AU665040B2 - 4-carboxamido-6(pyridin-4-yl substituted benzopyran derivatives - Google Patents

Description

I)

OPI DATE.22/06/94 A0,JP DATE 25/08/94 APPLN. ID :30826'92 PCT NUMBER PCT/EP92/62719 AU9230826, ?!cT) (51) International Patent classification 5: (11) International Publication Number: WO 94/12493 C07 4 5/1 61 31 44 31/ 45Al (43) International Publication Date: 9 June 1994 (09.06.94) (21) International Application Number: PCT/EP92/02719 (81) Designated States: AU, CA, CS, Fl, HU, JP, KR, KZ, NO, PL, RO, RU, US, European patent (AT, BE, CH, DE, D&, (22) International Filing Date: 25 November 1992 (25.11.92) ES. FR GB, GR, LE, IT, LU, MC, NL, PT, SE).

(71) Applicant (for AT only): SANDOZ-ERFINDUNGEN VER- Published WALTUNGSGESELLSCHAFT MBH [AT/ATl; Brunner With international search report.

Strasse 59, A-1230 Vienna (AT).

(71) Applicant (for DE only): SANDOZ-PATENT-GMBH, [DE/DE]; Humboldtstrasse 3, D-7850 Lbrrach (DE).

t' Applicant (for all designated States except AT DE US): SAN- 65 0Ah 4 0A], DOZ, LTD. [CHICH]; Lichtstrasse 35, CH-4002 Basle (CH).

(72) Inventor; and Inventor/Applicant (for US only): MANLEY, Paul, W.

[GB/CR]; Sierenzerstrasse 41, CH-4055 Basle (CM).

(74) Common Representative: SANDOZ LTD.; Patents Tradevr-Arks Division, Uchtsiasse 35, CH-4002 Basle (CR).

(54) Title: 2,2-DIALKYL- AND 2,2-DALKYL-3,4-DIYDRO-3-HYDROXY-2H-1-BENZOPYR ANS, THEIR USE AS PHARM1ACEU

TICALS

(57) Abstract 2,2-Di(Ci.5alkyl)- and trans-2,2di(Ci.salkyl)-3,4-dihydro-3-hydroxy- (iyridin-4-yl)-2H- 1-benzopyrans, e.g.

of formula in which RI and R2 H, alkyl, hydroxyalkyl or alkoxyalkyl, at least one being other than H, R 3 =typically a 2-piperidinone group, R4 H and R5 -OH or R 4

R

5 an additional bond, and R6, R7 are alkyl and Rs 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.

R 6 pp 7 WO 94/12493 PCT/EP92/02719 2,2-DIALKYL- AND 2.2-DIALKYL-3,4-DIHYDRO-3-HYDROXY- 2H-1-BENZOPYRANS, THEIR USE AS PHARMACEUTICALS The present invent.on relates to novel 2,2-dialkyl- and 2,2-dialkyl-3,4-dihydro-3-hydroxy- -2H-l-benzopyrans and salts, esters and N-oxides thereof and to processes for their production, as well as to their use as pharmaceuticals and pharmaceutical compositions comprising them.

More particularly the present invention provides in its broadest aspect: 1. A 2,2-di(Ci- 5 alkyl)- or trans-2,2-di(C_-alkyl)- -3,4-dihydro-3-hydroxy- -6-(pyridin-4-yl)-2H- 1-benzopyran having a carboxamido moiety at the 4-position and wherein the pyridin-4-yl group is substituted at the 2- and/or 3-position by one or two members selected from the group comprising Cl-shydroxyalkyl and C..

5 (alkoxyalkyl), or N-oxide thereof; or physiologically-hydrolysable and -acceptable ester of such a benzopyran or N-oxide or acid addition or quarternary ammonium salt of such a benzopyran, N-oxide or ester.

Alkyl groups and moieties of compounds as defined under 1.

above may be branched or straight chain. Preferred Ssignificances for substituents at the 2-position of the benzopyran nucleus as well as at the 2 and/or 3 position of the pyridinyl group are as set forth below in relation to formula I for R 6 and R 7 and R 1 and R 2 ft I 111 WO 94/12493 PCT/EP92/02719 2 As hereinafter described, compounds of the present invention, e.g. as defined under 1 above, have potassium (K channel opening activity [see e.g. Cook et al., "Potassium Channels: Structure, Classification, Function and Therapeutic Potential", ed. N.S.Cook, Ellis Horwood, I Chichester (1990), p.p. 181-255]. Benzopyran derivatives which are carboxamido-substituted at the 4-position, having K+-channel opening activity are extensively described in the art and comprise a substantial and recognisable compound class. The 4-carboxamido moiety in the compounds of the invention may comprise any of those known and described in the art in relation to K*-channel opening benzopyrans, including N-substituted, for example cyclic, carboxamido moieties. Preferred carboxamido moieties in relation to the compounds of the invention are those of the formula

-N(R

9 )-CORio as defined below.

I

As will be appreciz ed, the benzopyran nucleus of compounds defined under 1 may bear substituents in addition to those Sspecifically defined. In particular they may, for example, be 7-C-s 5 alkyl substituted, especially 7-methyl substituted, e.g. as hereinafter indicated in relation to formula I.

j n accordance with the present invention 2,2-di- (Ci-5alkyl)-3,4-dihydro-3-hydroxy-6-(pyridin-4-yl)-2H-1- -benzopyrans and/or -oxides, esters, and salts thereof as defined under 1 above are preferred. The 3-hydroxy group and the 4-carboxamido moiety in such compounds are disposed in Sthe trans-configuration as specified under 1. For this compound group (3S,4R)-enantiomers will generally be preferred, whether in pure or substantially pure form or in isomeric, e.g. racemic, mixture as hereinafter described in relation to compounds of formula I.

In a more specific aspect the present invention provides: WO 94/12493 PCTIEP92/02719 3 2. A compound of formula I R2 5 R4 R3 R 1 8 R7 wherein RI and R 2 are independently, hydrogen, Ci-salkyl, Cl- 5 hydroxyalkyl or Ci- 5 (alkoxyalkyl), whereby at least one of R 1 and R 2 is other than hydrogen,

R

3 is a group of formula -N(R 9 )-CORio wherein R 9 is hydrogen and Rlois pyridyl or R 9 and Rl 0 together are 1,3-butadienylene or represent a group of formula -(CH 2 or -(CH 2 in which n is an integer of from 3 to inclusive and m is 1 or 2,

R

4 is hydrogen and R 5 is hydroxy in the trans position with respect 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 -salkyl, and Re is hydrogen or Cl-salkyl, or N-oxide thereof; or physiologically-hydrolysable and -acceptable ester of such a compound or N-oxide, or acid addition or quarternary ammonium salt of such a compound, N-oxide or ester.

Alkyl groups as RI, R 2

R

6

R

7 and Re, as well as alkyl moieties of hydroxyalkyl and alkoxvalkyl groups as R 1 and R 2 may be branched or straight chain. Alkoxyalkyl groups are preferably (Ci-4alkoxy)-methyl, in particular methoxymethyl.

nh I I I I I I I l WO 94/12493 PCTIEP92/02719 4 Preferred hydroxyalkyl groups are 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 te meanings given above in relation to formula I and

R

2 is hydrogen or C 1 -salkyl (especially methyl), preferably hydrogen.

In a further preferred group of compounds of formula I, in the definition of R 3 Rg is hydrogen and Rio is pyridyl (especially 3-pyridyl) or Rg and Rio together are 1,3-butadienylene, trimethylene or tetramethylene. Most preferably R 9 and Rio together are tetramethylene.

Preferably R 4 is hydrogen and R 5 is tydroxy.

Benzopyrans of the invention, for example compounds of formula I, form N-oxides, e.g. at the nitrogen atom of the 6-pyridinyl group. Such N-oxides have comparable activity (as hereinafter described) and tolerability to the parent compounds and also form part of the present invention.

By "physiologically-hydrolysable and -acceptable ester" as used herein is meant an ester in which a hydroxy group in relation to formula I, hydroxy groups Rs and/or the hydroxy moiety of any hydroxyalkyl group present as RI and/or R 2 is esterified and which is hydrolysable under physiological conditions to yield an acid which is itself physiologically tolerable at doses to be administered. As will be appreciated such esters are pro-drug forms of conventional type and have comparable activity and tolerability to the parent compounds. Examples of such esters include, e.g. acetates.

Acid addition salts, e.g. of compounds of formula I, their N-oxides and defined esters thereof, include salts with both inorganic and organic acids. Such salts also have comparable

"I

i WO 94/12493 PCTEP92/02719 activity to the free compounds, N-oxides and esters.

Pharmaceutically acceptable acid addition salts for pharmaceutical use in accordance with the present invention as hereinafter described include e.g. hydrochloric, sulphuric and fumaric acid salts.

Quarternary ammonium salts, e.g. of compounds of formula I, their N-oxides and defined esters thereof, include e.g.

salts with organo-halides, e.g. alkyl halides.

Pharmaceutically acceptable quarternary ammonium salts for pharmaceutical use in accordance with the present invention include e.g. such salts with methyl iodide.

For pharmaceutical use in accordance with the present invention ester forms as aforesaid are generally less preferred.

Compounds of formula I in which R 4 is hydrogen and R 5 is hydroxy, as well as their N-oxides, esters and salts as aforesaid, have the configuration i.e. the configuration of the groups R 3 and R 5 at the 3- and 4-positions is trans. Compounds of the invention thus exist in enantiomeric form, i.e. as optically active antipodes having the [3S,4R] or [3R,4S] configuration. The present invention is to be understood as embracing both the individual enantiomers (optically active, [3S,4R] or [3R,4S], antipodes) as well as mixtures, e.g. racemic mixtures, thereof.

In that pharmaceutical utility in accordance with the invention is believed to reside, or reside predominantly, in the [3S,4R) enantiomers, these are preferred. Suitably the said [3S,4R] enantiomers will be, or will be employed in accordance with the invention, in purified form, i.e.

comprising less than 50% enantiomeric contaminants, more suitably in pure or substantially pure form, e.g. comprising less than 10%, preferably 5% or less, e.g. 1 or 2% or less i I

A

r if WO 94/12493 PCTIEP92/02719 6 of [3R,4S] enantiomeric contaminants.

