SK88994A3 - 2,2-dialkyl-2h-1-benzopyrans and 2,2-dialkyl-3,4-dihydro- -3-hydroxy-2h-1-benzopyrans - Google Patents

Abstract

2122494 9412493 PCTABS00032 2,2-Di(C1-5alkyl)- and trans-2,2-di(C1-5alkyl)-3,4-dihydro-3-hydroxy- -6-(pyridin-4-yl)-2H-1-benzopyrans, e.g. of formula (I) in which R1 and R2 = H, alkyl, hydroxyalkyl or alkoxyalkyl, at least one being other than H, R3 = typically a 2-piperidinone group, R4 = H and R5 = -OH or R4 + R5 = an additional bond, and R6, R7 are alkyl and R8 is H or alkyl, and N-oxides, esters and salts thereof, processes for their production and their uses as pharmaceuticals e.g. as K+-channel openers, bronchodilators and asthma prophylactic agents.

Description

Technical field

The present invention relates to novel 2,2-dialkyl-2H-1-benzopyranes

2,2-dialkyl-3,4-dihydro-3-hydroxy-2H-1-benzopyranes and their salts, esters and N-oxides, processes for their preparation and their use as medicaments and pharmaceutical preparations containing them .

SUMMARY OF THE INVENTION

In its broadest aspect, the present invention is based on:

1. 2,2-dialkyl-6- (pyridin-4-yl) -2H-1-benzopyranes or trans-

2,2-dialkyl-3,4-dihydro-3-hydroxy-6- (pyridin-4-yl) -2H-1-benzopyranes, wherein all alkyl groups contain 1 to 5 carbon atoms, these compounds having a carboxamide the 4-position and the pyridin-4-yl are substituted in the 2-position and / or 3 by one or two substituents selected from the group consisting of C 1 -C 5 alkyl, C 1 -C 5 hydroxyalkyl and C 1 alkoxyalkyl; up to 5 carbon atoms in the alkoxy and alkyl moieties, or N-oxides thereof, or physiologically hydrolysable and physiologically acceptable esters of these benzopyrans or N-oxides, or acid salts or quaternary ammonium salts of these benzopyrans, N-oxides or esters.

The alkyl groups or portions of the compounds defined in paragraph 1 may be branched or straight chain. Preferred meanings for the substituents at the 2-position of the benzopyran ring as well as the 2-position and / or 3-position of the pyridinyl group are given below

- 2 for the compounds of the formula I in the groups R 6 and R 8, and R 1 and R c.

As described below, the compounds of the invention, for example as defined in paragraph 1 above, have an effect on the opening of potassium (K ') channels (see, for example, Cook et al., Potassium Chanels: Structure, Classification, Function and Therapeutic Potential, ed. N.Sook, Ellis Horwood, Chichester (1990), p. 181-255]. Benzopyran derivatives which are substituted in the 4-position by a carboxamido group and which have an effect on the opening of the metal IC channel are extensively described in the literature and represent a significant and distinct class of compounds. The carboxamide moiety in the compounds of the invention may include any of these known and in the literature with respect to the opening of the K-channel metal of the described benzopyranes, including N-substituted, for example, cyclic, carboxamide moieties. Preferred carboxamide moieties with respect to the compounds of the invention are the groups of the formula -N (R 5) - COR 10 as defined below.

It will be appreciated that the benzopyran nucleus of the compounds defined in paragraph 1 may contain substituents in addition to those already defined. In particular, they may, for example, be substituted in the 7-position by an alkyl group having 1 to 5 carbon atoms, in particular in the 7-position by a methyl group, for example as mentioned for compounds of the formula I.

Preferred according to the invention are 2,2-dialkyl-3,4-dihydro-3-hydroxy-6- (pyridin-4-yl) -2H-1-benzopyranes, wherein the alkyl groups contain 1 to 5 carbon atoms, and / or their N-oxides, esters and salts as defined in paragraph 1 above. The 3-hydroxy and 4-carboxamide groups in these compounds are in the trans-configuration as described in paragraph 1. Of this group of compounds, (3S, 4R) -enantiomeric, for example racemic, mixtures are usually preferred, as discussed below. compounds of formula I.

According to an even more specific aspect, the invention is based on:

2. Compounds of formula I (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 in both the alkoxy and alkyl moieties, with at least one of R _x substituents and R; is other than a hydrogen atom,

R a is a group of the formula -N (R a) - COR _x o, where R 8 is a hydrogen atom and R 10 is a pyridyl or R ₉ and R 10 together form

Or 1,3-butadienyl or is - (CH 3) n - or

- Ch ₂ ) m

where n is an integer from 3 to 5 inclusive and m is 1 or 2,

R a is a hydrogen atom and R 5 is a hydroxy group in the trans position with respect to R _a , or

Ra and Rs together represent another bond, as indicated by the dotted line,

R 7 and R 7 are independently C 1 -C 5 alkyl, and

R _a is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or N-oxides thereof, or physiologically hydrolyzable and physiologically acceptable

I esters of these compounds or N-oxides, or acid salts or quaternary ammonium salts of these compounds, N-oxides or esters.

Alkyl groups such as R 1, R ₂ , R 6, R ₆ , R 6, R ₆ , R 6, R ₆ , R 6, and R ®, as well as the alkyl portions of hydroxyalkyl and alkoxyalkyl groups, such as R 1 and R ₂ , may be branched or straight chain. Alkoxyalkyl groups are preferably alkoxymethyl group having 1 to 4 carbon atoms in the alkoxy group, in particular methoxymethyl group. A preferred hydroxyalkyl group is a hydroxymethyl group. R © and R? both preferably represent a methyl group. R e is preferably a hydrogen atom or a methyl group, most preferably a hydrogen atom.

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

In another preferred group of compounds of formula I in R 5, R 6 is hydrogen and R 1c. pyridyl (especially 3-pyridyl) or R 1 and R 10 together form a 1,3-butadienylene group, a trimethylene group or a tetramethylene group. Most preferably, R 8 and R 10 together form a tetramethylene group.

Preferably R 1 is hydrogen and R 5 is hydroxy.

The benzopyranes of the invention, for example the compounds of formula I, form N-oxides, for example at the nitrogen atom of the 6-pyridinyl group. These N-oxides have comparable efficacy (as described below) and compatibility with the parent compounds and also form part of the present invention.

The term physiologically hydrolyzable and physiologically acceptable ester means an ester whose hydroxy group (for example, in formula I of the hydroxy group R 4 and / or the hydroxyl portion of any hydroxyalkyl group such as R 1 and / or R 1) is esterified and which is hydrolyzable under physiological conditions to produce an acid which is physiologically tolerable in its doses to be administered. It will be appreciated that these esters are a pro-drug of the conventional type and that they have comparable efficacy and tolerability to the parent compounds. Examples of such esters are, for example, acetates.

Acid salts of, for example, the compounds of formula I, their N-oxides and their defined esters include salts with both inorganic and organic acids. These salts also have comparable efficacy to the free compounds, N-oxides and esters. Pharmaceutically acceptable acid addition salts for pharmaceutical use of the present invention as described herein include, for example, salts with hydrochloric acid, sulfuric acid, and fumaric acid.

Quaternary ammonium salts of, for example, the compounds of formula I, their N-oxides and their defined esters include, for example, salts with organohalides, for example alkyl halides. The pharmaceutically acceptable quaternary ammonium salts for pharmaceutical use of the present invention as described herein include, for example, such salts with methyl iodide.

For the pharmaceutical use of the present invention, the above ester forms are usually less preferred.

The compounds of formula I in which R6 is a hydrogen atom and R5 is a hydroxy group, as well as their N-oxides, esters and salts as described above, have the (3S, 4R *) configuration, i. the configuration of Ra and Rs at positions 3 and 4 is trans. Thus, the compounds of the invention exist in enantiomeric form, i. as optically active antipodes having the (3S, 4R) or (3R, 4S) configuration. Of course, the present invention encompasses both the individual enantiomers (optically active, (3S, 4R) or (3R, 4S), antipodes), as well as mixtures thereof, for example racemic mixtures.

In the pharmaceutical use of the composition of the invention, the use of the (3S, 4R) enantiomers is preferred or predominantly envisaged, which are preferred. Suitably, the (3S, 4R) enantiomers of the present invention are used in pure form, i. that they contain less than 50% enantiomeric impurities, more preferably they can be used in pure or substantially pure form, for example that they contain less than 10%, preferably 5% or less, for example 1 or 2% or less of (3S, 4S) enantiomeric impurities.

