. The terms of C1-4-alcander, C2-6alcander and C2-14-alcander is defined similarly. The term "C(O)" refers to a carbonyl group.

Pharmaceutically acceptable salts of the acid accession referred to above include therapeutically active non-toxic form acid salts of adhesion, which are capable of forming slots, as inorganic acids, for example, kaleidostone acids, e.g. hydrochloric, Hydrobromic and others; sulfuric, nitric, phosphoric acid, and others; or organic acids such as acetic, propanoic, glycolic acid, 2-oxopropionate, ethicality, pronunciati, butanedioate, (Z)-2-botanically, (E)-2-botanically, 2-malic acid, 2,3-diablocody acid, 2-hydroxy-1,2,3-propanetricarboxylic, methansulfonate, econsultation, benzosulfimide, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-oksibenzoynoy, 4-amino-2-oksibenzoynoy and similar acids. Conversely, the salt form can be converted by treatment with alkali in the form of a free base.

The compounds of formula (I) containing an acidic proton may also be converted into their therapeutically active non-toxic salt form of joining metal or amine by treatment with appropriate organic and inorganic bases. Appropriate forms basic salts include, for example, ammonium salts, salts of alkali and alkaline earth metals, for example, salts of lithium, sodium, potassium, magnesium, calcium and other salts with organic bases, for example, Borat, the salt form can be converted by treatment with an acid in the form of the free acid.

The term salt of the accession also includes hydrates and forms of accession of the solvent, which is able to form compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholate, and the like.

The term "stereochemical isomeric form" here defines all the possible isomeric forms, which may be of the compounds of formula (I). If not specified, or not mentioned otherwise, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms, while mixtures containing all diastereomers and enantiomers of basic molecular structure. Even more, stereogenic centers may have the R - or S - configuration; substituents on bivalent radicals of the cyclic saturated hydrocarbon can have either a CIS - or TRANS-configuration and the radicals C3-6-alkenyl can have the E - or Z-configuration. Stereochemical isomeric forms of the compounds of formula (I) are also included in the scope of this invention.

R2usually methyl or hydrogen, better hydrogen;

R2usually methyl or hydrogen, better hydrogen;

R3usually methyl or hydrogen, Lou;

if R5and R6denote R5aand R6a, R5aand R6ausually form a bivalent radical of formula (A1), (A2), (A3), (A4), (a7), (a8), (all) or (A12);

X - usually O, S, or S(O)2preferably X Is O or S(O)2;

Y - usually O or S, preferably Y IS O;

Z - typically-O-C(O)- or-C(O)-O-;

if R5and R6denote R5band R6b,

R6b- typically, hydroxy, C1-6-alkyl, trihalomethyl, or a radical of formula (b1), (b2), (b3), (b4), (b5), (b6) or (b13);

R6b- preferably located in the 8-position dihydrobenzofuran;

R8- usually hydrogen or C1-6-allyloxycarbonyl better, if R6is hydrogen,

R9- usually hydrogen or C1-6-allyloxycarbonyl, preferably R7is hydrogen or methoxycarbonyl;

R10and R11each usually independently hydrogen or C1-6-alkyl, preferably R10and R11is hydrogen or methyl;

R12and R13each independently is hydrogen or hydroxy;

R14and R15each independently is hydrogen or C1-6-alkyl, preferably hydrogen;

R16and R17each independently hydrogen or C1-6-alkyl, preferably both hydrogen;

R18, RZnachit R5cand R6c;

then R5cand R6c- usually hydrogen, halogen or C1-6-alkyl, preferably hydrogen, chlorine, fluorine, methyl or ethyl;

Alk1- usually C1-3-alcander, preferably methylene;

Alk2- usually C2-6-alcander, preferably 1,3-propandiol;

if Q is a radical of the formula (aa),

R26- usually hydrogen, cyano, aminocarbonyl or methyl, preferably hydrogen or a piano;

R27- usually hydrogen or C1-6-alkyl, preferably hydrogen or methyl, or ethyl;

R28is hydrogen or C1-6-alkyl, preferably hydrogen or methyl;

the radical of the formula (bb),

R29and R30each independently hydrogen, hydroxy, halogen, methyl, preferably both radicals is hydrogen or R29is hydrogen and R30hydroxy;

the radical of the formula (OS),

R31- usually hydrogen, hydroxy, preferably hydrogen;

R32- usually hydrogen, or phenylmethyl, preferably hydrogen;

the radical of formula (dd),

q is preferably 2,

R33and R34- preferably both hydrogen;

R35- usually hydrogen or phenylmethyl, preferably hydrogen;

the radical of the formula (it)

R36usually fodoral formula (ff),

R37and R38each independently hydrogen, halogen or methyl, preferably R37and R38hydrogen or chlorine;

the radical of the formula (qq),

R39and R40usually each independently hydrogen, hydroxy, chlorine or methyl, preferably both are hydrogen, or R39is hydrogen and R40is hydroxy;

the radical of formula (hh),

R41and R42usually each independently hydrogen, hydroxy, halogen or methyl, preferably both are hydrogen, or R41is hydrogen and R42- chlorine;

radical of the formula (ii),

R43and R44each independently hydrogen, halogen, C1-6-alkyloxy, C1-6-alkylthio, amino, mono - or di(C1-16-alkyl)amino, preferably R43is hydrogen, chlorine, methylthio or amino and R44is hydrogen;

the radical of formula (jj),

R45and R46usually each independently hydrogen, halogen, C1-6-alkyl, preferably hydrogen or chlorine;

the radical of formula (kk),

r is preferably 2;

R47and R48- preferably both hydrogen;

the radical of the formula (ll),

R49- usually hydrogen or methyl, preferably hydrogen;

the radical of the formula (mm)

R50and R51taken together, usually form of UP> - usually hydrogen and R54usually hydroxy; and aryl is preferably phenyl.

A preferred group of compounds are compounds of formula (I) in which R1, R2, R3and R4the same as defined under formula (I), of which R5and R6denote R5aand R6awhere in formulas (a7) and (a8) t - 2;

Q is a radical of the formula (aa), (bb), (cc), (dd), where q is 1 or 2, (ee), where R55is hydrogen, (ff), (gg), (hh), (ii), (jj), (kk), where q is 1 or 2, (ll).

Another group of preferred compounds is those compounds of formula (I) in which R1, R2, R3are the same as defined under formula (I), R4is hydrogen, halogen, C1-6-alkyl; R5and R6denote R5band R6b, R5brepresents hydrogen and R6b- hydraxis1-6alkyl, carboxy1-6-alkyl, C1-6-allyloxycarbonyl1-6-alkyl, trihalomethyl, the radical of formula (b1), (b2), (b3), (b4), (b5), (b6), (b7), (b8), (b9), (b10), (b11), (b12); Q is a radical of the formula (aa), (bb), (cc), (dd), where q is 1 or 2, (ee), where R55is hydrogen, (ff), (gg), (hh), (ii), (jj), (kk), where q is 1 or 2, or (ll).

Another special group of compounds are those compounds of formula (I) in which R1, R2, R3are the same values that you have defined the(hh), (ii), (jj), (kk), where q is 1 or 2; (ll); a radical of the formula (bb), where R29- hydroxy on the carbon atom adjacent to the nitrogen atom; or a radical of the formula (bb), where R35is hydrogen and R33and R34taken together with the carbon atom to which they are attached form C(O) and q is 1 or 2.

Interesting compounds are those compounds of formula (I) in which R2- hydrogen.

Also interesting compounds in which R3- hydrogen.

Special compounds are the compounds of formula (I) in which R5and R6denote R5aand R6aand Q is radical of formula (bb), where R29and R30is hydrogen; or Q is a radical of the formula (dd), where q is 1 or 2 and R31and R32both hydrogen.

Also interesting compounds of formula (I) in which R5and R6denote R5band R6b, R5bis hydrogen and R6b- C1-6-allyloxycarbonyl-C1-6-alkyl, trihalomethyl, C1-6-allyloxycarbonyl-C1-6-alkyl-S-, aryl-S-, aryl-S(O)-, or R6bin the radical of formula (b1), where R8is hydrogen; (b2) where R9- C1-6-allyloxycarbonyl; (b3) where R10and R11both hydrogen; (b4), where R12and R13both hydrogen; (b5), where R14and R15both hydrogen; (b6), where R16-30is hydrogen; or Q is a radical of the formula (dd), where q is 1 or 2 and R31and R32both hydrogen.

