WO1989011477A1 - Benzoxepine and related compounds - Google Patents

Abstract

A compound of formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof wherein: A represents >C=X or a bond; X represents O or S; Y represents N or N+-O- or a moiety CR10; Z° represents O, CH2, NR or S(O)p; R represents hydrogen, alkyl or alkylcarbonyl; a process for preparing such compounds, pharmaceutical compositions containing such compounds and the use of such compounds and compositions in medicine.

Description

NOVEL COMPOUNDS

This invention relates to novel compounds having smooth muscle relaxant activity, to processes for their preparation and to their use as pharmaceuticals.

EP-A-76075, 91748, 93535, 95316, 107423, 120426, 120427, 126311, 126350, 126367, 138134, 205292 and European Patent Application Number 88312288.9 describe benzopyrans and pyrano(3,2-c)pyridine derivatives having inter alia antihypertensive activity.

A group of heterocyclyl derivatives has now been discovered, having smooth muscle relaxant activity, and such compounds are therefore potentially useful as bronchodilators in the treatment of disorders of the respiratory tract, such as reversible airways obstruction and asthma, and also in the treatment of hypertension. Such compounds are also indicated as of potential use in the treatment of disorders associated with smooth muscle contraction of the gastro-intestinal tract, uterus or the urinary tract including the ureter. Such disorders respectively include irritable bowel syndrome and diverticular disease; premature labour; incontinence; renal cholic and disorders associated with the passage of kidney stones. They are also indicated as of potential use in the treatment of cardiovascular disorders other than hypertension, such as congestive heart failure, angina, peripheral vascular disease and cerebral vascular disease; and also in the treatment and/or prophylaxis of disorders associated with pulmonary hypertension and of disorders associated with right heart failure. Accordingly, the present invention provides a compound of formula (I):

or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof

wherein: A represents >C=X or a bond; X represents O or S; Y represents N or N⁺-O- or a moiety CR₁₀ wherein R₁₀ is as defined below; Z° represents O, CH₂, NR or S(O)_p; R represents hydrogen, alkyl or alkylcarbonyl R₁, R₂, R₃ and R₄ each independently represent hydrogen or alkyl; or R₁ and R₂ together represent a C_2-7 polymethylene chain; or R₃ and R₄ together represent a C_2-7 polymethyene chain; R₅ represents hydrogen, hydroxy, alkoxy or acyloxy; R₆ is hydrogen or R₅ and R₆ together represent a bond; when A represents >C=X, then R₇ 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 alkanoyl 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 R₈ represents hydrogen or alkyl; or R₇ and R₈ together represent a linking chain of formula -A¹-A²-, A¹ being attached to the nitrogen atom of the moiety -N-A- and A² being attached to the group A on the said moiety, and wherein A¹ represents a substituted or unsubstituted methylene group, A² 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, alkanoyl, phenyl C_1-4-alkyl, arylcarbonyl wherein the aryl group may be substituted or unsubstituted; or R' is mono- or bi-cyclic- heteroarylcarbonyl; when A represents a bond, then R₇ and R₈ 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; R₉ and R₁₀ are each independently selected from the class of hydrogen, substituted or unsubstituted alkyl, alkoxy, C_3-8 cycloalkyl, hydroxy, nitro, cyano, halo, formyl, carboxy, a group of formula R^aT¹-, R^bR^cNT-, R^aT²NH-, R^dCO.O-, R^dCS.O-, R^d(OH)CH-, R^d(SH)CH-, R^dC(=N.OH)-, R^dC(=N.NH₂)- or alkenyl optionally substituted by alkylcarbonyl, nitro or cyano, providing that when Y is CR₁₀ then at least one of R₉ or R₁₀ is not hydrogen; R^a represents R^d or R^dO- and R^d represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, optional substituents for R^d being up to 3 substituents selected from alkyl, alkoxy, halo, haloalkyl, nitro and cyano; R^b and R^c each independently represent hydrogen, alkyl or alkylcarbonyl; T represents a bond or T¹, T¹ represents -CS- or T² and T² represents -CO-, -SO- or -SO₂-; and p represents zero or an integer 1 or 2.

Suitable substituents for any aryl or heteroaryl group represented by R₇ include one or more groups or atoms selected from alkyl, alkoxy, hydroxy, halogen, fluoroalkyl, nitro, cyano, carboxy or an ester thereof, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl.

When the linking chain -A¹-A²- 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 -A¹- is substituted.

Suitable substituents for any methylene group in -A¹-A²- include alkyl groups, especially methyl or ethyl and in particular methyl.

In one particular aspect when A represents >C=X, the linking chain -A¹-A²- (and thus R₇ and R₈ together) represent a moiety of formula -CH₂-(CH₂)_n-Z-(CH₂)_m- wherein m and n are 0 to 2 such that m + n is 1 or 2 and Z is CH₂ , O , S or NR ' wherein R ' is as defined above.

Suitably R' represents hydrogen, C_1-9 alkyl, C_2-7 alkanoyl, phenyl-C_1-4- alkyl, naphthylearbonyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl or naphthy1 ring by one or two of C_1-6 alkyl, C_1-6 alkoxy or halogen; or R' is mono- or bi-cyclic- heteroarylcarbonyl.

Suitably, when Y is N or N⁺-O-, R₉ is hydrogen.

Suitably, when Y is CR₁₀, then one of R₉ and R₁₀ is hydrogen.

In particular, when Y is CR₁₀, one of R₉ and R₁₀ is hydrogen and the other is selected from substituted or unsubstituted alkyl, alkoxy, C_3-8 cycloalkyl, hydroxy, nitro, cyano, halo, formyl, carboxy, a group of formula R^aT¹-, R^bR^cNT-, R^aT²NH-, R^dCO.O-, R^dCS.O-, R^d(OH)CH-, R^d(SH)CH-, R^dC(=N.OH)-, R^dC(=N.NH₂)- or alkenyl optionally substituted by alkylcarbonyl, nitro or cyano, wherein R^a, R^b, R^c, R^d, T, T¹ and T² are as defined in relation to formula (I).

Also to be mentioned are those compounds wherein one of R₉ and R₁₀ is hydrogen and the other is selected from the class of C_1-6 alkylcarbonyl, C_{1- 6} alkoxycarbonyl, C_1-6 alkylcarbonyloxy, C_{1- 6} alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C_1-6 alkylsulphinyl, C_1-6 alkylsulphonyl, C_1-6 alkoxysulphinyl, C_1-6 alkoxysulphonyl, C_1-6 alkylcarbonylamino, C_1-6 alkoxycarbonylamino, C_1-6 alkyl-thiocarbonyl, C_1-6 alkoxy-thiocarbonyl, C_1-6 alkyl-thiocarbonyloxy, C_1-6 alkyl-thiomethyl, formyl or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C_1-6 alkyl groups, or C_1-6 alkylsulphinylamino, C_1-6 alkylsulphonylamino C_1-6 alkoxysulphinylamino or C_1-6 alkoxysulphonylamino or ethenyl terminally substituted by C_1-6 alkylcarbonyl, nitro or cyano, or -C(C_1-6 alkyl)NOH or

-C(C_1-6 alkyl)NNH₂.

