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WO1989011477A1 - Benzoxepine et composes apparentes - Google Patents

Benzoxepine et composes apparentes Download PDF

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Publication number
WO1989011477A1
WO1989011477A1 PCT/GB1989/000588 GB8900588W WO8911477A1 WO 1989011477 A1 WO1989011477 A1 WO 1989011477A1 GB 8900588 W GB8900588 W GB 8900588W WO 8911477 A1 WO8911477 A1 WO 8911477A1
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alkyl
formula
hydrogen
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group
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Richard Andrew Bentley Webster
Frederick Cassidy
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Beecham Group PLC
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Beecham Group PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • 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.
  • disorders respectively include irritable bowel syndrome and diverticular disease; premature labour; incontinence; renal cholic and disorders associated with the passage of kidney stones.
  • 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.
  • the present invention provides a compound of formula (I):
  • X represents O or S
  • Y represents N or N + -O- or a moiety CR 10 wherein R 10 is as defined below
  • Z° represents O, CH 2 , NR or S(O) p
  • R represents hydrogen, alkyl or alkylcarbonyl
  • R 1 , R 2 , R 3 and R 4 each independently represent hydrogen or alkyl
  • R 1 and R 2 together represent a C 2-7 polymethylene chain
  • R 3 and R 4 together represent a C 2-7 polymethyene chain
  • R 5 represents hydrogen, hydroxy, alkoxy or acyloxy
  • R 6 is hydrogen or R 5 and R 6 together represent a bond
  • Suitable substituents for any aryl or heteroaryl group represented by R 7 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.
  • linking chain -A 1 -A 2 - 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 -A 1 - is substituted.
  • Suitable substituents for any methylene group in -A 1 -A 2 - include alkyl groups, especially methyl or ethyl and in particular methyl.
  • the linking chain -A 1 -A 2 - (and thus R 7 and R 8 together) represent a moiety of formula -CH 2 -(CH 2 ) n -Z-(CH 2 ) m - wherein m and n are 0 to 2 such that m + n is 1 or 2 and Z is CH 2 , O , S or NR ' wherein R ' is as defined above.
  • 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.
  • R 9 is hydrogen
  • R 9 and R 10 are those compounds wherein one of R 9 and R 10 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
  • 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:
  • X is oxygen or sulphur
  • Y is CR 10 as defined below, or is N or N + -O-;
  • R 1 and R 2 are independently selected from hydrogen or C 1-6 alkyl or together are C 2-7 polymethylene;
  • R 3 and R 4 are as defined for R 1 and R 2 above;
  • R 5 is hydrogen, hydroxy, C 1-6 alkoxy or C 1-7 acyloxy and R 6 is hydrogen or R 5 and R 6 together are a bond;
  • R 7 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 alk
  • R 8 is hydrogen or C 1-6 alkyl
  • R 7 and R 8 together are -CH 2 -(CH 2 ) n -Z-(CH 2 ) m - wherein m and n are 0 to 2 such that m + n is 1 or 2 and Z is CH 2 , O, S or NR 11 wherein R 11 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;
  • R 9 is hydrogen or, when Y is CR 10 , either one of R 9 and R 10 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
  • X is oxygen
  • Y is usually C-R 10 wherein R 10 is as defined in formula (I).
  • C 1-6 alkyl groups or alkyl containing moieties in R 1 to R 10 may be selected from methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl.
  • R 1 /R 2 , R 3 /R 4 also include C 3 , C 4 , C 5 , C 6 or C 7 polymethylene.
  • R 5 is C 1-6 alkoxy and R 6 is hydrogen
  • preferred examples of R 5 include methoxy and ethoxy, of which methoxy is more preferred.
  • R 5 is C 1-7 acyloxy and R 6 is hydrogen
  • a preferred class of R 5 is unsubstituted carboxylic acyloxy, such as unsubstituted aliphatic acyloxy (formyloxy or C 2-7 alkanoyloxy) or benzoyloxy.
  • R 5 and R 6 together are a bond, or R 5 and R 6 are both hydrogen, or, in particular, that R 5 is hydroxy and R 6 is hydrogen.
  • R 8 when R 7 and R 8 are not joined together, is hydrogen or methyl, most preferably hydrogen.
  • a sub-group of R 7 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.
  • R 7 when C 1-6 alkyl substituted by hydroxy, include methyl or ethyl terminally substituted by hydroxy.
  • a sub-group of R 7 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 R 7 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.
  • R 7 when C 1-6 alkyl substituted by carboxy include methyl or ethyl terminally substituted by carboxy.
  • R 7 when alkyl substituted by amino, optionally substituted by one or two independent C 1-6 alkyl groups include a group (CH 2 ) q NR a R 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 C 4 or C 5 polymethylene. Examples of q include 1 and 2, in particular 1.
  • R a and R b are each independently selected from hydrogen and methyl.
  • R 7 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.
  • R 7 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.
  • R 7 aryl examples include phenyl and naphthyl of which phenyl is preferred.
  • a sub-class of R 7 heteroaryl is 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl of which 5- or 6-membered monocyclic heteroaryl is preferred.
  • 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.
  • 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.
  • 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.
  • R 7 and R 8 when together are -CH 2 -(CH 2 ) n -Z-(CH 2 ) 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 R 7 and R 8 are joined together include those described in EP-A-107423.
  • 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.
  • Rxx is hydrogen, methyl, n-butyl, acetyl, benzyl, benzylcarbonyl, phenylcarbonyl or furylcarbonyl.
  • R 11 is hydrogen.
  • R 9 and R 10 When one of R 9 and R 10 is hydrogen, it is preferred that R 9 is hydrogen and R 10 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.
  • R 10 may be acetyl, nitro, cyano, methyl, ethyl, isopropyl or cyclopentyl.
  • R 9 and R 10 When one of R 9 and R 10 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 R 9 and R 10 is nitro, cyano or C 1-3 alkylcarbonyl, the other is amino, methylamino, dimethylamino or acetylamino. Most preferably, one of R 9 and R 10 is nitro or cyano, and the other is amino.
  • R 9 and R 10 are nitro, cyano or C 1-3 alkylcarbonyl
  • R 10 is nitro, cyano or C 1-3 alkylcarbonyl
  • R 9 is hydrogen
  • alkyl groups or alkyl moieties of alkyl-containing groups for R 9 or R 10 are, preferably, methyl or ethyl.
  • ''halogen'' refers to fluorine, chlorine, bromine and iodine; preferably fluorine.
  • 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.
  • alkenyl groups are C 2-12 groups especially C 2-6 alkenyl groups.
  • alkynyl groups are C 2-12 alkynyl groups especially C 2-6 alkynyl groups.
  • Suitable polymethylene groups include C 3 , C 4 , C 5 , C 6 and C 7 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 R 7 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.
  • esters of carboxy groups are pharmaceutically acceptable esters such as C 1-6 alkyl esters.
  • amides of carboxyl groups include pharmaceutically acceptable amides such as amides of formula -CO.NR s R 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 R 1 and R 2 and/or R 3 and R 4 are different, or wherein R 5 and R 6 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):