Other interesting compounds are the compounds of formula (I) in which R4is hydrogen; R5and R6denote R5c, R6c, R5cis hydrogen and R6cis hydrogen, halogen, C1-6-alkyl or C1-6-alkyloxy; Q is a radical of formula (aa), where R26is hydrogen, cyano or aminocarbonyl, R27- arils1-6alkyl, and R28is hydrogen or C1-6-alkyl, or R27and R28taken together with the nitrogen atom to which they are attached, form a pieperazinove ring, which is N-substituted C1-16-alkyl; a radical of the formula (bb), where R29- hydroxy on the carbon atom adjacent to the nitrogen atom; a radical of formula (dd), where R35the hydrogen and R33and R34taken together with the carbon atom to which they are attached form C(O); a radical of formula (ee), where R36is hydroxy and R55- aryl-C1-6-alkyl; a radical of formula (gg), where R39and R40each independently is hydrogen, C1-6alkyl or aminocarbonyl; a radical of formula (hh), where R41and R42each independently is hydrogen, halogen, hydroxy, C1-6is alkyl or aminocarbonyl; a radical of the formula (ii), where R44- bodoro idini; the radical of formula (jj), where R45and R46are both hydrogen; a radical of formula (kk), where R47and R48are both hydrogen; a radical of the formula (ll) wherein R49is hydrogen; a radical of the formula (mm), where R50is hydrogen, R51is hydroxy or R50and R51taken together form a bivalent radical of the formula (CH2)4and R52is hydrogen; or a radical of the formula (nn), where R53is hydrogen and R54is hydroxy.

The preferred compounds are:

N -[(2,3,4,7,8,9-hexahydrobenzo[2,1-b: 3,4-b']dipyran-2-yl)- methyl]-N'-2-pyrimidinyl-1,3-propandiamine;

N-[(2,3,4,7,8,9-hexahydrotriazine[h] -1-benzopyrane-2-yl)- methyl]-N'-2-pyrimidinyl-1,3-propandiamine;

()-N-[(2,3,4,8,9,10-hexahydrobenzo[2,1-b: 3,4-b'] dipyran-2-yl)methyl] -N'-2-pyrimidinyl-1,3 - propandiamine;

N-[(3,4,7,8,9,10-hexahydro-2H-oil[1,2-b] Piran-2-yl)-methyl] - N'-2-pyrimidinyl-1,3-propandiamine;

N-(4,5-dihydro-1H-imidazol-2-yl)-N'-[(2,3,4,7,8,9 - hexahydrocannabinol[h]-1-benzopyran-2-yl)methyl]-1,3-propandiamine;

N-[(2,3,4,7,8,9-hexahydrobenzo[2,1-b: 3,4-b'] dipyran-2-yl) methyl] -N'(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propandiamine;

N-[(2,3,4,7,8,9-hexahydrotriazine[h] -1-benzopyran-2-yl) methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propandiamine;

N-[(2,3,7,8-tetrahydro-N-pyrano[2,3-f] -1,4-benzodi-2-yl)-methyl] -N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propandiamine;

methyl 3-[6-fluoro-3,4-dihydro-2[[[3-(2-pyrimidinamine)-propyl] amino] methyl] -2H-1-benzopyran-8-yl]-2-propenoate;

N-[[6-fluoro-8-(2-furanyl)-3,4-dihydro-2H-1-benzopyran-2-yl] -methyl]-N'-2-pyrimidinyl-1,3-propandiamine;

N-[[6-fluoro-3,4-dihydro-8-(2-thienyl)-2H-1-benzopyran-2-yl] - methyl]-N'-(1,4,5,6-tetrahydro-2-piperidyl)-1,3-propandiamine;

N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl] -N'-(3,4,5,6 - tetrahydro-2-pyridinyl)-1,3-propandiamine;

N4-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl] amino] - propyl] -N2-methyl-2,4-pyrimidinediamine,

their pharmaceutically acceptable acid salt of accession and their stereochemical isomeric form.

The compounds of formula (I) can generally be obtained by reaction of a diamine of the formula (II) with a reagent of formula (III) in which W1- reactive leaving group such as, for example, halogen, namely, chlorine, bromine; alkyloxy, for example, methoxy, ethoxy and others; aryloxy, for example, phenoxy and others; alkylthio, for example, methylthio, ethylthio and others; aaltio, for example, sensatio etc.

In formulas (II), (III) and all subsequent formulae, the values of R1, R2, R3, R4, R5, R6, Alk1, Alk2and Q are the same as defined under formula (I), unless otherwise indicated.

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The decree is storytale, such as, for example, an alcohol, e.g. ethanol and others; halogenated hydrocarbon - trichlormethane etc. or ether - tetrahydrofuran, 1,4-dioxane, etc.; aromatic hydrocarbons, for example, methylbenzol and others, or their mixtures. To absorb the acid that can be formed during the reaction, you can add a base such as a carbonate of an alkali metal, e.g. sodium carbonate or potassium bicarbonate, alkali metal bicarbonate is sodium or potassium; a suitable organic base, such as N,N-diethylethanamine, pyridine and other grounds. The reaction can be accelerated by increased temperatures. It is advisable to carry out at the boiling temperature of the reaction mixture.

The compounds of formula (I) can also be obtained reductive N-alkylation of amino derivatives of formula (VI) with the appropriate aldehyde of formula (V) in which Alk3is a direct bond or C1-4-alcander.

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This reaction is performed by stirring the reactants in a suitable solvent, such as alcohol: ethanol and others; ether: THF and others; aromatic solvent: methylbenzol and others ; or their mixtures. To separate the water formed during the reaction, using a water separator. Then the resulting Imin you can recover the reaction is eating the catalyst, for example, palladium charcoal, platinized charcoal, skeletal Nickel catalyst and the other in an acceptable solvent such as, alcohol: methanol, ethanol and others; ether: THF and others; ester carboxylic acid: ethyl acetate, butyl acetate, and others; or carboxylic acid: acetic acid, propionic acid and other acids. It is possible to conduct the reaction at elevated temperatures and/or pressure.

The intermediate aldehyde of formula (V) can restore derived acyl of the formula (IV), in which Alk3is the same as defined above. Allalone can be obtained by reaction of the appropriate acid with a halogenation agent such as thionyl chloride, trichloride phosphorus, tribromide phosphorus, oxalicacid and others. The latter reaction can be carried out in excess of halogenation reagent or in appropriate solvents, such as halogenated hydrocarbons, e.g. dichloromethane, trichloromethane and others; aromatic hydrocarbons - methylbenzol; ethers include tetrahydrofuran, 1,4-dioxane, etc. or bipolar aprotic solvents such as N,N-dimethylformamide, N, N-dimethylacetamide, and others. Mixing and higher temperatures accelerate the reaction.

Restoring acylhomoserine formula and the barium sulphate, platinized charcoal and other appropriate solvents, such as ether: THF and others; better in the mix with bipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, and others. Perhaps adding a catalyst poison, such as thiophene, quinoline-sulfur and others.

The reaction starting from intermediate compounds of formula (IV) to yield compounds of formula (I) can be done in one reactor.

Intermediate compounds of formula (V) in which R5and R6denote R5aand R6ais defined as the intermediate compounds of formula (V-a); intermediate of formula (V) in which R5and R6denote R5band R6bis defined as an intermediate of formula (V-b). The intermediate of formula (V-a) and (V-b) are considered new.

The compounds of formula (I) can also be obtained reductive N-alkylation of an amine of formula (IX) with the aldehyde of formula (X) in which Alk4- C2-14-alcander. The reaction conditions are similar to those described for the reaction of intermediates of formula (V) with compounds of the formula (VI).

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The intermediate of formula (IX) in which R5and R6denote R5aand R6alisted as intermediate FC intermediate compounds of formula (IX-b). The intermediate of formula (IX-a) and (IX-b) is considered to be new.

The compounds of formula (I) can also be obtained N-alkylation of an amine of the formula (VI) an intermediate compound of formula (VII), in which Wb- reactive leaving group such as halogen, for example chlorine, bromine or iodine; sulfonyloxy, for example, methanesulfonate, methylbenzenesulfonate and others, in suitable solvents, such as ketones, for example, 2-butanone, etc.; ether: THF and others; aromatic hydrocarbons: methylbenzol and others; bipolar aprotic solvents such as N,N-DMF), N,N-dimethylacetamide, dimethyl sulfoxide, and others.

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Mixing and heating can accelerate the reaction. To absorb the acid formed during the reaction, it is possible to add a suitable base, for example, the carbonate of the alkali metal include sodium carbonate or potassium bicarbonate, alkali metal bicarbonate is sodium or potassium, and others; a suitable organic base, such as N,N-diethylethanamine, pyridine and others.

Intermediate compounds of formula (VII) in which R5and R6denote R5aand R6alisted here as an intermediate of formula (VII-a); intermediate compounds of formula (VII) in which R5and R6oboznachit (VII-b) are considered new.

The compounds of formula (I) in which R2is hydrogen, represented by the formula (I'), can be obtained by dibenzylammonium intermediate of formula (VIII).

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Dibenzylamine you can spend a well-known procedures, such as catalytic hydrogenation using a suitable catalyst, for example, platinized carbon, palladium charcoal in suitable solvents, such as alcohols: methanol, ethanol, 2-propanol, etc.; ethers: 1,1'-oxybisethane, THF, 2,2'-oxybisethane and others. Perhaps the use of elevated temperatures and pressure.

The compounds of formula (I) in which R5and R6denote R5band R6bare the compounds of formula (I-b). The compounds of formula (I-b) can be obtained aromatic substitution Alojamientos, preferably Izumisano, dihydrobenzofuran-substituted derivative of formula (XI). This aromatic substitution can hold a reagent of formula (XII) in a suitable solvent and in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine) palladium.

