RU2104277C1 - 2,2-dialkyl or trans-2,2-dialkyl-3,4-dihydro-3-hydroxy-6- (pyridin-4-yl)-2h-1-benzopyrans - Google Patents

Abstract

FIELD: pharmaceutical industry. SUBSTANCE: present invention describes 2,2-di- ($$$ alkyl) and trans-2,2-di-($$$ alkyl)-3,4-dihydro-6- (pyridin-4-yl)-2H-1-benzopyrans of formula (I): $$$ wherein $$$ and $$$ are hydrogen, alkyl, hydroxyalkyl or alkoxyalkyl, at least one of them is other than hydrogen, and $$$ is usually 2-piperadinone group; $$$ is H and $$$ is OH, or $$$ is additional bond and $$$ and $$$ are alkyl and $$$ is H or alkyl, or N-oxides, esters and salts thereof. Present invention describes methods of preparation thereof and use thereof as pharmaceutical agents, e.g. $$$ canal opening agents, broncho vasolidaling agents and prophylactic antiasthma agents. EFFECT: improved properties of the title compounds. 6 cl, 4 tbl

Description

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

More specifically, the invention in its broadest aspect includes:
1. 2,2-di- (C ₁ -C ₅ -alkyl) - or trans-2,2-di- (C ₁ -C ₅ -alkyl) -3,4-dihydro-3-hydroxy-6- / pyridin-4-yl / - 2H-1-benzopyran containing a carboxamide moiety at position 4 and wherein the pyridin-4-yl group is substituted at position 2 and / or 3 with one or two members selected from the group consisting of C ₁ -C ₅ alkyl, C ₁ -C ₅ hydroxyalkyl and / C ₁ -C ₅ / alkoxyalkyl;
or its N-oxide;
or a physiologically hydrolyzable and physiologically acceptable ester of such a benzopyran or N-oxide, or an acid addition salt, or a quaternary ammonium salt of such a benzopyran, N-oxide, or an ester.

Alkyl groups and fragments of compounds as defined in paragraph 1 may be a linear or branched chain. Preferred substituent values at position 2 of the benzopyran nucleus as well as at position 2 and / or 3 of the pyridinyl group are those indicated below with respect to formula (I) for R ₆ and R ₇ and R ₁ and R ₂ .

As described hereinafter, the compounds of the invention, for example, as defined in claim 1, exhibit potassium / K ⁺ / channel-opening activity [see e.g. Cook et al., "Potassium Channels: Structure, Classification. Function and Therapeutic Potential" ed. NS Cook, Ellis Horwood, Chechester / 1990 /, p. 181-255]. Benzopyran derivatives, which in position 4 contain a substituted carboxamide fragment and exhibit potassium channel-opening activity, are widely described in the art and belong to the class of important and recognized compounds. The 4-carboxamide moiety in the compounds of the invention may be any of those known and described in the prior art in connection with the K ⁺ -channel-opening benzopyranes, including N-substituted, for example, cyclic, carboxamide moieties. Preferred carboxamide moieties for the compounds of the invention are those of the formula —N / R ₉ / —COR ₁₀ , as described below.

It should be borne in mind that the benzopyran core of the compounds defined in paragraph 1 may contain substituents in addition to those specifically defined. In particular, they can be, for example, 7- / C ₁ -C ₅ / -alkyl-substituted, especially 7-methyl-substituted, for example, as described below in connection with formula I.

In accordance with the invention, 2,2-di- (C ₁ -C ₅ / -alkyl-3,4-dihydro-3-hydroxy-6- / pyridin-4-yl / -2H-1-benzopyranes and / or their preferred -oxides, esters and salts as described in claim 1. The 3-hydroxyl group and 4-carboxamide moiety in such compounds are in the trans configuration as described in paragraph 1. For this group of compounds, as a rule, the / 3S, 4R / enantiomers should be preferred in pure or mostly pure form, or in the form of a mixture of isomers, for example, in the form of a racemic mixture, as described below in connection with compounds of the formula / I /.

где R₁ и R₂ независимо друг от друга обозначают водород, C₁-C₅-алкил, C₁-C₅-гидроксиалкил или C₁-C₅-/алкоксиалкил/, причем по меньшей мере один из R₁ и R₂ является отличным от водорода;
R₃ обозначает группу формулы - N/R₉/-COR₁₀, где R₉ обозначает водород и R₁₀ обозначает пиридил или R₉ и R₁₀ вместе обозначают 1,3-бутадиенилен или обозначает группу формулы -/CH₂/_n- или -/CH₂/_m

, в которой "n" обозначает целое число от 3 до 5 и m обозначает 1 или 2;
R₄ обозначает водород и R₅ обозначает гидроксил в транс-положении по отношению к R₃, или
R₄ и R₅ вместе образуют дополнительную связь, как показано пунктирной линией;
R₆ и R₇ независимо друг от друга обозначают C₁-C₅-алкил и
R₈ обозначает водород или C₁-C₅ - алкил, или его N-оксид, или физиологически гидролизуемый и физиологически приемлемый сложный эфир такого соединения, или N-оксид, или соль присоединения кислоты или четвертичная аммониевая соль такого соединения, N-оксид или сложный эфир.In a more specific aspect, the invention includes:
2. The compound of formula / I /:

where R ₁ and R ₂ independently from each other are hydrogen, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -hydroxyalkyl or C ₁ -C ₅ - / alkoxyalkyl /, and at least one of R ₁ and R ₂ is other than hydrogen;
R ₃ is a group of the formula —N / R ₉ / —COR ₁₀ , where R ₉ is hydrogen and R ₁₀ is pyridyl or R ₉ and R ₁₀ together are 1,3-butadieneylene or a group of the formula - / CH ₂ / _n - or - / CH ₂ / _m

in which "n" is an integer from 3 to 5 and m is 1 or 2;
R ₄ is hydrogen and R ₅ is hydroxyl in the trans position with respect to R ₃ , or
R ₄ and R ₅ together form an additional bond, as shown by the dashed line;
R ₆ and R _{7 are} independently C ₁ -C ₅ alkyl and
R ₈ is hydrogen or C ₁ -C ₅ alkyl, or its N-oxide, or a physiologically hydrolyzable and physiologically acceptable ester of such a compound, or an N-oxide, or an acid addition salt or a quaternary ammonium salt of such a compound, N-oxide or ester.

Alkyl groups such as R ₁ , R ₂ , R ₆ , R ₇ and R ₈ , as well as alkyl fragments of hydroxyalkyl and alkoxyalkyl, as well as R ₁ and R ₂ , may be straight or branched. Alkoxyalkyl groups are preferably C ₁ -C ₄ alkoxy / methyl, especially methoxymethyl. A preferred hydroxyalkyl group is hydroxymethyl. R ₆ and R _{7 are} both preferably methyl. R _{8 is} preferably hydrogen or methyl, most preferably hydrogen.

In a preferred group of compounds of formula (I), R ₁ has any of the meanings specified for formula (I) and R ₂ is hydrogen or C ₁ -C ₅ alkyl [especially methyl], preferably hydrogen.

In a further preferred group of compounds of formula (I), R ₃ , R ₉ is hydrogen and R ₁₀ is pyridyl [especially 3-pyridyl] or R ₉ and R ₁₀ together are 1,3-butadiene, trimethylene or tetramethylene. Most preferably, R ₉ and R ₁₀ together are tetramethylene.

Preferably, R ₄ is hydrogen and R ₅ is hydroxyl. The benzopyranes of the invention, for example the compounds of formula / I, form N-oxides, for example on the nitrogen atom of the 6-pyridyl group. Such N-oxides have activity (as described below) and tolerance, mainly comparable to compounds, and also form part of this invention.

By the term “physiologically hydrolyzable and physiologically acceptable ester”, as used herein, is meant an ester in which a hydroxyl group [for example, with respect to formula / I /, hydroxyl groups R ₅ and / or hydroxyl moieties of any hydroxyalkyl group, referred to as R ₁ and / or R ₂ ] is esterified to an ester and which is hydrolyzed under physiological conditions to form an acid that is itself physiologically tolerated in the administered doses. It should be noted that such esters are prodrugs of the usual type and have activity and tolerance comparable to the basic compounds. Example. Such esters include, for example, acetates.

 Acid addition salts, for example, compounds of the formula (I), their N-oxides and their particular esters, include salts of both inorganic and organic acids. Such salts also have activity comparable to free compounds, N-oxides and esters. Pharmaceutically acceptable acid addition salts for pharmaceutical use according to the invention, as described below, are, for example, hydrochloric, sulfuric and fumaric acid salts.

 Quaternary ammonium salts, for example, compounds of the formula [I], their N-oxides and their particular esters, include, for example, salts with organohalogen compounds, for example, with alkyl halides. Pharmaceutically acceptable quaternary ammonium salts for pharmaceutical use according to the invention include, for example, such salts with methyl iodide.

 For pharmaceutical use according to the invention, ester forms, as indicated above, are usually less preferred.

The compounds of formula (I) in which R ₄ is hydrogen and R ₅ is hydroxyl, as well as their N-oxides, esters and salts, as indicated, have the configuration / 3S ^* , 4R ^* /, i.e. the configuration of the groups R ₃ and R ₅ at the 3- and 4-positions is a trans configuration. The compounds of the invention exist in enantiomeric form, i.e., in the form of optically active antipodes having the / 3S, 4R / - or / 3R, 4S / configuration. The invention encompasses both both individual enantiomers [optical active / 3S, 4R / or / 3R, 4S / antipodes], as well as mixtures thereof, for example racemic mixtures.

 For such pharmaceutical use according to the invention, it is believed that these compounds should preferably be present when prevailing as (3S, 4R) enantiomers. Accordingly, the aforementioned / 3S, 4R / enantiomers should be, or should be used, according to the invention in a purified form, that is, comprising less than 50% of the contaminating [other] enantiomer, more suitably in pure or substantially pure form, for example, containing less than 10%, preferably 5% or less, for example 1 or 2% or less, of a polluting / 3R, 4S / enantiomer.