The present invention further provides:

3. A process for the preparation of the benzopyranes as defined in paragraph 1 above, for example the compounds of formula I as defined in paragraph 2 above, or the N-oxides thereof, or the physiologically hydrolyzable and physiologically acceptable esters of these benzopyrans or N-oxides, or salts. with acids or quaternary ammonium salts of these benzopyrans, N-oxides or esters, which consists in

i) for the preparation of a benzopyran as aforesaid ^x) reacting a la, 7b-dihydro-2,2-dialkyl-6- (pyridin-4-y1) -2-oxireno / C // 1 / benzopyran, wherein the alkyl groups have 1 to And wherein the pyridinyl-4-yl group is substituted in the 2- and / or 3-position by one or two substituents selected from the group consisting of alkyl having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 5 carbon atoms and alkoxyalkyl having 1 to 5 carbon atoms. 1 to 5 carbon atoms in the alkoxy and alkyl moieties, for example a compound of formula II

(II) where Ri, Ra, Re-, R? and R _e have the meanings given for formula I above, with an alkali metal salt of a carboxamide group, for example a compound of formula III

R 10 -CO-N ° -R ₉ M ® (III) wherein R 5 and R 10 have the meanings given for formula I above and M 'is a lithium, sodium or potassium ion, or ² ) is acylated and, if necessary, alkylated amino 2,2-dialkyl-4-amino-6- (pyridin-4-yl) -2H-1-benzopyran or trans-2,2-dialkyl-3,4-dihydro-3-hydroxy-4-amino-6 (pyridin-4-yl) -2H-1-benzopyran, wherein the alkyl groups have 1 to 5 carbon atoms and wherein the pyridin-4-yl group is substituted in the 2- and / or 3-position by one or two substituents selected from the group consisting of (C 1 -C 5) alkyl, (C 1 -C 5) hydroxyalkyl and (C 1 -C 5) alkoxyalkyl in the alkoxy and alkyl moieties, for example, reacting a compound of formula (IV)

(IV) wherein Rx, Ra and R-> to Re have the meanings given for formula I, with a compound of formula V, V 'or V' '

R'io-CO-X ¹ (V)

(V) wherein R'io is a pyridyl group, and X, ^X and X ² are leaving groups, ii) the preparation of a benzopyran N-oxide or physiologically-hydrolysable and physiologically acceptable esters of the above benzopyran or benzopyran N-oxide is esterified benzopyran or benzopyran An N-oxide as defined in paragraph 1 above having a free hydroxy group or a hydroxyl moiety to introduce the corresponding ester group, for example reacting a compound of formula I as defined above, wherein R 5 is hydroxy and / or at least one of R 1 and R ₂ are hydroxyalkyl of 1 to 5 carbon atoms, or N 2 d d thereof, with an appropriate acid halide or acid anhydride, and / or oxidized benzopyran or a physiologically hydrolyzable and physiologically acceptable ester thereof as defined in paragraph 1 above, for example, oxidizing a compound of formula I as defined above, or o its physiologically hydrolyzable and physiologically acceptable ester, and the obtained benzopyran, benzopyran N-oxide or a physiologically hydrolyzable and physiologically acceptable ester thereof is isolated in the free form or in the form of an acid salt or in the form of a quaternary ammonium salt.

Process ( ¹ ) may be carried out by known methods, for example, the reaction may be carried out at room temperature to boiling point in the presence of an inert solvent or diluent such as tetrahydrofuran or dimethylsulfoxide. Suitably, the desired compound of formula (III) is prepared in advance herein, for example as described in Examples 1 to 11 and 21 below. Using the appropriate, e.g. sodium salts, the benzopyrans and dihydrobenzopyrans of the invention are obtained, for example as described in Examples 11 and 12 below. By using lithium salts, the dihydrobenzopyrans of the invention as described in Examples 1 to 10 below are obtained particularly or exclusively.

Process ( ² ) can also be carried out by known methods. A suitable leaving group X 1 - is halogen or an activated ester group and a suitable leaving group X ² is halogen. The reaction is conveniently carried out at temperatures from 0 ° C to 100 ° C in an inert solvent or diluent such as acetonitrile or dichloromethane, preferably in the presence of an acid binding agent, for example in trialkylamine or in an alkali metal carbonate. This procedure is described in Examples 13-20 below.

Process ii) may be carried out by conventional acylation / N-oxidation procedures, for example to obtain N-oxides by reaction with hydrogen peroxide, m-chloroperbenzoic acid or Collin reagent (CrOa.Pyz) as further described in Example 23.

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

Using the racemates of the compounds of formula II and IV, the 4-carboxamido-3,4-dihydro-3-hydroxybenzopyranes are obtained in the form of the trans-racemate (i.e. containing (3S, 4R) plus (3R, 4S) isomers. The racemates obtained can be separated into the individual enantiomers, i. (3R, 4S) or (preferred) (3S, 4R) enantiomer, for example, by chromatography using a chiral stationary phase. If the individual (3S, 4R) enantiomers are to be prepared, then it is preferable to use the corresponding isomers as the starting compounds, i. for a compound of formula II a 3S-4S-antipode and for a compound of formula IV a 3S, 4R-antipode. These can be suitably prepared as described below in Reaction Scheme A.

It will be appreciated that variants or alternatives of the above-described procedures known in the art may be used, for example, to interconvert the initially obtained compounds or to introduce alternative carboxyamide groups at the 4-position. Unstable groups may be protected, for example during acylation procedures, using conventional protecting groups, for example hydroxy protecting groups. Furthermore, if desired, the originally obtained benzopyrans can be converted to the corresponding other benzopyrans by dehydration of the 3,4-bond, again by known methods. Other possible alternatives are apparent to those skilled in the art.

Compounds of formula II can be prepared according to the following general reaction scheme A

(VII)

(VIII) partition of antipodes (II)

Steps (iii) to (vi) can be carried out by conventional methods, for example according to the general procedures described in Examples 24-4, A.5, A.5'a, and A.5'b below.

The starting compounds of formula IV can be prepared from the corresponding compounds of formula II by reaction with ammonia, for example according to the general procedures described in Example 24.A.6 'below.

By carrying out steps (m) and (iv), a compound of formula II is obtained as the cis-racemate, i. comprising (3R, 4R) and (3S, 4S) antipodes. of the corresponding chiral acyl (R) -alpha-methoxyphenylacetyl of formula VIII can be

Step (v) involves introducing a group (in Scheme A, for example, a group). The chiral racemate can be easily separated by column chromatography or fractional recrystallization into its individual (3R, 4S) and (3S, 4R) antipodes. Using the (3R, 4S) antipode and carrying out step (vi), the starting compound of formula II is obtained in pure or substantially pure (3S, 4S) enantiomeric form.

Compounds of formula VI can be prepared according to the following general reaction scheme B

(XI) wherein X '' is a leaving group, suitably a halogen atom, for example a chlorine atom. Steps (vii) to (ix) can be carried out by conventional methods, for example according to the general procedures described in Examples 24.A.2 and A.3 below, steps (viii) and (ix) can be carried out according to Example 24.A.3 without purification of the intermediate. As in Example 24.A.2, step (vii) is conveniently performed in an aprotic solvent such as acetone in the presence of a base such as K 2 CO 3 and in the presence of a catalyst such as KI.

Compounds of formula IX can be prepared by a variety of methods, for example as shown in the following general reaction scheme C

Steps (x) and (xi) and steps (xii) let (xiv) can be carried out by conventional methods, for example according to the general procedures described in Examples 24.A.la and b and 24.A.la 'ab' in general. and (xi) preferred for larger scale synthesis.

If it is desired to prepare compounds of the invention in which Ra and / or R8 are hydroxyalkyl or alkoxyalkyl groups, this can be achieved by converting the alkyl substituents in R1 / R-. Similarly, methyl groups such as R 1 / R 2 · are given. if desired, convert to higher alkyl groups. Suitably, these conversion reactions can be carried out in the synthesis step of a compound of formula VI using conventional methods, for example according to the general procedures described below in Examples 24.E.3, F.3, G.3a + G.3b and H.3. and + H.3.b

Compounds of formula VI in which R e is other than hydrogen are more conveniently prepared according to the following Reaction Scheme D

(XVII) (XVIII) R ₆ -CO-R ₇

(XXII) (VI)

Although Hal is a halogen atom, for example bromine, and R e is an alkyl group of 1 to 5 carbon atoms. Steps (xv) to (xxi) can be carried out by conventional methods, for example according to the general procedures described in Example 24.1 below.

The intermediates described above and in the following examples, in particular the intermediates of formulas II, IV and VI to VIII, are novel. These intermediates, in particular the intermediates of formulas II and IV, and processes for their preparation also form part of the present invention.

The following examples illustrate the processes of the present invention. All NMR spectra are measured at 360 MHz. All temperatures are in degrees Celsius and are not corrected.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of (-) - (3S, 4R) -1- / 3,4-dihydro-2,2-dimethyl-3-hydroxy-6- (2-methylpyridin-4-yl) -2H-1-benzopyran-4- (R) -2-piperidinone / formula I: R 1 = Re = R 2? = CH 3, R = R 3 = R a = H, R 3 = OH,

R ₃

pure or substantially pure (3S, 4R) enantiomer],

A stirred solution of 2-piperidinone (19.8 g) in anhydrous tetrahydrofuran (400 mL) at 10 was treated with a solution of lithium bis (trimethylsilyl) amide (200 mL / 1.0 M) under argon. in tetrahydrofuran and the reaction mixture was stirred at room temperature for 2 hours. The resulting suspension is stirred with a solution of (-) - (3S, 4S) -4- (1α, 7b-dihydro-2,2-dimethyl-2H-oxireno [c] 1-benzopyran-6-yl) -2 methylpyridine (26.7 g, see Example 24.5 'below) in anhydrous tetrahydrofuran (150 ml) and heated to boiling for 31 hours. Then the mixture was cooled to 15 ° C, treated with saturated aqueous NH 4 Cl (300 mL) and extracted with ethyl acetate (2 x 150 mL). The combined extracts were washed with brine (300 mL), dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure to give a crude product which was purified by chromatography (silica gel, 5% C 4 H 5 OH in CH 2 Cl 2) and recrystallized from a mixture of C 1 H 5 OH and pentane to give the title compound, mp 192 ^° C, [α] ²⁰ D = -83.2 ° (c = 1.06)

C-HsOH). MP hemimaleinátovej salt thereof is 146 to 148 ^{-7 C.}

The following compounds of formula Ia are prepared analogously

the preparation of the desired oxirene starting material is described in the example in the right column of the following table.