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The compounds of formula (I) can also be converted into each other by the transformation of functional groups. For example, the compounds of formula (I) in which Q p and procedures catalytic hydrogenation. In addition, the compounds of formula (I) bearing C3-6-Altenilpe or C3-6-altergroup, can be converted into the corresponding compounds bearing C1-6-altergroup by known techniques hydrogenation. The compounds of formula (I) bearing a cyano can be converted into the corresponding compounds bearing aminomethane Deputy, following known techniques hydrogenation. Compounds bearing alkoxylation can be converted to compounds bearing a hydroxy-group processing alkoxysilane the corresponding acid with a reagent such as galoidvodorodnykh acid, for example, Hydrobromic acid or trichromacy boron and others. Compounds bearing aminosalicylic, can N-allievate or N-alkilirovanii, following known procedures N-acylation or N-alkylation.

Intermediate compounds mentioned above, are new and can be obtained by known procedures, which are shown in the experimental part.

Stereochemical pure isomeric form of the present invention can be obtained by the application of known procedures. Diastereoisomer can be separated by physical methods of separation, such as selective crystallizationassisted their diastereomeric salt of optically active acids. Pure stereochemical isomeric form is also obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction takes place stereospecific. If you need a specific stereoisomer of the compound is synthesized stereospecific methods of getting. These methods use enantiomerically pure starting materials.

The compounds of formula (I), their pharmaceutically acceptable salts are acid accession and their stereochemical isomeric forms possess interesting pharmacological properties: they are 5HTI-like agonistic activity. The connections are good constrict the blood vessels. They are useful in the prevention or treatment of conditions that are associated with vasodilation. For example, they are useful in the treatment of conditions characterized by or associated with headache associated with vascular disorders, especially migraine. These compounds are also useful in the treatment of venous insufficiency and treatment of conditions associated with low blood pressure. The vasoconstrictor effect of compounds of formula (I) can be identified using in vitro test, as described in "Instantaneous changes of alpha-adrenoreceptor affinity caused by moderate cooling in canine cutaneous veins" in American J. th reaction of the compounds of the present invention was tested on the basilar arteries of pigs.

In view of their useful pharmacological properties, the compounds can be translated into various pharmaceutical forms for the appointment. To prepare the pharmaceutical compositions of this invention, an effective amount of a specific compound in the form of salts of acidic or basic accession as the active ingredient is thoroughly mixed with a pharmaceutically acceptable carrier, which has many forms, depending on the form of preparation desired for the purpose. These pharmaceutical compositions are easier to cook in a unified unit dosage for oral, rectal, percutaneous or parenteral destination. For example, for preparing the compositions in oral dosing form may be any of the usual pharmaceutical media, such as water, glycols, oils, alcohols, etc. in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, a lubricant, a binding agent, contributing to the decay and the other in the case of powders, pills, capsules and tablets. Because of the easiness of taking tablets and capsules are the most convenient form dosing unit oral assignments. D. is there and included other ingredients for example, contributing to the solubility. In injectable solutions, the carrier can contain a saline solution, glucose solution or a mixture. In the preparation of injectable suspensions you can use the appropriate liquid carriers, suspendresume agents and other components. In the compositions acceptable for percutaneous application, the carrier may include an agent that enhances the penetration and/or wetting agent, combined with additives of any nature in small amounts which do not harm the skin. Such supplements can facilitate the appointment through the skin and/or to be useful in the preparation of the desired compounds. These compositions can be assigned in different ways, for example, using transdermal pads, spot by way of or as an ointment. For ease of purpose it is better to translate the song into a unified unit dosage, which here refers to physically discrete units as uniform dose with the content in each specific quantity of active ingredient calculated on the product desired therapeutic action, together with the required pharmaceutical carrier. Examples of such unit dosage forms, tablets (coated and uncoated), capsules, pills, powders, lozenges,soedineniya of the present invention can be used as drugs in the States, characterized by vasodilatation, in particular, under reduced pressure, venous insufficiency, headache, especially migraine. It also features a method of treating warm-blooded animals suffering from conditions associated with vasodilation, such as, low pressure, venous insufficiency and especially headache and migraine, the use of effective amounts of compounds of formula (I), its pharmaceutically acceptable acid salt of accession or its stereoisomeric forms. Specialists can easily determine the effective amount from the test results presented below. In General, an effective amount can be considered I g/kg I mg/kg body weight, and in particular, from 2 g/kg 200 g/kg of body weight. The desired dose is better to appoint two, three, four or more receptions at intervals during the day and in the right dosage units containing, for example, from 0.005 to 20 mg, best of 0.1 - 10 mg of active ingredient per unit dosage.

Experimental part

A. Obtaining compounds of formula (I) in which R5and R6denote R5aand R6aand their intermediate compounds

Example 1-a

a) a Mixture of 2,3-dihydro-1H-inden-4-ol (0,37 M) and acetic anhydride (0,37 M) in sulfuric who water and 1,1'-oxybisethane. The organic layer was separated, dried (MgSO4), filtered and the solution was evaporated, to yield 75 g ( > 100% crude residue), 2,3-dihydro-1H-inden-4-ol acetate (ester) (InterMedia. 1-a).

b) Intermediate compound 1-a (0,37 M) was heated to 100oC. was Added aluminum chloride (200 g) and the reaction mixture is stirred for 1 hour at 120oC. the Reaction mixture was cooled and added to ice and then adding a mixture of water and concentrated hydrochloric acid. This mixture was extracted 1,1'-oxybisethane. The organic layer was separated, treated with activated carbon, dried (MgSO4), filtered and the filtrate was evaporated. The residue was purified by distillation (oil pump; 110oC), 29 g of 1-(2,3-dihydro-4 - hydroxy-1H-inden-5-yl)ethanone (InterMedia. 2-a).

c) sodium Methylate (24 g) were mixed in methylbenzene (300 ml). Dropwise added a mixture of diethyloxalate (0,16 M) and intermediate compound (2-a) (0,16 M) methylbenzene (10 ml). This mixture was stirred and boiled for 2 hours. The precipitate was filtered off and dried. The solid is stirred in a mixture of hydrochloric acid (10 ml) and acetic acid (500 ml). The reaction mixture is stirred and boiled,8,9-tetrahydro-4-oxocyclopent[h]-1-benzopyran-2-carboxylic acid (InterMedia. 3-a).

d) a Mixture of intermediate compound 3-a (0,09 M) in acetic acid (200 ml) was gerasoulis palladium on charcoal (1 g) as a catalyst. After uptake of hydrogen (3 equivalents), the catalyst was filtered off. The solution was evaporated. The residue was dried in vacuum, to yield 21 g ()-2,3,4,7,8,9 - hexahydrocannabinol[h]-1-benzopyran-2-carboxylic acid (InterMedia. 4-a).

e) a Mixture of intermediate compound 4-a (0,11 M) in tetrahydrofuran (250 ml) were mixed in a stream of nitrogen. Was added 1,1'-carbonylbis-1H-imidazole (0,11 M) and the reaction mixture is stirred 2 hours at room temperature. Then it was cooled to 80oC. was added dropwise a solution of diisobutylaluminium in methylbenzene (20%) (0,33 M) and the reaction mixture is stirred 2 hours at -80oC. the Mixture was decomposed with methanol, then was poured into water. The mixture was oxidized, and then was extracted 1,1'-oxybisethane. The separated organic layer was dried (MgSO4), filtered and the solution was evaporated, to yield 12 g ()-2,3,4,7,8,9-hexahydrotriazine[h]-1 - Benaojan-2-carboxaldehyde (InterMedia. 5-a).

In a similar manner there were obtained the following compounds:

()-2,3,7,8-tetrahydro-9H-pyrano [2,3-f] -1,4-benzodioxin- -9-carboxaldehyde(,4,7,8,9-hexahydrobenzo[2,1-b: 3,4-b']dipyran-2 - carboxaldehyde (InterMedia. 8-a).

Example 2-a

a) a Mixture of 4-oxo-4H-oil[1,2-b]Piran-2-carboxylic acid (12 g) and 2-methoxy-ethanol (100 ml) was gerasoulis under normal pressure and at room temperature in the presence of palladium on charcoal 10% (2 g) as a catalyst. After it was absorbed by the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated, to yield 7 g (61,4%) of 3,4-dihydro-2H-oil [1,2-b]Piran-2-carboxylic acid (InterMedia. 9-a).

b) a Mixture of intermediate compound 9-a (7 g), ethanol (160 ml) and sulfuric acid were mixed and boiled for 1 hour. The reaction mixture was evaporated and the oily residue was taken up with water. After treatment with sodium hydroxide, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, to yield 5 g (63,5%) of ethyl 3,4-dihydro-2H-oil[1,2-b] Piran-2 - carboxylate (InterMedia. 10-a).

c) a Mixture of intermediate compound 10-a (0,03 M) in methanol was saturated with ammonia (200 ml) and stirred at room temperature overnight. The precipitate was filtered off and rinsed with methanol. The product was used without further purification, yield 6.6 g (97%) ()-3,4-dihydro-2H-oil[1,2-b]Piran-2-carboxamide (InterMedia. II-a).

d) a Mixture of intermediate is plam was added acetic acid (0,1455 M) in 1,4-dioxane (20 ml) and the mixture was stirred and boiled for 2 hours 30 minutes. The mixture was evaporated to dryness. To the residue was added water. The mixture was oxidized with concentrated HCl and stirred for 30 minutes. The mixture was podslushivaet 50% NaOH solution and was extracted with dichloromethane. The organic layer was dried, filtered and evaporated to dryness. The residue was converted into the salt of hydrochloric acid and was released in a free state. The residue (2.9 g) was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH 9,75/0,25). Pure fractions were collected and evaporated, to yield 2.4 g (39%) ()-3,4-dihydro-2H-oil[1,2-b] Piran-2-methanamine (InterMedia. 12-a).

