CA2122494A1 - 2,2-dialkyl- and 2,2-dialkyl-3,4-dihydro-3-hydroxy-2h-1- benzopyrans - Google Patents

Abstract

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

wog4/124s3 21 ~ 2 'I 9 4 PCT~ ~2/02719 2,2-DIALKYL- AND 2.2-DIALKYL-3,4-DIHYDRO-3-HYDROXY- 2H-l-~ENZOPYRANS, THEIR
USE AS PHARMACEUTICALS

The present invention relates to novel 2,2-dialkyl- and 2, 2-dialkyl-3, 4-dihydro-3-hydroxy- -2H-1 -benzopyrans and salts, esters and N-oxides thereof and to processes for their production, a~ well as to their use as pharmaceuticals and pharmaceutical compositions comprising them.

More particularly the preQent invention pro~ides in its broadest aspect:

l. A 2,2-di(C1_5alkyl)- or trans-2,2-di(C1_salkyl)--3,4-dihydro-3-hydroxy- -6-(pyridin-4-yl)-2H-l-benzopyran having a carboxa~ido 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_5alkyl, :
C1_shydroxyalkyl and C1_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 l.
above may be branched or straight chain. Preferred significance~ for sub-Qtituents at the 2-poQition 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 R6 and R7, and R1 and R2.

WO94l12493 212 2 4 9 4 PCT~2/02719 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, Chichester (1990), p.p. 181-255]. Benzopyran deri~ati~es 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(Rg)-CORlo as defined below.

As will be appreciated, the benzopyran nucleus of compounds defined under 1 may bear substituents in addition to those specifically defined. In particular they may, for example, be 7-Cl_salkyl substituted, especially ~-methyl substituted, e.g. as hereinafter indicated in relation to formula I.

In accordance with the present invention 2,2-di- - -~Cl_5alkyl)-3,4-dihydro-3-hydroxy-6-(pyridin-4-yl)`-2H-l--benzopyrans and/or -oxides, e-~ters, 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 the 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.
i~ ~
~ In a more speci~i~ aspect the present invention provides:

:

WO94/12493 212 2 4 9 '1 PCT~ ~2/02719 2. A compound of formula I

R ~ (I) wherein Rl and R2 are independently, hydrogen, Cl_salkyl, C1_shydroxyalkyl or C1 s(alkoxyalkyl), whereby at least one of R1 and R2 is other than hydrogen, R3 iS a group of for~ula -N~Rg)-CORlo wherein Rg is hydrogen and R1ois pyridyl or Rg and R1o together are l,3-butadienylene or repre~ent a group of formula ~(cH2)n- or ~(CH2)m ~ in which n is an integer of from 3 to 5 inclusi~e and m is l or 2, R4 is hydrogen and R5 is hydroxy in the trans position with respect to R3, or R4 and R5 together represent an additional bond as indicated by the dotted line, R6 and R7 are, independently, C1_salkyl, and R8 i~ hydrogen or Cl_salkyl, : or N-oxide the~reof;
or physiologically-hydrolyQable and -acceptable ester of such a compound~or,N-oxide, or acid addition or quarternary ammonium salt of ~uch a compound, N-oxide or ester.
~ ~ .
Alkyl groups as R1, R2, R6, R7 and R8, as well as alkyl moieties of hydroxyalkyl and alkoxyalkyl groups as R1 and R2 may be branched or straight chain. Alkoxyalkyl groups are preferably ~Cl_~alkoxy)-methyl, in particular methoxymethyl. .

~: ~

WO94,'12493 21 2 2 4 9 4 PCT~2/02719 Preferred hydroxyalkyl groups are hydroxymethyl. R6 and R7 are both preferably methyl. R8 is preferably hydrogen or methyl, most preferably hydrogen.

In a preferred group of compounds of formula I, Rl has any of the meanings gi~en above in relation to formula I and R2 is hydrogen or C1_5alkyl (especially methyl), preferably hydrogen.

In a further preferred group of compound~ of formula I, in the definition of R3, Rg is hydrogen and Rlo is pyridyl ' (especially 3-pyridyl) or Rg and Rlo together are l,3-butadienylene, trimethylene or tetramethylene. Most preferably Rg and Rlo together are tetramethylene.

Preferab]y R4 is hydrogen and R~ is hydroxy.
8enzopyrans of the invention, for example compounds of formula I, form N-oxides, e.g. ~t the nitrogen atom of the 6-pyridinyl group. Such N-oxides ha~e comparable activity (as hereinafter described) and tolerability to the parent compounds and also form part of the present invention.

By "physiologically-hydrolysable and -acceptable e-~ter" as used herein is meant an ester in which a hydroxy group (e.g., in relation to formula I, hydroxy gxoups Rs` and/or the hydroxy moiety of any hydroxyalkyl group present as R
and/or R2) is esterified and which is hydroly-~able 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. ~xamples 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 ha~e comparable 21~2~
WO9411~93 ` PCT~ ~2/02719 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 R4 is hydrogen and Rs is hydroxy, as well as their N-oxides, esters and salts as aforesaid, have the configuration ~3S*,4R*), i.e. the configuration of the groups R3 and Rs at the 3- and 4-positions is trans. Compounds of the in~ention thus exist in enantiomeric form, i.e. as optically active antipodes having the t3S,4Rl or t3R,4S] configur~tion. The present invention ls to be under tood aQ embracing both the individual enantiomers ~optically active, t3S,4R] or t3R,-S], antipode9) as well as mixtures, e.g. racemic mixtures, thereof.

In that pharmaceuticallutility in accordance with the invention i~ 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 Qubstantially pure form, e.g. comprising less than 10%, preferably 5~ or less, e.g. l or 2% or less WO94/12493 212 2 4 9 4 PCT~2/02719 of [3~,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 l 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 quartern~ry 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(Cl_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 Cl_salkyl, C1_shydroxyalkyl and C1_s-(alkoxyalkyl), for example a compound of fonmula II

wherein R1, R2, R6, R7i and R8 have the meanings for formula I above, with an alkali metal salt of a carboxamide, for example a compound of formula III

R1o-C0-N-Rg M (III) wherein R9 and R1o have the meanings given for formula I
above and M' is a lithium, sodium or potassium ion; or WO9411~93 212 2 ~ 9 4 PCT~ ~2/02719 ~ 7 i2) acylating and, when required, alkylating the amino group of a 2,2-di(C1_salkyl)- or trans-2,2-di~C1 5 alkyl)--3,4-dihydro-3-hydroxy- -4-amino-6-(pyridin-4-yl)-2H-l-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 Cl_5alkyl, Cl_shydroxyalkyl and Cl_5(alkoxyalkyl), for example, reacting a compound of formula IV

R1 ~ (IV) wherein Rl, R2 and R4 to R8 have the meanings given for formula I, with a compound of formula V, V' or V'' : R'lo~CO~Xl SV) X2-(CH2)n-COXl ~V') ~ ,(CH2 )m~X
(V~

COX

wherein R'lo is pyridyl and Xl and X2 are leaving groups; :

ii) for the production of a benzopyran N-oxide or physiologically-hydrolysable and -acceptable ester of a benzopyran or benzopyran N-oxide a~ afore~aid, esterifying a benzopyran or benzopyran N-oxide as defined under l above having a free hydroxy group or moiety to introduce an appropriate ester grouping, for example reacting a compound of formula I as herein-W094/1~493 212 2 4 ~ 4 PCT~W2/02719 before defined wherein Rs is hydroxy and/or at least oneof Rl and R2 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 l above, for e~ample oxidising 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 t ester thereof in free or in acid addition or quarternary a~monium salt foxm.

