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Blood Pressure Abstract
Blood Pressure Claims 5. A pharmaceutical composition for the treatment of high blood pressure which comprises a pharmaceutically effective amount for said treatment of a compound of the formula I or a physiologically tolerated salt thereof as claimed in claim 1, together with a pharmaceutically acceptable carrier. 6. A method for the treatment of high blood pressure which comprises administering to a host in recognized need of said treatment a pharmaceutical composition as claimed in claim 5. 7. A method for the treatment of high blood pressure which comprises administering to a host in recognized need of said treatment a pharmaceutically effective amount of a compound of the formula I or a physiologically tolerated salt thereof as claimed in claim 1. 8. A pharmaceutical composition for the treatment of high blood pressure which comprises a pharmaceutically effective amount for said treatment of a compound of the formula I or a physiologically tolerated salt thereof as claimed in claim 4, together with a pharmaceutically acceptable carrier. 9. A pharmaceutical composition for the treatment of high blood pressure which comprises a pharmaceutically effective amount for said treatment of a compound of the formula I or a physiologically tolerated salt thereof as claimed in claim 3, together with a pharmaceutically acceptable carrier. 10. A pharmaceutical composition for the treatment of high blood pressure which comprises a pharmaceutically effective amount for said treatment of a compound of the formula I or a physiologically tolerated salt thereof as claimed in claim 2, together with a pharmaceutically acceptable carrier. 11. A method for the treatment of high blood pressure which comprises administering to a host in recognized need of said treatment a pharmaceutical composition as claimed in claim 10. 12. A method for the treatment of high blood pressure which comprises administering to a host in recognized need of said treatment a pharmaceutical composition as claimed in claim 9. 13. A method for the treatment of high blood pressure which comprises administering to a host in recognized need of said treatment a pharmaceutical composition as claimed in claim 8. 14. A method for the treatment of high blood pressure which comprises administering to a host in recognized need of said treatment a pharmaceutically effective amount of a compound of the formula I or a physiologically tolerated salt thereof as claimed in claim 4. 15. A method for the treatment of high blood pressure which comprises administering to a host in recognized need of said treatment a pharmaceutically effective amount of a compound of the formula I or a physiologically tolerated salt thereof as claimed in claim 3. 16. A method for the treatment of high blood pressure which comprises administering to a host in recognized need of said treatment a pharmaceutically effective amount of a compound of the formula I or a physiologically tolerated salt thereof as claimed in claim 2. 18. A pharmaceutical composition for the treatment of high blood pressure which comprises a pharmaceutically effective amount for said treatment of a compound of the formula I or a physiologically tolerated salt thereof as claimed in claim 17, together with a pharmaceutically acceptable carrier. 19. A method for the treatment of high blood pressure which comprises administering to a host in recognized need of said treatment a pharmaceutical composition as claimed in claim 18. 20. A method for the treatment of high blood pressure which comprises administering to a host in recognized need of said treatment a pharmaceutically effective amount of a compound of the formula I or a physiologically tolerated salt thereof as claimed in claim 17. Patent Information Search Body
Blood Pressure Description U-L-(O).sub.q -A (III) in which L, A and q are as defined above, and U is a leaving group, where appropriate eliminating again protective groups which have been temporarily introduced, and converting the resulting compounds of the formula I, where appropriate, into the physiologically tolerated salts thereof. Suitable leaving groups U are preferably nucleofugic groups (cf. Angew. Chem. 72 [1960]71) such as halogen, o-toluenesulfonate, mesylate or triflate. Processes for preparing the precursors of the formula II are disclosed in, inter alia, U.S. Pat. No. 4,355,044, EP-A-324,377 and EP-A-323,841. Other processes are described in G. L'abbe, Chem. Rev. 69, 345 (1969); T. Srodsky in "The Chemistry of the Azido Group", Wiley, N.Y., 1971, page 331; H. Wamhoff in "Comprehensive Heterocyclic Chemistry", S. Katritzky Ed., Pergamon Press, New York (1984). Suitable for the alkylation of the azoles of the formula II are, for example, appropriate benzyl halides, tosylates, mesylates or triflates or appropriate alkyl halides, tosylates, mesylates or triflates. The synthesis of these derivatives, such as benzofurans, benzothiophenes and indoles with benzylic CH.sub.3 group, has been described by, inter alia, R. P. Dickson et al. in J. Med. Chem. 29, 1637 (1986), and ibid. 29, 1643 (1986). Suitable hydroxybenzotriazoles can be prepared by the method of R. Geiger et al., Chem. Ber. 103, 788 (1970). The preparation of benzoimidazoles, benzothiazoles, benzodiazines, benzopyrones, benzothiazolones, benzotriazines, benzoxazines, benzoxazoles is outlined in the edition cited above "Comprehensive Heterocyclic Chemistry", S. Katritzky Ed. Pergamon Press, New York (1984). It was possible to obtain other heterocyclic compounds by the methods of E. Abignente et al. in J. Heterocyclic Chem. 26, 1875 (1989), A. Krubsack et al. in J. Org. Chem. 41, 3399 (1976) and of F. Santer et al. in Mh. Chem. 99, 715 (1968). The alkylation is carried out in an analogous manner by processes known in principle. The azole derivative of the formula II is metallated in the presence of a base, for example. Preferred bases are metal hydrides of the formula MH such as, for example, lithium, sodium or potassium hydride in, for example, DMF or DMSO as solvents or metal alkoxides of the formula MOR, where R is methyl, ethyl or t-butyl, and the reaction is carried out in the corresponding alcohol, DMF or