Similarly, it was obtained the following compound:

()-3,4,7,8,9,10-hexahydro-2H-oil[1,2-b] Piran-2 - methanamine (InterMedia. 13-a).

Example 3-a

A mixture of intermediate compound 5-a (0,03 M) and benzoylmethylene (0,073 M) 2,2'-oxybisethane (250 ml) and N,N-dimethylacetamide (10 ml) was gerasoulis palladium on charcoal (10%) (1 g) as a catalyst. After uptake of hydrogen (I EQ), the catalyst was filtered off. The filtrate was evaporated. The residue is stirred in a mixture of water and 1,1'-oxybisethane. The organic layer was separated, dried (MgSO4), filtered and the solution was evaporated, to yield 6.5 g ()-2,3,4,7,8,9-Huck is itocnode connection 14-a (0,02 M) and 2-propenenitrile (0,2 M) in ethanol (100 ml) was stirred and boiled all night. The solution was evaporated. The residue was dissolved in methanol. Was added palladium on charcoal (10%) (2 g) and the mixture was gerasoulis. After uptake of hydrogen (3 equiv.) the catalyst was filtered off and the filtrate was evaporated with the release of 5.2 g ()-N-[(2,3,4,7,8,9 - hexahydrotriazine[h] -1-benzopyran-2-yl)methyl] -1,3-propandiamine (InterMedia. 15-a).

Example 5-a

A solution of ethyl 6-oxo-2,3-dimethyl-6H-furo[3,2-h][I]benzopyran-8 - carboxylate (0.1 M) in methanol (250 ml) was gidrirovaniya 10 hours at 170oC (under pressure) on palladium on charcoal (PD 5%) (2 g) as a catalyst in the presence of 4% solution of thiophene (10 ml). After uptake of hydrogen (3 equiv.) the catalyst was filtered off and the filtrate was evaporated. The residue was purified flash chromatography on silica gel (eluent: CH2Cl2). The desired fractions were collected and the solvent was evaporated to yield 20 g (72,9%) (a)-ethyl 7,8-dihydro-2,3-dimethyl-6H-furo[3,2-h][l] benzopyran-8-carboxylate (InterMedia. 16-a).

Example 6-a

A mixture of intermediate compound (8a) (6,9 g of the crude solids and N-2-pyrimidinyl-1,2-propandiamine (0,02 M) in methanol (200 ml) was gerasoulis with palladium on charcoal (10%) (2 g) as a catalyst in the presence of a solution of thiophene (4%) (1 ml). After Ponoi chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH395/5). Pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanone and converted into the salt of ethicality (1:2), salt was filtered off and dried (vacuum; 60oC) to obtain 7.8 g (73,0%) ()-N-[(2,3,4,7,8,9-hexahydrobenzo[2,1-b: 3,4-b] - dipyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propandiamine of candiota (1:2), so pl. 190,4oC (Conn. I-a).

Example 7-a

A mixture of intermediate compound (13-a) (0,0088 M) and 3-(2-pyrimidinamine)propanal (0,0112 M) in methanol (100 ml) was gerasoulis with palladium on charcoal (10%) (1 g) as a catalyst at room temperature and 3 atmospheres. in the Parr apparatus. After uptake of hydrogen (1 EQ.), the catalyst was filtered off and the filtrate was evaporated to dryness. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH3/ 97/3)> Almost pure fractions were collected and evaporated. The residue was again purified GHUR on silica gel (eluent: CH2Cl2/CH3OH(NH3) 95/5). Pure fractions were collected and evaporated to yield of 0.85 g (27%) ()-N-[(3,4,7,8,9,10-hexahydro-2H-oil[1,2-b] Piran-2-yl) methyl] -N'-2-pyrimidinyl-1,3-propandiamine, so pl. 57,6oC (Conn. 5-a).

Example 8-a

The intermediate connection is camping diisobutylaluminium, 1.5 M solution in hexane (0.1 M) and the mixture stirred 1 hour at -70oC. was added dropwise methanol (15 ml) and the reaction mixture was heated to room temperature. The mixture was poured into water, oxidized hydrochloric acid and was extracted with diethyl ether. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was dissolved in methanol (150 ml). Was added N-2-pyrimidinyl-1,3-propandiamine (0,06 M) and the mixture was gerasoulis on palladium on coal (small amount) as the catalyst in the presence of thiophene, 4% solution (10 ml). After absorption of H2(1 EQ.), the catalyst was filtered off and the filtrate was evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH 90/10). Three fraction groups were collected and the solvent was evaporated to obtain residues (1), (2) and (3) (12 g). The sample residue (3) (3.6 g) was dissolved in 2-propanone and converted into the salt of ethicality (1:2) processing solution ethicality. H2O (0,020 M) in 2-propanone. The precipitate was filtered and dried to obtain 4.5 g (46,1%) (-N -[(7,8-dihydro-2,3-dimethyl-6H-furo-[3,2-h] [I] benzopyran-8-yl)methyl] -N'-2-pyrimidinyl-1,3-propandiamine of candiota (1:2), so pl. 208,8oC (Conn. 7-a).3OH 85/15). The desired fractions were collected and the solvent was evaporated. The residue (1.8 g) was dissolved in ethanol and converted into the salt of ethicality (1: 2) treatment ethicality (0,010 M). The precipitate was filtered and dried to yield 1.1 g (3,3%) ()-N-2-pyrimidinyl-N'- [3,6,7,8-tetrahydro-2,3-dimethyl-2H-furo[3,2-h] [I] benzopyran-8-yl) methyl]-1,3-propandiamine of candiota (1:2), so pl. 171,2o(Conn. 8-a).

Were obtained the compounds shown in table 2 a (see the end of the description).

Example 9-a

A mixture of intermediate (15-a) (0,02 M) and 2-methylthiazole of monohydrochloride (0,02 M) in ethanol (100 ml) was stirred and boiled for 16 hours. The solvent was evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/(CH3OH/NH3) 90/9/1). Pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted into the salt by treatment with hydrochloric acid (1:2) with HCl/2-propanol. The salt was filtered off and dried to yield 2.4 g (the)-N-(4,5-dihydro-1H-imidazol-2-yl)-N'-[(2,3,4,7,8,9 - hexahydrotriazine[h] -1-benzopyran-2-yl)methyl] -1,3-propandiamine dihydrochloride, hemihydrate; so pl. 180,7oC (Conn. 9-a).

Example 10-a

A mixture of compound I-a (0,0099 M) in the l). After uptake of hydrogen (2 equiv.) the catalyst was filtered off. The filtrate was evaporated and the residue crystallized from methanol. The precipitate was filtered and dried to obtain 0.9 g (16.9 per cent). The mother liquid was evaporated. The residue was dried to obtain 0.4 g (7,5%) ()-N-[(2,3,4,7,8,9 - hexahydrobenzo[2,1-b: 3,4-b']dipyran-2-yl)methyl-N'(1,4,5,6 - tetrahydro-2-pyrimidinyl)-1,3-propandiamine of candiota (1:2), so pl. 226,9oC (Conn. 10-a).

The compounds obtained are given in table. 2 b.

B. Obtaining compounds of formula (I) in which R5and R6denote R5band R6band their intermediate compounds

Example 1-b

a) 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol (0,093 M) was dissolved in acetic acid (100 ml). Monochloride iodine (0,150 M) was heated to 35oC and added in liquid form to a solution of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol in acetic acid. The reaction mixture was stirred and boiled for 24 hours. The mixture was cooled, poured on ice (200 ml) and was extracted CH2Cl2. The separated organic layer was dried, filtered and evaporated. The residue was purified flash column chromatography on silica gel (eluent: CH2Cl2). The desired fractions were collected and the solvent was evaporated the tx2">

b) Intermediate compound 1-b (or 0.035 M) was dissolved in N,N-diethylethanamine (250 ml). Through the solution for 15 minutes had passed N2. Added bio(triphenylphosphine) palladium (II) chloride (0,00042 M) and copper iodide (0,0015 M). Added trimethylsilylacetamide (0,065 M) and the reaction mixture is stirred for 30 minutes at 50oC (in the flow of N2). Blackened mixture was cooled and the solvent was evaporated. The residue was dissolved in methanol saturated with ammonia (50 ml) and stirred 4 hours at room temperature. The solvent was evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH 97/3). The desired fraction (a mixture of several compounds) were collected and the solvent was evaporated. The remainder (of 7.1 g) was dissolved in dichloromethane (150 ml). Was added N,N-diethylethanamine (15 ml) followed by addition of 4-methylbenzenesulfonamide (0,035 M) and the reaction mixture stirred overnight at room temperature. Water was added (150 ml). The organic layer was separated. The aqueous layer was filtered CH2Cl2(150 ml). The combined organic layers were dried (MgSO4), filtered and the solvent was evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Clo
C (InterMedia. 2-b).

