WO1989010925A1 - Nouveaux composes et traitement - Google Patents

Nouveaux composes et traitement Download PDF

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Publication number
WO1989010925A1
WO1989010925A1 PCT/GB1989/000492 GB8900492W WO8910925A1 WO 1989010925 A1 WO1989010925 A1 WO 1989010925A1 GB 8900492 W GB8900492 W GB 8900492W WO 8910925 A1 WO8910925 A1 WO 8910925A1
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WIPO (PCT)
Prior art keywords
alkyl
pharmaceutically acceptable
hydrogen
formula
dimethyl
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PCT/GB1989/000492
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English (en)
Inventor
Derek Richard Buckle
David Glynn Smith
Frederick Cassidy
Original Assignee
Beecham Group Plc
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Publication date
Priority claimed from GB888810929A external-priority patent/GB8810929D0/en
Priority claimed from GB888825508A external-priority patent/GB8825508D0/en
Application filed by Beecham Group Plc filed Critical Beecham Group Plc
Publication of WO1989010925A1 publication Critical patent/WO1989010925A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • This invention relates to certain 4-unsaturated heterocyclyl benzopyran derivatives, having smooth muscle relaxant activity, to processes for their preparation, to compositions containing such compounds and to the use of such compounds and compositions in medicine.
  • the invention also, particularly, relates to a method for the treatment of reversible airways obstruction and asthma, especially by inhaled administration, and to substances and compositions used in such method.
  • 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.
  • EP-A-205292 discloses certain pyrano[3,2-c]pyridine derivatives having inter alia blood pressure lowering activity.
  • EP-A-273262 discloses certain chroman derivatives including trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2(1H)-pyridon-1-yl)-2H-1-benzopyran-3-ol, 6-cyano-2,2-dimethyl-4-(2(1H)- ⁇ yridon-1-yl)-2H-1-benzopyran, trans-3,4-dihydro-2,2-dimethyl-6-trifluoromethyl-4-(2(1H)-pyridon-1-yl)-2H-1-benzopyran-3-ol, 2,2-dimethyl-6-trifluoromethyl-4-(2(1H)-pyridon-1-yl)-2H-1-benzopyran and trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(6(1H)-pyrimidon-1-yl)-2H-1-benzopyran-3-ol .
  • EP-A-296975 discloses certain chroman derivatives including trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2(1H)-pyridon-1-yl)-2H-1-benzopyran-3-ol and trans-3,4-dihydro-2,2-dimethyl-6-trifluoromethyl- (2(1H)-pyridon-1-yl)-2H-1-benzopyran-3-ol. These compounds are disclosed as having hypertensive and antiarrythmic activity.
  • EPC European Patent Convention
  • EP-A-308792 discloses certain azachroman derivatives including trans-3,4-dihydro-2,2-dimethyl-4-(2(1H)- pyridon-1-yl)-2H-pyrano[3,2-c]pyridine-3-ol), 2,2- dimethyl-4-(2(1H)- ⁇ yridon-1-yl)-2H-pyrano[3,2- c]pyridine and trans-3,4-dihydro-2,2-dimethyl-4-(2(1H)- pyrimidinon-1-yl)-2H-pyrano[3,2-c]pyridine-3-ol.
  • EPC European Patent Convention
  • EP-A-308792 are relevant to the present application via
  • a group of 4-unsaturated heterocyclyl benzopyran derivatives has now been discovered which surprisingly has 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.
  • 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.
  • a particular group of these compounds has also surprisingly been discovered to be of particular benefit for the treatment of reversible airways obstruction and asthma, especially when administered by inhaled administration.
  • These compounds are also of potential use in the treatment of irritable bowel syndrome and diverticular disease; premature labour; incontinence; renal cholic and disorders associated with the passage of kidney stones. They are also indicated to be of potential use in the treatment and/or propylaxis of disorders associated with pulmonary hypertension and of disorders associated with right heart failure.
