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WO1987007607A1 - DERIVES DE PYRANO (3,2-c) PYRIDINE, PROCEDE DE PREPARATION ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT - Google Patents

DERIVES DE PYRANO (3,2-c) PYRIDINE, PROCEDE DE PREPARATION ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT Download PDF

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WO1987007607A1
WO1987007607A1 PCT/GB1987/000386 GB8700386W WO8707607A1 WO 1987007607 A1 WO1987007607 A1 WO 1987007607A1 GB 8700386 W GB8700386 W GB 8700386W WO 8707607 A1 WO8707607 A1 WO 8707607A1
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compound
alkyl
hydrogen
optionally substituted
formula
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Frederick Cassidy
John Morris Evans
Geoffrey Stemp
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Beecham Group PLC
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Beecham Group PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

  • the present invention relates to novel pyranopy i ines having pharmacological activity, to a process and intermediates for preparing them, to pharmaceutical compositions containing them, and to their use in the treatment of mammals.
  • European Patent Publications 76075, 91748, 93535, 95316, 107423, 120426, 120427, 126311 and 126367 disclose classes of compounds that are described as having bloo ⁇ pressure lowering activity or anti-hypertensive activity.
  • Such disorders include peptic ulcers, irritable bowel syndrome and diverticular disease, reversible airways obstruction and asthma; premature labour; and incontinence. They are also indicated as of potential use in the treatment of cardiovascular disorders other than hypertension, such as congestive heart failure, angina, peripheral vascular disease and cerebral vascular disease. Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R j _ and R2 is hydrogen or C- j __ ⁇ alkyl and tne other is C j __4 alkyl or R- ⁇ and R 2 together are C 2 _5 polymethylerie;
  • R3 is hydrogen, hydroxy, C ⁇ __ 6 alkoxy or
  • R5 is hydrogen; C j __ alkyl optionally substituted by up to three halo atoms, by hydroxy, C ] __g alkoxy, C ⁇ __g alkoxycarbonyl, carboxy, or ami o optionally substituted by one or two independent C ⁇ __g alkyl groups or disubstituted by 04.5 polymethylene; C2-6 alkenyl; amino optionally substituted oy a C ⁇ __g alkyl or C j __g alkenyl group or by a C ⁇ __5 alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by C j __g alkyl, C j __ 6 alkoxy or halogen; or aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of C ⁇ __g alkyl, C j __g alkoxy,
  • Rg is hydrogen or C ⁇ _g alkyl
  • R 5 and Rg together are -CH2-(CH2)n" z ""( H 2)m- wherein m and n are 0 to 2 such that m + n is 1 or 2 and Z is CH2, 0, S or NR wherein R is hydrogen, C ] __g alkyl, C2-.7 alkanoyl, phenyl C ] __4-alkyl, naphthylcarbonyl, phenylcarbonyl or benzyl-carbonyl optionally substituted in the phenyl or naphthyl ring by one or two of C 1-6 alkyl, C 1-6 alkoxy or halogen; or R is heteroarylcarbonyl;
  • X is oxygen or sulphur
  • R5, Rg, X and N together are tetrahydroisoquinolinone or tetrahydr ⁇ isoquinolin-thione optionally substituted in the phenyl ring as defined for R above;
  • the nitrogen-containing group in the 4-position being trans to the R3 group when R3 is hydroxy, C ⁇ .g alkoxy or C ⁇ _7 acyloxy.
  • R ] _ and R are both C ⁇ __4 alkyl, in particular both methyl.
  • R3 When R3 is C- j __ 6 alkoxy and R 4 is hydrogen, preferred examples of R3 include methoxy and ethoxy, of which methoxy is more preferred.
  • R3 When R3 is C__7 acyloxy and R4 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 R are both hydrogen, or, in particular, that R3 is hydroxy and R is hydrogen.
  • R5 when C__g alkyl, include methyl, ethyl and n- and iso-propyl. Preferably such R5 is methyl.
  • Examples of R5, when C ⁇ __ 6 alkyl substituted by hydroxy, include methyl or ethyl terminally substituted by hydroxy.
  • a sub-group of R5, when C ] __g alkyl substituted by C j __g alkoxy is C j __g alkyl substituted by methoxy or ethoxy. Examples thereof include methyl or ethyl terminally substituted by methoxy or ethoxy.