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 l to ll 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 ll and 12 hereinafter. Use of l-thium salts leads primarily or exclusively to the preferred dihydro--benzopyrans of the invention as illustrated in Examples l to lO hereinafter.

Process step i2) may also be carried out in accordance with methods known in the art. Suitable leaving groups Xl are halogen and acti~ated e~ter groups and suitable leaving groups x2 are halogen. Reaction is suitably carried out at temperatures of from 0 to 100C 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 Examplès 13 WO94/12493 9 212 2 4 9 4 PCT~ ~2/02719 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 (Cr03.Py2) 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 [i.e. 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 WO94/1~93 212 2 4 9 4 PCT~2/02719 dehydration across the 3,4-linkage, again in accordance with standard techniques. Further alternatives will be apparen~ to those skilled in the art.

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

R6 (VI) (ii ~ CH3O
~ ~ I .
R2 OH R2 ~ CH-CO-O

~8 R7 ~ ~ R7 (VII) (iv)\ V -~ SEPARATION OF ANTIPODES
~ ~,.
~ (vi) Process stepq (iii) through (~i) 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.5'a, and A.5'b.
`:
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'.

.

W094/1~93 212 2 4 9 4 PCT~ ~2/02719 Proceeding via steps (iii) and (iv), 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, ~R)-~--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 u~e of the (3R,4S) antipode and proceeding via step (vi) compound II starting materials may be obtained in pure or substantially pure (3S,4S) enantio~eric form.

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

R

~ 6 ~ C(X'')-CeC~

2 ~ R7 ~ ~ c~c (XI) in which X'' i-q 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 :

2 1 2 2 ~ 12 -intermediate. As in Example 24.A.2 stap (vii) is suitably carried out in an aprotic solvent such as acetone, in the presence of a base such as K2 C03 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 ~equence C

(XII) ~ ~2 Cl (x) I ..

C2~s ~
(XIII) ( ~ (xiv) (IX) Proce~ teps (x) and (xi), 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 ~x) and (xi) will be preferred for larger scale ynthesis.

When it is desired to produce compounds of the invention in which R1 and!or R2 are hydroxyalkyl ox alkoxyalkyl, .:
this can also be achieved by conversion of alkyl .

W094/12493 1 3 212 2 4 ~ 4 PCT~ ~2/02719 substituents as R1~R2. Similarly methyl substituents as R1/R2 can if desired, be converted to higher alkyl substituents. Conveniently such conversion reactions are carried out at the formula VI ctage of synthesis employing con~entional techniques, e.g. in accordance with the general procedures hereinafter illustrated in ~xamples 24.E.3, F.3, G.3.a + G.3.b and H.3.a + H.3.b.

Compounds of formula VI wherein R8 is other than hydrogen may more conveniently be prepared in accordance with the following reaction sequence D.

~ (xv) ~ ~ (xvi) ~ ~

R8 ~ H0 8 H0 ~ ~ 0-C0-CH3 (XVI~ (XVII) (XVIII) SXVIII) ~ ~ ~ ~ 76 (XX) (XIX) R1 ~ Ha1 H I (xx) a1 ~ R7 (xxi (XXII) (XXI) V ~ , (VI) in which ~al i~ halo~en, e.g. bromine, and R~ is C1_~alkyl. Process steps (xv) through (xxi) may be carried out by conventional means, e.g. in accordance with the procedures hereinafter illustrated in Example 29.I.

wos4/1~93 212 2 4 9 ~ PCT~2/02719 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.

EXA~I.E 1 ,, Production of (~ 3S,4R)-l-[3,4-dihydro-2,2-dimethvl-3--hyd~ -6-(2-methYlPyridin-4-Yl)-2H-l-benzoPyran-4-vl]-2--piperidinone ~FORMULA I~
i ~ : pure or substantiallY Pure (3S,4R)_enantiomers~. 'N O
-:~
~ stirred solution of 2-piperidinone (l9.8g) in dry tetrahydrofuran (400ml) at 10C under argon is treated with a solution of lithium bi(trimethylsilyl)amide (200ml/l.OM) in tetrahydrofuran and stirred at room temperature for 2h.
The resulting ~u-~pension is treated with a solution of (-)-(3S,4S)-4-(la,7b-dihydro-2,2-dimethyl-2H-oxireno[c]~l]-benzopyran-6-yl)-2-methylpyridine (26.7g;~ee Example 24.A.5' hereinafter) in dry tetrahydrofuran (lSOml) and heated under reflux for 31h. The mixture is cooled to lSC, treated with a saturated aqueous solution of NH4Cl (300ml) and extracted with ethyl acetate (2 x 150ml). The combined extracts are washed with brine (300ml), dried (Na2SO4) and filtered. The solvent is evaporated off under reduced pressure to give a crude product which is purified by chromatography (silica gel, 5% C2H50H in CH2Cl2) and recrystallised from C2H50H -pentane to give the title compound, m.p. = 192C, ~]D20 =
-83.2 (c= l.06, C2HsOH). M.P~ for the hemimaleate salt =

WO94/1~93 212 2 4 9 4 PCT~2/02719 146-148C~

The following compounds of formula Ia 12 ~ 0 1 ~ = C~3 ~Ia) are prepared analogously, production of the required oxireno starting material being illustrated in the Example indicated in the right-hand column of the table.

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

. STARTING MATERIAL
. EXAMPLE Rl R2 Rs m-p C ACCORDING TO

. , __ 2 CH3- N H 184-185 A.5.

3 H CH3- H 205-206 D.5.
. .
4 C2Hs- H H 196-197 B.5.
.
~0-C~2- ~ N 200-201 G.5.

6 CH30-CH2- H H 182-183 H.5.

7 nC,3H7- HI H 178-179 !E.5.
. . .:. _ . ~ .
8 iC4Hg- H H 210-211 F.5.
:~ ~ . ..... _ ~ . _ : CH3- CN3- H 201-202 C.5. , CH3- ~ CH3 219-221 ._ _ ' W094/12493 21~ 2 4 9 4 PCT~W2/02719 Ea~A~eL13 11 Production of 1-[2,2-Dimethyl-6-(2-methylPYridin-4-yl)--2H-l-benzopvran-4-vl]-2-~i~eridinone [Formula I: Rl = R6 = R7 __ N~o A stirred solution of 2-piperidinone (0.90g-in dry dimethylsulphoxide (20ml) is treated with NaH (0.48g of a 55%
dispersion in oil) and stirred at 50C for 30 min. under argon. The mixture is cooled to 10C and treated with a solution of (~)-4-(la,7b-dihydro-2,2-dimethyl-2H-oxireno-[c]~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 NH4Cl (200ml) and extracted with CH2Cl2 (3xlOOml). The combined extracts are dried (Na2 S04 ) ~ filtered and the solvent is evaporated off under reduced pressure to yield a mixture. This i5 separated by chromatography (silica gel, 2% C2HsOH in CH2Cl2) to yield a less polar product (A) which is recrystallised from ethyl ether-pentane to give the title compound and a more polar compound (B) which is recrystallised from CH2Cl2-diethyl ether to give the same product as that of Example 2 above. M.P. for the title compound = 95-98C.

