WO1991009031A1 - Composes a substitution trifluoromethyle et composition pharmaceutique - Google Patents

Composes a substitution trifluoromethyle et composition pharmaceutique Download PDF

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Publication number
WO1991009031A1
WO1991009031A1 PCT/GB1990/001935 GB9001935W WO9109031A1 WO 1991009031 A1 WO1991009031 A1 WO 1991009031A1 GB 9001935 W GB9001935 W GB 9001935W WO 9109031 A1 WO9109031 A1 WO 9109031A1
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formula
compound
hydrogen
alkyl
group
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PCT/GB1990/001935
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English (en)
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John Morris Evans
Geoffrey Stemp
John Martin Tedder
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Beecham Group Plc
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Priority claimed from GB898927979A external-priority patent/GB8927979D0/en
Priority claimed from GB898927978A external-priority patent/GB8927978D0/en
Priority claimed from GB909005492A external-priority patent/GB9005492D0/en
Application filed by Beecham Group Plc filed Critical Beecham Group Plc
Publication of WO1991009031A1 publication Critical patent/WO1991009031A1/fr

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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
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • Trifluoromethyl substituted compounds and a. pharmaceutical composition.
  • 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, 93535, 95316, 107423, 120426, 126311, 126350, 126367 and 138134 describe certain benzopyran derivatives having inter alia antihypertensive activity.
  • EP-A-176689 also discloses that certain benzopyran derivatives are useful for the treatment of inter alia disorders of the respiratory system.
  • benzopyrans within the general class of benzopyrans described in the abovementioned European Patent Publications a particular class of benzopyrans has now been identified which surprisingly show good selectivity for airways smooth muscle relative to the vascular smooth muscle. These compounds may therefore be considered to be especially useful as bronchodilators in the treatment of disorders of the respiratory tract, such as reversible airways obstruction and asthma. Such compounds will also be of use in the treatment of hypertension and in the treatment of disorders associated with smooth muscle contraction of the gastro-intestinal tract, uterus or urinary tract. Such disorders include irritable bowel syndrome and diverticular disease; premature labour; and incontinence. Such compounds 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.
  • one of A- j ⁇ , A2 and A3 represents -CF3 and the remaining two variables of A ⁇ , A 2 and A each represent a hydrogen atom;
  • Y-L represents -0-, -CH2- or NR° wherein R° is hydrogen, alkyl or alkylcarbonyl;R 1 and R 2 independently represent hydrogen or alkyl; or R- ⁇ and R 2 together represent a C2- polymethylene moiety;
  • R represents hydrogen, hydroxy, alkoxy, acyloxy or O.
  • O2 and R 4 is hydrogen or R3 and R 4 together represent a bond;
  • a 4 represents either a moiety of formula (a) :
  • R5 represents -NH.Rg wherein Rg is hydrogen, alkyl
  • R is hydrogen or alkyl; or R and Rg together represent C 2 ⁇ 4 polymethylene;
  • T ⁇ represents >C-0H or N(0) n wherein n is zero or 1 and 2 together with C-T- ⁇ , when T- ⁇ is >C-OH, represents an optionally substituted aryl group or 2 together with C - ⁇ , when T-L is N(0) n , represents an optionally substituted, N- heteroaryl group;
  • L ⁇ represents 0 or NR- j n wherein R-, n represents hydrogen, alkyl, formyl, acetyl or hydroxymethyl, L 2
  • SUBSTITUTE SHEET represents N or CL 4 wherein L 4 is hydrogen, halogen, formyl or hydroxymethyl, L3 represents CH 2 , 0, S, >CHLc wherein L5 is halogen or NLg wherein Lg is hydrogen or alkyl and R ⁇ and R-L2 each independently represent hydrogen or alkyl or R- together with R 12 represents oxo or thioxo; and p represents 1,2 or 3.
  • a 2 or A3 represent CF3.
  • a 2 represents CF3.
  • ⁇ represents a moiety of formula (a) .
  • X represents 0.
  • R5 together with R represents a linking chain of formula -A ⁇ -Ag-
  • one particular linking chain is that chain having the formula -CH -(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 , 0, S or NR wherein R is hydrogen, alkyl, alkanoyl, aralkyl, arylcarbonyl or aralkylcarbonyl, the said aryl moieties being substituted or unsubstituted, or R is mono- or bi- cyclic heteroarylcarbonyl.