где R₁, R₂, R₆, R₇ и R₈ имеют указанные для формулы /I/ значения с солью щелочного металла карбоксамида, например с соединением формулы /III/: R₁₀ - CO - N^⊖ - R₉ M^⊕ /III/,
где R₉ и R₁₀ имеют указанные для формулы /I/ значения и M⁺ обозначают ион лития, натрия или калия; или
i²/ ацилирование и, если необходимо, алкилирование амино-группы 2,2-ди-/C₁-C₅ - алкил/- или транс-2,2-ди-/C₁-C₅-алкил/-3,4-дигидро-3-гидрокси-4-амино-6-/пиридин-4-ил/-2Н-1-бензопирана, где пиридин-4-ильная группа замещена в 2- и/или 3-положении одним или двумя членами, выбираемыми из группы, включающей C₁-C₅-алкил, C₁-C₅-гидроксиалкил и C₁-C₅-/алкоксиалкил/, например, взаимодействие соединения формулы /IV/:

где R₁, R₂ и R₄-R₈ имеют указанные для формулы /I/ значения с соединением формул /V/, /V'/ или /V''/:

где

обозначает пиридил и X¹ и X² обозначают удаляемые группы;
ii/ для получения N-оксида бензопирана или физиологически гидролизуемого и физиологически приемлемого сложного эфира бензопирана или N-оксид-бензопирана, как указано выше,
этерифицирование до сложного эфира бензопирана или бензопиран-N-оксида, как определено в п.1 содержащего свободную гидроксильную группу или фрагмент, для введения соответствующей сложно-эфирной группы, например взаимодействие соединения формулы /I/, как указанное выше, где R₅ обозначает гидроксил и/или по меньшей мере один из R₁ и R₂ обозначает C₁-C₅-гидроксиалкил, или его N-оксида с соответствующим галоидом кислоты или ангидридом, и/или окисление бензопирана или его физиологически гидролизуемого и физиологически приемлемого сложного эфира, как определено в п.1, например окисление соединения формулы /I/, как определено выше, или его физиологически гидролизуемого и физиологически приемлемого сложного эфира;
и регенерирование полученного бензопирана, бензопиран-N-оксида или его физиологически гидролизуемого и физиологически приемлемого сложного эфира в свободной форме или в форме соли присоединения кислоты или четвертичной аммониевой соли.In addition to the foregoing, the present invention also includes:
3. a method for producing a benzopyran such as described in paragraph 1., for example, a compound of formula / I /, and such as described in paragraph 2 or its N-oxide, or a physiologically hydrolyzable and physiologically acceptable ester of such benzopyran or N- an oxide or an acid addition salt or a quaternary ammonium salt of such a benzopyran, N-oxide or ester, the method comprising:
1 / to obtain the described benzopyran:
i ¹ 1 / interaction of Ia, 7b-dihydro-2,2-di [C ₁ -C ₅ -alkyl] -6- [pyridin-4-yl] -2H-oxireno / c / / 1 / -benzopyran, where pyridine The 4-yl group is substituted at the 2- and / or 3-position with one or two members selected from the group consisting of C ₁ -C ₅ alkyl, C ₁ -C ₅ hydroxyalkyl and C ₁ -C ₅ - (alkoxyalkyl) , for example, compounds of formula / II /:

where R ₁ , R ₂ , R ₆ , R ₇ and R ₈ have the meanings indicated for the formula / I / with a carboxamide alkali metal salt, for example with a compound of the formula / III /: R ₁₀ - CO - N ^⊖ - R ₉ M ^⊕ / III /,
where R ₉ and R ₁₀ have the meanings indicated for formula / I / and M ⁺ are lithium, sodium or potassium ion; or
i ² / acylation and, if necessary, alkylation of the amino group 2,2-di- / C ₁ -C ₅ -alkyl / - or trans-2,2-di- / C ₁ -C ₅ -alkyl / -3, 4-dihydro-3-hydroxy-4-amino-6- / pyridin-4-yl / -2H-1-benzopyran, where the pyridin-4-yl group is substituted at the 2- and / or 3-position with one or two members, selected from the group consisting of C ₁ -C ₅ alkyl, C ₁ -C ₅ hydroxyalkyl and C ₁ -C ₅ - (alkoxyalkyl), for example, the interaction of the compounds of formula / IV /:

where R ₁ , R ₂ and R ₄ -R ₈ have the meanings indicated for the formula / I / with the compound of the formulas / V /, / V ′ / or / V ″ /:

Where

denotes pyridyl and X ¹ and X ² denote leaving groups;
ii) to obtain benzopyran N-oxide or a physiologically hydrolyzable and physiologically acceptable benzopyran or N-benzopyran ester as described above,
etherification to a benzopyran or benzopyran-N-oxide ester as defined in claim 1 containing a free hydroxyl group or fragment to introduce an appropriate ester group, for example, reacting a compound of formula / I / as above, where R ₅ is hydroxyl and / or at least one of R ₁ and R ₂ is C ₁ -C ₅ hydroxyalkyl or its N-oxide with the corresponding acid halide or anhydride and / or the oxidation of benzopyran or its physiologically hydrolyzable and physiologically acceptable ester as defined in claim 1, for example, the oxidation of a compound of formula / I / as defined above, or a physiologically hydrolyzable and physiologically acceptable ester thereof;
and regenerating the resulting benzopyran, benzopyran-N-oxide or its physiologically hydrolyzable and physiologically acceptable ester in free form or in the form of an acid addition salt or a quaternary ammonium salt.

The method of step i ¹ / may be carried out according to a method known in the art, for example by reaction at room temperature to a reflux temperature in the presence of an inert solvent or diluent such as tetrahydrofuran or dimethyl sulfoxide. Accordingly, the necessary alkali metal salt, for example, a compound of the formula [III], is prepared previously in situ, for example, as described in Examples 1-11 and Example 21. By appropriate use of, for example, sodium salts, both benzopyranes and dihydro- can be obtained. benzopyranes according to the invention, for example, as illustrated in examples 11 and 12. The use of lithium salts leads initially or only to the preferred dihydro-benzopyranes according to the invention, as illustrated in examples 1-10.

The method of step i ² / can also be carried out according to known methods of the prior art. Suitable leaving groups X ¹ are halogens and activated ester groups, and suitable leaving groups X ² are halogens. The reaction is suitably carried out at 0-100 ^° C. in an inert solvent or diluent such as acetonitrile or dichloromethane, preferably in the presence of an acid binding agent, for example trialkylamines or alkali metal carbonates. The method is illustrated in examples 13-20.

The method of step ii / can be carried out according to conventional acylation / N-oxidation methods, for example for the production of N-oxides, by treatment with hydrogen peroxide, m-chloroperbenzoic acid or Collin / CrO ₃ • Pu ₂ / reagent, as illustrated in Example 23.

 The initially obtained free bases can be converted to acid addition salts or quaternary ammonium salts by reaction with acids or, for example, alkyl halides, such as methyl halides and vice versa.

 When using racemates of the compounds of formula (II) and formula (IV), the obtained 4-carboxamido-3,4-dihydro-3-hydroxy-benzopyranes must be in the form of trans racemates [t. e. including / 3S, 4R / - plus / 3R, 4S /, - isomers]. The racemates obtained can be separated to give an individual / 3R, 4S / - or [preferred] / 3S, 4R / - enantiomer, for example, chromatographically using a chiral stationary phase. When individual / 3S, 4R / enantiomers are required, however, this is preferably achieved by using the corresponding isomer as starting material, i.e. in relation to formula / II /, 3S, 4S-antipode and in relation to formula / IV /, 3S, 4R-antipode. A suitable preparation method is the method shown in Reaction Scheme A.

 As should be noted, can be used known in the prior art as variants or alternatives of these methods, for example, for interconversion of the originally obtained compounds or for the introduction of alternative carboxamide groups at the 4-position. Labile groups can be protected, for example, by acylation, using conventional protection, for example, with hydroxyl protecting groups. In addition, the initially obtained benzopyranes, if desired, can be converted to the corresponding benzopyranes by dehydration at the 3,4-bond, again in accordance with standard methods. Further alternatives should be known to the person skilled in the art.

Стадии /III/-/VI/ могут быть осуществлены обычным образом, например, в соответствии с обычными способами, проиллюстрированными в примерах 24.A.4; A.5; A.5'a; и A.5'b.Compounds of formula (II) can be prepared according to the following general reaction sequence A:

Stage / III / - / VI / can be carried out in the usual way, for example, in accordance with the usual methods illustrated in examples 24.A.4; A.5; A.5'a; and A.5'b.

 The starting materials of formula (IV) can be prepared from the corresponding compounds of formula (II) by reacting with ammonia, for example, in accordance with the general methods illustrated in Example 24. A.6 '.

 The compound of formula (II) obtained through stages (III) and / IV / is cis-racemate, i.e. includes / 3R, 4R / - and / 3S, 4S / antipodes. Stage / V / includes the introduction of the corresponding chiral acyl group [in scheme A, for example, due to / R / -α-methoxyphenylacetyl]. The chiral racemate / VIII / can be easily separated by column chromatography or fractional recrystallization into its individual / 3R, 4S / - and / 3R, 4S / - antipodes. By using the / 3R, 4S / antipode and carrying out step [VI], the compound [II] as a starting material can be obtained in pure or substantially pure / 3S, 4S / enantiomeric form.

в которой X'' обозначает удаляемую группу, обычно атом галогена, например хлор. Стадии /VII/-/IX/ могут быть осуществлены обычным образом, например, в соответствии с общими способами, проиллюстрированными в примерах 24. А. 2 и А.3, причем стадии /VIII/ и /IX/ осуществляются в примере 24.А.3 без очистки промежуточных продуктов. Как указано в примере 24.А.2, стадию /VII/ обычно осуществляют в апротонном растворителе, таком, как ацетон, в присутствии основания, такого, как K₂CO₃ и катализатора такого, как KI.Compounds of formula (VI) can be prepared according to the following general reaction scheme B:

in which X ″ represents a leaving group, usually a halogen atom, for example chlorine. Stage / VII / - / IX / can be carried out in the usual way, for example, in accordance with the General methods illustrated in examples 24. A. 2 and A.3, and stages / VIII / and / IX / are carried out in example 24.A .3 without purification of intermediates. As indicated in Example 24.A.2, step [VII] is usually carried out in an aprotic solvent, such as acetone, in the presence of a base such as K ₂ CO ₃ and a catalyst such as KI.