In one aspect, the present invention provides a compound of formula (IA) following wholly within the scope of the abovementioned formula (I) or, when the compound of formula (IA) contains a salifiable group, a pharmaceutically acceptable salt thereof:

wherein:

X is oxygen or sulphur;

Y is CR₁₀ as defined below, or is N or N⁺-O-;

R₁ and R₂ are independently selected from hydrogen or C_1-6 alkyl or together are C_2-7 polymethylene;

R₃ and R₄ are as defined for R₁ and R₂ above;

R₅ is hydrogen, hydroxy, C_1-6 alkoxy or C_1-7 acyloxy and R₆ is hydrogen or R₅ and R₆ together are a bond; R₇ is hydrogen; C_1-6 alkyl optionally substituted by up to three halo atoms, by hydroxy, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, carboxy or amino optionally substituted by one or two independent C_1-6 alkyl groups or disubstituted by C_4-5 polymethylene; C_2-6 alkenyl; amino optionally substituted by a C_1-6 alkyl or C_2-6 alkenyl group or by a C_1-6 alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by C_1-6 alkyl, C_1-6 alkoxy or halogen; or aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of C_1-6 alkyl, C_1-6 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C_1-12 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C_1-6 alkyl groups; or (when X is 0), R₇ is selected from the class of carboxy, C_1-6 alkoxycarbonyl, or aminocarbonyl optionally substituted by one or two C_1-6 alkyl groups; and

R₈ is hydrogen or C_1-6 alkyl; or

R₇ and R₈ together are -CH₂-(CH₂)_n-Z-(CH₂)_m- wherein m and n are 0 to 2 such that m + n is 1 or 2 and Z is CH₂, O, S or NR₁₁ wherein R₁₁ is hydrogen, C_1-6 alkyl, C_2-7 alkanoyl, phenyl C_1-4-alkyl, naphthylcarbonyl, phenylcarbonyl or benzyl-carbonyl optionally substituted in the phenyl or naphthyl ring by one or two of C_1-6 alkyl, C_1-6 alkoxy or halogen; or Rxx is heteroarylcarbonyl;

when Y is N or N⁺-O-, R₉ is hydrogen or, when Y is CR₁₀, either one of R₉ and R₁₀ is hydrogen and the other is selected from the class of C_1-6 alkylcarbonyl, C_1-6 alkoxycarbonyl, C_1-6 alkylcarbonyloxy, C_1-6 alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C_1-6 alkylsulphinyl, C_1-6 alkylsulphonyl, C_1-6 alkoxysulphiny1, C_1-6 alkoxysulphonyl, C_1-6 alkylcarbonylamino, C_1-6 alkoxycarbonylamino, C_1-6 alkyl-thiocarbonyl, C_1-6 alkoxy-thiocarbonyl, C_1-6 alkyl-thiocarbonyloxy, C_1-6 alkyl-thiomethyl, formyl or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C_1-6 alkyl groups, or C_1-6 alkylsulphinylamino, C_1-6 alkylsulphonylamino C_1-6 alkoxysulphinylamino or C_1-6 alkoxysulphonylamino or ethenyl terminally substituted by C_1-6 alkylcarbonyl, nitro or cyano, or -C(C_1-6 alkyl)NOH or -C(C_1-6 alkyl)NNH₂; or one of R₉ and R₁₀ is nitro, cyano or C_1-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C_1-6 alkyl or by C_2-7 alkanoyl; or R₉ is hydrogen and R₁₀ is C_1-6 alkyl or C_3-8 cycloalkyl; suitably R₈NCXR₇ being trans to the R₅ group when R₅ is hydroxy, C_1-6 alkoxy or C_1-7 acyloxy.

Preferably X is oxygen.

Y is usually C-R₁₀ wherein R₁₀ is as defined in formula (I).

C_1-6 alkyl groups or alkyl containing moieties in R₁ to R₁₀ may be selected from methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl. Examples of R₁/R₂, R₃/R₄ also include C₃, C₄, C₅, C₆ or C₇ polymethylene.

When R₅ is C_1-6 alkoxy and R₆ is hydrogen, preferred examples of R₅ include methoxy and ethoxy, of which methoxy is more preferred. When R₅ is C_1-7 acyloxy and R₆ is hydrogen, a preferred class of R₅ is unsubstituted carboxylic acyloxy, such as unsubstituted aliphatic acyloxy (formyloxy or C_2-7 alkanoyloxy) or benzoyloxy. However, it is preferred that R₅ and R₆ together are a bond, or R₅ and R₆ are both hydrogen, or, in particular, that R₅ is hydroxy and R₆ is hydrogen.

Favourably, R₈, when R₇ and R₈ are not joined together, is hydrogen or methyl, most preferably hydrogen.

A sub-group of R₇, when C_1-6 alkyl substituted by halogen is C_1-6 alkyl substituted by fluoro, chloro or bromo. Examples thereof include methyl or ethyl terminally substituted by one, two or three fluoro, chloro or bromo.

Examples of R₇, when C_1-6 alkyl substituted by hydroxy, include methyl or ethyl terminally substituted by hydroxy.

A sub-group of R₇, when C_1-6 alkyl substituted by C_1-6 alkoxy is C_1-6 alkyl substituted by methoxy or ethoxy. Examples thereof include methyl or ethyl terminally substituted by methoxy or ethoxy.

A sub-group of R₇, when C_1-6 alkyl substituted by C_1-6 alkoxycarbonyl is C_1-6 alkyl substituted by methoxycarbonyl or ethoxycarbonyl. Examples thereof include methyl or ethyl terminally substituted by methoxycarbonyl or ethoxycarbonyl.

Examples of R₇, when C_1-6 alkyl substituted by carboxy include methyl or ethyl terminally substituted by carboxy. Examples of R₇ when alkyl substituted by amino, optionally substituted by one or two independent C_1-6 alkyl groups include a group (CH₂)_qNR_aR_b where q is 1 to 6, and R_a and R_b are each independently hydrogen or C_1-6 alkyl or together are C₄ or C₅ polymethylene. Examples of q include 1 and 2, in particular 1. Preferably R_a and R_b are each independently selected from hydrogen and methyl.

Examples of R₇, when C_2-6 alkenyl include vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl, or 1-methylprop-2-enyl, in both their E and Z forms where stereoisomerism exists.

Examples of R₇ when amino optionally substituted as hereinbefore defined include an amino optionally substituted by a methyl, ethyl, propyl, butyl, allyl or trichloroacetyl group or by a phenyl group optionally substituted by one methyl, methoxy or chloro group or atom, in particular amino, methylamino and phenylamino optionally substituted in the phenyl ring by one methyl, methoxy or chloro group or atom.

Examples of R₇ aryl include phenyl and naphthyl of which phenyl is preferred.

A sub-class of R₇ heteroaryl is 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl of which 5- or 6-membered monocyclic heteroaryl is preferred. In addition, 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains one, two or three heteroatoms which are 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.

Examples of 5- or 6-membered monocyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and thiadiazolyl, and pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. Preferred examples of such groups include furanyl, thiophenyl, pyrrolyl and pyridyl, in particular 2- and 3-furanyl, 2- and 3-pyrrolyl, 2- and 3-thiophenyl, and 2-, 3- and 4-pyridyl.

Examples of 9- or 10-membered bicyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include benzofuranyl, benzothiophenyl, indolyl and indazolyl, quinolinyl and isoquinolinyl, and quinazoninyl. Preferred examples of such groups include 2- and 3-benzofuranyl, 2- and 3-benzothiophenyl, and 2- and 3-indolyl, and 2- and 3-quinolinyl.

Preferably, the number of groups or atoms for optional substitution of aryl or heteroaryl is one, two, three or four.

Preferred examples of the groups or atoms for optional substitution of aryl or heteroaryl include methyl, methoxy, hydroxy, bromo, chloro, fluoro, nitro or cyano.

