WO1993019755A1

WO1993019755A1 - Medicament for the treatment of airways inflammation and airways hyperresponsiveness

Info

Publication number: WO1993019755A1
Application number: PCT/GB1993/000632
Authority: WO
Inventors: Barbara Anne Spicer; Stephen Gerard Taylor
Original assignee: Smithkline Beecham Plc
Priority date: 1992-04-02
Filing date: 1993-03-26
Publication date: 1993-10-14
Also published as: IL105233A0; EP0633778A1; ZA932303B; HU9402816D0; HUT75702A; JPH07505381A; CA2133470A1; MX9301879A; AU3765193A; GB9207400D0; KR950700737A

Abstract

The use of a compound of formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of airways inflammation and airways hyperresponsiveness.

Description

Medi cament for the treatment of ai rways i nfl ammation and ai rways hyperrespon si veness

This invention relates to a novel use, in particular a use for the manufacture of a medicament for the treatment of airways inflammation and, in particular, airways hyperresponsiveness.

European Patent Application, Publication Number 314446 discloses certain benzopyran derivatives having smooth muscle relaxant activity.

Airways smooth muscle relaxants play an important role in the management of asthma, but it is recognised that bronchodilatation alone does not beneficially influence two cardinal features of asthma: airways inflammation and an underlying airways hyperresponsiveness, which may or may not be a consequence of airways inflammation (Barnes, P.J., 1989, The New England Journal of Medicine, 321. 1517- 27, Smith, H., 1992, Clinical and Experimental Allergy, 22, 187-197).

It has now surprisingly been discovered that the compounds of EP 314446 are potentially useful for reversing and preventing airways hyperresponsiveness, and for preventing lung cell damage associated with lung inflammation.

It has further been shown that these compounds are especially potent in inhibiting the release of inflammatory neuropeptides, as evidenced by their potency in preventing bronchoconstriction resulting from stimulation of non-adrenergic, non-cholinergic excitatory nerves. Moreover, these compounds have also been found to inhibit the release of inflammatory neuropeptides at doses that do not lower blood pressure.

These compounds are therefore, potentially, of particular use as prophylactic, disease-modifying drugs in the treatment of disorders of the respiratory tract, such as reversible airways obstruction and especially asthma.

Furthermore, whilst these compounds were previously disclosed to be relaxants of tension in normal airways smooth muscle, it is now discovered that they are especially effective in hyperresponsive tissue, thereby enhancing their value in diseases where the airways are hyperresponsive, such as asthma. Accordingly, the present invention provides the use of a compound of formula

(I):

(I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein: one of A or A2 represents hydrogen and the other represents a group CF3-Y- wherein Y represents -CF2-, >C=O, or -CH(OH)-;

Yl represents -O-, -CH2- or NR° wherein R° is hydrogen, alkyl or alkylcarbonyl; l and R2 independently represent hydrogen, or alkyl; or Rj and R2 together represent a C2-7 polymethylene moiety;

R3 represents hydrogen, hydroxy, alkoxy or acyloxy and R4 is hydrogen or R3 and R4 together represent a bond;

R5 represents either a moiety of formula (a):

(a)

wherein A represents >C=X wherein X is O, S or NRg wherein Rg represents CN, NO2, COR9 wherein R9 is alkyl, amino, monoalkylamino, fluoroalkyl, phenyl or substituted phenyl or Rg is SO2 9 wherein R9 is as defined above, or A represents a bond; when A represents >C=X wherein X is O or S, then Rg is hydrogen; alkyl optionally substituted by one or more groups or atoms selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxy or an ester or amide thereof, amino, monoalkylamino or dialkylamino; alkenyl; amino optionally substituted by an alkyl or alkenyl group or by an alkanoyi group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by alkyl, alkoxy or halogen; substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and R7 represents hydrogen or alkyl; or Rg and R7 together represent a linking chain of formula -A3-A4-, A3 being attached to the nitrogen atom of the moiety -N- A- and A4 being attached to the group A on the said moiety, and wherein A3 represents a substituted or unsubstituted methylene group, A4 represents 2 or 3 linking members, one of the linking members optionally representing O, S or NR and the other linking members each independently representing a substituted or unsubstituted methylene group; R represents hydrogen, alkyl, alkanoyi, phenyl C1- - alkyl, arylcarbonyl wherein the aryl group may be substituted or unsubstituted; or R is mono- or bi-cyclic- heteroarylcarbonyl; when A represents >C=X wherein X represents NRg, then Rg represents -NH.R10 wherein R^Q *^S hydrogen, alkyl, C3- cycloalkyl, alkenyl or alkynyl and R7 is hydrogen or alkyl; or R7 and Rio together represent C2-4 polymethylene; when A represents a bond, then Rg and R7 togetiier with the nitrogen atom to which they are attached, form an unsaturated heterocyclic ring having 5 to 7 ring atoms, which ring atoms comprise up to 2 further nitrogen atoms and a carbon atom, the carbon atom being substituted with either an oxo group or a thioxo group, the remaining ring atoms being substituted or unsubstituted; or R5 represents a moiety of formula (b):