Способы стадий /X/ и /XI/ и /XII/-/XIV/, могут быть осуществлены обычным образом, например, в соответствии с общими способами, проиллюстрированными в примерах 24. А1а и 24.А.1а' и в', соответственно. Обычно методика получения через стадии /X/ и /XI/ будет предпочтительна для синтезов в широком масштабе.The compounds of formula (IX) can be obtained in various possible ways, for example, as shown in the following General reaction scheme B:

The methods of steps / X / and / XI / and / XII / - / XIV / can be carried out in the usual way, for example, in accordance with the general methods illustrated in examples 24. A1a and 24.A.1a 'and b', respectively . Typically, the production procedure through steps / X / and / XI / will be preferred for syntheses on a large scale.

When it is desired to prepare compounds of the invention in which R ₁ and / or R ₂ are hydroxyalkyl or alkoxyalkyl, this can also be achieved by conversion of alkyl substituents such as R ₁ / R ₂ . Similarly, methyl substituents such as R ₁ / R ₂ , if desired, can be converted to higher alkyl substituents. Typically, such conversion reactions are carried out at the stage of synthesis of the compounds of formula / VI / using conventional techniques, for example, in accordance with the conventional methods illustrated in examples 24.E.3; F.3; G3.a- G3.b and H.3.aH.3.b.

в которой Hal обозначает галоген, например, бром, и R₈ обозначает C₁-C₅-алкил. Способы стадий /XV/-/XXI/ могут быть осуществлены обычным образом, например, в соответствии со способами, проиллюстрированными в примере 24.I.Compounds of formula (VI), where R ₈ is other than hydrogen, can usually be obtained in accordance with the following reaction scheme D:

in which Hal is halogen, for example bromine, and R ₈ is C ₁ -C ₅ alkyl. The methods of steps / XV / - / XXI / can be carried out in the usual way, for example, in accordance with the methods illustrated in example 24.I.

 The intermediates illustrated above and in the accompanying examples, especially intermediates of the formulas / II /, / IV / and / VI / - / VIII /, are new. Such intermediate compounds, in particular intermediate compounds of the formulas / II / and / IV / and methods for their preparation also form part of the invention.

 The following examples illustrate the methods of the invention. All NMR spectra are recorded at 360 MHz. All temperatures are given in degrees Celsius and without correction.

: чистый или практически чистый /3S,4R/- энантиомер/.Example. 1. Preparation of / - / - / 3S, 4R / -1- / 3,4-dihydro-2,2-dimethyl-3-hydroxy-6- / 2-methylpyridin-4-yl / -2H-1-benzopyran- 4-yl / -2-piperidinone / formula / I /:
R ₁ = R ₆ = R ₇ = CH ₃ ; R ₂ = R ₄ = R ₈ = H; R ₅ = -OH;

: pure or practically pure / 3S, 4R / - enantiomer /.

A stirred solution of 2-piperidinone / 19.8 g / in anhydrous tetrahydrofuran / 400 ml / at 10 ^o C and in an argon atmosphere is treated with a solution of bi / trimethylsilyl / lithium amide [200 ml / 1.0 M] in tetrahydrofuran and stirred at room temperature for 2 hours. The resulting suspension is treated with a solution of / - / - / 3S, 4S / -4- [1a, 7b - dihydro-2,2-dimethyl-2H-oxireno / c / 1 / -benzopyran-6-yl] -2- methylpyridine {26.7 g; see example 24.A.5 '} in anhydrous tetrahydrofuran / 150 ml / and refluxed for 31 hours. The mixture was cooled to 15 ^° C, treated with saturated aqueous ammonium chloride / 300 ml / and extracted with ethyl acetate / 2 times 150 ml /. The combined extracts were washed with brine / 300 ml /, dried / Na ₂ SO ₄ / and filtered. The solvent was evaporated under reduced pressure to obtain a crude product, which was purified by chromatography [silica gel, 5% C ₂ H ₅ OH in CH ₂ Cl ₂ ] and recrystallized from a mixture of ethanol and pentane to give the target compound; t. pl. = 192 ^o C, (α) $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -83.2 ^o / c = 1.06, ethanol /. The melting point of the semimaleate = 146-148 ^o C.

получают аналогичным образом, причем получение необходимого оксирено-исходного материала проиллюстрировано в примере, указанном в правой колонке табл.1.The following compounds of formula / Ia /:

receive in the same way, and the receipt of the necessary oxirene-source material is illustrated in the example shown in the right column of table 1.

 All compounds listed in Table 1 are in the form of transracemates.

].Example. 11. Preparation of 1- [2,2-dimethyl-6- {2-methylpyridin-4-yl} -2H-1-benzopyran-4-yl] -2-piperidinone [formula / I /: R ₁ = R ₆ = R ₇ = CH ₃ ; R ₂ = R ₈ = H; R ₄ - R ₅ = additional bond;

].

A stirred solution of 2-piperidinone (0.90 g) in anhydrous dimethyl sulfoxide / 20 ml) was treated with NaH [0.48 g of a 55% dispersion in oil] and stirred at 50 ^° C. for 30 minutes under argon atmosphere. The mixture is cooled to 10 ^o C and treated with a solution of / ± / -4- [1a, 7b - dihydro-2,2-dimethyl-2H-oxireno- (c / / 1 / -benzopyran-6-yl] -2-methylpyridine / 2.67 g, see example 24. A. 5 / and stirred at room temperature under argon for 14 hours. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NH ₄ Cl / 200 ml / and extracted with dichloromethane / 3 times in 100 ml /. The combined extracts were dried (sodium sulfate), filtered and the solvent was evaporated under reduced pressure to give a mixture. It was separated by chromatography [silica gel, 2% C ₂ H ₅ OH in CH ₂ Cl ₂ ] to give a less polar product / A /, which was recrystallized from a mixture of ethyl ether and pentane to give the target compound and a more polar compound / B /, which was recrystallized from a mixture of dichloromethane with diethyl ether, obtaining the same product as in example 2. So pl. target compound 95-98 ^o C.

]
Целевое соединение получают одновременно с продуктом примера 3, приведенного выше, исходя из продукта примера 24.Д.5., приведенного ниже, и поступая аналогично примеру 11. Физические характеристики целевого соединения: ¹H-ЯМР / δ -d⁶ ДМСО/: 1,41 /с., 3Н/; 1,45 /с., 3Н/; 1,77-1,96 /м., 3Н/; 2,26 /с. , 3Н/; 2,27-2,68 /м., 3Н/; 3,37-3,58 /м., 2Н/; 5,83 /с., 1Н/; 6,92 /д., 1Н/; 7,14-7,20 /м., 2Н/; 7,36 /м., 1Н/; 8,39 /д., 1Н/; и 8,45 /с., 1Н/.Example. 12. Preparation of 1- [2,2-dimethyl-6- / 3-methylpyridin-4-yl / -2H-1-benzopyran-4-yl] -2-piperidinone [formula / I /: R ₂ = R ₆ = R ₇ = CH ₃ ; R ₁ = R ₈ = H; R- ₄ - R ₅ = additional bond;

]
The target compound is obtained simultaneously with the product of example 3 above, starting from the product of example 24.D.5. Below, and proceeding analogously to example 11. Physical characteristics of the target compound: ¹ H-NMR / δ -d ⁶ DMSO /: 1 41 / s, 3H /; 1.45 / s., 3H /; 1.77-1.96 / m, 3H /; 2.26 / s , 3H /; 2.27-2.68 / m, 3H /; 3.37-3.58 / m, 2H /; 5.83 / s, 1H /; 6.92 / d, 1H /; 7.14-7.20 / m, 2H /; 7.36 / m, 1H /; 8.39 / d, 1H /; and 8.45 / s, 1H /.

чистый или в практически чистый /3S,4R/ - энантиомер.Example. 13. Preparation of / + / - / 3S, 4R / - [3,4-dihydro-2,2-dimethyl-3-hydroxy-6- / 2-methylpyridin-4-yl / -2H-1-benzopyran] -3 -pyridine-carboxamide {formula / I / R ₁ = R ₆ = R ₇ = CH ₃ ; R ₂ = R ₄ = R ₈ = H;

pure or practically pure / 3S, 4R / - enantiomer.

A stirred solution of / + / - / 3S, 4R / -4-amino-3,4-dihydro-2,2-dimethyl-6- / 2-methylpyridin-4-yl / -2H-1-benzopyran-3-ol [ 0.65 g, see example 24.A.6 'below], triethylamine / 0.50 g / and 4-dimethylaminopyridine / 0.002 g / in anhydrous dichloromethane / 30 ml / at 2 ^° C and under argon atmosphere are treated with nicotinoyl chloride hydrochloride / 0.445 g /. The mixture was stirred for 2 hours at room temperature, after which the mixture was treated with an aqueous solution of sodium carbonate - [100 ml / 2M] and extracted with a 3: 1 mixture of CH ₂ Cl ₂ / CH ₃ OH {3 times 100 ml}. The combined extracts were washed with brine, dried (sodium sulfate), filtered and the solvent was evaporated under reduced pressure to give an oil. The oil is purified by chromatography [silica gel, 2% C ₂ H ₅ OH in CH ₂ Cl ₂ ] and recrystallized from a mixture of ethanol and diethyl ether to give the desired compound in enantiomerically pure or substantially pure form; so pl. 247-248 ^o C; (α) $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = + 19.8 ^o / c = 0.965, ethanol /.

получают аналогично, причем получение необходимого 4-амино-бензопиран-3-ола в качестве исходного материала проиллюстрировано в примере, указанном в правой колонке табл.2.The following compounds of formula / Ib /:

receive similarly, and obtaining the necessary 4-amino-benzopyran-3-ol as starting material is illustrated in the example shown in the right column of table 2.

 All compounds listed in Table 2 are in the form of transracemates.