  • the present invention provides a compound of formula (I):
  • Y represents N or N + -O- or a moiety CR 6 wherein
  • R 6 is as defined below;
  • Z represents O, CH 2 , NR, or S(O) n wherein n represents
  • R represents hydrogen, alkyl or alkylcarbonyl
  • R 1 and R 2 independently represent hydrogen or alkyl
  • R 1 and R 2 together represent a polymethylene moiety
  • R 3 represents hydrogen, hydroxy, alkoxy or acyloxy
  • R 4 represents hydrogen or R 3 and R 4 together represent a bond; when Y is N or N + -O-, R 5 is hydrogen or, when Y is CR 6 , either one of R 5 and R 6 is hydrogen and the other is selected from the group consisting of: alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylhydroxymethyl, nitro, cyano, halogen, trifluoromethyl, alkylsulphinyl, alkylsulphonyl, alkoxysulphinyl, alkoxysulphonyl, alkylcarbonylamino, alkoxycarbonylamino, alkyl-thiocarbonyl, alkoxythiocarbonyl, alkyl-thiocarbonyloxy, alkyl-thiomethyl, formyl or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two alkyl groups, or alkylsulphinylamin
  • R 7 and R 8 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted pyridonyl group or a substituted or unsubstituted thiopyridonyl group.
  • R 8 .N.R 7 represents substituted or unsubstituted pyridonyl, favourably unsubstituted pyridonyl.
  • a favoured pyridonyl group is a 2-pyridon-1-yl group.
  • a favoured pyridonyl group is a 4-pyridon-1-yl group.
  • R 8 .N.R 7 represents substituted or unsubstituted pyrimidinonyl or thiopyrimidinonyl, favourably unsubstituted pyrimidinonyl or thiopyrimidinonyl, in particular pyrimidinonyl.
  • a favoured pyrimidinonyl group is a 4(1H)-pyrimidinon- 1-yl a 6(1H)-pyrimidinon-1-yl or a 2(1H)-pyrimidinon- 1-yl group.
  • a suitable substituent for the group R 8 .N.R 7 , and especially for the pyridonyl group, or the thiopyridonyl group is an alkyl group, suitably a C 1-6 alkyl group, such as a methyl group.
  • Y represents N or N + -O-.
  • Y represents N + -O- Most preferably, Y represents N.
  • Z represents O, CH 2 , NR or S(O) n wherein n represents
  • R represents hydrogen, alkyl or alkylcarbonyl
  • R 1 and R 2 independently represent hydrogen or alkyl
  • R 1 and R 2 together represent a polymethylene moiety
  • R 3 represents hydrogen, hydroxy, alkoxy or acyloxy
  • One subclass of formula (I) includes those compounds wherein:
  • Y represents N or N + -O- or a moiety CR 6 wherein R 6 is as defined below;
  • Z represents O, CH 2 or NR;
  • R represents hydrogen, C 1-6 alkyl or C 1-6 alkylcarbonyl
  • R 1 and R 2 independently represent hydrogen or C 1-6 alkyl; or R 1 and R 2 together represent a C 2-7 polymethylene moiety;
  • R 3 represents hydrogen, hydroxy, C 1-6 alkoxy or C 1-7 acyloxy
  • R 4 represents hydrogen or R 3 and R 4 together represent a bond; when Y is N or N + -O-, R 5 is hydrogen or, when Y is CR 6 , either one of R 5 and R 6 is hydrogen and the other is selected from the group consisting 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 aminosulphiny
  • R 5 and R 6 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
  • R 5 is hydrogen and R 6 is C 1-6 alkyl or C 3-8 cycloalkyl;
  • R 7 and R 8 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted pyridonyl group or a substituted or unsubstituted thiopyridonyl group.
  • a subclass of formula (I) includes those compounds wherein Z represents CH 2 , NR or S(O) n wherein n represents 0, 1 or 2, a further subclass being those wherein Z represents CH 2 or NR, yet a further subclass being those wherein Z represents CH 2 .
  • a subclass of formula (I) includes those compounds wheren R 3 and R 4 each represent hydrogen or wherein R 3 represents alkoxy and R 4 represents hydrogen.
