Abstract:
The invention provides novel 2,3,6 substituted quinazolinones having the formula: ##STR1## wherein R 6 , R and X are as described in the specification, which have activity as angiotensin II (AII) antagonists.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to certain 2,3,6 substituted quinazolinone compounds which have demonstrated activity as angiotensin II (AII) antagonists and are therefore useful in alleviating angiotensin induced hypertension and for treating congestive heart failure. 
     SUMMARY OF THE INVENTION 
     According to the present invention, there are provided novel compounds of Formula I which have angiotensin II antagonizing properties and are useful as hypertensives: ##STR2## wherein: 
     R is ##STR3## 
     X is lower alkyl of 3 to 5 carbon atoms; 
     R 6  is: ##STR4## 
     A is --(CH 2 ) n  --; 
     n is 1, 2, 3, or 4; 
     W is --CH 2  -- or ##STR5## or A and W are each ##STR6## and are connected by a --(CH 2 ) s  -- bridge, wherein S=1, 2 or 3; 
     Q is --O--, --CH 2  -- or ##STR7## 
     D is --(CH 2 ) m  --; 
     m is 3 or 4; 
     R 1  is H, lower alkyl of 1 to 4 carbon atoms (optionally substituted with --OR 5 , --CO 2  R 5 , --CN, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br)), pyridine, thiophene, furan, --CHO, --CO 2  R 5 , --CN, ##STR8## 
     R 2  is H, lower alkyl of 1 to 4 carbon atoms, (optionally substituted with --OR 5 , --CO 2  R 5 , --CN, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br)), pyridine, thiophene, furan, --CHO, --CO 2  R 5 , --CN, ##STR9## 
     R 3  is H, lower alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br), pyridine, thiophene, furan, --OR 5 , --N(R 5 )(R 7 ), --CO 2  R 5 , --CH 2  OR 5 , --CN, --CHO, ##STR10## 
     R 5  is H, lower alkyl of 1 to 4 carbon atoms; 
     R 11  is H, lower alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 or 6 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, P, Cl, or Br), pyridine, thiophene, furan, benzyl, substituted benzyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, P, Cl, or Br), --CO 2  R 5 , --SO 2  R 10 , ##STR11## 
     R 7  is H, lower alkyl of 1 to 4 carbon atoms; 
     R 8  is H, --CO 2  R 5 , --SO 2  R 10 , ##STR12## 
     R 10  is lower alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br); and pharmaceutically acceptable salts thereof. 
     The present invention also provides novel intermediate compounds, methods for making the novel 2,3,6 substituted quinazolinone angiotensin II antagonizing compounds, methods of using the novel quinazolinone angiotensin II antagonizing compounds to treat hypertension, congestive heart failure and to antagonize the effects of angiotensin II. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The novel compounds of the present invention are prepared according to the following reaction schemes. 
     Referring to Scheme I, the corresponding anthranilic acid 2 wherein R 9  is I, Br or CH 3 , are heated to reflux in alkyl acid anhydride 3 wherein X is lower alkyl of 3 to 5 carbon atoms to provide the 4H-3,1-benzoxazin-4-ones 4 which are isolated by concentrating the reaction mixtures and used without further purification. When the 4H-3,1-benzoxazin-4-ones 4 are refluxed in ethyl alcohol containing ammonia, or ammonium hydroxide solution, the quinazolinone intermediates 5 are obtained. ##STR13## 
     The quinazolinone intermediates 5 are modified according to the following reaction schemes to obtain the novel quinazolinone angiotensin II antagonizing compounds of the present invention. 