(b)

wherein T| represents >C-OH or N(O)_n wherein n is zero or 1 and T2 together with C-Tj, when T1 is >C-OH, represents an optionally substituted aryl group or T2 together with CTi, when Tj is N(O)_n, represents an optionally substituted, N- heteroaryl group; or R5 represents a moiety of formula (c):

(c)

wherein Lj represents O or NRJJ wherein R^j represents hydrogen, alkyl, formyl, acetyl or hydroxymethyl, L2 represents N or CL4 wherein L4 is hydrogen, halogen, formyl or hydroxymethyl, L3 represents CH2, 0, S, >CHL5 wherein L5 is halogen or NLg wherein Lg is hydrogen or alkyl and Rj2 and R13 each independently represent hydrogen or alkyl or R12 together with R13 represents oxo or thioxo; and p represents 1,2 or 3; for the manufacture of a medicament for the treatment of airways inflammation and airways hyperresponsiveness.

In a further aspect, the present invention provides a method for the treatment of airways inflammation and airways hyperresponsiveness in mammals, such as humans, which method comprises the administration of an effective, non-toxic amount of a compound of the hereinbefore defined formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. .

The invention also provides a pharmaceutical composition, for the treatment of airways inflammation and airways hyperresponsiveness, which comprises an effective, non-toxic amount of a compound of formula (I), or, where appropriate, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

The treatment of airways hyperresponsiveness encompasses in particular treatments for reversing and preventing airways hyperresponsiveness. The treatment of airways hyperresponsiveness encompasses most particularly the prevention of airways hyperresponsiveness.

The treatment of airways inflammation encompasses in particular treatments for preventing lung cell damage associated with lung inflammation.

In a further aspect, the invention provides the use of a compound of the hereinbefore defined formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for inhibiting the release of inflammatory neuropeptides, especially at doses that do not lower blood pressure.

The present invention also provides a method for inhibiting the release of inflammatory neuropeptides in mammals, such as humans, which method comprises the administration of an effective, non-toxic amount of a compound of the hereinbefore defined formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

The invention also provides a pharmaceutical composition, for inhibiting the release of inflammatory neuropeptides, which comprises an effective, non-toxic amount of a compound of formula (I), or, where appropriate, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

In yet a further aspect, the invention provides the use of a compound of the hereinbefore defined formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for relaxing tension in hyperresponsive airways.

The present invention also provides a method for relaxing tension in hyperresponsive airways in mammals, such as humans, which method comprises the administration of an effective, non-toxic amount of a compound of the hereinbefore defined formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

The invention also provides a pharmaceutical composition, for relaxing tension in hyperresponsive airways, which comprises an effective, non-toxic amount of a compound of formula (I), or, where appropriate, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier. Suitably, A\ represents CF3-Y- and A2 represents hydrogen.

Suitably, Y represents -CF2- or -CH(OH)-. Preferably, Y represents -CF2-.

Thus, preferably, A] represents C2F5 and A2 represents H. Preferably, Y\ represents -O-. When R4 is hydrogen, it is favoured if R3 represents hydrogen, hydroxy or acyloxy especially hydroxy.

Preferably R4 is hydrogen. Preferably, R5 represents a moiety of formula (a).

When R5 represents a moiety (a), one favoured subgroup of compounds are those wherein A represents >C=X wherein X is O or S, especially O, and Rg together with R7 represents a linking chain -A3-A4- as defined above.

Preferably, A3 represents an unsubstituted methylene group. Preferably, A4 represents -CH2CH2- or -CH2CH2CH2- especially -CH₂CH₂CH₂-. When the linking chain -A3-A4- comprises substituted methylene groups it is favoured if one or two of methylene groups are substituted, in particular it is favoured if the methylene group represented by -A3- is substituted.

Suitable substituents for any methylene group in -A3-A4- include alkyl groups, especially methyl or ethyl and in particular methyl. In one particular aspect when A represents >C=X, the linking chain -A3-A4-

(and thus Rg and R7 together) represent a moiety of formula -CH2-(CH2)π-Z-(CH2)_r- wherein q and r are 0 to 2 such that q + r is 1 or 2 and Z is CH2, O, S or NR wherein R is as defined above.

