HUT75702A - Medicament for the treatment of airways inflammation and airways hyperresponsiveness - Google Patents

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

In the general formula (I)

One of A, and A ₂ is hydrogen when the other is CF ₃ -Y-, wherein Y is -CF ₂ -,> C = O, or -CH (OH) -;

Y! is -O-, -CH ₂ -, or -NR 0 where

R 0 is hydrogen, alkyl or alkylcarbonyl;

Ri and _R2 are independently hydrogen or alkyl; obsession

Ri and _R2 together represent a C2-7 polymethylene group;

· · · · *.

/ «···· * ·! · ·· ·· · ····. - 2 f

R ₃ is hydrogen, hydroxy, alkoxy or acyloxy, and

R ₄ is hydrogen, or

R ₃ and R ₄ together form a bond;

_R5 is an (a), (b) or (c) a group of formula.

Representative:

Danubia Patent and Trademark Office Ltd. Budapest

SSS? ^EU ft

z.Kts Á (- M

A pharmaceutical composition for the treatment of respiratory tract inflammation and hypersensitivity, and a method of administering it for this purpose.

SMITHKLINE BEECHAM PLC, Brentford, Middlesex, GB

inventors:

SPICER, Barbara Anne,

TAYLOR, Stephen, Gerard,

SmithKIine Beecham Pharmaceuticals,

Great Burgh, Epsom, Surry, GB

InternationalInformation Date: March 26, 1993

International Application Number: PCT / WO93 / 19755 Priority 4/02/1992 (9207400.4) GB

International Publication Number: WO 93/19755

File No. 80366-3072-TF / KmO

- 2 1 il

The present invention relates to novel pharmaceutical compositions for use in the treatment of airway inflammation and hypersensitivity; the invention also relates to a treatment method for this purpose.

European Patent Application Publication No. 314,446 discloses benzopyran derivatives having smooth muscle relaxant properties.

Airway smooth muscle relaxants play an important role in the treatment of asthma, but it has been found that bronchodilation alone is not sufficient to positively influence two of the basic symptoms of asthma: to alleviate the inflammatory and respiratory hypersensitivity of the airways, which it may also be a consequence of respiratory inflammation (Barnes, PJ, The New England Journal of Medicine, 321: 1517-1527 (1989), Smith). H., Clinical and Experimental Allergy, 22, 187-197 (1992).

Surprisingly, it has been found that the compounds disclosed in European Patent Application 314,446 are useful in the treatment and prevention of respiratory hypersensitivity and in the prevention of lung cell damage associated with inflammatory conditions of the lungs.

These compounds have also been found to be particularly effective in inhibiting the release of inflammatory neuropeptides, which demonstrate their ability to prevent bronchoconstriction due to stimulation of non-adrenergic, non-cholinergic stimuli. In addition to that

These compounds have been found to inhibit the release of inflammatory neuropeptides even at doses that do not lower blood pressure.

Consequently, these compounds are useful in the prophylactic and curative treatment of respiratory disorders such as reversible airway obstruction, particularly asthma.

Prior to our invention, these compounds have been recognized as relaxants of normal airway smooth muscle tension, and have been found to be particularly effective in hypersensitive tissues, and thus their use is particularly valuable in the treatment of hypersensitivity airways such as asthma.

The present invention relates to the use of the compounds of the formula I and their pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, wherein:

One of A ₁ and A ₂ is hydrogen and the other is CF ₃ -Y-, wherein Y is -CF ₂ -,> C = O, or -CH (OH) -;

Y 1 is -O-, -CH ₂ -, or -NR 0 where

R 0 is hydrogen, alkyl or alkylcarbonyl;

Ri and _R2 are independently hydrogen or alkyl; or Ri and _R2 taken together are C2-7 polymethylene;

- 4 R ₃ is hydrogen, hydroxy, alkoxy or acyloxy, and

R ₄ is hydrogen, or

R ₃ and R ₄ together represent a valence bond,

R ₅ is a group of formula (a) wherein:

A is> C = X, wherein X is O, S or -NR ₈ wherein R _e is -CN, -NO ₂ , -COR ₉ where

R ₉ is alkyl, amino, monoalkylamino, fluoroalkyl, phenyl or substituted phenyl, or

R ₈ is -SO ₂ R _{9 in} which

R ₉ is as defined above, or

A is a bond;

if A is> C = X, wherein X is O or S, then

R ₆ is hydrogen; alkyl optionally substituted with one or more halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxyl or esters or amides thereof, and amino, monoalkylamino or dialkylamino; alkenyl; amino optionally substituted with an alkyl or alkenyl or alkanoyl group optionally substituted with 1 to 3 halogen atoms, the phenyl being optionally substituted with an alkyl group;

- has 5 or alkoxy or halogen atoms; optionally substituted aryl or optionally substituted heteroaryl; R ₇ is hydrogen or alkyl;

or R ₆ and R ₇ together represent a linking chain of formula -A ₃ -A ₄ - wherein A ₃ is attached to the nitrogen atom of the -NA- moiety, and

₄ binds to component A of this group, wherein A ₃ represents an optionally substituted methylene group, A ₄ represents a two or three membered chain wherein one member is optionally oxygen, sulfur or -NR and the other members are independently optionally substituted. CH; R is hydrogen, alkyl, alkanoyl, phenyl (C 1 -C 4) alkyl, arylcarbonyl, wherein the aryl may optionally be substituted; or R is a mono- or bicyclic heteroarylcarbonyl group;

in the case when A represents> C = X wherein X represents a group of formula _NR8, then _R6 represents -NH.R _10, wherein R ₁₀ is hydrogen, alkyl of 3-6 carbon atoms, alkenyl or alkynyl and R ₇ is hydrogen or alkyl, or R ₇ and R ₁₀ together are C 2-4 polymethylene;

in the case when A is a bond, then R ₆ and R ₇ together with the nitrogen to which they are attached form a heterocyclic ring unsaturated 5-7 members in the ring one or two further nitrogen atom and one oxo or thioxo substituted there is a carbon atom wherein the other atoms in the ring optionally carry a substituent;

or R ₅ is a group of formula (b)