EXA~PL~ 12 Production of 1-~2,2-dimethYl-6-(3-methYlPyridin-4-vl) -2H-1-benzopyran-4-vl]-2-piperidinone [Formula I: R
= CH3-; R1 - Rg = H; R4 + Rs _ itional bond; R~ = ~ ].
N-~
The title compound is obtained together with the product of Example 3 above, starting from the product of Example 24.D.S.
hereinafter and proceeding analogously to Example 11 above.
Physical characteristics for the title compound:

W094/1~93 l 7 2 ~ 2 2 4 ~ 4 PCT~2,027l9 ~ _NMR (~-d6 DMSO): 1.41 (s,3H), 1.45 ~s,3H), 1.77-1.96 ~m,3H), 2.26 (s,3H), 2.27-2.68 ~m,3H), 3.37-3.58 (m,2H), S.83 (s,lHj, 6.92 (d,lH), 7.14-7.20 ~m,2H), 7.36 (m,lH), 8.39 (d,lH) and 8.4S ~s,lH).

RXAMPL~ 13 Production of (+)-~3S,4R)-[3,4-dihvdro-2,2-dimethyl-3--hydroxv-6-~2-methYlPvridin-4-vl)-2H-l-benzopYran~-3-PYridine -carboxamide [Fonmula I: R1~ R6~_R7 ~ CH3; R?_~ R4 ~ R8 H;
R3 . ~ CO-NH-: Pure or substantially pure (3S,4R) enantiomerJ

A stirred solution of (+)-~3S,4R)-4-amino-3,4-dihydro-2,2--dimethyl-6-~2-methylpyridin-4-yl)-2H-1-benzopyran-3-ol (0.65g: ~ee Example 24.A.6' hereinafter), triethylamine (O.SOg) and 4-dimethylaminopyridine (0.002g) in dry CH2Cl2 ~30ml) at 2C under argon i~ treated with nicotinoyl chloride, hydrochloride (0~445g). The mixture is ~tirred for 2 hour~ at room temperature after which the mixture i~ treated with aqueou~ Na2CO3 (lOOml/2M) and extracted with 3:1 CH2 C12 /CH3~H
(3xlOOml). The combined extract~ are wa~hed with brine, dried (Na2SO4), filtered and the qolvent evaporated off under reduced pre-~ure to yield an oil. The oil i~ purified by ~-chromatography (~ilica gel, 2% C2H50H in CH2Cl2) and recry~talli~ed from C2H5OH-diethyl ether to give the title compound in enantiomerically pure or ~ub-~tantially pure form, m.p. 247-248C, t]D20 _ l19.8 ~c-0.965, C2HsOH).
$h~ follo~ing coqpound~ of fon~ula Ib N

~2 NH
Rl ~ OH3 ~Ib) wos4/1~s3 PCT~2102719 2122~'1 1 8 are prepared analogou~ly, 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 compound~ ted in thi~ table are in the form of the trans racemate.

~_ STARTING MATERIAL
EXAMPLE Rl R2 Ra m.p C ACCORDING TO
~XAMPLE 24 14 C~3- H H 230-231 A.6.

15 C2H5- H H 192-193 B. 6.

16CH3 OCH2- H H 206-208 H.6.
... _........ _ ~ _ 17nC3H7- H H 206-207 E.6.
..... _ ...... _ _ __ .
18iC~H9- H H 240-241 F.6.
.. . . l -~
19 CH3- CH3- H 239-241 C.6 .

20¦ Cl3- ¦ H ¦ CH ¦ 234-236 ¦ I 6 ~XA~PL~ 21 Production of trans-(+)-1-[3,4-dihvdro-2,2-dimethvl-3--hYdroxv-6-(2-me~hylPyridin-4-yl~-2H-l-benzopvran-4-yl]-2(lH) -p~ridinone ~Formula I: R~ - R6 R7 ~ CH3-; R2_~ R4_~ Ra - H;
R3 - ~ a3 th- tran~ racemate]

A stirred ~olution of 2-hydroxypyridine (0.42g~ in dry C2Hs0H
:~ .
(20ml) iq treated with NaH (0.21g of a 55~ dispersion in oil) ~ and stirred at room temperature for 15 min. under argon. The ;~ mixture i~ then cooled to 2C and treated with a solution of ~ .

W094/12493 l 9 ~12 2 4 3 4 PCT~2tO2719 (+)-4-(la,7b-dihydro-2,2-dimethyl-2H-oxireno[c][l]benzopyran--6-yl)-2-methylpyridine (1.07g (~ee Example 24.A.5) and stirred for 96h at room temperature. The solvent is evaporated off under reduced pres~ure and the reqidue treated with saturated aqueou~ NH4Cl (lOOml) and extracted with CH2Cl2 (3xlOOml). The combined extract~ are ~ried ~Na2SO4), filtered and the ~olvent i~ evaporated off under reduced pre~ure to yield the crude product which i9 purified by chromatography (silica gel, 2% C2HsOH in CH2C12) and recry~talli~ed from C2HsOH-diethyl ether to give the title compound, m.p.
21~-214C.

EXA~PLE 22 Production of Tran~-(+)-2-r3,4-Dihydro-2,2-dimethvl-3-hvdroxv-6-t2-methyl-pyridin-4-Yl)-2H-1-ben2opyran-4-yl~-2,3-di hYdro-lH-isoindol-l-one [Formula I: Rl = R6 ~ R7 ~ CH3-; R2 =
R4 = R~ - H; R~_~ ~ N- as th~ tran~ racemate]

A stirred ~olution of tran9-(+)-4-amino-3,4-dihydro-2,2--dimethyl-6-(2-methylpyridin-4-yl~-2~-1-benzopyran-3-ol (2-84g) ~see Example 24.A.6) and 2-bromomethylbenzoic acid methyl e~ter ~2-30g) in dry acetonitrile ~100 ml) i9 treated with K~ (0-84g) and then X2CO3 (4-20g) under argon. The reaction mixture is ~tirred for lh at 20C, lh at 60C and then lSh at 85. The ~olvent i~ evaporated off under reduced presQure and the residue treated with H20 ~300ml) and extracted with 2% CH30H in CH2C12 (4xl50ml). The combined extract~ are washed with sodium thio~ulphate solution (lOOml/2~), dried (Na2 S04 ) and filtered. ~he solvent i~
evaporated off under reduced pre~sure to yield a crude product which i~ purified by chromatography (silica gel, 5% C2H50H in CH2Cl2) and recrystalli~ed from C2H50H-acetone to give the title compound, m.p. 222-224C.