  • R 5 represents substituted or unsubstituted aryl, suitably phenyl, particular optional substituents include alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, acyl, amino or amino carbonyl the latter two groups being optionally substituted with one or two alkyl groups.
  • R 5 is alkyl it is suitably C- ⁇ alkyl, such as methyl or ethyl, an example being ethyl.
  • Rg is hydrogen
  • the present invention provides a compound of formula (I) or, when the compound of formula (I) contains a salifiable group, a pharmaceutically acceptable salt thereof, wherein:
  • R- j ⁇ and R2 is hydrogen or C- - ⁇ alkyl and the other is C-1-4 alkyl or R- ⁇ and R2 together are 2-5 polymethylene;
  • R3 is hydrogen, hydroxy, C- ⁇ - alkoxy or ⁇ - ⁇ acyloxy and R4 is hydrogen or R3 and R4 together are a bond;
  • R5 is hydrogen, C- ⁇ -g alkyl optionally substituted by halogen, hydroxy C- ⁇ -g alkoxy, C- ⁇ -g alkoxycarbonyl, carboxy or amino optionally substituted by one or two independent C-L ⁇ g alkyl groups, or C2 ⁇ g alkenyl, amino optionally substituted by a C- ⁇ -g alkyl or C2 ⁇ g alkenyl group or by a C- ⁇ -g alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by Ci-g alkyl, C- ⁇ -g alkoxy or halogen; or aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of C ⁇ -g alkyl, - ⁇ -g alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, I-T carboxylic acyl, or amino or aminocarbonyl optionally substituted
  • SUBSTITUTE SHEET X is oxygen or sulphur; and one of A- ⁇ , A 2 and A represents CF3, the remaining two variables of A- ⁇ , A 2 and A each representing hydrogen.
  • the nitrogen-containing group in the 4-position is disposed trans to the R3 group when R3 is hydroxy, C- ⁇ - alkoxy, suitably alkoxy, or C-L- 7 acyloxy.
  • R ⁇ and R 2 are both ⁇ - ⁇ alkyl, in particular both represent methyl.
  • R3 is alkoxy, suitably C- ⁇ - alkoxy, and R4 is hydrogen
  • preferred examples of R include methoxy and ethoxy, of which methoxy is more preferred.
  • R is acyloxy, suitably C ⁇ - ⁇ acyloxy, and R 4 is hydrogen
  • a preferred class of R3 is unsubstituted carboxylic acyloxy, such as unsubstituted aliphatic acyloxy.
  • R3 and R4 together are a bond, or that R3 and R4 are both hydrogen, or in particular, that R is hydroxy and R4 is hydrogen.
  • R when Re is alkyl, suitably C- ⁇ -g alkyl, include methyl, ethyl and n- and iso-propyl.
  • R ⁇ is methyl.
  • Rg is ethyl.
  • a sub-group of Rg when Rg is alkyl substituted by halogen, is C- ⁇ -g alkyl substituted by chloro or bromo. Examples thereof include methyl or ethyl terminally substituted by chloro or bromo.
  • Rg when Rg is alkyl, suitably C- ⁇ - alkyl, substituted by hydroxy, include methyl or ethyl terminally substituted by hydroxy.
  • a sub-group of Rg when Rg is alkyl substituted by alkoxy, is c l ⁇ 6 alk y 1 substituted by methoxy or ethoxy.
  • SUBSTITUTE SHEET thereof include methyl or ethyl terminally substituted by methoxy or ethoxy.
  • Rg when alkyl, suitably C- ⁇ -g alkyl, substituted by carboxy include methyl or ethyl terminally substituted by carboxy.
  • Rg when alkyl, suitably C- ⁇ g alkyl, substituted by amino optionally substituted by one or two independent alkyl, suitably C- ⁇ -g alkyl groups, includes a group (CH 2 ) n NR s R t where n is 1 to 6 and R s and R t are each independently hydrogen or C- ⁇ -g alkyl. Examples of n include 1 and 2.
  • R g and R ⁇ . are each independently selected from hydrogen and methyl.
  • Rg when alkenyl suitably C2 ⁇ g alkenyl, include vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl, or l-methylprop-2-enyl, in both their E and Z forms where stereoisomerism exists.
  • Rg 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.
  • Rg when aryl as defined includes phenyl and naphthyl, of which phenyl is preferred.
  • the phenyl group may be substituted or unsubstituted.
  • a preferred substituent is a halogen atom especially a fluorine atom.