Suitably R represents hydrogen, C1-9 alkyl, C2-7 alkanoyi, phenyl-Cι-4- alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl or naphthyl ring by one or two of Cj-g alkyl, Cj-g alkoxy or halogen; or R is mono- or bi-cyclic- heteroarylcarbonyl.

When A represents a bond, suitable unsaturated, heterocyclic rings represented by the moiety R7.N.Rg include 5- or 6- membered rings, favourably 6- membered rings.

Suitable optional substituents for the ring atoms of the unsaturated, heterocyclic ring represented by R7.N.R include alkyl, hydroxyl, halogen, alkoxy, alkanoyloxy, nitro, amino, acylamino, carboxy or alkoxy carbonyl. Suitably, Rg and R7 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted pyridonyl group or a substituted or unsubstituted thiopyridonyl group.

Suitably the moiety R7-N.Rg represents substituted or unsubstituted pyridonyl, favourably unsubstituted pyridonyl.

A favoured pyridonyl group is a 2-pyridon-l-yl group. A favoured pyridonyl group is a4-pyridon-l-yl group. Suitably, when the moiety R.7.N.R6 comprises further nitrogen atoms, it comprises 1 further nitrogen atom. Suitably, R7-N.Rg represents substituted or unsubstituted pyrimidinonyl or thiopyrimidinonyl, favourably unsubstituted pyrimidinonyl or thiopyrimidinonyl, in particular pyrimidinonyl. A favoured pyrimidinonyl group is a 4(lH)-pyrimidinoπ- 1-yl a 6(lH)-pyrimidinon-l-yl or a 2(lH)-pyri__idinon- 1-yl group.

A preferred substituent for the group R7.N.Rg, and especially for the pyridonyl group, or the thiopyridonyl group is an alkyl group, suitably a Cj-g alkyl group, such as a methyl group.

When R5 represents a moiety (a) in which A is >C=NRg, Rg is preferably cyano.

When Rg represents -NH.R10, RlO is suitably hydrogen, methyl, -CH-CH=C__2, CH2-C=CH or cyclopropyl, preferably methyl, and R7 is hydrogen. When R7 and R^o together represent C2-4 polymethylene, they favourably represent -CH2CH2-.

When moiety (b), represented by R5, represents a substituted or unsubstituted aryl group, suitable aryl groups include monocyclic or bicyclic aryl groups which, in addition to the hydroxy group in the 2-position, can optionally contain one or more additional substitutents selected from halogen, cyano and lower alkyl.

When moiety (b) represented by R5 represents an optionally substituted N- heteroaryl group, suitable N-heteroaryl groups include monocyclic or bicyclic N-heteroaryl groups which contains one or more nitrogen atoms and which, in addition to the h droxy or N-oxide group in the 2-position, can optionally contain one or more additional substituents selected from halogen, amino, hydroxy, benzyloxy, phenyl, (lower alkyl)-phenyl, lower alkyl, lower alkoxy and lower alkoxycarbonyl. In one particular aspect the present invention provides a compound falling wholly within the scope of formula (I) in which R5 represents a moiety of formula (a), or where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof wherein:

A represents >C=X, wherein X represents O or S, or A represents a bond; one of A 1 or A2 represents hydrogen the other represents a group CF3-Y-, wherein Y represents -CF2-, >C=O or -CH(OH)-;

R\ and R2 independently represent hydrogen or Cj-g alkyl; or Rj and R2 together represent a C2-7 polymethylene moiety;

R3 represents hydrogen, hydroxy, Ci-g alkoxy or C1-7 acyloxy and R4 is hydrogen or R3 and R4 together represent a bond; when A represents >C=X, then Rg is hydrogen; Cj-g alkyl optionally substituted by halogen, hydroxy, Ci-g alkoxy, Cι~g alkoxycarbonyl, carboxy or amino optionally substituted by one or two independent Cj-g alkyl groups; or C2~g alkenyl; amino optionally substituted by a Cj-g alkyl or C2-g alkenyl group or by a C^-g alkanoyi group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by Cj-g alkyl, Cj-g alkoxy or halogen; or aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of Ci -g alkyl, C^-g alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, Cj-i2 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two Cj-g alkyl groups; and

R7 represents hydrogen or Cj-g alkyl; or Rg and R7 togetiier represent -Cj__2-(CH2)q-Z-(CH2)_r- wherein q and r are O to 2 such that q + r is 1 or 2 and Z is CH2, 0, S or NR wherein R is hydrogen, Ci -9 alkyl, C2-7 alkanoyi, phenyl C1-4- alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl or naphthyl ring by one or two of Cj-g alkyl, Cχ-g alkoxy or halogen; or R is mono- or bi-cyclic- heteroarylcarbonyl; when A represents a bond, then Rg and R7 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted pyridonyl group or a substituted or unsubstituted thiopyridonyl group. Preferably, when A represents >C=X then X is oxygen.