Production of (-)-(3S,4R)-4- r~, 4-Dihydro-2, 2-dimethYl--3-hydroxv-4-(2-oxo-piperidin-1-yl)-2H-1-benzopyran-6-vl]-2-methvlpvridine-N-oxide A solution of the product of Example 1 (2.6g) in CH2Cl2 (40 ml) is treated with 3-chloroperoxybenzoic acid (1.92 g of 90%) 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 tsilica gel, 5%
C2HsOH in CH2C12) and recrystallised from acetone-diethyl ether to give the title compound, m.p. 202-205C.

EXAMoeLE 24 Production of startin~ materials for Examples 1 throuqh 23 "

A.l. Preparation of 4-(4-methoxy~henyl)-2-methYlPyridine A.l.a. 4-(4-MethoxvPhenYl)-2-methvl-1~-4H)-pyridinecarboxYlic acid ethvl ester Ethyl chloroformate (10.85 g) is added to a stirred mixture of 2-picoline ~9.30 g) and copper (I) iodide (0.77 g) in dry tetrahydrofuran (150 ml), at -20C under argon. The whole is stirred for 3 hours at -20C 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 tetra-hydrofuran (100 ml) at such~a rate that the temperature remains between -15 and -20C. The mixture iis stirred at -15 for 1 hour, and 16 hours at 20C and then treated with a saturated aqueous isolution of NH4Cl (300 ml) and extracted with ethyl acetate (4 x 200 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, SO~ toluene in hexane) .

:

WO 94/12493 21~ 2 4 9 4 PCTIEP92/~2719 to give the title compound as a pale yellow oil.

A.l.b 4-(4-MethoxyphenYl)-2-methylpYridine The product of step A.l.a (16.9 g) and sulphur ~2.0 g) in decahydro~aphthalene (100 ml) is stirred at 200C for 3 hours.
The solvent is evaporated off under reduced pressure and the residue dissolved in ethyl acetate (500 ml) and extracted with HCl (3 x 200 ml of 2M). The combined extracts were washed with ethyl acetate (2 x 100 ml), basified with ice-cooling to pH ~1 with NaO~ and extracted with CH2C12 (3 x 200 ml). The combined extracts are dried (Na2 S04 ), filtered and the solvent evaporated off under reduced pressure to yield the crude ~
product. This is purified by chromatography (silica gel, 2% ' C2H50H/CH2C12) and recrystallised from C2HsOH-ethyl acetate to yield the ~itle compound, m.p. 88-91C.

The titl~ compound may alternatively be produced via the following route:

A.l.a' 2,2',6'-Trimet~ 4-oxo-1 t 1 ~ (4'H)-bipvridinium--tetrafluoroborate 2-Methylpyridine (111.7g) is added to a freshly prepared solution of hydroxylamine-O-sulphonic acid (45.2 g, 90%) in H20 ~260 ml) at 0C. The mixture is heated to 95C, stirred for a further 45 min, cooled to 10C and cautiously treated with K2C03 (55 g). The mixture is washed with diethyl ether (2 x 100 ml) and the water evaporated off at 40C under reduced pressure,. The residue is tre,at,ed with C2H5OH ~600 ml) and the K2 S04 precipitate removed by filtration. The filtrate is treated with HCl (120 ml of 18M) and evaporated to dryness at 50C under reduced pressure to give a residue which is treated with dehy~roacetic acid (68.6g) and HCl (150 ml of 18M) and heated under reflux for 90 min. The -~olution is evaporated to dryness at 50 under reduced pressure and the residue stirred for lS min with C2H50H (200 ml), filtered and the precipitate W094/1~93 PCT~ ~2/02719 21224~4 22 -washed with C2H50H (200 ml). The combined filtrate and washings are treated with tetrafluoroboric acid in ethyl ether (50 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 20C, m.p. 206-208C.

A.l.b' 4-(4-MethoxvPhenyl)-2-methvl-P~ridine A stirred solution of 4-methoxyphenylmagne~ium bromide prepared from 4-bromoanisole (56-1 g) and Mg turnings (7.92,g) in dry tetrahydrofuran ~400 ml) at 0-5 is treated with the product of step (A.l.a') (30.2 g) under an argon atmosphere.
The mixture is stired at room temperature for 48h, washed with saturated aqueous NH4Cl (300 ml) and the aqueous phase is extracted with CH2C12 (3xlOO ml). The combined tetrahydrofuran solution and CH2Cl2 extract~ are dried (Na2SO4), filtered and the -Qolvent is evaporated off under reduced pre~sure to yield crude 4'-(4-methoxyphenyl)-2,2',6'-trimethyl-~1,1'(4H,4'H)--bipyridin]-4-one. The crude product is di~olved in dry dimethylformamide (400 ml) and heated under reflux for 4 h.
The solvent i~ evaporated off under reduced pre~sure to give a residue which is purified by chromatography (~ilica gel, 2%
C2H50H in CH2Cl2) and recryQtallised from C2H50H to yield the title compound m.p. 88-91.

A.2. PreParation of 4-(4-hYdroxvphenvl)-2-methvlPvridine A solution of the product of Example A.l. (6-45 g) in HBr (100 ml of 48 %) is heated at 135 for 3h. The exce-q~ HBr is evaporated off under reduced pre~ure to give a re~idue which is neutrali~ed with aqueous NaHCO3 and extracted with 3:1 CH2Cl2/C2H50H (3xlSO ml). The combined extracts are dried (Na2 S04 ), filtered and the solvent is evaporated off under re-duced pres~ure to give the crude product. This is recrystalli-~ed from C2 HsOH-diethyl ether to give the title ~ compound, m.p. 203-204.

::

W094/12493 212 2 4 9 4 PCT~2/02719 A.3 Preparation of 2,2-dimethyl-6-(?-methylpyridin-4-y -2H-l-benzopyran.

A stirred mixture of the product of Example A.2. (4 07 g), anhydrous K2C03 (6-9 g) and KI (1 0 g) in dry acetone (75 ml) under argon is treated with 3-chloro-3-me~hylbutyne (5-65 g) and heated 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-methylpyri-dine. This is dissolved in 1,2-dichlorobenzene (SO ml) and heated at 170 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~ C2H50H in CH2C12), to give the title compound, m.p. 37-40C.

The following compounds may be prepared analogously to Example A.1 to A.3 above proceeding either via steps (A.l.a) + (A.l.b) or (A.l.a' + (A.l.b~); 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-1-benzopyran;

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

E.3. Preparation of 2,2-dimethvl-6-(2-prop~lpvridin-4-yl)--2H-1-benzoPyran To a stirred solution of the product of Example A~3. (5.02g) in dry tetrahydrofuran (50ml) at -25C under argon is added a solution of n-butyl lithium (12.5ml, 1.6M) in hexane. The resulting mixture is stirred at 10C for 40 min, cooled to -5C
and 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 NH4Cl (lOOml) and extracted with ethyl acetate (2 x lOOml). The combined extracts are dried `
(Na2 S04 ), filtered and the solvent is evaporated off under WO9~/124~3 212 2 ~ 9 4 PCT~2/02719 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.butylPvridin-4-vl)--?H-l-benzopyran The title compound, prepared analogously to Example E.3.
employing isopropyl iodide in lieu of ethyl iodide, is obtai~ed as an oil.