All compounds listed in the following table are in the form of trans-racemate.

example ri ra re mp ° C starting compound by of Example 24 2 CH H H 184-185 A. 5 3 H CH H 205-206 D. 5 4 C2H5 H H 196-197 (B) 5 5 HO-CH H H 200-201 G. 5 6 CH 3 O-CH 2 H H 182-183 H 5 7 NCAHE-out H H 178-179 E. 5 8 IC Hs. H H 210-211 F. 5 9 CH CH H 201-202 C. 5 10 CH . H CH 3 219-221 b. 5

Example 11

Preparation of 1- (2,2-dimethyl-6- (2-methylpyridin-4-yl) -2H-1-benzopyran-4-yl) -2-piperidinone / Formula I: R 1 = Re = R 2? = CH ₃ , R 2 = R 5 = H, R 5 + R 5 = other

A stirred solution of 2-piperidinone (0.90 g ·) in anhydrous dimethylsulfoxide (20 mL) was stirred with NaH (0.48 g of a 55% dispersion in oil) and stirred at 50 ° C for 30 minutes under an argon atmosphere. The mixture was then cooled to 10 ° C and treated with a solution of (+) - 4- (1α, 7b-dihydro-2,2-dimethyl-2H-oxireno [c] 1 benzopyran-6-yl). ) -2-methylpyridine (2.67 g, see Example 24.A.5) and the mixture was stirred at room temperature for 14 hours under an argon atmosphere. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NH 4 Cl (200 mL) and extracted with CH 2 Cl 2 (3 x 100 mL). The combined extracts were dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure to give a mixture. This was separated by chromatography (silica gel, 2% CaH 5 OH in CH 2 Cl 2) to give the less polar product (A) which was recrystallized from ethyl ether-pentane to give the title compound and more of the polar compound (B) from which recrystallized from a mixture of CH 2 Cl 2 and diethyl ether to give the same product as in Example 2 above. The melting point for the title compound is 95-98 ° C.

Example 12

Preparation of 1- (2,2-dimethyl-6- (3-methylpyridin-4-yl) -2H-1-benzopyran-4-yl) -2-piperidinone / Formula I:

bond

from the product according to

Starting below and proceeding analogously to give the compound of Example 3 above, the title nin is Example 24.D.5. according to Example 11 above, in the title together with the product characteristics for compounds physically following:

^X H-NMR (.delta · d 'DMSO):

(m, 3H)

2.26

5.83 (s, (s, 3H));

6.92 (d,

1.41 (s, 3H), 1.45

2.27-2.68 (m, 3H);

1H), 7.14-7.20 (m,

8.39 (d,

1H) a

8.45 (s, (s, 3H), 1.77-1.96)

3.37-3.58 (m, 2 H),

2H), 7.36 (m, IH),

Example 13

Preparation of (+) - (3S, 4R) - [3,4-Dihydro-2,2-dimethyl-3-hydroxy-6- (2-methylpyridin-4-yl) -2H-1-benzopyran] -3-piperidinecarboxamide / Formula I: R 1 ⁼ R 2 = R 2? - CHs, R ?. - R <= Re - H,

pure or substantially pure (3S, 4R) enantiomer].

Mixed grew ·. (+) - (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 CH-Cln (30 mL) were treated at 2 ° C under an argon atmosphere. nicotinyl chloride hydrochloride (0.445 g). The reaction mixture was stirred at room temperature for 2 hours, then treated with aqueous Na 2 CO 3 (100 mL / 2 M) and extracted with 3: 1 CH-Cl 1 / CH 3 OH (3 x 100 mL).

The combined extracts were washed with brine, dried (Na-SO-a), filtered and the solvent was evaporated under reduced pressure to give an oil. This oil is purified by chromatography (silica gel, 2% CdisOH in CHCl 3) and recrystallized with a mixture of C-Tk.OH and diethyl ether to give the title compound in enantiomerically pure or substantially pure form, m.p. 247-248 °. C, / alpha / ⁰ = +19.8

D (c = 0.965, C 2 H & OH).

The following compounds of formula (Ib) are prepared analogously

(Ib) wherein the preparation of the desired starting 4-aminobenzopyran-3-ol is carried out according to the example in the right column in the following table.

híLíÍ itf & manage · '4imí'

All compounds listed in this table are in the form of the trans-racemate.

example ra R.-. re mp C the starting compound of Example 24 14 CH H H 230-231 A. 6 15 C2H5 H H 192-193 B. 6 16 CHaOCHo H H 206-208 H. 6 17 n C ₃ H 7 / H H 206-207 E. 6 18 i C 4 H H H 240-241 F. 6 19 CH CH H 239-241 C. 6 • 20 CH H CH 234-236 I. 6

Example 21

Preparation of trans - (+) - 1- [3,4-dihydro-2,2-dimethyl-3-hydroxy-6- (2-methylpyridin-4-yl) -2H-1-benzopyran-4-yl] -2 (1H) -pyrimidine

as a trans racemate.

A stirred solution of 2-hydroxypyridine (0.42 g) in anhydrous CH 2 OH (20 mL) was treated with NaOH (0.21 g 55% dispersion in oil) and the reaction mixture was stirred at room temperature for 15 minutes under argon. The mixture was then cooled to 2 ° C and a solution of (±) -4- (1α, 7b-dihydro-2,2-dimethyl-2H-oxireno [c] 1-benzopyran-6-yl) -2-methylpyridide was added. tin (1.07 g, see Example 24.A.5) and stirred at room temperature for 96 hours. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NH 4 Cl (100 mL) and extracted with CH 3 Cl 2 (3.times.100 mL). The combined extracts were dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure to give a crude product which was purified by chromatography (silica gel, 2% C 11 H 5 OH and CH 2 Cl 2) and recrystallized from a mixture of C 2 H 5 OH and diethyl ether. . The title compound is obtained, m.p. 213-214 ° C.

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? ⁼ CH? , R? ⁼ R <1 = R e = H,

R = ₃ / Tx / trans racemate as X /.

To a stirred solution of (±) -4-amino-3,4-dihydro-2,2-dimethyl-16- (2-methylpyridin-4-yl) -2H-1-benzopyran-3-ol (2.84 g, cf. Example 24.A.6) and 2-bromomethylbenzoic acid methyl ester (2.30 g) in anhydrous acetonitrile (100 mL) under a nitrogen atmosphere were added KI (0.84 g) followed by K = CO ₃ (4.20 g) . The reaction mixture was stirred at 20 ° C for 1 hour, at 60 ° C for 1 hour and then at 85 ° C for 15 hours. The solvent was evaporated under reduced pressure and the residue was treated with HnO (300 mL) and extracted with 2% CH 3 OH in CH 2 Cl 2 (4 x 150 mL). The combined extracts were washed with sodium thiosulfate solution (100 mL / 2%), dried (Na-SCU) and filtered. The solvent was evaporated under reduced pressure to give a crude product which was purified by chromatography (silica gel, 5 'C 1 H 5 OH in CH 2 Cl 2) and recrystallized from a mixture of C-H 5 OH and acetone. The title compound is obtained, m.p. 222-224 ° C.

Example 23

Preparation of (-) - (3S, 4R) -4- / 3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxopiperidin-1-yl) -2H-1-benzopyran-6 -? 1 / -2-methylpyridine-N21 oxide.

A solution of the product of Example 1 (2.6 g) in CH-Cl- (40 mL) was treated with 3-chloroperoxybenzoic acid (1.92 g, 90%) and stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure to give 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 acetone and diethyl ether. The title compound is obtained, m.p. 202-205 ° C.

Example 24

Preparation of the starting compounds for Examples 1 to 23

A.I. Preparation of 4- (4-methoxyphenyl) -2-methylpyridine

A.l.a. 4- (4-Methoxyphenyl) -2-methyl-1- (4H) -pyridine-carboxylic acid ethyl ester

To a stirred mixture of 2-picoline (9.30 g) and copper (I) iodide (0.77 g) in anhydrous tetrahydrofuran (150 mL) was added ethyl chloroformate (10.85 g) at -20 ° C under argon. The mixture is stirred at -20 ° C for 3 hours and then a solution of 4-methoxyphenylmagnesium bromide prepared from

Of 4-bromoanisole (18.7 g) and magnesium chips (2.64 g), in anhydrous tetrahydrofuran (100 mL) at such a rate that the temperature remains between -15 ° C and -20 ° C. The reaction mixture was stirred at -15- ° C for 1 hour and then added saturated, extracted with ethyl acetate (dried four times (Na-SCU), filtered under reduced pressure to give chromatography (silica gel, 50%, at 20 ° C). ° C for 16 aqueous NH? Cl solution (300 mL) and

200 ml). The combined extracts and solvent were evaporated to give the crude product. This was purified by toluene in hexane) to give the title compound as a pale yellow oil.