  • R 3 represents hydroxy and R 4 represents hydrogen.
  • R 3 and R 4 together represent a bond.
  • a subclass of formula (I) includes those compounds wherein one of R 5 or R 6 represents hydrogen and the other represents alkylhydroxymethyl or alkylthiomethyl or ethenyl terminally substituted by alkylcarbonyl, nitro or cyano or -C(alkyl)NOH or -C(alkyl)NNH 2 .
  • a subclass of formula (I) includes those compounds wherein one of R 5 or R 6 represents methoxy and the other represents nitro, cyano or C 1-3 alkylcarbonyl.
  • a subclass of formula (I) includes those compounds wherein R 5 is hydrogen and R 6 represents cycloalkyl.
  • R 7 .N.R 8 does not represent 1H-2-pyridon-1-yl
  • - E represents a nitrogen atom or a group C(R' 4 );
  • R' 1 represents hydrogen, a methyl group or a hydroxyl group and R' 2 and R' 3 each independently represent hydrogen or a methyl group, it being possible for only one of the substituents R' 1 , R'2 and R' 3 to be methyl; and
  • R' 4 represents a hydrogen atom, a halogen atom, a methyl group or a hydroxyl group.
  • a subclass of formula (I) includes those compounds wherein R 7 .N.R 8 represents 4(1H)-pyrimidinon-1-yl.
  • a subclass of formula (I) includes those compounds wherein R 7 .N.R 8 is 4(1H)-thiopyrimidinon-1-yl;
  • a subclass of formula (I) includes those compounds wherein R 7 .N.R 8 represents thiopyridonyl.
  • a subclass of formula (I) includes those compounds wherein R 7 .N.R 8 represents 4-pyridon-1-yl.
  • a further subclass of formula (I) includes those compounds wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y and Z are as defined in relation to formula (I) providing that when Z represents O, R 1 and R 2 both represent C 1-6 alkyl; R 3 represents hydroxyl or R 3 and R 4 each represent a bond; one of R 5 or R 6 represents hydrogen and the other represents acetyl, C 1-6 -alkoxycarbonyl, nitro, cyano, halogen or CF 3 ; and R 7 and R 8 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted pyridonyl group or a substituted or unsubstituted thiopyridonyl group; then Y must represent N or N + -O-.
  • R 1 and R 2 are both C 1-6 alkyl, and in particular R 1 and R 2 are both methyl.
  • R 3 is C 1-6 alkoxy and R 4 is hydrogen
  • preferred examples of R 3 include methoxy and ethoxy, of which methoxy is more preferred.
  • R 3 is C 1-7 acyloxy and R 4 is hydrogen
  • a preferred class of R 3 is unsubstituted carboxylic acyloxy, such as unsubstituted aliphatic acyloxy.
  • R 3 and R 4 together are a bond, or that R 3 and R 4 are both hydrogen, or in particular, that R 3 is hydroxy and
  • R 4 is hydrogen.
  • R 6 is preferably selected from the class of C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, trifluoromethyl, nitro or cyano, especially when R 5 is hydrogen.
  • R 6 may be acetyl, trifluoromethyl, nitro, cyano, methyl, ethyl, isopropyl or cyclopentyl.
  • R 5 and R 6 represents nitro, trifluoromethyl, cyano or C 1-3 alkylcarbonyl the other is preferably hydrogen.
  • the alkyl group or the alkyl moiety of an alkyl-containing group represented by R 5 or R 6 is preferably ethyl.
  • 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) include 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 5 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, hydrobromide malonate or methanesulphonate salts , an example being the malonate.
  • 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 in the form of solvates, preferably hydrates, and the invention extends to such solvates. In a further aspect the present invention also extends to include the solvates of such of the compounds which are excluded from formula (I).
  • the carbon atoms of formulae (I) and (IA) marked with an asterisk ''*'' are chiral carbon atoms when R 3 and R 4 do not represent a bond and, for the ring carbon atom attached to R 3 , when R 3 is other than hydrogen and the carbon atom marked with a double asterisk ''**'' is chiral when R 1 and R 2 are different.