  • Rg group is a 4- fluorophenyl group.
  • a sub-group of Rg when 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 heteroato s which are selected form 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 furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazyl and triazyl.
  • Preferred examples of such groups include furyl, thienyl, pyrrolyl and pyridyl, in particular 2- and 3-furyl, 2- and 3-pyrrolyl 2- and 3-thienyl, and 2-, 3- and 4-pyridyl.
  • 9- or 10-membered bicyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include benzofuryl, benzothienyl, indolyl and indazolyl, quinolinyl and isoquin ⁇ linyl, and quinazolinyl.
  • Preferred examples of such groups include 2- and 3-benzofuryl, 2- and 3-benzothienyl, 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.
  • SUBSTITUTE SHEET Preferred examples of the groups or atoms for optional substitution of aryl or heteroaryl include methyl, methoxy, hydroxy, chloro, nitro or cyano.
  • a sub-group of Rg is phenyl or naphthyl or a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl, the phenyl, naphthyl or heteroaryl group being optionally substituted by one, two, three or four groups or atoms selected from the class of C- ⁇ - alkyl, C- ⁇ -g alkoxy, halogen, trifluoromethyl, nitro or cyano.
  • a preferred sub-group of phenyl optionally substituted as hereinbefore defined is phenyl, 4-substituted phenyl, 3-substituted phenyl, 3,4-disubstituted phenyl and 3, 4, 5-trisubstituted phenyl.
  • a preferred sub-group of 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl optionally substituted as hereinbefore defined is unsubstituted or mono-substituted 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl, in particular unsubstituted 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl.
  • R and Rg together represent a linking chain -Ag-Ag-, suitably the abovedefined moiety -Cf ? -(CH 2 ) n -Z- (CH2, m -, the resulting radical substituting the benzopyran in the 4-position is preferably either pyrrolidinyl or piperidinyl.
  • R when Z is NR include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec- and text- butyl, benzyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl ring by methyl, methoxy, chloro or bromo; furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or
  • R is hydrogen, methyl, n-butyl, acetyl, benzyl, benzylcarbonyl, phenylcarbonyl or furylcarbonyl. Most preferably R is methyl.
  • Rg and Rg together are C3 or C4 polymethylene.
  • X is oxygen
  • ''halogen'' refers to fluorine, chlorine, bromine and iodine; preferably chlorine.
  • alkyl groups or alkyl groups forming part of other groups such as in the alkoxy group, are ⁇ -- ⁇ alkyl groups especially C- ⁇ -g alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.
  • alkenyl groups are groups especially C2 ⁇ alkenyl groups.
  • Suitable alkynyl groups are C 2 ⁇ 12 alkynyl groups especially C 2 ⁇ 6 alk Y n Y 1 groups.
  • Suitable acyloxy groups include alkylcarbonyloxy groups wherein the alkyl group is as defined above.
  • ''fluoroalkyl'' includes alkyl groups as defined above when substituted by one or more fluorine atoms, particular examples being trifluoromethyl and pentafluoroethyl.
  • 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl,
  • 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 Rg group.
  • Examples of pharmaceutically acceptable salts of carboxy groups include metal salts, such as alkali metal salts, or optionally substituted ammonium salts.
  • the compounds of formula (I) may also exist as hydrates and the invention extends to these.
  • the compounds of formula (I) wherein 3 is hydrogen, hydroxy, alkoxy, suitably C- ⁇ -g alkoxy, acyloxy, suitably C- - ⁇ acyloxy or O.N0 2 , and R4 is hydrogen, are asymmetric, and, therefore, can exist in the form of optical isomers.
  • the present invention extends to all such isomers individually and as mixtures, such as racemates.
  • Examples of compounds of formula (I) include the compounds prepared in the Examples hereinafter.