And. B.

4- (4-methoxyphenyl) -2-methylpyridine

The product of step A.l.a. (16.9 g) and sulfur (2.0 g) in decahydronaphthalene (100 mL) were stirred at 200 ° C for 3 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (500 mL) and extracted with HCl (3 x 200 mL 2 M). The combined extracts were washed with ethyl acetate (2 x 100 mL), basified with NaOH to pH 11 under ice-cooling, and extracted with CH-Cl- (3 x 200 mL). The combined extracts were dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure to give the crude product. This was purified by chromatography (silica gel, 2% CH3OH / CH-Cl) and recrystallized from CH3OH / ethyl acetate. The title compound is obtained, m.p. 88-91 ° C.

Alternatively, the title compound can be prepared as follows:

A.l.a '2,2', 6'-trimethyl-4-oxo-1,1 (4 Ή) bipyridinium tetrafluoroborate

To a freshly prepared solution of hydroxylamine-O-sulfonic acid (45.2 g, 90%) in H-O (260 mL) at 0 ° C was added 2-methylpyridine (111.7 g). The mixture was heated to 95 ° C, stirred further for 45 minutes, cooled to 10 ° C, and carefully treated with K-COa (55 g). The mixture was washed with diethyl ether (2 x 100 mL) and the water was evaporated at 40 ° C under reduced pressure. CaH 5 OH (600 mL) was added to the residue and the precipitated K 2 SO 4 was removed by filtration. The filtrate was treated with HCl (120 mL of 18 M) and evaporated to dryness under reduced pressure at 50 ° C to give a residue to which was added dehydroacetic acid (68.6 g) and HCl (150 mL of 18 M) and heat to reflux for 90 minutes. The solution was evaporated to dryness under reduced pressure at 50 ° C and the residue was stirred with CaHsOH (200 mL) for 15 minutes, filtered and the precipitate washed with CalIsOH (200 mL). The combined filtrates and washings ... were treated with tetrafluoroboric acid in ethyl ether (50 mL, 50%) and diluted with diethyl ether (250 mL). On standing, the title compound crystallizes, is filtered off and dried under reduced pressure at 20 ° C, m.p. 206-208 ^° C.

A.1.b '4- (4-methoxyphenyl) -2-methylpyridine

To a stirred solution of 4-methoxyphenylmagnesium bromide, prepared from 4-bromoanisole (56.1 g) and cucurbitol (7.92 g), in anhydrous tetrahydrofuran (400 mL) at 0-5 ° C was added Ala '( 30.2 g) under an argon atmosphere. The mixture was stirred at room temperature for 48 hours, washed with saturated NH 3 Cl (300 mL), and the aqueous phase was extracted with CH-Cl- (w × 100 mL). The combined tetrahydrofuran solution and CH 2 Cl 2 extracts were dried (Na = SO 4), filtered and the solvent was evaporated under reduced pressure to give 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 heated to reflux for 4 hours. The solvent was evaporated under reduced pressure to give a residue which was purified by chromatography (silica gel, 2% C-HsOH in ChaCla) and recrystallized from C-1 HsOH to give the title compound, mp 88-91 ° C. .

A.2. Preparation of 4- (4-hydroxyphenyl) -2-methylpyridine

Product solution according to Example A.l. (6.45 g) in HBr (100 mL, 48 µL) was heated at 135 ° C for 3 hours. Excess Hbr was evaporated under reduced pressure to give a residue which was neutralized with aqueous NaHCO 3 and extracted from 3: 1 CH 2 Cl 2 / CH 2 OH (3 x 150 mL). The combined extracts were dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure to give the crude product. This was recrystallized from a mixture of C 1 H 5 OH and diethyl ether to give the title compound, mp 203-204 ° C.

Preparation of 2,2-dimethyl-6- (2-methylpyridin-4-yl) -2H-1-benzopyran

Mixed product mixture according to Example A.2. (4.07 g), anhydrous K 2 CO 3 (6.9 g) and KI (1.0 g) in anhydrous acetone (75 mL) were treated with 3-chloro-3-methylbutin (5.65) under an argon atmosphere. g) and heated to reflux for 120 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to give crude 4- [4- (1,1-dimethyl-2-propynyl) oxyphenyl] -2-methylpyridine. This was dissolved in 1,2-dichlorobenzene (50 mL) and heated at 170 ° C for 1 hour. The solvent was evaporated under reduced pressure to give the crude title compound which was purified by chromatography (silica gel, 2 'C-H 5 OH in CHCl 3 -). The title compound is obtained, m.p. 37-40 ° C.

Analogously to Examples A.1 to A.3 above, the following compounds were prepared, either by performing steps (A.l.a) + (A.l.b) or steps (A.l.a ') and (A.l.b'). All compounds obtained are oils.

B. 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,

D. 3. 2,2-Dimethyl-6- (3-methylpyridin-4-yl) -2H-1-benzopyran.

• E.3. Preparation of 2,2-dimethyl-6- (2-propylpyridin-4-yl) -2H-1-benzopyran

To the stirred solution of the product of Example A.3. (5.02 g) in anhydrous tetrahydrofuran (50 mL) was added a solution of n-butyllithium (12.5 mL, 1.6 M) in hexane at -25 ° C under argon. The resulting mixture was stirred at 10 ° C for 40 minutes, cooled to -5 ° C and ethyl iodide (2.4 mL) was added. The reaction mixture was allowed to warm to room temperature, stirred for an additional 2 hours, and then saturated aqueous NH 4 Cl (100 mL) was added and extracted with ethyl acetate (2 x 100 mL). The combined extracts were dried (Na ₂ SO 4), filtered and the solvent was evaporated under reduced pressure to give the crude product which was purified by chromatography (silica gel, 10¾ acetone in hexane).

n ^c >

The title compound is obtained as an oil.

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

The title compound was prepared analogously to Example E.3. using isopropyl iodide instead of ethyl iodide to give the compound as an oil.

G. 3. Preparation of 2,2-dimethyl-6- (2-hydroxymethylpyridin-4-yl) -2H-

1-benzopyránacetátu

G.3.a 4- (2,2-Dimethyl-2H-1-benzopyran-6-yl) -2-methylpyridine-Noxi d

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

G. 3.b (2,2-Dimethyl-6- (2-hydroxymethylpyridin-4-yl) -2H-1-benzopyranoacetate)

A mixture of step G.3.a (4.8 g) and acetic anhydride (50 ml) was heated at 80 ^° C under argon for 1 hour. The solvent was evaporated under reduced pressure to give a crude product which was purified by chromatography (silica gel, 10% ethyl acetate in toluene). The title compound is obtained as an oil.

H. 3. Preparation of 2,2-dimethyl-6- (2-methoxymethylpyridin-4-yl) -2H-

1-benzopyran

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

You know the product according to Example G.3. (69.5 g), Na ₂ CO ₃ (95.4 g), HaO (160 mL) and C.-HsOH (600 mL) were stirred at room temperature for 22 hours. Then the mixture was filtered and the filtrate was evaporated to dryness under reduced pressure and the residue was treated with HaO (400 mL) and extracted with CH 2 Cl 2 (3 × 150 mL). The combined extracts were dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure to give the crude product. This was purified by chromatography (silica gel, ethyl acetate) and recrystallized from pentane to give the title compound, mp 86-88 ° C.

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

To a stirred solution of the product of Step H.3.a (8.0 g) in anhydrous tetrahydrofuran (150 mL) under argon at 15 ° C was added NaH (0.90 g, 80¾ dispersion in oil) and the reaction mixture was stirred at room temperature. Stir at room temperature for 45 minutes. Methyl iodide (4.26 g) was then added and the mixture was stirred at room temperature for 18 hours. Saturated aqueous NH 4 Cl (200 mL) was then added and the mixture was extracted with ethyl acetate (2 x 200 mL). The combined extracts were dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure to give the crude product. This was purified by chromatography (silica gel, 20¾ acetone in hexane). The title compound is obtained as an oil.

I. Preparation of 6- (2-methylpyridin-4-yl) -2,2,7-trimethyl-2H-1-benzopyran

a. 4-bromo-3-metylfenolacetát

To a stirred mixture of 4-bromo-3-methylphenol (184.1 g) and aqueous

NaOH (850 mL, 2 M) was added acetic anhydride (136 mL) at 20 ° C and the mixture was stirred at room temperature for 1 hour. The suspension was extracted with diethyl ether (3 x 300 mL) and the combined extracts were washed with aqueous NaOH (2 x 100 mL, 2 M), dried (Na 2 SO 4) and filtered. The solvent was evaporated under reduced pressure to give the title compound as an oil.

b. l- (3-bromo-2-hydroxy-5-methylphenyl) ethanone

The mixture (152.6 g) minutes.

