Benzopyrane, the retrieval method, intermediate compounds and pharmaceutical compositions

 

(57) Abstract:

Describes new benzopyrane formula I, where R1represents phenyl, methoxyphenyl, forfinal or pyridyl, triptoreline, R2represents H, or C1-5-alkyl or C2-5-alkylen associated with R1, R3represents a group of formula-N(R9)2COR10where R9represents hydrogen, and R10represents phenyl or pyridyl, or R9and R10together represent a 1,3-butadienyl or a group of the formula -(CH2)nin which n is an integer from 3 to 5 inclusive, R4represents hydrogen and R5represents a hydroxyl in the TRANS-position with respect to R3or R4and R5together represent an additional bond, as indicated by the dashed line, R6and R7independently of one another represent C1-5-alkyl and R8represents hydrogen, or a physiologically hydrolyzable and physiologically acceptable ester of this compound, or an acid additive salt or Quaternary ammonium salt of this compound or a complex ester. Also describes the method of production thereof, the intermediate connection which means hyperresponsiveness of the Airways, for example, for use in the treatment of asthma. 5 C. and 1 C.p. f-crystals, 1 PL.

The present invention relates to new 2,2-dialkyl - 2,2-dialkyl-3,4-dihydro-3-hydroxy-2H-1-benzopyrane, their salts, esters and N-oxides and methods for their production and their use as pharmaceuticals and pharmaceutical compositions containing them.

More specifically, the present invention provides in its broadest aspect:

1) 2,2-di(C1-5-alkyl)- or TRANS-2,2-di(C1-5-alkyl)-3,4-dihydro-3-hydroxy-4-carboxamido - 6-(N-arylsulfonamides)-2H-1-benzopyran; or its N-oxide; or a physiologically hydrolyzable and physiologically acceptable ester of such benzopyran or N-oxide; or a salt accession acid or Quaternary ammonium salt such benzopyrane, N-oxide or ether.

Alkyl groups and components of the compounds defined above in paragraph (1) may be branched or normal. Fit arylsulfonamides components include sulfamidihappo, which is N-substituted aryl, or N,N-disubstituted-aryl and C1-5-alkyl, or N,N-disubstituted-aryl and C2-5-alkylene related for the formation of aryl bicyclic Ie aromatic group, possibly containing one or more nitrogen atoms, for example phenyl, naphthyl or pyridyl which may be substituted, for example, 1-3 substituents selected from halogen, C1-5-alkyl, (halo)1-3-C1-5-alkyl or C1-5-alkoxyl, especially phenyl, forfinal, triptoreline, methoxyphenyl or pyridyl.

As described below, the compounds of the present invention, such as that defined above in paragraph (1), have activity opening potassium (K+) channels [Cook et al., "Potassium Channels: Structure, Classification, Function and Therapeutic Potential", (1990), p.p.181-255]. Replaced by carboxamido in position 4 derivatives benzopyrano with activity open TO+channels are widely described in the literature and constitute a significant and recognized class of compounds. 4 Carboxamido-component in the compounds according to the invention may include any of the known and described in the literature, related to the opening of K+-channels to benzopyranyl, including N-substituted, for example circular, carboxamido components. The preferred carboxamido components in the compounds according to the invention are components of the formula-N(R9)-COR10as defined by the ti deputies, apart from those mentioned above. In particular, they can be, for example, 7-C1-5-alkyl substituted, especially 7-methylseleninic, for example, as shown below in formula I.

In accordance with the present invention, preferred are 2,2-di(C1-5-alkyl)-3,4-dihydro-3-hydroxy-4-carboxamido-6-(N-arylsulfonamides)-2H-1 - benzopyrane and/or their N-oxides, esters and salts, as defined above in paragraph (1). 3-hydroxy-group and 4-carboxamido-component of such compounds are in the TRANS configuration, as specified in paragraph (1). For this group of compounds, in most cases, preference will be given to (3S, 4R)-enantiomers in pure or substantially pure form, or isomeric, for example racemates, mixtures, as described below for compounds of formula I.

In a narrower aspect of the present invention includes:

2) the compound of the formula I

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where R1represents aryl,

R2represents H or C1-5-alkyl or C2-5-alkylen associated with R1,

R3represents a group of formula-N(R9)-COR10where R9is hydrogen, a R10is phenyl or pyridium, or R9and R10together represent a 1,3-butadienyl liiklusele, a m is 1 or 2,

R4represents hydrogen, and

R5represents a hydroxyl group in the TRANS-position with respect to R3or

R4and R5together represent an additional bond, as indicated by the dashed line,

R6and R7independently of one another represent C1-5-alkyl, and

R8represents hydrogen or C1-5-alkyl; or an N-oxide; or a physiologically hydrolyzable and physiologically acceptable ester of such compound, or an N-oxide, or salt accession acid or Quaternary ammonium salt of such a compound, N-oxide or ether.

The alkyl groups of R2, R6, R7and R8can be branched or normal. R6and R7both are preferably methyl. R8represents preferably hydrogen or methyl, most preferably hydrogen.

In a preferred group of compounds of the formula I R1represents phenyl, forfinal, triptoreline, methoxyphenyl or pyridyl; and/or R2represents methyl, ethyl or H; or R1and R2together with N form a group 1,2,3,4-tetrahydroquinolin-1-yl.

th hydrogen, a R10represents pyridyl (especially 3-pyridyl), or R9and R10together represent a 1,3-butadienyl, trimethylene or tetramethylene. Most preferably R9and R10together represent tetramethylene.

Preferably R4represents hydrogen, a R5represents hydroxyl.

Especially preferred are the compounds of formula Ia, IB and IC

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Formula Ia

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The formula IB

< / BR>
The formula IB

where R1, R2, R6, R7and R8such as defined above.

2,2-Di-(C1-5-alkyl)- or TRANS-2,2-di-(C1-5-alkyl)-3,4-dihydro-3-hydroxy-4 - carboxamido-6-(N-arylsulfonamides)-2H-1-benzopyran include the following connections:

a) TRANS-1,2,3,4-tetrahydro-1-[[3,4-dihydro-2,2-dimethyl-3 - hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-yl]sulfonyl] quinoline;

b) TRANS-N-phenyl-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide;

C) TRANS-N-(4-methoxyphenyl)-3,4-dihydro-2,2-dimethyl-3 - hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide;

d) TRANS-N-methyl-N-phenyl-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfon-6-sulfonamide;

(e) TRANS-N-methyl-N-(3-methoxyphenyl)-3,4-dihydro-2,2-dimethyl-3 - hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide;

W) TRANS-N-methyl-N-(4-forfinal)-3,4-dihydro-2,2-dimethyl-3 - hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide;

C) TRANS-N-methyl-N-(4-triptoreline)-3,4-dihydro-2,2-dimethyl - 3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide;

and) TRANS-N-methyl-N-(3-triptoreline)-3,4-dihydro-2,2 - dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6 - sulfonamide;

K) TRANS-N-methyl-N-(pyridin-4-yl)-3,4-dihydro-2,2 - dimethyl-3 - hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6 - sulfonamide;

l) TRANS-N-methyl-N-(pyridin-3-yl)-3,4-dihydro - 2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran - 6-sulfonamide;

m) of TRANS-N-ethyl-N-phenyl-3,4-dihydro-2,2-dimethyl - 3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide;

h) TRANS-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6- [(1,2,3,4-tetrahydroquinolin-1-yl)sulfonyl]-2H-1-benzopyran-4-yl]- 3-pyridine-carboxamide;

a) TRANS-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6-[(N-methyl-N - phenylamino)sulfonyl]-2H-1-benzopyran-4-yl]-3-pyridinecarboxamide;

p) TRANS-[3,4-dihydro-2,2-dimethyl-6-[(N-ethyl-N-phenylamino) sulfonyl]-3-hydroxy-2H-1-benzopyran-4-yl]-3-pyridinecarboxamide;

R)R>
C) N-methyl-N-phenyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl - 2H-1-benzopyran-6-sulfonamide;

t) (3S, TRANS)-N-methyl-N-phenyl-3,4-dihydro-4-(1,2 - dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-3-hydroxy-2H-1-benzopyran - 6-sulfonamide;

y) (3S, TRANS)-[3,4-dihydro-2,2-dimethyl-3 - hydroxy-6-[(N-methyl-N-phenylamino)sulfonyl]-2H-1-benzopyran - 4-yl]-3-pyridinecarboxamide;

f) (3S, TRANS)-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6- [(1,2,3,4-tetrahydroquinolin-1-yl)sulfonyl]-2H-1 - benzopyran-4-yl]-3-pyridinecarboxamide;

x) (3S, TRANS)-N-phenyl-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide.