  • Examples of R5, when C ⁇ _ alkyl substituted by carboxy include methyl or ethyl terminally substituted by carboxy.
  • R5 when alkyl substituted by amino optionally substituted by one or two independent C1-6 alkyl groups include a group (CH2) n RgR 1Q where n is 1 to 6, and Rg and R]_g are each independently hydrogen or C ⁇ __5 alkyl or together are C or C5 polymeth lene.
  • n include 1 and 2, in particular 1.
  • Rg and R ] _ are each independently selected from hydrogen and methyl.
  • R 5 when C2-6 alkenyl include vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, put-2-enyl, but-3-enyl, 1-methylenepropyl, or l-methylprop-2-enyl, in both their E and Z forms where stereoisomerism exists.
  • R5 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, me-chylamino, and phenylamino optionally substituted in the phenyl ring by one methyl, methoxy or chloro group or atom.
  • R5 when aryl include phenyl and naphthyl, of which phenyl is preferred.
  • a sub-group of R5 heteroaryl or heteroaryl for an R moiety in Z is 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl of which 5- or 6-membered monocyclic heteroaryl is preferred.
  • 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur and which, in the case of there being more than one heteroatom, are the same or different.
  • Examples of 5- or 6-membered monocyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazyl and triazyl.
  • Examples of such groups include furanyl, thienyl, pyrryl and pyridyl, in particular 2- and 3-furyl, 2- and 3-pyrryl, 2- and 3-thienyl, and 2-, 3- and 4- ⁇ yridyl.
  • 9- or 10-membered bicyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include benzofuranyl, benzothienyl, indolyl and indazolyl, quinolyl and isoquinolyl, and quinazonyl.
  • Preferred examples of such groups include 2- and 3-benzofuryl, 2- and 3-benzothienyl, and 2- and 3-indolyl, and 2- and 3-quinolyl.
  • the number of groups or atoms for optional substitution of aryl or heteroaryl is one, two, three or four.
  • Preferred examples of the groups or atoms for optional substitution of aryl or heteroaryl include methyl, methoxy, hydroxy, chloro, fluoro, nitro or cyano, most preferably fluoro.
  • a sub-group of R5 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 j __g alkyl, C]__5 alkoxy, halogen, trifluoromethyl, nitro or cyano.
  • phenyl optionally substituted as hereinoefore defined is phenyl, 4-substitute ⁇ phenyl, 3-substituted phenyl, 2-substituted phenyl, 2,4, 2,6 and 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.
  • examples of R5 also include carboxyl, methoxycarbonyl, ethoxycarbonyl,' aminocarbonyl, methylamino-carbonyl and dimethylaminocarbonyl.
  • R5 and Rg when together are -CH2-(CH2) n -Z-(CH2) m - as defined the resulting radical substituting the pyranopyridine in the 4-position is preferably either pyrrolidonyl or piperidonyl.
  • 4-substituents when R5 and R ⁇ are joined together include those described in EP-A-107423.
  • R when Z is NR include hydrogen, methyl , ethyl , n- and iso-propyl , n-, sec- and tert- butyl, benzyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl ring by methyl, methoxy, chloro or brorao; furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or indolylcarbonyl.
  • R is hydrogen, methyl, n-butyl, acetyi, benzyl, benzylcarbonyl, phenylcarbonyl or furylcarbonyl. Most preferably R is hydrogen.
  • R5 and Rg are R5 is methyl or halophenyl, such as 2- or 4-fluorophenyl and g hydrogen and R5 and R 6 together are C3 or C polymethylene.
  • X is oxygen
  • Examples of a pharmaceutically acceptable salt of a compound of formula (I), when the compound contains a salifiable substituent which is an optionally substituted amino group, include acid addition salts such as the hydrochloride and hydrobromide salts.
  • Such a salifiable group may be within an R5 group.
  • a carboxy group within R5 may also be salified to form metal salts, such as alkali metal salts, or optionally substituted ammonium salts.
  • pyridine in the compound of formula (I) is also salifiable, to give pyridine salts with acids, such as those with HC1 and HBr.
  • internal salts such as the N-Oxide may be formed by per-acid oxidation of the corresponding compound of formula (I).