- 6 • · · · · · where Τ ^- ! is> C-OH or N (O) _n , where n is 0 or 1, and T ₂ is C-Ϊ! an optionally substituted aryl group together with> C-OH, or

T ₂ stands for CT! together with an optionally substituted N-heteroaryl when T 1 is N (O) _n ; obsession

R ₅ represents a group (c) wherein in the formula

L.! is O or NR _1b wherein R _{1 (} is hydrogen, alkyl, formyl, acetyl or hydroxymethyl),

L ₂ is N or CL ₄ , wherein L ₄ is hydrogen, halogen, formyl or hydroxymethyl,

L ₃ is CH ₂ , O, S,> CHL ₅ , wherein L ₅ is halogen or NL ₆ wherein

L ₆ is hydrogen or alkyl and

R ₁₂ and R ₁₃ are each independently hydrogen or alkyl, or R ₁₂ and R ₁₃ together are oxo or dioxo; and p is 1, 2 or 3.

These compounds can be used in the manufacture of a pharmaceutical composition for use in the treatment of airway inflammation and airway hypersensitivity.

The present invention also relates to a method of treatment of a mammal, including a human patient, for the treatment of airway inflammation and airway hypersensitivity; an effective non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

··· »····

The invention further relates to pharmaceutical compositions for the treatment of respiratory tract inflammation and respiratory hypersensitivity, wherein the compositions comprise an effective, non-toxic amount of a compound of formula (I) or, preferably, a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof. suitable excipients and carriers are present.

Treatment of respiratory hypersensitivity includes treatment primarily for the prevention of respiratory hypersensitivity and for the treatment of the disease.

The treatment of respiratory sensitivity is most preferably directed to the prevention of respiratory sensitivity.

The treatment of airway inflammation is primarily aimed at preventing lung cell damage associated with inflammatory conditions of the lungs.

The invention further relates to the use of the compounds of the formula I and, where appropriate, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates, for the preparation of a pharmaceutical composition for inhibiting the release of inflammatory neuropeptides, in particular at a dose that does not lower blood pressure. .

The present invention also provides a method of treatment that can be used to inhibit the release of inflammatory neuropeptides in a mammal, such as a human patient, which method comprises administering an effective, non-toxic amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable solvate thereof.

The present invention also relates to pharmaceutical compositions which inhibit the release of inflammatory neuropeptides comprising an effective, non-toxic amount of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier. .

In addition, the present invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, for the preparation of a medicament for the reduction of hypersensitivity airways.

The present invention also relates to a method of treating a hypersensitive airway in a mammal, including a human patient, comprising administering to said patient an effective, non-toxic amount of a compound of Formula (I) or a pharmaceutically acceptable or a suitable salt or solvate thereof.

The present invention also relates to pharmaceutical compositions for use in reducing hypersensitivity airways, an effective non-toxic amount of a compound of formula (I) or, where appropriate, a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof; · ····

- Contains 9 pharmaceutically acceptable excipients and carriers.

Preferably, -CF _{3 is} -Y- and A ₂ is hydrogen.

Preferably Y is -CF ₂ - or -CH (OH).

Preferably, Y is -CF ₂ -.

Preferably A! is C ₂ F ₅ and A ₂ is hydrogen.

Preferably Y ₅ is -O-.

When R ₄ is hydrogen, it is preferred that R ₃ is hydrogen, hydroxy or acyloxy, preferably hydroxy.

Preferably R ₄ is hydrogen.

Preferably, R ₅ represents a group (a) of the formula.

In cases where a preferred group R ₅ is (a) a group of formula The compounds of the invention are those wherein A represents> C = X, wherein X is O or S, preferably O, and _R6 and _R7 combined is a -A ₃ -A ₄ - linking chain as defined above.

Preferably, A ₃ is unsubstituted methylene.

Preferably A ₄ is -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -, preferably -CH ₂ CH ₂ CH ₂ -.

In those instances where -A ₃ -A ₄ - is a linking group metiléncsoportokból substituted, it is preferred that one of the methylene groups substituted with one or two substituents is especially advantageous if the methylene group in the ₃ in substituted.

Include groups composed of general formula methylene preferred substituents for the alkyl group ··· - -A ₃ -A _4:

• · • · · '* · • ♦ · · · ·

10 capsules, especially methyl or ethyl, most preferably this substituent is a methyl group.

In a preferred case, when A represents> C = X group in -A3-A4- coupling chain (and thus _R6 and _R7 together represent a) -CH ₂ - (CH _{2) q} -Z- (CH _{2) r} represents a group wherein q and r are 0, 1 or 2 such that q + r is 1 or 2; and Z is CH ₂ , O, S or NR, wherein R is as defined above.

Preferably R is hydrogen, (C 1 -C 9) alkyl, (C 2 -C 7) alkanoyl, phenyl (C 1 -C 4) alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl, wherein the phenyl or naphthyl ring may be substituted with one or two C 1-6 -alkyl, C 1-6 -alkoxy or halogen; Further, R is preferably mono- or bicyclic heteroarylcarbonyl.

In the case where A is a bond, the R ₇ .NR ₆ , preferably unsaturated heterocyclic ring, has 5 or 6 members, preferably 6 members.