     In Scheme II, 6-methylquinazolinone 6, as prepared by Scheme I, is brominated with N-bromosuccinimide to give the bromomethyl compound 7. Hydrolysis of the bromide with aqueous potassium carbonate in dimethylsulfoxide yields the primary alcohol 8. The alcohol 8 is oxidized with pyridinium dichromate in N,N-dimethylformamide to afford aldehyde 9. The aldehyde 9 is reacted with a variety of Grignard Reagents R 1  MgBr or lithium reagents R 1  Li in tetrahydrofuran where R 1  is hereinbefore defined, with the proviso that for this reaction scheme R 1  cannot contain a carbonyl group or be H, --CO 2  R 5 , or ##STR14## to give the desired secondary alcohol 10. Alcohol 10 is oxidized with pyridinium dichromate in N,N-dimethylformamide to afford ketone 11. ##STR15## 
     In an alternate route to 9, as shown in Scheme III, 2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 12 is reacted via a palladium catalyzed formylation to give aldehyde 9. Additionally, 12 is converted to ester 13 by palladium (II) catalyzed coupling in the presence of carbon monoxide and methanol. Reduction of 13 with lithium aluminum hydride in tetrahydrofuran gives alcohol 8. Alcohol 8 is oxidized with pyridinium dichromate to yield aldehyde 9. ##STR16## 
     As shown in Scheme IV, the palladium (II) catalyzed coupling of (trimethylsilyl)acetylene with 2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 12 yields the acetylenic quinazolinone 14. Desilylation of the acetylene with sodium hydroxide in water-methanol gives the terminal acetylene 15. Hydration of acetylene is with catalytic mercuric sulfate-sulfuric acid in acetic acid affords methyl ketone 16. The palladium (II) catalyzed coupling of substituted acetylenes where R 17  is defined as lower alkyl of 1 to 4 carbon atoms with 2-alkylsubstituted-6-iodo-4(1H)- quinazolinone 12 yields the acetylenic quinazolinone 17. Hydration of 17 with catalytic mercuric sulfate-sulfuric acid in acetic acid gives ketone 18. ##STR17## 
     As described in EP 0,497,150, biphenyl 19 is attached to quinazolinone intermediate 11 by initially alkylating the quinazolinone with a para-substituted benzyl bromide and subsequently attaching a second phenyl moiety containing a trityl protected tetrazole or a cyano via a transition metal catalyzed coupling at the para position of the first phenyl ring. Quinazolinone intermediates 16 and 18 are similarly reacted. Alternatively, the coupling of quinazolinone intermediate 11 where X and R 1  are hereinbefore defined with biphenyl 19 where R 18  is a trityl protected tetrazole prepared by the methods of N. B. Mantlo, J. Chem., 34, 2919-2922 (1991) or cyano prepared by the methods outlined in D. J. Carini, J. Med. Chem. 34, 2525-2547 (1991) is illustrated in Scheme V and gives coupled product 20 by dissolving 11 and 19 in acetone or another suitable solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, methanol, ethanol, t-butanol, tetrahydrofuran, dioxane or dimethylsulfoxide, in the presence of excess potassium carbonate or another suitable base such as sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, lithium methoxide, sodium t-butoxide, potassium t-butoxide, lithium diisopropylamide (LDA) or lithium hexamethyldisilazide for 2-48 hours, at 20°-60° C. The obtained alkylated quinazolinone 20 may be purified by chromatography or used as is in further transformations and/or deprotection. Quinazolinone intermediates 16 and 18 are similarly reacted. ##STR18## 
     As shown in Scheme VI, aldehyde or ketone 20, where R 1  and x are hereinbefore defined, is reacted with an N-substitutedhydroxylamine 21, where R 2 , R 3 , W, Q and A are hereinbefore defined prepared by the method of W. Oppolzer et al., Tetrahedron, 41, #17, 3497-3509(1985), at room temperature in chloroform in the presence of molecular sieves to give a nitrone 22. Heating the nitrone 22 at reflux in toluene gives a mixture of bicyclic-substituted quinazolinone 23 and bicyclic-substituted quinazolinone 24. 
     Reaction of 23 or 24 where R 18  is cyano with sodium azide in the presence of tri-n-butyltin chloride in refluxing xylene affords the desired tetrazole 25 or 26. Contemplated equivalents to tri-n-butyltin chloride include tri-(loweralkyl C 1  -C 4 ) tin chlorides and bromides. Contemplated equivalents to sodium azide include potassium azide, and lithium azide. Hydrolysis of 23 or 24 where R 18  is a trityl protected tetrazole with methanol-tetrahydrofuran at room temperature to reflux or with an aqueous solution containing a catalytic amount of hydrochloric acid or other suitable acid such as sulfuric, trifluoroacetic or hydrogen chloride for 10 minutes to 24 hours at room temperature affords the free tetrazole 25 or 26. 