In a similar way were obtained:

()-methyl 3-[6-fluoro-3,4-dihydro-2-[[[(4-were) sulfonyl]oxy]methyl]-2H-1-benzopyran-8-yl]-2-propenoate (InterMedia. 3-b).

Example 2-b

Suspension ()-methyl-6-fluoro-3,4-dihydro-8-iodine-2H-1-benzopyran-2 - carboxylate (0,026 M), (trifluoromethyl)trimethylsilane (of 0.081 M), copper iodide (0.1 M) and potassium fluoride (of 0.081 M) in a mixture of DMF (50 ml) and 1-methyl-2-pyrrolidinone (50 ml), stirred 3 hours at 60oC. the Cooled reaction mixture was poured into a solution of ferric chloride (III) (200 g) and hydrochloric acid (50 ml) in water (300 ml). This mixture was extracted three times with diethyl ether (150 ml). The combined organic layers were washed with 5% aqueous solution of Na2S2O3(discoloration), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (eluent: CH2Cl2). Pure fractions were collected and the solvent was evaporated to yield 5.7 g (78,8%). This fraction was precrystallization from DIPE. The precipitate was filtered and dried to yield 1.2 g (16,6%) ()-methyl-6-fluoro-3,4-dihydr>a) a Solution of intermediate compound 1-b (0,022 M), 2-tributylstannyl (0,024 M) and tetrakis/triphenylphosphine/palladium (0,0005 M) in 1-methyl-2-pyrrolidinone (50 ml), stirred for 16 hours at 100oC. the Cooled reaction mixture was poured into water (200 ml) and the resulting mixture was extracted DIPE (200 ml). The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was mixed in methanol saturated with ammonia (50 ml) for 16 hours. The solvent was evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/hexane 50/50, enrichment to clean CH2Cl2). The desired fractions were collected and the solvent was evaporated to yield 4.5 g (82,4%) ()-6-fluoro-8- (2-furanyl)-3,4-dihydro-2H-1-benzopyran-2-methanol (InterMedia. 5-b).

b) 4-Methylbenzenesulfonyl chloride (0,021 M) was added to a solution of intermediate compound 5-b (0,018 M) in CH2Cl2(50 ml). There was added N,N-diethylethanamine (5 ml) and the reaction mixture stirred at room temperature for 24 hours. The reaction mixture was poured into water, and the resulting mixture was extracted CH2Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated. OS the work was going, and the solvent was evaporated. The residue is stirred in DIPE, and the white residue was filtered off and dried with a yield of 5.2 g (71,8%) 4-methylbenzenesulfonate ()-6-fluoro-8-(2-furanyl)- 3,4-dihydro-2H-1-benzopyran-2-methanol; so pl. 110,4oC (InterMedia. 6-b).

In a similar way were obtained:

4-methylbenzenesulfonate ()-6-fluoro-3,4-dihydro-8-(2-thienyl)- 2H-1-benzopyran-2-methanol (InterMedia. 7-b);

()-6-fluoro-3,4-dihydro-8-phenyl-2H-benzopyran-2-methyl ether 4-methylbenzenesulfonate (InterMedia. 8-b);

4-methyl-bansilalpet ()-6-fluoro-3,4-dihydro-8-(2-pyridinyl)-2H-1-benzopyran-2-methanol (InterMedia. 9-b);

methanesulfonate ()-8-(ethylthio)-6-fluoro-3,4-dihydro-2H-1 - benzopyran-2-methanol; so pl. to 107.7oC (InterMedia. 10-b); and

methanesulfonate ()-6-fluoro-3,4-dihydro-8-(phenylthio)-2H-1-benzopyran-2-methanol (InterMedia. 11-b).

Example 4-b

A solution of intermediate compound (11)-b (0,016 M) in dichloromethane (15 ml) was added in drops to a mixture of Al2O3(16 g, neutral, moist and 2 KHSO5KHSO4K2SO4(0,016 M) in dichloromethane (65 ml). The reaction mixture is stirred overnight at room temperature. Then filtered, rinsed CH2Cl2and the filtrate was dried (MgSO4), filtered and the solvent was evaporated. The remainder of PTS who were eralis and the solvent was evaporated. The residue (7.2 g) was purified column chromatography on silica gel (eluent : CH2Cl2enriched up to CH2Cl2/(CH3/NH3) 50/50). Pure fractions were collected and the solvent was evaporated to obtain 3.8 g (61,8%) methansulfonate ()-6-fluoro-3,4-dihydro-8-(phenylsulfonyl)-2H-1-benzopyran-2 - methanol (InterMedia. 12-b).

Example 5-b

a) ()-Methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (0,26 M) was added to the mixed nitric acid (300 ml). The reaction mixture is stirred 10 minutes at 40oC, then 60 minutes at 60oC. the Mixture was poured into water. The precipitate was filtered off. The filtrate was extracted CH2Cl2. The separated organic layer was evaporated to obtain 33 g of the residue and the output was 33 g ()-6-fluoro-3,4-dihydro-8-nitro-2H-1-benzopyran-2-carboxylic acid (InterMedia. 13-b).

b) 1 M solution (CH3)2S BH3in dichloromethane (0,28 M) drops were added to a mixture of intermediate compound 13-b (0.25 M) in tetrahydrofuran (800 ml), stirred in a stream of nitrogen. The distillation was removed about 60 ml of the solvent. The reaction mixture was stirred and boiled for 2 hours. The mixture was cooled, decomposed, CH3OH (20 ml), poured into H2O/NaOH and was extracted CH2Clbeen to obtain 59 g ()-6-fluoro-3,4-dihydro-8-nitro-2H-1-benzopyran-2-methanol (104% crude residue) (InterMedia. 14-b).

c) a Mixture of intermediate 14-b (0.25 M), 3,4-dihydro-2H-Piran (0,50 M) and hydrochloric acid in 2-propanol (0.5 ml) in trichloromethane (700 ml) were mixed for 3 hours in a water bath. The reaction mixture was washed with 10% NaOH solution. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated to obtain 81 g ()-6-fluoro-3,4-dihydro-8-nitro-2-[[tetrahydro-2H-Piran-2-yl) oxy] methyl] -2H-1-benzopyran (104% crude residue) (InterMedia. 15-b).

d) a Mixture of intermediate compound 15-b (0,47 M) in methanol (600 ml) was gerasoulis on palladium on charcoal as catalyst, a palladium content of 10% (5 g) in the presence of 4% solution of thiophene (3 ml). After absorption of H2(3 equiv.) the catalyst was filtered off, infiltration was evaporated to obtain 130 g (98,3%) ()-6-fluoro-3,4-dihydro-2-[[(tetrahydro-2H-Piran-2-yl)oxy] methyl]-2H-1-benzopyran-8-amine (InterMedia. 16-b).

e) a Mixture of intermediate 16-b (0.036 M), 2,5-dimethoxytetrahydrofuran (0.22 M) and PTSA (catalytic amount) in DMF (140 ml) was mixed for 90 minutes at 100oC. the Solvent was evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed once with water, dried (MgSO4), filtered, and raised] -2H - 1-benzopyran (InterMedia. 17-b).

f) 10% hydrochloric acid solution (25 ml) was added to a mixture of intermediate compound 17-b (0,019 M) in methanol (65 ml). The reaction mixture is stirred for 60 minutes at room temperature. The solvent was evaporated. The residue was divided between CH2Cl2and H2O. the Organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified on silica gel on a glass filter (eluent: CH2CL2/CH3OH 98/2). Pure fractions were collected and the solvent was evaporated to yield 3.4 g (72,4% ()-6-fluoro-3,4-dihydro-8-(1H-pyrrol-1-yl)-2H-1-benzopyran-2 - methanol (InterMedia. 18-b).

g) N,N-diethylethanamine (7 ml) drops were added to a mixture of intermediate 18-b (0,024 M) and methanesulfonyl chloride (0,035 M) in 2-propanone (30 ml), all stirred and cooled in an ice bath. The reaction mixture is stirred for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed with an aqueous solution of hydrochloric acid, dried (MgSO4), filtered and the solvent was evaporated to obtain 7.6 g (97,3%) methansulfonate ()-6-fluoro-3,4-dihydro-8-(1H-pyrrol-1-yl)-2H - 1-benzopyran-2-methanol (InterMedia. 19-b).

hanata ()-6-fluoro-3,4 - dihydro-8-(2-thienyl)-2H-1-benzopyran-2-methanol (0.01 M) in dichloromethane (50 ml), stirred at 0oC. the Reaction mixture was poured into water. The organic layer was separated, dried, filtered and the solvent was evaporated to yield 3.8 g (76,4%) 4-methylbenzenesulfonate ()-8-(5-bromo-2-thienyl)-6-fluoro-3,4-dihydro- -1H-1-benzopyran-2-methanol (InterMedia. 20-b)

Example 7-b

Calcium oxide was added (5 g) to a solution of intermediate compound 2-b (of 0.0125 M) and (N-2-pyrimidinyl-1,3-propandiamine (0,019 M) in tetrahydrofuran (100 ml) and the reaction mixture stirred overnight at 150oC (high-pressure apparatus). The reaction mixture was cooled and filtered. The filtrate was evaporated. The residue was purified column chromatography on silica gel: CH2Cl2enriched up to CH2Cl2/CH3OH 90/10). Two desired fractions were collected and the solvent was evaporated to obtain 1.2 g of the pure fractions. This fraction was dissolved in methanol (100 ml) and was transferred to salt ethicality (1:1) by treatment with hydrate of ethicality (0,620 g). The mixture was concentrated, was added 2-propanone and the precipitate was filtered and dried to yield 1.2 g (22,3%) ()-N-[(8-ethinyl-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)- methyl] -N'-2-pyrimidinyl-1,3-propandiamine of candiota (1; 1); so pl. 201,1oC (Conn. 1-b).