Preferred substituents for R ₇ NR ₆ include alkyl or hydroxy, halogen, alkoxy, alkanoyloxy, nitro, amino, acylamino, carboxyl or alkoxycarbonyl.

Preferably Re and R ₇ taken together with the adjacent nitrogen atom form a substituted or unsubstituted, or a substituted or unsubstituted piridonilcsoport tiopiridonil group.

»· Γ · · · ·

- 11 ₆ .nr _R7 preferably represents optionally substituted pyridone, preferably unsubstituted pyridonyl group substituted.

Suitable pyridonyl groups include 2-pyridon-1-yl.

Preferred pyridonyl groups include 4-pyridon-1-yl.

It is preferred that the group R ₇ .NR ₆ contains further nitrogen atoms, more preferably another nitrogen atom is present. Preferably R ₇ .NR ₆ is an optionally substituted pyrimidinonyl or thiopyrimidinonyl group, preferably an unsubstituted pyrimidinonyl or thiopyrimidinonyl group, most preferably a pyrimidinonyl group. Preferred pyrimidinonyl groups include 4 (1H) -pyrimidinon-1-yl, 6- (1H) -pyrimidinon-1-yl, and 2 (1H) -pyrimidinon-1-yl. yl.

Suitable substituents on R ₇ NR ₆ include pyridonyl or thiopyridonyl, preferably alkyl having 1 to 6 carbon atoms, such as methyl.

In the case when R ₅ represents a group (a) wherein A is> C = NR _8, R ₈ is preferably a cyano group.

When R ₆ is -NH.R ₁₀ , R ₁₀ is preferably hydrogen, methyl, -CH-CH = CH ₂ , -CH ₂ -C = CH or cyclopropyl, preferably methyl, and R ₇ is hydrogen.

In the case where R ₇ and R ₁₀ together are one

C2-4 polymethylene group, this is preferably a -CH ₂ CH ₂ - group.

<t ·

- 12 In the case where R ₅ represented is a group (b) is preferably an optionally substituted aryl, demyelinating preferably present at aryl groups are monocyclic or bicyclic aryl groups which are optionally in addition to the hydroxy group at 2-position with one or more additional they may also be substituted with halogen, cyano or lower alkyl.

In the case where R ₅ is an optionally substituted N-heteroaryl, it is preferred that the N-heteroaryl is a monocyclic or bicyclic N-heteroaryl containing one or more nitrogen atoms, and which may optionally carry one or more substituents at the 2-position of the hydroxy or N-oxy group, wherein the substituent is halogen, amino, hydroxy, benzyloxy, phenyl, (lower alkyl) phenyl, , lower alkyl, lower alkoxy or lower alkoxycarbonyl.

According to a preferred embodiment of the invention, in the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, R ₅ is a group of formula (a);

A is> C = X, wherein X is O or S, or A is a bond; THE! and A ₂ is hydrogen and the other is -CF ₃ -Y, wherein Y is -CF ₂ -,> C = O or -CH (OH) -;

ϊ ·· ':

- 13 »

R 1 and R ₂ are each independently hydrogen or C 1-6 alkyl; or Ri and _R2 together form a C2-7 polymethylene;

R ₃ is hydrogen, hydroxy, C 1-6 alkoxy, or C 1-7 acyloxy, and R ₄ is hydrogen, or R ₃ and R ₄ together are a bond;

when A is> C = X then R ₆ is hydrogen; C 1 -C 6 alkyl optionally substituted with halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, carboxyl or amino, wherein the amino group is optionally substituted with 1 to 2 carbon atoms; May carry a C 6 alkyl group; or C 2 -C 6 alkenyl; amino optionally substituted with C 1-6 alkyl or C 2-6 alkenyl, or C 1-6 alkanoyl optionally substituted with 1 to 3 halogens, or the amino substituent substituted with a phenyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halogen; or an aryl or heteroaryl group optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and C 1-12 acyl. or an amino or aminocarbonyl group, the latter two groups being optionally substituted by one or two C 1-6 alkyl groups; and

- 14 R ₇ is hydrogen or C 1-6 alkyl; obsession

R ₆ and R _{7 taken} together are -CH ₂ - (CH ₂ ) _q -Z- (CH ₂ ) _r - wherein q and r are 0-2 and Z is CH ₂ , O, S or NR wherein R is hydrogen, (C 1 -C 9) alkyl, (C 2 -C 7) alkanoyl, phenyl (C 1 -C 4) alkyl, naphthylcarbonyl, phenylcarbonyl, or benzylcarbonyl; optionally substituted on the phenyl or naphthyl ring with one or two halogens or C 1-6 alkyl or C 1-6 alkoxy; or R is a mono- or bicyclic heteroarylcarbonyl group;

the case where A is a bond, R ₆ and R ₇ taken together with the nitrogen to which they are attached, an optionally substituted pyridone or an optionally substituted group tiopiridonil.

Preferably, when A is > C = X, then X is oxygen.

Preferably R 1 and R ₂ are both C 1 -C 6 alkyl, and preferably R ₂ and R ₂ are both methyl.

When R ₃ is alkoxy and R ₄ is hydrogen, then R ₃ is preferably methoxy or ethoxy, most preferably R ₃ is methoxy. When R ₃ is acyloxy and R ₄ is hydrogen, the preferred meaning of R ₃ is an acyloxy derivative derived from an unsubstituted carboxylic acid, such as an unsubstituted aliphatic group. «Acyloxy group. More preferably, when R ₃ and R ₄ are a single bond, or when R ₃ and R ₄ are both hydrogen, it is most preferred that R ₃ is hydroxy and R ₄ is hydrogen.