     As shown in Scheme VII, aldehyde or ketone 11, where R 1  and X are hereinbefore defined is reacted with an N-substitutedhydroxylamine 27 where R 11  is hereinbefore defined to give nitrone 28. Reaction of 28 with olefin 29 where A, Q, W, R 2  and R 3  are as defined hereinbefore gives quinazolinone 30. ##STR19## 
     Quinazolinone intermediate 30 wherein X, A, Q, W, R 1 , R 2 , R 3  and R 11 , are hereinbefore defined is coupled with with biphenyl 19 by the methods described hereinabove for scheme V to give coupled product 33. The obtained alkylated quinazolinone 33 may be purified by chromatography or used as is in further transformations and/or deprotection. 
     Reaction of 33 where R 18  is cyano with sodium azide in the presence of tri-n-butyltin chloride in refluxing xylene affords the desired tetrazole 35. Contemplated equivalents to tri-n-butyltin chloride include tri-(loweralkyl C 1  -C 4 ) tin chlorides and bromides. Contemplated equivalents to sodium azide include potassium azide, and lithium azide. Hydrolysis of 33 where R 18  is a trityl protected tetrazole with methanol-tetrahydrofuran at room temperature to reflux or with an aqueous solution containing a catalytic amount of hydrochloric acid or other suitable acid such as sulfuric, trifluoroacetic or hydrogen chloride for 10 minutes to 24 hours at room temperature affords the free tetrazole 35. ##STR20## 
     As shown in Scheme VIII, aldehyde or ketone 20, where R 1 , R 18  and X are hereinbefore defined is reacted with amine 37 where R 2 , R 3  and D are hereinbefore defined to give quinazolinone intermediate 38. Aza-allyl anion cyclization of 38 with LDA using the method of W. H. Pearson, J. Am. Chem. Soc. 108, 2769-2771 (1986) gives 39 which is converted to substituted intermediate 40 where R 11  is hereinbefore defined. Reaction of 40 where R 18  is cyano with sodium azide in the presence of tri-n-butyltin chloride in refluxing xylene affords the desired tetrazole 41. Contemplated equivalents to sodium azide included potassium azide and lithium azide. Hydrolysis of 40 where R 18  is a trityl protected tetrazole with methanol-tetrahydrofuran at room temperature to reflux or with an aqueous solution containing a catalytic amount of hydrochloric acid or other suitabled acid such as sulfuric, trifluoroacetic or hydrogen chloride for 10 minutes to 24 hours at room temperature affords the free tetrazole 41. ##STR21## 
     As outlined in Scheme IX, aldehyde or ketone 20, where R 1 , R 18  and X are hereinbefore defined is reacted with amine 42, where R 2 , R 3 , R 11 , W, Q and A are hereinbefore defined and cyclized using the method of W. Oppolzer et al., Tet. Lett 17, 1707-1710 (1972) to give quinazolinone intermediate 43. Reaction of 43 where R 18  is cyano with sodium azide in the presence of tri-n-butyltin chloride in refluxing xylene affords the desired tetrazole 44. Contemplated equivalents to sodium azide include potassium azide and lithium azide. Hydrolysis of 43 where R 18  is a trityl protected tetrazole with methanol-tetrahydrofuran at room temperature to reflux or with an aqueous solution containing a catalytic amount of hydrochloric acid or other suitable acid such as sulfuric, trifluoroacetic or hydrogen chloride for 10 minutes to 24 hours at room temperature affords the free tetrazole 44. 
     Reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformations proposed. This may necessitate judgement as to the order of synthetic steps, protecting groups, if required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions. Such restrictions to the substituents which are compatible with the reaction conditions will be apparent to one skilled in the art. 
     Pharmaceutically suitable salts include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington&#39;s Pharmaceutical Sciences, 17th Edition, pg. 1418 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hydroseopicity and solubility. Preferred salts of this invention for the reasons cited above include potassium, sodium, calcium, magnesium and ammonium salts. 
     Some of the compounds of the hereinbefore described schemes have centers of asymmetry. The compounds may, therefore, exist in at least two and often more stereoisomeric forms. The present invention encompasses all stereoisomers of the compounds whether free from other stereoisomers or admixed with other stereoisomers in any proportion and thus includes, for instance, racemic mixture of enantiomers as well as the diastereomeric mixture of isomers. The absolute configuration of any compound may be determined by conventional X-ray crystallography. 