  • the present invention also provides a process for the preparation of a compound of formula (I) or, where appropriate a pharmaceutically acceptable salt thereof,
  • R l f R 2 and Y- ⁇ are as defined hereinbefore, A- j , A 2 ' and A3' each respectively represent A- j _, A 2 or A3 as defined in relation to formula (I) or protected forms thereof, R3 1 is hydrogen, hydroxy, alkoxy or acyloxy, and R 1 is hydrogen or alkyl,
  • L 7 is a leaving group
  • R-,3 is hydrogen, alkyl optionally substituted by halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxy or amino optionally substituted as hereinbefore defined for Rg, alkenyl or optionally substituted aryl or heteroaryl as hereinbefore defined for Rg, or a group convertible to R as hereinbefore defined, and thereafter, when R g is hydrogen and R- ⁇ is Y2(CH2) 2 , wherein z is 3 or 4 and Y2 is a leaving group, cyclising the resultant compound;
  • R 14 is hydrogen, alkyl, alkenyl, alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by alkyl, alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R 14 is hydrogen, optionally converting R14; or
  • R ⁇ g and R- ⁇ together represent a linking chain of formula -Ag-Ag-;
  • R- ⁇ , R 2 , R4, Rg and Y ⁇ are as defined in relation to formula (I) and A- ⁇ , A 2 ', A3' and R3 1 are as defined in relation to formula (II) , with phosgene (COCI2) and either cyanamide (for compounds wherein R 7 is CN) or sulphamide (for compounds wherein R 7 is S0 2 NH 2 ); or
  • R l R 2 , R 4 and Y are as defined in relation to formula (I)
  • a j ', A 2 ', A3' and R3 1 are as defined in relation to formula (II)
  • T- ⁇ represents >C-0 ⁇ 4 wherein T 4 is a hydroxyl protecting group and T ? together with CT ⁇ represents an optionally substituted aryl group; or
  • R- ⁇ , R 2 , R3 , , A- ⁇ ', A 2 ', A3' and Y- ⁇ are as defined above and T 2 together with C-N represents an optionally substituted or N-heteroaryl group; or
  • L ⁇ , L 2 , 3, R ⁇ , R- ⁇ 2 and p are as defined in relation to moiety (c) of formula (I) ;and thereafter if required, carrying out one or more of the following optional steps:
  • SUBSTITUTE SHEET (a) converting A- ⁇ ' to A- ⁇ and/or converting A 2 ' to A 2 and/or converting A ' to 3;
  • the leaving group L 7 is a group that is displaceable by a primary or secondary amino nucleophile. Examples of such a group include alkanoyloxy, and halogen, such as chloro and bromo.
  • the acylating agent of formula (III) 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 carboxyliic acid and an acid halide, although this is less preferred than using the halide itself.
  • Rg in the desired compound of formula (I) is an Rg optionally substituted amino-substituted alkyl group as hereinbefore defined
  • the R ⁇ halo substituent in the resultant compound of process variant i) a) may be converted to an Rg substituent which is amino optionally substituted as hereinbefore defined by a conventional amination reaction with ammonia or a corresponding alkyl- or dialkylamine.
  • R13 may be alkyl substituted by protected amino, protected alkylamino or amino substituted by two independent alkyl groups, it being necessary to protect the Rg amino function in process variant i) a) .
  • the acylation of the compound of formula (II) 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 (II) is, preferably, carried out in a non-aqueous medium, such as dichloromethane, in the presence of an acid acceptor, such as triethylamine, trimethylamine, pyridine, picoline or calcium, potassium or sodium carbonate.
  • a non-aqueous medium such as dichloromethane
  • an acid acceptor such as triethylamine, trimethylamine, pyridine, picoline or calcium, potassium or sodium carbonate.
  • the reaction may be carried out under controlled conditions such that only the amine, Rg NH-is acylated, for example, by using a 2 ⁇ acyloxy group as the leaving group L 7 , in the acylating agent of formula (III) 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.
  • R3 may be C ⁇ - ⁇ acyloxy in a compound of formula (II) , although less preferably if R3 in the resultant compound of formula (I) is to be hydroxy, and, after reaction with the acylating agent of formula (III) , be converted into hydroxy, as described hereinafter.
  • R- j is Y2(CH 2 ) Z where the variables are as hereinbefore defined, the leaving group Y 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 is Y (CH 2 ) 2 where the variables are as hereinbefore defined is preferably carried out in an inert solvent such as dimethylformamide.
  • reaction between the compounds of formulae (II) and (IV) is, preferably, carried out in a solvent, such as dichloromethane, at below room temperature, in particular below 10°C.
  • reaction between the compounds of formulae (II) and (IV) 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 hydrochloride acid.
  • a slightly elevated temperature such as 50 to 90°C is apt.
  • a suitable activated form of a compound of formula (VI) 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 (VI) , for example, in the presence of an alkali metal base such as potassium t-butoxide or sodium hydride.
  • reaction between the compounds of formula (V) and (VI) 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 an elevated temperature,for example 40°C.