G.3. Preparation of 2,2-dimethvl-6-(2-hYdroxymethYlPyridin--4-yl)-2H-1-benzopyran acetate G.3.a 4-(2,2-Dimethyl-2H-1-benzopvran-6-Yl)-2-methYlPYridine--N-oxide A solution of the product of Example A.3. (13.4g) in CH2C12 (200ml) is treated with 3-chloroperoxybenzoic acid (13.5g of 70%) 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% C2H50H in CH2C12) to give the title compound as a yellow gum.
.
G.3 b (2,2-Dlmethyl-6-(2-~ oxymethYlpvridin-4-vl)-2H-1 -benzo~yran acetate A mixture of the product of;step G.3.a (4.8g) and acetic anhydride (50ml) is heated at 80C under argon for lh. The solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 10% ethyl acetate in toluene) to give the title compound as an oil.

:

W094/12493 212 2 4 9 4 PCT~ ~2/02719 H.3. Preparation of 2,2-Dimethvl-6-(2-methoxYmethYlpvridin -4-yl)-2H-l-benzoPYran ~3.a (2,2-Dimethyl-2H-1-benzopyran-6-yl)-2-pyridinemethanol mixture of the product of Example G.3. ~69.5g), Na2CO3 ~95.4g), H20 (160ml) and C2H50H ~600ml) is stirred at room temperature for 22h. The mixture is filtered and the filtrate evaporated to dryness under reduced pres~ure to give a residue which is treated with H20 (400ml) and extracted wlth C~2Cl2 (3xlSOml). The combined extracts are dried (Na2 S04 ) 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. 86-88C.

.3.b (2,2-~imethvl-2H-1-benzoPYran-6-yl)-2-methoxvmethyl Pvridine ,, ' .
A stirred solution of the product of step H.3.a (8.0g) in dry tetrahydrofuran (150ml3 at 15C under argon is treated with NaH
(0~9Og 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 ~aturated aqueous NH4Cl ~200ml) and extracted with -ethyl acetate (2x200ml). The combined extracts are dried (Na2SO4), 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 compound as-an oil.
-I. Preparation of 6-(2-methylPyridin-4-vl)-2~2~7-trimeth -2~-1-benzopyran a. 4-Bromo-3-methvlphenol acetate :
A stirred mixture of 4-bromo-3-methylphenol (184.lg) and 2122~ 2~

aqueous NaOH ~850 ml, 2M) at 20C 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 NaOH (2 x 100 ml-2M), dried (Na2 S04) 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-methvlphenYl)ethanone A mixture of the product of step a (195.6g) and aluminium chloride (152.6g) is stirred under argon at 165C for 45 min. The cooled mixture is treated with ice-cold HCl (2000 ~-ml, 2 M) and extracted with CH2Cl2 (4 x 600ml). The combined extracts are washed with brine, dried (Na2 S04 ), 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.
81-82C.

c. 6-Bromo-3,4-dihYdro-2,2,7-trimethvl-2H-l-benzoPyran-4-one A mixture of the product of step b ~48g), acetone (31ml) and pyrrolidine (21ml) in dry benzene (5aOml) is stirred at room temperature for 3h and then at reflux for 6h with water formed b~ing removed via a Dean-Stark apparatus. The cooled mixture is treated with HCl (200ml, 2M), stirred for 10 min, basified with aqueous NaOH (lM) and extracted with CH2C12 (3x300ml). The combined extracts are dried (K2CO3), 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.
95-96C.

Wo94/12493 21 2 2 4 9 4 PCT~ ~2/02719 d. 6-Bromo-3,4-dihvdro-4-hydroxy-2,2,7-trimethyl-2H-l--benzopyran A stirred solution of the product of ~tep c ~26.9g) in C2HsOH (200 ml) at 5C is treated with codium borohydride (1.95g) and stirred at room temperature for 12h. The solvent is evaporated off under reduced pre~sure to give a residue which is treated with H20 (500 ml) and extracted with diethyl ether (3x200ml). The combined extracts are dried (Na2 S04 ), filtered and the solvent is evaporated off unde~
reduced pre~sure to yield the crude product. This i8 ::
purified by chromatography (silica gel, 10% acetone in hexane) and recrystallised from diethyl ether-pentane to give the title compound, m.p. 92-93C. -e. 6-Bromo-2,2,7-trimethvl-2H-1-benzoPyr~n - A stirred solution of the product of step d (27.lg) in dry toluene (300ml) is treated with p-toluene-~ulphonic acid ~1.15g) and heated under reflux for 2h with water formed being removed via a Dean-Stark apparatu~. The cooled -~
solution is wa~hed with aqueou~ sodium carbonate (lOOml, ~-2M), dried (Na2 S04 ), 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-methvlPvridin-4-vl)-2~2~7-trimethyl-2H-l-benzopvran ~A solution of the product of step e (7.60g) in dry tetrahydrofuran (30ml) is added over 15 min. to a stirred mixture of magne~ium turnings (0.85g) and iodine (0.06g) in dry tetrahydrofuran (25ml) at 45C under an argon atmo~phere. The mixture is heated under reflux for 3h, cooled to 5C, 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 W094/12493 PCT~2/02719 212249~ - 28 -temperature for 18h. The mixture is treated with HCl (140ml, lM) and extracted with diethyl ether (2x~0ml). The combined ether extracts are washed with HCl. The combined acid solutions are basified to pH 10 with K2C03, extracted with di~thyl ether (3xlOOml), dried (Na2SO4~, filtered and the solvent is evaporated off under reduced pressure to yield the 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:
H-NMR(~-CDCl3): 1.44 (s,6H), 2.21 (s,3H), 2.59 (s,3H), 5~.60 (d,lH), 6.31 (d,lH), 6.70 (s,lH), 6.82 ~s,lH), 7.04 ~dd,lH), 7.09 (d,lH) and 8.49 (d,lH).

A.4. Preparation of trans-~1)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 H20 (0-36 ml) at 0C. After exothermic reaction has subsided, stirring ii~ continued for an additional lh and the reaction is quenched with saturated aq-ueous NH4Cl (200 ml) and extracted with CH2Cl2 (3xlOO ml). The co~bined extracts are dried (Na2 S04 ), filtered and the solvent is evaporated off~under reduced pressure to yield the crude product. This ii~ purified by chromatography ~iilica gel, 2%
C2H5OH in CH2C12) and recrystalliised from C2H5OH-diethyl ether to give the title compound, m.p. 212-214C.