Especially preferred compounds of formula I are compounds of formula Ia, IB or IC, where

R1represents phenyl;

R2represents H or methyl, or trimethylene associated with R1so that R1and R2together with N form a 1,2,3,4-tetrahydroquinolin-1-idgruppo;

R6and R7both represent methyl; and R8represents hydrogen.

Certain benzopyran according to the invention, form N-oxides, for example, the nitrogen atom in peredelnoj group. Such N-oxides with respect to the compounds predecessors have comparable activity (as described below) and n is the range and physiologically acceptable ester" refers to an ether, in which a hydroxyl group (for example, in the formula I is hydroxyl group, R5) esterified, and that can either hydrolyzed under physiological conditions to form acid, which is itself physiologically acceptable doses intended for injection. As will be shown, such esters are proletarienne forms of standard type, and in comparison with compounds predecessors have comparable activity and tolerability. Examples of such esters include the esters of C2-5-carboxylic acid, benzoic acid and salicylic acid.

Salt accession acids, for example, compounds of formula I, their N-oxides and esters include salts of accession as inorganic and organic acids. Such salts are also comparable with the free compounds, N-oxides and ethers activity. Below salt accession acids, pharmaceutically acceptable for use in accordance with the present invention, include, for example, salts of hydrochloric, sulfuric and fumaric acids.

Quaternary ammonium salt, for example, compounds of formula I, their N-oxides and ethers include, for example, salts with organohalide, such as alcohol use, in accordance with the present invention, include, for example, such salts with methyliodide.

Esters for pharmaceutical use in accordance with the present invention, as mentioned above, in most cases less preferred.

The compounds of formula I in which R4represents hydrogen, a R5is hydroxyl, as well as their N-oxides, esters and salts, as already mentioned, have a configuration (3S*,4R*), that is, the configuration of the groups R3and R4in 3 - and 4-positions is a TRANS-configuration. Thus, the compounds according to the invention exist in enantiomeric form, i.e. in the form of optically active antipodes, with [3S,4R] or [3R,4S] configuration. It should be understood that the present invention covers both individual enantiomers (optically active, [3S,4R] or [3R,4S] antipodes), and mixtures thereof, such as racemic mixtures.

As for pharmaceutical use according to the invention, it is assumed that the application of the characteristic or dominant prevalent [3S, 4R] -enantiomers, is preferred. Accordingly, these [3S, 4R] -enantiomers will be or will be used in accordance with this invention in purified form, i.e. containing less than 50% of the EN is Ino 5% or less, for example, 1% or 2% or less [3R,4S]-enantiomeric impurities.

Compounds according to the above paragraphs 1) or 2), for example, formula I, can be obtained from the corresponding 1a, 7b-dihydro-2,2 - di(C1-5-alkyl)-6-(aryl(or 2,2-dimethylpropyl)sulphonamido) -2H-oxirane[I] [1]benzopyran (for example, the intermediate product 2, as described in more detail below, in accordance with the following Reaction scheme (where Hal means halogen, preferably bromine, M means a metal or a metal halide, such as lithium halide or magnesium (HalMg is, for example, BrMg-), and R groups are the same as defined above in formula I). The reaction scheme As shown in the end of the description.

The intermediate product I can be obtained in two ways in accordance with the following General Reaction scheme B, is given at the end of the description, where R is a group such as defined above, and X is a leaving group, for example halogen, preferably chlorine. The last stage (the cyclization of ester) is conducted by heating (for example, when 200oC) in a suitable high boiling solvent, for example N,N-diethylaniline or 1,2-dichlorobenzene. The formation of ester by alkylation of phenolic compounds the compound of the formula XC(R6)(R7 using anhydrous metal carbonate (for example, potassium carbonate as base in an aprotic solvent (for example, butane-2-Ohe) in the presence as catalyst of silver compounds (e.g., silver oxide), or using 1,8-diazabicyclo[5,4,0]-undec-7-ene as a base in a suitable solvent (e.g. acetonitrile) in the presence of a copper salt as a catalyst (for example, copper chloride (I)).

The invention thus further provides:

3) the method of producing benzopyrane, such as defined above in paragraph (1), for example, the compounds of formula I, as defined above in paragraph 2), or its N-oxide, or a physiologically hydrolyzable and physiologically acceptable ester of such benzopyran or N-oxide, or salt accession acid or Quaternary ammonium salt such benzopyrane, N-oxide or ester, in which

a) to obtain benzopyrane, such as above

and1) 1A, 7b-dihydro-2,2-di(C1-5-alkyl)-6-(aryl (or 2,2-dimethylpropyl)sulphonamido)-2H-oxirane[I] [1] benzopyran (for example, the intermediate product 2) is subjected to interaction with the salt of an alkali metal carboxamide, for example, a compound of formula R10-CO-N-R9M+where R9and R10have the meanings given by way of 3,4-dihydrobenzofuran possible dehydrogenation to obtain the corresponding benzopyran; or

and2) acelerou and, if required, alkylate the amino 2,2-di(C1-5-alkyl)- or TRANS-2,2-di(C1-5-alkyl)-3,4-dihydro-3-hydroxy-4-amino - 6-(aryl (or 2,2-dimethylpropyl)sulphonamido)-2H-benzopyran, for example, acelerou the above intermediate product 3 suitable acylhalides, such as nicotinanilide; or

b) to obtain the N-oxide benzopyran or physiologically hydrolyzable and physiologically acceptable complex ester benzopyran or N-oxide benzopyrane, such as defined above, atrificial benzopyran or N-oxide benzopyran, as defined above in paragraph (1), having a free hydroxyl group or component for the introduction of a suitable ether groups, for example, is subjected to the interaction of the compound of formula I, such as defined above, where R5represents hydroxyl, or N-oxide with the appropriate halide or acid anhydride, and/or oxidize benzopyran or its physiologically hydrolyzable and/or its N-oxide with the appropriate halide or acid anhydride, and/or oxidize benzopyran or its physiologically hydrolyzable and physiologically acceptable ester, such as defined above in paragraph (1), for example, oxidizing a compound of the above is benzopyran, N-oxide benzopyran or its physiologically hydrolyzable and physiologically acceptable ester in free form or in salt form accession acid or Quaternary ammonium salt.

Stage and1) the method can be performed according to known prior art methods, for example, the interaction at temperatures from ambient temperature to a temperature of education phlegmy in the presence of an inert solvent or diluent, such as tetrahydrofuran or dimethyl sulfoxide. Accordingly, the necessary salt of an alkali metal get preliminary in situ, for example, as described below in examples 1-13. If used creatively, for example, sodium salts, can be obtained as benzopyrene and dihydrobenzofuran according to the invention. The use of lithium salts leads predominantly or exclusively to the preferred dihydrobenzofuran according to the invention as shown in examples 1-13.

Stage and2) method can also be carried out according to known prior art methods. Interaction respectively carried out at temperatures from 0o100oC in an inert solvent or diluent, such as acetonitrile, dichloromethane or dimeta alkali metal. This procedure is illustrated below in examples 14-17.

Stage b) of the method can be performed according to standard techniques acylation/N-oxidation, for example, to obtain the N-oxides by treatment with hydrogen peroxide, m-chloroperbenzoic acid or peracetic acid.

Originally obtained free base can be converted into a salt accession acids or Quaternary ammonium salt by reacting with acids or, for example, alkyl-, in particular, metalhalide, and Vice versa.

As will be shown, variations of the above procedures or alternatives can be used, as known from the prior art, for example, for interconversion originally derived compounds or for the introduction of alternative carboxamidine in position 4. Labile group may be protected, for example, in the process of acylation using conventional protective groups, for example hydroxy-protective groups. In addition, originally obtained 3,4-dihydrobenzofuran can be optionally converted into the corresponding benzopyran by degidrirovaniya on 3,4-bond, according to standard techniques, for example as described in example 19. Other variants of the by-products 1, 2 and 3, illustrated above and in the respective examples, are new compounds, for example compounds of the formula I-1, I-2 and I-3

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< / BR>
< / BR>
where R1, R2, R6, R7and R8the same as in the above formula I. Such intermediate compounds, in particular intermediates 1A-1m, 2A-2E and 3A-g described and shown in the examples below, and methods for their production, are also part of the present invention.