     While the invention has been illustrated using the trityl protecting group on the tetrazole, it will be apparent to those skilled in the art that other nitrogen protecting groups may be utilized. Contemplated equivalent protecting groups include, benzyl, p-nitrobenzyl, propionitrile or any other protecting group suitable for protecting the tetrazole nitrogen. Additionally, it will be apparent to those skilled in the art that removal of the various nitrogen protecting groups, other than trityl, may require methods other than dilute acid. 
    
    
     The compounds of this invention and their preparation are illustrated by the following non-limiting examples. 
     EXAMPLE 1 
     2-Butyl-6-(methyl)-4(1H)-quinazolinone 
     To 20.0 g of 2-amino-5-methylbenzoic acid is added 60 ml of valeric anhydride. The mixture is heated at reflux for 18 hours and then concentrated under reduced pressure. The resulting brown solid residue is dissolved in a mixture of 200 ml of 30% of ammonium hydroxide solution and 300 ml of ethyl alcohol. This mixture is heated at reflux for 5 hours and then allowed to cool to room temperature. After cooling, the precipitate is collected by filtration. The cake is washed with ethanol and water, then dried under vacuum to give 8.92 g of the quinazolinone as a white solid. 
     CI MASS SPEC MH +  =217. 
     EXAMPLE 2 
     2-Butyl-6-iodo-4(1H)-quinazolinone 
     The method of Example 1 is used with 2-amino-5-iodobenzoic acid to prepare the desired product, m.p. 257°-258° C. 
     EXAMPLE 3 
     2-Butyl-6-(bromomethyl)-4(1H)-quinazolinone 
     To a suspension of 3.50 g of 6-methylquinazolone in 100 ml of chloroform is added 3.39 g of N-bromosuccinimide and 0.25 g of benzoyl peroxide. The reaction mixture is heated at reflux for 18 hours and then filtered hot. A precipitate of 2.21 g of an inseparable mixture of the desired bromide and starting 6-methyl-quinazolinone is obtained and used in Example 4 without further purification. 
     EXAMPLE 4 
     2-Butyl-6-(hydroxymethyl)-4(1H)-quinazolinone 
     To a suspension of 2.0 g of impure 2-butyl-6-(bromomethyl)-4(1H)-quinazolinone (Example 3) in 35 ml of dimethylsulfoxide and 20 ml of water is added 1.0 g of potassium carbonate. The reaction mixture is heated at reflux for 6 hours, resulting in a complete solution. Upon cooling slowly to room temperature a white precipitate forms and is collected by filtration. The filter cake is purified by flash chromatography on silica gel, eluting with 9:1 chloroform-methanol to give 0.67 g of the desired product as a white solid. 
     CI MASS SPEC 233(M+H). 
     EXAMPLE 5 
     2-Butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde 
     To a solution of 0.3 g of 2-butyl-6-(hydroxymethyl)-4(1H)-quinazolinone in 3.5 ml of dry N,N-dimethylformamide is added 1.7 g of pyridinium dichromate. The reaction mixture is stirred at room temperature for 16 hours and then poured into 125 ml of water. The resulting precipitate is removed by filtration and the filtrate extracted with 9:1 chloroform-methanol. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuo and combined with the precipitate above. The combined solids are purified by flash chromatography on silica gel by eluting with 1:1 ethyl acetate-hexanes to give 0.27 g of the desired product. 
     CI MASS SPEC 231(M+H). 
     EXAMPLE 6 
     2-Butyl-6-(l-hydroxyethyl)-4(1H)-quinazolinone 
     To a solution of 0.60 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 30 ml of dry tetrahydrofuran, cooled to 0° C. is added dropwise, 2.61 ml of a 3.0M solution of methylmagnesium bromide in diethyl ether. The reaction is stirred at 0° C. for 30 minutes and then quenched with 10 ml of aqueous ammonium chloride. After diluting with 10 ml of water, the reaction mixture is extracted with 9:1 chloroform-methanol. The combined extracts are dried with magnesium sulfate, filtered and concentrated to yield 0.64 g of the desired product. 
     CI MASS SPEC 247(MH + ). 