  • the compounds of formula (I) can exist in up to 8 optical isomers.
  • the present invention extends to all such isomers whether as individual isomers or as mixtures thereof in any proportion, including racemates.
  • the compounds of formula (I) may also exist in geometrical isomeric forms all of which are encompassed by the present invention , and including those wherein the R 8 . N . R 7 moiety and R 3 are disposed either mutually trans with respect to one another or mutually cis with respect to one another.
  • the R 8 .N.R 7 moiety is trans to R 3 .
  • Suitable alkyl groups or 'alkyl' moieties include straight or branched chain alkyl groups comprising up to 12 carbon atoms, suitable from 1 to 6 carbon atoms.
  • Suitable C 1-6 alkyl groups or C 1-6 alkyl moieties may be selected from methyl, ethyl, n- and iso-propvl, n-, iso-, sec- and tert-butvl.
  • Suitable polymethylene groups are C 3-8 polymethylene groups including C 3 , C 4 , C 5 , C 6 and C 7 polymethylene groups.
  • Suitable acyloxy groups are C 1-7 acyloxy groups.
  • 'halogen' refers to fluorine, chlorine, bromine or iodine, suitably chlorine.
  • the present invention also provides a process for the preparation of a compound of formula (I) or, where appropriate a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, which comprises reacting a compound of formula (II):
  • R 1 , R 2 and Z are as hereinbefore defined in relation to formula (I), R 5 1 represents R 5 or a group or atom convertible into R 5 and Y 1 represents Y or a group convertible into Y, with an activated form of a pyridone of formula (III):
  • R' 7 and R' 8 and the -NH- group to which they are attached form a substituted or unsubstituted pyridone
  • a suitable activated form of a compound of formula (III) 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 (III), for example, in the presence of an alkali metal base such as potassium t-butoxide or sodium hydride or a base such as tetrabutylammonium fluoride.
  • an alkali metal base such as potassium t-butoxide or sodium hydride
  • a base such as tetrabutylammonium fluoride.
  • reaction between the compounds of formula (II) and (III) may be carried out in any suitable aprotic solvent, for example dimethylsulphoxide or tetrahydrofuran, 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, conveniently at ambient temperature.
  • a suitable aprotic solvent for example dimethylsulphoxide or tetrahydrofuran
  • R 5 1 represents R 5 .
  • Y 1 represents Y.
  • compound of formula (III) may itself be used as the solvent for the reaction between compounds of formulae (II) and (III).
  • Suitable conversions of a compound of formula (I) to a further compound of formula (I) include:
  • R 8 .N.R 7 represents a pyridonyl group to provide a compound of formula (I) wherein R 8 .N.R 7 represents a thiopyridonyl group.
  • R 3 in a compound of formula (I) into another R 3 examples are generally known in the art.
  • R 3 when R 3 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 it may be acylated using a carboxylic acid chloride or the appropriate anhydride in a non-hydroxylic solvent, such as toluene or dichloromethane, in the presence of an acid acceptor such as triethylamine .
  • an acid acceptor such as triethylamine
  • R 3 when R 3 is C 1-6 alkoxy, it may be converted into hydroxy by any suitable dealkylation technique, for example by treatment with trimethylsilyliodide in an aprotic solvent. Also when R 3 is C 1-7 acyloxy it may be converted into hydroxy by conventional hydrolysis using, for example a dilute mineral acid.
  • the optional conversion of a compound of formula (I), wherein R 3 and R 4 are hydroxy and hydrogen respectively, into another compound of formula (I), wherein R 3 and R 4 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 3 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 3 and R 4 together represent 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 3 and R 4 together are a bond, into another compound of formula (I), wherein R 3 and R 4 are each hydrogen, may be carried out by hydrogenation using a catalyst of palladium on charcoal.
  • the thiation of the R 8 .N.R 7 group in a compound of formula (I) is suitably 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 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 methylene chloride.