  • the compounds of formula (I) may also exist as solvates such as hydrates and the invention extends to these; such solvates are included wherever a compound of formula (I) is herein referred to.
  • 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 tne Examples hereinafter.
  • the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises;
  • R-. and R 2 are as hereinbefore defined, R is hydroxy, C ] __g alkoxy or G 1 _ 7 acyloxy, and Rg 1 is hydrogen or C 1-6 alkyl, the R ⁇ H group being trans to the R3 1 group,
  • L]_ is a leaving group
  • R3 is hydrogen, C]__5 alkoxycarbonyl, C ⁇ _g alkyl optionally substituted by halogen, hydroxy, C__g alkoxy, C ⁇ __g alkoxycarbonyl, carboxy or amino optionally substituted as hereinbefore defined for R5 ⁇ 2-6 alkenyl or optionally substituted aryl or heteroaryl as hereinbefore defined for R5, or a group convertible to R5 as hereinbefore defined, and thereafter, when Rg is hydrogen and R Q is Y(CH2) Z ' where z is 3 or 4 and Y is a leaving group, cyclising tne resultant compound;
  • R j _ ⁇ is hydrogen, C ] __ alkyl, _g alkenyl, G l-6 alkanoyl optionally substituted by up to three nalo atoms, or phenyl optionally substituted by C ⁇ __g alkyl, C ] __g alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R ] _ j _ is hydrogen, optionally converting R ] _ ⁇ _; or
  • w h erein Rio is R5 as defined and R]_ 2 is aminocarbonyl; R]_2 and R 13 together are -CH 2 -(CH2) n -Z-(CH 2 ) m - or R13 HCOR12 is tetrahydroisoquinolinone; optionally converting R3 in the resulting compound into another R3 ; in the case where R3 and R in the resulting compound are hydroxy and hydrogen respectively, optionally dehydrating the compound to give another compound wherein R3 and R4 together are a bond, and optionally reducing the resulting compound wherein R3 and R4 together are a bond, to give another compound, wherein R3 and R are each hydrogen; and optionally thiating the Rg-N-CO-Rs group in the resulting compound to give a compound wherein X is sulphur; and optionally forming a pharmaceutically acceptable salt thereof.
  • the leaving group ] _ is a group that is displaceable by a primary or secondary amino nucleophile.
  • examples of such a grbup include C j __ 4 alkanoyloxy, , and halogen, such as chloro and bro o or hydroxy.
  • 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.
  • wnen R5 in the desired compound of formula (I) is an R5 optionally substituted amino-substituted alkyl group as hereinbefore defined, it is preferred that R3 is a group convertible to the R5 substituted alkyl group as hereinbefore defined, in particular that it is C]__6 alkyl substituted by halo, especially bromo.
  • the Rs hai ° substituent in the resultant compound of process variant i) a) may be converted to an R5 substituent which is amino optionally substituted as hereinbefore defined by a conventional amination reaction with ammonia or a corresponding alkyl- or dialkylamine.
  • R3 is C j __galkoxycarbonyl, this may be converted to R5 is carboxy by conventional hydrolysis.
  • R g may be C ] __ ⁇ alkyl substituted by protected amino, protected C ⁇ -g alkylamino or amino substituted by two independent CI__Q alkyl groups, it being necessary to protect the R3 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, or calcium, potassium or sodium caroonate.
  • a non-aqueous medium such as dichloromethane
  • an acid acceptor such as triethylamine, trimethylamine, or calcium, potassium or sodium caroonate.
  • acylating agent of formula (III) is an acid
  • acylation of a compound of formula (II) is conveniently performed in the presence of a dehydrating agent, such as dicyclohexyldicarbodiimide in an inert solvent, such as dimethylformamide at a temperature of 0°C to ambient.
  • a dehydrating agent such as dicyclohexyldicarbodiimide
  • an inert solvent such as dimethylformamide
  • R3I in a compound of formula (II) is hydroxy
  • the reaction may be carried out under controlled conditions such that only the amine, Rg ⁇ H- is acylated, for example, by using a C2-.9 acyloxy group as the leaving group L ] _, 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.
  • R3I may be C__7 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.
  • Rg is Y(CH2) 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.