The production of intermediate products

The intermediate product 1

The connection of the intermediate product 1 (formula I-1 above) can be obtained by the reaction scheme As follows:

(1A) 1,2,3,4-tetrahydro-1-[(2,2-dimethyl-2H-1-benzopyran-6-yl) sulfonyl] -quinoline

A solution of n-utility in hexane (20 ml, 1.6 M, 32 mmol) is added to a stirred solution of 6-bromo-2,2-dimethyl-2H-1 - benzopyran (7,17 g, 30 mmol) in dry tetrahydrofuran (100 ml) at -78oC in argon atmosphere. The mixture is stirred for 1 hour at -78oC and then the flow of gaseous sulfur dioxide is bubbled through the solution for 30 minutes, after which the resulting mixture is left to warm to 20oC. the mixture is Then evaporated to dryness under reduced pressure with an image of what astora of sulfurylchloride (2,53 ml, is 4.21 g, 31 mmol) in dry hexane (30 ml). The resulting mixture was stirred for 30 minutes at 0oC, then for 60 minutes at 20oC and then evaporated to dryness under reduced pressure to get crude sulphonylchloride, which are suspended in 1,1,1-trichloroethane (200 ml), treated with triethylamine (4,00 ml, 2,90 g, 29 mmol) and 1,2,3,4-tetrahydroquinoline (7,6 ml, 8,03 g, 60 mmol) and stirred at 20oC for 16 hours. The solvent and excess reagent is evaporated under reduced pressure to get crude product. Its clear column chromatography on silica gel, eluent 5% acetone in hexane, to obtain the compounds specified in the header, in the form of a yellow oil having the following physical characteristics:

1H-NMR ( - CDCl3): of 1.32 (s, 6H), 1.69 in (m, AMX, 2H), 2.49 USD (m, AMX, 2H), 3,78 (m, AMX, 2H), 5,65 (d, J=10,8 Hz, 1H), 6,20 (d, J=10, 8 Hz, 1H), of 6.71 (d, J=8,4 Hz, 1H), 7,01 (dd, 7.5 Hz, 1H), 7,06 (ddd, 1H), 7,20 (d, J=2.4 Hz, 1H), 7,29 (dd, 2) J=2,4, and 8.4 Hz, 1H) and 7,76 (d, J=8.6 Hz, 1H).

The following connections get similarly using the appropriate amine:

(1B) 2,2-dimethyl-N-phenyl-2H-1-benzopyran-6-sulfonamide,

(1B) 2,2-dimethyl-N-(4-methoxyphenyl)-2H-1-benzopyran-6-sulfonamide,

(1G) 2,2-dimethyl-N-methyl-N-phenyl-2H-1-benzopyran-6-sulfonamide,

(1D) the-1-benzopyran-6 - sulfonamide,

(1G) 2,2-dimethyl-N-(4-forfinal)-N-methyl-2H-1-benzopyran - 6-sulfonamide,

(1Z) 2,2-dimethyl-N-[4-(1,1,1-trifluoromethyl)phenyl] -N-methyl - 2H-1-benzopyran-6-sulfonamide,

(1i) 2,2-dimethyl-N-[3-(1,1,1-trifluoromethyl)phenyl] -N-methyl - 2H-1-benzopyran-6-sulfonamide,

(1K) 2,2-dimethyl-N-methyl-N-(4-pyridyl)-2H-1-benzopyran-6 - sulfonamide,

(1l) 2,2-dimethyl-N-methyl-N-(3-pyridyl)-2H-1-benzopyran-6 - sulfonamide,

(1m) 2,2-dimethyl-N-ethyl-N-phenyl-2H-1-benzopyran-6 - sulfonamide.

The connection of the intermediate product 1 can also be obtained by reaction scheme B, for example, as follows:

(1b) 2,2-dimethyl-N-phenyl-2H-1-benzopyran-6-sulfonamide (1) 4-hydroxy-N-vinylbenzenesulfonic: thionyl chloride (109 ml, 1.5 M) is added dropwise over 25 minutes to a stirred mixture of 4-hydroxybenzenesulfonate (69.7 g, 300 mmol) and dimethylformamide (1.5 ml) in 1,2-dichloroethane (400 ml). The resulting mixture was stirred at 80oC for 12 hours, cooled to less than 20oC, poured into water (1000 ml) and extracted with 1,2-dichloroethane (3 x 100 ml). The combined extracts are dried (Na2SO4) and filtered. The resulting solution of 4-hydroxybenzenesulfonate treated with aniline (69 ml, 750 mmol) and then stirred at 80oC for 2 hours. The mixture is then included reduced pressure to obtain the crude product, which is purified by recrystallization from a mixture of ether/cyclohexane to obtain specified in the title compounds as a pale yellow crystalline solid, so pl. 140-141oC.

Other phenolic intermediate products for use in reaction scheme B receive similarly using the appropriate amine, for example,

4-hydroxy-N-methyl-N-vinylbenzenesulfonic, so pl. 151-152oC, 1,2,3,4-tetrahydro-2-(4-hydroxyphenylethyl)quinoline, so pl. 119-120oC.

These phenolic intermediate products are then subjected to O-alkylation and cyclist, for example, as follows:

(2) 2,2-dimethyl-N-phenyl-2H-1-benzopyran-6-sulfonamide: copper Chloride(I) (0,44 g, 4.4 mmol) is added to a stirred suspension of N-phenyl-4-hydroxybenzenesulfonate (110,5 g, 443 mmol) in dry acetonitrile (1660 ml) at 0oC in argon atmosphere. The mixture is stirred for 15 minutes at 0oC and then treated dropwise within 30 minutes of 1,8-diazabicyclo[5,4,0]undec-7-Yong (78,1 ml, 523 mmol). In the next 30 minutes at 0oC, the suspension is treated dropwise 3-chloro-3-methyl-1-Butina (50 g, 487 mmol) and stirred for additional 2 hours at 0oC and 18 hours at 20oC. the Obtained wash (1000 ml 1.0 M solution) and extracted with ethyl acetate (3 x 500 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to obtain crude N-phenyl-4-(1,1-dimethyl-2-PROPYNYL) oxybenzenesulfonate. It is dissolved in N, N-diethylaniline (100 ml) and added dropwise under stirring for 60 minutes to the N,N-diethylaniline (200 ml) at 200oC. the Reaction mixture was incubated for another 1 hour at 200oC, then cooled to room temperature, diluted with ethyl acetate (1000 ml) and washed with hydrochloric acid (5 x 800 ml). An ethyl acetate solution is dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to get crude product. Its clear by chromatography on silica gel, eluent 10% ethyl acetate in hexane, and recrystallized from a mixture of ether/hexane to obtain specified in the title compound as a colourless crystalline solid, so pl. 91-93oC.

Other compounds of intermediate product I, formula I-1 are similarly from the corresponding compounds of phenol, obtained from the corresponding amines analogously to stage (1).

The intermediate product

(2A) 1,2,3,4-tetrahydro-1-[(1A, 7b-dihydro-who stirred solution of the intermediate product Ia (6,80 g, of 19.1 mmol) in dimethyl sulfoxide (70 ml) and water (0,89 g, 0.50 mmol) in 15oC. the Mixture is stirred for 2 hours and then treated with a solution of sodium hydroxide (4.0 g, 100 mmol) in a mixture of dioxane/water and stirred at 20oC for 30 minutes. The mixture is concentrated to 25% of its volume by evaporation under reduced pressure, treated with saturated aqueous ammonium chloride (300 ml) and extracted with ethyl acetate (CH ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to get crude product, which was purified by column chromatography (silica gel, 10% acetone in hexane) to obtain the specified title compound as a yellow oil having the following physical characteristics:

1H-NMR ( CDCl3): 1,24 (s, 3H), and 1.56 (s, 3H), by 1.68 (m, AMX, 2H), 2,47 (m, AMX, 2H), 3,50 (d, J=6.0 Hz, 1H), 3,79 (m, AMX, 2H), 3,84 (d, J=6.0 Hz, 1H), 6,76 (d, J=8.5 Hz, 1H), 6,98 (d, J=7.5 Hz, 1H), 7,05 (ddd, 1H), 7,19 (ddd,1H), 7,43 (dd, J=2,3, 8.5 Hz, 1H), to 7.61 (d, J=2.3 Hz, 1H), and 7.78 (d, J= 8,3 Hz, 1H).