In the case where R ₆ is alkyl, the alkyl group, preferably a methyl, ethyl, n- or iso-propyl.

Preferably Re is methyl.

A _{6-substituted} in the alkyl group R is preferably a halogen atom is present as a substituent, for example, whether or not substituted by chlorine or bromine: include, _R6 is suitably a methyl, ethyl or propyl, preferably n-propyl, which carries terminus substituent is chloro or bromo, preferably chloro; .

In case where R ₆ is alkyl substituted with hydroxy, in this case, examples include hydroxyl-substituted ethyl or methyl group carrying a hydroxyl substituent on the terminal carbon atom.

In the case where R ₆ is alkyl substituted with alkoxy, preferably methoxy or ethoxy group is present Alkoxy; a preferred example is the methyl and ethyl group having a methoxy or ethoxy group on the terminal carbon atom as a substituent.

In the case where R ₆ is alkyl substituted with an alkoxycarbonyl group, a suitable alkoxycarbonyl group is a methoxycarbonyl or ethoxycarbonyl group may be present. As an example we mention the methyl or ethyl group \ ·· -:

{* * ·

16 capsules wherein the terminal carbon atom has a methoxycarbonyl or ethoxycarbonyl group as a substituent.

In the case where R ₆ is substituted by a carboxy group, this group is preferably a carboxyl group on the terminal carbon atom with methyl or ethyl.

In the case where R _e is an alkyl substituted by an amino group, where the amino group itself may be optionally substituted by one or two independent alkyl groups, the meaning of this group includes - (CH ₂ ) _s R _t R _{u in} which s is 1 - integer between 6 and R _t and R _u are each independently hydrogen or alkyl. Preferably s is 1 or 2, in particular 1.

R _t and R _u are independently hydrogen or methyl.

When R ₆ is alkenyl, this group may be vinyl, prop-1-enyl, prop-2-enyl, 1-methyl-vinyl, but-1-enyl, but-2-enyl, , but-3-enyl, 1-methylene-propyl, or 1-methyl-prop-2-enyl, wherein these groups may be present in E or Z form to form a stereoisomer of the compound.

In the case where R ₆ is an optionally substituted amino group, it may be mentioned among the preferred substituents, if present, are methyl, ethyl, propyl, butyl, allyl or trichloroacetyl group, and a phenyl group having optionally optionally substituted with a methyl or methoxy group or a chlorine atom, the phenyl group being optionally substituted

Preferably 17 may be replaced by an amino, methylamino, or phenylamino group; the phenyl in the phenylamino group may optionally carry a methyl or methoxy group or a chlorine atom on the phenyl ring.

In the case where R ₆ is aryl, preferably phenyl or naphthyl árucsoportként referenced, it is preferred that R ₆ is phenyl.

In the case where _R6 is heteroaryl, it is preferably a 5- or 6-membered monocyclic or 9-10-membered bicyclic heteroaryl group, that group is preferably a 5- or 6-membered monocyclic heteroaryl ring.

Preferred 5- or 6-membered monocyclic and 9- or 10-membered bicyclic heteroaryl groups are those containing one, two or three heteroatoms such as oxygen, nitrogen or sulfur, and where more than one heteroatom is present they may be the same or different.

The 5- or 6-membered monocyclic heteroaryl may be furylthienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl or thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazyl or triazyl. 5-membered or 6-membered heteroaryl is preferably furyl, thienyl, pyrrolyl or pyridyl, with 2- or 3-furyl, 2- or 3-pyrrolyl being particularly preferred,

2- or 3-thienyl or 2-, 3- or 4-pyridyl.

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

Preferred meanings of 10-membered bicyclic heteroaryl groups

18 and 2- and 3-benzofuryl, 2- and 3-benzothienyl and 2- and 3-indolyl as well as 2- and 3-quinolinyl are mentioned.

Consisting of R ₆ substituted aryl and heteroaryl is preferably substituted by one or more substituents from the preferred substituents are alkyl, alkoxy, hydroxy, halogen, fluoroalkyl, nitro, cyano, carboxyl, and ester thereof, and alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl. For optionally substituted aryl or optionally substituted heteroaryl, the preferred number of substituents is 1, 2, 3 or 4.

Substituted aryl or substituted heteroaryl groups may preferably have a methyl, methoxy, hydroxy, nitro or cyano substituent as well as a chlorine atom or a fluorine atom.

It is suitable group consisting of R _{E is} a ₆ reports the location of R is phenyl or naphthyl or a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl, wherein said phenyl, naphthyl or heteroaryl is substituted with 1, They may have 2, 3 or 4 substituents and may be substituted with C 1-6 alkyl, C 1-6 alkoxy, halogen, trifluoromethyl, nitro or cyano.

In the case where R ₆ is an optionally substituted phenyl group, it may be mentioned among the preferred meanings of phenyl, 4-substituted phenyl, 3-substituted phenyl, 3,4-disubstituted phenyl and 3,4,5 trisubstituted phenyl groups such as R ₆ are preferably 4-fluorophenyl.

In the case where R ₆ is an optionally substituted 5- or 6-membered monocyclic heteroaryl or an optionally substituted 9- or 10-membered bicyclic heteroaryl, then there are suitable, the preferred meanings unsubstituted 5- or 6-membered monocyclic heteroaryl or mono-substituted 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl groups, of which unsubstituted 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl are particularly preferred.

In the case where R ₆ and R ₇ together represent -A ₃ -A ₄ - chain of the formula, then A ₃ is preferably a substituted or unsubstituted methylene, and A ₄ is -CH ₂ CH ₂ - or -CH ₂ CH ₂ A CH ₂ - group such as -CH ₂ CH ₂ CH ₂ -.