  • reaction of a compound of formula (V) with a compound of formula (VI) it is particularly preferred that the reaction is carried out under basic conditions so as to facilitate the formation of the anion of the compound of formula (VI), for example, in the presence of sodium hydride.
  • 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 potassium hydroxide, or it may be acylated using a carooxylic acid chloride or annydride in a non-hydroxylic solvent in the presence of an acid acceptor.
  • R when R is C ⁇ ⁇ j acyloxy or C ] __5 alkoxy, it may be converted into hydroxy by conventional hydrolysis or dealkylation respectively.
  • the optional dehydration of the resulting compound of formula (I), wherein R 3 and R 4 are hydroxy and hydrogen respectively, into another compound of formula (I), wherein R3 and R4 together are a bond may be carried out under conventional dehydration conditions, for example, by using a dehydrating agent, such as sodium hydride, in an inert solvent, such as dry tetrahydrofuran, at reflux temperature.
  • a dehydrating agent such as sodium hydride
  • an inert solvent such as dry tetrahydrofuran
  • the optional thiation of the R5-N-CO-R5 group in a compound of formula (I) to give another compound of formula I, wherein X is sulphur is, preferably, carried out with conventional thiation agents, such as hydrogen sulphide, phosphorus pentasulphide and Lawesson's reagent ("p-methoxyphenylthiophosphine sulphide dimer) .
  • 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.
  • the use of hydrogen sulphide is, preferably, acid catalysed by, for example, hydrogen chloride in a polar solvent, such as acetic acid or etnanol.
  • the preferred use of Lawesson's reagent is, preferably, carried out under reflux in a dry solvent, such as toluene or methylene chloride.
  • a pharmaceutically acceptable salt may oe carried out conventionally. It should be appreciated that formation of an N-Oxide by oxidation may affect other substituents and appropriate modification of reaction conditions and/or protection will be taken where necessary.
  • a compound of formula (II) may be prepared by reacting a compound of formula (V) , or an N-oxide thereof, as hereinbefore defined, with a compound of formula (VII):
  • Rg is as hereinbefore defined; and optionally converting R3 1 hydroxyl in the resulting compound of formula (II) into another R3 1 .
  • the reaction is normally carried out in a solvent, such as a C ] __ 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 ] __ 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 removed from the reaction mixture by removal of the solvent, for example, by evaporation under reduced pressure. Any epoxide impurity may be removed conventionally, for example by chromatograph .
  • a compound of formula (V) may be prepared by reacting a compound of formula (VIII) or an N-oxide therof:
  • R- j _ and R2 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 aqueous dioxan. It is preferred that the compound of formula (V) is used directly in the reaction with (VI) .
  • a compound of formula (VIII) may be prepared in accordance with analogous processes to those described in the aforementioned European publications, i.e. by the process depicted below:
  • a blocking moiety such as bromo
  • the bromo moiety may be removed at a convenient later stage, using butyl lithium.
  • the intermediates in the above scheme are preferably in the form of the N-oxide.
  • the N-oxide formation is favourably carried out between stages (c) and (d) and subsequent reduction to form the unoxidised form may be carried out at a convenient later stage, by reduction, using hydrogenation or, in particular, a reducing agent such as that described in J. Am Chem. Soc. 91 , 2788, 1969.
  • the intermediates of formulae (II), (V), (VIII), (IX) and (X) are believed to be novel and represent part of the present invention.
  • the intermediates of formulae (III), (IV), (VI) and (VII) are known or may be prepared in accordance with an appropriate known process for preparing structurally similar known compounds.
  • the compounds of formula (I) have been found to have blood-pressure lowering activity. They are therefore useful in the treatment of 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.
  • the present invention provides an anti-hypertensive pharmaceutical composition which comprises an anti-hypertensive effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically accejtaole carrier.
  • compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration for patients suffering from heart failure.
  • compositions are as described for the compounds of EP-A-205292.
  • the present invention further provides a method of prophylaxis or treatment of hypertension in mammals including man, which comprises administering to the suffering mammal an anti-hypertensive 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 1 to 100 mg of a compound of the invention and more usually from 2 to 50 mg, for example 5 to 25 mg such as 6, 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 5 to 200 mg for a 70 kg human adult and more particularly from 10 to 100 mg.