Preferably, R\ and R2 are both Cj-g alkyl, and in particular Rj and R2 are both methyl. —

When R3 is alkoxy and R4 is hydrogen, preferred examples of R3 include methoxy and ethoxy, of which methoxy is more preferred. When R3 is acyloxy and R4 is hydrogen, a preferred class of R3 is unsubstituted carboxylic acyloxy, such as unsubstituted aliphatic acyloxy. However, it is more preferred that R3 and R4 together are a bond, or that R3 and R4 are both hydrogen, or in particular, that R3 is hydroxy and R4 is hydrogen.

When Rg represents alkyl, suitable alkyl groups include methyl, ethyl and n- and iso-propyl. Preferably Rg is methyl.

A suitable halogen substituent for any alkyl represented by Rg, is a chloro or bromo substituent; favoured examples include methyl, ethyl or propyl, especially n-propyl, terminally substituted by chloro or bromo, especially chloro. When Rg represents alkyl substituted by hydroxy, favoured examples include methyl or ethyl terminally substituted by hydroxy.

When Rg represents alkyl substituted by alkoxy, a suitable alkoxy group is a methoxy or emoxy group; favoured examples include metiiyl or ethyl terminally substituted by methoxy or etiioxy.

When Rg represents alkyl substituted by alkoxycarbonyl, a suitable alkoxycarbonyl group is a methoxycarbonyl or ethoxycarbonyl group; examples include methyl or ethyl terminally substituted by methoxycarbonyl or ethoxycarbonyl. When Rg represents alkyl substituted by carboxy, favoured examples include methyl or ethyl terminally substituted by carboxy.

When Rg represents alkyl substituted by amino wherein the amino group is optionally substituted by one or two independent alkyl groups, favoured values include a group (CH2)_sR_fR_u where s is 1 to 6, and R_t and R_u are each independently hydrogen or alkyl. Suitable values for s include 1 and 2, in particular 1.

Preferably R_t and R_u are each independently selected from hydrogen and metiiyl.

When Rg represents alkenyl, suitable values include vinyl, prop-1-enyl, prop-2-eπyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl, or l-methylprop-2-enyl, in both their E and Z forms where stereoisomerism exists. When Rg represents optionally substituted amino, suitable optional substituents for the amino group include a methyl; ethyl; propyl; butyl; allyl or a trichloroacetyl group; or a phenyl group optionally substituted by one methyl, methoxy group or one chloro atom, and in particular a phenyl group optionally substituted with amino, methylamino or phenylamino; the phenyl group in the phenylamino substituent being optionally substituted in the phenyl ring by one methyl or methoxy group or one chloro atom.

When Rg represents aryl, favoured examples include phenyl and naphthyl, preferably phenyl. When Rg represents heteroaryl, suitable heteroaryl groups include 5- or

6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl groups, preferably 5- or 6-membered monocyclic heteroaryl groups.

Preferred 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl groups are those containing one, two or three heteroatoms selected from the class of oxygen, nitrogen and sulphur and which, in the case of there being more than one heteroatom, are the same or different.

Suitable 5- or 6-membered monocyclic heteroaryl moieties include furyl, thienyl, pyrrolyl, oxazolyl, thiazoiyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazyl and triazyl. Preferred 5- or 6- membered heteroaryl groups include furyl, thienyl, pyrrolyl and pyridyl, in particular 2- and 3-furyl, 2- and 3-pyrrolyl 2- and 3-thienyl, and 2-, 3- and 4-pyridyl.

Suitable 9- or 10-membered bicyclic heteroaryl moieties include benzofuryl, benzothienyl, indolyl and indazolyl, quinolinyl and isoquinolinyl, and quinazolinyl. Preferred 9- or 10- membered bicyclic heteroaryl groups include 2- and 3-benzofuryl, 2- and 3-benzothienyl, and 2- and 3-indolyl, and 2- and 3-quinolinyl.

Suitable substituents for any aryl or heteroaryl group represented by Rg include one or more groups or atoms selected from alkyl, alkoxy, hydroxy, halogen, fluoroalkyl, nitro, cyano, carboxy or an ester d ereof, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl.

In any optionally substituted aryl or optionally substituted heteroaryl group, the preferred number of substituents is 1, 2, 3 or 4. Preferred substituents for any substituted aryl or heteroaryl group include methyl, methoxy, hydroxy, chloro, fluoro, nitro or cyano.

One preferred sub-group of values for Rg is that wherein Rg represents phenyl or naphthyl or a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl, the phenyl, naphthyl or heteroaryl group being optionally substituted by one, two, three or four groups or atoms selected from the class of Cj-g alkyl, Cj-g alkoxy, halogen, trifluoromethyl, nitro or cyano.