; в виде транс-рацемата}.Example. 21. Preparation of trans - / + / - 1 / [3,4-dihydro-2,2-dimethyl-3-yhydroxy-6- / 2-methylpyridin-4-yl / -2H-1-benzopyran-4-yl] -2H-1-pyridinone {formula / I /: R ₁ = R ₆ = R ₇ = CH ₃ -; R ₂ = R ₄ R ₈ = H;

; as a trans racemate}.

A stirred solution of 2-hydroxypyridine (0.42 g) in anhydrous ethanol / 20 ml / is treated with NaH {0.21 g of a 55% dispersion in oil} and stirred at room temperature for 15 minutes under argon. The mixture was then cooled to 2 ^° C. and treated with a solution of / ± / -4- [1a, 7b-dihydro-2,2-dimethyl-2H-oxireno / c / / 1 / -benzopyran-6-yl] -2-methylpyridine { 1.07 g, see example 24.A.5.} And stirred for 96 hours at room temperature. The solvent is evaporated under reduced pressure and the residue is treated with a saturated aqueous solution of ammonium chloride / 100 ml / and extracted with methylene chloride / 3 times 100 ml /. The combined extracts were dried (sodium sulfate), filtered off and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by chromatography [silica gel, 2% C ₂ H ₅ OH in CH ₂ Cl ₂ ] and recrystallized from a mixture of ethanol and diethyl ether to give target compound. Mp 213-214 ^o C.

в виде транс-рацемата.Example. 22. Preparation of trans - / + / - 2- [3,4-dihydro-2,2-dimethyl-3-hydroxy-6- / 2-methylpyridin-4-yl / -2H-1-benzopyran 4-yl] - 2,3-dihydro-1H-isoindol-1-one [formula / I /: R ₁ = R ₆ = R ₇ = CH ₃ ; R ₂ = R ₄ = R ₈ = H;

in the form of a trans racemate.

Stirred solution of trans - / ± / -4-amino-3,4-dihydro-2,2-dimethyl-6- / 2-methylpyridin-4-yl / -2H-1-benzopyran-3-ol / 2.84 g / [cm. Example 24.A.6] and 2-bromomethylbenzoic acid methyl ester / 2.30 g / in anhydrous acetonitrile / 100 ml / was treated with KI / 0.84 g / and then K ₂ CO ₃ / 4.20 g /, in an argon atmosphere. The reaction mixture was stirred for 1 h at 20 ^o C, for 1 h at 60 ^o C and then for 15 h at 85 ^o C. The solvent was evaporated under reduced pressure, and the residue was treated with water / 300 ml / and extracted with 2 % CH ₃ OH in methylene chloride / 4 times 150 ml /. The combined extracts were washed with sodium thiosulfate / 100 ml / 2% / solution, dried [sodium sulfate] and filtered. The solvent was evaporated under reduced pressure to obtain a crude product, which was purified by chromatography (silica gel, 5% C ₂ H ₅ OH in CH ₂ Cl ₂ ) and recrystallized from a mixture of ethanol and acetone to give the target compound. Mp 222-224 ^o C.

 Example. 23. Preparation of / - / - / 3S, 4R / -4- [3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 2-oxo-piperidin-1-yl / -2H-1- benzopyran-6-yl] -2-methylpyridin-N-oxide.

A solution of the product of Example 1 / 2.6 g / in CH ₂ Cl _2/40 ml / is treated with 3-chloroperoxybenzoic acid / 1.92 g, a 90% / and stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure to obtain a crude product, which is purified by chromatography / silica gel, 5% C ₂ H ₅ OH in CH ₂ Cl ₂ / and recrystallized from a mixture of acetone and diethyl ether, to obtain the target compound. Mp 202-205 ^o C.

Example. 24. Obtaining starting materials of examples 1-23
A.1. Preparation of 4- / 4-methoxyphenyl / -2-methylpyridine.

 A. 1. a Ethyl 4- [4-methoxyphenyl] -2-methyl-1 / 4H] -pyridinecarboxylic acid.

Ethyl chloroformate / 10.85 g / is added to a stirred mixture of 2-picoline / 9.30 g / and iodide copper- / I / / 0.77 g / in anhydrous tetrahydrofuran / 150 ml /, at -20 ^o C and in argon atmosphere . All was stirred for 3 hours at -20 ^° C. and then treated by adding dropwise 4-methoxyphenyl magnesium bromide solution obtained from 4-bromoanisole / 18.7 g / and magnesium shavings / 2.64 g / in anhydrous tetrahydrofuran / 100 ml /, and added dropwise at such a rate that the temperature remains between (-15) - (- 20) ^o C. The mixture is stirred at -15 ^o C for 1 h and for 16 hours at 20 ^o C, and after that treated with a saturated aqueous solution of NH ₄ Cl / 300 ml / and extracted with ethyl acetate / 4 times 200 ml /. The combined extracts were dried (sodium sulfate), filtered and the solvent was evaporated under reduced pressure to give a crude product. It is purified by chromatography (silica gel, 50% toluene in hexane) to give the desired compound as a pale yellow oil.

 A.1.c. 4- / 4-methoxyphenyl / -2-methylpyridine.

The product of stage A.1.a. / 16.9 g / and sulfur / 2.0 g / in decahydronaphthalene / 100 ml / was stirred for 3 hours at 200 ^° C. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate / 500 ml / and extracted with hydrochloric acid / 3 times 200 ml, 2M /. The combined extracts were washed with ethyl acetate / 2 × 100ml /, basified with ice-cooling to pH = 11 with NaOH and extracted with CH ₂ Cl _2/3 times with 200 ml /. The combined extracts were dried (sodium sulfate), filtered and the solvent was evaporated under reduced pressure to give a crude product. It is purified by chromatography (silica gel, 2% C ₂ H ₅ OH in CH ₂ Cl ₂ ) and recrystallized from a mixture of ethanol and ethyl acetate to obtain the target compound. Mp 88-91 ^o C.

 The target compound can alternatively be obtained in the following way.

 A.1.a ', 2,2', 6'-Trimethyl-4-oxo-1,1 '- / 4'H / bipyridinium tetrafluoroborate.

2-Methylpyridine / 11.7 g / is added to a freshly prepared solution of hydroxylamine-0-sulfonic acid / 45.2 g, 90% / in water / 260 ml / at 0 ^o C. The mixture is heated to 95 ^o C, stirred for the next 45 minutes, cooled to 10 ^o C and carefully treated with potassium carbonate / 55 g /. The mixture was washed with diethyl ether / 2 times 100 ml / and the water was evaporated at 40 ^° C. under reduced pressure. The residue was treated with ethanol (600 ml) and the precipitated K ₂ SO _{4 was} removed by filtration. The filtrate is treated with hydrochloric acid / 120 ml, 18 M / and evaporated to dryness at 50 ^° C. under reduced pressure to obtain a residue which is treated with dehydroacetic acid / 68.6 g / and HCl / 150 ml, 18 M / and refluxed within 90 minutes The solution was evaporated to dryness at 50 ^° C. under reduced pressure, and the residue was stirred with ethanol / 200 ml / for 15 minutes, filtered off and the precipitate washed with ethanol / 200 ml /. The combined filtrate and washings are treated with tetrafluoroboric acid in diethyl ether / 50 ml, 50% /, diluted with diethyl ether / 250 ml /. The target compound is left to crystallize and it is filtered off and dried in vacuo at 20 ^° C. 206-208 ^o C.

A.1.c '. 4- / 4-methoxyphenyl / -2-methyl-pyridine
A stirred solution of 4-methoxyphenyl magnesium bromide obtained from 4-bromoanisole / 56.1 g / and magnesium shavings / 7.92 g / in anhydrous tetrahydrofuran / 400 ml /, at 0-5 ^o C, is treated with the product of stage / A.1.a '/ (30.2) in an argon atmosphere. The mixture was stirred at room temperature for 48 hours, washed with saturated aqueous ammonium chloride / 300 mL / and the aqueous phase was extracted with CH ₂ Cl _2/3 times with 100 ml /. The combined tetrahydrofuran solution and CH ₂ Cl ₂ extracts were dried (sodium sulfate), filtered off and the solvents were evaporated under reduced pressure to obtain crude 4 '- [4-methoxyphenyl] -2,2', 6'-trimethyl- {1,1 ' / 4H, 4'H / bipyridine} -4-one. The crude product was dissolved in anhydrous dimethylformamide / 400 ml / and refluxed for 4 hours. The solvent was evaporated under reduced pressure to obtain a residue, which was purified by chromatography / silica gel, 2% C ₂ H ₅ OH in CH ₂ Cl ₂ / and recrystallized from ethanol to obtain the target compound. Mp 88-91 ^o C.

 A.2. Preparation of 4- / 4-hydroxyphenyl / -2-methylpyridine.

A solution of the product of example / A.1./ / 6.45 g / in HBr / 100 ml, 48% / is heated at 135 ^° C. for 3 hours. The excess HBr is evaporated under reduced pressure to obtain a residue which is neutralized with an aqueous solution of NaHCO ₃ and extracted with a 3: 1 mixture of CH ₂ Cl ₂ / C ₂ H ₅ OH [3 times 150 ml]. The combined extracts were dried (sodium sulfate), filtered and the solvent was evaporated under reduced pressure to give a crude product. It is recrystallized from a mixture of ethanol and diethyl ether to give the desired compound. Mp 203-204 ^o C.

 A.3. Obtaining 2,2-dimethyl-6- / 2-methylpyridin-4-yl / -2H-1-benzopyran.

A stirred mixture of the product of example A.2. / 4.07 g /, anhydrous K ₂ CO ₃ / 6.9 g / and KI / 1.0 g / in anhydrous acetone, in an argon atmosphere, is treated with 3-chloro-3-methylbutin / 5.56 g / and refluxed for 120 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to obtain crude 4- [4- / 1,1-dimethyl-2-pyropinyl / hydroxyphenyl] -2-methylpyridine. The latter was dissolved in 1,2-dichlorobenzene / 50 ml / and heated at 170 ^° C for 1 h. The solvent was evaporated under reduced pressure to obtain the crude target compound, which was purified by chromatography [silica gel, 2% C ₂ H ₅ OH in CH ₂ Cl ₂ ], obtaining the target compound. Mp 37-40 ^o C.