In addition to the foregoing the present invention also provides: 3. A process for the production of a benzopyran as defined under 1 above, for example a compound of formula I as defined under 2 above, or N-oxide thereof, or physiologically-hydrolysable and -acceptable ester of such a benzopyran or N-oxide or acid additon or quarternary ammonium salt of such a benzopyran, N-oxide or ester, which process comprises: i) for the production of a benzopyran as aforesaid: il) reacting a la,7b-dihydro-2,2-di(C l -salkyl)-6-(pyridin- -4-yl)-2H-oxireno[c][l]benzopyran wherein the pyridin-4-yl group is substituted at the 2- and/or 3-position by one or two memebers selected from the group comprising C 1 -salkyl, Ci-shydroxyalkyl and C1- 5 (alkoxyalkyl), for example a compound of formula II

R

2

R

7 wherein RI, R 2

R

6

R

7 and Re have the meanings for formula I above, with an alkali metal salt of a carboxamide, for example a compound of formula III

R

1 0 -CO-N-R9 M (III) wherein Rg and Rio have the meanings given for formula I above and M+ is a lithium, sodium or potassium ion; or

-LIDIM~~

WO 94/12493 PCT/EP92/02719 7 i 2 acylating and, when required, alkylating the amino group of a 2,2-di(Ci- 5 alkyl)- or trans-2,2-di(C 1 -3,4-dihydro-3-hydroxy- -4-amino-6-(pyridin-4-yl)- 2H-l-b nzopyran wherein the pyridin-4-yl group is subsL.iuted at the 2- and/or 3-position by one or two members selected from the group comprising C 1 -salkyl,

C

1 -shydroxyalkyl and C1-5(alkoxyalkyl), for example, reacting a compound of formula IV R2

NH

2 R1 R

R

(IV)

8 R j wherein Ri, R 2 and R4 to Rg have the meanings given for formula I, with a compound of formula V, V' or V"' I! I R' 1 0 -CO-X

X

2

-(CH

2 )n-COX 1 2 2 m

COX

1 i I wherein R'o 1 is pyridyl and X 1 and X 2 are leaving groups; yj i ii) for the production of a benzopyran N-oxide or physiologically-hydrolysable and -acceptable ester of a benzopyran or benzopyran N-oxide as aforesaid, esterifying a benzopyran or benzopyran N-oxide as defined under 1 above having a free hydroxy group or moiety to introduce an appropriate ester grouping, for example reacting a compound of formula I as herein- I

I

WO 94/12493 PCT/EP92/02719 8 before defined wherein R 5 is hydroxy and/or at least one of R 1 and R 2 is C1-5 hydroxyalkyl or N-oxide thereof with an appropriate acid halide or anhydride, and/or oxidising a benzopyran or physiologically-hydrolysable and -acceptable ester thereof as defined under 1 above, for example oxidisjng a compound of formula I as hereinbefore defined or physiologically-hydrolysable and -acceptable ester thereof; and recovering the obtained benzopyran, benzopyran N-oxide or physiologically-hydrolysable and-acceptable ester thereof in free or in acid addition or quarternary ammonium salt form.

Process step il) above may be carried out in accordance with methods known in the art, for example by reaction at ambient temperatures to reflux in the presence of an inert solvent or diluent such as tetrahydrofuran or dimethylsulfoxide. Suitably the required alkali metal salt, e.g. compound of formula III, is pre-formed in situ, for example as described in Examples 1 to 11 and 21 hereinafter. By appropriate use of e.g. Na salts, both benzopyrans and dihydro-benzopyrans of the invention may be obtained, e.g. as illustrated in Examples 11 and 12 hereinafter. Use of lithium salts leads primarily or exclusively to the preferred dihydro- -benzopyrans of the invention as illustrated in Examples 1 to 10 hereinafter.

Process step i 2 may also be carried out in accordance with methods known in the art. Suitable leaving groups

X

1 are halogen and activated ester groups and suitable leaving groups X 2 are halogen. Reaction is suitably carried out at temperatures of from 0* to 100°C in an inert solvent or diluent such as acetonitrile or dichloromethane, preferably in the presence of an acid binding agent, e.g. trialkylamine or alkali metal carbonate. The procedure is illustrated in Examples 13 it 7 WO 94/12493 9 PCT/EP92/02719 to 20 hereinafter.

Process step ii) may be carried out in accordance with conventional acylation/N-oxidation procedures, e.g. for the obtention of N-oxides by treatment with hydrogen peroxide, m-chloroperbenzoic acid or Collin's reagent (Cr0 3 .Py 2 as hereinafter illustrated in Example 23.

Initially obtained free bases may be converted into acid addition or quarternary ammonium salts by reaction with acids or e.g. alkyl, for example methyl, halides, and vice versa.

Employing racemates of the formula II and formula IV compounds, 4-carboxamido-3,4-dihydro-3-hydroxy- -benzopyrans obtained will be in the form of the trans-racemate comprising the (3S,4R) plus (3R,4S) isomers). Obtained racemates may be separated to provide the individual (3R,4S) or (preferred) (3S,4R) enantiomer, e.g. chromatographically using a chiral stationary phase. Where individual (3S,4R) enantiomers are desired, however, this is preferably achieved using the corresponding isomer as starting material, i.e. in relation to formula II, the 3S,4S-antipode and, in relation to formula IV, the 3S,4R-antipode. These are suitably produced as hereinafter described in relation to reaction sequence A.

As will be appreciated, variants of or alternatives to the above procedures may be employed as known in the art, e.g. for the interconversion of initially obtained compounds or for the introduction of alternative carboxamido groups at the 4-position. Labile groups may be protected e.g. during acylation procedures, employing conventional protecting, e.g. hydroxy-protecting groups.

In addition, initially obtained benzopyrans may, if desired, be converted to corresponding benzopyrans by ii

I:*

WO 94/12493 PCT/EP92/02719 10 dehydration across the 3,4-linkage, again in accordance with standard techniques. Further alternatives will be apparent to those skilled in the art.

Compounds ance with of the formula II may be prepared in accordthe following general reaction sequence A

(VI)

(iii) CH 0

=I

(VII)

SEPARATION OF ANTIPODES

(II)(

Process steps (iii) through (vi) may be carried out by conventional means, e.g. in accordance with the general procedures hereinafter illustrated in Examples 24.A.4, A.5'a, and Starting materials of formula IV may be prepared from the corresponding compounds of formula II by reaction with ammonia, e.g. in accordance with the general procedures hereinafter illustrated in Example 24.A.6'.

_I

I

r~~ WO 94/1249.3 PCT/EP92/02719 11 Proceeding via steps (iii) and the formula II compound is obtained as the cis-racemate, i.e.

comprising the (3R,4R) and (3S,4S) antipodes. Step v involves introduction of an appropriate chiral acyl group [in sequence A, by way of example, -methoxyphenylacetyl]. The chiral racemate VIII may readily be separated by column chromatography or fractional recrystallisation into its individual (3R,4S) and (3S,4R) antipodes. By use of the (3R,4S) antipode and proceeding via step (vi) compound II starting materials may be obtained in pure or substantially pure (3S,4S) enantiomeric form.

Compounds of formula VI may be prepared in accordance with the following general reaction sequence B

(IX)

OCH

3 S OH R0 8

R

7 (ix)

(VI)

C joCH

R

6 0 R7

(XI)

in which is a leaving group, suitably a halogen atom, e.g. chlorine. Steps (vii) to (ix) may be carried out by conventional means, e.g. in accordance with the general procedures hereinafter illustrated in Examples 24.A.2 and A.3, steps (viii) and (ix) being carried out in Example 24.A.3 without purification of the 4 I- I- I WO 94/12493 PCT/EP92/02719 11 Proceeding via steps (iii) and the formula II compound is obtained as the cis-racemate, i.e.

comprising the (3R,4R) and (3S,4S) antipodes. Step v involves introduction of an appropriate chiral acyl group [in sequence A, by way of example, -methoxyphenylacetyl]. The chiral racemate VIII may readily be separated by column chromatography or fractional recrystallisation into its individual (3R,4S) and (3S,4R) antipodes. By use of the (3R,4S) antipode and proceeding via step (vi) compound II starting materials may be obtained in pure or substantially pure (3S,4S) enantiomeric form.

Compounds of formula VI may be prepared in accordance with the following general reaction sequence B

(IX)

(vii) c

OCH

3 (viii

A

OH

R8 6> C(X' ')-C-CH c .CH

R

6 0

R

(ix)V Lh (VI)

(XI)

in which is a leaving group, suitably a halogen atom, e.g. chlorine. Steps (vii) to (ix) may be carried out by conventional means, e.g. in accordance with the general procedures hereinafter illustrated in Examples 24.A.2 and A.3, steps (viii) and (ix) being carried out in Example 24.A.3 without purification of the WO 94/12493 PCT/EP92/02719 12 intermediate. As in Example 24.A.2 step (vii) is suitably carried out in an aprotic solvent such as acetone, in the presence of a base such as K 2 C0 3 and a catalyst such as KI.

Compounds of formula (IX) may be prepared by a variety of possible routes, for example as shown in the following general reaction sequence C (xii)

(XII)

R

R

1

NH

2 gBr. (xiii)

R

(x) CH 3

(XIV)

(XV)

j? 'i i: i i 7

C

2

H

5

CO

OCH

3 v 0 S(xiv)

CH

3

(XIII)

(IX)

Process steps and and (xii) through (xiv), may be carried out by conventional means, e.g. in accordance with the general procedures hereinafter illustrated in Examples 24.A.la and b and 24.A.la' and b' respectively.

In general, procedure via steps and (xi) will be preferred for larger scale synthesis.

When it is desired to produce 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 r Z ::t L~-ili- li-; i WO 94/12493 PCT/EP92/02719 substituents as R 1

/R

2 Similarly methyl substituents as

RI/R

2 can if desired, be converted to higher alkyl substituents. Conveniently such conversion reactions are carried out at the formula VI stage of synthesis employing conventional techniques, e.g. in accordance with the general procedures hereinafter illustrated in Examples 24.E.3, F.3, G.3.a G.3.b and H.3.a H.3.b.