When Rg represents optionally substituted phenyl, preferred values include phenyl, 4-substituted phenyl, 3-substituted phenyl, 3,4-disubstituted phenyl and 3, 4, 5-trisubstituted phenyl, for example Rg may suitably represent 4-fluorophenyl. When Rg represents an optionally substituted 5- or 6-membered monocyclic heteroaryl or an optionally substituted 9- or 10-membered bicyclic heteroaryl group, preferred values

5- or 6- membered monocyclic heteroaryl or mono-substituted 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, in particular unsubstituted 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl.

Preferably, when Rg and R7 together represent a linking chain -A3-A4-, A3 represents a substituted or unsubstituted methylene group and A4 represents a -CH2CH2- or -CH2CH2CH2- group, for example -CH2CH2CH2-.

When A represents a substituted methylene group it is preferably substituted by an alkyl group especially a methyl group.

Preferably, when Rg and R7 together represent the moiety -CH2-(CH2)q-Z-(CH2)_r-as hereinbefore defined, the moiety Rg-N.CX.R7 represents either pyrrolidonyl or piperidonyl, preferably piperidonyl. A most preferred moiety Rg-N.CX.R7 is a 2-oxopiperidin-l-yl group.

When Z is other than CH2, q is often 0 or 1 and r is often 0 or 1.

Favoured examples of R when Z is NR include hydrogen, methyl, ethyl, n- and tso-propyl, n-, sec- and ten- butyl, benzyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl ring by methyl, methoxy, chloro or bromo; furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or indolylcarbonyl.

Preferably R is hydrogen, methyl, n-butyl, acetyl, benzyl, benzylcarbonyl, phenylcarbonyl or furylcarbonyl.

Most preferably R is methyl. When used herein die term "halogen" refers to fluorine, chlorine, bromine and iodine; preferably chlorine.

Suitably alkyl groups, or alkyl groups forming part of odier groups such as in the alkoxy group, are C\-\2 alkyl groups especially Cj-g alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups. Suitably alkenyl groups are C2-12 groups especially C2-g alkenyl groups.

Suitable alkynyl groups are C2-12 alkynyl groups especially C2~g alkynyl groups.

Suitable acyloxy groups include alkylcarbonyloxy groups wherein the alkyl group is as defined above. When used herein the term "fluoroalkyl" includes alkyl groups as defined above when substituted by one or more fluorine atoms, particular examples being trifluoromethyl and pentafluoroethyl.

When used herein the term 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl alkylcarbonyloxy, or alkylcarbonyl groups.

Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts and salts of carboxy groups.

Examples of pharmaceutically acceptable acid addition salts of the compounds of formula (I) includes acid addition salts of optionally substituted amino groups, such as the hydrochloride and hydrobromide salts. Such a salifiable group may form part of an R5 group.

Examples of pharmaceutically acceptable salts of carboxy groups include metal salts, such as alkali metal salts, or optionally substituted ammonium salts. The compounds of formula may also exist in the form of solvates, preferably hydrates, and the invention extends to such solvates.

The compounds of formula (I), may exist in the form of optical isomers. For example chirality is present in those compounds of formula (I) wherein R3 is hydrogen, hydroxy, alkoxy or acyloxy and R4 is hydrogen, wherein R\ and R2 are different or wherein Rg and R7 together represent a linking group -A3-A4-, the said linking group possessing up to 4 chiral carbon atoms. The present invention includes all optical isomers of the compounds of formula (I) whether in the form of single isomers or of mixtures thereof, such as racemates.

When R3 is hydroxy, alkoxy or acyloxy and R4 is hydrogen one isomer is that having the sterochemistry 4S, 3R, another is that having the stereochemistry 4R, 3S. The compounds of formula (I) may also exist in geometrical isomeric forms all of which are encompassed by the present invention, including those wherein R5 and R3 are disposed either mutually trans with respect to one another or mutually cis with respect to one another, preferably mutally trans with respect to one another. The compounds of formula (I) and where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, comprise all compounds having the suitable, favoured and preferred variables disclosed in EP 0376524.

The compounds of formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof in particular comprise the specific examples of EP 0376524, especially the compound of Example 6. Thus, a preferred compound of formula (I) is (-)-trans-3,4-dihydro-2,2- dimethyl-4-(2-oxopiperidin- 1 -yl)-6-penta-fluoroethyl-2H- 1 -benzopyran-3-ol. The compounds of formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof may be prepared according to procedures disclosed in EP 0376524.

The medicament of the invention is generally in pharmaceutical composition form.