  • the present * invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of hypertension.
  • valeroylamino compound of description 7 (0.44 g) was dissolved in dry tetrahydrofuran (10 ml) and sodium hydride (45 mg ; 80% dispersion in oil) was added to the stirred solution under nitrogen. The reaction mixture was stirred for 16 h. Water was cautiously added and the solution reduced in volume and extracted with chloroform (-4x) . The material from the first two extractions was chromatographed on the chromatotron (chlorofor —methanol gradient, silica gel) and the desired material (140 mgm) combined with the product of the last two extractions (110 mgm). Recrystallisation from ethyl acetate-methanol gave the piperidone compound of example 2 as crystals (120 mgm) of m.p. 258-259°C.
  • 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, 21_, 1 9 (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 >170 mmHg were considered hypertensive.
  • the compound of example 1 lowered systolic blood pressure by 40 ⁇ 14 at 4 post dose, on administration of a dose of 10 mg/kg p.o. to a group of 6 rats.

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Abstract

Composés de formule (I) et leurs sels pharmaceutiquement acceptables. Dans la formule, R1 est hydrogène ou alkyle, R2 est alkyle ou R1 et R2 sont polyméthylène et R3 est hydrogène, hydroxy, alkoxy, aciloxy; R4 est hydrogène ou R3 et R4 sont une liaison; R5 est hydrogène, un alkyle éventuellement substitué, alkényle, un amino éventuellement substitué, un aryle ou un hétéroaryle éventuellement substitué, carboxy, alkoxy carbonyle ou amino carbonyle; R6 est hydrogène ou alkyle ou R5 et R6 sont ensemble -CH2-(CH2)n-Z-(CH2)m-, où m et n valent de 0 à 2, m + n est égal à 1 ou 2, Z est CH2, O, S, NR; R est hydrogène, alkyle, alkanoïle, phénylalkyle, naphtylcarbonyle, phénylcarbonyle, benzylcarbonyle, ou hétéroarylcarbonyle; X et O, S ou R5, R6, X et N sont ensemble tétrahydroisoquinolinone ou tétrahydroisoquinolinethione. Ces composés présentent un effet anti-hypertensif.
PCT/GB1987/000386 1986-06-06 1987-06-05 DERIVES DE PYRANO (3,2-c) PYRIDINE, PROCEDE DE PREPARATION ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT Ceased WO1987007607A1 (fr)

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0323745A3 (en) * 1988-01-06 1990-03-21 Beecham Group Plc Pharmaceutical preparations
EP0360621A1 (fr) * 1988-09-23 1990-03-28 Ortho Pharmaceutical Corporation Thienopyrannes substitués comme agents antihypertensives
US4931454A (en) * 1987-09-24 1990-06-05 Merck Patent Gesellschaft Mit Beschrankter Haftung Azachroman derivatives with effects on the cardiovascular system
EP0405298A1 (fr) * 1989-06-27 1991-01-02 Chemisch Pharmazeutische Forschungsgesellschaft m.b.H. Dérivés de thiénopyrannes, un procédé pour leur préparation et leur utilisation
US5140031A (en) * 1989-05-31 1992-08-18 E. R. Squibb & Sons, Inc. Pyranyl cyanoguanidine derivatives
US5310932A (en) * 1991-04-15 1994-05-10 E. R. Squibb & Sons, Inc. Chromanyl substituted indole potassium channel openers
EP0600617A1 (fr) * 1992-11-10 1994-06-08 E.R. Squibb & Sons, Inc. Procédé de préparation d'intermédiaires utiles dans la préparation de dérivés de pyranylcyanoguanidine
US5374643A (en) * 1992-09-11 1994-12-20 E. R. Squibb & Sons, Inc. Aryl urea (thiourea) and cyanoguanidine derivatives
US5393771A (en) * 1993-05-12 1995-02-28 Brisol-Myers Squibb Company 4-substituted benzopyran and related compounds
US5401758A (en) * 1993-10-07 1995-03-28 Bristol-Myers Squibb Company Pyridinyl cyanoguanidine compounds
US5453421A (en) * 1992-09-11 1995-09-26 E. R. Squibb & Sons, Inc. Aryl and heterocyclic substituted propenamide derivatives