Compounds of formula VI wherein R 8 is other than hydrogen may more conveniently be prepared in accordance with the following reaction sequence D.

8 tHal I o (xv) RR HO HR 8HO

(XVI)(XVI

(XVII)

R

6

-CO-

Hal CO-CH 3 (XVIII) j(xvi Oi) 0 (x vi i) 0 H Hal (x vi)

(XVIII)

6 (XX)

(XIX)

lal 0 6 8 7

(XXII)

(XXI)

(VI)

in which Hal is halogen, e.g. bromine, and R 8 is Ci- 5 alkyl. Process steps (xv) through (xxi) may be carried out by conventional means, e.g. in accordance with the procedures hereinafter illustrated in Example 24.1.

ML.-

A

WO 94/12493 PCTIEP92/02719 14 Intermediates illustrated above and in the accompanying Examples, notably intermediates of formulae II, IV and VI to VIII are new. Such intermediates, in particular the intermediates of formulae II and IV, and processes for their production also constitute part of the present invention.

The following Examples are illustrative of the processes of the present invention. All NMR spectra are recorded at 360 MHz. All temperatures are in degrees celsius and are uncorrected.

EXAMPLE 1 Production of (-)-(3S,4R)-1-[3,4-dihydro-2,2-dimethyl-3- -hydroxy-6-(2-methylpyridin-4-yl)-2H-l-benzopyran-4-yl]-2- -piperidinone [FORMULA I: R 1 Rg R 7

CH

3 R R 4 R H; Rs -OH; R 3 pure or substantially pure (3S,4R) enantiomers]. O A stirrpd solution of 2-piperidinone (19.8g) in dry tetrahydrofuran (400ml) at 10 0 C under argon is treated with a solution of lithium bi(trimethylsilyl)amide (200ml/1.0M) in tetrahydrofuran and stirred at room temperature for 2h.

The resulting suspension is treated with a solution of 4S)-4-(la,7b-dihydro-2,2-dimethyl-2H-oxireno[c] benzopyran-6-yl)-2-methylpyridine (26.7g;see Example 24.A.5' hereinafter) in dry tetrahydrofuran (150ml) and heated under reflux for 31h. The mixture is cooled to 15 0 C, treated with a saturated aqueous solution of NH 4 Cl (300ml) and extracted with ethyl acetate (2 x 150ml). The combined extracts are washed with brine (300ml), dried (Na 2

SO

4 and filtered. The solvent is evaporated off under reduced pressure to give a crude product which is purified by chromatography (silica gel, 54 C 2

H

5 0H in CH 2 C1 2 and recrystallised from C 2 H50H pentane to give the title compound, m.p. 192 0 C, [aID 2 0 -83.20 1.06, C 2 H50H). M.P. for the hemimaleate salt I b

A

PCT/EP92/02719 WO 94/12493 15 146-1480C.

The following compounds of formula Ia (I a) BCH3 are prepared analogously, production of the required oxireno starting material being illustrated in the Example indicated in the right-hand co?-'mn of the table.

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

STARTING MATERIAL' EXAMPLE R 1

R

2 RB Mn.P. *C ACCORDING TO EXAMPLE 24 2 CH 3 H H 184-185 3 H CH 3 H 205-206 4 C 2

H

5 H H 196-197

HO-CH

2 H H 200-201 6 CH 3

O-CH

2 H H 182-183 7 nC 3

H

7 H H 178-179 8 iC 4

H

9 H H 210-211 9 CH 3

CH

3 H 201-202

CH

3 H CH 3 219-221

I-

I

WO 94/12493 PCT/EP92/02719 16 EXAMPLE 11 Production of 1-[2,2-Dimethyl-6-(2-methylpyridin-4-yl)- -2H-l-benzopyran-4-yl]-2-piperidinone [Formula I: R 1

R

6

R

CH

3

R

2 R H; R 4

R

5 additional bond; R 3 A stirred solution of 2-piperidinone (0.90g-in dry dimethylsulphoxide (20ml) is treated with NaH (0.48g of a dispersion in oil) and stirred at 50 0 C for 30 min. under argon. The mixture is cooled to 10°C and treated with a solution of (±)-4-(la,7b-dihydro-2,2-dimethyl-2H-oxireno- [l]benzopyran-6-yl)-2-methylpyridine (2.67g, see Example 24.A.5) and stirred for 14h at room temperature under argon.

The solvent is evaporated off under reduced pressure and the residue treated with saturated aqueous NH 4 Cl (200ml) and extracted with CH 2 C12 (3xl00ml). The combined extracts are dried (Na 2 S0 4 filtered and the solvent is evaporated off under reduced pressure to yield a mixture. This is separated by chromatography (silica gel, 2% C 2 H50H in CH 2 C12) to yield a less polar product which is recrystallised from ethyl ether-pentane to give the title compound and a more polar compound which is recrystallised from CH 2 Cl 2 -diethyl ether to give the same product as that of Example 2 above. M.P. for the title compound 95-98 0

C.

EXAMPLE 12 Production of 1-[2,2-dimethyl-6-(3-methylpyridin-4-yl)- -2H-l-benzopyran-4-yl]-2-piperidinone [Formula I: R 2

R

7

CH

3 Ri Re H; R 4 R additional bond; R 3 r L The title compound is obtained together with the product of Example 3 above, starting from the product of Example 24.D.5.

hereinafter and proceeding analogously to Example 11 above.

Physical characteristics for the title compound: I WO 94/12493 1 7 PCTIEP92/02719 1 H-NMR DMSO): 1.41 1.45 1.77-1.96 58 .26 227-.68(m,3H), 3.37-3.58 58 6.92 7.14-7.20 (m,iAd), 7.36 8.39 (d,1H) and 8.45 (s,1H) EXAMPLE 13 Production of (+)-(3S,4R)-[3,4-dihydro-2,2-dimethyl-3- -hydroxy-6- (2-methylpyridin-4-yl) -2H-1-benzopyran]I-3-py ridine- -carboxamide (Formula I: R, R 6

=R

7

CH

3

R,

2

R

4 Re H;

R

3 C-H:pr rsbtnilypr 3,R enantiomerj A stirred solution of (+)-(3S,4R)-4-amino-3,4-dihydro-2,2- -dimethyl-6- (2-methylpyridin-4-yl) -2H-l-benzopyran-3-ol (0.65g: see Example 24.A.6' hereinafter), triethylamine (0.50g) and 4-dimethylaminopyridine (0.002g) in dry CH 2 Cl 2 (30m1) at 2*C under argon is treated with nicotinoyl chloride, hydrochloride (0.445g). The mixture is stirred for 2 hours at room temperature after which the mixture is treated with aqueous Na 2

CO

3 (1Q0ml/2M) and extracted with 3:1 CH 2 Cl 2

/CH

3 0H (3xlOOml). The combined extracts are washed with brine, dried (Na 2

SO

4 filtered and the solvent evaporated off under reduced pressure to yield an oil. The oil is purified by chromatography (silica gel, 2% C 2 HSOH in CH2C12) and recrystallised from C 2

H

5 OH-diethyl ether to give the title compound in enantiomerically pure or substantially pure form, m.p. 247-248*C, (a]D 0 +19.8 (c-0.965, C 2

H

5

OH).

The following compounds of formula lb 0 R 1O N H 3 R 8 CH3

I-

A

WO 94/12493 PCT/EP92/02719 18 are prepared analogously, production of the required 4-amino-benzopyran-3-ol starting material being illustrated in the example indicated in the right hand column of the table.

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

STARTING MATERIAL EXAMPL RI R 2

R

8 M.P. 0 C ACCORDING TO El__ EXAMPLE 24 14 CH 3 H H 230-231 A.6.

C

2

H

5 H H 192-193 B.6.

16 CH 3 0CH 2 H H 206-208 H.6.

17 nC 3

H

7 H H 206-207 E.6.

18 iC 4

H

9 H H 240-241 F.6.

19 CH 3

CH

3 H 239-241 C.6

CH

3 H CH 3 -1 234-236 1.6 EXAMPLE 21 Production of tran3- 4-dihydro-2,2-dimethvl-3- -hydroxy-6-- (2-methylpyridin-4-yl)-21-1-benzopyran-4-yaJ -2 (lH)- -pyridinone [Formula I: R, Rc R 7

CH

3 R5- RA RA H;

R

3 0O as the trans racemate] A stirred solution of 2-hydroxypyridine (0.42g) in dry C 2

H

5

OH

(20m1) is treated with NaH (0.21g of a 55% dispersion in oil) and stirred at room temperature for 15 min. under argon. The mixture is then cooled to 26C and treated with a solution of U W941431 9 F!CT/EP92,102719 (±)-4-(la,7b-dihydro-2,2-dimethyl-2H-oxireno~cJ [l~benzopyran- -6-yl)-2-methylpyridine (1.07g (see Example 24.A.5) and stirred for 96h at room temperature. The solvent is evaporated off under reduced pressure and the residue treated with satuzi':".ed aqueous NH 4 Cl (lO0rnl) and extracted with CH 2 Cl 2 (3xlOOml) The combined extracts are dried (Na 2

SO

4 filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 2% C 2

H

5 OH in CH 2 Cl 2 and4 recrystallised from

C

2

H

5 OH-diethyl ether to give the title compound, m.p.

213-214 0

C.