The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example in the form of a spray, aerosol or other conventional method for inhalation; or parenteral administration for patients suffering from heart failure. Other alternative modes of administration include sublingual or transdermal administration. One particular form of administration is inhaled administration.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions. In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.

The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns for example diameters in the range of 1-50 microns, 1-10 microns or 1-5 microns. Where appropriate, small amounts of other anti-asthmatics and bronchodilators, for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.

The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration. A preferred range for inhaled administration is 10-99%, especially 60-99%, for example 90, 95 or 99%.

Suitable carriers are those used conventionally in the art, for example lactose.

Microfine powder formulations may suitably be administered in an aerosol as a metered dose or by means of a suitable breath-activated device. Suitable metered dose aerosol formulations comprise conventional propellants, cosolvents, such as ethanol, surfactants such as oleyl alcohol, lubricants such as oleyl alcohol, desiccants such as calcium sulphate and density modifiers such as sodium chloride.

Suitable solutions for a nebulizer are isotonic sterilised solutions, optionally buffered, at for example between pH 4-7, containing up to 20mg ml- 1 of compound but more generally 0.1 to lOmg ml-¹, for use with standard nebulisation equipment.

An effective amount will depend on the relative efficacy of the compounds of the present invention, the severity of the disorder being treated and the weight of the sufferer. Suitably, a unit dose form of a composition of the invention may contain from 0.001 to lOOmg of a compound of the invention (0.001 to lOmg via inhalation) and more usually from 0.01 to 50mg, for example 0.05 to 25 or 0.5 to 25mg such as 0.1, 1, 2, 5, 10, 15 or 20mg. Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 3 times a day, in a manner such that the daily dose is from 0.002 to 200mg for a 70 kg human adult and more particularly from 0.005 to lOOmg. That is in the range of about 2.5.10-^ mg/kg/day to 3 mg/kg/day and more particularly in the range of about 5.10-5 mg/kg/day to 1.5 mg/kg/day.

The following Examples illustrate the invention but do not limit it in any way. Example 1: Prevention of lung parenchymal hyperreactivity and lung cell fragility associated with a Sephadex particle-induced eosinophilia

Test Compound:

The compound under test (Compound [1]) was the compound of Example 6 of EP 314446 i.e. (-)-trans-3,4-dihydro-2,2- dimethyl-4-(2-oxopiperidin- l-yl)-6-penta- fluoroe__yl-2H-l-ben_opyran-3-ol.

This was prepared according to procedures disclosed in EP 314446.

Test Procedure:

Sephadex G200 (particle size 40 to 120μm when fully swollen in water) was suspended in saline at 0.5mg/ml for 48h before injecting lml i.v. into the hind foot vein of 250-350g rats on days 0, 2 and 5. In separate experiments rats in a control group received saline. Compound [1] or vehicle was given orally 30 min before each dose of Sephadex. Measurements were made on day 7 or 8.

Total and differential (May-Grunwald and Giesma stains) cell counts were conducted on 2x20μl blood from the tail vein. For the measurement of responsiveness to 5-hydroxytryptamine (5-HT) lung strips were set up under lg tension and cumulative dose-response curves to 5-HT (1.4 x 10" to 1.2 x 10"^M in approximately fivefold increasing concentrations at 3 min intervals) were constructed. The area under the log concentration-response (above lg tension) curve was calculated. Lung cell fragility was assessed by cutting the remainder of the lungs into 2-4 mn_3 pieces and incubating them at 37°C for 60 min in 2ml Minimal Essential Medium (with Earle's salts but minus L-glutamate) containing 1 mg/ml type H and 1 mg/ml type IV collagenase. Dispersed cells were filtered, passed through a column of nylon wood and red cells were removed by hypotonic lysis widi ammonium chloride. The washed pellet was resuspended in the culture medium containing deoxyribonuclease (65 u/ml) and cell viability was assessed by dye exclusion using trypan blue and the number of eosinophils assessed using eosin stain. Experiment Number 2 3

Dose of Compound [ 1 ] 1

(mg/kg,p.o.)

% of blood eosinophil count 73 ± 13 124 + 17 119 ± 15 for Sephadex-treated controls

% of area under 5-HT curve 60 ± 8 70 ± 17 54 ± 13 for Sephadex-treated (P<0.05) controls number of rats with more not determined than 10% viable cells (out of 6) % viable cells (range) 81 (58-96) 5 (0-25)

Results are shown ± S.E. (n=6). In naive animals the blood eosinophil count was 14% and the area under the 5-HT curve 27% of the value for Sephadex-treated control animals. Cells from naive animals were 71% viable compared to 8% for

Sephadex-treated animals (Spicer et al., 1990, Br. J. Pharmacol. 101, 821-828; Cook, 1990, Clin. Expt. All.20, 511-517).