  • a compound of formula (II) may be prepared by reaction of a compound of formula (IV):
  • R 1 , R 2 , R 5 1 , Y 1 and Z are as hereinbefore defined, the bromine atom being trans to the hydroxy group, with a base, such as potassium hydroxide, in a solvent, such as ether or aqueous dioxan.
  • a base such as potassium hydroxide
  • a compound of formula (IV) may be prepared by reaction of a compound of formula (V):
  • R 1 , R 2 , R 5 1 and Y 1 are as hereinbefore defined, with N-bromosuccinimide in a solvent, such as aqueous dimethyl sulphoxide.
  • a compound of formula (II) wherein Y represents CR 6 may also be prepared directly from a compound of the hereinbefore defined formula (V), by reacting the compound of formula (V) with a per-acid, preferably a perbenzoic acid, and in particular with meta-chloroperbenzoic acid.
  • a per-acid preferably a perbenzoic acid, and in particular with meta-chloroperbenzoic acid.
  • reaction between the compound of formula (V) and the per-acid may be carried out in any suitable inert solvent such as dichloromethane at any suitable temperature, conveniently at ambient temperature.
  • a compound of formula (II), wherein Y represents N or N + -O- and Z represents CH 2 may also be prepared by reacting together an appropriate azadiene and an appropriate cyclic enone in a Diels Alder reaction (using conventional Diels Alder conditions, for example those disclosed in J.Amer.Chem. Soc. 1975, (97), 4409) to provide an appropriate bicyclic ketone which may then be converted by further conventional chemistry to the said compound of formula (II).
  • Suitable protecting groups are those conventional protecting groups that may be prepared and removed using known procedures and which protect the appropriate chemical group during the preparation of compounds of formula (I)
  • Any conversion of Y 1 to Y or R 5 1 to R 5 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.
  • the compounds of formula (I), the pharmaceutically acceptable salts thereof or the pharmaceutically acceptable solvates thereof 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, where appropriate, 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 and disorders associated with pulmonary hypertension or disorders associated with right heart failure; 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.
  • 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, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or
  • 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.
  • the present invention further provides a method for the treatment of reversible airways obstruction and asthma, especially asthma, in mammals, including humans, which method comprises the administration to the mammal in need thereof, a compound of the abovedefined formula (IA), or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
  • a compound of the abovedefined formula (IA) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
  • the present invention also provides the use of a compound of the abovedefined formula (IA) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of reversible airways obstruction and asthma, especially asthma.
  • the invention further provides a composition for the treatment of reversible airways obstruction and asthma, especially asthma, which composition comprises a compound of the abovedefined formula (IA) or, where appropriate, a pharmaceutically acceptable salt thereof, of a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefore.
  • Suitable modes of administration and the appropriate forms of compositions used in the administration of the compounds of formula (IA) are, of course, equivalent to those indicated above.
  • the abovementioned treatment of reversible airways obstruction and asthma comprises inhaled administration and thus comprises the use of a composition (or medicament) formulated for inhaled administration.
  • compositions of this invention are 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.
  • Suitable solutions for a nebulizer are isotonic sterilised solutions, optionally buffered, at for example between pH 4-7, containing up to 20mg ml -1 of compound but more generally 0.1 to 10mg ml -1 , for use with standard nebulisation equipment.
  • a powder is of particular value in administration via insufflation.
  • the present invention further provides a pharmaceutical composition, in particular a composition for inhaled administration, which comprises a compound of the abovedefined formula (IA) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the form of a microfine powder and optionally a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier are those used conventionally in the art, for example lactose.
  • Microfine powder formulations may suitably be administered in an aerosol as a metered dose or by means of a suitable breath-activated device.
  • Suitable metered dose aerosol formulations comprise conventional prepellants, cosolvents, such as ethanol, surfactants such as oleyl alcohol, lubricants such as oleyl alcohol, desiccants such as calcium sulphate and density modifiers such as sodium chloride.
  • the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns.