EXAMPLE 22 Production of Trans- 4-Dihydro-2, 2-dimethyl-3hydroxy-6- (2-methyl-pyridin-4-yl) -2H-1-benzopyran-4-yl] 3-di hydro-lH-i soindol-1 -one (Formula I L 1 R6 OH 3

R

2 R= H; R 3 Q- as the trans racemate]- A stirred solution of trans-(±)-4-amino-3,4-dihydro-2,2- -dimethyl-6- (2-methylpyridini-4-yl) -2H-l-benzopyran-3-ol (2-84g) (see Example 24.A.6) and 2-bromomethylbenzoic acid methyl ester (2-30g) in dry acetonitrile (100 ml) i treated with 1(1 (0-84g) and then K 2 C0 3 (4-20g) under argon. The reaction mixture is stirred for lh at 2000, lh at 60 0 C and then 15h at 850. The solvent is evaporated off under reduced pressure and the residue treated with H 2 0 (300m1) and extracted with 2% CH 3 0OH in CH 2 Cl 2 (4x150m1). The combined extracts are washed with sodium thiosulphate solution (1O0ml/2%), dried (Na 2

SO

4 and filtered. The solvent is evaporated off under reduced pressure to yield a crude product which is purified by chromatography (silica gel, 5% C 2 HSOH in

CH

2 Cl 2 and recrystallised from C 2

H

5 OH-acetone to give the title compound, m.p. 222-2240C.

r !f WO 94/12493 PCT/EP92/02719 20 EXAMPLE 23 Production of (-)-(3S,4R)-4-[3,4-Dihydro-2,2-dimethyl- -3-hydroxy-4-(2-oxo-piperidin-l-yl)-2H-l-benzopyran-6-yl]-2methylpyridine-N-oxide A solution of the product of Example 1 (2.6g) in CH2C1 2 ml) is treated with 3-chloroperoxybenzoic acid (1.92 g of and stirred at room temperature for 18 h. The solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel,

C

2 H50H in CH 2 C1 2 and recrystallised from acetone-diethyl ether to give the title compound, m.p. 202-205 0

C.

EXAMPLE 24 Production of starting materials for Examples 1 through 23 A.1. Preparation of 4-(4-methoxyphenyl)-2-methylpyridine A.1.a. 4-(4-Methoxyphenyl)-2-methyl-1(4H)-pyridinecarboxylic acid ethyl ester Ethyl chloroformate (10.85 g) is added to a stirred mixture of 2-picoline (9.30 g) and copper iodide (0.77 g) in dry tetrahydrofuran (150 ml), at -20 0 C under argon. The whole is stirred for 3 hours at -20°C and then treated dropwise with a solution of 4-methoxyphenyl magnesium bromide, prepared from 4-bromoanisole (18.7 g) and Mg turnings (2.64 g) in dry tetrahydrofuran (100 ml) at such a rate that the temperature remains between -150 and -20 0 C. The mixture is stirred at -150 for 1 hour, and 16 hours at 20 0 C and then treated with a saturated aqueous solution of NH 4 C1 (300 ml) and extracted with ethyl acetate (4 x 200 ml). The combined extracts are dried (Na 2 S0 4 filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, 50% toluene in hexane) c r I- WO 94/12493 PCT/EP92/02719 21 to give the title compound as a pale yellow oil.

A.1.b 4-(4-Methoxyphenyl)-2-methylpyridine The product of step A.l.a (16.9 g) and sulphur (2.0 g) in decahydronaphthalene (100 ml) is stirred at 200 0 °C for 3 hours.

The solvent is evaporated off under reduced pressure and the residue dissolved in ethyl acetate (500 ml) and extracted with HC1 (3 x 200 ml of 2M). The combined extracts were washed with ethyl acetate (2 x 100 ml), basified with ice-cooling to pH 11 with NaOH and extracted with CH 2 Cl 2 (3 x 200 ml). The combined extracts are dried (Na 2

SO

4 filtered and the solvent evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, 2%

C

2

H

5

OH/CH

2 Cl 2 and recrystallised from C 2

H

5 OH-ethyl acetate to yield the title compound, m.p. 88-91 0

C.

The title compound may alternatively be produced via the following route: A.1.a' 2,2',6'-Trimethyl-4-oxo-1,l'(4'H)-bipyridinium- -tetrafluoroborate 2-Methylpyridine (111.7g) is added to a freshly prepared solution of hydroxylamine-0-sulphonic acid (45.2 g, 90%) in

H

2 0 (260 ml) at 0 C. The mixture is heated to 95°C, stirred for a further 45 min, cooled to 10°C and cautiously treated with K2C03 (55 The mixture is washed with diethyl ether (2 x 100 ml) and the water evaporated off at 40 0 C under reduced pressure. The residue is treated with C 2 HsOH (600 ml) and the

K

2 S0 4 precipitate removed by filtration. The filtrate is treated with HC1 (120 ml of 18M) and evaporated to dryness at under reduced pressure to give a residue which is treated with dehydroacetic acid (68.6g) and HC1 (150 ml of 18M) and heated under reflux for 90 min. The solution is evaporated to dryness at 500 under reduced pressure and the residue stirred for 15 min with C 2 HsOH (200 ml), filtered and the precipitate

I-

WO 94/12493 PCT/EP92/02719 22 washed with C 2 H0OH (200 ml). The combined filtrate and washings are treated with tetrafluoroboric acid in ethyl ether ml of 50%) and diluted with diethyl ether (250 ml). On standing the title compound crystallises out and is filtered off and dried in vacuo at 20 0 C, m.p. 206-208 0

C.

A.l.b' 4-(4-Methoxyphenyl)-2-methyl-pyridine A stirred solution of 4-methoxyphenylmagnesium bromide prepared from 4-bromoanisole (56-1 g) and Mg turnings (7.92 g) in dry tetrahydrofuran (400 ml) at 0-50 is treated with the product of step (30.2 g) under an argon atmosphere.

The mixture is stired at room temperature for 48h, washed with saturated aqueous NH 4 Cl (300 ml) and the aqueous phase is extracted with CH 2 Cl 2 (3x100 ml). The combined tetrahydrofuran solution and CH 2 C12 extracts are dried (Na 2

SO

4 filtered and the solvent is evaporated off under reduced pressure to yield crude 4'-(4-methoxyphenyl)-2,2',6'-trimethyl-[1,1'(4H,4'H)- -bipyridin]-4-one. The crude product is dissolved in dry dimethylformamide (400 ml) and heated under reflux for 4 h.

The solvent is evapora.:ed off under reduced pressure to give a residue which is purified by chromatography (silica gel, 2%

C

2

H

5 0H in CH 2 C12) and recrystallised from C 2 H50H to yield the title compound m.p. 88-910.

A.2. Preparation of 4-(4-hydroxyphenyl)-2-methylpyridine A solution of the product of Example A.I. (6-45 g) in HBr (100 ml of 48 is heated at 1350 for 3h. The excess HBr is evaporated off under reduced pressure to give a residue which Sis neutralised with aqueous NaHC0 3 and extracted with 3:1

CH

2 C12/C 2 HsOH (3x150 ml). The combined extracts are dried (Na 2

SO

4 filtered and the solvent is evaporated off under reduced pressure to give the crude product. This is recrystallised from C 2 H50H-diethyl ether to give the title compound, m.p. 203-204°.

I I- I II II I I .II- WO 94/12493 2 PCT/EP92/02719 A.3. Preparation of 2,2-dimethyl-6-(2-methylpyridin-4-yl)- -2H-l-benzopyran.

A stirred mixture of the product of Example A.2. (4-07 g), anhydrous K 2 C0 3 (6,9 g) and KI (1-0 g) in dry acetone (75 ml) unde, irgon is treated with 3-chloro-3-methylbutyne (5-65 g) and L..ated under reflux for 120 h. The mixture is filtered and the solvent evaporated off under reduced pressure to yield crude 4-[4-(1,1-dimethyl-2-propynyl)oxyphenyl]-2-methylpyridine. This is dissolved in 1,2-dichlorobenzene (50 ml) and heated at 1700 for 1 h. The solvent is evaporated off under reduced pressure to give the crude title compound which is purified by chromatography (silica gel, 2% C 2

H

5 0H in CH 2 Cl 2 to give the title compound, m.p. 37-40 0

C.

The following compounds may be prepared analogously to Example A.1 to A.3 above proceeding either via steps (A.l.b) or all are recovered as 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-l-benzopyran; D.3. 2,2-Dimethyl-6-(3-methylpyridin-4-yl)-2H-l-benzopyran.

E.3. Preparation of 2,2-dimethyl-6-(2-propylpyridin-4-yl)- -2H-1-benzopyran To a stirred solution of the product of Example A.3. (5.02g) in dry tetrahydrofuran (50ml) at -25 0 C under argon is added a solution of n-butyl lithium (12.5ml, 1.6M) in hexane. The resulting mixture is stirred at 10 0 C for 40 min, cooled to -5 0

C

Sand treated with ethyl iodide (2.4ml). The mixture is allowed to warm to room temperature, stirred for an additional 2h and then treated with saturated aqueous NH4C1 (100ml) and extracted with ethyl acetate (2 x 100ml). The combined extracts are dried (Na 2 S0 4 filtered and the solvent is evaporated off under r i WO 94/12493 PCT/UP92/02719 24 reduced pressure to yield the crude product which is purified by chromatography (silica gel, 10% acetone in hexane) to yield the title compound as an oil.

F.3. Preparation of 2,2-dimethyl-6-(2-i.butylpyridin-4-yl)- -2H-l-benzopyran The title compound, prepared analogously to Example E.3.

employing isopropyl iodide in lieu of ethyl iodide, is obtained as an oil.

G.3. Preparation of 2,2-dimethyl-6-(2-hydroxymethylpyridin- -4-yl)-2H-l-benzopyran acetate G.3.a 4-(2,2-Dimethyl-2H-l-benzopyran-6-yl)-2-methylpyridine- -N-oxide A solution of the product of Example A.3. (13.4g) in CH 2 C12 (200ml) is treated with 3-chloroperoxybenzoic acid (13.5g of and stirred at room temperature for lh. The solvent is evaporated off under reduced pressure to give a residue which is purified by chromatography (silica gel, 5% C 2

H

5 0H in CH 2 C12) to give the title compound as a yellow gum.