The following connections get similarly using the appropriate benzopyran-6-sulfonamida:

(2B) 1A, 7b-dihydro-2,2-dimethyl-N-phenyl-2H-oxirane[I] [1] benzopyran-6-sulfonamide intermediate product 1B,

(2B) 1A, 7b-Digue (2G) 1A,7b-dihydro-2,2-dimethyl-N-methyl-N-phenyl-2H-oxirane[I] [1]benzopyran-6-sulfonamide intermediate product 1D,

(2D) 1A, 7b-dihydro-2,2-dimethyl-N-(4-methoxyphenyl)-2H - oxirane[I] [1] benzopyran-6-sulfonamide intermediate product 1D,

(2E) - 1A, 7b-dihydro-2,2-dimethyl-N-(3-methoxyphenyl)-N-methyl-2H - oxirane[I] [1]benzopyran-6-sulfonamide intermediate product 1E,

(2ZH) 1a,7b-dihydro-2,2-dimethyl-N-(forfinal)-N-methyl-2H - oxirane[I] [1] benzopyran-6-sulfonamide intermediate product 1G,

(2H) 1A, 7b-dihydro-2,2-dimethyl-N-[4-(1,1,1-trifluoromethyl) phenyl]-2H-oxirane[I] [1]benzopyran-6-sulfonamide intermediate product 1Z,

(2) 1A, 7b-dihydro-2,2-dimethyl-N-[3-(1,1,1-trifluoromethyl)phenyl] -N-methyl-2H-oxirane[I] [1]benzopyran-6-sulfonamide intermediate 5 product 1i,

(2K) 1A,7b-dihydro-2,2-dimethyl-N-methyl-N-(4-pyridyl) -2H-oxirane[I] [1] benzopyran-6-sulfonamide intermediate product 1

(2) la,7b-dihydro-2,2-dimethyl-N-methyl-N-(3-pyridyl)-2H - oxirane[I] [1] benzopyran-6-sulfonamide intermediate product 1l,

(2m) 1A, 7b-dihydro-2,2-dimethyl-N-ethyl-N-phenyl-2H-oxirane[I] [1]benzopyran-6-sulfonamide intermediate product 1m,

(2n) (3S, 4S)-tetrahydro-1-[(1A,7b-dihydro-2,2-dimethyl-2H - oxirane [I] [1] benzopyran-6-yl)sulfonyl]quinoline.

The mixture of aqueous sodium hypochlorite (300 ml of 14% aqueous solution) and water 15 sodium phosphate, dibasic, (130 (S, S)-(+)-N, N'-bis(3,5-decret. - butylchloride)-1,2-cyclohexanedimethanol(III) chloride (4.0 g, 7,3 mmol) in isopropylacetate (300 ml) at 50oC. the Mixture is stirred for another 4 hours, filtered and extracted with ethyl acetate (2 x 500 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to get crude product, which was purified by chromatography on silica gel, eluent 10 to 50% ethyl acetate in hexane, to obtain specified in the title compound as a yellow oil.

The following connections get similarly with suitable intermediate connections:

(2) (3S,4S)-N-methyl-N-phenyl-[1A,7b-dihydro-2,2-dimethyl-2H - oxirane[I] [1]benzopyran-6-sulfonamide] from the intermediate product 1D; []2D0-25,4o(c= 1,00, DMF);

(2R) (3R,4R)-N-methyl-N-phenyl-[1A,7b-dihydro-2,2-dimethyl-2H - oxirane[I] [1] benzopyran-6-sulfonamide] of the intermediate product 1 g and (R,R)-(-)-N, N'-bis(3,5-decret. -butylchloride)-1,2-cyclohexanediamine - manganese(III) chloride instead of (S, S)-(+)-N,N'-bis(3,5 - decret.-butylchloride)-1,2-cyclohexanedimethanol (III) chloride;

(2R) (3R, 4R)-1,2,3,4-tetrahydro-1-[1A,7b-dihydro - 2,2-dimethyl-2H-oxirane[I] [1] benzopyran-6-yl)sulfonyl] quinoline, 2 - cyclohexanedimethanol(III) chloride with obtaining specified in the connection header, having the optical rotation []2D0= +24,4o(c=1,00, DMF).

The intermediate product 3

(3A) TRANS-1,2,3,4-tetrahydro-1-[(4-amino-3,4-dihydro - 2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-yl)sulfonyl] quinoline

Intermediate 2A (3,49 g, 9.4 mmol) is treated with a saturated solution of ammonia in ethanol (60 ml) and heated at 90oC in an autoclave for 15 hours. The solvent is evaporated under reduced pressure to get crude product, which was purified by chromatography on silica gel, eluent 25% aqueous NH3-MeOH-tBuOMe (1:5:94), obtaining specified in the connection header in the form of a foam having the following physical characteristics:

1H-NMR ( -CDCl3): of 1.18 (s, 3H), 1,50 (s, 3H), of 1.66 (m, AMX, 2H), 2,42 (m, AMX, 2H), 3,26 (d, J= 9.9 Hz, 1H), 3,52 (d, J=9.9 Hz), with 3.79 (m,AMX,2H), 6,76 (d, J=8.5 Hz, 1H), 6,99 (d, J=7.5 Hz, 1H), 7,07 (ddd. 1H), 7,20 (ddd. 1H), 7,42 (dd, J=2,3, 8.5 Hz, 1H), 7,44 (m, 1H) and 7,81 (d, J=8,3 Hz, 1H).

The following connections get similarly using the appropriate epoxide:

(3b) TRANS-N-methyl-N-phenyl-(4-amino-3,4-dihydro-2,2-dimethyl-2H-1 - benzopyran)-6-sulfonamide intermediate product 2G,

(3C) of TRANS-N-ethyl-N-phenyl-(4-amino-3,4-dihydro-2,2-dimethyl-2H-1 - benzopyran)-6-sulfonamide intermediate product 2m,

(3G) (3S,TRANS)-1,2,3,4-t is oduct 2H, []2D0= +33,2o(C = 1,00, DMF),

(3D) (3S, TRANS)-N-methyl-N-phenyl-(4-amino-3,4-dihydro - 2,2-dimethyl-3-hydroxy-2H-1-benzopyran)-6-sulfonamide intermediate product 2O, []2D0= +29,2o(c= 1,00, DMF),

(3E) (3R-TRANS)-N-methyl-N-phenyl-(4-amino-3,4-dihydro-2,2 - dimethyl-2H-1-benzopyran)-6-sulfonamide intermediate product 2P,

(G) (3R-TRANS)-1,2,3,4-tetrahydro-1-[(4-amino-3,4 - dihydro-2,2-dimethyl-3-hydroxy-2H-benzopyran-6-yl)sulfonyl] quinoline intermediate product 2P, []2D0= -25,0o(C = 1,00, DMF).

Example 1:

Obtaining TRANS-1.2.3.4-tetrahydro-1-[(3,4-dihydro-2,2-dimethyl-3-hydroxy - 4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-yl)sulfonyl] quinoline (compounds of formula I, where R1represents phenyl, a R2represents trimethylene associated with R1with the formation of 1,2,3,4-tetrahydroquinolin-1-yl group; R3represents a group of formula-N(R9)-COR10where R9and R10together represent a group of formula -(CH2)n-, in which n is 4; R4represents hydrogen and R5represents a hydroxyl in the TRANS-position with respect to R3; R6and R7represent methyl; the mole) in dry tetrahydrofuran (50 ml) at 0oC in an atmosphere of argon is treated with a solution of bis(trimethylsilyl)amide lithium in tetrahydrofuran (10 ml, 1.0 M solution, 10 mmol) and stirred at 20oC for 2 hours. The resulting suspension is treated with a solution of 1,2,3,4-tetrahydro-1-[(1A,7b-dihydro-2,2-dimethyl-2H-oxirane [I] [1] benzopyran-6-yl)sulfonyl]quinoline (intermediate 2A; 1.86 g, 5 mmol) in dry tetrahydrofuran (20 ml) and heated at 80oC for 17 hours. The mixture is cooled to 15oC and treated with saturated aqueous ammonium chloride (100 ml). The precipitated product is filtered, washed with water, dried and recrystallized from ethanol to obtain specified in the title compound as a colourless crystalline solid, so pl. 290-292oC.