R₇ and R₈, when together are -CH₂-(CH₂)_n-Z-(CH₂)_m- as defined, the resulting radical substituting the aryl-oxepine in the 5-position is preferably either pyrrolidonyl or piperidonyl. Other examples or 5-substituents when R₇ and R₈ are joined together include those described in EP-A-107423.

When Z is other than CH₂, m is often 0 or 1 and n is often 0 or 1. Suitable examples of Rxx when Z is NRxx include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec- and tert- butyl, benzyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl ring by methyl, methoxy, chloro or bromo; furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or indolylcarbonyl. Preferably Rxx is hydrogen, methyl, n-butyl, acetyl, benzyl, benzylcarbonyl, phenylcarbonyl or furylcarbonyl. Most preferably R₁₁ is hydrogen.

When one of R₉ and R₁₀ is hydrogen, it is preferred that R₉ is hydrogen and R₁₀ is selected from the class of C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6 alkylcarbonyl, C_1-6 alkoxycarbonyl, nitro, trifluoromethyl or cyano. In particular, R₁₀ may be acetyl, nitro, cyano, methyl, ethyl, isopropyl or cyclopentyl.

When one of R₉ and R₁₀ is nitro, cyano or C_1-3 alkylcarbonyl the other is, preferably, amino optionally substituted by one or two C_1-6 alkyl or by C_2-7 alkanoyl. In particular, when one of R₉ and R₁₀ is nitro, cyano or C_1-3 alkylcarbonyl, the other is amino, methylamino, dimethylamino or acetylamino. Most preferably, one of R₉ and R₁₀ is nitro or cyano, and the other is amino.

When one of R₉ and R₁₀ is nitro, cyano or C_1-3 alkylcarbonyl, it is preferred that R₁₀ is nitro, cyano or C_1-3 alkylcarbonyl. It is generally preferred, however, that R₉ is hydrogen.

The alkyl groups or alkyl moieties of alkyl-containing groups for R₉ or R₁₀ are, preferably, methyl or ethyl.

When used herein the term ''halogen'' refers to fluorine, chlorine, bromine and iodine; preferably fluorine.

_Suitably alkyl groups, or alkyl groups forming part of other groups such as in the alkoxy group, are C_1-12 alkyl groups especially C_1-6 alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups, unless otherwise indicated.

Suitably alkenyl groups are C_2-12 groups especially C_2-6 alkenyl groups.

_Suitable alkynyl groups are C_2-12 alkynyl groups especially C_2-6 alkynyl groups.

Suitable polymethylene groups include C₃, C₄, C₅, C₆ and C₇ polymethylene groups.

Suitable acyloxy groups include alkylcarbonyloxy groups wherein the alkyl group is as defined above.

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 R₇ group. It will also be appreciated that when Y in the compound of formula (I) represents N, then the resulting pyridine moiety may yield acid addition salts, such as the hydrochloride or hydrobromide salts. Alternatively, internal salts such as the N-oxide may be formed by per-acid oxidation of the corresponding compound of formula (I).

Examples of pharmaceutically acceptable salts of carboxy groups include metal salts, such as alkali metal salts, or optionally substituted ammonium salts.

Examples of esters of carboxy groups are pharmaceutically acceptable esters such as C_1-6 alkyl esters.

Examples of amides of carboxyl groups include pharmaceutically acceptable amides such as amides of formula -CO.NR^sR^t wherein R^s and R^t each independently represent hydrogen or C_1-6 alkyl.

The compounds of formula (I) may also exist in the form of solvates, preferably hydrates, and the invention extends to such solvates.

The compounds of formula (I), wherein R₁ and R₂ and/or R₃ and R₄ are different, or wherein R₅ and R₆ do not together form a bond, are asymmetric and, therefore, can exist in more than one stereoisomeric form. The invention extends to all isomers individually and to mixtures thereof, including racemates.

The invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof which comprises the conversion of an intermediate of formula (II):

wherein R¹ to R⁴ and Z^o are as defined hereinbefore, Y¹ and R₉ ¹ are Y and R₉ respectively or groups or atoms convertible thereto and the dotted line represents anoptionally present bond; to the required compound formula (I), according to the methods generally described in the aforementioned European patent publications for conversion of the correspondingbenzopyrans and pyranopyridines to their 4-substitutedderivatives. The present invention also provides a process for thepreparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises; i) acylating a compound of formula (III):

wherein, Y¹ is Y or a group convertible thereto, R₉ ¹ is R₉ or a group or atom convertible thereto, R₁ to R₄ and Z^o are as hereinbefore defined, R₅ ¹ is hydroxy, C_1-6 alkoxy or C_1-7 acyloxy, and R₈ ¹ is hydrogen or C_1-6 alkyl, the R₈ ¹NH group being trans to the R₅ ¹ group,

a) with an acylating agent of formula (IV):

R₁₂-CO-L₁ (IV)

wherein L₁ is a leaving group, and R₁₂ is hydrogen; C_1-6 alkoxycarbonyl; C_1-6 alkyl optionally substituted by halogen, hydroxy, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, carboxy or amino optionally substituted as hereinbefore defined for R₇; C_2-6 alkenyl or optionally substituted aryl or heteroaryl as hereinbefore defined for R₇; or a group convertible to R₇ as hereinbefore defined, and thereafter, when R₈ is hydrogen and R₁₂ is (CH₂)_zL₂, where z is 3 or 4 and L₂ is a leaving group, cyclising the resultant compound;

b) with a compound of formula (V):

X=C=N.R₁₃ (V)

wherein R₁₃ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_1-6 alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by C_1-6 alkyl, C_1-6 alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R₁₃ is hydrogen, optionally converting R₁₃; or

ii) for compounds of formula (I) wherein R₇ and R₈ together represent a linking chain of formula -A¹-A² as defined above in relation to formula (I), by reacting a compound of formula (VI):

wherein R₁, R₂, R₃, R₄, R₉ ¹, Y¹ and Z^o are as hereinbefore defined with a compound of formula (VII):

R₁₅NHCOR₁₄ (VII)

wherein R₁₄ and R₁₅ together represent a linking chain -A¹-A²-; or

iii) for compounds of formula (I) wherein A represents a bond and R₇ and R₈ together with the nitrogen to which they are attached form the above defined unsaturated heterocyclic ring, by reacting a compound of formula (VI) as defined above with an activated form of a compound of formula (VIIA) :

R₈NHR₇ (VIIA)

wherein R₇ and R₈ are as defined above;

and thereafter if required, carrying out one or more of the following optional steps:

(i) converting a compound of formula (I) into a further compound of formula (I); (ii) converting Y¹ to Y; (iii) converting R₉ ¹ to R₉; (iv) forming a pharmaceutically acceptable salt of the compound of formula (I); or (v) forming a pharmaceutically acceptable solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Preferably in (VI), p = 2 when Z^o is S(O)_p.

In the process variant i) a) acylation of a compound of formula (III) with an acylating agent of formula (IV), the leaving group L₁ is a group that is displaceable by a primary or secondary amino nucleophile. Examples of such a group include C_1-4 alkanoyloxy, and halogen, such as chloro and bromo or hydroxy. When the leaving group L₁ is either of these examples, the acylating agent of formula (IV) is either an acid anhydride or an acid halide. When it is an acid anhydride, it may be a mixed or simple anhydride. If it is a mixed anhydride, it may be prepared in situ from a carboxylic acid and an acid halide, although this is less preferred than using the halide itself. When L₁ is hydroxy, conventional coupling methods using dicyclohexylcarbodiimide are suitable.