  • the compound of formula (VI) may itself be used as the solvent for the reaction between compounds of formulae (V) and (VI) .
  • a suitable activated form of a compound of formula (VIA) 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 (VIA) , for example, in the presence of an alkali metal base such as potassium t-butoxide or sodium hydride.
  • reaction between the compounds of formulae (V) and (VIA) 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
  • the reaction is preferably carried out in an inert solvent, such as tetrahydrofuran, at -10 to +25°C, preferably around 0°C to ambient, in an inert atmosphere, for example, under nitrogen, preferably in the presence of a base, such as diisopropylethylamine.
  • an inert solvent such as tetrahydrofuran
  • a base such as diisopropylethylamine
  • reaction suitably takes place 10 at elevated temperatures, preferably at reflux temperatures, in an inert solvent, such as toluene.
  • reaction conditions for proces variant v) are generally equivalent to those described in European Application, 15 Publication Number 298452.
  • reaction is suitably effected by using an anionic form of compound (XI) formed in situ by using a strong base, for example sodium hydride.
  • a strong base for example sodium hydride.
  • reaction conveniently takes place in an inert solvent, for example in dimethylformamide, dimethyl sulphoxide, tetrahydrofuran, dimethylpropylene-urea or mixtures thereof, at low, medium or high temperatures, preferably at room temperature, for example at about 20 to
  • Suitable conversions of a compound of formula (I) to a further compound of formula (I) include:
  • R3 when R3 is hydroxy, it may be alkylated using an alkyl iodide in an inert solvent, such as toluene, in the presence of a base, such as sodium hydride or potassium hydroxide, or it may be acylated using a carboxylic acid chloride or an appropriate anhydride in a non-hydroxylic solvent, such as toluene or dichloromethane, in the presence of an acid acceptor such as triethylamine.
  • an alkyl iodide in an inert solvent, such as toluene
  • a base such as sodium hydride or potassium hydroxide
  • R may be acylated using a carboxylic acid chloride or an appropriate anhydride in a non-hydroxylic solvent, such as toluene or dichloromethane, in the presence of an acid acceptor such as triethylamine.
  • SUBSTITUTE SHEET alkoxy it may be converted into a hydroxy group by any conventional dealkylation method for example by treatment with trimethylsilyliodide in an aprotic solvent.
  • R3 when R3 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 R3 and R4 are hydroxy and hydrogen respectively, into another compound of formula (I) , wherein R3 and R4 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 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 R3 and R together represent a bond.
  • a dehydrating agent such as sodium hydride
  • inert solvent such as dry tetrahydrofuran
  • the thiation of the Rg.N.A.Rg moiety in a compound of formula (I) to give another compound of formula (I) is, preferably, carried out with conventional thiation agents, such as hydrogen sulphide, phosphorus pentasulphide and Lawesson's reagent (p-methoxyphenylthiophosphine sulphide dimer) .
  • 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,
  • SUBSTITUTE SHEET preferably, acid catalysed by, for example, hydrogen chloride in a polar solvent, such as acetic acid or ethanol.
  • a polar solvent such as acetic acid or ethanol.
  • Lawesson's reagent is, preferably, carried out under reflux in a dry solvent, such as toluene or methylene chloride.
  • the interconversion of the cis and trans configuration of the variables R 3 and R 4 is generally carried out by changing the configuration of variable R3, especially when R3 represents hydroxyl, by means of any convenient conventional procedure.
  • solvates for example hydrates, may be prepared using any convenient conventional procedure.
  • a compound of formula (II) may be prepared by reacting a compound of formula (V) , as defined hereinbefore, with a compound of formula (XII) :
  • Rg 1 is as defined hereinbefore; and optionally converting R3 hydroxyl in the resulting compound of formula (II) into another R3 -
  • the reaction is normally carried out in a solvent, such as a C-L- 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-L- alcohol, in particular methanol, ethanol or propanol
  • the reaction proceeds particularly smoothly if carried out in ethanol under reflux.
  • the resulting compound of formula (II) may be isolated from the reaction mixture by removal of the solvent, for example,
  • a compound of formula (V) may be treated with a source of azide ions, such as sodium azide, and thereafter the resulting azide reduced to the required product using conventional reduction methods.