The results indicate that Compound [1] does not reduce the Sephadex-induced eosinophilia but tends to reduce the associated lung strip hyperreactivity and the sensitivity of the cells to collagenase digestion.

Example 2: Reversal of lung parenchymal hyperreactivity

Rats (300-400g) were treated widi Sephadex as described in biological example 1, except that the third injection of Sephadex was on day 4 and lung strips were taken on both day 7 and day 14. Cumulative concentration-response curves were constructed to 5-HT or carbachol (both 10"^ to 3 x 10'^M). The tissues were then washed and when the baseline had recovered a second concentration-response curve was constructed in the presence of compound [1] (10^*9 to 10"^M) or vehicle. Maximum contractions are given for the initial concentration-response curve, and percentages of these maxima are given for the 10"^ and 3 x 10'^M concentrations of 5-HT and carbachol as means ± S.E. (n>4). Maximal contraction (mg tension) to 5-HT or carbachol in initial concentration- response experiment

5-HT Carbachol

Naive rats 78 ± 7 64 ± 10

Sephadex, Day 7 174 ± 12 254 ± 15

Sephadex, Day 14 169 ±28 246 ±35

% of maximal contraction to 5-HT or carbachol in initial concentration- response experiment

Cmpd [1] cone. 5HT Carbachol

*P<0.05 compared to value in absence of Compound [1]. **P<0.01 ***P<0.001

These results show that Compound [1] had no effect on the 5-HT or carbachol concentration-response curves in tissues from naive animals, but the hyperreactivity to 5-HT and carbachol in tissues from Sephadex-treated animals was suppressed. Example 3

Guinea-pig bronchial rings were mounted between platinum electrodes and stimulated in the presence of propranolol (lμM) and atropine (lμM) by the application of 10 sec. trains of 60-70V, biphasic, 0.5 msec pulses at a frequency of 10Hz, with at least 15 min. between successive stimuli. Guinea-pig tracheal spirals were prepared and contracted using EC70 concentrations of spasmogens as described by Taylor ej. al. (Br. J. Pharmacol., 1988, 95, 795P). Guinea-pig portal veins were set up under 2g tension and, after equilibrating for one hour, tone was induced with K⁺ (30 mM). Concentration response curves for the effects of levcromakalim and compound [1] on tension were conducted in bronchial rings with washing between each addition of an increased concentration. Cumulative concentration response curves were conducted in tracheal spirals and portal vein. IC50 values are geometric means of at least 4 determinations.

Tracheal . Histamine 1.12 0.041 27 spirals (5μM)

Leukotriene D4 0.30 0.020 16 (0.003UM)

Prostaglandin E2 0.32 0.021 15 (0.01)

Spontaneous 0.22 0.019 12

5-hydroxy- 0.14 0.018 7.8 tryptamine (0.8μM)

Portal vein KC1 (30mM) 0.060 0.021 2.8

Compound [1] is 27-fold more potent than levcromakalim in inhibiting NANCe-mediated contraction, which indicates Λat it is similarly more potent in inhibiting sensory neuropeptide release (see Good ≤∑. &.- 1992, Br. J. Pharmacol, 105. 933-940). This improvement in potency is equal to the greatest difference found for the direct smooth muscle relaxant effects in tracheal spirals and much greater d an Λat in portal vein.

Claims

1. The use of a compound of formula (I):

(I)

or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein: one of Ai or A2 represents hydrogen and the odier represents a group CF3-Y- wherein Y represents -CF2-, >C=O, or -CH(OH)-;

Y represents -O-, -CH2- or NR° wherein R° is hydrogen, alkyl or alkylcarbonyl; Ri and R2 independendy represent hydrogen or alkyl; or Ri and R2 together represent a C2-7 polymetiiylene moiety;

R3 represents hydrogen, hydroxy, alkoxy or acyloxy and R4 is hydrogen or R3 and

R4 together represent a bond;

R5 represents either a moiety of formula (a):

(a)

wherein A represents >C=X wherein X is O, S or NRg wherein Rg represents CN, NO2, COR9 wherein R9 is alkyl, amino, monoalkylamino, fluoroalkyl, phenyl or substituted phenyl or Rg is SO2 9 wherein R9 is as defined above, or A represents a bond; when A represents >C=X wherein X is O or S, then Rg is hydrogen; alkyl optionally substituted by one or more groups or atoms selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxy or an ester or amide thereof, amino, monoalkylamino or dialkylamino; alkenyl; amino optionally substituted by an alkyl or alkenyl group or by an alkanoyi group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by alkyl, alkoxy or halogen; substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and R7 represents hydrogen or alkyl; or Rg and R7 together represent a linking chain of formula -A3-A4-, A3 being attached to the nitrogen atom of die moiety -N-A- and A4 being attached to the group