The product from step a (195.6 g) was stirred under argon at rt

The cooled mixture was a much spracuj aluminum chloride at 165 C for ^rj ice-cold HC1 (2000 ml, the extracts (Na 2 So <),

CH 4 L · (4 x 600 mL). Combined sodium, dried and the solvent was evaporated under reduced crude product. This was purified by chromatography (10% toluene in hexane) and recrystallized to give the title compound in a chloride solution.

M) and extracted, washed with filtered, and obtained by refining (silica gel, diethyl ether / hexane).

melting point 81-82 ° C.

/

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

A mixture of the product of step 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 heated to reflux while water formed. is removed using a Dean-Stark device. To the cooled mixture was added HCl (200 mL, 2 M), stirred for 10 minutes, basified with aqueous NaOH (1 M), and extracted with CH 2 Cl 2 (3 x 300 mL). The combined extracts were dried (K 2 CO 3), filtered and the solvent was evaporated under reduced pressure to give the crude product. This was purified by chromatography (silica gel, 50% toluene in hexane) and recrystallized from diethyl ether-pentane. The title compound is obtained, m.p. 95-96 ° C.

d. ' 6-bromo-3,4-dihydro-4-hydroxy-2,2,7-trimethyl-2H-benzopyran

To a stirred solution of the product of step c (26.9 g) in CH 3 OH (200 mL) at 5 ^° C was added sodium borohydride (1.95 g) and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and H 2 O (500 mL) was added to the resulting residue and extracted with diethyl ether (3 x 200 mL). The combined extracts were dried (Na 2 SO ₄ ), filtered and the solvent was evaporated under reduced pressure to give the crude product. This product was purified by chromatography (silica gel, 10% acetone in hexane) and recrystallized from diethyl ether / pentane. The title compound is obtained, m.p. 92-93 ^° C.

e. 6-bromo-2,2,7-trimety1-2H-1-benzopyran

To a stirred solution of the product of step d (27.1 g) in anhydrous toluene (300 mL) was added p-toluenesulfonic acid (1.15 g) and the mixture was heated at reflux for 2 hours while the resulting water was removed. with Dean-Stark's extension. The cooled solution was washed with aqueous sodium carbonate solution (100 mL, 2 M), dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure to give the crude product. This was purified by chromatography (silica gel, hexane) to give the title compound as an oil.

f. 6- (2-methylpyridin-4-yl) -2,2,7-trimety1-2H-1-benzopyran

A solution of the product of step e (7.60 g) in anhydrous tetrahydrofuran (30 ml) was added over 15 minutes to a stirred mixture of magnesium trichlorides (0.85 g) and iodine (0.06 g) in anhydrous tetrahydrofuran (25 ml). ml) under argon at 45 ° C.

The mixture was heated at reflux for 3 hours, then cooled to 5 ° C, bis- (three-phenylphosphine) nickel (II) chloride (0.32 g) and a solution of 4-bromopicolin (4, 8 g) in anhydrous tetrahydrofuran (50 mL) and the mixture was stirred at room temperature for 18 hours. HCl (140 mL, 1 M) was added to the mixture and extracted with diethyl ether (2 x 60 mL). The combined ether extracts were washed with HCl. The combined acidic solutions were basified to pH 10 with K 2 CO 3, extracted with diethyl ether (3 x 100 mL), dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure to give the crude product. This was purified by chromatography (silica gel, 10% acetone in hexane). The title compound is obtained in the form of an oil having the following physical characteristics:

1 H-NMR (δ-COCls): 1.44 (s, 6H), 2.21 (s, 3H), 2.59 (s, 3H), 5.60 (d, 1H), 6.31 (s) 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

To the stirred product solution according to Example prí.3. (2.50 g) in dimethylsulfoxide (6 mL) and H 2 O (0.36 mL) at 0 ° C were added portionwise n-bromosuccinimide (2.20 g). After the exothermic reaction was complete, stirring was continued for an additional hour and saturated aqueous NH 4 Cl (200 mL) was added to the reaction mixture, followed by extraction with CH 2 Cl 2 (3 x 100 mL). The combined extracts were dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure to give the crude product. This was purified by chromatography (silica gel, 2% C-HsOH in CH 2 Cl 2) and recrystallized from a mixture of C 1 H 5 OH and diethyl ether to give the title compound, mp 212-214 ° C.

A.5. Preparation of (±) -4- (1α, 7b-Dihydro-2,2-dimethyl-2H-oxireno [c] 1-benzopyran-6-yl) -2-methylpyridine

To the product solution of Example A.4. (3.5 g) in anhydrous tetrahydrofuran (80 mL) was added NaOH (0.90 g -5% dispersion in oil) and the reaction mixture was stirred under argon at room temperature for 1 hour. Saturated aqueous NH 4 Cl solution (150 mL) was then added and extracted with diethyl ether (3 x 100 mL). The combined extracts were dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure to give a residue which was purified by chromatography (silica gel, 2% C 1 H 5 OH in CH 2 Cl 2). The title compound is obtained in the form of an oil having the following physical characteristics:

@ 1 H-NMR (.delta.) -d ^e DMSO): 1, 24 (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, 1 H), 7.56 (s, 1 H), 7.19 (dd, 1H) , 7.96 (d, 1H) and 8.47 (d, 1H).

Analogously to the above Examples A4 and A5, but carrying out the reaction in a single vessel, the following compounds of formula II can be prepared in which R @ 1 and R @ 2. are each methyl and R1, R.-, and R6 have the meanings listed in the following table. This reaction is carried out by diluting the mixture obtained after the exothermic reaction and stirring the mixture according to Example A.4 with dioxane, adding aqueous NaOH (0.6 M) and stirring at room temperature for a further about 1 hour. Purification is then carried out analogously to Example A.5 after evaporation of dioxane. The starting compounds are shown in column 2 of the table. All products are obtained as (±) -acetates as an oil.

example the starting compound of the example ri R re L5 B3 CH ₅ H H C5 C3 CHb CH H D5 D3 H CH H E5 E3 n ČAHV H H F 5 F3 i - CiH & H H G5 G3 hoch ₂ H H H5 H3 CH3OCH2 H H 15 I CH H CH

Characteristic data

B. 5. @ ³ H-NMR (delta CDCls): 1, 31 (with , 3H), 1, 37 (T, 3H), 1.62 (s, 3H) , 2.89 (q, 2H) 3, 56 (D, 1H), 3.99 (D, 1H), 6.91 (d, 1 H) , 7.28 (dd, 1 H) , 7 , 34 (Π). , 1H) , 7.54 (d d, 1H) , 7, (d, 1 H) and 8.5 > 4 (dd, 1 H). C. 5 ¹ H-NMR (delta • CDCla): 1, 32 (WITH, 3H), 1.61 (with, 3H), 2.20 (s, 3H) , 2.61 (s, 3H) 3, 54 (D, 1H), 3.39 (D, 1H), 6.87 (d, 1 H) , 6.98 (d, 1 H), 7, 17 (dd, - 1H), , 7.26 (d (1H), and

8.32 (d, IH).

D. 5 ^T H-NMR (CDCl delta'-p) (s, 3H), 3.55 (d, 1H), (d, 1H), 7.23 (dd, 1H), 8.49 (s, 1H) . 1.33 (s, 3H), 1.62 (s, 3H), 2.31 1H), 7.13 , 1H), and 3.95 7.31 (d, 1H); 6.89 (d, 1H); (s, 1H). 8.45 (d E. 5 ³ H-NMR (δ-CDCl 3): 1, 01 (t, 3H), 1.30 (with , 3H), 1.62 (s, 3H), 1.82 (sex, 2H) , 2.8 2 (t, 2H); 3.54 (d, 1H); 3.90 (d, 1H); 6.91 (d, 1H); 1H), 7.28 (dd, IH), 7 32 (b, 1H) 7.53 (dd, IH); 7.63 (d, 1H); 1H) 8.54 (d, 1 H) • F. 5 ³ H-NMR (δ-CDCl 3): 0.96 (d, 6H), 1.30 (with , 3H), 1.62 (s, 3H), 2.15 (dt, 1 H), 2.70 (d, 2H), 3.54 (d (1H), 3.93 (d, 1H); 6.90 (d, 1H); 1H), 7.22 - 7.30 (m 9 T H, 7.53 (dd, 1 H), 7.63 (d, 1 H) and 8.5 4 (d, 1 H). G. 5 ^X H-NMR (CDCl delta): 1, 31 (s, 3H) 1.63 ( WITH , 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, 1 H). I. 5 ¹ H-NMR (d6-CDCl3): 1, 29 (s, 3H) 1.59 (with , 3H), 2.21 (s, 3H), 2.60 (s, 3H), 3.50 (d, 1H), 3.89 (D, 1H), 6.74 (s, 1H), 7.04 (dd, IH), 7.10 (d, 1 H), 7, 18 (s, 1 H) and 8.50 (d, IH).

