WO1992013853A1 - Agent therapeutique - Google Patents

Agent therapeutique Download PDF

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Publication number
WO1992013853A1
WO1992013853A1 PCT/GB1992/000214 GB9200214W WO9213853A1 WO 1992013853 A1 WO1992013853 A1 WO 1992013853A1 GB 9200214 W GB9200214 W GB 9200214W WO 9213853 A1 WO9213853 A1 WO 9213853A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
ethyl
biphenyl
tetrazol
methoxy
Prior art date
Application number
PCT/GB1992/000214
Other languages
English (en)
Inventor
Alan Charles Barker
Robert James Pearce
David Anthony Roberts
Simon Thomas Russell
Original Assignee
Imperial Chemical Industries Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Imperial Chemical Industries Plc filed Critical Imperial Chemical Industries Plc
Publication of WO1992013853A1 publication Critical patent/WO1992013853A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a new pharmaceutical agent and, more particularly, to a new physical form of a substituted quinoline derivative with valuable pharmacological properties in antagonising wholly or in part one or more of the actions of the substances known as angiotensins, and in particular of that known as angiotensin II (hereinafter referred to as "All").
  • the invention also concerns pharmaceutical compositions containing the new physical form and for use in treating diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role.
  • the invention also concerns a process for the manufacture of the new physical form and the use of the form in treating one of the afore-mentioned diseases or medical conditions and for the production of novel pharmaceuticals for use in such medical treatments.
  • the angiotensins are key mediators of the renin-angiotensin- aldosterone system, which is involved in the control of homeostasis and fluid/electrolyte balance in many warm-blooded animals, including man.
  • the angiotensin known as All is produced by the action of angiotensin converting enzyme (ACE) from angiotensin I, itself produced by the action of the enzyme renin from the blood plasma protein angiotensinogen. All is a potent spasmogen especially in the vasculature and is known to increase vascular resistance and blood pressure.
  • ACE angiotensin converting enzyme
  • the angiotensins are known to stimulate the release of aldosterone and hence result in vascular congestion and hypertension via sodium and fluid retention mechanisms.
  • a compound may often ekist in the solid state in one or more different and discrete physical forms which have different physical properties including melting point and solubility. This phenomenon is known as polymorphism. Some of these physical forms may be intrinsically more stable than others, for example, as a result of the different energies associated with the crystal lattices involved. It is desirable in the production of pharmaceutical formulations for medical use that the active ingredients are in a physical form which is both physically stable and can be prepared to reproducible quality standards substantially free of impurities and other physical forms. This latter requirement is especially important because different physical forms can have markedly different bioavailabilities.
  • references in this specification to the gamma crystalline form of the compound A, essentially anhydrous and substantially free of other physical forms refer to material containing less than 0.5% by weight of water and in which material at least 95% by weight of the compound A is present in that single physical form.
  • X-ray powder diffraction spectra may be determined in conventional manner, for example, using a Philips PW1130 X-ray generator with a broad focus copper tube and approximately 0.5 g of sample material mounted in a standard Philips pack holder over the scanning range of 4-40° 2 ⁇ counting for 4 seconds per point at 0.02 ⁇ intervals to produce a trace of spacings against intensity for this range.
  • An X-ray diffraction spectrum of a typical sample of the gamma crystalline form of the compound A is shown in Figure 1 attached hereinafter. It will be understood that the 2 ⁇ values obtained in practice may vary slightly from one machine to another and so the values quoted hereinabove are not to be construed as absolute.
  • the melting characteristics of samples of the compound A vary with their purity, degree of hydration and physical form and may be determined by conventional procedures well known in the art, for example, by differential scanning calorimetry.
  • the melting point characteristics of a typical sample of the gamma form of compound A are given for illustration in Example 3 hereinafter.
  • the compound A may be obtained by procedures well known in the chemical art for the production of chemically analogous compounds such as the procedures described in our aforementioned European patent application. Typical procedures are described in the accompanying Examples. Such known procedures tend to give material of different crystalline form and degree of hydration or solvation than the gamma form of compound A of the present invention. This can be inferred from the different physical properties of the forms. Thus, for example the melting characteristics, X-ray powder spectra and Fourier transform infra-red spectra are different to those of the gamma form of compound A of the invention.
  • the gamma form is intrinsically more stable and has a more compact crystal form than the alpha form of compound A and is consequently generally preferred for pharmaceutical purposes.
  • a process for the preparation of the gamma form of compound A as defined above which comprises heating at elevated temperature a source of compound A in one or more suitable polar organic solvents, optionally reducing the volume of the resultant solution by partial evaporation, optionally followed by adding a non-hydroxylic organic solvent or diluent and then cooling the mixture obtained to about 0 to 20 degrees Celsius (°C).
  • the source of compound A may typically contain predominantly the form now known as the alpha form of compound A, for example as may be obtained by one of the procedures described hereinafter.
  • Suitable polar organic solvents include, for example, hydroxylic solvents, such as methanol, ethanol, propanol and 2-methoxyethanol, or a mixture thereof, especially a mixture of ethanol containing up to about 10% by volume of methanol.
  • Suitable non-hydroxylic solvents for use as specified in the above process include, for example, ethyl acetate and butyl acetate.
  • the process preferably requires the heating to be carried out at elevated temperature, for example from about 40 to 130°C, conveniently at or about the boiling point of the solvent or solvent mixture. It will be understood that it is necessary to carry out the process for sufficient time to permit complete conversion to the gamma from to occur. In general this will require several hours, preferably at least 1 to 12 hours, of heating.
  • One preferred process comprises dissolving the source of compound A by heating in a hydroxylic solvent (especially ethanol) at or near the boiling point of said solvent, adding another more polar and lower boiling hydroxylic solvent (especially methanol) and then removing the lower boiling point solvent by fractional distillation prior to addition of a suitable non-hydroxylic solvent (especially ethyl acetate).
  • a hydroxylic solvent especially ethanol