 The following compounds can be obtained analogously to examples A.1.-A.3., Carrying out or stage / A.1.a./-/A.1.v./ or /A.1.a'/-/A. 1. in '/; all compounds are obtained in the form of oils.

 AT 3. 2,2-Dimethyl-6- / 2-ethylpyridin-4-yl / -2H-1-benzopyran.

 C.3. 2,2-Dimethyl-6- / 2,3-dimethylpyridin-4-yl / -2H-1-benzopyran.

 E.3. 2,2-Dimethyl-6- / 3-methylpyridin-4-yl / -2H-1-benzopyran.

 E.3. Obtained 2,2-dimethyl-6- / 2-propylpyridin-4-yl / -2H-1-benzopyran.

To a stirred solution of the product of example A.3. / 5.02 g / in anhydrous tetrahydrofuran / 50 ml /, at -25 ^° C and under argon atmosphere, a solution of n-butyllithium [12.5 ml / / 1.6 M] in hexane is added. The resulting mixture was stirred at 10 ^o C for 40 min, cooled to -5 ^o C and treated with ethyl iodide / 2.4 ml /. The mixture was allowed to warm to room temperature, stirred for an additional 2 hours and then treated with a saturated aqueous solution of NH ₄ Cl / 100 ml / and extracted with ethyl acetate / 2 times 100 ml /. The combined extracts were dried (sodium sulfate), filtered off and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by chromatography (silica gel, 10% acetone in hexane) to give the target compound as an oil.

 F.3. Preparation of 2,2-dimethyl-6- / 2-isobutylpyridin-4-yl / -2H-1-benzopyran.

 The target compound is prepared analogously to example E.3. When using isopropyl iodide instead of ethyl iodide, it is obtained as an oil.

 G. 3. Preparation of 2,2-dimethyl-6- / 2-hydroxymethylpyridin-4-yl / -2H-1-benzopyran acetate.

 G.3.a. 4- / 2,2-Dimethyl-2H-1-benzopyran-6-yl / -2-methylpyridin-N-oxide.

The product solution of example A.3. / 13.4 g / in CH ₂ Cl _2/200 mL / treated with 3-chloroperoxybenzoic acid / 13.5 g, 70% -s / and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to obtain a residue, which is purified by chromatography / silica gel, 5% C ₂ H ₅ OH in CH ₂ Cl ₂ / to give the title compound as a yellow gum.

 G. 3. c. (2,2-Dimethyl-6- / 2-hydroxymethylpyridin-4-yl) -2H-1-benzopyranacetate.

The mixture of the product of stage G. 3. a. (4.8 g) and acetic anhydride (50 ml) are heated at 80 ^° C. under argon for 1 hour. The solvent is evaporated off under reduced pressure to obtain a crude product which is purified by chromatography / silica gel, 10% ethyl acetate in toluene /, getting the target compound in the form of oil.

 H. 3. Preparation of 2,2-dimethyl-6- / 2-methoxymethylpyridin-4-yl / -2H-1-benzopyran.

 H.3.a. (2,2-Dimethyl-2H-1-benzopyran-6-yl) -2-pyridinomethanol.

The product mixture of example G.3. (69.5 g), Na ₂ CO ₃ / 95.4 g /, H ₂ O / 160 ml / and C ₂ H ₅ OH / 600 ml / was stirred for 22 hours at room temperature. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure to obtain a residue, which is treated with water / 400 ml / and extracted with dichloromethane / 3 times 150 ml /. The combined extracts were dried (sodium sulfate) and the solvent was evaporated under reduced pressure to give a crude product. It is purified by chromatography (silica gel, ethyl acetate) and recrystallized from pentane to give the target compound. Mp 86-88 ^o C.

 H.3.b. (2,2-Dimethyl-2H-1-benzopyran-6-yl) -2-methoxymethyl-pyridine.

A stirred solution of the product of stage H.3.a. (8.0 g) in anhydrous tetrahydrofuran (150 ml) at 15 ^° C and in an argon atmosphere, it is treated with NaH / 0.90 g of an 80% dispersion in oil / and stirred at room temperature for 45 minutes. Methyl iodide (4.26 g) was added and the mixture was stirred at room temperature for 18 hours. The mixture was treated with saturated aqueous NH ₄ Cl / 200 ml / and extracted with ethyl acetate / 2 times 200 ml /. The combined extracts were dried (sodium sulfate), filtered and the solvent was evaporated under reduced pressure to give a crude product. It is purified by chromatography (silica gel, 20% acetone in hexane) to give the title compound as an oil.

 l. Preparation of 6- [2-methylpyridin-4-yl] -2,2,7-trimethyl-2H-1-benzopyran.

 a. 4-bromo-3-methylphenol acetate.

A stirred mixture of 4-bromo-3-methylphenol / 184.1 g / and an aqueous solution of NaOH / 850 ml, 2M / at 20 ^° C was treated with acetic anhydride / 136 ml / and stirred at room temperature for 1 h. The suspension was extracted with diethyl ether / 3 times 300 ml /, and the combined extracts are washed with an aqueous solution of NaOH / 2 times 100 ml, 2M /, dried / sodium sulfate / and filtered. The solvent was evaporated under reduced pressure to obtain the target compound as an oil.

 b. 1- / 3-Bromo-2-hydroxy-5-methylphenyl / ethanone.

A mixture of the product of step (a) (195.6 g) and aluminum chloride (152.6 g) was stirred under argon at 165 ^° C. for 45 minutes. The cooled mixture was treated with ice-cold hydrochloric acid / 2000 ml, 2M / and extracted with CH ₂ Cl _2/4 × 600 ml /. The combined extracts were washed with brine, dried (sodium sulfate), filtered and the solvent was evaporated under reduced pressure to give a crude product. It is purified by chromatography (silica gel, 10% toluene in hexane) and recrystallized from a mixture of diethyl ether with hexane to give the target compound. Mp 81-82 ^o C.

 c. 6-Bromo-3,4-dihydro-2,2,7-trimethyl-2H-1-benzopyran-4-one.

A mixture of the product of stage (b) / 48 g /, acetone / 31 ml / and pyrrolidine / 21 ml / in anhydrous benzene / 500 ml / was stirred at room temperature for 3 hours and then refluxed for 6 hours, the resulting water is removed through a Dean-Stark nozzle. The cooled mixture was treated with hydrochloric acid / 200 ml, 2M /, stirred for 10 min, basified with aqueous solution of NaOH / 1 M / and extracted with CH ₂ Cl _2/3 times with 300 ml /. The combined extracts were dried (K ₂ CO ₃ ), filtered and the solvent was evaporated under reduced pressure to give a crude product. It is purified by chromatography (silica gel, 50% toluene in hexane) and recrystallized from a mixture of diethyl ether with pentane to obtain the target compound. T. pl. 95-96 ^o C.

 d. 6-Bromo-3,4-dihydro-4-hydroxy-2,2,7-trimethyl-2H-1-benzopyran.

A stirred solution of the product of stage (c) / 26.9 g / in ethanol / 200 ml / at 5 ^° C was treated with sodium borohydride / 1.95 g / and stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure to give a residue which is treated with water / 500 ml / and extracted with diethyl ether / 3 times 200 ml /. The combined extracts were dried (sodium sulfate), filtered and the solvent was evaporated under reduced pressure to give a crude product. It is purified by chromatography (silica gel, 10% acetone in hexane) and recrystallized from a mixture of diethyl ether with pentane to obtain the target compound. Mp 92-93 ^o C.

 e. 6-Bromo-2,2,7-trimethyl-2H-1-benzopyran.

 A stirred solution of the product of stage (d) / 27.1 g / in anhydrous toluene / 300 ml / is treated with p-toluenesulfonic acid / 1.15 g / and refluxed for 2 hours, the resulting water being removed through a Dean-Stark nozzle. The cooled solution was washed with an aqueous solution of sodium carbonate (100 ml, 2M), dried (sodium sulfate), filtered off and the solvent was evaporated under reduced pressure, to give a crude product. It is purified by chromatography (silica gel, hexane) to give the title compound as an oil.

 f. 6- / 2-Methylpyridin-4-yl / -2,2,7-trimethyl-2H-1-benzopyran.

A solution of the product of stage (e) / 7.60 g / in anhydrous tetrahydrofuran / 30 ml / is added over 15 minutes to a stirred mixture of magnesium shavings / 0.85 g / iodine / 0.06 g / in anhydrous tetrahydrofuran / 25 ml / at 45 ^o C and in an argon atmosphere. The mixture is refluxed for 3 hours, cooled to 5 ^° C., treated with bis / triphenylphosphine / nickel chloride / II / / 0.32 g / and a solution of 4-bromopicolin / 4.8 g / in anhydrous tetrahydrofuran / 50 ml / and stirred at room temperature for 18 hours. The mixture is treated with hydrochloric acid / 140 ml, 1M / and extracted with diethyl ether / 2 times 60 ml /. The combined ether extracts are washed with hydrochloric acid. The combined acid solutions were alkalinized to pH = 10 with potassium carbonate, extracted with diethyl ether / 3 times 100 ml /, dried / sodium sulfate /, filtered and the solvent was evaporated under reduced pressure to give a crude product. It is purified by chromatography / silica gel, 10% acetone in hexane /, to obtain the target compound in the form of an oil, which has the following physical characteristics:
¹ H-NMR / δ CDCl ₃ /: 1.44 / s, 6H /; 2.21 / s, 3H /; 2.59 / s, 3H /; 5.60 / d. , 1H /; 6.31 / d, 1H /; 6.70 / s, 1H /; 6.82 / s, 1H /; 7.04 / dd. 1H /; 7.09 / d. , 1H /; and 8.49 / d, 1H /.