Compounds with different R1and R2group and the same R3-R10group, as in example 1, get similarly using suitable epoxy intermediate (see table).

Example 13:

Obtaining TRANS-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6- [(1,2,3,4-tetrahydroquinolin-1-yl)sulfonyl]-2H-1-benzopyran-4-yl]-3 - pyridinecarboxamide (i.e. the compounds of formula I, where R1represents phenyl, a R2represents timepo formula-N(R9)-COR10where R9represents hydrogen and R10represents pyridyl; R4represents hydrogen and R5represents a hydroxyl in the TRANS-position with respect to R3; R6and R7represent methyl; R8represents hydrogen).

Mix a solution of TRANS-1,2,3,4-tetrahydro-1-[(4-amino-3,4 - dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-yl)sulfonyl] quinoline (intermediate 3A; and 1.00 g, 2.6 mmol), triethylamine (0,80 ml of 0.58 g, 5.7 mmol) and 4-dimethylaminopyridine (of 0.081 g, 0.67 mmol) in dry dimethylformamide (50 ml) in an argon atmosphere is treated with nicotinergic hydrochloride (0.51 g, 2.8 mmol) and stirred at 18oC for 20 hours. The solvent is evaporated under reduced pressure to get crude product, which was purified by chromatography on silica gel, eluent 25% aqueous NH3-MeOH-tBuOMe (1: 2: 97), and recrystallized from a mixture of tetrahydrofuran/hexane to obtain specified in the title compound as a colourless crystalline solid, so pl. 217-219oC.

The following examples 14-16, having different substituents on the R1and R2and the same R3-R10groups receive similar is)sulfonyl] -3-hydroxy-2H-1-benzopyran-4-yl]-3-pyridinecarboxamide. so pl. 238-240oWith, of intermediate 3b.

Example 15: TRANS-[3,4-dihydro-2,2-dimethyl-6-[(N-ethyl-N-phenylamino)sulfonyl] -3-hydroxy-2H-1-benzopyran-4-yl]-3-pyridinecarboxamide. so pl. 232-233oC, of the intermediate product 3b.

Example 16:

Obtain TRANS-N-methyl-N-phenyl-3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)- 2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-sulfonamida (i.e. the compounds of formula I, where R1represents phenyl, R2represents methyl, R3represents a group of formula-N(R9)-COR10where R9and R10together represent a 1,3-butadienyl; R4represents hydrogen, R5represents a hydroxyl in the TRANS-position with respect to R3; R6and R7represent methyl; R8represents hydrogen).

Mix a solution of intermediate 2 (2,48 g, 7.2 mmol) in dry isopropanol (50 ml) containing pyridine (3 ml), treated with 2-hydroxypyridine (1.64 g, 13,2 mmol) and heated at 110oC for 18 hours. The solvent is evaporated under reduced pressure to get crude product, which was purified by chromatography on silica gel, eluent 10% ethanol in toluene, and per escitalo crystalline solid, so pl. 251-254oC, having the following physical characteristics:

1H-NMR (d6DMSO), 120oC): 1,26 (s, 3H), of 1.48 (s, 3H), of 3.00 (s, 3H), 4,18 (br. s, 1H), 5,48 (br.d,1H), 5,70 (br.s,1H), 6,1 (dd, 1H), to 6.19 (ddd, 1H), 6,27 (dd,1H), to 6.39 (dd, 1H), 6,91 (d,1H), 7,00 (dd, 1H), 7.18 in-the 7.43 (m, 5H).

Example 17:

Obtaining N-methyl-N-phenyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2 - dimethyl-2H-1-benzopyran-6-sulfonamida (i.e. the compounds of formula I, as for example 16, except that R4and R5together form a double bond).

Stir a solution of the compound from example 16 (1,17 g, to 2.65 mmol) and sodium hydroxide on the media (0.8 to 1.6mm, 14 to 25 mesh ASTM; Cat No.1567, E. Merck; 1,17 g) in dry dioxane (50 ml) is heated at 110oC for 30 minutes in an argon atmosphere. The solution is filtered and the solvent is evaporated under reduced pressure to get crude product, which was purified by chromatography on silica gel, eluent 5% ethanol in toluene, and recrystallized from a mixture of dichloromethane/pentane to obtain specified in the connection header in paste form crystalline solids, so pl. 179-181oC.

When necessary, the compounds according to the invention can be obtained in optically active form, as shown in examples 18-22.

Presenteren-6-sulfonamida

Stir a solution of (3S,4S)-N-methyl-N-phenyl-[1A,7b-dihydro-2,2 - dimethyl-2H-oxirane [I] [1] benzopyran-6-sulfonamida] (intermediate 2; 2,80 g, 8.1 mmol) in dry isopropanol (28 ml) containing pyridine (1.5 ml), treated with 2-hydroxypyridine (1.54 g, 16.2 mmol) and heated at 90oC for 18 hours. The solvent is evaporated under reduced pressure to get crude product, which was purified by chromatography on silica gel, eluent 25% ethyl acetate in cyclohexane and recrystallized from a mixture of tert.- butyl methyl ether/ethyl acetate to obtain specified in the title compound as a colourless crystalline solid, so pl. 262-265oC []2D0= -130,2o(c= 1,00, DMF).

Example 19:

Obtain (3S, TRANS)-[3,4-dihydro-2,2-dimethyl-6- [(N-methyl-N-phenylamino)sulfonyl]-3-hydroxy-2H-1-benzopyran-4-yl] - 3-pyridinecarboxamide

Stir a solution of (3S,TRANS)-N-methyl-N-phenyl-(4-amino-3,4 - dihydro-2,2-dimethyl-2H-1-benzopyran)-6-sulfonamida (intermediate product 3D; 3.12 g, 8,61 mmol), triethylamine (4.0 ml, 2,90 g, 28.6 mmol) and 4-dimethylaminopyridine (0.312 g, 2.55 mmol) in dry dichloromethane (86 ml) in an argon atmosphere is treated with nicotinergic hydrochloride (1,61 g, 9,04 mmol is the doctrine of the mixture, which is then treated with an aqueous ammonia (100 ml, 0.5 M solution) and extracted with a mixture of 10% ethanol in ethyl acetate (3 x 100 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to get crude product, which was purified by recrystallization from a mixture of ethyl acetate/diethyl ether to obtain specified in the title compound as a colourless crystalline solid, so pl. 210-212oC []2D0=- 41,7o(c= 1,00, DMF).

The following compounds are prepared analogously using the appropriate amine intermediate product:

Example 20:

(3R-TRANS)-[3,4-dihydro-2,2-dimethyl-6-[(N-methyl-N-phenylamino) sulfonyl] -3-hydroxy-2H-1-benzopyran-4-yl] -3-pyridinecarboxamide of intermediate 3E; so pl. 117 - 180oC []2D0= +43,4o(C=1,00, DMF).

Example 21:

(3S, TRANS)-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6- [(1,2,3,4-tetrahydroquinolin-1-yl)sulfonyl] -2H-1-benzopyran-4-yl] -3-pyridinecarboxamide of the intermediate product 3G; so pl. 199-205oC []2D0= -58,0o(C= 1,00, DMF).

Example 22:

(3R-TRANS)-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6-[(1,2,3,4 - tetrahydroquinolin-1-yl)Sul is SUB>0= +58,1o(C = 1,00, DMF).