G.3.b (2,2-Dimethyl-6-(2-hydroxymethylpyridin-4-yl)-2H-1 -benzopyran acetate A mixture of the product of step G.3.a (4.8g) and acetic anhydride (50ml) is heated at 80°C under argon for lh. The solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, ethyl acetate in toluene) to give the title compound as an oil.

i 7 WO 94/12493 PCT/EP92/02719 25 H.3. Preparation of 2,2-Dimethyl-6-(2-methoxymethylpyridin- 4 -yl)-2H-l-benzopyran H.3.a (2,2-Dimethyl-2H-l-benzopyran-6-yl)-2-pyridinemethanol A mixture of the product of Example G.3. (69.5g), Na 2 C03 (95.4g), H 2 0 (160ml) and C 2

H

5 0H (600ml) is stirred at room temperature for 22h. The mixture is filtered and the filtrate evaporated to dryness under reduced pressure to give a residue which is treated with H 2 0 (400ml) and extracted with CH 2 C12 (3x150ml). The combined extracts are dried (Na 2 S0 4 and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, ethyl acetate) and recrystallised from pentane to give the title compound, m.p. 86-88 0

C.

H.3.b (2,2-Dimethyl-2H-l-benzopyran-6-yl)-2-methoxymethyl pyridine A stirred solution of the product of step H.3.a (8.0g) in dry tetrahydrdfuran (150ml) at 15°C under argon is treated with NaH (0.90g of an 80% dispersion in oil) and stirred at room temperature for 45 min. Methyl iodide (4.26g) is added and the mixture is stirred at room temperature for 18h. The mixture is treated with saturated aqueous NH 4 C1 (200ml) and extracted with ethyl acetate (2x200ml). The combined extracts are dried (Na 2 S0 4 filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, 20% acetone in hexane) to give the title compouni as an oil.

I. Preparation of 6-(2-methylpyridin-4-yl)-2,2,7-trimethyl- -2H-l-benzopyran a. 4-Bromo-,3-methylphenol acetate A stirred mixture of 4-bromo-3-methylphenol (184.lg) and c a WO 94/12493 26 PCT/EP92/02719 aqueous NaOH (850 ml, 2M) at 20 0 C is treated with acetic anhydride (136 ml) and stirred at room temperature for lh.

The suspension is extracted with diethyl ether (3 x 300 ml) and the combined extracts are washed with aqueous Na0H (2 x 100 ml 2M), dried (Na 2 S0 4 and filtered. The solvent is evaporated off under reduced pressure to yield the title compound as an oil.

b. 1-(3-Bromo-2-hydroxy-5-methylphenyl)ethanone A mixture of the product of step a (195.6g) and aluminium chloride (152.6g) is stirred under argon at 165°C for min. The cooled mixture is treated with ice-cold HC1 (2000 ml, 2 M) and extracted with CH 2 C12 (4 x 600ml). The combined extracts are washed with brine, dried (Na 2 S0 4 filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, 10% toluene in hexane) and recrystallised from diethyl ether-hexane to give the title compound, m.p.

81-820C.

c. 6-Bromo-3,4-dihydro-2,2,7-trimethyl-2H-1-benzopyran-4-one A mixture of the product of step b (48g), acetone (31ml) and pyrrolidine (21ml) in dry benzene (500ml) is stirred at room temperature for 3h and then at reflux for 6h with water formed being removed via a Dean-Stark apparatus. The cooled mixture is treated with HC1 (200ml, 2M), stirred for 10 min, basified with aqueous NaOH (1M) and extracted with CH2Cl 2 (3x300ml). The combined extracts are dried (K 2 C0 3 filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, 50% toluene in hexane) and recrystallised from diethyl ether-pentane to give the title compound, m.p.

95-96 0

C.

r r- III I I r

&A

WO 94/12493 PCT/EP92/02719 27 d. 6-Bromo-3,4-dihydro-4-hydroxy-2,2,7-trimethyl-2H-l- -benzopyran A stirred solution of the product of step c (26.9g) in

C

2

H

5 0H (200 ml) at 5 0 C is treated with sodium borohydride (1.95g) and stirred at room temperature for 12h. The solvent is evaporated off under reduced pressure to give a residue which is treated with H 2 0 (500 ml) and extracted with diethyl ether (3x200ml). The combined extracts are dried (Na 2 S0 4 filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, 10% acetone in hexane) and recrystallised from diethyl ether-pentane to give the title compound, m.p. 92-93 0

C.

e. 6-Bromo-2,2,7-trimethyl-2H-l-benzopyran A stirred solution of the product of step d (27.1g) in dry toluene (300ml) is treated with p-toluenesulphonic acid (1.15g) and heated under reflux for 2h with water formed being removed via a Dean-Stark apparatus. The cooled solution is washed with aqueous sodium carbonate (100ml, 2M), dried (Na 2 S0 4 filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This 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-l-benzopyran A solution of the product of step e (7.60g) in dry tetrahydrofuran (30ml) is added over 15 min. to a stirred mixture of magnesium turnings (0.85g) and iodine (0.06g) in dry tetrahydrofuran (25ml) at 45 0 C under an argon atmosphere. The mixture is heated under reflux for 3h, cooled to 5 0 C, treated with bis-(triphenylphosphine)nickel (II) chloride (0.32g) and a solution of 4-bromopicoline (4.8g) in dry tetrahydrofuran (50ml) and stirred at room I il WO 94/12493 PCT/EP92/02719 28 temperature for 18h. The mixture is treated with HC1 (140ml, 1M) and extracted with diethyl ether (2x60ml). The combined other extracts are washed with HC1. The combined acid solutions are basified to pH 10 with K 2

CO

3 extracted with diethyl ether (3x100ml), dried (Na 2 S0 4 filtered and the solvent is evaporated off under reduced pressure to yield Sthe crude product. This purified by chromatography (silica gel, 10% acetone in hexane) to give the title compound as an oil, having the following physical characteristics: 1 H-NMR(3-CDC1 3 1.44 2.21 2.59 5.60 6.31 6.70 6.82 7.04 (dd,lH), 7.09 (d,lH) and 8.49 (d,lH).

A.4. Preparation of trans-(±)3-Bromo-3,4-dihydro-2,2- -dimethyl-6-(2-methylpyridin-4-yl)-2H-l-benzopyran-4-ol N-Bromosuccinimide (2-20 g) is added in portions to a stirred solution of the product of Example A.3. (2-50g) in dimethylsulphoxide (6 ml) and H 2 0 (0-36 ml) at 0°C. After exothermic reaction has subsided, stirring is continued for an additional lh and the reaction is quenched with saturated aqueous NH 4 Cl (200 ml) and extracted with CH 2 C12 (3x100 ml). The combined extracts are dried (Na 2

SO

4 filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, 2%

C

2

H

5 0 H in CH 2 C12) and recrystallised from C 2

H

5 0 H-diethyl ether to give the title compound, m.p. 212-214 0

C.

Preparation of (±)-4-(la,7b-Dihydro-2,2-dimethyl-2H-oxireno[c] []benzopyran-6-yl)-2-methylpyridine A solution of the product of Example A.4. (3-5 g) in dry tetrahydrofuran (80 ml) is treated with NaH (0-90 g of a 55 dispersion in oil) and stirred at room temperature under argon for 1 h. The reaction is quenched with a saturated aqueous solution of NH 4 C1 (150 ml) and extracted with diethyl ether (3x100 ml). The combined extracts are dried (Na 2

SO

4 filtered

I

r wtW WO 94/12493 PCT/EP92/02719 29 and the solvent is evaporated off under reduced pressure to give a residue which is purified by chromatography (silica gel, 2% C 2 H50H in CH 2 C12) to give the title compound as an oil having the following physical characteristics: 1 H-NMR (8-d 6 DMSO): 1-23 1-50 2-52 3-75 4.14 6-89 7-47 (dd,1H), 7-56 (s,lH), 7.19 (dd,lH), 7-96 (d,lH) and 8-47 (d,lH).

The following compounds of formula II in which R 6 and R7 a,'e each methyl and Ri, R 2 and R 8 have the significances indicated may be prepared analogously to Examples A4 and A5 above, but carrying out reaction by a one-pot procedure. This is done by diluting the mixture obtained subsequent to exothermic reaction and stirring according to Example A.4. with dioxan, treating with aqueous NaOH (0.6M) and stirring at room temperature for ca. lh further. Purification then proceeds analogously to Example A.5. following evaporation of dioxan. The starting materials are as shown in column 2 of the table. All products are obtained as the racemate in the form of an oil.

EXAMPLE STARTING R 1

R

2

RB

MATERIAL

FROM EXAMPLE B3 C 2

H

5 H H C3 CH 3

CH

3

H

D3 H CH 3

H

E3 nC 3

H

7 H H F3 iC 4

H

9 H H G3 HOCH 2 H H H3 CH30CH 2 H H I CH 3 H CH 3 r WO094/12493 PCT/EP92/02719 CHARACTERISING DATA 1HNMR (3-CDC1 3 1.31 1.37 1.62 (s,3H), 2.89 3,56 3.99 6.91 7.28 (dd,lH), 7.34 7,54 (dd,1H) 7.63 (d,1H) and 8.54 (dd, 1H).

'H-NMR (8-CDC1 3 )l 1.32 1.61 2.20 (s,3H), 2.61 3.54 3.39 6.87 6.98 7.17 (dd,1H), 7.26 (d,1H) and 8.32 (d,114).

1 H-NMR (8-ODC1 3 1.33 1.62 2.31 (s,3H), 3.55 3.95 6.89 7.13 7.23 (dd,1H), 7.31 8.45 (d,1H) and 8.49 (s,1H).

1 .M-NMR (6-CDCl 3 1.01 1.30 1.62 (s,3H), 1.82 (sex,2H), 2.82 3.54 3.98 (d,1H), 6.91 7.28 (dd,1H), 7.32 (d,lfl), 7.53 (dd,1E), 7.63 (d,1H) and 8.54 (d,1H).

1H-NMR (5-CDCl 3 0.96 1.30 1.62 (s,3H), 2.15 (dt,1H), 2.70 3.54 3.93 (dIH), 6.90 7.22-7,30 7.53 (dd,1H), 7.63 and 8.54 (d,lH).

1H-NMR (8-CDC1 3 1.31 1.63 3.55 (d,1H), 3.98 4.83 6.92 7.35-7.45 (m,2H), 7.54 (dd,1H), 7.64 (d,1H) and 8.57 (d,lH).