 A. 4. Preparation of trans - / + / - 3-bromo-3,4-dihydro-2,2-dimethyl-6- / 2-methylpyridin-4-yl / -2H-1-benzopyran-4-ol.

N-Bromosucciniminide (2.20 g) was added in portions to a stirred solution of product A.3. / 2.50 g / in dimethyl sulfoxide / 6 ml / and water / 0.36 ml / at 0 ^o C. After the termination of the exothermic reaction, continuously stirred for an additional 1 h and the reaction was interrupted by saturated aqueous solution of NH ₄ Cl / 200 ml / and the mixture was extracted with CH ₂ Cl _2/3 times with 100 ml /. The combined extracts were dried (sodium sulfate), filtered and the solvent was evaporated under reduced pressure to give a crude product. It is purified by chromatography [silica gel, 2% C ₂ H ₅ OH in CH ₂ Cl ₂ ] and recrystallized from a mixture of ethanol and diethyl ether to give the desired compound. Mp 212-214 ^o C.

 A.5. Preparation of / + / - 4- [1a, 7b-dihydro-2,2-dimethyl-2H-oxireno / c / / 1 / -benzopyran-6-yl] -2-methylpyridine.

The product solution of example A.4. (3.5 g) in anhydrous tetrahydrofuran / 80 ml) was treated with NaH {0.90 g of a 55% dispersion in oil} and stirred at room temperature in argon atmosphere for 1 h. The reaction was stopped with a saturated aqueous solution NH ₄ Cl / 150 ml / and the reaction mixture is extracted with diethyl ether / 3 times 100 ml /. The combined extracts were dried (sodium sulfate), filtered off and the solvent was evaporated under reduced pressure to obtain a residue which was purified by chromatography / silica gel, 2% C ₂ H ₅ OH in CH ₂ Cl ₂ / to give the target compound as an oil, which has the following characteristics:
¹ H-NMR / δ -d ⁶ DMSO /: 1.23 / s, 3H /; 1.50 / s., 3H /; 2.52 / s., 3H /; 3.75 / d , 1H /; 4.14 / d, 1H /; 6.89 / d, 1H /; 7.47 / dd, 1H /; 7.56 / s, 1H /; 7.19 / dd. 1H /; 7.96 / d, 1H /; and 8.47 / d, 1H /.

The following compounds of formula (II), in which R ₆ and R ₇ are each methyl, and R ₁ , R ₂ and R ₈ have the indicated meanings, can be obtained analogously to examples A4 and A5, but by reacting by one-pot procedure. This is accomplished by diluting the mixture obtained after the exothermic reaction and mixing according to Example A.4. dioxane, treatment with an aqueous solution of NaOH / 0.6 M / and stirring at room temperature for another 1 hour. Purification is then carried out analogously to Example A.5., followed by evaporation of dioxane. The starting materials are indicated in column 2 of the table. 3. All products are obtained in the form of / ± /-racemates as an oil.

Characteristic:
B. 5. ¹ H-NMR / δ-CDCl ₃ /: 1.31 / s, 3H /; 1.37 / t, 3H /; 1.62 / s., 3H /; 2.89 / l, 2H /; 3.56 / d, 1H /; 3.99 / d, 1H /; 6.91 (dsl., 1H); 7.28 / dd, 1H /; 7.34 / m, 1H /; 7.54 / dd. 1H /; 7.63 / d, 1H /; and 8.54 / dd. 1H /.

C. 5. ¹ H-NMR / δ-CDCl ₃ /: 1.32 / s, 3H /; 1.61 / s., 3H /; 2.20 / s, 3H /; 2.61 / s , 3H /; 3.54 / d, 1H /; 3.39 / d, 1H /; 6.87 / d, 1H /; 6.98 / d, 1H /; 7.17 / dd. 1H /; 7.26 / d, 1H /; and 8.32 / d, 1H /.

M. 5. ¹ H-NMR / δ-CDCl ₃ /: 1.33 / s, 3H /; 1.62 / s., 3H /; 2.31 / s, 3H /; 3.55 / d, 1H /; 3.95 / d, 1H /; 6.89 / d, 1H /; 7.13 / d, 1H /; 7.23 / dd. 1H /; 7.31 / s, 1H /; 8.45 / d, 1H /; and 8.49 / s, 1H /.

E. 5. ¹ H-NMR / δ-CDCl ₃ /: 1.01 / t, 3H /; 1.30 / s, 3H /; 1.62 / s., 3H /; 1.82 / sextet, 2H /; 2.82 / t, 2H /; 3.54 / d, 1H /; 3.98 / d, 1H /; 6.91 / d, 1H /; 7.28 / dd. , 1H /; 7.32 / d, 1H /; 7.53 / dd., 7.63 / d. 1H /; and 8.54 / d, 1H /.

F. 5. ¹ H-NMR / δ-CDCl ₃ /: 0.96 / d, 6H /; 1.30 / s, 3H /; 1.62 / s., 3H /; 2.15 / dt. 1H /; 2.70 / d, 2H /; 3.54 / d, 1H /; 3.93 / d, 1H /; 6.90 / d, 1H /; 7.22-7.30 / m, 2H /; 7.53 / dd. 1H /; 7.63 / d, 1H /; and 8.54 / d, 1H /.

G. 5. ¹ H-NMR / δ-CDCl ₃ /: 1.31 / s, 3H /; 1.63 / s., 3H /; 3.55 / d, 1H /; 3.98 / d, 1H /; 4.83 / s, 2H /; 6.92 / d, 1H /; 7.35-7.45 / m, 2H /; 7.54 / dd. 1H /; 7.64 / d, 1H /; and 8.57 / d, 1H /.

I. 5. ¹ H-NMR / δ-CDCl ₃ /: 1.29 / s, 3H /; 1.59 / s., 3H /; 2.21 / s, 3H /; 2.60 / s, 3H /; 3.50 / d, 1H /; 3.89 / d, 1H /; 6.74 / s, 1H /; 7.04 / dd. 1H /; 7.10 / d, 1H /; 7.18 / s, 1H /; and 8.50 / d, 1H /.

 A. 5 'Preparation of / - / - / 3S, 4S / 4- {1a, 7b-dihydro-2,2-dimethyl-2H-oxireno / c / / 1 / benzopyran-6-yl} -2-methyl-pyridine .

 A. 5 '. a. 3-Bromo-3,4-dihydro-2,2-dimethyl-6- / 2-methylpyridin-4-yl / -2H-1-benzopyran-4-yl ester - [1R- / 1α {3R, 4S}, β] - and [1R- / 1 α {3S, 4R}, 4 β] - α-methoxybenzeneacetic acid.

A solution of the product of Example A.4 / 9,80 g /, / - / - / R / - α -metoksifeniluksusnoy acid / 5.65 g / and 4-dimethylaminopyridine / 0.45 g / in anhydrous CH ₂ Cl ₂ / 330ml / treated with N, N-dicyclohexylcarbodiimide / 6.81 g / and stirred for 90 min at room temperature. The mixture was filtered and the solvent was evaporated under reduced pressure to give a crude mixture of distereisomers, which was purified by chromatography {silica gel, 5% acetone in CH ₂ Cl ₂ } to give a polar product / A /, which was recrystallized from a mixture of acetone and pentane to give [1R - {1 α / 3R, 4S /, 4 β} -isomers of the target compound, mp 137-138 ^o C, (α) $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -75.4 ^o / c = 0.955, ethanol /; and more polar product / B /, [1R - {1 α / 3S, 4R /, 4 β} is the isomer of the target compound in the form of oil;
(α) $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -22 ^o / c = 0.975, ethanol /.

 A. 5'b. / - / - / 3S, 4S / -4- [1a, 7b-dihydro-2,2-dimethyl-2H-oxireno / c / / 1 / -benzopyran-6-yl] -2-methylpyridine.

The solution of [1R- {1 α / 3R, 4S /, 4 β} - isomer from the stage /A.5'.a/ / 3.16 g / in dioxane / 75 ml / at 20 ^o C is treated with an aqueous solution of NaOH / 45 ml 0,58M / and stirred for 10 minutes at 20 ^o C. The dioxane was evaporated under reduced pressure and the residue treated with water / 100 mL / and extracted with CH ₂ Cl _2/3 times with 100 ml /. The combined extracts were dried (sodium sulfate), filtered off and the solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography / silica gel, 5% C ₂ H ₅ OH in CH ₂ Cl ₂ / to give the desired compound in pure or essentially pure enantiomeric form in the form of a colorless oil. (α) $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -72 ^o / c = 1.125, ethanol /.

 A. 6 '. Preparation of / + / - / 3S, 4R / -4-amino-3,4-dihydro-2,2-dimethyl-6- {2-methylpyridin-4-yl} -2H-1-benzopyran-3-ol.

The solution of the product of example A.5 '/ 0.64 g / was treated with a saturated solution of ammonia in ethanol / 15 ml / and heated at 80 ^° C. in an autoclave for 15 hours. The solvent was evaporated under reduced pressure to obtain a crude product, which was purified by chromatography. / silica gel, 5% C ₂ H ₅ OH in CH ₂ Cl ₂ / to obtain the target compound as a foam: (α) $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = + 100 ^o / c = 1.00, ethanol /.

The following compounds of formula [IV], in which R ₄ is hydrogen, R ₅ is hydroxyl, R ₆ and R ₇ are each methyl and R ₁ , R ₂ and R ₈ have the indicated meanings, can be obtained analogously from the indicated starting material. All compounds listed in the table. 4 are in the form of trans racemates and, with the exception of the product of Example B6, are obtained in the form of an oil.

Physical Characteristic:
A. 6. ¹ H-NMR / δ ⁶ -DMSO /: 1.12 / s, 3H /; 1.38 / s, 3H /; 2.06 / wide, 2H /; 2.50 / s., 3H /; 3.23 / dd. 1H /; 3.59 / d, 1H /; 5.47 / d, 1H /; 6.81 / d, 1H /; 7.43 / dd. , 1H /; 7.51 / s, 1H /; 7.55 / dd. 1H /; 7.99 / m, 1H /; and 8.44 / d, 1H /;
B.6. Mp 140-141 ^o C.

C. 6. ¹ H-NMR / δ-CDCl ₃ /: 1.27 / s, 3H /; 1.54 / s, 3H /; 2.15 / s, 3H /; 2.2-2.5 / sh. s., 3H /; 2.57 / s, 3H /; 3.41 / d, 1H /; 3.71 / d, 1H /; 6.85 / d, 1H /; 6.99 / d, 1H /; 7.10 / dd., 1H /; 7.31 / dd. 1H /; and 8.31 / d, 1H /.