Example 23:

Obtain (3S,TRANS)-N-phenyl-3,4-dihydro-3-hydroxy - 2,2-dimethyl-4-(2-oxo-1-piperidinyl)-2H-1-benzopyran-6 - sulfonamida

(23a) 1,1-dimethyl ether [3,4-dihydro-2,2-dimethyl-2H - 1-benzopyran-6-sulfonyl] phenylcarbinol acid

Mix a solution of 2,2-dimethyl-N-phenyl-2H-1-benzopyran-6 - sulfonamida (intermediate product 1B; 6,30 g, 20 mmol) and 4-dimethylaminopyridine (200 mg, 1.6 mmol) in acetonitrile (60 ml) is treated with dicret.-BUTYLCARBAMATE (to 4.81 g, 22 mmol) and stirred at 18oC for 2 hours. The solvent is evaporated under reduced pressure to obtain residue, which is treated with an aqueous sodium bicarbonate (200 ml, 2M solution) and extracted with ethyl acetate (2 x 100 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to obtain the product, which is recrystallized from a mixture of tert. -butyl methyl ether/hexane to obtain specified in the title compound as a colourless crystalline solid, so pl. 117-120oC.

(23B) 1,1-dimethylethylene ether (3S,4S)-[1A,7b-dihydro-2,2-dimethyl-2H-oxirane [I] [1] benzopyran-6-sulfonyl] phenylcarbinol acid

down) are added to stir the mixture of 1,1-dimethylethylene ether [3,4-dihydro-2,2 - dimethyl-2H-1-benzopyran-6-sulfonyl] phenylcarbinol acid (5,46 g, of 13.1 mmol) and (S, S)-(+)-N, N'-bis(3,5-decret. - butylchloride)-1,2-cyclohexanedimethanol(III) chloride (0.54 g, 1.0 mmol) in isopropylacetate (40 ml) and 17oC. the Mixture is stirred for 30 minutes, diluted with saturated aqueous sodium chloride (200 ml), filtered and extracted with ethyl acetate (3 x 300 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to get crude product, which was purified by chromatography on silica gel, eluent 10% ethyl acetate in cyclohexane and recrystallized from a mixture of ethyl acetate/hexane to obtain specified in the title compound as a colourless crystalline solid, so pl. 148-150oC []2D0= -35,0o(C = 1,00, DMF).

(23C) (3S, TRANS)-N-phenyl-3,4-dihydro-3-hydroxy-2,2-dimethyl - 4-(2-oxo-1-piperidinyl)-2H-1-benzopyran-6-sulfonamide

Mix a solution of anhydrous 2-piperazinone (9,92 g, 100 mmol) in dry tetrahydrofuran (100 ml) at 0oC in an atmosphere of argon is treated with a solution of bis(trimethylsilyl)amide lithium in tetrahydrofuran (100 ml, 1.0 M solution, 100 mmol) and stirred at 20oC for 2 hours. The resulting suspension is treated with a solution of 1.1 nd acid (7.20 g, of 16.7 mmol) in dry tetrahydrofuran (35 ml) and heated at 50oC for 17 hours. The mixture is cooled to 15oC, treated with saturated aqueous ammonium chloride (400 ml) and extracted with ethyl acetate (2 x 200 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to get crude product, which was purified by recrystallization from a mixture of ethanol/ethyl acetate to obtain specified in the title compound as a colourless crystalline solid, so pl. 272-276oC []2D0= -92,0o(C= 1,00, DMF).

Example 24:

Obtain (3R, TRANS)-N-phenyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo - 1-piperidinyl)-2H-1-benzopyran-6-sulfonamida

(24A) 1,1-dimethyl (3R,4R)-[1A,7b-dihydro-2,2-dimethyl-2H-oxirane[I] [1]benzopyran-6 - sulfonyl]phenylcarbinol acid

Using the procedure described in example 23B, but using (R,R)-(+)-N, N'-bis(3,5-decret. -butylchloride)-1,2 - cyclohexanedimethanol (III) chloride instead of (S,S)-(+)-N,N'- bis(3,5-decret.-butylchloride)-1,2-cyclohexanedimethanol (III) chloride, get the connection specified in the header, in the form of a colorless crystalline solid, Roxi - 2,2-dimethyl-4-(2-oxo-1-piperidinyl)-2H-1-benzopyran-6 - sulfonamide

Using the procedure described in example 23C, but using 1,1-dimethyl (3R,4R) -[1a, 7b-dihydro-2,2 - dimethyl-2H-oxirane[I] [1]benzopyran-6-sulfonyl] phenylcarbinol acid instead of 1,1-dimethyl ester (3S, 4S)-1a, 7b-dihydro-2,2-dimethyl-2H-oxirane[I] [1] benzopyran - 6-sulfonyl] phenylcarbinol acid, receive the connection specified in the header, in the form of a colorless crystalline substance, so pl. 272-276oC []2D0=+90,6o(c= 1,00, DMF).

Benzopyrene and dihydrobenzofuranyl, as defined above in paragraph (1), for example, the compounds of formula I, as defined above, and their N-oxides and physiologically hydrolyzable and physiologically acceptable esters and pharmaceutically acceptable salts accession acids and Quaternary ammonium salts of the above benzopyrano/dihydropyrano/N-oxide/ether (hereinafter referred to as the AGENTS ACCORDING to the INVENTION) are useful as pharmaceuticals.

The AGENTS ACCORDING to the INVENTION have miorelaksantnoe activity for smooth muscle and are able to activate potassium channels in plasmalemma, as was shown by their effects at concentrations in the range 1-500 nm on the preparations of various smooth muscles in accordance with or Ana the AK agents, the opening TO the+the channels. The AGENTS ACCORDING to the INVENTION is accordingly useful for the treatment of pathological conditions and disorders for which treatment is shown therapy using agents that opens TO+the channels. Therapeutic use as agents that opens TO+the channels may be, in addition, demonstrated in standard pharmacological tests, for example, on the measurement of cardiovascular activity in vitro and in vivo. So, the impact on blood pressure can be observed in shot catheterized and having normal blood pressure in rats after 1-hour catheterized introduction vnutriaortalina. Anti-ischemic activity can be demonstrated in accordance with the methods described in Hof et al., Circ. Rec., 62, 679 (1988). The AGENTS ACCORDING to the INVENTION is accordingly applicable as smooth muscle relaxants, especially as vasodilating agents, for example, in the treatment of hypertension or chronic heart failure. They are also applicable as anti-ischemic and protivosudorojnaya agents, for example, for use in the treatment of circulatory problems, such as heart, skeletal muscle or mo is tivoliland agents; for the treatment of peripheral circulatory disorders such as syndrome Charcot, disease, Raynaud's disease or venous ulcers; as well as for the treatment, including prevention, cerebral ischemia, dementia, seizures, subarachnoid hemorrhage and other related diseases and disorders and their consequences.

The AGENTS ACCORDING to the INVENTION, moreover, is indicated for use as an antispasmodic agents in the gastrointestinal tract, the uterus and the urinary tract, for example in the treatment of chronic pain of the bowels, with diarrhea, diverticulitis, when the risk of miscarriage due to premature birth, and urinary incontinence.

The AGENTS ACCORDING to the INVENTION, moreover, is indicated for use as substances that stimulate the growth of hair, for example, in the treatment of baldness in the aging process, for example, when male alopecia or structural loss, or disease-related hair loss, for example, due to infection or disorders of the immune system, for example, after cancer hemoterapia or radiation therapy.

The appropriate dose for such applications, of course, differ, for example, depending on the specifics of passtoyanie, is indicated for the treatment, the characteristics of the AGENT Panaco, in General, an acceptable daily dose for oral administration, for example, when anti-hypertensive use, will be from about 0.03 to about 2.0 mg/kg, and when, for example, anti-ischemic application of from about 0.015 g to about 0.3 mg/kg For the larger mammals, for example humans, shows oral daily dose will be, therefore, from about 2 to about 150 mg with anti-hypertensive use, or from about 1 to about 20 mg with anti-ischemic application, with the introduction of once a day or divided into two doses per day. Forms doses by oral administration at the above indications will be, thus, accordingly to range from approximately 0.5 or 1.0 to about 20, or 150 mg of the AGENT ACCORDING to the INVENTION together with a pharmaceutically acceptable diluent or carrier.

For use as agents for stimulating hair growth, the AGENTS ACCORDING to the INVENTION will be applied respectively locally, for example, on the basis of a suitable cream, gel or emulsion, such as those already known in this field.