  • R 1 to R 4 and Z o are as defined hereinbefore, Y 1 and R 9 1 are Y and R 9 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):
  • Y 1 is Y or a group convertible thereto
  • R 9 1 is R 9 or a group or atom convertible thereto
  • R 1 to R 4 and Z o are as hereinbefore defined
  • R 5 1 is hydroxy, C 1-6 alkoxy or C 1-7 acyloxy
  • R 8 1 is hydrogen or C 1-6 alkyl, the R 8 1 NH group being trans to the R 5 1 group
  • L 1 is a leaving group
  • R 12 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 R 7 ; C 2-6 alkenyl or optionally substituted aryl or heteroaryl as hereinbefore defined for R 7 ; or a group convertible to R 7 as hereinbefore defined, and thereafter, when R 8 is hydrogen and R 12 is (CH 2 ) z L 2 , where z is 3 or 4 and L 2 is a leaving group, cyclising the resultant compound;
  • R 13 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 R 13 is hydrogen, optionally converting R 13 ; or
  • R 14 and R 15 together represent a linking chain -A 1 -A 2 -;
  • R 7 and R 8 are as defined above;
  • the leaving group L 1 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.
  • 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.
  • L 1 is hydroxy
  • conventional coupling methods using dicyclohexylcarbodiimide are suitable.
  • R 7 in the desired compound of formula (I) is an R 7 optionally substituted amino-substituted alkyl group as hereinbefore defined
  • R 12 is a group convertible to the R 7 substituted alkyl group as hereinbefore defined, in particular that it is C 1-6 alkyl substituted by halo, especially bromo.
  • the R 12 halo substituent in the resultant compound of process variant i) a) may be converted to an R 7 substituent which is amino optionally substituted as hereinbefore defined by a conventional amination reaction with ammonia acid corresponding alkyl- or dialkylamine.
  • R 12 is C 1-6 alkoxycarbonyl, this may be converted to R 7 is carboxy by conventional hydrolysis.
  • R 12 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 R 12 amino function in process variant i) a).
  • 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.
  • an acid acceptor such as sodium acetate
  • 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.
  • a non-aqueous medium such as dichloromethane
  • an acid acceptor such as triethylamine, trimethylamine, or calcium, potassium or sodium carbonate.
  • acylating agent of formula (IV) is an acid
  • 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.
  • R 5 1 in a compound of formula (III) is hydroxy
  • the reaction may be carried out under controlled conditions such that only the amine, R 8 1 NH- is acylated, for example, by using a C 2-9 acyloxy group as the leaving group L 1 , 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.
  • R 5 1 may be C 1-7 acyloxy in a compound of formula (III), although less preferably if R 5 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.
  • R 12 is (CH 2 ) z L 2 where the variables are as hereinbefore defined, the leaving group L 2 is a group that is displaceable by a secondary amino nucleophile adjacent to a carbonyl function.
  • a preferred example is chloro.
  • 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.
  • 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.
  • 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.
  • an alkali metal base such as potassium t-butoxide or sodium hydride.
  • 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.
  • the compound of formula (VII) may itself be used as the solvent for the reaction between compounds of formulae (VI) and (VII).
  • a suitable activated form of a compound of formula (VIIA) is an ionic form.
  • 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 .
  • 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.
  • a suitable aprotic solvent for example dimethylsulphoxide
  • Suitable conversions of a compound of formula (I) to a further compound of formula (I) include:
  • R 5 when R 5 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.
  • R 5 when R 5 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.
  • R 5 when R 5 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 R 5 and R 6 are hydroxy and hydrogen respectively, into another compound of formula (I), wherein R 5 and R 6 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 R 5 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 R 5 and R 6 together repressnt a bond.
  • a dehydrating agent such as sodium hydride
  • inert solvent such as dry tetrahydrofuran
  • the reduction of a compound of formula (I), wherein R 5 and R 6 together are a bond, into another compound of formula (I), wherein R 5 and R 6 are each hydrogen, may be carried out by hydrogenation using a catalyst of palladium on charcoal.
  • the thiation of the R 8 .N.CX.R 7 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).
  • 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.
  • 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 R 5 and R 6 is generally carried out by changing the configuration of variable R 5 , especially when R 5 represents hydroxyl, by means of any convenient conventional procedure. Any conversion of Y 1 to Y or R 9 1 to R 9 may be carried out using the appropriate conventional chemical procedure.
  • a pharmaceutically acceptable salt when the resulting compound of formula (I) contains a salifiable group, may be carried out conventionally.
  • 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):
  • R 8 1 is as hereinbefore defined; and optionally converting R 5 1 hydroxyl in the resulting compound of formula (II) into another R 5 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.
  • a solvent such as a C 1-4 alcohol, in particular methanol, ethanol or propanol
  • 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.
  • 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.
  • a per-acid such as m-chloroperbenzoic acid
  • 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.
  • R' represents R 1 or R 2 as required, the remaining 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.
  • 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.
  • 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.
  • 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.
  • 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 star
  • 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.
  • suspending agents for example sorbitol, syrup, methyl cellulose,
  • 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.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • 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.
  • 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.
  • the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns.
  • 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.
  • 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
  • ACTH adrenal stimulants
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 (MgSO 4 ).
  • 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.
  • 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.
  • 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.
  • test (a) in vitro the compound of Example 1 had an IC 50 of 1.41 ⁇ 10 -5 M
  • 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.
  • 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 .
  • rats 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