  • another more polar and lower boiling hydroxylic solvent especially methanol
  • a suitable non-hydroxylic solvent especially ethyl acetate
  • Another preferred process comprises heating a source of compound A in a mixture of ethanol containing up to 10% by volume of methanol (conveniently that mixture known in the UK as industrial methylated spirits) at or near the boiling point of said mixture for at least 2 hours, followed by cooling to about 0 to 20°C.
  • the process may be carried without complete solution of the source of compound A, that is with the material as a slurry in the polar organic solvent.
  • the procedure of the invention may optionally be preceded by a preliminary purification step.
  • This step involves the conversion of the compound A into its free base form and subsequently into its sodium salt form which latter is purified by extraction into a suitable organic solvent mixture and then reconverted into the hydrochloride salt to give compound A.
  • the gamma form of compound A is particularly suitable for incorporation into pharmaceutical compositions and especially into conventional solid state pharmaceutical compositions suitable for oral administration, such as tablets, capsules and powders, which compositions may be formulated in a conventional manner.
  • a pharmaceutical composition which comprises the gamma form of compound A as defined hereinbefore together with a pharmaceutically acceptable diluent or carrier.
  • the compound A will have beneficial pharmacological effects in warm-blooded animals (including man) in diseases and medical conditions where amelioration of the vasoconstrictor and fluid retaining properties of the renin- angiotensin-aldosterone system is desirable, at least in part by antagonism of one or more of the physiological actions of All.
  • the compound A will thus be useful in the treatment of diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the r'enin-angiotensin-aldosterone system plays a significant causative role.
  • antagonism of one or more of the physiological actions of All and, in particular, the antagonism of the interaction of All with the receptors which mediate its effects on a target tissue may be assessed using one or more of the following, routine laboratory procedures:
  • Test A This i ⁇ vitro procedure involves the incubation of the test compound initially at a concentration of 100 micromolar (or less) in a buffered mixture containing fixed concentrations of radiolabelled All and a cell surface membrane fraction prepared from a suitable angiotensin target tissue.
  • the source of cell surface membranes is the guinea pig adrenal gland which is well known to respond to All.
  • concentrations of the test compound are ordinarily chosen to allow testing over at least four orders of magnitude centred about the predicted approximate IC , which latter is subsequently determined from a plot of percentage displacement against concentration of the test compound.
  • the compound A shows significant inhibition in Test A at a concentration of 50 micromolar or much less.
  • Test B This in vitro test involves the measurement of the antagonistic effects of the test compound against All-induced contractions of isolated rabbit aorta, maintained in a physiological salt solution at 37°C. In order to ensure that the effect of the compound is specific to antagonism of All, the effect of the test compound on noradrenaline-induced contractions may also be determined in the same preparation.
  • the compound A shows significant inhibition in Test B at a final concentration of 50 micromolar or much less.
  • Test C This in vivo test involves using terminally- anaesthetised or conscious rats in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure.
  • the All antagonistic effects of the test compound following oral or parenteral administration, are assessed against angiotensin II-induced pressor responses.
  • the effect of the test compound on vasopressin-induced pressor responses may also be determined in the same preparation.
  • the compound A shows specific All-antagonist properties in Test C at a dose of 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.
  • Test D This in vivo test involves the stimulation of endogenous All biosynthesis in a variety of species including rat, marmoset and dog by introducing a diet of low sodium content and giving appropriate daily doses of a saluretic known as frusemide. The test compound is then administered orally or parenterally to the animal in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure.
  • the compound A shows All-antagonist properties in Test D as demonstrated by a significant reduction in blood pressure at a dose of 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.
  • the compound A will generally be administered to man so that, for example, a daily oral dose of up to 50 mg/kg body weight (and preferably of up to 10 mg/kg) or a daily parenteral dose of up to 5 mg/kg body weight (and preferably of up to 1 mg/kg) is received, given in divided doses as necessary, the precise amount of compound (or salt) administered and the route and form of administration depending on size, age and sex of the person being treated and on the particular disease or medical condition being treated according to principles well known in the medical arts.
  • the compounds A is also useful in the veterinary treatment of similar conditions affecting commercially valuable warm-blooded animals, such as dogs, cats, horses and cattle. In general for such treatment, the compound A will generally be administered in an analogous amount and manner to those described above for administration to humans.
  • This procedure may also be modified by heating a slurry of 2-ethyl-4-[(2'-(lH-l,2,3,4-tetrazol—5-yl)biphenyl-4-yl)methoxy]- quinoline hydrochloride in a mixture of industrial methylated spirit (about 5% methanol, 95% ethanol) under reflux for at least two hours, cooling the slurry to ambient temperature, separating the solid by filtration, to give the gamma crystalline form of compound A in essentially anhydrous state and with essentially the same physical properties as those given above.
  • the starting 2-ethyl-4-([2'-(2-triphenylmethyl-2H-tetrazol- 5-yl)biphenyl-4-yl]methoxy)quinoline may be obtained as a solid, m.p. 173-174°C (decomposition); NMR: 1.4(t,3H), 2.96(q,2H), 5.16(s,2H), 6.73(s,lH), 6.9-6.94(m,6H), 7.18-7.32(m,13H), 7.33-7.55(m,4H), 7.67(dt,lH), 7.99(m,2H), 8.11(d,lH); microanalysis, found: C,81.1; H,5.4; N,10.9%; C 44 H 35 N 5 0 requires C,81.4; H,5.4; N,10.8%, by alkylating at ambient temperature a solution of the sodium salt of 2-ethyl-4-quinolone (prepared by the method described in Org.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne un nouvel agent pharmaceutique comprenant une nouvelle forme cristalline d'un dérivé de quinoléine substitué (défini ci-dessus) qui constitue un antagoniste puissant de l'angiotensine AII et qui est utilisé pour le traitement de troubles tels que l'hypertension, la cardiopathie congestive ou l'hyperaldostéronisme. On décrit également un procédé permettant d'obtenir cette nouvelle forme cristalline et des compositions pharmaceutiques contenant celle-ci.
PCT/GB1992/000214 1991-02-08 1992-02-05 Agent therapeutique WO1992013853A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9102727.6 1991-02-08
GB919102727A GB9102727D0 (en) 1991-02-08 1991-02-08 Pharmaceutical agent