E. 6. ¹ H-NMR / δ-CDCl ₃ /: 1.00 / t, 3H /; 1.27 / s, 3H /; 1.55 / s., 3H /; 1.80 / s , 2H /; 2.0-2.4 (br s, 3H); 2.80 / t, 2H /; 3.41 / d, 1H /; 3.74 / d, 1H /; 6.89 / d , 1H /; 7.25-7.36 / m, 2H /; 7.47 / dd. 1H /; 87.70 / d, 1H /; and 8.51 / d, 1H /.

F. 6. ¹ H-NMR / δ-DMSO /: 0.90 / d, 6H /; 1.13 / s, 3H /; 1.41 / s., 3H /; 2.0-2.2 (br s, 2H); 2.09 / dt. 1H /; 2.65 / d, 2H /; 3.24 / dd, 1H /; 3.63 / d, 1H /; 5.45 (br s, 1H); 6.84 / d, 1H /; 7.48 / m, 2H /; 7.58 / dd. 1H /; 8.00 / d , 1H /; and 8.46 / d, 1H /.

I. 6. ¹ H-NMR / δ-CDCl ₃ /: 1.24 / s, 3H /; 1.53 / s, 3H /; 2.1-2.4 (br s, 3H); 2.20 / s, 3H /; 2.60 / s, 3H /; 3.38 / d, 1H /; 3.67 / d, 1H /; 6.73 / s, 1H /; 7.05 / d, 1H /; 7.10 / s, 1H /; 7.21 / s, 1H / and 8.49 / d, 1H /.

 Benzopyranes and dihydrobenzopyranes as defined in claim 1, for example, compounds of formula / I / and their N-oxides, and their physiologically hydrolyzable and physiologically acceptable esters as well as pharmaceutically acceptable acid addition salts and quaternary ammonium salts of these benzopyranes, dihydrobenzopyranes, N -oxides, esters [collectively referred to below as the Agents of the invention] are suitable as pharmaceuticals.

The agents of the invention have relaxing smooth muscle activity and exhibit potassium channel-opening activity against the cell membrane, as demonstrated by their effect in concentrations ranging from 1-500 nM on voltage B, and on the release of Rb ⁺ from various smooth muscle preparations in accordance or by analogy with the methods described in Quast. Brit. J. Pharmac., 91, 569-578 (1987). In this regard, the agents of the invention are characterized as opening K ⁺ channels agents.

The agents of the invention are thus suitable for the treatment of conditions or disorders for which therapy using an K ⁺ channel opening agent is indicated. The therapeutic suitability as K ⁺ channel opening agents can then be demonstrated in standard pharmacological tests, for example, cardiovascular activity, in vitro and in vivo. This effect on blood pressure can be shown on an anesthetized, normally stressed, cannulated (cannulated) rat after intraduodenal administration 1 hour after cannulation. Anti-ischemic activity can be demonstrated in accordance with the methods described by Hof et al., Circ. Res., 62, 679/1988 /. Agents of the invention exhibit hypotonic activity in a standard test method at threshold doses of about 0.03-1.0 mg / kg intraduodenally and anti-ischemic activity in the latter test method in doses of about 0.001-0.03 mg / kg intravenously.

 The agents of the invention are suitable, for example, as smooth muscle relaxants, in particular for use as vasodilating agents, for example, for the treatment of hypertension or chronic heart failure. Further, they are suitable as anti-ischemic and anti-vasospatic agents, for example, for use in the treatment of impaired blood supply, for example, in relation to the heart, skeletal muscle or brain. They are also suitable, for example, for the treatment of angina pectoris, myocardial ischemia or myocardial infarction; as antifibrillator agents; for the treatment of peripheral circulatory disorders, such as periodic limping, venous ulcer or Morbus Raynaud ulcer, as well as for the treatment of prophylaxis, cerebral ischemia, senile dementia, paralysis, subarachnoid hemorrhage and other related or logical diseases.

 The agents of the invention are also indicated for use as antispastic agents in the gastrointestinal, urinary and uterine tract, for example, for the treatment of gastric and duodenal ulcers, irritation of the colon, diverticulitis, the risk of miscarriage followed by premature birth and urinary incontinence.

 The agents of the invention are also indicated for use as hair growth promoting agents, for example, for treating hair loss due to aging, for example, bald or partially bald men, or a disease associated with hair loss, for example due to infection or an immune system disorder.

 Suitable dosages for such use may vary, for example, depending on the individual condition of the patient, the type of agent used, the route of administration and the desired effect. However, usually a sufficient daily oral dose, for example for use against hypertension, is about 0.03-2.0 mg / kg, and for example for anti-ischemic use, about 0.015-0.3 mg / kg. For large mammals, for example humans, the daily oral dose is about 2-150 mg when used against hypertension, or about 1-20 mg for anti-ischemic use, and the administration is carried out once a day or in divided doses 2 times a day. Oral dosage forms used for the indicated indications respectively contain from about 0.5 or 1.0 to about 20 or 150 mg of the agent of the invention together with a pharmaceutically acceptable diluent or carrier. For use as a hair growth promoter, the agents of the invention are suitably applied topically, for example, in the form of an appropriate cream, gel or emulsion or the like, which are known in the art.

 According to the invention, as the most important property, it was found that the agents of the invention have bronchodilator activity and reduce or alter airway hyperreactivity. These activities can also be demonstrated in a pharmaceutical test model in vivo and in vitro, for example, as follows.

 Test 1: Bronchodilator activity.

 1.1. On a guinea pig.

 Guinea pigs (Dunkin-Hartley, males weighing 400-600 g) are anesthetized with phenobarbital (100 mg / kg intraperitoneally) and pentobarbital (30 mg / kg intraperitoneally) and paralyzed with gallamine (8 mg-kg intramuscularly) and ventilated with using a mixture of air with oxygen (45:55 by volume). Animals are ventilated through a tracheal cannula (10 ml / kg, 1 Hz). The value of blood pressure and heart failure is recorded through the carotid artery. Ventilation is controlled using a flow sensor. When flow measurements are made corresponding to changes in chest pressure, the control is carried out directly through the intrathoracic trocar, allowing you to see the differential pressure related to the trachea. Each breath is calculated from this information and resistance and change.

 An intravenous infusion of bombesin (100 ng / kg / h) causes a prolonged bronchospasm. The ability of the test substance to nullify the reaction when it is administered by the intratracheal route is a measure of the effectiveness of nullifying the resulting bronchospasm. The bronchodilator effect is expressed in a quantitative decrease in the maximum response to bombesin, measured at regular intervals.

 In the specified model test, the agents of the invention are effective in canceling bronchospasm in doses of about 0.001-1.0 mg / kg.

 1.2. Rhesus monkey.

 Rhesus macaques (male and female, weighing 6.8-11.8 kg), which are known to normally respond to methacholine (MeCH), are anesthetized (first: ketamine 20 mg / kg intramuscularly; to maintain: thiopental 8 mg / kg / g intravenously ) Then inserted into the trachea, slightly striking with a hand; pediatric endotracheal tube (5.0 cm) (xylocaine: topical administration to the epiglottis) and baseline lung resistance is measured.

 After performing these manipulations, 2 ml of xylocaine (1 wt.% Solution) is introduced into the keel (carina) using a pediatric fibrooptic bronchoscope. After 10 min, pulmonary resistance was measured again. Xylocaine does not affect underlying resistance. The test substance is administered in a similar manner to xylocaine pretreatment, in the form of a suspension with lactose as an excipient (1 mg / ml; 1 ml of injection volume) cumulatively in the range of 30 minutes. At a time point of 15 minutes, one MeCH is administered (the amount of 0.6-2.5 mg / ml of the solution, calculated approximately to achieve an approximately 50-100% change in the baseline) and the% inhibition from the reaction after administration of the excipient is calculated.

 The agents of the invention have a strong, dose-dependent bronchodilator effect in the specified test method at doses of about 10 ng / kg-10 μg / kg.

 Test: 2 Suppression of airway hyperresponsiveness.

 2.1. PAF-induced hyperreactivity.

 Guinea pigs are prepared for registration of pulmonary function, as described in test 1.1. An intravenous injection of histamine (1.8-3.2 mcg / kg) makes the airways susceptible to spasmogenicity. After infusion of PAF (platelet activating factor) for more than 1 h (full dose of 600 ng / kg), repeated injection of histamine causes the development of airway hyperreactivity, which for convenience can be expressed as a pair difference between the previous response amplitude and that after exposure to PAF.

 With the introduction of the agents of the invention intratracheally, after exposure to PAF, in doses of about 0.1-100 μg / kg, the induction of airway hyperreactivity is canceled.

 2.2. Immune complex induced hyperreactivity.

 Guinea pigs are prepared for registration of pulmonary function, as described in test 1.1. An allergic reaction is caused by intravenous injection of a pre-formed immune complex (prepared by adding 30 μg of bovine gamma globulin in 0.05 ml of saline to 0.05 ml of anti-bovine gamma globulin anti-serum guinea pig) at regular (10 min) intervals within 30 minutes Intravenous histamine injections (1.0-3.2 mcg / kg at 10-minute intervals) are used to determine the sensitivity of previous airways before and after the last administration of the immune complex. Airway hyperreactivity is expressed as a paired difference in the maximum value of pulmonary resistance in response to the histamine introduced before and after repeated injection of the immune complex. Test compounds are administered intratracheally.

 Induced airway hyperreactivity is markedly reduced in the test method due to pretreatment with the agents of the invention at doses from about 10 ng / kg to about 10.0 μg / kg.