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Abstract

Sont décrits un composé de formule (I) ou bien, le cas échéant, son sel pharmaceutiquement acceptable, ou encore son solvate pharmaceutiquement acceptable, où A représente >C=X ou bien une liaison; X représente O ou S; Y représente N ou N+-O- ou une partie CR10; Z° représente O, CH2, NR ou S(O)p; R représente hydrogène, alkyle ou alkylcarbonyle; un procédé pour préparer de tels composés, des compositions pharmaceutiques les contenant et l'emploi de ces composés et compositions en médecine.
PCT/GB1989/000588 1988-05-28 1989-05-30 Benzoxepine et composes apparentes Ceased WO1989011477A1 (fr)

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GB888812765A GB8812765D0 (en) 1988-05-28 1988-05-28 Novel compounds

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2698873A1 (fr) * 1992-12-07 1994-06-10 Lipha Benzocycloheptènes, benzoxépines et benzothiépines activateurs des canaux potassiques, procédé de préparation, composition pharmaceutique les contenant.
WO1994013292A1 (fr) * 1992-12-11 1994-06-23 Smithkline Beecham Plc Activateurs des vannes a potassium utilises en therapie
RU2202549C2 (ru) * 1996-03-11 2003-04-20 Джи. Ди. Сирл Энд Ко. Бензотиепины, фармацевтическая композиция на их основе, способ профилактики или лечения гиперлипидемического состояния

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0234656A2 (fr) * 1986-02-27 1987-09-02 Janssen Pharmaceutica N.V. Dérivés d'acide 1H-imidazole-5-carboxylique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0234656A2 (fr) * 1986-02-27 1987-09-02 Janssen Pharmaceutica N.V. Dérivés d'acide 1H-imidazole-5-carboxylique

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2698873A1 (fr) * 1992-12-07 1994-06-10 Lipha Benzocycloheptènes, benzoxépines et benzothiépines activateurs des canaux potassiques, procédé de préparation, composition pharmaceutique les contenant.
WO1994013658A3 (fr) * 1992-12-07 1994-08-04 Merck Patent Gmbh Benzocycloheptenes, benzoxepines et benzothiepines
LT3167B (en) 1992-12-07 1995-02-27 Merck Patent Gmbh Benzocycloheptenes,benzoxepines and benzothiepines
WO1994013292A1 (fr) * 1992-12-11 1994-06-23 Smithkline Beecham Plc Activateurs des vannes a potassium utilises en therapie
RU2202549C2 (ru) * 1996-03-11 2003-04-20 Джи. Ди. Сирл Энд Ко. Бензотиепины, фармацевтическая композиция на их основе, способ профилактики или лечения гиперлипидемического состояния

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