Example 8-b

Rasenia 4-b (0,018 M) methylbenzene (50 ml), stirred at -70oC. This mixture was mixed for 1 hour at -70oC. was Added methanol (10 ml) and the mixture was heated to room temperature, poured into water, oxidized HCl, then was extracted with dichloromethane. The separated organic layer was evaporated. A mixture of the residue and N-2-pyrimidinyl-1,3-propandiamine (0,014 M) gerasoulis palladium (2 g) as a catalyst in the presence of a solution of thiophene (4%, 2 ml). After uptake of hydrogen (250 ml), the catalyst was filtered off and the filtrate was evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH 90/10). Pure fractions were collected and the solvent was evaporated. The residue (2.2 g) was dissolved in ethanol (50 ml) and was transferred to salt ethicality (1:1) by treatment with ethicality (0,024 M). The precipitate was filtered off and dried. This fraction was precrystallization from methanol (300 ml). The precipitate was filtered and dried to obtain 0,950 g (13,6%) ()-N- [[6-fluoro-3,4-dihydro-8-[trifluoromethyl)-2H-1-benzopyranyl] methyl-N'- 2-pyrimidinyl-1,3-propandiamine of candiota (1:1), so pl. 216,3oC (Conn. 2-b)

Example 9-b

The solution of the free base of the compound 2-b (0,00313 M) and dihydrate ethicality (0,00635 M) in methanol (50 ml) was gidrirovaniya 2 hours at 50oC what was filtrovala and the filtrate was concentrated. The precipitate was filtered (*) and was dried to obtain 0,310 g (17,2%) of product. The corresponding (*) the filtrate was treated with 2-propanone and the precipitate was filtered and dried to obtain 0,500 g (27,7% ()-N-[[6-fluoro-3,4-dihydro-8-(trifluoromethyl)-2H-1 - benzopyran-2-yl] methyl] -N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)- 1,3-propandiamine of candiota (1:2) hemihydrate, so pl. 177,1oC (Conn. 3-b).

Example 10-b

The reaction was carried out in a stream of N2. The solution Bu3SnCH2COOE+ (0,011 M) methylbenzene (40 ml) drops were added to a mixture of intermediate compound 1-b (0,011 M) and tetrakis(triphenylphosphine) palladium (0,00029 M) methylbenzene (160 ml). The reaction mixture was stirred and boiled overnight, then cooled, washed with a 10% solution of KP, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified on silica gel on a glass filter (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanone and converted into the salt of ethicality (1:2). The precipitate was filtered off and dried (vacuum, 60oC) with the release of 4.4 g (65,1%) (a)-ethyl[[6-fluoro-3,4-dihydro-2-[[[3-(2-pyrimidinamine)propyl] - amino]-methyl]-2H-1-benzopyran-8-yl]thio]acetate floor is R>
A mixture of 3,6-dichloropyridazine (has 0.168 M), 1,3-propandiamine (0.84 M) and sodium carbonate (0.17 M) in ethanol (500 ml) was stirred and boiled all night. The reaction mixture was filtered through sigalit. The filtrate was evaporated. The residue is crystallized from acetonitrile. The crystals were filtered and dried to obtain 20.7 g of N-(6-chloro-3-pyridazinyl)-1,3-propandiamine; so pl. 124,9oC (InterMedia. 1-e).

In a similar way were obtained:

N-3-pyridazinyl-1,3-propandiamine the dihydrochloride; so pl. 210,9oC (InterMedia. 2-e)

N-(6-methyl-3-pyridazinyl)-1,3-propandiamine (InterMedia. 3-e).

Example 2-c

a) a Mixture of()-3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl] (phenylmethyl)-amino] propanenitrile (0,069 M) in methanol (250 ml) was gerasoulis on skeletal Nickel catalyst (5 g). After uptake of hydrogen (2 equivalents. ) the catalyst was filtered off and the filtrate was evaporated to yield 20 g (94% crude residue) ()-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl] -N'- (phenylmethyl)-1,3-propandiamine (InterMedia. 4-c).

b) a Mixture of intermediate 4-c (0.01 M) and 2-methylthio-4(1H)- pyrimidinone (0.01 M) was heated 2 hours at 150oC. the Residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH 95/5). Pure fractions were collected and dissolved what was kristallizuetsya of 1,1'-oxybisethane. The salt was filtered off and dried to obtain 2.8 g(56,5%) ()-2-[[3-[[3,4-dihydro-2H-1-benzopyran-2-yl)methyl] (phenylmethyl)-amino] propyl] amino] -4(1H)-pyrimidinone the dihydrochloride monohydrate; so pl. 150,2oC (InterMedia. 5-c, see table. 1 (C).

Example 3-c

a) a Mixture of 2-chlorocarbonyl-3,4-dihydro-2H-1-benzopyran (0,47 M) in N,N-dimethylacetamide (100 ml) solution of thiophene (4%, 3 ml) and 2,2'-oxybisethane (400 ml) was gerasoulis with palladium on charcoal (10%, 5 g) as a catalyst. After uptake of hydrogen (1 EQ.) the catalyst was filtered off and the filtrate was evaporated. The remainder, potassium acetate (20 g) and benzoylmethylene (50 g) in N,N-dimethylacetamide (2 ml) and methanol (300 ml) was gerasoulis on palladium on charcoal (10%, 5 g). After uptake of hydrogen (1 EQ.) the catalyst was filtered off and the filtrate was evaporated. The residue in methanol (500 ml) was gidrirovaniya on palladium on charcoal (10%, 5 g). After uptake of hydrogen (1 EQ.) the catalyst was filtered off and the filtrate was evaporated. The residue was taken in 1,1'-oxybisethane and were washed with NaOH solution. The organic layer was dried (MgSO4), filtered and evaporated. The residue (70 g) was distillable at 70oC (0.1 mm, RT. Art.) with the release of 48.7 g (63,5%) ()-3,4-dihydro-2H-1-benzopyran-2 - methanamine and was boiled for 4 hours. The solvent was evaporated to obtain 27 g of crude residue()-3-[[ (3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]-propanenitrile (InterMedia. 16-c).

(C) a Mixture of intermediate 16-c (0.12 M) in methanol saturated with ammonia (500 ml), was gerasoulis on skeletal Nickel catalyst (6 g). After uptake of hydrogen (2 equiv.) the catalyst was filtered off and the filtrate was evaporated. The residue was purified by distillation to obtain 24 g (90,8%) ()-N- [(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-1,3-propandiamine (InterMedia. 17-c).

B. obtain the final compounds (-C), which are listed in the table. 2 - 10 seconds

Example 4-

A mixture of intermediate compound 1-c (0,058 M), 3,4-dihydro - 2H-1-benzopyran-2-carboxaldehyde (0,064 M) and potassium acetate (7,1 g)in methanol (200 ml) was gerasoulis on palladium on charcoal (5%, 2 g) as a catalyst in the presence of 4% solution of thiophene (1 ml). After uptake of hydrogen (1 EQ. ) the catalyst was filtered off. The residue was dissolved in H2O/CH2Cl2and podslushivaet NaOH. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH 90/10). Two fractions were collected, Nero. The second fraction was evaporated, and the residue was crystallized from 2-propanol. The crystals were filtered and dried to obtain to 3.09 g (16%) ()-N -(6-chloro-3-pyridazinyl)-N'-[(3,4-dihydro-2H-1-benzopyran-2-yl)- methyl]-1,3-propandiamine, so pl. 107,8oC (Conn. 1-c).

Example 5-c

The intermediate compound 5-c (0.005 M) was gerasoulis in methanol (250 ml) palladium on charcoal (2 g) as a catalyst. After uptake of hydrogen (1 EQ. ) the catalyst was filtered off. The solvent was evaporated. The residue (2 g) was precrystallizer from methanol. The crystals were filtered and dried to yield 0.7 g(36%) ()-2-[[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl] amino] propyl] amino]-4(1H)-pyrimidine dihydrochloride (Conn. 8-c).