  • particles of diameters in the range 1-50 microns, 1-10 microns or 1-5 microns are envisaged.
  • small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutam ⁇ l, 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, salbutam ⁇ l, phenylephrine and ephedrine
  • xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH
  • ACTH adrenal stimulants
  • the present invention further provides a method of treatment of respiratory tract disorders or hypertension in mammals including man, which method comprises administering to the mammal in need thereof an effective, non-toxic amount of a compound of formula (I), or, where appropriate, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof.
  • the present invention provides a method for the treatment of irritable bowel syndrome and diverticular disease; premature labour; incontinence; renal cholic and disorders associated with the passage of kidney stones and/or the treatment and or prophylaxis of disorders associated with pulmonary hypertension and of disorders associated with right heart failure in mammals including man, which method comprises administering to the mammal in need thereof an effective, non-toxic amount of either: a compound of the abovedefined formula (IA); or, alternatively, a compound selected from the group consisting of: trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2(1H)- pyridon-1-yl)-2H-1-benzopyran-3-ol,6-cyano-2,2- dimethyl-4-(2(1H)-pyridon-1-yl)-2H-1-benzopyran, trans-3,4-dihydro-2,2-dimethyl-6-trifluoromethyl- 4-(2(1H)-pyridon-1-
  • the present invention also provides the use of of either: a compound of the abovedefined formula (IA); or, alternatively, a compound trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2(1H)-pyridon-1-yl)-2H-1-benzopyran-3-ol,6-cyano-2,2-dimethyl-4-(2(1H)-pyridon-1-yl)-2H-1-benzopyran, trans-3,4-dihydro-2,2-dimethyl-6-trifluoro-methyl-4-(2(1H)-pyridon-1-yl)-2H-1-benzopyran-3-ol and 2,2-dimethyl-6-trifluoromethyl-4-(2(1H)-pyridon-1-yl)-2H-1-benzopyran or trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(6(1H)-pyrimidon-1-yl)-2H-1-benzopyran-3-o
  • compositions may contain from 0.1% to 99% by weight, suitably 10-99% preferably from 10-60% by weight, of the active material, depending on the method of administration, thus a preferred range for inhaled administration is 10-99%, especially 60-99% for example 90, 95, or 99%.
  • a unit dose form of a composition of the invention may contain from 0.01 to 100mg of a compound of the invention and more usually from 0.1 to
  • Inhalation doses suitably comprise 0.01 to
  • compositions may be administered from 1 to 6 times a day, more usually from 1 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
  • the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or, where appropriate, a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
  • the present invention further provides a compound of formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of respiratory tract disorders or hypertension.
  • the present invention further provides the use of a compound of formula (I), or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof for the manufacture of a medicament for the treatment of respiratory tract disorders or hypertension.
  • Example 1 The benzopyran-3-ol (Example 1) was triturated with ether to give white solid (0.038g), m.p. 240-244°C (sublimes from 230°C).
  • Example 2 The benzopyran (Example 2) was triturated with ether to give a white solid (0.063g), m.p. 149-151°C.
  • the benzopyran-3-ol (Example 4) was obtained as a white solid, m.p. 178-182°C.
  • the benzopyran (Example 5) was obtained as a white solid, m.p. 126-129°C.
  • This example was also prepared by heating an equimolar mixture of 4(3H)-pyrimidone and 3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-pyrano[3,2-c]pyridine at 60°C for 1 hour followed by chromatography as above.
  • 4(3H)-Pyrimidone (0.772g, 8 mmol) was dissolved in dimethylsulphoxide (10ml) and treated with potassium tert-butoxide (0.440g, 4 mmol). The mixture was stirred for 30 minutes at ambient temperature and 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1- benzopyran (1.278g, 6 mmol) added. The resulting mixture was heated at 90°C for 30 minutes, cooled and poured into water.
  • This solution may be used with conventional nebulisation equipment.
  • the active compound is powdered in conventional manner to provide a microfine powder of particle size 1-5 microns.