A.5. Preparation of (+)-4-(la,7b-Dihydro-2,2-dimethyl-2H-oxi-reno[c]~l]benzopyran-6-yl)-2-methylPvridine A solution of the product of Example A.4. (3-5 g) in dry tetra-hydrofuran (80 ml) is treated with NaH (0-90 g of a 55 ~
dispersion in oil) and i3tirred at room temperature under argon for 1 h. The reaction is quenched with a iiaturated aqueous solution of NH4Cl ~150 ml) and extracted with diethyl ether (3xlOO ml). The combined extracts are dried (Na2 S04 ), filtered W094/12493 212 2 4 9 4 PCT~ ~2/02719 and the solvent is evaporated off under reduced pressure to ~;~
give a residue which is purified by chromatography (silica gel, 2% C2H50H in CH2Cl2) to give the title compound as an oil having the follawing physical characteristics:
H-NMR (~-d6 DMSO): l-23 (s,3H), l 50 (s,3H), 2-52 (s,3H), 3 75 (d,lH~, 4-14 (d,lH), 6-89 ~d,lH), 7-47 (dd,lH), 7-56 (s,lH), 7 l9 (dd,lH), 7-96 (d,lH) and 8-47 (d,lH?.

The following compounds of formula II in which R6 and R7 are each methyl and Rl, R2 and R8 have the significances indicate~d 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 Rl R2 Rs MATERIAL
FROM ExAMoeLE
, .. ~.

: ~
E5 E3 nÇ3H7~ H H
. . _ . _ _ _ F5 F3 iC4Hg- H H
_ . _ -H5 H3 CH3OcH2- H

¦ I5 l I ¦ CH3- ¦ H ¦ CH3-WO94/12493 212 2 4 9 4 PCT~2/02719 CHARACTERISING DATA
B.5. lHNMR (~-CDC13): 1.31 (s,3H), 1.37 (t,3H), 1.62 (s,3H), 2.89 (q,2H), 3,56 (d,lH), 3.99 (d,lH), 6.91 (d,lH), 7.28 (dd,lH3, 7.34 (m,lH), 7,54 (dd,lH) 7.63 (d,lH) and 8.54 (dd,lH).
C.5. lH-NMR (~-CDC13): 1.32 (s,3H), 1.61 (s,3H), 2.20 ~s,3H), 2.61 (s,3H), 3.54 (d,lH), 3.39 (d,lH), 6.87 (d,lH), 6.98 (d,lH), 7.17 ~dd,lH), 7.26 (d,lH) and 8.32 (d,lH).
D.5 lH-NMR (~-CDC13): 1.33 (s,3H), 1.62 (s,3H), 2.31 (s,3H), 3.55 (d,lH), 3.95 (d,lH), 6.89 (d,lH), 7.13 (d,lH), 7.23 (dd,lH), 7.31 (s,lH), 8.45 (d,lH) and 8.49 (s,lH).
.5. lH-NMR (~-CDC13): 1.01 (t,3H), 1.30 (s,3H), 1.62 (s,3H), 1.82 (sex,2H), ~.82 (t,2H), 3.54 (d,lH), 3.98 (d,lH), 6.91 (d,lH), 7.28 (dd,lH), 7.32 (d,lH), 7.53 Idd,lH), 7.63 (d,lH) and 8.54 (d,lH).
F.5. lH-NMR (~-CDC13): 0.96 (d,6H), 1.30 (s,3H), 1.62 (s,3H), 2.15 (dt,lH), 2.70 (d,2H~, 3.54 (d,lH), 3.93 (d,lH), 6.90 (d,lH), 7.22-7.30 (m,2H), 7.53 (dd,lH), 7.63 (d,lH) and 8.54 (d,lH).
G.5. lH-NMR (~-CDC13): 1.31 (s,3H), 1.63 (s,3H), 3.55 (d,lH), 3.98 (d,lH), 4.83 (s,2H), 6.92 (d,lH), 7.35-7.45 (m,2H), 7.54 (dd,lH), 7.64 (d,lH) and 8.57 (d,lH).
I.5~ lH-NMR (~-CDC13): 1.29 (s,3H), 1.59 (s,3H), 2.21 (s,3H), ~`
2.60 (s,3H), 3.50 (d,lH), 3.89 (d,lH), 6.74 (s,lH), 7.04 (dd,lH), 7.10 (d,lH), 7.18 (s,lH) and 8.50 (d,lH).

A.5' PreParation of (-)-(3S,4S)-4-(la,7b-dihydro-2,2-dimethyl-2H-oxireno~c][l]benzoPyran-6-yl)-2-meth vridine A.5.'a ~lR-[1~(3R,4S),4~]- and [lR-tla(3S,4R),4~]---methoxvbenzene acetic acid, 3-bromo-3,4-dihvdro--2,2-dimethYl-6 (2-methylpyridin-4-vl)-2H-l-benzopyran--4-vl, ester.

A solution of the product of Example A.4. (9-80 g), -(-)-(R)--methoxyphenylacetic acid (5-65 g) and 4-dimethylaminopyridine (0,45 g) in dry CH2C12 (330 ml), is treated with N,N-dicyclohexylcarbodiimide (6-81 g) and stirred for 90 min at room temperature. The mixture is :

W094/12493 3 1 212 2 4 9 4 PcT~2/027l9 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 CH2Cl2) to yield a less polar product (A) which is recrystallised from acetone-pentane to give the [lR-[la(3R,4S),4~] isomer of the title compound, m.p. 137-138C, []D20 - -75.4 (c = 0.955, C2H5OH) and, as a more polar product, ~B) the [lR-[la~3S,4R),-4~] isomer of the title compound as an oil, [a]D20 = -22 (c = -~
0.975, C2HsOH). :~

A.5'.b (-)-(3S,4S)-4-(la,7b-Dihvdro-2,2-dimethyl-2H--oxireno[c][l]benzopyran-6-vl)-2-msthvlpyridine A solution of [lR-[1~(3R,4S),4~] isomer product of step (A.5'.a) (3.16 g) in dioxan (75 ml) at 20C is treated with aqueous NaOH (45 ml of 0-58 M) and stirred for 10 min at 20C.
The dioxan is evaporated off under reduced pressure and the residue treated with H20 (100 ml) and extracted with CH2Cl2 (3 -~
x 100 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to give a residue which is purified by column chromatography (silica gel, 5~ C2H50H in CH2Cl2) to give the title compound in pure or substantially pure enatiomeric form as a colourless oil, ~~D20 = -72 (c = 1-125, C2HsO~).
~ .
A.6'. Preparation of (I)-(3S,4R)-4-amino-3,4-dihYdro-2,2- --dimethYl-6-(2-methvlPyridin-4-yl)-2H-l-benzopvran-3-ol ;

A solution of the product of Example A.5' (0.64 g~ is treated with saturated NH3 in C2HsOH (1~5 ml) and heated at 80C in autoclave for 15 hours. The solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 5~ C2HsOH in CH2Cl2) to give the title compound as a foam: [~]20D = ~100, (c = 1.00, C2HsOH).

The following compounds of formula IV in which R4 is H, Rs .

WO94/12493 PCT~2/02719 is hydroxy, R6 and R7 are each methyl and Rl, R2 and R8 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 racemate and, except for the product of Example B6, are obtained as an oil.