Example 6-c

A mixture of intermediate compound 17-c (0.03 M) and 2-methylthio-4(1H)- pyrimidinone (0.03 M) 2-methoxyethanol (50 ml) was stirred and boiled all night. The solvent was evaporated. The residue was mixed with water and was extracted with dichloromethane. The separated organic layer was dried (MgSO4was filtered and the solvent was evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). Pure fractions were collected and the solvent wipes and crystallized from methanol. Solid (1.2 g) was filtered off and dried to obtain 1.0 g(7,4%) ()-2-[[3-[[3,4-dihydro-2H-1-benzopyran-2-yl)methyl] amino] propyl] amino] -4(3H)-pyrimidine-ethanoate (2: 3); so pl. 206,7oC (Conn. 9-c).

Example 7-c

A mixture of ()-N2-[3-[[(3,4-dihydro-2H-1-benzopyran-2 - yl)methyl)amino]-propyl] -N4N4-dimethyl-2,4-pyrimidinediamine dihydrochloride (0,0067 M) in methanol (150 ml) was gerasoulis on palladium on charcoal 10% (2 g) as a catalyst in the presence of hydrochloric acid in 2-propanol (2 ml). After uptake of hydrogen (2 EQ.) the catalyst was filtered off. The filtrate was evaporated and the residue crystallized twice from methanol. The crystals were filtered and dried to yield 0.32 g(13,1%) ()-2-[[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl] -amino] -propyl]-amino]-5,6-dihydro-4(3H)-pyrimidine dihydrochloride; so pl. 273,6oC (Conn. 12-c).

Example 8-c

A mixture of compound 17-c (0.02 M) in methanol (200 ml) was gerasoulis on palladium on charcoal 10% (2 g) as a catalyst. After uptake of hydrogen (2 EQ.) the catalyst was filtered off. The filtrate was evaporated. The residue was dissolved in 2-propanol and converted into the salt of hydrochloric acid (1: 2) by HCl/2-propanol. Sol-pyridinyl)-1,3-propandiamine dihydrochloride; so pl. 211,3oC (Conn. 15-c).

Example 9-c

A mixture of compound free base (19-c) (0,0145 M) and skeletal Nickel catalyst for hydrogenation (5 g) in tetrahydrofuran (150 ml) was stirred and boiled for 1 hour. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 2-propanol and converted into the salt of ethicality (1:2). The salt was filtered off (3 g) and precrystallization from methanol (600 ml). The crystals were filtered and dried to yield 2.5 g (36.2%) of ()-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl] -N'-4 - pyrimidinyl-1,3-propandiamine of candiota (1:2), so pl. to 222.2oC (Conn. 20-c).

D. Pharmacological tests

Example 1-d

The segments of the basilar arteries from pigs (shot by pentobarbital sodium) were fixed in trays for Desk isometric stretching. The drugs were immersed in a solution of Krebs-Henseleit. The solution was maintained at a temperature of 37oC and was flushed with a mixture of 95% O2-5% CO2. The drugs were stretched to a stable basal tension of 2 grams. Drugs narrowed serotonin (310-7M). Was measured response to the addition of serotonin and then serotonin was washed out. This procedure was repeated until reaching stearate. This is the response of contraction was expressed as a percentage of the response to serotonin in the previous measurements. The lowest active concentration was determined as the concentration that achieved 50% of the response to serotonin.

In table. 1 d - 4d presents the lowest active concentration of the compounds of formula (I).

E. Examples on the track

"Active ingredient" (A. I.) in these examples is a compound of formula (I), its pharmaceutically acceptable acid salt of accession or its stereochemical isomeric form.

Example 1-e: Drops for oral destination

500 g of A. I. was dissolved in 0.5 l of 2-oxopropanoic acid and 1.5 l of the polyethylene glycol at 60-80oC. After cooling to 30-40oC to the mixture was added 35 l of polyethylene glycol and the mixture is mixed well. Then was added a solution of 1750 g of saccharin sodium 2.5 l of purified water and while stirring was added 2.5 l of aroma of cocoa and g polyethylene glycol.s. up to a volume of 50 l with obtaining solution drops for oral purposes, containing 10 mg/ml A. I. the resulting solution was filled in the correct containers.

Example 2-e: the Solution is for oral purpose

9 g of methyl 4-hydroxybenzo ALIS first, 10 g of 2,3-diablocody acid and then 20 g of A. I. The latter solution was combined with the rest of the first solution and thereto was added 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 g of saccharin sodium were dissolved in 0.5 l of water and added 2 ml strawberry essences and 2 ml essences gooseberry. The latter solution was combined with the first, had water up to a volume of 20 l with obtaining a solution for oral purposes, containing 5 mg of active ingredient in a teaspoon (5 ml). The resulting solution was filled in suitable containers.

Example 3-e: Capsules

20 g of the active ingredient, 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate was vigorously mixed together. The resulting mixture was filled 1000 hard gelatin capsules containing each 20 mg of the active ingredient.

Example 4-e: Tablets film-coated

Cooking basics tablets

A mixture of 100 g A. I., 570 g lactose and 200 g starch is mixed well and then moistened with a solution of 5 g of nitrilotriacetate and 10 g polyvinylpyrrolidone approximately 200 g of water. Wet powder mixture sifted, dried and re-sifted. Then it was added 100 g microcrystalline allucaneet 10,000 tablets containing each 10 mg of the active ingredient.

Floor

To a solution of 10 g of methyl cellulose in 75 g of denatured ethanol was added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then was added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Melted 10 g of polyethylene glycol was dissolved in 75 ml of dichloromethane. The latter solution was added to the first and thereto was added 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated ink suspension and the mixture was gomogenizirovannykh. Fundamentals of tablets covered with a mixture of a device for coating.

Example 5-e: Solution for injection

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate was dissolved in approximately 0.5 l of boiling water for injection. After cooling to about 50oC there with stirring was added 4 grams lactic acid, 0.05 g of polyethylene glycol and 4 g of A. I. the Solution was cooled to room temperature and had water for injection g.s. up to 1 l with obtaining a solution containing 4 mg/ml A. I. the Solution was sterilized by filtration (USP XVII, page 811) and filled into sterile ampoules.

Example 6-e: Suppositories

3 g A. I. was dissolved in a solution of 3 g of 2,3-diablocody acid in 25 ml of polyethylene glycol 400. Together melted 12 g Pervym solution. Thus obtained mixture was poured into moulds at a temperature of 37-38oC with 100 suppositories containing each 30 mg/ml A. I.

Example 7-e: Solution for injection

60 g A. I. and 12 g of benzyl alcohol were thoroughly mixed and added sesame oil g.s. up to 1 l with obtaining a solution containing 60 mg/ml A. I. the Solution was sterilized and filled into sterile ampoules.

1. Derived dihydrobenzofuran formula I

< / BR>
its pharmaceutically acceptable salt formed by the addition of acid or base, or its stereochemical isomeric form,

where R1, R2and R3each independently hydrogen or C1-6-alkyl;

R4is hydrogen, halogen or C1-6-alkyl;

R5and R6denote R5aand R6ain which R5aand R6ataken together form a bivalent radical which is attached in the 7 - and 8-position to the fragment dihydropyran, and has the formula

-CH=CH-CH=CH- (a1),

-(CH2)n- (a2),

-(CH2)m-X- (a3),

-X-(CH2)m- (a4),

-CH=CH-X- (a5),

-X-CH=CH- (a6)

-O-(CH2)t-Y- (a7),

-Y-(CH2)t-O- (a8),

in these bivalent radicals one or two hydrogen atoms of mo is every m - independently 2 or 3;

each Y independently represents-O-;

each t is independently 1 or 2;

or R5and R6denote R5band R6bin which R5bis hydrogen and R6b- carboxyl-C1-6-alkyl, C1-6-allyloxycarbonyl-C1-6-alkyl, trihalomethyl, C1-6-allyloxycarbonyl-C1-6-alkyl-S-, carboxyl-C1-6-alkyl-S-, C1-6-alkyl-S-(O)-, C1-6-alkyl-S-, aryl-S-, aryl-S(O)-, or R6bis a radical of the formula

< / BR>
R8and R9each independently hydrogen, carboxyl, C1-6-allyloxycarbonyl;

R10, R11, R12, R13, R14, R15, R16, R17and R25each independently hydrogen, halogen or C1-6-alkyl;

or R5and R6denote R5cand R6cand in this case, R4can only mean hydrogen; and R5cand R6ceach independently hydrogen, halogen, C1-6-alkyl, hydroxy, C1-6-alkyloxy;

Alk1- C1-6-alcander;

Alk2- C2-15-alcander;

Q is a radical of the formula

< / BR>
in which R26is hydrogen, cyano, aminocarbonyl;

R27is hydrogen, C1-6-alkyl, C3-6-cycloalkyl or aryl-C1-6-alkyl;

R28- hydrogen 1-6
-alkyl;

R31, R37, R38, R41, R42, R44, R45, R46, R47, R48, R49and R52is hydrogen;

R29, R30, R36and R55each independently hydrogen, hydroxy, C1-6-alkyl, C1-6-alkyloxy or aryl-C1-6-alkyl;

q is 1 or 2;

R33and R34each hydrogen or taken together with the carbon atom to which they are attached, they may form C(O);

R39and R40each independently hydrogen, C1-6is alkyl or aminocarbonyl;

R42is hydrogen, halogen, cyano, C1-6-alkyl, aminocarbonyl, hydroxy or C1-6-alkyloxy;

R43is hydrogen, C1-6-alkylthio, C1-6-alkyloxy, mono - or di(C1-6-alkyl)amino or piperidinyl;

r is 1 or 2;

R47and R48each hydrogen or taken together with the carbon atom to which they are attached, they may form C(O);

R33, R34, R53and R54each independently hydrogen or hydroxy;

R50is hydrogen;

R51is hydroxy; or R50and R51taken together may form a bivalent radical of the formula (CH2)3or (CH2)4;

aryl represents the FDS is that if R4is hydrogen and R5and R6denote R5cand R6cthen Q must be a radical of the formula (gg), (hh), (ii), (jj), (kk), (ll), (mm), (nn); a radical of formula (aa), in which R27represents a C3-6-cycloalkyl or aryl-C1-6-alkyl; a radical of formula (aa), in which R27and R28taken together with the nitrogen atom to which they are attached, form a piperazine which may be substituted C1-6-alkyl; a radical of the formula (bb), in which R29- hydroxy on the carbon atom adjacent to the nitrogen atom; a radical of formula (dd), in which R35is hydrogen, and R33and R34taken together with the carbon atom to which they are attached form C(O); a radical of formula (ee) in which R55- aryl-C1-6-alkyl.