  • a source of azide ions such as sodium azide
  • a compound of formula (V) may be prepared by reacting a compound of formula (XIII) :
  • A- j , A 2 ', A3', R l r R 2 and Y- are as hereinbefore defined, the bromine atom being trans to the hydroxy group, with a base, suitably an alkali metal base such as a potassium alkoxide, for example potassium t-butoxide, or potassium hydroxide, in a solvent, such as ether aqueous dioxan or dimethylsulphoxide.
  • a base suitably an alkali metal base such as a potassium alkoxide, for example potassium t-butoxide, or potassium hydroxide
  • a compound of formula (V) may be
  • SUBSTITUTE SHEET prepared jLn situ, preferably in anhydrous conditions, by reaction of a compound of formula (XIII) with a strong base, preferably an alkali metal alkoxide, for example potassium t-butoxide, andthereafter the said compound of formula (V) may be reacted in the abovedefined process ii) , iii) or vi) to provide a compound of formula (I) .
  • a strong base preferably an alkali metal alkoxide, for example potassium t-butoxide
  • a compound of formula (XIII) may be prepared by reaction of a compound of formula (XIV) :
  • A- ⁇ ', A 2 ' , A ', R- ⁇ , R 2 and Y ⁇ _ are as defined hereinbefore, with N-bromosuccinimide in a solvent, such as aqueous dimethyl sulphoxide.
  • a compound of formula (V) may also be prepared from a compound of formula (IX) by reaction with a peracid, preferably m-chloroperbenzoic acid, in an inert solvent such as dichloromethane at ambient temperature.
  • a peracid preferably m-chloroperbenzoic acid
  • a compound of a formula (XIV) may be prepared in accordance with analogous processes to those described in the aforementioned European Patent publications, i.e. by the process depicted below:
  • some of the compounds of formula (I) may exist in optically active forms, and the processes of the present invention produce mixtures of such forms.
  • the individual enantiomers may be resolved by conventional methods.
  • a mixture of enantiomers of a compound of formula (I) may be derivatised with an optically active derivatising agent to provide a mixture of diastereoisomeric derivatives, which may then be separated using any convenient procedure, for example chromatography.
  • a suitable derivatising agent is an optically active isocyanate, such as (-)- ⁇ -methylbenzylisocyanate, which provides the corresponding carbamate.
  • SUBSTITUTE SHEET The compounds of formula (I) have been found to have particularly advantageous bronchodilator activity. They also have blood-pressure lowering activity. These compounds 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, 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,
  • SUBSTITUTE SHEET 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 [Bcellulose; 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.
  • suspending agents for example sorbitol, syrup, methyl
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and,
  • SUBSTITUTE SHEET 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,
  • 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 lOOmg of a compound of the invention (0.01 to lOmg 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 0.05to lOOmg.
  • 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.
  • IR (film) cm- 2900, 1610, 1590, 1460, 810, 790, 745, 713.
  • N-Bromosuccinimide (8.81g, 49.56mmol) was added to a cold (4°C) solution of 2,2-dimethyl-7-trifluoromethyl- 2H-1-benzopyran (5.65g, 24.76mmol) in dimethyl sulphoxide (50ml) and water (0.89ml). After the exothermic reaction, the solution was stirred at room temperature for 16 hours then poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulphate, filtered and evaporated leaving the crude bromohydriii, 8g (100%)
  • SUBSTITUTE SHEET A mixture of 4-(trifluoromethyl)-phenol (5.1g), potassium carbonate (5g) , potassium iodide (0.2g) and
  • the title compound (m.p. 165°C) was prepared by an analogous method to that used in Example 10, but replacing propionyl chloride with 4-fluorobenzoyl chloride.
  • R3 and Rg.N.CX.Rg are configurated in the trans configuration with respect to each other.
  • 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. Duringthis 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 preparations were dosed cumulatively with the test compound (10- 8 -2xlO- 5 M) , and finally a maximum relaxation achieved by addition of 10- 3 M 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- ⁇ M isoprenaline.
  • Appropriate concentration-relaxation curves were then constructed and values for potency (ICg 0 ) and intrinsic activity (I.A.) were obtained.
  • 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 lOOg 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.
  • 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, 5-HT being given at a dose that caused approximately 60% bronchoconstriction.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé ayant la formule (I) ou, dans les cas appropriés, un de ses sels ou un de ses solvates pharmaceutiquement acceptables. Dans la formule (I), A1, A2, A3, A4, R1, R2, R3, R4 et Y ont la définition décrite. Procédé de préparation de ce composé, composition pharmaceutique contenant ce composé, utilisation de ce composé et de cette composition en médecine.