DMSO. The salts of the azoles formed in this way are dissolved in an aprotic solvent such as DMF or DMSO, and a suitable amount of alkylating reagent is added. An alternative possibility for the deprotonation of the azole derivatives is, for example, reaction with potassium carbonate in DMF or DMSO. The reactions are carried out at temperatures below room temperature up to the boiling point of the reaction mixture, preferably between +20.degree. C. and the boiling point of the reaction mixture, for about 1 to 10 hours. The compounds of the formula I according to the invention have an antagonistic action on angiotensin II receptors and can therefore be used for treating hypertension which is dependent on angiotensin II. Additional possible uses are for cardiac insufficiency, cardioprotection, myocardial infarct, cardiac hypertrophy, arteriosclerosis, nephropathy, kidney failure and vascular disorders of the brain such as transient ischemic attacks and stroke. Renin is a proteolytic enzyme which belongs to the class of aspartyl proteases and which is secreted as a consequence of various stimuli (volume depletion, sodium deficiency, .beta.-receptor stimulation) by the juxtaglomerular cells of the kidney into the blood circulation. There it cleaves the decapeptide angiotensin I off the angiotensinogen which is secreted by the liver. The former is converted by angiotensin converting enzyme (ACE) into angiotensin II. Angiotensin II plays an essential part in the regulation of blood pressure because it increases the blood pressure directly by vasoconstriction. In addition, it stimulates the secretion of aldosterone from the adrenal and, in this way, increases, via inhibition of sodium excretion, the extracellular fluid volume which, in turn, contributes to an increase in blood pressure. Post-receptor effects are, inter alia, stimulation of phosphoinositol turnover (Ca.sup.2+ release), activation of protein kinase C, and facilitation of cAMP-dependent hormone receptors. The affinity of compounds of the formula I for the angiotensin II receptor can be determined by measuring the .sub.125 I-angiotensin II or .sup.3 H-angiotensin II displacement from receptors on zona glomerulosa membranes of bovine adrenals. The dissected membranes are suspended in buffer at pH 7.4 for this purpose. In order to prevent degradation of the radioligand during the incubation, aprotinin, a peptidase inhibitor, is added. Additionally used are approximately 14,000 cpm of a tracer with a specific activity of 74 TBq/mmol (commercially available from Amersham Buchler) and an amount of receptor protein which binds 50% of the tracer. The reaction is started by adding 15 .mu.l of membrane suspension to a mixture of 100 .mu.l of buffer+aprotinin; 50 .mu.l of buffer with or without angiotensin II or receptor antagonist and 50 .mu.l of tracer. After an incubation time of 60 minutes at 25.degree. C., bound and free radioligand are separated by a filtration assay with Whatmann.RTM. GFIC filters on a Skatron.RTM. cell collector. Non-specific binding is prevented by treating the filters with 0.3% polyethyleneimine pH=10 (Sigma, No. 3143). The strength of the displacement of the radioligand from the receptor is determined by measuring the radioactivity in a gamma scintillation counter. The IC.sub.50 values, which are the concentrations of the inhibitor needed to displace 50% of the ligand, are determined by the method of Chem. et al. J. Theor. Biol. 59, 253 (1970). For the compounds of the formula (I) they are in the range 1.times.10.sup.-4 -1.times.10.sup.-9 M. To determine the antagonistic effect of the compounds of the formula (I), it is possible to measure their effect on the increase in blood pressure induced by angiotensin II in anesthetized Sprague-Dawley rats. The anesthetic used is sodium thiobarbital (Trapanal.RTM., Byk Gulden) in an i.p. dosage of 100 mg/kg. The i.v. administration takes place into the jugular vein. The blood pressure is measured in the carotid artery. The animals are firstly pretreated with pentolinium tartrate (10 mg/kg i.m.) so that a lower blood pressure level is reached (ganglion blockade). ANG II (Hypertensin.RTM., CIBA) is administered i.v. in the volume of 0.1 ml/100 g in 10-minute intervals. The dose is 0.5 .mu.g/kg. The compounds of the formula (I) are dissolved in distilled water and administered intravenously or intraduodenally in the dosages 0.1-1; 10 and 100 mg/kg. The compounds of the formula (I) are active in the range 0.1-100 mg/kg. The invention likewise relates to pharmaceutical compositions composed of a compound of the formula I and other active substances such as, for example, diuretics or nonsteroidal anti-inflammatory active substances. The compounds of the formula I can also be used as diagnostic aids for the renin-angiotensin system. Pharmaceutical products contain an effective amount of the active substance of the formula I and, possibly, other active substances together with an inorganic or organic pharmaceutically utilizable excipient. Intranasal, intravenous, subcutaneous or oral use is possible. The dosage of the active substance depends on the warm-blooded species, the body weight, age and on the mode of administration. The pharmaceutical products of the present invention are prepared in dissolving, mixing, granulating or coating processes known per se. For a form for oral use, the active compounds are mixed with the additives customary for this purpose, such as excipients, stabilizers or inert diluents, and converted by customary methods into suitable dosage forms; such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, especially corn starch. This preparation can be both as dry and wet granules. Examples of suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil and fish liver oil. For subcutaneous or intravenous administration, the active compounds or the physiologically tolerated salts thereof are converted, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries into solutions, suspensions or emulsions. Examples of suitable solvents are: water, physiological saline solutions or alcohols, for example ethanol, propanediol or glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
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