_ STARTING
MATERIAL
EXAMPLE Rl R2 R8 ACCORDING TO
EXAMPLE
. .

s6 C2H5- H H B5 . .

E6 nC3H7- H H E5 . .__ ~ , .
F6 iC4Hg- H H F5 , _ _ _ H6 . CH30CH2- CH3 H H5 PHYSICAL DATa A.6. lH-NMR (~6-DMSO): 1.12 (s,3H), 1.38 (s,3H), 2.06 (broad, 2H), 2.50 (s,3H), 3.23 (dd,lH), 3.59 (d,lH), 5.47 (d,lH), 6.81 (d,lH), 7.43 ~dd,lH), 7.51 (s,lH), 7.55 (dd,lH), 7.99 (m,lH) and 8.44 (d,lH) B.6. M.P. = 140-141C.
.
C.6. lH-NMR (~-CDCl~): 1.27 (s,3H), 1.54 (s,3H), 2.15 (s,3H), : 2.2-2.5 (br.s,3H), 2.57 (s,3H), 3.41 (d,lH), 3.71 (d,lH), 6.85 (d,lH), 6.99 (d,lH), 7.10 (dd,lH), 7.31 (dd,lH) and 8.31 (d,lH). `;
' WO94/l2493 2 1 2 2 4 9 4 PCT~2/02719 E.6. lH-NMR (~CDCl3): 1.00 (t,3H), 1.27 (s,3H), 1.55 (s,3H), 1.80 (s,2H), 2.0-2.4 (br. St 3H), 2.80 (t,2H), 3.41 (d, lH), 3.74 (d,lH), 6.89 (d,lH), 7.25-7.36 (m,2H), 7.47 (dd, lH), 7.70 (d,lH) and 8.51 (d,lH). ~-F.6. lH-NMR (~-DMSO): 0.90 (d,6H), 1.13 (s,3H), 1.41 (s,3H), 2. 0-2.2 (br.s,2H), 2.09 (dt,lH), 2.65 (d,2H), 3. 24 (dd,lH), 3.63 (d,lH), 5.45 (br.d,lH), 6.84 (d,lH), 7.48 (m,2H)~ 7.58 (dd,lH), 8.00 (d,lH) and 8.46 (d, lH).

I~6. lH-NMR (~-CDCl3): 1.24 (s,3H), 1.53 ~,3H), 2.1-2.4 (br.s,3H), 2.20 (s,3H), 2.60 (s,3H), 3.38 (d,lH), 3.67 (d,lH), 6.73 (s,lH), 7.05 (d, lH), 7.10 (s, lH), 7.21 (s,lH) and 8.49 (d, lH).

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

AGENTS OF THE INVENTION possess smooth mu~cle relaxant acti~ity and exhibit potassium channel opening activity in relation 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., 9I, 569-578 (1987).
AGENTS OF THE INVENTION are thereby characteri~ed as K+
channel opening agents.

AGENTS OF THE INVENTION are accordingly useful for the ':
' WO94/12493 212 2 ~ ~ ~ 34 - PCT~2/02719 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 pharm~cological 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 l hr post cannulation. Anti-i~chemic 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 l.0 mg/kg i.d. and anti-ischemic activity in the latter te~t method at doses of from about 0.00l to about 0.03 mg/kg i.v.............. -AGENTS OF THE INYENTION 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-~asospastic agents, e.g. for use in the treatment of disturbed blood supply, for example to the heart, skeletal muscle or brain. They are thus useful e.g. for the treatment of angina pectoris, myocardial ischaemia or myocardial infarction; as antifibrillatory agents; for the treatment of disorders of peripheral circulation, e.g.
claudic?tio intermittens, Morbus Raynaud or venous ulcer; as ~-we}l 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 WO94/12493 212 2 4 ~ 4 PCT~ ~2/02719 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 howe~er 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. Thesejactivities may also be demonstrated~in pharmaceutical test models in vivo and in vitro, for example as follows:

WO94/12493 212 2 4 9 4 PCT~2/02719 TEST 1. BRONCHODILATOR ACTIVITY
.

1.1 In the Guinea-Piq Guinea-pigs (Dunkin-Hartley, male, 400-600g) are anaesthetised with ~henobarbital ~100 mg/kg i.p.) and pentobarbital (30 mg/kg i.p.) and paralysed with gallamine (8 mg/kg i.m.) and ventilated with a mixture of air and oxygen (45:55, v/v).
Animals are ventilated via a tracheal cannula (10 ml/kg, lHz).
Blood pressure and heart rate are recorded from the carotidi ~-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 bronchospa~m. Capacity of test substance to reverse ~
respon~e when administered by the intratracheal route ~erves --as a measure of efficacy in reversing eQtablished broncho-spasm. The bro~chodilator respon~e i~ 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 0.001 to about 1.0 mg/kg. ~;

1.2 In the Rhe~us 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 i.m., maintenance: thiopental 8mg/kg/h i.v.). A cuffed pediatric endotracheal tube (5.0 cm) is then introduced into the trachea (xylocaine: topical administration at the epiglottus) and basal lung resistance W~94/12493 21 2 2 4 9 4 PCT~ ~2/02719 measured.

Following these manoeuvres, 2ml xylocaine ~1% w/v solution) is administered at the carina with a pediatric fibreoptic bronchoscope. l0 minutes later, lung resistance is again measured. Xylocaine has no effect on base-line resistance.
Test substance is adminis~ered in a similar manner to xylocaine pretreatment, in a lactoqe vehicle suspension (lmg/ml, lml delivered volume) in a cumulative manner at 30 min. intervals. At the 15 minute time point, a single MeCH
challenge (0.6 to 2.5 mg/ml solut~on, estimated to produce approximately a 50-100% change from baseline~ is performed and the % inhibition calculated from the response after vehicle administration.

AGENTS OF THE INV~NTION produce potent, dose-dependent bronchodilator effect in the above test method at dosages of from about l0 ng/kg to about l0 ~g/kg.

l~:ST 2. SUPPRESSION OF AIRWAYS HYPERREACTIVITY

Z.1 PAF-induced hyperreactivitY

Guinea-pigs are prepared for recording of lung function as described under Test l.l above. Intravenous injection of histamine ~l.8-3.2 ~g/kg) e~tablishes airways sensitivity to spa~mogen. Following infusion of PAF (platelet activating factor) over l hour (total dose 600 ng/kg), repeated injection of hi~tamine revealq development of airways hyperreactivity, which can convenientlylbe expreqsed 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 doqage~ of from about 0.l to about l00~g/kg, reversal of airways hyperreactivity induction is observed.