PCT/GB1990/001935 1989-12-11 1990-12-11 Composes a substitution trifluoromethyle et composition pharmaceutique WO1991009031A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB8927978.0 1989-12-11
GB898927979A GB8927979D0 (en) 1989-12-11 1989-12-11 Novel compounds
GB898927978A GB8927978D0 (en) 1989-12-11 1989-12-11 Novel compounds
GB8927979.8 1989-12-11
GB909005492A GB9005492D0 (en) 1990-03-12 1990-03-12 Novel compounds
GB9005492.5 1990-03-12

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0587188A2 (fr) * 1992-09-11 1994-03-16 E.R. SQUIBB & SONS, INC. Dérivés de propèneamides substitués par des aryles ou des hétérocycles
WO1994013292A1 (fr) * 1992-12-11 1994-06-23 Smithkline Beecham Plc Activateurs des vannes a potassium utilises en therapie
US5612370A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phenylglycine and phenylalaninen amido benzopyran derivatives
US5612323A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phosphinic ester substituted benzopyran derivatives
US5629429A (en) * 1995-06-07 1997-05-13 Bristol-Myers Squibb Company Process for preparing 4-arylamino-benzopyran and related compounds
US5869478A (en) * 1995-06-07 1999-02-09 Bristol-Myers Squibb Company Sulfonamido substituted benzopyran derivatives

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Publication number Priority date Publication date Assignee Title
EP0172352A2 (fr) * 1984-06-22 1986-02-26 Beecham Group Plc Composés benzopyranniques actifs
EP0176689A2 (fr) * 1984-07-31 1986-04-09 Beecham Group Plc Composés benzopyranniques pour le traitement de la contraction des muscles lisses
EP0273262A2 (fr) * 1986-12-23 1988-07-06 MERCK PATENT GmbH Dérivés de chromane
WO1989005808A1 (fr) * 1987-12-23 1989-06-29 Beecham Group Plc Esters d'acide nitrique et preparation pharmaceutique
DE3811017A1 (de) * 1988-03-31 1989-10-19 Hoechst Ag Ungesaettigte n-benzopyranyllactame
WO1989010925A1 (fr) * 1988-05-09 1989-11-16 Beecham Group Plc Nouveaux composes et traitement

Patent Citations (6)

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Publication number Priority date Publication date Assignee Title
EP0172352A2 (fr) * 1984-06-22 1986-02-26 Beecham Group Plc Composés benzopyranniques actifs
EP0176689A2 (fr) * 1984-07-31 1986-04-09 Beecham Group Plc Composés benzopyranniques pour le traitement de la contraction des muscles lisses
EP0273262A2 (fr) * 1986-12-23 1988-07-06 MERCK PATENT GmbH Dérivés de chromane
WO1989005808A1 (fr) * 1987-12-23 1989-06-29 Beecham Group Plc Esters d'acide nitrique et preparation pharmaceutique
DE3811017A1 (de) * 1988-03-31 1989-10-19 Hoechst Ag Ungesaettigte n-benzopyranyllactame
WO1989010925A1 (fr) * 1988-05-09 1989-11-16 Beecham Group Plc Nouveaux composes et traitement

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0587188A2 (fr) * 1992-09-11 1994-03-16 E.R. SQUIBB & SONS, INC. Dérivés de propèneamides substitués par des aryles ou des hétérocycles
EP0587188A3 (fr) * 1992-09-11 1994-04-13 E.R. SQUIBB & SONS, INC. Dérivés de propèneamides substitués par des aryles ou des hétérocycles
US5453421A (en) * 1992-09-11 1995-09-26 E. R. Squibb & Sons, Inc. Aryl and heterocyclic substituted propenamide derivatives
WO1994013292A1 (fr) * 1992-12-11 1994-06-23 Smithkline Beecham Plc Activateurs des vannes a potassium utilises en therapie
US5612370A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phenylglycine and phenylalaninen amido benzopyran derivatives
US5612323A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phosphinic ester substituted benzopyran derivatives
US5629429A (en) * 1995-06-07 1997-05-13 Bristol-Myers Squibb Company Process for preparing 4-arylamino-benzopyran and related compounds
US5869478A (en) * 1995-06-07 1999-02-09 Bristol-Myers Squibb Company Sulfonamido substituted benzopyran derivatives

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