In process variant i) a), when R₇ in the desired compound of formula (I) is an R₇ optionally substituted amino-substituted alkyl group as hereinbefore defined, it is preferred that R₁₂ is a group convertible to the R₇ substituted alkyl group as hereinbefore defined, in particular that it is C_1-6 alkyl substituted by halo, especially bromo. The R₁₂ halo substituent in the resultant compound of process variant i) a) may be converted to an R₇ substituent which is amino optionally substituted as hereinbefore defined by a conventional amination reaction with ammonia acid corresponding alkyl- or dialkylamine. when R₁₂ is C_1-6 alkoxycarbonyl, this may be converted to R₇ is carboxy by conventional hydrolysis.

Less favourably R₁₂ may be C_1-6 alkyl substituted by protected amino, protected C_1-6 alkylamino or amino substituted by two independent C_1-6 alkyl groups, it being necessary to protect the R₁₂ amino function in process variant i) a).

When the acylating agent of formula (IV) is an acid anhydride, the acylation of the compound of formula (III) may be carried out in the presence of an acid acceptor, such as sodium acetate, optionally using the anhydride as the solvent.

When the acylating agent of formula (IV) is an acid halide, the acylation of the compound of formula (III) is, preferably, carried out in a non-aqueous medium, such as dichloromethane, in the presence of an acid acceptor, such as triethylamine, trimethylamine, or calcium, potassium or sodium carbonate.

When the acylating agent of formula (IV) is an acid the acylation of a compound of formula (III) is conveniently performed in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide in an inert solvent, such as dimethylformamide at a temperature of 0°C to ambient.

When R₅ ¹ in a compound of formula (III) is hydroxy, there is a risk of a side-reaction between the hydroxy group and the acylating agent of formula (IV). However, the reaction may be carried out under controlled conditions such that only the amine, R₈ ¹NH- is acylated, for example, by using a C_2-9 acyloxy group as the leaving group L₁, in the acylating agent of formula (IV) in the manner as previously described for an acid anhydride, and/or effecting the reaction at relatively low temperature, e.g. at below 10°C. Alternatively R₅ ¹ may be C_1-7 acyloxy in a compound of formula (III), although less preferably if R₅ in the resultant compound of formula (I) is to be hydroxy, and, after reaction with the acylating agent of formula (IV), be converted into hydroxy, as described hereinafter.

When R₁₂ is (CH₂)_zL₂ where the variables are as hereinbefore defined, the leaving group L₂ is a group that is displaceable by a secondary amino nucleophile adjacent to a carbonyl function. A preferred example is chloro.

The cyclisation reaction when R₁₂ is (CH₂)_zL₂ where the variables are as hereinbefore defined is preferably carried out in an inert solvent such as dimethylformamide.

In process variant i) b), when R₁₃ in a compound of formula (V) is C_1-6 alkyl, C_1-6 alkanoyl optionally substituted as hereinbefore defined, or phenyl optionally substituted as hereinbefore defined, the reaction between the compounds of formulae (III) and (V) is, preferably, carried out in a solvent, such as methylene chloride, at below room temperature, in particular below 10°C.

When R₁₃ is hydrogen, the reaction between the compounds of formulae (III) and (V) is, preferably, carried out using a corresponding alkali metal, cyanate or thiocyanate, for example that of sodium or potassium, in an optionally methanolic aqueous medium acidified with a mineral acid, such as dilute hydrochloric acid. A slightly elevated temperature such as 50 to 90°C is apt.

In the process variant ii), that is the reaction between a compound of formula (VI) and a compound of formula (VII), it is particularly preferred that the reaction is carried out under basic conditions so as to facilitate the formation of the anion of the compound of formula (VII), for example, in the presence of an alkali metal base such as potassium t-butoxide or sodium hydride.

The reaction between the compounds of formula (VI) and (VII) may be carried out in any suitable aprotic solvent at a temperature that provides a convenient rate of formation of the compound of formula (I), such as at ambient temperature or at a slightly elevated temperature, for example 40°C.

Conveniently, the compound of formula (VII) may itself be used as the solvent for the reaction between compounds of formulae (VI) and (VII).

In process variant iii), a suitable activated form of a compound of formula (VIIA) is an ionic form. Thus in the reaction between a compound of formula (VI) and a compound of formula (VIIA), it is preferred that the reaction is carried out under basic conditions so as to facilitate the formation of the anion of the compound of formula (VIIA), for example, in the presence of an alkali metal base such as potassium t-butoxide or sodium hydride .

The reaction between the compounds of formulae (VI) and (VIIA) may be carried out in any suitable aprotic solvent, for example dimethylsulphoxide, at a temperature that provides a convenient rate of formation of the compound of formula (I), such as at ambient temperature or at an elevated temperature, but conveniently at ambient temperature.

Suitable conversions of a compound of formula (I) to a further compound of formula (I) include:

(i) converting R₅ in the resulting compound of formula (I) into another R₅; (ii) converting a compound of formula (I) wherein R₅ and R₆ represent hydroxy and hydrogen respectively to give another compound of formula (I), wherein R₅ and R₆ together represent a bond; (iii) reducing any compound of formula (I) wherein R₅ and R₆ together represent a bond; to give another compound of formula (I), wherein R₅ and R₆ each represent hydrogen; (iv) thiating the R₈.N.CX.R₇ group in the compound of formula (I), wherein X is oxygen, to give a compound wherein X is sulphur; (v) converting a compound of formula (I) wherein p represents zero to a compound of formula (I) wherein p represents 2; (vi) converting a compound of formula (I) wherein p represents 2 to a compound of formula (I) wherein p represents zero; or (vii) when R₅ is other than hydrogen, interconverting the cis and trans mutual configuration of the variables R₅ and R₆. The reaction of the compounds of formulae (III) with (IV) or (V) results in a compound of formula (I) wherein R₅ is hydroxy, alkoxy or acyloxy, whereas the reaction of the compounds of formulae (VI), (VII) and (VIIA) results in a compound of formula (I) wherein R₅ is hydroxy. Examples of an optional conversion of R₅ in a compound of formula (I) into another R₅ are generally known in the art. For example, when R₅ is hydroxy, it may be alkylated using an alkyl iodide in an inert solvent, such as toluene, in the presence of a such as sodium hydride or potassium hydroxide, or it may be acylated using a carboxylic acid chloride or or an appropriate anhydride in a non-hydroxylic solvent, such as toluene or dichloromethane, in the presence of an acid acceptor, such as triethylamine. When R₅ is acyloxy or alkoxy, it may be converted into hydroxy by means of any conventional dealkylation method, such as by treatment with trimethylsilyliodide in an aprotic solvent. In addition when R₅ is acyloxy it may be converted into hydroxy by conventional hydrolysis using, for example, dilute mineral acid.

The optional conversion of a compound of formula (I), wherein R₅ and R₆ are hydroxy and hydrogen respectively, into another compound of formula (I), wherein R₅ and R₆ together are a bond, may be carried out by dehydration under conventional dehydration conditions, for example, by using a dehydrating agent, such as sodium hydride, in inert solvent, such as dry tetrahydrofuran, at reflux temperature; alternatively the hydroxy group represented by R₅ may be converted into a leaving group such as a mesyloxy or tosyloxy group and the resulting compound treated with a base such as sodium hydride to provide the compound of formula (I) wherein R₅ and R₆ together repressnt a bond.