In the case of A! is a substituted methylene group, preferably substituted with an alkyl group, preferably a methyl group.

In the case where R ₆ and R ₇ together are a group -CH ₂ - (CH ₂ ) _q -Z- (CH ₂ ) _r , wherein Z, q, r are as defined above, then R ₆ .N.CX.R ₇ is preferably piperidonyl or pyrrolidonyl group, preferably piperidonyl group.

Preferably R ₆ .N.CX.R ₇ is 2-oxo-piperidin-1-yl.

• ·

When Z is other than CH ₂ , q is often 0 or 1 and r is very often 0 or 1.

When Z is NR, R is preferably hydrogen, methyl, ethyl, n- or isopropyl, η, chair or tert-butyl, benzyl, phenylcarbonyl. or a benzylcarbonyl group wherein the phenyl ring may be optionally substituted with methyl, methoxy, chlorine or bromine; Further preferred values of R include furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or indolylcarbonyl.

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

Most preferably, R is methyl.

As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine; this term preferably refers to a chlorine atom.

Suitable alkyl groups, including alkyl groups present in other groups such as alkoxy, include C 1 -C 12 alkyl groups, preferably C 1 -C 6 alkyl groups such as methyl, ethyl, η-propyl, and the like. , isopropyl, η-butyl, isobutyl or tert-butyl.

Preferred alkenyl groups include C2-C12, preferably C2-C6-alkenyl.

· · «* • • • •>>>>>>>>>

Of the expedient meanings of alkynyl groups, mention is made

Alkynyl groups having from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms.

Suitable meanings for acyloxy groups include alkylcarbonyloxy groups, whereby the alkyl group may be as defined above.

As used herein, the term "fluoroalkyl" refers to alkyl groups as defined above containing one or more fluorine atoms, with trifluoromethyl and pentafluoroethyl being preferred examples.

As used herein, the term "aryl" refers to phenyl and naphthyl, which may have 1 to 5, preferably 3, substituents, including halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyl, and the like. such as amino, nitro, carboxyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, and alkylcarbonyl groups.

Pharmaceutically acceptable salts of the compounds of formula I include acid addition salts and salts of the carboxy group.

Examples of pharmaceutically acceptable acid addition salts of the compounds of formula (I) include acid addition salts with optionally substituted amino groups, such as the hydrochloride and hydrobromide salts. These salt-forming groups may be part of R ₅ .

Examples of pharmaceutically acceptable salts with carboxy groups include metal salts such as

- 22 alkali metal salts or optionally substituted ammonium salts.

The compounds of formula (I) may also be formed in the form of solvates, of which hydrates are preferred, these solvates are also part of the invention.

The compounds of formula I may form optical isomers. For example, optically active centers can be found in compounds of formula I wherein R ₃ is hydrogen, hydroxy, alkoxy or acyloxy, and R ₄ is hydrogen, wherein R 1 and R ₂ are different from each other, and wherein R ₆ and R ₇ together represent a linking chain of formula -A ₃ -A ₄ -, wherein this linking chain contains from 1 to 4 chiral carbon atoms. The present invention relates to optical isomers of the compounds of formula (I), which may form single isomers or mixtures thereof, such as their racemates.

When R ₃ is hydroxy, alkoxy or acyloxy and R ₄ is hydrogen, one isomer has a 4S, 3R stereo structure and the other has a 4R, 3S stereo structure.

The compounds of formula (I) may also be geometric isomers, all of which are within the scope of the present invention, including those wherein R ₅ and R ₃ are in trans or relative to each other in cis; preferred are those compounds wherein R ₃ and R ₅ are in transposition to one another.

• ·· * »***

The compounds of formula (I), and their pharmaceutically acceptable salts and pharmaceutically acceptable solvates, include all compounds, and preferred variants thereof, as disclosed in EP 0376524.

Among the compounds of formula (I), and optionally pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, the compounds of the examples of EP 0376524, in particular

Example 6. Thus, (-) - trans-3,4-dihydro-2,2-dimethyl-4- (2-oxo-piperidin-1-yl) -6-pentafluoroethyl is highly preferred among the compounds of formula (I). 2H-1-benzopyran-3-ol derivatives.

The compounds of formula (I) as well as the pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof may be prepared according to the methods described in EP 0376524.

In general, pharmaceutical compositions are used for the treatment of the present invention.

The pharmaceutical compositions are conveniently formulated for oral administration, but may also be formulated for administration by other routes, such as spray, aerosol, or other inhalation formulation; and for parenteral administration to patients with heart failure. Other forms of administration for administration by other means include sublingual and transdermal formulations.

implications. A particular treatment is administration by inhalation.

The pharmaceutical compositions may be in the form of tablets, capsules, powders, granules, suppositories, soluble powders or liquid preparations such as oral or sterile parenteral solutions or suspensions.

In order to ensure uniformity of dosage, the compositions of the invention may be prepared in unit dosage form.

Unit dosage forms for oral administration may be presented as tablets or capsules, which may contain the usual excipients, including binders such as syrup, acacia, gelatin, sorbitol, tragacanth and polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine, tablet lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate, and microcrystalline cellulose; and pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

Solid compositions for oral administration may be prepared by conventional mixing, loading, or tabletting techniques. Where large amounts of filler are used, repeated mixing steps may be incorporated to distribute the active ingredient evenly throughout the formulation. Of course, these operations are well known to those skilled in the art. Pills are a well-known method of general medical practice • · · ·

25 may be coated, with enteric coatings being preferred.