Publications (1)

Publication Number Publication Date
WO1992013853A1 true WO1992013853A1 (fr) 1992-08-20

Family

ID=10689748

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1992/000214 WO1992013853A1 (fr) 1991-02-08 1992-02-05 Agent therapeutique

Country Status (12)

Country Link
CN (1) CN1064809A (fr)
AP (1) AP9200355A0 (fr)
AU (1) AU1189392A (fr)
CA (1) CA2060825A1 (fr)
GB (2) GB9102727D0 (fr)
HU (1) HUT60489A (fr)
IE (1) IE920243A1 (fr)
IL (1) IL100793A0 (fr)
MX (1) MX9200532A (fr)
PT (1) PT100097A (fr)
WO (1) WO1992013853A1 (fr)
ZA (1) ZA92729B (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
EP3311845A1 (fr) 2013-09-16 2018-04-25 Astrazeneca AB Nanoparticules polymères thérapeutiques et leurs procédés de fabrication et d'utilisation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW297025B (fr) * 1992-02-14 1997-02-01 Squibb & Sons Inc

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0315399A2 (fr) * 1987-11-03 1989-05-10 Rhone-Poulenc Rorer International (Holdings) Inc. Dérivés de la quinoléine, leur utilisation pour le traitement des maladies hypersensibles et compositions pharmaceutiques de ces composés
EP0412848A2 (fr) * 1989-08-11 1991-02-13 Zeneca Limited Dérivés de quinoléine, procédés pour leur préparation et leur utilisation comme médicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0315399A2 (fr) * 1987-11-03 1989-05-10 Rhone-Poulenc Rorer International (Holdings) Inc. Dérivés de la quinoléine, leur utilisation pour le traitement des maladies hypersensibles et compositions pharmaceutiques de ces composés
EP0412848A2 (fr) * 1989-08-11 1991-02-13 Zeneca Limited Dérivés de quinoléine, procédés pour leur préparation et leur utilisation comme médicaments

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP3311845A1 (fr) 2013-09-16 2018-04-25 Astrazeneca AB Nanoparticules polymères thérapeutiques et leurs procédés de fabrication et d'utilisation

Also Published As

Publication number Publication date
PT100097A (pt) 1993-04-30
HUT60489A (en) 1992-09-28
MX9200532A (es) 1992-08-01
GB9202377D0 (en) 1992-03-18
GB9102727D0 (en) 1991-03-27
AU1189392A (en) 1992-09-07
ZA92729B (en) 1992-11-25
IE920243A1 (en) 1992-08-12
AP9200355A0 (en) 1993-08-03
GB2252557A (en) 1992-08-12
CA2060825A1 (fr) 1992-08-09
HU9200354D0 (en) 1992-04-28
IL100793A0 (en) 1992-09-06
CN1064809A (zh) 1992-09-30

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