The reduction of a compound of formula (I), wherein R₅ and R₆ together are a bond, into another compound of formula (I), wherein R₅ and R₆ are each hydrogen, may be carried out by hydrogenation using a catalyst of palladium on charcoal.

The thiation of the R₈.N.CX.R₇ group in a compound of formula (I), wherein X is oxygen, to give another compound of formula (I), wherein X is sulphur, is, preferably, carried out with conventional thiation agents, such as hydrogen sulphide, phosphorus pentasulphide and Lawesson's reagent (p-methoxyphenylthiophosphine sulphide dimer). The use of hydrogen sulphide and phosphorus pentasulphide may lead to side-reactions and, therefore, the use of Lawesson's reagent is preferred.

The thiation reaction conditions are conventional for the thiation agent employed. For example, the use of hydrogen sulphide is, preferably, acid catalysed by, for example, hydrogen chloride in a polar solvent, such as acetic acid or ethanol. The preferred use of Lawesson's reagent is, preferably, carried out under reflux in a dry solvent, such as toluene or dichloromethane.

The interconversion of the cis and trans configuration of the variables R₅ and R₆ is generally carried out by changing the configuration of variable R₅, especially when R₅ represents hydroxyl, by means of any convenient conventional procedure. Any conversion of Y¹ to Y or R₉ ¹ to R₉ may be carried out using the appropriate conventional chemical procedure.

The optional formation of a pharmaceutically acceptable salt, when the resulting compound of formula (I) contains a salifiable group, may be carried out conventionally. Similarly, pharmaceutically acceptable solvates, for example hydrates, may be prepared using any convenient conventional procedure.

A compound of formula (III) may be prepared by reacting a compound of formula (VI), as hereinbefore defined, with a compound of formula (VIII):

R₈ ¹NH₂ (VIII)

wherein R₈ ¹ is as hereinbefore defined; and optionally converting R₅ ¹ hydroxyl in the resulting compound of formula (II) into another R₅ ¹.

The reaction is normally carried out in a solvent, such as a C_1-4 alcohol, in particular methanol, ethanol or propanol at an ambient or an elevated temperature, for example 12 to 100°C. The reaction proceeds particularly smoothly if carried out in ethanol under reflux.

The resulting compound of formula (III) may be removed from the reaction mixture by removal of the solvent, for example, by evaporation under reduced pressure. Any epoxide impurity may be removed conventionally, for example by chromatography.

The optional conversion of the hydroxy group for R₅ ¹ in the resulting compound of formula (II) into a C_1-6 alkoxy or C_1-7 acyloxy group may be carried out as described hereinbefore in relation to the corresponding conversion of R₅ in a compound of formula (I).

Compounds of the formula (VI) are preferably prepared by the reaction of the compound of formula (II) wherein the optional bond is present, with a per-acid, such as m-chloroperbenzoic acid; as described in Description 4 hereinafter.

Alternatively, the compound of formula (II) wherein the optional bond is present may be converted to the corresponding bromohydrin which is in turn converted to the epoxide as described in the aforementioned European Patent Publications.

Compounds of the formula (II) may be prepared according to the following general reaction scheme.

; the variables being as defined hereinbefore.

When Y is C-NO₂ and R₉ is hydrogen, the reaction steps (a) and (b) are conveniently carried out with intermediates wherein Y is C-H and R₉ ¹ is hydrogen, the nitro group subsequently introduced by nitration with concentrated/fuming HNO₃ and steps (c) and (d) carried out with intermediates wherein Y is C-NO₂ and R₉ ¹ is hydrogen. It will be appreciated that, according to the nature of the groups Y and R₉, it may be necessary to introduce substituents R₉ and/or R₁₀ at different stages in the synthesis, before or after the cyclisation step b).

Alternatively it may be necessary to utilise a different synthesis from a corresponding chroman type by ring expansion techniques viz:

; wherein R' represents R¹ or R² as required, the remaining variables being as defined hereinbefore.

; the variables being as defined hereinbefore.

The intermediates of formulae (II), (III), and (VI) represent part of the present invention. The intermediates of formulae (IV), (V), (VII), (VIIA) and (VIII) are known and may be prepared in accordance with an appropriate known process. The starting compounds in schemes 1, 2 and 3 are also believed to be known or prepared by analogous processes to known compounds.

The compounds of formula (I) have been found to have bronchodilator activity and/or blood-pressure lowering activity. They are therefore useful in the treatment of respiratory tract disorders, such as reversible airways obstruction, diverticular disease and asthma and also hypertension. They may also be of potential use in the treatment of other disorders hereinbefore described. The present invention accordingly provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

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, for treating respiratory tract disorders; or parenteral administration for patients suffering from heart failure. Other alternative modes of administration include sublingual or transdermal 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 of this invention 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. 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 on the method of administration.

The present invention further provides a method of treatment of respiratory tract disorders or hypertension in mammals including man, which comprises administering to the suffering mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

An effective amount will depend on the relative efficacy of the compounds of the present invention, the severity of the respiratory tract disorder or hypertension being treated and the weight of the sufferer. However, a unit dose form of a composition of the invention may contain from 0.01 to 100mg of a compound of the invention (0.01 to 10mg via inhalation) and more usually from 0.1 to 50mg, for example 0.5 to 25mg such as 1, 2, 5, 10, 15 or 20mg. Such compositions may be administered from 1 to 6 times a day, more usually from 2 to 4 times a day, in a manner such that the daily dose is from 0.02 to 200mg for a 70 kg human adult and more particularly from 0.05 to 100mg.

The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of respiratory tract disorders or hypertension.

The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of respiratory tract disorders or hypertension. In addition to respiratory tract disorders and hypertension, the present invention also encompasses uses and methods of treatment comprising each of the indications and disorders mentioned hereinbefore. The abovementioned compositions, unit dose forms and effective amounts are also suitable for these last mentioned indications and disorders.

No toxicological effects are indicated at the aforementioned dosage ranges.

The following descriptions relate to the preparation of intermediates and the following examples relate to the preparation of compounds of formula (I).

Description 1 7-Nitro-2 , 3 , 4 , 5-tetrahydro-1-benzoxepin-5-one 0

To a solution of 2,3,4,5-tetrahydro-1-benzoxepine-5-one (2.15g, 13.3mmol) in concentrated HNO₃ (20ml) at -20°C was added with stirring over 90 mins fuming HNO₃ (18ml) during which time the temperature rose to 0°C. The solution was poured into H₂O (200ml), the resulting solid collected by filtration, washed with H₂O (2 × 50ml) and dried to give the title compound (2.13g, 77%), m.p. 127°C; δ 2.34 (2H, quin, J=7Hz, 3,3'-H), 2.96 (2H,t, J=7Hz, 4,4'-H), 4.38 (2H,t, J=Hz, 2,2'-H), 7.19 (1H,d, J=9HZ, 9-H), 8.26 (1H, d.d, J=9Hz, 3Hz, 8-H), 8.63 (1H,d, J = 3Hz, 6-H); υ max (nujol) 1685 (C=0) cm^-1. Found: C, 57.89; H, 4.49; N, 6.73. C₁₀H₉NO₄ requires C, 57.97; H, 4.38; N, 6.76%.