US5514690A (en) * 1992-11-17 1996-05-07 E. R. Squibb & Sons, Inc. Aminocarbonyl (thiocarbonyl) and cyanoguanidine derivatives of quinoline and indoline
US5547966A (en) * 1993-10-07 1996-08-20 Bristol-Myers Squibb Company Aryl urea and related compounds
US5612323A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phosphinic ester substituted benzopyran derivatives
US5612370A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phenylglycine and phenylalaninen amido benzopyran derivatives
US5629429A (en) * 1995-06-07 1997-05-13 Bristol-Myers Squibb Company Process for preparing 4-arylamino-benzopyran and related compounds
US5837702A (en) * 1993-10-07 1998-11-17 Bristol-Myers Squibb Co. 4-arylamino-benzopyran and related compounds
US5869478A (en) * 1995-06-07 1999-02-09 Bristol-Myers Squibb Company Sulfonamido substituted benzopyran derivatives
US8759523B2 (en) 2010-07-20 2014-06-24 Glaxo Group Limited Process for preparing pyrano—[2,3-C]pyridine derivatives

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US4931454A (en) * 1987-09-24 1990-06-05 Merck Patent Gesellschaft Mit Beschrankter Haftung Azachroman derivatives with effects on the cardiovascular system
EP0308792A3 (en) * 1987-09-24 1990-07-04 Merck Patent Gesellschaft Mit Beschrankter Haftung Azachromane derivatives
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EP0323745A3 (en) * 1988-01-06 1990-03-21 Beecham Group Plc Pharmaceutical preparations
EP0360621A1 (fr) * 1988-09-23 1990-03-28 Ortho Pharmaceutical Corporation Thienopyrannes substitués comme agents antihypertensives
US5140031A (en) * 1989-05-31 1992-08-18 E. R. Squibb & Sons, Inc. Pyranyl cyanoguanidine derivatives
EP0405298A1 (fr) * 1989-06-27 1991-01-02 Chemisch Pharmazeutische Forschungsgesellschaft m.b.H. Dérivés de thiénopyrannes, un procédé pour leur préparation et leur utilisation
US5310932A (en) * 1991-04-15 1994-05-10 E. R. Squibb & Sons, Inc. Chromanyl substituted indole potassium channel openers
US5453421A (en) * 1992-09-11 1995-09-26 E. R. Squibb & Sons, Inc. Aryl and heterocyclic substituted propenamide derivatives
US5374643A (en) * 1992-09-11 1994-12-20 E. R. Squibb & Sons, Inc. Aryl urea (thiourea) and cyanoguanidine derivatives
EP0600617A1 (fr) * 1992-11-10 1994-06-08 E.R. Squibb & Sons, Inc. Procédé de préparation d'intermédiaires utiles dans la préparation de dérivés de pyranylcyanoguanidine
US5463059A (en) * 1992-11-10 1995-10-31 E. R. Squibb & Sons, Inc. Process for the preparation of intermediates useful in the preparation of pyranyl cyanoguanidine derivatives
AU660239B2 (en) * 1992-11-10 1995-06-15 E.R. Squibb & Sons, Inc. Process for the preparation of intermediates useful in the preparation of pyranyl cyanoguanidine derivatives
US5514690A (en) * 1992-11-17 1996-05-07 E. R. Squibb & Sons, Inc. Aminocarbonyl (thiocarbonyl) and cyanoguanidine derivatives of quinoline and indoline
US5393771A (en) * 1993-05-12 1995-02-28 Brisol-Myers Squibb Company 4-substituted benzopyran and related compounds
US5401758A (en) * 1993-10-07 1995-03-28 Bristol-Myers Squibb Company Pyridinyl cyanoguanidine compounds
US5547966A (en) * 1993-10-07 1996-08-20 Bristol-Myers Squibb Company Aryl urea and related compounds
US5837702A (en) * 1993-10-07 1998-11-17 Bristol-Myers Squibb Co. 4-arylamino-benzopyran and related compounds
US5612323A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phosphinic ester substituted benzopyran derivatives
US5612370A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phenylglycine and phenylalaninen amido 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
US8759523B2 (en) 2010-07-20 2014-06-24 Glaxo Group Limited Process for preparing pyrano—[2,3-C]pyridine derivatives

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