     EXAMPLE 7 
     2-Butyl-6-(l-hydroxypropyl)-4(1H)-quinazolinone 
     To a solution of 0.25 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 10 ml of dry tetrahydrofuran, cooled to a0° C., is added 1.63 ml of 2.0M ethyl magnesium bromide in tetrahydrofuran. The reaction mixture is stirred for 30 minutes at 0° C. and quenched with 20 ml of saturated ammonium chloride solution and 20 ml of water. The reaction mixture is extracted with 9:1 chloroform-methanol, dried over magnesium sulfate, filtered and evaporated in vacuo to give 0.26 g of the desired product. 
     CI MASS SPEC 261(MH + ). 
     EXAMPLE 8 
     2-Butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde 
     To a solution of 1.0 g of 2-butyl-6-iodo-4(1H)-quinazolinone and 0.355 g of tetrakis(triphenylphosphine)palladium in 15 ml of tetrahydrofuran and 5 ml of N,N-dimethylformamide, heated to 55° C. under an atmosphere of carbon monoxide is added a solution of 1.40 g of tri-n-butyltin hydride in 2.5 ml of toluene over 6 hours via a syringe pump. After the addition is complete the reaction is allowed to cool to room temperature, diluted with brine and extracted with chloroform. The combined organics are concentrated in vacuo and the resulting residue triturated with ether. The precipitate is collected by filtration and purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate-hexanes to give 0.35 g of the desired product, m.p. 242°-244° C. 
     EXAMPLE 9 
     2-Butyl-6-[(trimethylsilyl)ethylnyl]-4(1H)-quinazolinone 
     To a solution of 1.0 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.043 g of bis(triphenylphosphine) palladium (II) chloride and 5.8 mg of copper (I) iodide in 5.0 ml of N,N-dimethylformamide and 5.0 ml of triethylamine is added 0.36 g of (trimethylsilyl) acetylene. The resulting reaction mixture is heated at 45° C. for 1 hour and then 65° C. for 5 hours. Upon cooling, the reaction mixture is concentrated in vacuo and the residue purified by flash chromatography on silica gel, eluting with 1:3 ethyl acetate-hexane to yield 0.75 g of the desired product as a white solid. 
     CI MASS SPEC 299(MH + ). 
     EXAMPLE 10 
     2-Butyl-6-ethylnyl-4(1H)-quinazolinone 
     To a solution of 0.70 g of 2-butyl-6-[(trimethylsilyl)ethynyl]-4(1H)-quinazolinone in 20 ml of methanol and 20 ml of tetrahydrofuran is added 10.0 ml of 1.0N sodium hydroxide solution. The reaction is stirred at room temperature for 2 hours and then diluted with 5% hydrochloric acid solution until the pH is 2. The resulting tan precipitate is collected by filtration and dried in vacuo to yield 0.50 g of the desired product. 
     CI MASS SPEC 227(MH + ). 
     EXAMPLE 11 
     6-Acetyl-2-butyl-4(1H)-quinazolinone 
     To a solution of 1.20 g of 2-butyl-6-ethynyl-4(1H)-quinazolinone in 90 ml of acetic acid is added 0.45 g of mercuric sulfate, 0.9 ml of water and 0.3 ml of sulfuric acid. The reaction mixture is heated at reflux for 5 hours, cooled to room temperature and quenched with 150 ml of water. The resulting mixture is concentrated in vacuo, diluted with 150 ml of water and extracted with 6:1 chloroform-methanol. The combined organics are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate-hexanes to give 0.67 g of the desired product as a white solid. 
     CI MASS SPEC 245(MH + ). 
     EXAMPLE 12 
     2-Butyl-6-(hydroxyphenylmethyl)-4(1H)-quinazolinone 
     To a stirred solution of 2.00 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 100 ml of tetrahydrofuran, cooled at 0° C., is added 13.0 ml of 2.0M phenyllithium and stirring continued is for 1 hour. The cooling is removed and the reaction allowed to reach room-temperature followed by an additional 30 minutes at room temperature. The reaction is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried, evaporated to a residue, which is purified by chromatography on silica gel by elution with 0.25:100 methanol-chloroform to give 0.932 g of the desired product. 
     CI MASS SPEC 309(MH + ). 
     EXAMPLE 13 
     Methyl 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate 
     To a solution of 1.00 g of 2-butyl-6-iodo-4(1H)-quinazolinone and 6.0 ml of triethylamine in 25 ml of methanol and 5 ml of N,N-dimethylformamide is added 0.275 g of bis-(triphenylphosphine)palladium (II) chloride. The reaction mixture is heated at reflux under an atmosphere of carbon monoxide for 16 hours, then allowed to cool and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate-hexanes to give 0.389 g of the desired product as a white solid. 