  • the powder is admixed with lactose in the proportions of 1:50 (active compound to lactose).
  • the active compound is used without lactose.
  • the formulations may be used with conventional breath actuated devices.
  • Triethylamine (3.72ml, 2.7g, 2eq) and mesyl chloride (3.05g, 2.05ml, 2eq) were slowly added, simultaneously, to a vigorously stirred suspension of the chromanol (3.633g, 13.36mmole) in tetrahydrofuran (THF, 50ml) at room temperature under nitrogen. Following complete addition the reaction was stirred for a further 30 minutes when thin layer chromatography indicated that all of the starting material had been consumed. The mixture was added to chloroform (500ml) and washed with water (50ml). The aqueous phase was then extracted with chloroform (2 ⁇ 300ml) and the combined organic phase was dried (MgSO 4 ) and evaporated.
  • 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.
  • 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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Abstract

L'invention concerne un composé de la formule (I) ou, le cas échéant, un sel pharmaceutiquement acceptable ou un solvate pharmaceutiquement acceptable dudit composé, où Y représente N+-O- ou une partie CR6 dans laquelle R6 est défini comme ci-dessous; Z représente 0, CH2, NR ou S(O)n dans lequel n représente 0, 1 ou 2; R représente, l'un de l'autre, hydrogène, alkyle ou alkylcarbonyle; R1 ou R2 représentent, indépendamment, l'un de l'autre, hydrogène ou alkyle, ou représentent ensemble une partie de polyméthylène; R3 représente hydrogène, hydroxy, alkoxy ou acyloxy; R4 représente hydrogène, hydroxy, alkoxy ou acyloxy; R4 représente hydrogène, ou R3 et R4 représentent ensemble une liaison. Lorsque Y ne représente pas N ou N+-O-, R5 représente hydrogène ou, lorsque Y représente CR, R5 ou R6 représente hydrogène, l'autre étant choisi dans le groupe composé de: alkylcarbonyle, alkoxycarbonyle, alkylcarbonyloxy, alkylhydroxyméthyle, nitro, cyano, halogène, trifluorométhyle, alkylsulfinyle, alkylsulfonyle, alkoxysulfinyle, alkoxysulfonyle, alkylcarbonylamino, alkoxycarbonylamino, alkyl-thiocarbonyle, alkoxy-thiocarbonyle, alkyl-thiocarbonyloxy, alkyl-thiométhyle, formyle ou aminosulfinyle, aminosulfonyle ou aminocarbonyle, la partie d'amino pouvant être remplacée par un ou deux groupes alkyle, ou alkylsulfinylamino, alkylsulfonylamino, alkoxysulfinylamino ou alkoxysulfonylamino ou éthényle à terminaison remplacée par alkylcarbonyle, nitro ou cyano, ou -C(alkyle)NOH ou -C(alkyle)NNH2; ou R5 ou R6 représente nitro, cyano ou alkylcarbonyle contenant 1 à 3 atomes de carbone, l'autre représentant méthoxy ou amino optionnellement remplacé par un ou deux alkyles ou par de l'alkanoyle contenant 2 à 7 atomes de carbone; ou R5 représente hydrogène et R6 représente alkyle ou cycloalkyle. R7 et R8 forment avec l'atome d'azote auquel ils sont fixés un anneau hétérocyclique non saturé à 6 éléments, à substitution ou sans substitution, ledit anneau étant un anneau simple et comprenant jusqu'à 2 autres atomes d'azote, ainsi que l'atome de carbone d'un groupe C=X dans lequel X représente O ou S et avec certaines conditions. L'invention concerne également un procédé de préparation desdits composés, une composition pharmaceutique les contenant ainsi que l'utilisation de tels composés et compositions en médecine.