Description 2

5-Hydroxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine

To 7-nitro-2,3,4,5-tetrahydro-1-benzoxepin-5-one (1.5g, 7.24mmol) suspended in EtOH (25ml) was added sodium borohydride (300mg, 8mmol) and the mixture stirred for 2h at 5°C. The mixture was poured into H₂O (300ml), extracted with CH₂CI₂ (3 × 75ml) and the combined extracts dried (MgSO₄). Concentration in vacuo of the organic phase afforded a solid (1.35g) which was purified by column chromatography on silica eluting with CH₂CI_2. The title compound was obtained as a white solid (1.2g, 81%), m.p. 78-80°C; δ 1.87-2.18 (4H,m, 3,3',4,4'-H), 2.46 (1H,d, J=5.3Hz, exchangeable OH), 3.90 (1H,m, 2 or 2'-H), 4.30 (1H,m, 2 or 2'-H), 4.96 (1H,m, 5-H) , 7.07 (1H,d, J=8.8Hz, 9-H), 8.06 (1H, d.d, J=8.8HZ, 2.75Hz, 8-H), 8.37 (1H,d, J=2.75Hz, 6-H). Found: C, 57.50; H, 5.37; N, 6.65. C₁₀H₁₁NO₄ requires C, 57.41; H, 5.30; N, 6.70%.

Description 3

2,3-Dihvdro-7-nitro-1-benzoxepine

5-Hydroxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine (1.14g, 5.45mmol) and p-toluene sulphonic acid (250mg, 1.13mmol) were heated together in refluxing toluene (125ml) for 90 min under nitrogen. The solution was allowed to cool, filtered and the filtrate concentrated in vacuo to afford an off white solid (lg). Purification by column chromatography on silica eluting with CH₂CI₂ afforded the title compound as a white solid (990mg, 95%), m.p. 93-5°C; δ 2.73 (2H, d.d.t, J=4.7Hz, 1.5Hz, 3,3'-H), 4.32 (2H, t, J=4.7Hz, 2,2'-H), 6.15 (1H, d.t, J=11.7Hz, 4.6Hz, 4-H), 6.37 (1H, d.t, J=11.7Hz, 1.6Hz, 5-H), 7.02 (1H, d, J=9Hz, 9-H), 7.98 (1H, d.d, J=9Hz, 2.75Hz, 8-H), 8.10 (1H,d, J=2.75Hz, 6-H).

Found: C, 62.63; H, 4.85; N, 7.35. C₁₀H₉NO₃ requires C, 62.82; H, 4.75; N, 7.33%.

Description 4

4,5-Epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine

2,3-Dihydro-7-nitro-1-benzoxepine (925mg, 4.84mmol) and 3-chloroperbenzoic acid (1.16g, 6.72mmol) were stirred together in CH₂CI₂ (50ml) at room temperature for 18h. The solution was washed with saturated aqueous sodium bicarbonate solution (50ml) and H2O (50ml), dried (MgSO₄) and concentrated in vacuo to afford a white solid (1.35g). Purification by column chromatography on silica eluting with CH2CI2 afforded the title compound as a white solid (922mg, 92%), m.p. 123-4°C; δ 2.50 (1H, m, 3-H or 3'-H), 2.70 (1H, m, 3-H or 3'-H), 3.74 (1H, m, 4-H), 3.91 (1H, d, J=4Hz, 5-H), 4.08-4.22 (2H, m, 2,2'-H), 6.98 (1H, d, J=9Hz, 9-H), 8.10 (1H, d.d, J=9Hz, 2.75Hz, 8-H) , 8.41 (1H, d, J=2.7_.5Hz, 6-H). Found: C, 57.79; H, 4.37; N, 6.68. C₁oNgNU4 requires C, 57.97; H, 4.43; N, 6.76%.

Description 5

Trans 5-Azldo-4-hydroxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine

A solution of 4,5-epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine (182mg, 0.88mmol) and sodium azide (63mg, 0.97mmol) in dioxane (10ml) and water (2ml) was heated under reflux for 5 hours, allowed to cool and diluted with water (40ml). The mixture was extracted with diethyl ether (2×30ml), the organic extract dried, (MgSO₄) and concentrated in vacuo to afford the title compound as a solid (200mg, 91%), m.p. 86-88°C; δ 1.90-2.60 (2H, m), 3.10 (1H, br, exchangeable OH), 3.90-4.20 (2H, m), 4.45 (1H, m), 4.83 (1H, d, J=7Hz), 7.15 (1H, d, J=9Hz), 8.20 (1H, dd., J=9Hz, 2Hz), 8.37 (1H, d, J=2Hz); v_max (KBr) 3440 (OH), 2120 (N₃) cm^-1.

Description 6

Trans 4-amino-5-hydroxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine

Triphenylphosphine (183mg, 0.7mmol) was added to a solution of 4-azido-5-hydroxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine (160mg, 0.69mmol) in dry tetrahydrofuran (25ml) at room temperature and the mixture stirred for 18 hours. The solution was diluted with water (100ml), extracted with chloroform (3×50ml) and the combined extracts dried (MgSO₄). Concentration in vacuo of the organic phase afforded a solid (360mg) which was purified by column chromatography on silica eluting with CHCl₃:MeOH (3:1v/v) to yield the title compound (100mg, 64%); δ 1.83 (1H, m), 2.08 (2H, br s, exchangeable NH₂), 2.20 (1H, m), 3.58 (1H, m), 3.99 (1H, d, J=7.7Hz), 4.03 (1H, m), 4.32 (1H, m), 5.12 (1H, s, exchangeable OH), 7.09 (1H, d, J=8.8HZ), 8.04 (1H, dd., J=8.8HZ, 3HZ), 8.34 (1H, d, J=3Hz); v_max (KBr) 3370, 3290 (NH₂), 3100 (OH) cm^-1. Example 1

Trans 4-Hvdroxy-7-nitro-5-(2-oxopyrrolidin-1-yl) -2,3,4,5-tetrahydro-1-benzoxepine

2-Pyrrolidinone (370mg, 4.34mmole) in dry THF (10ml) at room temperature under nitrogen was treated with potassium bis (trimethylsilyl) amide (5.9ml of a 0.75M solution in toluene, 4.34mmol). The mixture was stirred for 90 mins and 4,5-epoxy-7-nitro-2,3,4,5 -tetrahydro-1-benzoxepine (450mg, 2.17mmol) in dry THF (15ml) added dropwise over 10 min. The solution was stirred overnight, poured into 1N aq. HCl solution and extracted with ethyl acetate (3 × 50ml). The combined extracts were dried (MgSO₄), concentrated in vacuo and the resulting solid purified by column chromatography on silica eluting with CHCI₃ to afford the title compound (143mg, 23%), m.p. 172-4°C; δ 2.09-2.34 (4H,m) 2.66-2.82 (2H,m, 3,3'-H), 3.44-3.58 (2H,m), 4.05-4.14 (1H, d.t, J=12Hz, 2.2Hz), 4.28-4.36 (1H, d.t, J=12Hz, 3.8Hz), 4.48 (1H, d.d, J=3.8Hz, 2.6Hz, 4-H), 4.81 (1H, s, 5-H), 5.66 (1H, br s, exchangeable OH), 7.19 (1H,d, J=8.6Hz, 9-H), 7.79 (1H,d, J=2.75Hz, 6-H), 8.14 (1H, d.d, J=8.8Hz, 2.75Hz, 8-H), 7.26 ( 0.2H,s, CHCI₃); v max (nujol) 3270 (OH), 1655 (C=O amide) cm^-1. Found: C, 55.32; H, 5.21; N, 8.70. C₁₄H₁₆N₂O₅.0.15CHCI₃ requires C, 54.79; H, 5.25; N, 9.03%.