WO94/12493 212 2 4 9 4 pcT~2lo27ls 2.2 Immune-complex-induced hyperreactivitY

Guinea pigs are prepared for recording of lung-function as described under Test l.l above. An allergic reaction is initiated by intravenous injection of preformed immune-complexes ~prepared by adding 30 ~g 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 (l0 min) intervals for 30 min. Intravenous injections of histamine (l.0-3.2 ~g/kg at l0 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 l0ng/kg to about l0.0 ~g/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 diæease, in particular asthma. As bronchodilator agents, AGENTS OF THE INVENTION may be employed, in particular as rescue therapy, to treat bronchoconstrictor attack, e.g. in asthma. In addition, by continued administration, AGENTS OF
THE INVENTION may be u~ed for the control, restriction or reversal of airways hyperreactivity or to provide advance protection against recurrence of bronchoconstrictor attack con~equential 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 :. ~

W094112493 212 2 4 3 4 PCT~2/02719 of obstructive or inflammatory airways disease, in particular asthma, are accordingly to be understood as embracing both .
prophylactic as well as symptomatic (i.e. 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.1 A method for the symptomatic treatment of inflammatory or obstructive airways disease, e.g. of effecting 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:

5. An AGENT OF THE INVENTION for use as a pharmaceuticaI, e.g. for use in the treatment of any diqea-qe or condition as herein Ypecified, in pàrticular 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 THE INVENTION for use in the preparation of a pharmaceutical composition, for use WO94/1~93 PCT~2/02719 21~2~94 40 -in the treatment of any disease or condition herein specified, in particular for use as set forth under 5 above.

Inflammatory or obstructive airways disea~es to which the present invention is applicable include asthma of whatever -type or genesis including both intrinsic and, e~pecially, extrinsic asthma. They are useful for the treatment of aller-gic asthma, whether atopic, (i.e. 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 tha~ 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 efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of ~ymptomatic -~
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 (e.g. corticosteroid~ or bronchodilatory (e.g. ~2 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 WO94/12493 212 2 4 9 4 PCT~W2/02719 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 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. ~-agonist bronchodilator therapy, including in particular usage of AGENTS OF THE 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 diqease 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 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.

WO94/12493 PCT~2/02719 21 22~ 9 q - 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.l~g to about l00~g, in par~icular from about l.0~g to about 50.0~g, suitably administered from an inhaler device with administration effected once or from 2 to 4x daily, in a series of from l to 4 puffs at each administration.

For oral administration a suitable daily dosage will general~y be of the order of from about 0.l to about 30~g/kg. A suitable oral daily dosage for larger mammals, e.g. humans, will thus be of the order of from about 7~g to about 2.lmg, administered in a single dose, in divided doses administered from 2 to 4x daily, or in sustained relea~e form. Oral unit dosage forms for such use will thus suitably comprise from about l.75~g to about 2.lmg 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 T~E 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 to 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

WO94/12493 212 2 4 3 ~ PCT~ ~2102719 INVENTION in finely di~ided disperse particulate form, e.g.
together with finely divided lactose as a carrier/diluent to form an inhalable powder.

As pre~iously 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 l in pure or substantially pure (3S,4R) enantiomeric form an established ID50 in one test run carried out in accordance with Test l.l hereinbefore is 0.02 mg/kg, i.t.. An established IDso in the same test method for the known inhaled bronchodilator drug salbutamol [~l-[[(l,l-Dimethyl ethyl)amino3-methyl~-4-hydroxy-l,3-benze-nemethanol] is 0.00l mg/kg, i.t.. Appropriate dosages of the Example l 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 SaIbutamol.
.

Claims (10)

44

1. A 2,2-di(C1-5alkyl)- or trans-2,2-di(C1-5alkyl)--3,4-dihydro-3-hydroxy- -6-(pyridin-9-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 C1-5alkyl, C1-5hydroxyalkyl and C1-5(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.

2. A compound of formula I

(I) wherein R1 and R2 are independently, hydrogen, C1-5alkyl, C1-5hydroxyalkyl or C1-5(alkoxyalkyl), whereby at least one of R1 and R2 is other than hydrogen, R3 is a group of formula -N(R9)-COR10 wherein R9 is hydrogen and R10 is pyridyl or R9 and R10 together are 1,3-butadienylene or represent a group of formula -(CH2)n- or in which n is an integer of from 3 to 5 inclusive and m is 1 or 2, R4 is hydrogen and R5 is hydroxy in the trans position with respect to R3, or R4 and R5 together represent an additional bond as indicated by the dotted line, R6 and R7 are, independently, C1-5alkyl, and R8 is hydrogen or C1-5alkyl, 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 wherein:
R4 is hydrogen, R5 is hydroxy in the trans position with respect to R3, R6 and R7 are each methyl and A) R3 is a group of formula and A1) R1 is methyl, ethyl, n-propyl, i-butyl, hydroxymethyl or methoxymethyl and R2 and R8 are each hydrogen, or A2) R1 and R8 are each hydrogen and R2 is methyl, or A3) R1 and R8 are each methyl and R2 is hydrogen; or B) R3 is a group of formula and B1) R1 is methyl, ethyl, n-propyl, butyl or methoxy-methyl and R2 and R8 are each hydrogen, or B2) R1 and R8 are each hydrogen and R2 is methyl, or B3) R1 and R8 are each methyl and R8 is hydrogen; or C) R3 is a group of formula or R1 is methyl and R2 and R8 are each hydrogen;

or wherein R1 is methyl and R2 is hydrogen or R1 is hydrogen and R2 is methyl, R6 and R7 are each methyl, R8 is hydrogen, R4 and R5 together represent an additional bond and R3 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.

4. A compound of formula I as illustrated in claim 1 wherein R1, R6 and R7 are each methyl, R2, R4 and R8 are each hydrogen R5 is hydroxy in the trans position with respect to R3 and R3 is a group of formula or N-oxide thereof or acid addition salt of such a compound or N-oxide.

5. A trans-2,2-di(C1-5alkyl)-3,4-dihydro-3-hydroxy-6--(pyridin-4-yl)-3H-1-benzopyran, N-oxide, ester or salt as claimed in claim 1 or compound of formula I as illustrated in claim 2 wherein R4 is hydrogen and R5 is hydroxy in the trans position with respect to R3 and R1, R2, R3, R6, R7 and R8 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:

i) for the production of a benzopyran as aforesaid:

i1) reacting a 1a,7b-dihydro-2,2-di(C1-5alkyl)-6-(pyridin--4-yl)-2H-oxireno[c][1]benzopyran wherein the pyridln-4-yl group is substituted at the 2- and/or 3-position by one or two memebers selected from the group comprising C1-5alkyl, C1-5hydroxyalkyl and C1-5-(alkoxyalkyl), with an alkali metal salt of a carboxamide; or i2) acylating and, when required, alkylating the amino group of a 2,2-di(C1-5alkyl)- or trans-2,2-di(C1-5alkyl)-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 C1-5alkyl, C1-5hydroxyalkyl and C1-5(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 quarternary ammonium salt form.

8. A benzopyran, N-oxide, ester or pharmaceutically acceptable salt as claimed in claim 1 for use as a pharmaceutical.

9. A pharmaceutical composition comprising a benzopyran, N-oxider ester or pharmacetically acceptable salt as claimed in claim l together with a pharmaceutically acceptable diluent or carrier therefor.

10. A method of treating obstructive or inflammatory airways disease in a subject in need thereof which method comprises administering to said subject an effective amount of a benzopyran, N-oxide, ester or pharmaceutically acceptable salt as claimed in claim 1.