More importantly, in accordance with the present invention it was found that the AGENTS ACCORDING to the INVENTION have protivorechashiy activators potassium channels AGENTS ACCORDING to the INVENTION does not detect adverse effects on the cardiovascular system, resulting from inhalation of drugs in doses sufficient to suppress or relieve increased activity of the respiratory tract and relieve or prevention of bronchostenosis. These activities can be demonstrated in the pharmacological test models, such as the following.

TEST 1. REDUCED HYPERRESPONSIVENESS OF THE AIRWAYS

a) In Guinea-pig

Acute injection prior immune complex causes of Guinea pigs increased sensitivity to histamine. The dose of histamine causing bronchostenosis, only to a small extent before the introduction of the immune complex has a much stronger effect after injection. Protivovospalitelnye and cardiovascular effects are evaluated simultaneously in order to determine a convenient time for therapeutic application of test compounds to reduce the hyperresponsiveness of the Airways.

Guinea pigs (line Dunkin-Hartley, male, 400-600 g) anaesthetize phenobarbital (100 mg/kg intraperitoneally) and pentobarbital (30 mg/kg intraperitoneally) and immobilizes gallamine (10 mg/kg intramuscularly), while breathing a mixture of air and oxygen (45:55./vol.). Breathing a mixture of 8 ml/kg, 1 Hz) animals served on fuck atomen track sensor of blood flow. Simultaneously with the measurement of blood flow using thoracic trocar directly remove data about the changes of pressure in the chest, gaining the ability to monitor the pressure gradient relative to the trachea. From this information calculate the resistance and the change in volume of the lungs at a pressure of at every breath.

Allergic reaction are by intravenous infusion prepared immune complexes (prepared by adding 30 μg bovine gamma globulin in 0.05 ml of physiological solution to 0.05 ml of Guinea pig antisera against bovine gamma globulin) three times at 10-minute intervals. Intravenous injection of histamine (1,0-3,2 mg/kg at 10-minute intervals) was used to determine the sensitiveness of the respiratory tract before and after the last exposure to the immune complex. Increased activity of the respiratory tract expressed as steam the difference between the maximum resistance value of the lungs in response to histamine before and after repeated injections of an immune complex. The control compound is administered vnutritrahealno as in the form of solutions, and in the form of a suspension in gum of tragakant. Values of the dose of the agent, removing the Hyper reactivity of the respiratory PU'u (ED20), determine

graphically by curves dose-response; they represent respectively the values of doses that lead to a 50% reduction hyperresponsiveness of the Airways and 20% decrease in blood pressure.

The AGENTS ACCORDING to the INVENTION, especially those described in examples 17, 19, 21 or 23, are strong inhibitors hyperresponsiveness of the Airways, with ED50for this model from about 0.005 to 1 mg/kg, the onset of action after approximately 2.5 minutes and a duration of more than 30 minutes after intratracheal injection. The AGENTS ACCORDING to the INVENTION, moreover, in effective doses have no significant adverse effects on the cardiovascular system, and the ED20in case of reduction in blood pressure of approximately 10-100 µg/kg, so that they have a wide therapeutic application to reduce the hyperresponsiveness of the Airways.

b) In rhesus monkeys:

Similar selectivity in action observed in rhesus monkeys. Rhesus monkeys (males and females weighing 6-15 kg), known as the organisms that normally meet on the effects of methacholine (Mesn), euthanized (primary component: ketamine, 10 mg/kg intramuscularly, the main supporting componendo tube with an inflatable cuff (5.0 cm) (xylocain: local introduction to the epiglottis) and measure the basal resistance of the lung. The effects of the drug on the cardiovascular parameters (heart rate, systolic and diastolic blood pressure) and respiratory rate are measured at the same time.

By inhalation with the help of spray injected control substance in aerosol form of a solution or suspension in a suitable filler (for example, 30% polyethylene glycol in water or 5% ethanol in water) for 10 minutes while breathing. 15 minutes after injection of the agent spend a single stimulation methacholine (0.6 to 2.5 mg/ml solution, designed to generate approximately 50-100% change from baseline) and calculate the percentage of inhibition relative to the first metacholine answer.

The AGENTS ACCORDING to the INVENTION exhibit a strong, dose-dependent effect of suppressing bronchostenosis in the above control method, in concentrations of from about 0.025 mg/ml to about 50 mg/ml of the Compound of example 21, for example, suppresses metacholine-induced bronchostenosis 77% at a dose of 1 mg/ml without any significant measurable effect on the parameters of the cardiovascular system and the respiratory rate.

TEST 2: BRONCHOMALACIA

The AGENTS ACCORDING to the INVENTION is tested for frozen drug bronchi person. MA the p tone. The curves of the concentration-response is determined by the total number of additives control connections, and each connection is added to the moment when the maximum effect develops from previously added concentration. At the end of the curves of the concentration-response type papaverine (300 μm) to achieve complete relaxation of the drug, and this effect is taken for 100% relaxation.

The AGENTS ACCORDING to the INVENTION exhibit a strong bronchomalacia action on these drugs human tissues with an efficiency of about 83-98% at concentrations below 1 μm.

The AGENTS ACCORDING to the INVENTION, respectively, applicable as bronchodilator agents and as tools for the treatment of hyperresponsiveness of the Airways, for example, as agents for symptomatic and prophylactic treatment of obstructive or inflammatory diseases of the respiratory tract, particularly asthma. As bronchodilators AGENTS ACCORDING to the INVENTION can be particularly useful as emergency therapy for the treatment of attack bronchostenosis, for example, in asthma. In addition, prolonged exposure to the AGENTS ACCORDING to the INVENTION can be used to control, limit or reduce hyperresponsiveness the stomach is placed reliable protection from relapses or attacks bronchostenosis due to obstructive or inflammatory airway disease, especially in asthma. The words "treatment" and "therapeutic effect" used in the present description and in the claims in relation to the use of the AGENTS ACCORDING to the INVENTION for the treatment of obstructive or inflammatory diseases of the respiratory tract, particularly asthma, and in accordance with this mean and encompass both preventive and symptomatic (i.e. bronchodilators) methods of treatment, except where otherwise indicated.

In connection with the foregoing the present invention also covers:

4. The method of treatment of any disease or pathological condition, here specified, in particular

4. A. A method of treating obstructive or inflammatory Airways disease, including

4. A. 1. The method of symptomatic treatment of inflammatory or obstructive diseases of the respiratory tract, for example, affect the dilation of the bronchi; or

4. A. 2. A method of prophylactic treatment of inflammatory or obstructive diseases of the respiratory tract, for example, for the treatment of hyperresponsiveness of the Airways; to a subject in need of these treatments, in which the above-mentioned effect subject an effective amount of AGAY is on medication, for example, for use in the treatment of any specified disease or pathological condition, in particular, for use in the treatment of obstructive or inflammatory Airways disease, for example, specified above in paragraph 4.A. 1 or 4.A. 2; or

6. The pharmaceutical composition containing the AGENT ACCORDING to the INVENTION, or the use of an AGENT ACCORDING to the INVENTION in obtaining pharmaceutical compositions for use in the treatment of any specified disease or pathological condition, in particular, for use as set forth above in paragraph 5.

Inflammatory or obstructive diseases of the respiratory tract to which this invention is applicable, includes asthma of any type or origin, including hereditary bronchial and, especially, acquired bronchial asthma. They are useful in the treatment of allergic asthma, and atopic (i.e. due to IgE) and diatopically, as well as, for example, bronchial asthma, asthma induced exercise, occupational asthma, asthma caused by bacterial infection and other non-allergic asthma. The asthma treatment includes treatment, covering patients under the age of 4-5 lead the diagnosis of the child, suffering from shortness of breath", a certain category of patients included in the category of big medicine and more correctly defined currently as asthmatics initial and early stages. (For convenience, this particular asthmatic condition called "syndrome wheezing baby").

Reduced frequency or severity of symptomatic attack, for example, acute asthma or bronchostenosis attacks will serve as proof of prophylactic efficiency when treating asthma. Further efficiency can be demonstrated by the reduction of other necessary therapies, for example, symptomatology therapy, i.e. therapy aimed at preventing or exclusion of symptomatic attack in case of its appearance, for example, anti-inflammatory (e.g., corticosteroids or bronchodilators (for example,2adrenergic therapy.