Liquid preparations for oral use may be formulated, for example, as emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. These liquid preparations may contain conventional excipients such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxylmethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan monooleate, or acacia; anhydrous carriers (these include edible oils); for example, almond oil, fractionated coconut oil, oil esters such as glycerol esters, propylene glycol, or ethyl alcohol; preservatives, such as methyl p-hydroxybenzoate or propyl ester or sorbic acid, and if desired, the compositions may also contain flavoring or coloring agents.

For parenteral administration, liquid unit dosage forms are prepared containing the active compounds of the present invention and a sterile vehicle, depending on the concentration of the preparation, which is suspended or dissolved in the vehicle. During preparation of the solutions, the active ingredient may be dissolved in water for injection and then sterilized by filtration prior to loading and sealing in a suitable glass jar or ampoule. Advantageously, adjuvants such as a local anesthetic, a preservative or a buffer may be dissolved in the vehicle. To enhance stability, the resulting composition may be frozen after filling into a glass vessel and the water removed in vacuo. Parenteral suspensions are prepared in substantially the same manner, except that the active ingredient is suspended in the vehicle instead of being reconstituted, and sterilization cannot be accomplished by filtration. In this case, the active ingredient may be sterilized with ethylene oxide prior to suspension in the sterile vehicle. A surfactant or wetting agent may conveniently be included in the composition to ensure uniform distribution of the active ingredient.

The compositions of the invention may be formulated for administration to the respiratory tract, preferably in the form of an aerosol, or as a nebulizer, or as a very fine powder for inhalation; the active ingredient may be administered alone or in combination with an inert excipient or carrier, including lactose. In this case, the active ingredient to be administered should have a particle size of less than 50 μm, preferably less than 10 μm, such as for example 1 to 50 μ, 1 to 10 μ or 1 to 5 μm in diameter. When preferred, small amounts of other anti-asthmatic or bronchodilator agents can be added to the compositions, including, for example, sympathomimetic amine derivatives such as isoprenaline, isoetarin, salbutamol, phenylephrine and ephedrine; xanthine derivatives may also be added to the compositions, such as

27 theophylline or aminophylline or corticosteroids such as prednisolone or adrenaline stimulants such as ACTH.

Depending on the mode of administration, the composition may contain from 0.1 to 99% by weight, preferably from 10 to 60% by weight, of the active ingredient. For administration by inhalation, the active ingredient is preferably present in an amount of from 10 to 99%, more preferably from 60 to 99%, such as 90, 95 or 99%.

Preferably, the carrier is a conventional material, such as lactose.

Formulations of the microfine powder are conveniently administered in aerosolized dosage form or by use of a suitable inhalation device.

The metered dose aerosol formulations conveniently contain a conventional propellant as well as a co-solvent such as ethanol, surfactants such as oleyl alcohol, (cis-9-octadecene alcohol) lubricant such as oleyl alcohol, and a desiccant such as calcium sulfate; and a density modifying agent such as sodium chloride.

Preferably, isotonic sterile solutions, optionally containing a buffer, are added to the nebulizer, adjusting the pH of the solution to, for example, 4-7; these solutions contain up to 20 mg / ml of the active ingredient, usually in the range of 0.1 to 10 mg / ml of the solution for conventional nebulizers.

The magnitude of the effective amount administered will depend upon the relative efficacy of the compound of the invention, the severity of the disease being treated, and the patient's weight.

The unit dose of the compositions of the invention preferably contains from 0.001 to 100 mg of the compound of the invention (in the case of inhalation, it is from 0.001 to 10 mg), usually from 0.01 to 50 mg, e.g. , 5 to 25 mg, such as 0.1, 1, 2, 5, 10, 15 or 20 mg. These compositions may be administered 1 to 6 times daily, more frequently 1 to 3 times daily, with a daily dose in the range of 0.002 to 200 mg in a 70 kg human treated patient, preferably 0.005 to 100 mg. mg. That is, the dose is in the range of about 2.5 to about ⁵ mg / kg / day to about 3 mg / kg / day, preferably about 5.10 to about ⁵ mg / kg / day to about 1.5 mg / kg / day.

The invention is illustrated by the following non-limiting examples.

Example 1

Prevention of eosinophilia-related lung cell fragility and parenchymal lung hypersensitivity caused by Sephadex particles

Test compound: For the following test, (-) - trans-3,4-dihydro-2,2-dimethyl-4- (2-oxo-piperidin-1-yl) -6- as described in Example 6 of EP 314446. pentafluoroethyl 2H-1-benzopyran-3-ol (compound 1) was used.

This compound was prepared according to the procedure described in EP 314446.

- 29 Test method:

Sephadex G200 (particle size 400-120 µm after full swelling in water) is suspended in saline to form a suspension of 0.5 mg / ml 48 hours prior to injection; Rats of 250 to 350 g were injected intravenously with 1 ml of the suspension prepared above on days 0, 2 and 5. Animals in the control group of rats were given saline only. 30 minutes prior to each dose of Sephadex, Compound # 1 or vehicle alone is administered orally. Evaluation was performed on days 7 or 8.

2 x 20 μΙ blood was collected from the tail vein of the animals and subjected to complete and differential (May-Grunwald and Giesma staining) cell counts. To evaluate hypersensitivity to 5-hydroxytryptamine (5-HT), the lungs of the lungs of animals were exposed to 1 g and cumulative dose responses (1.4 χ 10 ′ ⁹ to 1) were constructed. 2 χ 10 ^{4 4} mol / l, given in about 5-fold increasing doses at 3-minute intervals). The area under the logarithmic concentration response curve (measured over a load of 1 g) is taken as the basis for evaluation. For evaluation of lung cell fragility, the remaining lung sections are cut into 2 to 4 mm ³ pieces and incubated for 60 minutes at 37 ° C in 2 ml of minimal essential medium (which contains Earle's salt instead of L-glutamine) and where the medium contains 1 mg / ml type II collagenase and 1 mg / ml type IV collagenase. The dispersed cells were filtered, filtered through a column filled with nylon cotton, and the red cells were removed by hypotonic cell destruction with ammonium chloride. The washed residue remaining on the filter was resuspended in deoxyribonuclease-containing medium (65 μl / ml) and the viability of the cells was evaluated by a dye-exclusion method using trypan blue; the number of eosinophils is determined by eosin staining.