Example 2

Trans 5-(4-fluorobenzoylamlno)-4-hydroxy-7-nitro- 2,3,4,5-tetrahydro-1-benzoxepine

4-Fluorobenzoylchloride (0.05ml, 0.4mmol) was added to a stirred solution of trans 5-amino-4-hydroxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine (83mg, 0.37mmol) in dry dimethylformamide 95ml) and Et₃N (0.2ml) under nitrogen at room temperature. After 4 hours the mixture was poured into water (50ml), extracted with chloroform (3×25ml), the combined extracts dried (MgSO₄) and concentrated in vacuo to an oil. Separation by column chromatography on silica eluting with CH₂CI₂ followed by recrystallisation (Et2θ/EtoAc/hexane) afforded the title compound (40mg, 33%), m.p. 171-3°C; δ (DMSO) 1.90 (1H, m), 2.16 (1H, m), 4.01 (1H, m), 4.14 (1H, m), 4.57 (1H, m), 5.30-5.36 (2H, m, 5H, exchangeable OH), 7.16 (1H, d, J=9.3Hz) 7.35 (2H, m, aromatic H), 8.0 (2H, m, 8H, aromatic H), 8.10 (2H, m, 6H, aromatic H), 8.86 (1H, d, J=8Hz, exchangeable NH), v_max (KBr) 3340, 3290, 1640 (C=O amide). Found: C, 58.79; H, 4.42; N, 8.02. C₁₇H₁₅FN₂O₅ Requires C, 58.96; H, 4.37; N, 8.02%. Pharmacological Data

1. Bronchodilator Activity

(a) Bronchodilation in vitro; guinea pig tracheal spiral preparations.

Male guinea pigs (300-600g) were stunned by a blow to the head and bled from the carotid artery. The trachea was exposed, dissected free of connective tissue, and transferred to oxygenated krebs solution at 37°C. Next, spirals (2 per trachea) were prepared by cutting the whole trachea spirally along its longitudinal axis and then dividing this spiral lengthwise. Each preparation was mounted, using silk thread, in a 10ml organ bath filled with krebs solution at 37°C and bubbled with 5% CO₂ with O₂. The resting tension of the preparations was set at 2g and changes in muscle tension were monitored isometrically by means of a UFI (2oz) force and displacement transducer (Ormed Ltd) connected to a Linseis pen recorder. All preparations were allowed to equilibrate for 60 minutes. During this equilibration period the preparations were washed by upward displacement at 15 minute intervals and, if necessary, the resting tension was readjusted to 2g using a mechanical micromanipulator system.

Once a steady resting tension had been obtained, the preparations were dosed simultaneously with the test compound (10^-8-2×10^-5M), and finally a maximum relaxation achieved by addition of 10^-3M isoprenaline. The fall in tension evoked by the test compound was expressed as a percentage of the total relaxation evoked in the presence of 10^-3M isoprenaline. Appropriate concentration-relaxation curves were then constructed and values for potency (IC₅₀) were obtained.

The composition of Krebs solution is: sodium chloride 118.07mM, sodium hydrogen carbonate 26.19mM, potassium chloride 4.68mM, potassium orthophosphate 1.18mM, magnesium sulphate septahydrate 1.8mM and calcium chloride 2.52mM;pH ca. 7.45.

(b) Bronchodilation in vivo by the Konzett Rossler method.

Animals were prepared according to the methodology described by Konzett and Rossler (1). Guinea pigs were anaesthetized by an intraperitoneal injection of Urethane (1500mg/kg) and then prepared with tracheal, arterial and venous cannulae. The animals were connected to a respiratory pump which was adjusted to deliver a volume of 1ml per 100g body weight to the guinea pig. The back pressure of the Ugo Basile 7020 overflow sensor was then adjusted to give a constant, resting overflow volume. The animals were then allowed to equilibrate for 10 minutes before experimentation began.

Arterial blood pressure was recorded with a pressure transducer (Bell and Howell 4-422-0001) connected via a Devices 3552 pressure pre-amplifier to a Devices pen recorder. Changes in overflow volume - an index of total pulmonary resistance - were expressed as a percentage of the maximum bronchoconstriction obtained by total occlusion of the tracheal cannula. In all determinations of bronchoconstrictor activity, peak overflow volumes were used. In experiments in which non-immunized animals were used, bronchoconstriction was produced by a bolus injection of a submaximal dose of 5-hydroxytryptamine (5-HT) into the jugular vein. The bronchodilator activity of the test compound was assessed by its ability to inhibit a subsequent 5-HT-induced bronchoconstriction. In other experiments, the ability of compounds to inhibit anaphylactic bronchoconstriction in actively sensitized animals was determined.

1. H. Konzett and R. Rossler (1940) Arch. Exp. Path. Pharmak (Naunyn Schmiedeberg) 195, 71-74.

In test (a) in vitro, the compound of Example 1 had an IC₅₀ of 1.41 × 10^-5M, and in test (b), in vivo, at a dose of img/kg i.v., the compound of Example 1 gave 30 ± 10% protection from the effects of 5-HT.

2. Antihypertensive Activity

Blood Pressure Lowering Activity

Systolic blood pressures were recorded by a modification of the tail cuff method described by I.M. Claxton, M.G. Palfreyman, R.H. Poyser, R.L. Whiting, European Journal of Pharmacology, 37, 179 (1976). A W+W BP recorder, model 8005 was used to display pulses . Prior to all measurements rats were placed in a heated environment (33.5 ± 0.5°C) before transfer to a restraining cage. Each determination of blood pressure was the mean of at least 6 readings. Spontaneously hypertensive rats (ages 12-18 weeks) with systolic blood pressures >180 mmHg were considered hypertensive. Compound of Time Post % Change in Cystolic Example 1 Dose, Hours Blood Pressure

6 rats 1 -26 ± 3

Dose 3mg/kg, p.o. 2 -22 ± 3

Initial Blood 4 -22 ± 3

Pressure 6 -11 ± 3

289 ± 0.49 mmHg

Claims

Claims A

1. A compound of formula (I):

or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof

wherein: A represents >C=X or a bond; X represents O or S; Y represents N or N⁺-O- or a moiety CR₁₀ wherein R₁₀ is as defined below; Z^o represents O, CH₂, NR or S(O)_p; R represents hydrogen, alkyl or alkylcarbonyl R₁, R₂, R₃ and R₄ each independently represent hydrogen or alkyl; or R₁ and R₂ together represent a C_2-7 polymethylene chain; or R₃ and R₄ together represent a C_2-7 polymethyene chain; R₅ represents hydrogen, hydroxy, alkoxy or acyloxy; R₆ is hydrogen or R₅ and R₆ together represent a bond; when A represents >C=X, then R₇ 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 alkanoyl 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 R₈ represents hydrogen or alkyl; or R₇ and R₈ together represent a linking chain of formula -A¹-A²-, A¹ being attached to the nitrogen atom of the moiety -N-A- and A² being attached to the group A on the said moiety, and wherein A¹ represents a substituted or unsubstituted methylene group, A² 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, alkanoyl, phenyl C_1-4-alkyl, arylcarbonyl wherein the aryl group may be substituted or unsubstituted; or R' is mono- or bi-cyclic- heteroarylcarbonyl; when A represents a bond, then R₇ and R₈ 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; R₉ and R₁₀ are each independently selected from the class of hydrogen, substituted or unsubstituted alkyl, alkoxy, C_3-8 cycloalkyl, hydroxy, nitro, cyano, halo, formyl, carboxy, a group of formula R^aT¹-, R^bR^cNT-, R^aT²NH-, R^dCO.O-, R^dCS.O-, R^d(OH)CH-, R^d(SH)CH-, R^dC(=N.OH)-, R^dC(=N.NH₂)- or alkenyl optionally substituted by alkylcarbonyl, nitro or cyano, providing that when Y is CR₁₀ then at least one of R₉ or R₁₀ is not hydrogen; R^a represents R^d or R^dO- and R^d represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, optional substituents for R^d being up to 3 substituents selected from alkyl, alkoxy, halo, haloalkyl, nitro and cyano; R^b and R^c each independently represent hydrogen, alkyl or alkylcarbonyl; T represents a bond or T¹, T¹ represents -CS- or T² and T² represents -CO-, -SO- or -SO₂-; and p represents zero or an integer 1 or 2.