Preventive advantage in the case of asthma can especially occur for patients prone to "morning swim". "Morning swim" is recognized asthmatic syndrome, manifested in the morning hours, for example between 4 and 6 a.m., that is, in hours, is substantially remote from the treatment used before is that applicable to this invention, also include pneumoconiosis (an inflammatory, commonly occupational disease of the lungs, frequently accompanied by obstruction of the respiratory tract, whether chronic or acute form, and which is the consequence of repeated inhalation of dusts) of any type and origin, including, for example, aluminas, antraks, asbestosis, helicos, Philos, sideros, silicosis, tabacos and, especially, bessines.

Other inflammatory or obstructive diseases and pathological conditions of the respiratory tract to which the present invention is applicable, include respiratory distress syndrome in adults (rdsw), chronic obstructive pulmonary disease or respiratory (COPD or HOST), bronchitis and exacerbation of hyperresponsiveness of the Airways following the treatment, other drugs, especially treatment inhaled medicines, for example, therapy bronchodilators-agonist, including, in particular, the use of AGENTS ACCORDING to the INVENTION as broncholytics for the treatment of chronic or acute airway obstruction and dyspnoea, associated with one of the above diseases or pathological conditions.

For use in the treatment of visionem way in particular enterline, e.g. orally, for example in the form of tablets or capsules, or parenterally, e.g. in the form of injection solutions or suspensions. However, the preferred will be the introduction on the respiratory tract, for example, by inhalation through the appropriate inhaler, nebulizer or similar device known in this field.

Doses used in the treatment of inflammatory or obstructive diseases of the respiratory tract, of course, will vary depending on the characteristics of pathological conditions, is indicated for the treatment of the characteristics of the applied AGENT ACCORDING to the INVENTION, the mode of action and desired action. Installed in the above-described control method Ia ID50for known broncholytic salbutamol [albuterol;1[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy - 1,3-benzoimidazol] approximately 0,008 mg/kg, vnutritrahealno. Appropriate doses of the AGENTS ACCORDING to the INVENTION (for example, in examples 17, 19, 21 or 23) for administration by inhalation, for example, to reduce the hyperresponsiveness of the Airways in the treatment of asthma in humans, will, therefore, be approximately the same amount or slightly higher than the dose normally required the day a suitable daily dose, injected into the lungs, will be of the order of from 1 μg to 1000 μg, in particular from about 10 μg to about 500 μg, respectively, introduced by inhalation using a special apparatus-nebulizer with effective treatment once or 2-4 times a day, in the series by 1-4 injections at each impact.

For oral administration, the corresponding daily dose will be in most cases of the order of from 0.1 to 30 μg/kg of the Corresponding oral daily dose for large mammals, such as humans, will be, thus, the value of the order of from about 7 μg to about 2.1 mg in a 70 kg individual, with the introduction of a single dose, doses, separated for the introduction to from 2 to 4 times a day, or in the form of a product of prolonged action. In this application, the oral form of the standard dose will be, thus, accordingly to be around 1.75 μg to about 2.1 mg of the AGENT ACCORDING to the INVENTION together with a pharmaceutically acceptable diluent or carrier.

In this regard, it is particularly important to emphasize that the AGENTS ACCORDING to the INVENTION in most cases are active as bronchodilators or agents of the undesirable effects on the cardiovascular system as a result of this therapy, for example, hypotensive/tachycardial effect will be small or portable within the acceptable range with respect to the applied therapy.

In accordance with the foregoing the present invention also provides:

7. Pharmaceutical composition comprising the AGENT ACCORDING to the INVENTION together with a pharmaceutically acceptable diluent or carrier, for example, in the form applicable to inhalation.

Such compositions can be produced in a standard way, for example for insertion through the respiratory system, by compounding

The AGENT ACCORDING to the INVENTION in the form of a finely ground dispersion of particles with, for example, micronized lactose as a carrier/diluent prior to the formation of powder for inhalation by inhalation,

The AGENT ACCORDING to the INVENTION in a form suitable for administration via the respiratory tract, can be entered using the appropriate inhalation device, such as a nebulizer with adjustable dosage, so that the invention additionally includes

8. Inhalation device, such as an inhaler with adjustable dosage containing the AGENT ACCORDING to the INVENTION in a form suitable for inhalation.

1. Benzopyran pyridyl;

R2represents H, or C1-5-alkyl or C2-5-alkylen associated with R1;

R3represents a group of formula-N(R9)-COR10where R9represents hydrogen, and R10represents phenyl or pyridyl, or R9and R10together represent a 1,3-butadienyl or a group of the formula -(CH2)n-, in which n is an integer from 3 to 5 inclusive;

R4represents hydrogen and R5represents a hydroxyl in the TRANS-position with respect to R3or R4and R5together represent an additional bond as indicated by the dotted line;

R6and R7independently of one another represent C1-5-alkyl;

R8represents hydrogen,

or physiologically hydrolyzable and physiologically acceptable ester of this compound, or an acid additive salt or Quaternary ammonium salt of this compound or complex ester.

2. Connection on p. 1, selected from

a) TRANS-1,2,3,4-tetrahydro-1-[[3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-yl]sulfonyl]quinoline,

b) TRANS-N-phenyl-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-exocoetidae-1-yl)-2H-1-benzopyran-6-sulfonamide,

d) TRANS-N-methyl-N-phenyl-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide,

d) TRANS-N-methyl-N-(4-methoxyphenyl)-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide,

(e) TRANS-N-methyl-N-(3-methoxyphenyl)-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide,

W) TRANS-N-methyl-N-(4-forfinal)-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide,

C) TRANS-N-methyl-N-(4-triptoreline)-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide,

and) TRANS-N-methyl-N-(3-triptoreline)-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide,

K) TRANS-N-methyl-N-(pyridin-4-yl)-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide,

l) TRANS-N-methyl-N-(pyridin-3-yl)-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide,

m) of TRANS-N-ethyl-N-phenyl-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide,

h) TRANS-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6-[(1,2,3,4-tetrahydroquinolin-1-yl)sulfonyl]-2H-1-benzopyran-4-yl]-3-pyridinecarboxamide,

a) TRANS-[3,4-di is Rance-[3,4-dihydro-2,2-dimethyl-6-[(N-ethyl-N-phenylamino)-sulfonyl]-3-hydroxy-2H-1-benzopyran-4-yl]-3-pyridinecarboxamide,

R) TRANS-N-methyl-N-phenyl-3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-sulfonamide,

C) N-methyl-N-phenyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-sulfonamide,

t) (3s, TRANS)-N-methyl-N-phenyl-3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-sulfonamide,

y) (3s, TRANS)-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6-[(N-methyl-N-phenylamino)sulfonyl]-2H-1-benzopyran-4-yl]-3-pyridinecarboxamide,

f) (3s, TRANS)-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6-[(1,2,3,4-tetrahydroquinolin-1-yl)sulfonyl]-2H-1-benzopyran-4-yl]-3-pyridinecarboxamide,

x) (3s, TRANS)-N-phenyl-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(2-oxopiperidin-1-yl)-2H-1-benzopyran-6-sulfonamide.

3. The compound according to any one of paragraphs.1 - 2 for use as pharmaceuticals.

4. Pharmaceutical compositions suitable for the treatment or prevention of obstructive or inflammatory diseases of the respiratory tract and containing a compound according to any one of paragraphs.1 to 3, possibly in combination or conjunction with a pharmaceutically acceptable diluent or carrier.

5. The compounds of formula I-1, I-2 or I-3

< / BR>
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where R1, R2, R6, R7and R8such as ,2-di(C1-5-alkyl)-6-(N-arylsulfonamides)-2H-oxirane[s] [I]benzopyran formula I-2

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where R1, R2, R6, R7and R8have the specified values,

subjected to interaction with the salt of an alkali metal carboxamide and, if necessary, conduct dehydrogenization obtained product alkylate the amino 2,2-di(C1-5-alkyl)- or TRANS-2,2 di(C1-5-alkyl)-3,4-dihydro-3-hydroxy-4-amino-6-(N-arylsulfonamides)2H-1-benzopyran and produce the target product in free form or in the form of its acid additive salts, or Quaternary ammonium salt, or, if necessary, atrificial received benzopyran having a free hydroxyl group, and receive physiologically hydrolyzable and physiologically acceptable ester benzopyran.

 

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),

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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,

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