     CI MASS SPEC 261(MH + ). 
     EXAMPLE 14 
     2-Butyl-6-(hydroxymethyl)-4(1H)-quinazolinone 
     To a suspension of 0.013 g of lithium aluminum hydride in 5.0 ml of tetrahydrofuran is added 0.100 g of methyl 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate followed by stirring at room temperature for 5 hours. An additional 20 mg of lithium aluminum hydride is added and stirring continued for 18 hours. An additional 20 mg of lithium aluminum hydride is added and stirring continued for an additional 8 hours. The reaction mixture is poured into 75 ml of water and extracted with ethyl acetate. The extract is evaporated in vacuo to a residue which is stirred with acetone and filtered to give 0.040 g of the desired product as a white solid. 
     CI MASS SPEC 233 (MH + ). 
     EXAMPLE 15 
     2-Butyl-6-(hydroxymethyl)-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl-4(3H)-quinazolinone 
     A mixture of 0.198 g of 2-butyl-6-(hydroxymethyl)-4(1H)-quinazolinone, 0.477 g of 5-[4&#39;-(bromomethyl)[1,1&#39;-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole and 0.500 g of potassium carbonate in 15.0 ml of dry acetone is heated at reflux for 18 hours. The reaction mixture is allowed to cool to room temperature and evaporated to a residue. The residue is diluted with water and extracted with chloroform. The organic layer is washed with brine, dried with Na 2  SO 4  and evaporated in vacuo to a residue which is purified on thick layer silica gel chromatography plates using 1:1 ethyl acetate-hexanes to give 0.14 g of the desired product. FAB MASS SPEC 709 (M+H). 
     EXAMPLE 16 
     2-Butyl-3,4-dihydro-4-oxo-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-6-quinazolinecarboxaldehyde 
     A mixture of 6.48 g of 2-Butyl-6-(hydroxymethyl)-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl-4(3H)quinazolinone and 5.16 g of pyridinium dichromate in 20 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is diluted with 100 ml of ether and filtered through a short pad of MGSO 4 . The filtrate is concentrated in vacuo to give the desired product as a residue. FAB MASS SPEC 729 (M+Na). 
     EXAMPLE 17 
     2-Butyl-6-(9-oxa-1-azabicyclo[4.2.1]non-8-yl)-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl-4(3H)-quinazolinone 
     A mixture of 0.198 g of 2-Butyl-3,4-dihydro-4-oxo-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-6-quinazolinecarboxaldehyde and 0.034 g of N-(5-hexenyl)hydroxylamine in 5.0 ml of toluene is heated at reflux for 18 hours then concentrated in vacuo to a residue. The residue is purified by column chromatography on silica gel using 1:1 ethyl acetate-hexanes to give 47 mg of the desired product. 
     EXAMPLE 18 
     cis-2-Butyl-6-(9-oxa-1-azabicyclo[4.2.1]non-8-yl)-3-[[2&#39;-(1H-tetrazol-5-yl)[1,1&#39;-biphenyl]-4-yl-methyl-4(3H)-quinazolinone 
     A mixture of 0.154 g of 2-Butyl-6-(9-oxa-1-azabicyclo[4.2.1]non-8-yl)-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl-4(3H)-quinazolinone in 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at reflux for 18 hours. The volatiles are evaporated in vacuo to give 0.053 g of the desired product. FAB MASS SPEC 562 (M+H). 
     EXAMPLE 19 
     2-Butyl-6-(7-oxa-1-azabicyclo[3.2.1]-oct-8-yl)-3-[[2&#39;-[1-(triphenylmethyl))-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
     EXAMPLE 20 
     2-Butyl-6-(8-oxa-1-azabicyclo[3.2.1]oct-7-yl)-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
     A mixture of 0.487 g of N-(4-pentenyl)hydroxylamine oxalate and 20 ml of 6N KOH is stirred and extracted with ether. The organic layer is separated and dried with solid NAOH. The organic layer is separated and combined with 0.900 g of 2-butyl-3,4-dihydro-4-oxo-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-6-quinazolinecarboxaldehyde and the volatiles concentrated in vacuo to a residue which is dissolved in CHCl 3  and 4A molecular sieves added. The reaction mixture is stirred overnight at room temperature and filtered. The filtrate is evaporated in vacuo to a residue which is purified by column chromatography on silica gel using 1:1 ethyl acetate-hexanes to all ethyl acetate to afford 0.716 g of residue which is dissolved in 30 ml of toluene and heated at reflux for 12 hours. The volatiles are evaporated in vacuo to afford a residue which is purified by high pressure liquid chromatography on silica gel using 1:2 ethyl acetate-hexanes to give 0.134 g of the first desired product as a pale yellow foam and 2 mg of the second desired product as a yellow glass. FAB MASS SPEC 812 (M+Na). 