1 H-NMR (5-CDCl 3 1.29 1.59 2.21 (s,3H), 2.60 3.50 3.89 6.74 7.04 (dd,1H), 7.10 7.18 (s,1H) and 8.50 (d,1H).

Preparation of (-)-(3S,4S)-4-(la,7b-dihydro-2,2dimethyl-2H-oxireno(c] E1]benzopyran-6-yl) -2-methyl- 4 Pyridine [lR-(laU3R,4S),4p3i- and rlR-[1a(3S,4R),4r3)- -a-methoxybenzene acetic acid, 3-bromo-3,4-dihydro- 2-dimethyl-6- (2-methylpyridin-4-yl) -2H-1-benzopyran- -4-yl, ester.

A solution of the product of Example A.4. (9-80 g), (-)-(R)-a-methoxyphenylacetic acid (5.65 g) and 4-dimethylaminopyridine (0,45 g) in dry CH 2 C1 2 (330 ml), is tretedwith N,N-dicyclohexylcarbodiimide (6.81 g) and stirred for 90 min at room temperature. The mixture is

I-

WO 94/12493 3 1 PCT/EP92/02719 filtered and the solvent evaporated off under reduced pressure to give a crude mixture of diastereoisomers which is purified by chromatography (silica gel, 5% acetone in CH 2 C12) to yield a less polar product which is recrystallised from acetone-pentane to give the [1R-[1a(3R,4S),4] isomer of the title compound, m.p. 137-138 0 C, [a]D 20 -75.40 (c 0.955,

C

2

H

5 0H) and, as a more polar product, the [1R-[la(3S,4R),- 4p] isomer of the title compound as an oil, [a]D 2 0 -220 (c 0.975, C 2 HsH) (-)-(3S,4S)-4-(la,7b-Dihydro-2,2-dimethyl-2H- -oxireno[c] [1]benzopyran-6-yl)-2-methylpyridine A solution of [1R-[la(3R,4S),43] isomer product of step (3.16 g) in dioxan (75 ml) at 20 0 C is treated with aqueous Na0H (45 ml of 0.58 M) and stirred for 10 min at 20 0

C.

The dioxan is evaporated off under reduced pressure and the residue treated with H 2 0 (100 ml) and extracted with CH 2 Cl 2 (3 x 100 ml). The combined extracts are dried (Na 2

SO

4 filtered Sand the solvent is evaporated off under reduced pressure to give a residue which is purified by column chromatography (silica gel, 5% C 2

H

5 0H in CH 2 C12) to give the title compound in pure or substantially pure enatiomeric form as a colourless i oil, [a]D 2 0 -720 (c 1*125, C 2 HsOH).

Preparation of (+)-(3S,4R)-4-amino-3,4-dihydro-2,2- -dimethyl-6-(2-methylpyridin-4-yl)-2H-l-benzopyran-3-ol SA solution of the product of Example A.5' (0.64 g) is treated with saturated NH 3 in C 2

H

5 0H (15 ml) and heated at 800C in autoclave for 15 hours. The solvent is evaporated off under reduced pressure to yield the crude product which is purified Sby chromatography (silica gel, 5% C 2 H50H in CH 2 C12) to give the title compound as a foam: [a]2 0 D +1000, (c 1.00,

C

2

H

5

OH).

The following compounds of formula IV in which R 4 is H, R

I-

I

WO 94/12493 PCT/EP92/02719 32 is hydroxy, R 6 and R 7 are each methyl and R, R 2 and R 8 have the meanings shown may be produced analogously from the indicated starting material. All compounds listed in this table are in the form of the trans :acemate and, euxcept for the product of Example B6, are obtained as an oil.

STARTING

MATERIAIL

EXAMPLE R 1

R

2

R

8 ACCORDING TO

EXAMPLE

A6 CH 3 H H B6 C 2

H

5 H H C6 CH3- CH 3 H E6 nC 3

H

7 H H F6 iC 4 H9- H H H6 CH 3

OCH

2

CH

3 H 16 CH 3 H CH 3 1 PHYSICAL DATA A.6. 1 H-NMR (8 6 -DMSO) :1.12 1.38 2.06 (broad, 2H), 2.50 3.23 (dd,1H), 3.59 5.47 (d,1H), 6.81 7.43 (dd,1H), 7.51 7.55 (dd,1H), 7.99 (m,1H) and 8.44 (d,1H) B.6. M.P. =140-141*C.

C.6. 1H-NMR (8-CDCl 3 1.27 1.54 2.15 (s,3H), 012-.2.5 (br.s,3H), 2.57 3.41 3.71 (d,lH), 6.85 6.99 7.10 (dd,1H), 7.31 (dd,1H) and 8.31 (d,1H).

LI

WO 94/12493 PCT/EP92/02719 33 E.6. 1H-NMR (6-CDC1 3 1.00 1.27 1.55 (s,3H), 1.80 2.0-2.4 (br.s,3H), 2.80 3.41 (d,1H), 3.74 6.89 7.25-7.36 7.47 (dd,1H), 7.70 (d,lH) and 8.51 (d,lH).

F.6. 1 H-NMR (8-DMSO): 0.90 1.13 1.41 (s,3H), 2.0-2.2 (br.s,2H), 2.09 (dt,lH), 2.65 3.24 (dd,1H), 3.63 5.45 (br.d,1H), 6.84 7.48 7.58 (dd,lH), 8.00 (d,1H) and 8.46 (d,1H).

1.6. 1 H-NMR (8-CDC13): 1.24 1.53 2.1-2.4 (br.s,3H), 2.20 2.60 3.38 3.67 6.73 7.05 7.10 7.21 (s,lH) and 8.49 (d,1H).

Benzopyrans and dihydrobenzopyrans as defined under 1. above, for example compounds of formula I as hereinbefore defined, and their N-oxides, and physiologically-hydrolysable and -acceptable esters thereof, as well as pharmaceutically acceptable acid addition and quarternary ammonium salts of said benzopyrans/dihydrobenzopyrans/N-oxides/esters, (hereinafter collectively AGENTS OF THE INVENTION) are useful as pharmaceuticals.

AGENTS OF THE INVENTION possess smooth muscle relaxant activity and exhibit potassium channel opening activity in Srelation to the plasmalemma membrane as demonstrated by their influence at concentrations in the region of 1 to 500nM on tension in, and of Rb+ efflux from, various smooth muscle preparations in accordance with or analogously to the methods described in Quast, Brit. J. Pharmac., 91, 569-578 (1987).

AGENTS OF THE INVENTION are thereby characterised as K channel opening agents.

AGENTS OF THE INVENTION are accordingly useful for the I WO 94/12493 PCT/EP92/02719 34 treatment of conditions or disorders for which therapy employing a K+ channel opening agent is indicated. Therapeutic utility as K+ channel opening agents may further be demonstrated in standard pharmacological tests, e.g. of cardio-vascular activity, in vitro or in vivo. Thus influence on blood-pressure may be demonstrated in the anaesthetised, cannulated normotensive rat following intra duodenal administration 1 hr post cannulation. Anti-ischemic activity may be demonstrated in accordance with the methods described in Hof et al., Circ. Res., 62, 679 (1988). AGENTS OF THE INVENTION exhibit hypotensive activity in the former test method at threshold doses of from about 0.03 to about mg/kg i.d. and anti-ischemic activity in the latter test method at doses of from about 0.001 to about 0.03 mg/kg i.v..

AGENTS OF THE INVENTION are accordingly useful, e.g. as smooth muscle relaxants, in particular for use as vasodilating agents, for example for the treatment of hypertension or chronic cardiac insufficiency. They are further useful as anti-ischaemic and anti-vasospastic agents, e.g. for use in 1 the treatment of disturbed blood supply, for example to the heart, skeletal muscle or brain. They are thus useful e.g. for I the treatment of angina pectoris, myocardial ischaemia or myocardial infarction; as antifibrillatory agents; for the treatment of disorders of peripheral circulation, e.g.

claudicatio intermittens, Morbus Raynaud or venous ulcer; as well as for the treatment, including prophylaxis, of cerebral ischaemia, senile dementia, stroke, subarachnoidal hemorrhage and other related or consequential diseases or disorders.

AGENTS OF THE INVENTION are yet further indicated for use as gastro-intestinal, uterine and urinary tract antispastic agents, e.g. for the treatment of duodenal or peptic ulcer, irritable colon, diverticulitis, danger of miscarriage following premature labour and urinary incontinence.

AGENTS OF THE INVENTION are yet further indicated for use as Si 7 -i i WO 94/12493 PCTIEP92/02719 35 hair-growth stimulating agents, e.g. for the treatment of hair loss due to ageing, e.g. male alopecia or pattern baldness, or disease-related hair loss for example consequent to infection or disturbance of the immune system.

Suitable dosages for such use will of course vary, e.g.

depending on the particular condition to be treated, the particular AGENT OF THE INVENTION employed the mode of administration and the effect desired. In general however a suitable oral daily dosage, e.g. for anti-hypertensive uses, will be from about 0.03 to about 2.0 mg/kg and for, e.g.

anti-ischemic uses, from about 0.015 to about 0.3 mg/kg. For larger mammals, e.g. humans, an indicated oral daily dosage will thus be from about 2 to about 150 mg for anti-hypertensive uses, or from about 1 to about 20 mg for anti-ischemic uses, administered once or in divided doses 2x daily. Oral dosage forms for use in the above indications will thus suitably comprise from about 0.5 or 1.0 to about 20 or 150 mg AGENT OF THE INVENTION together with a pharmaceutically acceptable diluent or carrier therefor.

For use as hair-growth stimulating agents AGENTS OF THE INVENTION will appropriately be applied topically, e.g. in an appropriate cream, gel or emulsion base or the like as known in the art.

More importantly it has in accordance with the present invention been found that AGENTS OF THE INVENTION possess bronchodilator activity and reduce or reverse airways hyperreactivity. These activities may also be demonstrated in pharmaceutical test models in vivo and in vitro, for example as follows: WO 94/12493 PCT/EP92/02719 -36- TEST 1. BRONCHODILATOR ACTIVITY 1.1 In the Guinea-Pig Guinea-pigs (Dunkin-Hartley, male, 400-600g) are anaesthetised with phenobarbital (100 mg/kg and pentobarbital mg/kg and paralysed with gallamine (8 mg/kg and ventilated with a mixture of air and oxygen (45:55, v/v).