The results are summarized in the table below.

Number of experiments First Second Third Dose of Compound (1) (mg / kg, p.o.) 1 2 2 The percentage of eosinophil cells in the blood control compared to 73 ± 13 124 ± 17 119 ± 15 Area under the 5-HT curve in% of Sephedex- control compared to 60 ± 8 (P <0.05) 70 + 17 54 ± 13 Number of rats with viable cells number is above 10% (in Figure 6). group) we did not decide and 6 1 % Of viable cells (province) 81 (58-96) 5 (0-25)

The results take into account the tstandard error (n = 6). In untreated animals, the eosinophil cell in the blood.

The number of 31 rats was 14%, the area under the 5-HT curve was 27% compared to the control animals treated with Sephadex. 71% of cells harvested from untreated animals were found to be viable, showing only 8% in Sephadex-treated animals [Spicer et al., Br. J. Pharmacol. 101: 821-828 (1990); Cook, Clin. Exp. 20: 511-517 (1990)].

The results indicate that the test compound [1] does not reduce Sephadex-induced eosinophilia, but seems to decrease the sensitivity of the lung slice tested and the sensitivity of the cells to digestion with collagenase.

Example 2

Reduction of lung parenchymal hypersensitivity

Rats weighing 300-400 g were treated with Sephadex as described in Biological Example 1, except that the third injection of Sephadex was administered only on day 4 and that lung slices were removed on days 7 and 14. both. Cumulative concentration response curves to make a 5-HT or carbachol (in both cases the concentration of 10 ⁸ - 10 was 3 χ ^'4 M). Subsequently washed in the pulmonary tissues when the base line is displayed again, constructed of a second concentration response curve, in which the compound (1) was used for 10 ^'9-10' at a concentration of ⁶ mol / l or vehicle alone was administered. For the first concentration-response curve, the maximum concentration was used, and then specific percentages of this peak were added to the 10 ' ⁵ and 5-HT and carbachol

- 32 for tests at concentrations of 3 χ 10 ' ⁴ mol / l (± standard error (n> 4) Jt

The results are summarized in the tables below.

Maximum contraction (load in mg) after treatment with 5-HT or carbachol at concentration and response

5-HT carbachol Untreated rats 78 ± 7 64 ± 10 Sephadex, Day 7 174 ± 12 254 ± 15 Sephadex, Day 14 169 ± 28 246 ± 35

Maximum contraction value in% when tested with 5-HT or carbachol at concentration and response

Concentration of compound (1) 5-HT 5 carbachol (Mol / l) 10 " mol / l 3x10 " mol / l 10 " mol / l 3x10 * mol / l untreated rats 0 24 ± 5 61 ± 4 22 ± 5 48 ± 6 · 10 ' 24 + 8 54 ± 9 23 ± 3 48 ± 9 Sephadex, 0 36 ± 6 67 ± 5 48 ± 6 77 ± 3 7 days 31 ± 7 68 ± 9 47 ± 3 87 ± 5 ICP 41 ± 12 71 ± 6 42 ± 6 72 ± 9

- 33 ··· <····

Concentration of compound (1) 5-HT 5 carbachol (Mol / l) 10 " mol / l 3 x 10 " mol / l 10 " mol / l 3x10 " mol / l Job ⁵ ® 30 ± 9 62 ± 13 26 ± 4 * 52 ± 4 ** 10 '' 24 ± 7 45 ± 4 * 28 ± 6 45 ± 5 ** Sephadex, 0 21 ± 4 84 ± 8 47 ± 10 83 ± 12 Day 14 rent ⁹ 28 ± 5 99 ± 11 47 ± 12 68 ± 13 to ^ 14 ± 3 67 ± 4 * 18 ± 3 * 37 ± 5 * 10 6 ± 2 " 48 * 4 "* 23 ± 2 * 42 ± 4 ** 10 " 14 ± 7 51 ± 13 * 17 ± 5 * 33 ± 7 **

Ρ <0.05 relative to the value obtained without compound (1) ** P <0.01 *** P <0.001

The above results show that Compound (1) has no effect on the 5-HT and carbachol concentration-response curves in untreated animal tissues, however, in the tissue from Sephadex-treated animals, the hypersensitivity reaction to 5-HT or carbachol can be suppressed, It can be reduced.

Example 3

Guinea-pig bronchial rings are mounted between platinum electrodes in the presence of propranolol (1 pmol / l) and atropine (1 pmol / l), and tissue sections are held for 10 seconds (60-70 V, biphasic, 0.5 msec pulses, 10 Hz) ) stimuli are given, where between successive stimuli ···················

- 34 breaks of at least 15 minutes. Preparing tracheal spirals from guinea pigs and causing them to contract; for this, EC ₇₀ spasmogens were used [Taylor et al., Br. J. Pharmacol. 95, 795P (1988)].