A.5 'Preparation of (-) - (3S, 4S) * - 4- (1α, 7b-dihydro-2,2-dimethyl-2H-oxireno [c] 1-benzopyran-6-yl) -2-methylpyridine

A. 5'a 3-Bromo-3,4-dihydro-2,2-dimethyl-6- (2-methylpyridin-4-yl) -2H-1-benzopyran-4-yl ester (1R-) -1-alpha - (3 R, 4 S).

4-beta / - and 1R- / 1-alpha- (3S, 4R) -4-beta-.alpha.-methoxybenzeneacetic acid

To the product solution of Example A.4. (9.80 g), (-) - (R) -alpha-methoxyphenylacetic acid (5.65 g) and 4-dimethylaminopyridine (0.45 g) in lead CH 2 Cl 2 (330 mL) were added N, Nd and cyclohexylcarbodiimide (6.81 g) and the reaction mixture was stirred at room temperature for 90 minutes. The mixture was filtered and the solvent was evaporated under reduced pressure to give a crude mixture of diastereomers which was purified by chromatography (silica gel, 5% acetone in CH 2 Cl 2). The less polar product (A) is obtained, which is recrystallized from a mixture of acetone and pentane to give the 1R- / 1-alpha- (3R, 4S), 4-beta / isomer of the title compound, m.p. 137-138. [.Alpha.] D @ ²⁰ = -75.4 DEG

l>

(c = 0.955, C-H with OH), a. furthermore the polar product (B), [1R] 1-alpha- (3S, 4R), 4-beta / isomer of the title compound as an oil, [.alpha.] D @ ²⁰ = -22 DEG (c = 0.975, C2 H5 OH).

r>

A.5'.b (-) (3S, 4S) -4- (1α, 7b-dihydro-2,2-dimethyl-2H-oxo-reno [c] benzopyran-6-yl) -2- mety1pyridín

A solution of the (1R- / 1-alpha- (3S, 4S), 4-beta) isomer of the product of (A, 5'.a) (3.16 g) in dioxane (75 mL) at 20 ° C NaOH (45 mL, 0.58 M) was added and the reaction mixture was stirred at 20 ° C for 10 minutes. The dioxane was evaporated under reduced pressure and water (100 mL) was added to the residue and extracted with CH 2 Cl 2 (3 x 100 mL). The combined extracts were dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure to give a residue which was purified by column chromatography (silica gel, 5% Cp.HsOH in CH 2 Cl 2). Give the title compound in pure or substantially pure enantiomeric form-as a colorless oil / alpha / ²⁰ = -72 ⁰ (c = 1.125, C ^ HsOH).

D

A.6 '. Preparation of (+) - (3S, 4R) -4-Amino-3,4-dihydro-2,2-dimethyl-16- (2-methylpyridin-4-yl) -2H-1-benzopyran-3-ol

The solution of the product of the invention A.5 '(0.64 g) is mixed with a saturated solution of NH 3 in C 2 H 5 OH (15 mL) and the mixture is heated in an autoclave at 80 ° C for 15 hours. The solvent was evaporated under reduced pressure to give the crude product which was purified by chromatography (silica gel, 5% C 2 H 5 OH in CH 2 Cl 2) to give the title compound as a foam:

[.alpha.] D @ ³⁰ = +100 DEG (c = 1.00, C11 H5 OH).

Analogously, starting with the compounds listed in the table below the following compounds of formula IV wherein is H, R _p is hydroxyl to, R ₆ and R v are both methyl and R, R and R are as defined in the table below. All compounds are in the form of the trans-racemate and, except for the product of Example B6, are in the form of an oil.

example ri rc R e. the starting compound according to the example A6 CH ₃ H H A5 B 6 C :: He. H H B5 C6 CH CH 3 H C5 E6 n-CSH? H H E5 F6 ~ C H H'P H H F5 H6 CH3OCH2 CH ₃ H H5 16 CH 3 H CH 3 15

Physical data

A.6. ^X H-NMR (de1ta ^e -DMS0): 1.12 (s, 3H), 1.38 (s, 3H), 2.06 (broad, 2H), 2.50 (s, 3H), 3.23 (dd, 1H); 3.59 (d, IH); 5.47 (d, IH); 6.81 (d, 1H); 1H), 7.43 (dd, 1H) 7.51 (s, 1 H) 7.55 (dd, 1H); 7.99 (m. , 1H) 8.44 (d, 1 H)

B. 6. Melting point = 140-141 ^° C.

C. 6. 1 H-NMR (δ-CDCl 3): 1.27 (s, 3H), 1.54 fs, 3H), 2.15 (s, 3H), 2.2-2.5 (broad s, 3H) ), 2.57 (s, 3H), 3.41

(d, 1H), 3.71 (D, 1H), 6.85 (d (1H), 6.99 (d, 1 H), 7.10 (dd, 1 H), 7.31 (d , 1H) a 8, 31 (d, 1 H). ^X H-NMR (delta CDC1 a): 1, 00 (t, 3H), 1.27 (s, 3H) 1, 55 (s, 3H) 1.80 (with , 2H), 2,0- n 4 (wide p 3H) 2 80 (t, 2H), 3.41 (D, 1H), 3.74 (d (1H), 6.89 (d, 1 H), 7.25- 7.36 (m, 2H). 7.47 (d d, 1H), 7, 70 (d, 1H) and 8.51 (d , 1H).

F.6. ^and H-NMR (DMSO-de1ta): 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 (d (1H), 3.63 (d, 1H ), 5.45 (wide d, 1H) , -6.84 (d, 1H), 7.48 (m, 2H) 7.5 8 (dd, 1 H) , 8.00 (d, 1H) and 8.46 (D, 1H). 1.6. ^{: |} H NMR (delta- CDC1 3): 1 2.4 (s, 3H); 1 53 (S, 3H), 2.1 - 2.4 (wide with, 3H) , 2.20 (s, 3H), 2, 60 (s, 3H) , 3.38 (d, 1H) , 3.67 (d, 1H), 6.73 (s, 1 H), 7, 05 (d, 1 H) , 7.10 (with , 1H), 7.21 (with , 1H) a 8.49 (d, IH)

Benzopyrans and dihydrobenzopyrans as defined in paragraph 1 above, for example compounds of formula I as defined herein and their N-oxides, and physiologically hydrolyzable and physiologically acceptable esters thereof, as well as pharmaceutically acceptable acid salts or quaternary ammonium salts these benzopyrans / dihydrobenzopyrans / oxides / esters (hereinafter referred to as compounds of the invention) can be used as medicaments.

The compounds of the invention exhibit the effect of smooth muscle relaxant and the effect of potassium channel opening in plasma membranes, as demonstrated by their effect at concentrations of 1 to 500 mM on tension and elution of Rb · from various smooth muscle preparations, by the method or analogously to the methods described in Quast. , Brit. J. Pharmac. 91: 569-578 (1978). The compounds of the invention can therefore be characterized as K-channel opening agents.

The compounds of the invention are therefore used for the treatment of conditions or disorders for which K channel-channeling agents are indicated. Therapeutic utility as K * channel opening agents can be further demonstrated in standard pharmacological tests, for example by cardiovascular action, in vitro or in vivo. The effect on blood pressure can be demonstrated in anesthetized normotensive rats with drainage followed by intraduodenal administration 1 hour after drainage. The anti-ischemic effect can be demonstrated by following the methods described by Hof. et al., Circ. Res. 6, 679 (1988). The compounds of the invention exhibit a hypotensive effect according to the previously described test method at threshold doses of about 0.03. up to about 1.0 mg / kg intraduodenal and anti-ischemic effect according to the latter method at doses from about 0.001 to about 0.03 mg / kg intravenously.

The compounds of the invention are therefore useful, for example, as smooth muscle relaxants, in particular as vasodilators, for example for the treatment of hypertension or chronic cardiac insufficiency. They are further used as anti-schematic and anti-vasospastic agents, for example, for the treatment of blood supply disorders, for example, to the heart, muscle or brain. They can also be used, for example, for the treatment of angina pectoris, myocardial ischemia or myocardial infarction, as anti-fibrillation agents, for the treatment of peripheral circulation disorders, for example intermittent curvature, Raynaud's disease or vascular ulcers, , stroke, subarachnoid hemorrhage, and other related or subsequent diseases or disorders.

The compounds of the invention are further indicated for use as antispastic agents of the gastrointestinal tract, uterus or urinary tract, for example, for the treatment of duodenal or peptic ulcers, irritable colon, inflammatory bowel disease, the risk of spontaneous abortion after premature labor and inability to maintain urine.

The compounds of the invention are further indicated as hair growth promoting agents, e.g. aging, for example, baldness of men or baldness or a disease associated with hair loss, for example after infection or immune system disorder.

Appropriate dosages for such use are, of course, varied, for example depending on the particular conditions to be treated, the type of compound of the invention, the mode of administration and the effect desired. In general, however, an appropriate dosage for oral administration, for example, in antihypertensive use is from about 0.03 to about 2.0 mg / kg, and in anticoagulant use from about 0.015 to about 0.3 mg / kg. For larger mammals, for example humans, an oral daily dose of from about 2 to about 150 mg for antihypertensive use, or from about 1 to about 20 mg for anti-ischemic use, is administered once or in divided doses twice daily. Thus, oral dosage forms for the above indications preferably contain from about 0.5 or 1.0 to about 20 or 150 mg of a compound of the invention together with a suitable pharmaceutically acceptable diluent or carrier.