     EXAMPLE 21 
     2-Butyl-6-(7-oxa-1-azabicyclo[3.2.1]oct-8-yl)-3-[[2&#39;-(1H-tetrazol-5-yl)[1,1&#39;-biphenyl]-4-yl]-methyl-4(3H)-quinazolinone 
     A mixture of 0.124 g of 2-butyl-6-(7-oxa-1-azabicyclo[3.2.1]oct-8-yl)-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl-4(3H)-quinazolinone in 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at reflux for 16 hours, cooled and concentrated in vacuo to a residue which is purified by column chromatography on silica gel using 9:1 chloroform-methanol to give 0.073 g of the desired product as a white solid. FAB MASS SPEC 548 (M+H). 
     EXAMPLE 22 
     2-Butyl-6-[(methylimino)methyl]-4(1H)-quinazolinone N 6  -oxide 
     To a stirred solution of 2.7 g of sodium methoxide in 50 ml of ethyl alcohol, cooled to 0° C. is added 4.1 g of N-methylhydroxylamine hydrochloride. After stirring for 10 minutes, 2.3 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde is rapidly added. The cooling bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are evaporated in vauco to a yellow solid residue which is stirred with water, filtered, the cake washed with water and air dried to afford 2.3 g of the desired product as a yellow solid, m.p. 206° C. 
     EXAMPLE 23 
     2-Butyl-6-[[(phenylmethyl)imino]methyl]-4(1H)-quinazolinone N 6  -oxide 
     This reaction is performed under the same conditions as Example 22 using 2.3 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde, 1.2 g of sodium methoxide, 25 ml of ethyl alcohol and 3.18 g of N-benzylhydroxylamine hydrochloride to give 2.9 g of the desired product as a yellow solid, m.p. 180° C. 
     EXAMPLE 24 
     2-Butyl-6-[(cyclohexylimino)methyl]-4(1H)-quinazolinone N 6  -oxide 
     This reaction is performed under the same conditions as Example 22 using 4.0 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazoline carboxaldehyde, 2.65 g of sodium methoxide, 150 ml of ethyl alcohol and 7.55 g of N-cyclohexylhydroxylamine hydrochloride to give 4.2 g of the desired product as a yellow solid. Mass Spec (EI) 327. 
     EXAMPLE 25 
     (3α,3aα,6aα) -2-butyl-6- (hexahydro-2-methyl-4-oxo-2H-cyclopent[d]isoxazol-3-yl-4(1H)-quinazolinone 
     A mixture of 1.0 g of 2-butyl-6-[(methylimino)methyl]-4(1H)-quinazolinone N 6  -oxide and 2 ml of 2-cyclopenten-3-one in 15 ml of toluene is heated at reflux for 8 hours then allowed to cool. The volatiles are evaporated in vacuo to give a residue which is purified by chromatography on silica gel using 60% ethyl acetate-hexanes to give 1.1 g of the desired product as a yellow solid, m.p. 182° C. 
     Examples 26-36 in Table I are prepared under substantially the same conditions as Example 25 from the appropriately substituted hydroxylamine, quinazolinone N 6  -oxide and olefin starting materials. 