PCT/GB1989/000492 1988-05-09 1989-05-09 Nouveaux composes et traitement WO1989010925A1 (fr)

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GB8810929.3 1988-05-09
GB888810929A GB8810929D0 (en) 1988-05-09 1988-05-09 Novel compounds
GB888825508A GB8825508D0 (en) 1988-11-01 1988-11-01 Novel compounds
GB8825508.8 1988-11-01

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009031A1 (fr) * 1989-12-11 1991-06-27 Beecham Group Plc Composes a substitution trifluoromethyle et composition pharmaceutique
US5095016A (en) * 1989-08-11 1992-03-10 Kaken Pharmaceutical Co., Ltd. Benzopyran compounds, processes for their production and pharmaceutical compositions
US5132307A (en) * 1988-11-08 1992-07-21 Merck Patent Gesellschaft Mit Beschrankter Haftung Tetralin compounds
US5250547A (en) * 1991-08-29 1993-10-05 Syntex (U.S.A.) Inc. Benzopyran derivatives
US5314895A (en) * 1991-12-19 1994-05-24 G. D. Searle & Co. Benzopyran class III antiarrhythmic agents
WO2004029042A1 (fr) * 2002-09-26 2004-04-08 Pfizer Limited Derives de pyrazole utilises en tant qu'inhibiteurs de la transcriptase inverse
US7230025B2 (en) 2002-09-26 2007-06-12 Pfizer, Inc. Pyrazole derivatives

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU618007B2 (en) * 1987-06-23 1991-12-12 Sanofi 2,2-dimethylchroman-3-ol derivatives, process for their preparation and pharmaceutical compositions in which they are present
TW257762B (fr) * 1991-06-14 1995-09-21 Nippon Chemicals Pharmaceutical Co Ltd

Citations (4)

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Publication number Priority date Publication date Assignee Title
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
EP0296975A1 (fr) * 1987-06-23 1988-12-28 MERCK PATENT GmbH Dérivés du diméthyl-2,2 chromannol-3, procédé d'obtention et compositions pharmaceutiques les contenant
EP0308792A2 (fr) * 1987-09-24 1989-03-29 MERCK PATENT GmbH Dérivés d'azachromane

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Publication number Priority date Publication date Assignee Title
FR2621587B1 (fr) * 1987-10-12 1990-02-09 Sanofi Sa Derives du dimethyl-2,2 chromene, procede pour leur preparation et composition pharmaceutiques les contenant
DE3811017A1 (de) * 1988-03-31 1989-10-19 Hoechst Ag Ungesaettigte n-benzopyranyllactame
AU628331B2 (en) * 1988-05-06 1992-09-17 Merck Patent Gesellschaft Mit Beschrankter Haftung Chroman derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP0296975A1 (fr) * 1987-06-23 1988-12-28 MERCK PATENT GmbH Dérivés du diméthyl-2,2 chromannol-3, procédé d'obtention et compositions pharmaceutiques les contenant
EP0308792A2 (fr) * 1987-09-24 1989-03-29 MERCK PATENT GmbH Dérivés d'azachromane

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5132307A (en) * 1988-11-08 1992-07-21 Merck Patent Gesellschaft Mit Beschrankter Haftung Tetralin compounds
US5095016A (en) * 1989-08-11 1992-03-10 Kaken Pharmaceutical Co., Ltd. Benzopyran compounds, processes for their production and pharmaceutical compositions
WO1991009031A1 (fr) * 1989-12-11 1991-06-27 Beecham Group Plc Composes a substitution trifluoromethyle et composition pharmaceutique
US5250547A (en) * 1991-08-29 1993-10-05 Syntex (U.S.A.) Inc. Benzopyran derivatives
US5447943A (en) * 1991-08-29 1995-09-05 Syntex (U.S.A.) Inc. Novel benzopyran derivatives
US5314895A (en) * 1991-12-19 1994-05-24 G. D. Searle & Co. Benzopyran class III antiarrhythmic agents
WO2004029042A1 (fr) * 2002-09-26 2004-04-08 Pfizer Limited Derives de pyrazole utilises en tant qu'inhibiteurs de la transcriptase inverse
US7230025B2 (en) 2002-09-26 2007-06-12 Pfizer, Inc. Pyrazole derivatives

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AU3553489A (en) 1989-11-29
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