When used as hair growth stimulating agents, the compounds of the invention are applied topically, for example on the basis of a suitable cream, gel or emulsion, or a similar method known in the art.

In the context of the present invention, it has now been found that the compounds of the invention exhibit bronchodilator and latency action and reduce or abolish airway hyperactivity. These activities can be demonstrated in in vivo and in vitro pharmaceutical models, for example as follows:

Test 1. Bronchodilator effect.

Test in guinea pigs.

Guinea pigs (Dunkin-Hartley, male, 400-600 g) are anasthetized with phenobarbital (100 mk / kg intraperitoneally) and pentobarbital (30 mk / kg intraperitoneally) and paralyzed with gallamine (8 mg / kg intramuscularly) and allowed to inhale air mixtures and oxygen (45:55, v / v). Animals breathe using a tracheal tube (10 mL / kg, 1 Hz). Blood pressure and heart rate are taken from the carotid artery. Respiration is monitored by a flow transducer. For flow measurement, simultaneous changes in thorax pressure are monitored directly through the intrathoracic trocar, which allows to show the pressure differences with respect to the trachea. From this information, the resistance and compliance of each breath is calculated.

Permanent bronchospasm is induced by intravenous infusion of bombesin (100 ng / kg / h). The ability of the test substance to reverse the response when administered intratracheally serves as a measure of efficacy in reversing induced bronchospasm. The bronchodilator response is taken as a percentage reduction in the maximum response to bombesin measured at regular intervals.

In the above-described test model, the compounds of the invention interfere with bronchospasm at doses from about 0.001 to about 1.0 mg / kg.

1.2 Test on Rhesus monkeys

Rhesus monkeys (males and females, weighing 6.8 to 11.8 kg), known to respond normally to methacholine (MeCH), are anesthetized (first with ketamine 20 mg / kq intramuscularly, then to be maintained by thiopental 8 mg / kg (h intravenously). A pediatric endotracheal tube (5.0 cm) with cuff (xylocaine, topical application in epiglott) is then inserted into the trachea and the baseline pulmonary resistance is measured.

Following these steps, 2 ml of xylocaine (1% w / v solution) is applied at the edge with a pediatric fibroptic bronchoscope. After 10 minutes, the pulmonary resistance is measured again. Xylocaine has no effect on baseline resistance. Thereafter, in the same manner as the administration of xylocaine, the test compound is administered as a suspension in a lactose carrier (1 mg / ml, delivered 1 ml volume) at 30 minute intervals. At a time point of 15 minutes, a single dose of MeCH (0.6-2.5 mg / ml solution, calculated for approximately 50-100% change from baseline) is applied to elicit a response and the percent inhibition is calculated from the carrier response.

The compounds of the invention are effective as dose-dependent bronchodilators, and are effective at doses of about 10 ng / kg to about 10 pg / kg in the above assay.

Test 2. Suppression of hyperactivity in even the airways.

PAF-induced hyperactivity

Guinea pigs shall be prepared for monitoring pulmonary function as described in Test 1.1 above. Intravenous injection of histamine (1.8-3.2 ng / kg) causes airway sensitivity to spasmogen. After infusion of PAF (platelets activate the factor) for an hour (total dose 600 ng / kg), repeated injections of histamine manifest themselves in the development of airway hyperactivity, which may be appropriately expressed as a doubled difference between the amplitude of the reaction before and after PAF exposure:

After administration of the compounds of the invention intratracheally after administration of PAF at doses of from about 0.1 to about 100 pg / kg, an airway hyperactivity reversal is observed.

I i,

2.2 Hyperactivity induced by the immune complex.

Guinea pigs are prepared to monitor pulmonary function;

as described in Test 1.1 above. The allergic reaction is initiated by intravenous injection into a preformed immune complex (prepared by adding 30 µg of bovine gamma-1 globulin in 0.05 ml of saline to 0.05 ml of guinea pig anti-!

bovine gamma-globulin anti-serum) at regular (10 minute) intervals for 30 minutes. Intravenous injections of histamine (1.0-3.2 µg / kg at 10 minute intervals) are used to define airway sensitivity before and after the last exposure of the immune complex. Airway hyperacti ions are expressed as a pairwise difference for the maximum value of lung resistance in response to histamine before and after repeated injection of the immune complex. Test compounds are administered intratracheally.

The induced airway hyperactivity decreases significantly with the above test method when the compounds of the invention are administered in advance at doses of about 10 ng / kg to about 10.0 pg / kg.

In particular, the compounds of the invention are useful as bronchodilators and as agents for the treatment of airway hyperactivity, for example, as agents for the symptomatic as well as prophylactic treatment of obstructive or inflammatory airways diseases, particularly asthma. As bronchodilators, the compounds of the invention may be used in particular in salvage therapy, for the treatment of pulmonary constriction, for example in asthma. In addition, the continuous administration of the compounds of the invention may be used to control, reduce or reverse airway hyperactivity or to provide early protection against recurrence of bronchoconstrictor attack due to obstructive or inflammatory airway diseases, particularly asthma. The terms treatment as used in the specification and claims in relation to the use of the compounds of the invention for the treatment of obstructive or inflammatory respiratory diseases, particularly asthma, are intended to include both prophylactic and symptomatic (ie bronchodilator) therapy, unless unless otherwise stated.

According to the above, the present invention also relates to:

4. A method of treating any disease or condition specified herein, in particular

4.a method of treating obstructive or inflammatory airways diseases, including

4.a.l a method of symptomatic treatment of inflammatory or obstructive airways diseases, for example affecting bronchodilation, or

4. a.2 a method for the prophylactic treatment of inflammatory or obstructive airways diseases, for example for the treatment of hyperactivity in the airways of a subject in need thereof, the method comprising administering to said subject an effective amount of a compound of the invention, or alternatively:

5. the compounds of the invention for use as medicaments, for example for use in the treatment of any disease or condition as specified above, in particular for use in the treatment of obstructive or inflammatory airways diseases, for example as set forth in paragraphs 4.a1, 4. .a.2, or

6. A pharmaceutical composition comprising a compound of the invention or the use of a compound of the invention for the preparation of a pharmaceutical composition useful for the treatment of diseases or conditions as specified herein, in particular for use according to paragraph 5 above. j, i t f Inflammatory and obstructive diseases to which it is applicable | Including the present invention include asthma of any type or origin, including both intrinsic asthma and, in particular, external asthma. The compounds of the invention may be used to treat allergic asthma, either atopic (i.e., caused by;

IgE) or non-atopic, as well as, for example, bronchial asthma, exercise-induced asthma, occupational-induced asthma, asthma following bacterial infection and other types of non-allergic asthma. Treatment of asthma may also include treating subjects, for example, less than 4 or 5 years of age, exhibiting wheezing symptoms, especially at night, and diagnosed or diagnosed as wheezing infants, a typical patient category of most medical facilities, and which is now more appropriately referred to as early or early stage asthma.

(For simplicity, this condition is referred to as wheezing syndrome).

Prophylactic efficacy in the treatment of asthma is evidenced by a reduced number or severity of a symptomatic seizure, such as an acute or bronchoconstrictive seizure.

It can further be demonstrated by reducing the requirements for further symptomatic therapy, i. for therapy that is being used or intended to be used to reduce or interrupt a symptomatic seizure that has already occurred, for example anti-inflammatory (e.g. corticosteroids) or bronchodilator (e.g. beta-adrenergic) therapy.

Prophylactic benefit in asthma is particularly evident in persons prone to morning seizures. Morning seizures are recognized as asthmatic syndromes common to a substantial percentage of metal asthma and are characterized by asthma attacks, for example between 4 am and 6 am, i.e. at a time that is substantially remote from any previous therapy for symptomatic asthma.

Inflammatory or obstructive airways diseases to which the present invention is applicable also include pneumoconiosis (inflammatory pulmonary disease, usually by profession, often accompanied by airway obstruction, either chronic or acute and caused by repeated inhalation of dusts) of any type or origin, including for example diseases such as aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tobacco and especially byssinosis.

Other inflammatory or obstructive airway diseases and conditions to which the present invention is applicable include adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary or respiratory disease (COPD or COAD), and bronchitis, as well as esacerbation of airway hyperactivity which following other therapeutic therapy, in particular other inhalation therapies, for example beta-agonist bronchodilator therapy, including the use of the compounds of the invention as a bronchodilator for the treatment of chronic or acute airway obstruction, as well as shortness of breath associated with any such disease or condition.

For use in the treatment of inflammatory or obstructive airways diseases, the compounds of the invention may be administered in conventional manner, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions. However, they are preferably administered pulmonally, for example by inhalation with appropriate nebulizers, inhalers or similar devices known in the art.