Animals are ventilated via a tracheal cannula (10 ml/kg, 1Hz).

Blood pressure and heart rate are recorded from the carotid artery. Ventilation is monitored by a flow transducer. When making measurements of flow, coincident pressure changes in the thorax are monitored directly via an intrathoracic trochar, permitting display of differential pressure relative to the trachea. From this information resistance and compliance are calculated at each inspiration.

Intravenous infusion of bombesin (100 ng/kg/h) induces sustained bronchospasm. Capacity of test substance to reverse response when administered by the intratracheal route serves as a measure of efficacy in reversing established bronchospasm. The bronchodilator response is taken as the percentage reduction of the maximal response to bombesin, measured at regular intervals.

In the above test model, AGENTS OF THE INVENTION effect dose related abrogation of bronchospasm at dosages of from about S0.001 to about 1.0 mg/kg.

i 1.2 In the Rhesus Monkey Rhesus monkeys (male and female, body wt 6.8-11.8kg) known to be normal responders to methacholine (MeCH), are anaesthetised (initial: ketamine 20mg/kg maintenance: thiopental 8mg/kg/h A cuffed pediatric endotracheal tube (5.0 cm) is then introduced into the trachea (xylocaine: topical administration at the epiglottus) and basal lung resistance iI I -I r i: -iii i s ii WO 94/12493 PCT/EP92/2719 37 measured.

Following these manoeuvres, 2ml xylocaine w/v solution) is administered at the carina with a pediatric fibreoptic bronchoscope. 10 minutes later, lung resistance is again measured. Xylocaine has no effect on base-line resistance.

Test substance is administered in a similar manner to xylocaine pretreatment, in a lactose vehicle suspension (Img/ml, 1ml delivered volume) in a cumulative manner at min. intervals. At the 15 minute time point, a single MeCH challenge (0.6 to 2.5 mg/ml solution, estimated to produce approximately a 50-100% change fron baseline) is performed and the inhibition calculated from the response after vehicle administration.

AGENTS OF THE INVENTION produce potent, dose-dependent bronchodilator effect in the above test method at dosages of from about 10 ng/kg to about 10 pg/kg.

TEST 2. SUPPRESSION OF AIRWAYS HYPERREACTIVITY 2.1 PAF-induced hyperreactivity Guinea-pigs are prepared for recording of lung function as described under Test 1.1 above. Intravenous injection of histamine (1.8-3.2 pg/kg) establishes airways sensitivity to spasmogen. Following infusion of PAF (platelet activating factor) over 1 hour (total dose 600 ng/kg), repeated injection of histamine reveals development of airways hyperreactivity, which can conveniently be expressed as the paired difference between the response amplitude before and after PAF exposure.

On administration of AGENTS OF THE INVENTION intratracheally after PAF exposure at dosages of from about 0.1 to about 100pg/kg, reversal of airways hyperreactivity induction is observed.

i *i WO 94/12493 PCTIEP92/02719 38 2.2 Immune-complex-induced hyperreactivity Guinea pigs are prepared for recording of lung-function as described under Test 1.1 above. An allergic reaction is initiated by intravenous injection of preformed immune-complexes (prepared by adding 30 pg of bovine gamma globulin in 0.05 ml of saline to 0.05 ml of guinea pig anti-bovine gamma globulin anti-serum) at regular (10 min) intervals for 30 min. Intravenous injections of histamine (1.0-3.2 pg/kg at 10 min intervals) are used to define the sensitivity of the airways prior to and following the last exposure to immune-complex. Airways hyperreactivity is expressed as the paired difference for the maximal value of lung resistance in response to histamine before and after repeated injection of immune-complex. Test compounds are administered intratracheally.

Induced airways hyperreactivity is significantly reduced in the above test method by prior treatment with AGENTS OF THE INVENTION, at dosages of from about 10ng/kg to about 10.0 pg/kg.

AGENTS OF THE INVENTION are accordingly useful in particular as bronchodilator agents and as agents for the therapy of airways hyperreactivity e.g. as agents for the symptomatic as well as prophylactic treatment of obstructive or inflammatory airways disease, in particular asthma. As bronchodilator Sagents, AGENTS OF THE INVENTION may be employed, in particular as rescue therapy, to treat bronchoconstrictor attack, e.g. in i asthma. In addition, by continued administration, AGENTS OF THE INVENTION may be used for the control, restriction or reversal of airways hyperreactivity or to provide advance protection against recurrence of bronchoconstrictor attack consequential to obstructive or inflammatory airways disease, in particular asthma. The words "treatment" and "treating" as used throughout the present specification and claims in relation to use of AGENTS OF THE INVENTION for the treatment i rI r 1 I

'I

WO 94/12493 PCT/EP92/02719 39 of obstructive or inflammatory airways disease, in particular asthma, are accordingly to be understood as embracing both prophylactic as well as symptomatic bronchodilator) modes of therapy, unless otherwise specified.

In accordance with the foregoing the present invention also provides: 4. A method for the treatment of any disease or condition herein specified; in particular 4.a A method for the treatment of obstructive or inflammatory airways disease; including 4.a.l A method for thEi symptomatic treatment of inflammatory or obstructive airways disease, e.g. of effecting I bronchodilatation; or 4.a.2 A method for the prophylactic treatment of inflammatory or obstructive airways disease, e.g. for the treatment of airways hyperreactivity; in a subject in need thereof, which method comprises administering to said subject an effective amount of an AGENT OF THE INVENTION: or, in the alternative: An AGENT OF THE INVENTION for use as a pharmaceutical, Se.g. for use in the treatment of any disease or condition as herein specified, in particular for use in the treatment of obstructive or inflammatory airways disease, e.g. as indicated under 4.a.l or 4.a.2 above; or 6. A pharmaceutical composition comprising an AGENT OF THE INVENTION, or use of an AGENT OF 2HE INVENTION for use in the preparation of a pharmaceutical composition, for use I I I I

A

WO 94/12493 PCT/EP92/02719 40 in the treatment of any disease or condition herein specified, in particular for use as set forth under above.

Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic and, especially, extrinsic asthma. They are useful for the treatment of allergic asthma, whether atopic, IgE-mediated) or non-atopic, as well as, for example, bronchitic asthma, exercise induced asthma, occupational asthma, asthma induced following bacterial infection and other non-allergic asthmas. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms, in particular at night, and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now more correctly identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "wheezy-infant syndrome".) Prophylactic .cacy in the treatment of asthma will be evidenced by Jed frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack.

It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory corticosteroid) or bronchodilatory P2 adrenergic) therapy.

Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant from any previously 1 WO 94/12493 PCT/EP92/02719 41 administered symptomatic asthma therapy, Inflammatory or obstructive airways diseases to which the present invention is applicable also include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic i or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and, in particular, byssinosis.

Further inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary or airways disease (COPD or COAD), and bronchitis, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy, e.g. p-agonist bronchodilator therapy, including in particular usage of AGENTS OF TH, INVENTION as bronchodilators for the treatment of chronic or acute airways obstruction as well as dyspnea, associated with any of the said diseases or conditions.

For use in the treatment of inflammatory or obstructive airways disease may be administered by any conventional route, in particular AGENTS OF THE INVENTION enterally, e.g. orally, for example in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions. Preferably however they will be administered by 1 the pulmonary route, e.g. by inhalation from an appropriate nebulizer, inhaler or like device as known in the art.

Dosages employed in the treatment of inflammatory or obstructive airways disease will of course vary depending, e.g. on the particular condition to be treated, the particular AGENT OF THE INVENTION employed, the mode of administration and the effect desired.

S IiI r 7

A

i 1 WO 94/12493 PCTIEP92/02719 42 In general however, for pulmonary administration for larger mammals, e.g. humans, a suitable daily dosage delivered to the lungs will be of the order of from about 0.lpg to about 100pg, in particular from about 1.0pg to about 50.0pg, suitably administered from an inhaler device with administration effected once or from 2 to 4x daily, in a series of from 1 to 4 puffs at each administration.

For oral administration a suitable daily dosage will generally be of the order of from about 0.1 to about 30pg/kg. A suitable oral daily dosage for larger mammals, e.g. humans, will thus be of the order of from about 7pg to about 2.1mg, administered in a single dose, in divided doses administered from 2 to 4x daily, or in sustained release form. Oral unit dosage forms for such use will thus suitably comprise from about 1.75pg to about 2.1mg AGENT OF THE INVENTION together with a pharmaceutically acceptable diluent or carrier therefor.

In this connection it is in particular to be noted that AGENTS OF THE INVENTION are generally active as bronchodilators or as agents for the treatment of airways hyperreactivity at dosages, in particular inhaled dosages, at which cardiovascular effects which would be undesirable in relation ito such therapy, e.g. hypotensive/tachycardial effect are non-significant or within acceptable limits of tolerability in relation to the therapy practiced.

In accordance with the foregoing the present invention also provides: 7. A pharmaceutical composition comprising an AGENT OF THE INVENTION together with a pharmaceutically acceptable diluent or carrier therefor.

Such compositions may be manufactured in conventional manner, e.g. for pulmonary administration by compounding AGENT OF THE

I--

WO 94/12493 PCT/EP92/02719 43 INVENTION in finely divided disperse particulate form, e.g.

together with finely divided lactose as a carrier/diluent to form an inhalable powder.

As previously indicated, therapeutic dosage requirements in practicing the present invention will vary depending on a variety of factors. Dosaging for any particular AGENT OF THE INVENTION will also depend on its relative potency of action.