Guinea-pig portal vein fragments were placed under a load of 2 g, the system was equilibrated for 1 hour, and voltage was induced with 30 mM K ⁺ ions. Concentration response curves for Levcromakalim and Compound (1) are plotted using the bronchial ring; the system is rinsed again before increasing solutions are added. Cumulative concentration-response curves are obtained using tracheal spirals and portal curves. IC ₅₀ values are calculated from the geometric mean of at least four determinations. The results are summarized in the table below.

employee fabric The voltage induction documentation in method IC ₅₀ (pmol / l) Impact Scale: (1) chemical let / levkro- -makalin Levkro- Makale (1) compound bronchial rings electronic 0.53 0,020 27 Air Tube Muscle spirals histamine (5 pmol / l) 1.12 0.041 27 Leukotriene d ₄ (0.003 pmol / l) 0.30 0,020 16

employee The tense- IC ₅₀ (pmol / l) Impact Scale: fabric indulgence (1) chemical documentation in Levkro- (1) let / levkro- method Makale compound -makalin Prostaglandin E ₂ (0.01) 0.32 0,021 15 Spontaneous 0.22 0.019 12 5-hydroxy- tryptamine (0.8 pmol / L) 0.14 0,018 7.8 Is portal vein KCl (30 mmol / l) 0,060 0,021 2.8

Compound (1) is 27 times more potent than levochromacalin in inhibiting NANCe-induced contraction, which also means that it is similarly effective in inhibiting sensory neuropeptide release. See Good et al., Br. J. Pharmacol. 105: 933-940 (1992). This increase in activity is most pronounced for the direct smooth muscle relaxant effect on the tracheal spirals, which is significantly higher than the portal vein values.

- 36 Patent claims

Claims (5)

Use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, for the preparation of a medicament for the treatment of airway inflammation and hypersensitivity, wherein: THE! and one of A ₂ is hydrogen when the other is CF ₃ -Y-, wherein Y is -CF ₂ -,> C = O, or -CH (OH) -; Y 1 is -O-, -CH ₂ -, or -NR 0 where R 0 is hydrogen, alkyl or alkylcarbonyl; R ₄ and R ₂ are each independently hydrogen or alkyl; obsession R 1 and R ₂ together are C 2-7 polymethylene; R ₃ is hydrogen, hydroxy, alkoxy or acyloxy, and R ₄ is hydrogen, or R ₃ and R ₄ together form a bond; R ₅ is a group of formula (a) wherein: A is> C = X, wherein X is O, S or NR ₈ wherein R ₈ is -CN, -NO ₂ , -COR ₉ where - 37 R _g is alkyl, amino, monoalkylamino, fluoroalkyl, phenyl or substituted phenyl, or R ₈ is -SO ₂ R _{9 in} which R ₉ is as defined above, or A is a bond; if A is> C = X, wherein X is O or S, then Re is hydrogen; alkyl optionally substituted with one or more halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxyl or ester or amide derivatives thereof, and amino, monoalkylamino or dialkylamino; alkenyl; an amino group optionally substituted with an alkyl or alkenyl or alkanoyl group optionally substituted with 1 to 3 halogens or phenyl groups, the phenyl group itself being optionally substituted with an alkyl or alkoxy group or a halogen atom; optionally substituted aryl or optionally substituted heteroaryl; and R ₇ is hydrogen or alkyl; or R ₆ and R ₇ together represent a linking chain of formula -A ₃ -A ₄ -, wherein A ₃ is bonded to the nitrogen atom of the -NA- group and A ₄ is bonded to a component of this group, wherein ₃ is an optionally substituted methylene group, - 38 ι :. . · ··· · «·« * ··· « ₄ is a two- or three-membered chain wherein one member is optionally oxygen, sulfur or -NR and the other members are independently optionally substituted methylene; R is hydrogen, alkyl, alkanoyl, phenyl (C 1 -C 4) alkyl, arylcarbonyl, where the aryl may optionally be substituted; or R is mono or bicyclic heteroarylcarbonyl; in the case when A represents> C = X wherein X represents a group of formula _NR8, then _R6 represents -NH.R _10, wherein R ₁₀ is hydrogen, alkyl of 3-6 carbon atoms, alkenyl or alkynyl; and R ₇ is hydrogen or alkyl, or R ₇ and R ₁₀ together are C 2-4 polymethylene, when A is a bond, R ₆ and R ₇ together with the adjacent nitrogen to which they are attached form a 5-7 membered heterocyclic ring, wherein the ring contains an additional one or two nitrogen atoms, and one of the carbon atoms in the ring is replaced by an oxo group or a dioxo group, wherein the other atoms of the ring optionally carry a substituent; or R ₅ is a group of formula (b) wherein Ϊ! is> C-OH or N (O) _n , wherein n is 0 or 1 and T ₂ are CT! together with an optionally substituted aryl group when Ti is> C-OH, or T ₂ , together with the group, is an optionally substituted N-heteroaryl group when T 1 is hydrogen; is N (O) _n , or - 39 R ₅ represents a group (c) of formula wherein: L ₄ is O or NR _11t where R _n is hydrogen, alkyl, formyl, acetyl or hydroxymethyl, 1-2 is N or CL ₄ L ₄ is hydrogen, halogen, formyl or hydroxymethyl; 1-3 is CH ₂ , O, S,> CHL ₅ , wherein L5 is a halogen atom or a group of formula NL _{6 in} which L ₆ is hydrogen or alkyl and R ₁₂ and R ₁₃ are each independently hydrogen or alkyl; or R ₁₂ and R ₁₃ together are oxo or dioxo; and p is 1, 2 or 3. Use according to claim 1 for the prevention or treatment of airway hypersensitivity. Use according to claim 1 or 2 for the prevention of airway hypersensitivity. Use according to claim 1 for the prevention of damage to lung cells associated with an inflammatory condition of the lungs. 5. Use according to claim 1, characterized in that the active ingredient is a compound of the formula (I) in which A; is -C ₂ F ₅ and A ₂ is hydrogen.