2. A compound according to claim 1, of formula (IA), or when the compound of formula (IA) contains a salifiable group, a pharmaceutically acceptable salt thereof:

wherein:

X is oxygen or sulphur;

Y is CR₁₀ as defined below, or is N or N⁺-O-;

R₁ and R₂ are independently selected from hydrogen or C_1-6 alkyl or together are C_2-7 polymethylene;

R₃ and R₄ are as defined for R₁ and R₂ above; R₅ is hydrogen, hydroxy, C_1-6 alkoxy or C_1-7 acyloxy and R₆ is hydrogen or R₅ and R₆ together are a bond;

R₇ is hydrogen; C_1-6 alkyl optionally substituted by up to three halo atoms, by hydroxy, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, carboxy or amino optionally substituted by one or two independent C_1-6 alkyl groups or disubstituted by C_4-5 polymethylene; C_2-6 alkenyl; amino optionally substituted by a C_1-6 alkyl or C_2-6 alkenyl group or by a C_1-6 alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by C_1-6 alkyl, C_1-6 alkoxy or halogen; or aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of C_1-6 alkyl, C_1-6 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C_1-12 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C_1-6 alkyl groups; or (when X is 0), R₇ is selected from the class of carboxy, C_1-6 alkoxycarbonyl, or aminocarbonyl optionally substituted by one or two C_1-6 alkyl groups; and

R₈ is hydrogen or C_1-6 alkyl; or

R₇ and R₈ together are -CH₂-(CH₂)_n-Z-(CH₂)_m- wherein m and n are 0 to 2 such that m + n is 1 or 2 and Z is CH₂, O, S or NR₁₁ wherein R₁₁ is hydrogen, C_1-6 alkyl, C_2-7 alkanoyl, phenyl C₁_₄-alkyl, naphthylcarbonyl, phenylcarbonyl or benzyl-carbonyl optionally substituted in the phenyl or naphthyl ring by one or two of C_1-6 alkyl, C_1-6 alkoxy or halogen; or R₁₁ is heteroarylcarbonyl; when Y is N or N⁺-O-, R₉ is hydrogen or, when U is CR₁₀, either one of R₉ and R₁₀ is hydrogen and the other is selected from the class of C_1-6 alkylcarbonyl, C_1-6 alkoxycarbonyl, C_1-6 alkylcarbonyloxy, C_1-6 alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C_1-6 alkylsulphinyl, C_1-6 alkylsulphonyl, C_1-6 alkoxysulphinyl, C_1-6 alkoxysulphonyl, C_1-6 alkylcarbonylamino, C_1-6 alkoxycarbonylamino, C_1-6 alkyl-thiocarbonyl, C_1-6 alkoxy-thiocarbonyl, C_1-6 alkyl-thiocarbonyloxy, C_1-6 alkyl-thiomethyl, formyl or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C_1-6 alkyl groups, or C_1-6 alkylsulphinylamino, C_1-6 alkylsulphonylamino C_1-6 alkoxysulphinylamino or C_1-6 alkoxysulphonylamino or ethenyl terminally substituted by C_1-6 alkylcarbonyl, nitro or cyano, or -C(C_1-6 alkyl)NOH or -C(C_1-6 alkyl)NNH₂; or one of R₉ and R₁₀ is nitro, cyano or C_1-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C_1-6 alkyl or by C_2-7 alkanoyl; or R₉ is hydrogen and R₁₀ is C_1-6 alkyl or C_3-8 cycloalkyl; suitably R₈NCXR₇ being trans to the R₅ group when R₅ is hydroxy, C_1-6 alkoxy or C_1-7 acyloxy.

3. A compound according to claim 1 or claim 2, wherein R₁, R₂, R₃ and R₄ each represent hydrogen.

4. A compound according to any one of claims 1 to 3, wherein R₅ is hydroxy and R₆ is hydrogen.

5. A compound according to any one of claims 1 to 4, wherein the moiety R₈NAR₇ represents a pyrrolidonyl group.

6. A compound according to claim 1, being trans 4-hydroxy-7-nitro-5-(2-oxopyrrolidin-1-yl)-2,3,4,5- tetrahydro-1-benzoxepine; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

7. The preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof which comprises;

i) acylating a compound of formula (III):

wherein, Y¹ is Y or a group convertible thereto, R₉ ¹ is R₉ or a group or atom convertible thereto, R₁ to R₄ and Z^o are as hereinbefore defined, R₅ ¹ is hydroxy, C_1-6 alkoxy or C_1-7 acyloxy, and R₈ ¹ is hydrogen or C_1-6 alkyl, the R₈ ¹NH group being trans to the R₅ ¹ group,

a) with an acylating agent of formula (IV):

R₁₂-CO-L₁ (IV)

wherein L₁ is a leaving group, and R₁₂ is hydrogen; C_1-6 alkoxycarbonyl; C_1-6 alkyl optionally substituted by halogen, hydroxy, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, carboxy or amino optionally substituted as hereinbefore defined for R₇; C_2-6 alkenyl or optionally substituted aryl or heteroaryl as hereinbefore defined for R₇; or a group convertible to R₇ as hereinbefore defined, and thereafter, when R₈ is hydrogen and R₁₂ is (CH₂)_zL₂, where z is 3 or 4 and L₂ is a leaving group, cyclising the resultant compound;

b) with a compound of formula (V):

X=C=N.R₁₃ (V)

wherein R₁₃ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_1-6 alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by C_1-6 alkyl, C_1-6 alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R₁₃ is hydrogen, optionally converting R₁₃; or

ii) for compounds of formula (I) wherein R₇ and R₈ together represent a linking chain of formula -A¹-A² as defined above in relation to formula (I) by reacting a compound of formula (VI):

wherein R₁, R₂, R₃, R₄, R₉ ¹, Y¹ and Z^o are as hereinbefore defined with a compound of formula (VII):

R₁₅NHCOR₁₄ (VII) wherein R₁₄ and R₁₅ together represent a linking chain -A¹-A²-; or iii) for compounds of formula (I) wherein A represents a bond and R₇ and R₈ together with the nitrogen to which they are attached form the above defined unsaturated heterocyclic ring, by reacting a compound of formula (VI) as defined above with an activated form of a compound of formula (VIIA) :

R₈NHR₇ (VIIA)

wherein R₇ and R₈ are as defined above;

and thereafter if required, carrying out one or more of the following optional steps:

(i) converting a compound of formula (I) into a further compound of formula (I); (ii) converting Y¹ to Y; (iii) converting R₉ ¹ to R₉; (iv) forming a pharmaceutically acceptable salt of the compound of formula (I); or (v) forming a pharmaceutically acceptable solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

9. A method of treatment of respiratory tract disorders or hypertension in mammals, which comprises administering to the suffering mammal an effective amount of a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

10. A compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of respiratory tract disorders or hypertension.