For the preferred AGENT OF THE INVENTION, namely the product of Example 1 in pure or substantially pure (3S,4R) enantiomeric form an established ID 50 in one test run carried out in accordance with Test 1.1 hereinbefore is 0.02 mg/kg, An established ID 50 in the same test method for the known inhaled bronchodilator drug salbutamol [al-[[(1,1-Dimethyl ethyl)amino]-methyl]-4-hydroxy-1,3-benzenemethanol] is 0.001 mg/kg, Appropriate dosages of the Example 1 compound for administration by inhalation, e.g. for bronchodilator effect in asthma therapy, will thus be anticipated to be ca. 20x those conventionally required using i Salbutamol.

i

SI-

Claims (3)

1. A 2,2-di(CI- 5 alkyl)- or trans-2,2-di(Cj. 5 alkyl)-

4-dihydro-3--hydroxy- (pyridin-4-yl) -2H- I -l-benzopyran having a carboxamido moiety at the 4-position and wherein the pyridin-4-yl group is substituted at the 2- and/or 3-position by one or two members selected from the group comprising C 1 5 alkyl, C 1 5 (alkoxyalkyl), etro or -oxdethereof; such a benzopyran or N-oxide or acid addition or quarternary ammonium salt of such a benzopyran, N-oxide or ester. 2. A compound of fotmula I RR R 67 0 wherein R, and R 2 are independently, hydrogen, C 1 5 alkyl, Cl.. 5 hydroxyalkyl or C 1 5 (alkoxyalkyl), whereby at least one of R, and R2 is other thanf R 3 is a group of formula -N(Rg)-COR 1 a R 10 together are 1,3-butadienylene or represent weinRishdo.nadRi yiylrR 9 a

100-7943 45 group of formula -(CH 2 or -(CH2)m in which n is an integer of from 3 to 5 inclusive and m is 1 or 2, R 4 is hydrogen and R 5 is hydroxy in the trans position with respect to R 3 or R 4 and Rs together represent an additional bond as indicated by the dotted line, R 6 and R 7 are, independently, C 1 -salkyl, and R 8 is hydrogen or C -salkyl, or N-oxide thereof; or physiologically-hydrolysable and -acceptable ester of such a compound or N-oxide, or acid addition or quarternary ammonium salt of such a compound, N-oxide or ester. 3. A compound of formula I as illustrated in claim 1 iwherein: R 4 is hydrogen, R 5 is hydroxy in the trans position with respect to R 3 R 6 and R 7 are each methyl and A) R 3 is a group of formula 4t I S* j. and A) R 1 is methyl, ethyl, n-propyl, i-butyl, hydroxymethyl or methoxymethyl and R 2 and Re are each hydrogen, or A 2 RI and Rg are each hydrogen and R 2 is methyl, or A 3 R 1 and Re are each methyl and R 2 is hydrogen; or 11 1 I I 100-7943 46 B) R 3 is a group of formula CO-NH- and B 1 R 1 is methyl, ethyl, n-propyl, i-butyl or methoxy- methyl and R 2 and Re are each hydrogen, or B 2 R 1 and Re are each hydrogen and R 2 is methyl, or B 3 R 1 and R 8 are each methyl and Re is hydrogen; or C) R 3 is a group of formula or N- 0 RI is methyl and R 2 and Re are each hydrogen; or wherein RI is methyl and R 2 is hydrogen or RI is hydrogen and R 2 is methyl, R 6 and R 7 are each methyl, Re is hydrogen, R 4 and R 5 together represent an additional bond and R 3 is a group of formula or N-oxide thereof; or physiologically-hydrolysable and -acceptable ester of such a compound or N-oxide or acid addition or quarternary ammonium salt of such a compound, N-oxide or ester. A compound of formula I as illustrated in claim 2 lt IrI I 100-7943 47 wherein R 1 R 6 and R7 are each methyl, R 2 R 4 and R 8 are each hydrogen R 5 is hydroxy in the trans position with respect to R 3 and R 3 is a group of formula S0 or N-oxide thereof or acid addition salt of such a compound or N-oxide. A trans-2,2-di(C 1 -salkyl)-3,4-dihydro-3-hydroxy-6- -(pyridin-4-yl)-3H-l-benzopyran, N-oxide, ester or salt as claimed in claim 1 or compound of formula I as illustrated in claim 2 wherein R 4 is hydrogen and Rs is hydroxy in the trans position with respect to R 3 and RI, R 2 R3, R 6 R 7 and R 8 have the meanings given in claim 2 or N-oxide, ester or salt thereof as defined in claim 2, in (3S,4R) enantiomeric form. 6. A compound as claimed in claim 4 in (3S,4R) enantiomeric form. 7. A process for the production of a benzopyran, N-oxide, ester or salt as claimed in claim 1 which process comprises: 4, i) for the production of a benzopyran as aforesaid: i i reacting a la,7b-dihydro-2,2-di(Ci-salkyl)-6-(pyridin- -4-yl)-2H-oxireno[c] 1]benzopyran wherein the pyridin-4-yl group is substituted at the 2- and/or 3-position by one or two memebers selected from the group comprising C.-salkyl, CI-5hydroxyalkyl and C1_ 5 A\ (alkoxyalkyl), with an alkali metal salt of a carboxamide; or -48- i 2 acylating and, when required, alkylating the amino group of a 2,2-di(C 1 5 alkyl)- trans-2,2-di(C 1 5 alkyl)-3,4- dihydro-3-hydroxy-4-amino-6-(pyridin-4-yl)-2H-1- benzopyran wherein the pyridin-4-yl group is substituted at the 2- and/or 3-position by one or two members selected from the group comprising C1- 5 alkyl, C 1 hydroxyalkyl and Ci_ 5 (alkoxyalkyl); ii) for the production of a benzopyran N-oxide or physiologically-hydrolysable and -acceptable ester of a benzopyran or benzopyran N-oxide as aforesaid, esterifying a benzopyran or benzopyran N-oxide as aforesaid having a free hydroxy group or moiety to introduce an appropriate ester grouping and/or oxidising a benzopyran or physiologically-hydrolysable and -acceptable ester thereof as aforesaid; and recovering the obtained benzopyran, benzopyran N- oxide or physiologically-hydrolysable and -acceptable ester thereof in free or in acid addition or qu.aternary ammonium salt form. I 8. A pharmaceutical composition comprising a benzopyran, N- oxide, ester or pharmaceutically acceptable salt as i 25 claimed in claim 1 together with a pharmaceutically I: acceptable diluent or carrier therefor. S1 9. A method of treating obstructive or inflammatory airways disease in a subject in need thereof which method 30 comprises administering to said subject an effective amount of a benzopyran, N-oxide, ester or pharmaceutically acceptable salt as claimed in claim 1. 9S092S3p-Mp\dab,30826,spe,48 A i~ i i 1- -49- Benzopyrans, N-oxides, esters or salts as claimed in claim 1, processes for their production, pharmaceutical compositions containing them or methods of treatment involving them, substantially as hereinbefore described with reference to the Examples. DATED this 25th day of September, 1995 Sandoz Ltd. By Its Patent Attorneys DAVIES COLLISON CAVE i:: 4 S. s 9SO92,p'oper\&db,.826spt,49 INTERNkrIONAL SEARCH REPORT Intaritalonal Apiadton No PCT/EP 92/027 19 1. CLASSIFICATION OFSUBJECT MATTER (if several classficatdon symboLs apply, Indicate all06 According to Intaaooej Patent alasifiwon (lPC or to both National OuClajlton and WPC Int.Cl. 5 C07D405/14; A61K31/44; A61K31/445 U. FIELDS SEARCHED Minimum Documentation Senrched 7 Classification System Cassification Symbols Int.Cl. 5 C07D Documentation Searched other than Minimum Doaamsentadwo to the Extent that such Documents are Included in the Fields Sea i11. DOCUMENTS CONSIDERED TO BE RELEVANT9 caegry 0 Citation of Documnent, 11with inication, whtere aprprliate, of the relevant passailes' Relevnt to aalus No.1 3 X EP,A,0 346 724 (MERCK) 1,3-9 December 1989 see page 15 page 16; claims; example 4 A EP,A,0 488 301 URIACH,BARCELONA) 1,8,9 3 June 1992 see page 1 page 16; claims 0 Spocai ctegores o dieddocuents 10 lat ruent published after the International filing iato ~A oaientdefnla th mm l ~of r piorty ateand not in conflict with the application but ',dcuntide t e ealsae of pa reevn e onwihImdied to understnd the pinciple or then undslyng the 'E earlier klacument but publise on or after the international Ir document of particular relevance; the claimed Invention filing datit cannot be considere! aount or canno be considered to W document whIch may throw doubts ad proit lm(s) or Involv an taveative step which Is cited to establish the publictiondat of another Yr document of particular relevance; the claimed invention citation or otbe, special reason (as specified) cannot be considered to Involve an laventive stop whient the "Ow document referring to an wr'I disclo sa~ e. exhbItIon or document is combined with one or more other sucha docu- othe nowsmets such combiaation being obvious to a person skilled 'r document published prior to tho, internadoesl ag date but InteU1. later thwan the priority deit dallied document member of itho same pateai' family IV, CErTUKC41DON Date of the Actual Completion of the latevhatoaa Search Date of Malin~g C-1 this IneatltOMa Search ROpor JULY 1993 12. 07. 93 InternatMOn Searching Antbort.y Sigature of Authodlie Officer TrUROPEAN PATENT OMFCE FRANCOIS J.C.I You PCT/walo (wead OW) (jamary if" So win M scomwaltag Sliest ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. EP 9202719 SA 67161 71is- hats tie patent aamiy maberx reiating to the patmist domumnts cited in n bmbewmmhosed wnpad..oal aahreport. The w.br e as contined in the Europeam paen nffim EDP mea on The Euro~ea Patent Office is in no way liabl for th mptalrm~ which ame meiy given for the pum powm of infomnaion. 05/07/93 Patent doming poeliemion Pat" tautl Publication cited is march report date )dt EP-A-0346724 20-12-89 DE-A- 3820506 21-12-89 DE-A- 3835011 19-04-90 AU-B- 626549 06-08-92 AU-A- 3644089 21-17-89 JP-A- 2040375 09-02-90 AU-B- 628331 17-09-92 AU-A- 3390189 09-11-89 AU-B- 628395 17-09-92 AU-A- 4256589 26-04-90 EP-A- 0340718 08-11-89 EP-A- 0363883 18-04-90 JP-A- 1319481 25-12-89 JP-A- 2145584 05-06-90 US-A- 5013853 07-05-91 EP-A-0488301 03-06-92 None ia For imr dtaiis abouat thin na -z offiW Journal of the Ewroea Point Office, No. 12/12 I-