The dosages used to treat inflammatory and obstructive airways diseases may, of course, vary depending upon, for example, the particular condition to be treated, the particular compound of the invention used, the mode of administration and the desired effect.

Typically, however, for pulmonary administration in most mammals, for example humans, a suitable daily dose administered to the lungs is of the order of from about 0.1 pg to about 100 pg, particularly from about 1.0 pg to about 50.0 pg, the dosage being suitably injected from the inhalation device one or two to four times a day in a series of 1 to 4 breaths per administration.

For oral administration, a suitable daily dose is generally of the order of from about 0.1 to about 30 pg / kg. Thus, a suitable oral daily dose for larger mammals, for example humans, is of the order of from about 7 µg to about 2.1 mg administered as a single dose, in divided doses two to four times daily, or as a sustained release drug. Thus, oral unit dosage forms for such use suitably contain from about 1.75 µg to about 2.1 mg of a compound of the invention together with a pharmaceutically acceptable diluent or carrier.

In particular, it should be noted that the compounds of the invention are generally effective as bronchodilators or as agents for treating airway hyperactivity, in doses, in particular inhalation doses, in which cardiovascular effects which are undesirable in relation to such therapy, such as hypotensive effect or tachycardia, are not significant or are within acceptable limits in relation to the therapy being practiced.

Accordingly, the present invention also relates to:

7. A pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable diluent or carrier.

These compositions may be prepared in conventional manner, for example for pulmonary administration, by mixing the compound of the invention in finely dispersed form with, for example, finely divided lactose as a carrier or diluent to obtain a powder suitable for inhalation.

and

As mentioned above, the requirements for therapeutic doses in the practice of the present invention vary and depend on a number of factors. The dosages for a particular compound of the invention are also dependent on their relative efficacy. For a preferred compound of the invention, namely for the product 1 'of Example 1 in pure or substantially pure (3S, 4R)!

in the enantiomeric form, &lt;

and

Idso 0.02 mg / kg, IT in the same assay for a known and an inhalation Ný bronchodilators and 1 ator - Salbutamol - / Al f ⁱ - // (1, 1-di methyl-ethyl-1 j 1 -i amino / - methyl (-4-hydroxy-1,3-benzenemethanol) found value

ID 50 0.001 mg / kg. Thus, the appropriate doses of the compound of Example 1 for inhaled administration, for example, for the bronchodilator effect in the treatment of asthma, are about 20 times the salbutamol commonly used.

Claims (10)

PATENT CLAIMS ί 1,3-butadiene or a group of the formula - (CH 2) n - or - (CH-) -, Uí t where n is an integer from 3 to 5 inclusive and m is 1 or 2, R 8 is a hydrogen atom and R 8 is a hydroxy group in the trans position with respect to R 6 or R 6 R 6 and R 8 together represent another bond, as indicated by a dot-; bathtub,; R 1 and R 2 are independently C 1 -C 5 alkyl, and Ro is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or N-oxides thereof, or physiologically hydrolysable and physiologically acceptable esters of these compounds or N-oxides, or acid salts or quaternary ammonium salts of these compounds, N-oxides or esters . 1. 2,2-dialkyl-6- (pyridin-4-yl) -2H-1-benzopyranes; à trans-2,2-dialky1-3,4-dihydro-3-hydroxy-6- (4-pyridíη-y1) -2-1 | benzopyranes in which all alkyl groups contain 1 to < 2,2-dialkyl-4-amino-6- (pyridin-4-yl) -2H-1-benzopyran or trans-2,2-dialkyl-3,4-dihydro-3-hydroxy-4-amino-6 (pyridin-4-yl) -2H-1-benzopyran in which the alkyl groups have 1 to 5 carbon atoms and wherein the pyridin-4-yl group is substituted in the 2 and / or 3 position by one or two substituents selected from the group consisting of (C 1 -C 5) alkyl, (C 1 -C 5) hydroxyalkyl and (C 1 -C 5) alkoxyalkyl in the alkoxy and alkyl moieties (ii) for the preparation of benzopyran-N-oxides or physiologically hydrolyzable and physiologically acceptable esters of the abovementioned benzopyranes or benzopyran-N-oxides is esterified with benzopyran or benzopyran-N-oxide as defined above having a free hydroxy group or hydroxyl moiety to introduce the corresponding ester group and / or oxidize the benzopyran or its physiologically hydrolyzable and physiologically acceptable Ný ester thereof, as defined above, and the obtained benzopyran, benzopyran N-oxide or physiologically hydrolysable and acceptable ester, physiologically t is isolated in free form or as a salt or as a quaternary ammonium salt. 3 with one or two substituents selected from the group consisting of (C1 -C5) alkyl, (C1 -C5) hydroxyalkyl and (C1 -C5) alkoxyalkyl and (C1 -C5) alkyl, with an alkali metal salt of a carboxamide group, or i -) is acylated and, if desired, alkylated with an amino group 3. Compounds of formula (I) as described in claim 1, wherein: R 8 is a hydrogen atom, R 8 is a hydroxy group in the trans position with respect to R a, R c and R c. are both methyl groups and A) Ra is a group of formula Ά ¹ ) R j is methyl, ethyl, n-propyl, isobutyl, hydroxymethyl or methoxymethyl; and R ·. and R e are hydrogen atoms, or ri and R 6 are hydrogen atoms and R; is methyl, or Ά ⁵ ) ri and R e are methyl groups and R is a hydrogen atom, or B) R < is a group of formula B ¹ ) R.V. is a methyl group, ethyl group, i z obutýlová group group a R ;; and Re are atoms or B ^Ľ ) rj and R o are atoms hydrogen and R r; is a methyl group, or B ³ ) R: i and Re are methyl groups and R is a a hydrogen atom, or C) R 3 is a group · of formula a group, n-propyl or methoxymethyl; or R u. Rä is methyl and Ra is hydrogen, or í v those ri is a methyl group and ra is a a hydrogen atom; or Rí is a hydrogen atom; and r ₂ is a methyl, R e. and R> are methyl groups, Re is a hydrogen atom, R 1 and R 2 together represent another bond a R 5 is a group of the formula or N-oxides thereof, or physiologically hydrolyzable and physiologically acceptable esters of these compounds or N-oxides or acid salts or quaternary ammonium salts of these compounds, N-oxides or esters. 4-yl) -2H-oxireno [c] 1 benzopyran in which the alkyl groups have 1 to 5 carbon atoms and in which the pyridin-4-yl group is substituted in the 2-position and / or 4. A compound of formula I as described in claim 1, wherein _R>, R>, and R are each methyl, R =, R = => and R 8 are each hydrogen, R ~. it is hydroxy in the trans position with respect to R1 _: and R5 is a group of the formula or the N-oxides or acid salts thereof of the compounds or N-oxides. 5. Trans-2,2-dialkyl-3,4-dihydro-3-hydroxy-6- (pyridin-4-yl) -2H-1-benzopyranes in which all alkyl groups contain 1 to 5 carbon atoms, N-oxides, esters or salts ako.sú as defined in claim 1 or a compound of formula I as defined in claim 2, wherein R »is H and _R is hydroxy in the trans position relative to R, and R, R, R, R R 2 and R 2 are as defined in claim 2, or the N-oxides, esters or salts thereof as defined in claim 2, in the (3S, 4R) -enantiomeric form. These compounds have a carboxamide group at the 4-position and the pyridin-4-yl group is substituted with 5-carbon atoms. in the 2- and / or 3-position by one or two substituents selected from the group consisting of C 1 -C 5 alkyl, C 1 -C 5 hydroxyalkyl, and C 1 -C 5 alkoxyalkyl both in the alkoxy and alkyl moieties, or the N-oxides thereof, or the physiologically hydrolyzable and physiologically acceptable esters of these benzopyranes or N-oxides, or of acid salts or quaternary ammonium salts of these benzopyranes, Noxides or esters. Compounds of formula I wherein R.I. and R? independently of one another are hydrogen, alkyl of 1 to 5 carbon atoms, hydroxyalkyl of 1 to 5 carbon atoms or alkoxyalkyl of 1 to 5 carbon atoms in the alkoxy and alkyl moieties, at least one of R 1 and R 2 being other than hydrogen atom; The F, L; R _j is a group of the formula -N (R ') -COR <->, wherein R · represents hydrogen and R :, o is pyridyl or R and R together tvoriaí of WF · Compounds according to claim 4 in (3S, 4R) -enantiomeric form. A process for the preparation of benzopyrans, N-oxides, esters or salts as defined in claim 1, characterized in that: (i) for the preparation of the abovementioned benzopyrans » i ') is reacted with 1 a, 7b-dihydro-2,2-dialkyl-6- (pyridine- Benzopyrans, N-oxides, esters or pharmaceutically acceptable salts as defined in claim 1 for use as medicaments. A pharmaceutical composition comprising benzopyran, an N-oxide, an ester or a pharmaceutically acceptable salt as defined in claim 1, together with a pharmaceutically acceptable diluent or carrier. 10. A method of treating obstructive or inflammatory airways diseases in a subject in need of such treatment comprising administering to said subject an effective amount of benzopyran, an N-oxide, an ester, or a pharmaceutically acceptable salt as defined in claim 1.