A on the said moiety, and wherein A3 represents a substituted or unsubstituted methylene group, A4 represents 2 or 3 linking members, one of the linking members optionally representing O, S or NR and the other linking members each independentiy representing a substituted or unsubstituted methylene group; R represents hydrogen, alkyl, alkanoyi, phenyl C1-4- alkyl, arylcarbonyl wherein die aryl group may be substituted or unsubstituted; or R is mono- or bi-cyclic- heteroarylcarbonyl; when A represents >C=X wherein X represents NRg, then Rg represents -NH.R10 wherein RI_Q is hydrogen, alkyl, C3-g cycloalkyl, alkenyl or alkynyl and R7 is hydrogen or alkyl; or R7 and RIQ togetiier represent C2-4 polymethylene; when A represents a bond, men Rg and R7 together with the nitrogen atom to which they are attached, form an unsaturated heterocyclic ring having 5 to 7 ring atoms, which ring atoms comprise up to 2 further nitrogen atoms and a carbon atom, the carbon atom being substituted with either an oxo group or a thioxo group, the remaining ring atoms being substituted or unsubstituted; or R5 represents a moiety of formula (b):

(b)

wherein Ti represents >C-OH or N(O)_n wherein n is zero or 1 and T2 togetiier witii C-Tj, when T is >C-OH, represents an optionally substituted aryl group or T2 together with CT , when Ti is N(O)_a, represents an optionally substituted, N- heteroaryl group; or R5 represents a moiety of formula (c):

(c)

wherein Li represents O or NRn wherein Ru represents hydrogen, alkyl, formyl, acetyl or hydroxymethyl, L2 represents N or CL4 wherein L4 is hydrogen, halogen, formyl or hydroxymethyl, L3 represents CH2, O, S, >CHL5 wherein L5 is halogen or

NLg wherein Lg is hydrogen or alkyl and R 2 and R 3 each independently represent hydrogen or alkyl or R12 together with R 3 represents oxo or thioxo; and p represents 1 ,2 or 3; for the manufacture of a medicament for the treatment of airways inflammation and airways hyperresponsiveness.

2. A use according to claim 1, wherein the treatment is the reversal and prevention of airways hyperresponsiveness.

3. A use according to claim 1 or claim 2, wherein the treatment is the prevention of airways hyperresponsiveness.

4. A use according to claim 1, wherein the treatment is the prevention of lung cell damage associated with lung inflammation.

5. A use according to any one of claims 1 to 4, wherein Ai represents C2F5 and A2 represents H in the compound of formula (I).

6. A use according to any one of claims 1 to 5, wherein Yi represents -O- in the compound of formula (I).

7. A use according to any one of claims 1 to 6, wherein R4 is hydrogen and R3 represents hydroxy in the compound of formula (I).

8. A use according to any one of claims 1 to 7, wherein the moiety Rg.N.CX.R7 represents piperidonyl in the compound of formula (I).

9. A use according to any one of claims 1 to 8, wherein R5 and R3 in the compound of formula (I) are disposed mutually trans with respect to one another.

10. A use according to any one of claims 1 to 9, wherein in the compound of formula (I) R3 is hydroxy, alkoxy or acyloxy, R4 is hydrogen having the sterochemistry 4R, 3S.

11. A use according to any one of claims 1 to 10, wherein the compound of formula (I) is (-)-trans-3,4-dihydro-2,2- dimethyl-4-(2-oxopiperidin- l-yl)-6-penta- fluoroethyl-2H- 1 -benzopyran-3-ol.

12. A use according to any one of claims 1 to 11, wherein the medicament is in pharmaceutical composition form.

13. A use according to claim 12, wherein the compositions are adapted for oral, inhaled, parenteral, sublingual or transdermal administration.

14. A use according to any one of claims 12 or 13, wherein the composition is in the form of a unit dose.

15. A use according to claim 14, wherein the composition is in microfine powder form

16. A use according to claim 15, wherein die composition is adapted for administration as an aerosol as a metered dose or by means of a breath-activated device.

17. A use according to any one of claims 14 to 16, wherein the unit dose contains from 0.001 to lOOmg of active compound or, if administered via inhalation, 0.001 to lOmg.

18. A use according to any one of claims 1 to 17, wherein die the daily dose of die active compound is in die range of about 2.5.10-5 mg kg day to 3 mg/kg day.

19. The use of a compound of formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for inhibiting the release of inflammatory neuropeptides.

20. The use of a compound of formula (I) or, where appropriate, a pharmaceutically acceptable salt tiiereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for relaxing tension in hyperresponsive airways.