2. Connection on p. 1, in which R1, R2, R3and R4are the same as those defined in paragraph 1, and in which R5and R6denote R5aand R6awhere in formulas (a7) and (a8) t -2; Q is a radical of the formula (aa), (bb), (cc), (dd), in which q is 1 or 2; (ee), where R55is hydrogen, (gg), (ff), (hh), (ii), (jj), (kk), where q is 1 or 2; (ll).

3. Connection on p. 1, in which R1, R2, R3have the same values as defined in paragraph 1, R4is hydrogen, halogen, C1-6-alkyl; R5and R6aryloxyalkyl-C1-6-alkyl, trihalomethyl, the radical of formula (b1), (b2), (b3), (b4), (b5), (b6), Q is a radical of the formula (aa), (bb), (cc), (dd), where q is 1 or 2; (ee), where R55is hydrogen, (ff), (gg), (hh), (ii), (jj), (kk), where q is 1 or 2; (ll).

4. Connection on p. 1, in which R1, R2, R3are the same as those defined in paragraph 1, R4is hydrogen, R5and R6denote R5cand R6cand Q is radical of formula (gg), (hh), (ii), (jj), (kk), where q is 1 or 2; (ll); a radical of the formula (bb), where R29- hydroxy on the carbon atom adjacent to the nitrogen atom; a radical of formula (dd), where R35is hydrogen and R33and R34taken together with the carbon atom to which they are attached form C(O) and q is 1 or 2.

5. Connection on p. 1, which is:

N - [(2,3,4,7,8,9-hexahydrobenzo [2,1-b : 3,4-b'] dipyran-2-yl)methyl] - N' -2-pyrimidinyl-1,3-propandiamine;

N - [(2,3,4,7,8,9-hexahydrotriazine [h] -1-benzopyran-2-yl)methyl] - N' -2-pyrimidinyl-1,3-propandiamine;

() - N - [(2,3,4,8,9,10-hexahydrobenzo [2,1-b : 3,4-b'] dipyran-2-yl)methyl] - N' -2-pyrimidinyl-1,3-propandiamine;

N - [(3,4,7,8,9,10-hexahydro-2H-oil [1,2-b] Piran-2-yl)-methyl] - N' -2-pyrimidinyl-1,3-propandiamine;

N -(4,5-dihydro-1H-imidazol-2-yl)- N' - [(2,3,4,7,8,9-hexahydrotriazine [h] -1-benzopyran-2-yl)methyl] -1,3-propandiamine;

N - [(2,3,4,7,8,9-hexahydroazepin [h] -1-benzopyran-2-yl)methyl] - N' - (1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propandiamine;

N - [(2,3,7,8-tetrahydro-9H-pyrano [2,3-f]-1,4-benzo-dioxin-9-yl)methyl] - N' -(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propandiamine;

N - [(3,4,7,8,9,10-hexahydro-2H-oil [1,2-b] Piran-2-yl)-methyl] - N' -(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propandiamine;

methyl 3- [6-fluoro-3,4-dihydro-2- [[[3-(2-pyrimidinamine)-propyl]amino] methyl] - 2H-1-benzopyran-8-yl] -2-propenoate;

N - [[(6-fluoro-8-(2-furanyl)-3,4-dihydro-2H-1-benzopyran-2-yl] methyl] - N' -2-pyrimidinyl-1,3-propandiamine;

N - [[(6-fluoro-3,4-dihydro-8-(2-thienyl)-2H-1-benzopyran-2-yl]-methyl] - N' -(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propandiamine;

N-(3,4-dihydro-2H-1-benzopyran-2-yl)methyl] - N' -(3,4,5,6-tetrahydro-2-pyridinyl)-1,3-propandiamine;

N4- [3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl] amino] propyl] -NR-methyl-2,4-pyrimidinediamine;

their pharmaceutically acceptable salt, acid or accession their stereochemical isomeric form.

6. Pharmaceutical composition having vasoconstrictive action, including pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of the compounds under item 1.

7. A method of obtaining a pharmaceutical composition according to p. 6, characterized in the subject by the media.

8. The intermediate compound of formula V-a

< / BR>
its pharmaceutically acceptable acid salt of accession or its stereochemical isomeric form,

in which R3, R5aand R6ahave the same values as defined in paragraph 1,

Alk3- C1- C4-alcander.

9. Connection on p. 1 with vasoconstrictive action.

10. The method of obtaining compounds on p. 1, characterized in that conduct the interaction of the intermediate compounds of formula II

< / BR>
in which R1, R2, R3, R4, R5, R6, R7, Alk1and Alk2are the same as those defined in paragraph 1,

with a reagent of formula III

W1-Q

in which Q is the same as in paragraph 1;

W1- reactive leaving group,

if necessary, the compounds of formula I is subjected to hydrogenation, or dialkoxybenzene, or N-acylation, N-alkylation, and, if desired, converting the compounds of formula I in a therapeutically active non-toxic acid salt accession, or, on the contrary, transforming a salt of an acid accession by treatment with alkali in the form of free base, and/or getting their stereochemical isomeric form.

11. The method of obtaining with the ora R3, R4, R5and R6- the same as in paragraph 1;

Alk3- C1- C4-alcander,

and reductive N-alkylation of the intermediate compounds of formula VI

< / BR>
where R1, R2, Alk2and Q are the same as those defined in paragraph 1,

with the obtained aldehyde of formula V

< / BR>
in which R3, R4, R5and R6are the same as those defined in paragraph 1;

Alk3- C1- C4-alcander,

if necessary, the compound of formula I is subjected to hydrogenation, or dialkoxybenzene, or N-acylation, N-alkylation, and, if desired, converting the compounds of formula I in a therapeutically active non-toxic acid salt accession, or Vice versa, transforming a salt of an acid accession by treatment with alkali in the form of free base, and/or getting their stereochemical isomeric form.

12. A method of obtaining a connection on p. 1, characterized in that the conducting N-alkylation of an amine of the formula VI

< / BR>
in which R1, R2, Alk2and Q are the same as those defined in paragraph 1,

the intermediate compound of formula VII

< / BR>
in which R3, R4, R5, R6and Alk1- the same as in paragraph 1;

W2- reactive leaving group, aniu, or N-alkylation, and, if desired, converting the compounds of formula I in a therapeutically active non-toxic acid salt accession, or Vice versa, transforming a salt of an acid accession by treatment with alkali in the form of free base, and/or getting their stereochemical isomeric form.

 

Same patents:

The invention relates to a new method of obtaining the previously described connections of a number of dibenzo[b, e]pyrano[3,2-b]-1-benzopirilievyh salts of General formula (I),

< / BR>
where X 0;

R1a hydrogen atom;

R2-R4the atom of hydrogen or halogen, C1-C6alkyl or C1-C6alkoxygroup, the nitro-group;

R5, R6, R7the atom of hydrogen or C1-C6alkyl,

that exhibit fluorescent properties and are used as dyes for dyeing films and aminomethylating fibers (DOS 2942931 (1980), BASF, Erf

The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form the second alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6

The invention relates to 5-nitrofurfurylidene 2-chloro-5,6,7,8-tetrahydroquinolin-4-carboxylic acid with bacteriostatic activity against Staphylococcus aureus with MIC of 1 g/l and E. coli was 3.9 g/ml at LD50more than 500 MK/kg

The invention relates to a new diisobutylaluminum connection, which has an excellent activity, which increases potassium exchange by opening potassium channels and therapeutic agents for the treatment of hypertension, angina pectoris and asthma, which contain diazabicyclo connection as the active agent

The invention relates to certain condensed to errorcorrection that selectively associated with GABA receptors

The invention relates to methods for taxan with side chain and their intermediates and to new compounds of the formula III obtained by these methods

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-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents 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

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-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents 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

The invention relates to new derivatives of pianolasociety, pharmaceutical compositions containing these derivatives, their use for the treatment of hypertension or asthma in mammals, including humans, and method for producing the above compounds and compositions

The invention relates to a method for producing new derivatives benzocycloheptene acids
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