 The agents of the invention are therefore particularly suitable as bronchodilator agents and as agents for treating airway hyperreactivity, for example, as agents for symptomatic and also prophylactic treatment of obstructive or inflammatory airway disease, in particular asthma. As bronchodilating agents, the agents of the invention can be used, in particular, as an anti-disease therapy for treating an attack due to narrowing of the bronchi, for example, in asthma. Additionally, by continuous administration, the agents of the invention can be used to control, limit, or nullify airway hyperreactivity or to successfully defend against a relapse of a bronchial constriction attack due to obstructive or inflammatory airway disease, especially asthma. The terms “treatment” and “treatment” as used in the description and in the claims in relation to the use of the agents of the invention for the treatment of obstructive or inflammatory diseases of the respiratory tract, especially asthma, therefore, it is necessary to understand both prophylactic and also symptomatic (i.e. bronchodilatory) treatments if nothing else is indicated.

In accordance with the above, the invention also includes:
4. a method of treating any disease or condition described herein;
4.a. A method of treating obstructive or inflammatory disease of the respiratory tract, including:
4. a.1. a method of symptomatic treatment of obstructive or inflammatory disease of the respiratory tract, for example, by performing an expansion of the bronchi or
4. a. 2. a method for the prevention of inflammatory or obstructive airway disease, for example, for the treatment of airway hyperresponsiveness;
in the case of a subject in need of such treatment, the method comprising administering to said subject an effective amount of an agent of the invention or
alternatively:
5. an agent of the invention for pharmaceutical use, for example, for use in the treatment of any disease or condition described herein, in particular for use in the treatment of obstructive or inflammatory respiratory disease, for example, as described in paragraphs. 4.a.1 or 4.a.2, or
6. A pharmaceutical composition containing an agent of the invention, or the use of an agent of the invention for the preparation of a pharmaceutical composition used to treat any disease or condition described herein, especially for use as described in claim 5.

 Inflammatory or obstructive airway diseases to which the invention is applicable include asthma of any type or genesis, including both internal and especially external asthma. The agents of the invention are suitable for the treatment of allergic asthma, both atopic (i.e., Ig E-indirect) and non-atopic, as well as, for example, bronchial asthma induced by bacterial infection, or other types of non-allergic origin of asthma. Asthma treatment has also been studied in patients with asthma less than 4 or 5 years old, especially at night, who are diagnosed or diagnosed as "infant sniffles," as an established category of patients that attract the primary attention of doctors, and more specifically are currently identified as primary or in the early phase of asthma. (For convenience, this particular asthmatic condition is referred to as the "initial asthma syndrome").

 Prophylactic efficacy in the treatment of asthma can be proven by reducing the frequency or severity of a symptomatic attack, for example, an acute asthmatic or bronchoconstrictive attack.

Further, this effectiveness can be detected by the reduced need for another symptomatic therapy, i.e. therapy during an attack or implying a limitation or termination of a symptomatic attack when it occurs, for example, as anti-inflammatory (e.g., corticosteroid) or bronchodilator (e.g., β ₂ -adrenergic) therapy.

 The usefulness of asthma prevention in particular can be visually shown in subjects prone to "morning diving." "Morning immersion" is a known asthmatic syndrome, common in a significant number of asthmatics and characterized by an attack of asthma, for example, in parts of about 4-6, i.e. at a time usually remote from any symptomatic treatment of asthma that has been previously implemented.

 Inflammatory or obstructive airway diseases to which the invention is applicable also include pneumoconiosis (inflammatory, usually occupational, chronic or acute, lung disease, often accompanied by airway obstruction and occasionally due to repeated inhalation of dust) of any type or genesis, including for example, aluminos, anthracosis, asbestosis, chalycosis, poultry, siderosis, silicosis, tobaccoosis and in particular byssinosis.

 Further inflammatory or obstructive diseases and airway conditions to which the invention is applicable include mature respiratory distress syndrome (ARDS), chronic obstructive pulmonary or respiratory disease (COPD or COAD), and bronchitis as well as exacerbation of airway hyperreactivity due to another drug therapy, in particular another, due to inhalation of a drug, therapy, for example, as a β-agonistic bronchodilator therapy, including in particular the use of agents of the invention Nia as bronchodilators for the treatment of chronic or acute airways obstruction as well as dyspnea, associated with any of said diseases or conditions.

 For use in the treatment of inflammatory or obstructive airway disease, the agents of the invention can be administered in any conventional manner, especially enteric, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of tablets or capsules, or parenterally, for example in the form of solutions or suspensions for injection. However, they can preferably be administered by pulmonary route, for example, by inhalation from a suitable nebulizer, inhaler, or the like, known in the art.

 The doses used to treat inflammatory or obstructive airway disease vary depending, for example, on the individual condition of the subject being treated, the particular agent of the invention used, the route of administration and the desired effect.

 However, usually for pulmonary administration in the case of large mammals, for example humans, a suitable daily dose administered to the lungs should be on the order of about 0.1-100 μg, in particular 1.0-50.0 μg, with the administration being carried out respectively through one or 2-4 times a day in portions from 1 to 4 injections for each introduction.

 For oral administration, a suitable daily dose is usually on the order of about 0.1-30 μg / kg. A suitable daily oral dose in the case of large mammals, for example humans, is on the order of about 7 mcg-2.1 mg, administered as a single dose, in divided doses, which are administered 2-4 times a day or in prolonged form. Oral unit dosage forms for such use, respectively, include about 1.75 μg-2.1 mg of an agent of the invention together with a pharmaceutically acceptable diluent or carrier.

 In this regard, it should be noted in particular that the agents of the invention are usually active as bronchodilator agents or as agents for treating airway hyperresponsiveness in doses, especially inhaled doses, at which cardiovascular effects that may be undesirable in connection with such therapy, for example, hypotonic / tachycardial effect, are insignificant or are within acceptable tolerance limits with respect to the therapy being carried out.

In accordance with the foregoing, the present invention also includes:
7. A pharmaceutical composition comprising an agent of the invention together with a pharmaceutically acceptable diluent or carrier.

 Such compositions can be prepared in the usual manner, for example, for pulmonary administration, by mixing the agent of the invention in a finely divided, highly dispersed form, for example, together with finely divided lactose as a carrier / diluent to obtain an inhalable powder.

As indicated, the therapeutic dosage required to carry out the invention may vary depending on various factors. The dosage for any individual agent of the invention also depends on its relative effectiveness. For a preferred agent of the invention, namely the product of example 1, in a pure or substantially pure (3S, 4R) enantiomeric form, the ID ₅₀ established in the first demonstrated test carried out in accordance with said test 1.1 is 0.02 mg / kg intratracheal. Established by the same test method for the known, inhaled, bronchodilator drug Salbutamol [α ¹ - {/ (1,1-dimethylethyl) amino / methyl] -4-hydroxy-1,3-benzenemethanol] ID ₅₀ is 0.001 mg / kg intratracheally. Appropriate dosages of the compound of Example 1 for administration by inhalation, for example, for bronchodilating effects in the treatment of asthma, can thus be about 20 times higher than those usually required when using Salbutamol.

Claims (5)

1. 2,2-Dialkyl- or trans-2,2-dialkyl-3,4-dihydro-3-hydroxy-6- (pyridin-4-yl) -2H-1-benzopyran of the general formula I

where R ₁ and R _{2 are} independently hydrogen, C ₁ —C ₅ alkyl, C ₁ C ₅ hydroxyalkyl or C ₁ —C ₅ alkoxyalkyl, wherein at least one of R ₁ and R ₂ is other than hydrogen;
R _{3 is a} group of the formula —N (R ₉ ) —COR _{1 0} , where R _{9 is} hydrogen, R _{1 0 is} pyridyl or R ₉ and R _{1 0 are} together 1,3-butadiene, or a group of the formula - (CH ₂ ) _n - or

in which n 3 5, an integer, m 1 or 2;
R _{4 is} hydrogen;
R ₅ hydroxyl in transposition to R ₃ or R ₄ and R ₅ together represent an additional bond, as indicated by the dotted line;
R ₆ and R _{7 are} independently C ₁ -C ₅ alkyl;
R ₈ hydrogen or C ₁ C ₅ -alkyl,
or its N-oxide, or a physiologically hydrolyzable and physiologically acceptable ester of such a compound or N-oxide, or an acid addition salt, or a quaternary ammonium salt of such a compound, N-oxide or ester. 2. The compound of formula I according to claim 1, where R _{4 is} hydrogen, R ₅ is hydroxyl in transposition with respect to R ₃ , R ₆ and R _{7 are} each methyl, and A) R _{3 is a} group of the formula

and R ^{1 is} methyl, ethyl, n-propyl, isobutyl, hydroxymethyl or methoxymethyl, R ₂ and R _{8 are} each hydrogen or R ₁ and R _{8 are} each hydrogen and R _{2 is} methyl, or R ₁ and R _{8 are} each methyl and R _{2 is} hydrogen, or B) R _{3 a} group of the formula

R _{1 is} methyl, ethyl, n-propyl, isobutyl or methoxymethyl or R ₂ and R _{8 are} each hydrogen, or R ₁ and R _{2 are} each methyl and R _{8 are} hydrogen, or R ₁ and R _{8 are} each methyl and R _{2 is} hydrogen, or C) R _{3 a} group of the formula

R ₁ methyl and R ₂ and R ₈ each hydrogen, or R ₁ methyl and R ₂ hydrogen or R ₁ hydrogen and R ₂ methyl, R ₆ and R ₇ each methyl, R ₈ hydrogen, R ₄ and R ₅ together an additional bond and R ₃ group of the formula

or an N-oxide thereof, or a physiologically hydrolyzable and physiologically acceptable ester of such a compound or its N-oxide, or an acid addition salt or a quaternary ammonium salt of such a compound, an N-oxide or an ester. 3. The compound of formula I according to claim 1, where R ₁ , R ₆ and R _{7 are} each methyl, R ₂ , R ₄ and R _{8 are} each hydrogen, R ₅ is hydroxyl in a transposition to R ₃ and R _{3 is a} group of the formula

or an N-oxide thereof, or an acid addition salt of such a compound or N-oxide. 4. Trans-2,2-di- (C ₁ -C ₅ -alkyl) -3,4-dihydro-3-hydroxy-6- (pyridin-4-yl) -3H-1-benzopyran, N-oxide, ester or salt according to claim 1, where R _{4 is} hydrogen, R ₅
hydroxyl in transposition.  5. The compound according to claim 4 in the (3S, 4R) -enantiomeric form.

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