     
                                           TABLE I__________________________________________________________________________ ##STR22##                        Starting      m.p. °C.Ex.                   Starting                        RNHOH.HCl                               Reaction                                      or MassNo.   R.sup.6     X      Olefin R      Time (Hours)                                      Spec.__________________________________________________________________________26    ##STR23##  (CH.sub.2).sub.3 CH.sub.3                 Cis-cyclo- octene                        CH.sub.3                               48     167°27    ##STR24##  (CH.sub.2).sub.3 CH.sub.3                 Cis-cyclo- octene                        CH.sub.3                               48     176-180°28    ##STR25##  (CH.sub.2).sub.3 CH.sub.3                 2(5H)-- furanone                        CH.sub.3                               24     190-193°29    ##STR26##  (CH.sub.2).sub.3 CH.sub.3                 Norbor- nylene                        CH.sub.3                               24     166°30    ##STR27##  (CH.sub.2).sub.3 CH.sub.3                 1-cyclohex- ene-3-one                        CH.sub.3                               48     186°31    ##STR28##  (CH.sub.2 ).sub.3 CH.sub.3                 cyclo- pentene                        CH.sub.3                               48     147-149°32    ##STR29##  (CH.sub.2).sub.3 CH.sub.3                 1-cyclopen- tene-3-one                        CH.sub.3                                8     182°33    ##STR30##  (CH.sub.2).sub.3 CH.sub.3                 1-cyclopen- tene-3-one                        PhCH.sub.2                               24     418(M + H)34    ##STR31##  (CH.sub.2).sub.3 CH.sub.3                 1-cyclopen- tene-3-one                        PhCH.sub.2                               24     418(M + H)35    ##STR32##  (CH.sub.2).sub.3 CH.sub.3                 2(5H)- furanone                        PhCH.sub.2                               24     176°36    ##STR33##  (CH.sub.2).sub.3 CH.sub.3                 2(5H)- furanone                        PhCH.sub.2                               24     151°__________________________________________________________________________ 
    
     EXAMPLES 37 AND 38 
     (3α,3aα,6aα)-2-butyl-6-(hexahydro-2-methyl-4-oxofuro[3,4-d]isoxazol-3-yl)-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone and 
     (3α,3aα,6aα) -2-butyl-6-(hexahydro-2-methyl-4-oxofuro[3,4-d]isoxazol-3-yl)-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone isomer 2 
     A mixture of 343 mg of (3α,3aα,6aα)-2-butyl-6-(hexahydro-2-methyl-4-oxofuro[3,4-d]isoxazol-3-yl)-4(1H)-quinazolinone, 552 mg of 5-[4&#39;-(bromomethyl)[1,1&#39;-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole and 2 g of K 2  CO 3  in 200 ml of acetone is heated at reflux for 24 hours. The reaction mixture is filtered and the filtrate evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexanes to give 400 mg of the first desired product as a solid and 250 mg of the second desired product as a solid. 
     Examples 39-47 in Table II are prepared under substantially the same conditions as Examples 37 and 38 from the appropriately substituted quinazolinone starting materials. 
     
                       TABLE II______________________________________ ##STR34##                          Ex. No.                                 m.p. °C.Ex.                            S.     or MassNo.  R.sup.6        X          Material                                 Spec.______________________________________39 ##STR35##     (CH.sub.2).sub.3 CH.sub.3                          31     803 (M + H)40 ##STR36##     (CH.sub.2).sub.3 CH.sub.3                          29     829 (M + H)41 ##STR37##     (CH.sub.2).sub.3 CH.sub.3                          30     831 (M + H)42 ##STR38##     (CH.sub.2).sub.3 CH.sub.3                          27     846 (M + H)43 ##STR39##     (CH.sub.2).sub.3 CH.sub.3                          32     893 (M + H)44 ##STR40##     (CH.sub.2).sub.3 CH.sub.3                          33     894 (M + H)45 ##STR41##     (CH.sub.2).sub.3 CH.sub.3                          36     895 (M + H)46 ##STR42##     (CH.sub.2).sub.3 CH.sub.3                          35     895 (M + H)47 ##STR43##     (CH.sub.2).sub.3 CH.sub.3                          34     893 (M + H)______________________________________ 
    
     EXAMPLE 48 
     (3α,3aα,6aα)-2-butyl-6-(hexahydro-2-methyl-4-oxo-2H-cyclopent[d]-isoxazol-3-yl)-3-[[2&#39;-(1H-tetrazol-5-yl)[1,1&#39;-biphenyl]-4-yl]methyl-4(3H)-quinazolinone 
     A mixture of 250 mg of (3α,3aα,6aα)-2-butyl-6-(hexahydro-2-methyl-2H-cyclopent[d]-isoxazol-3-yl)-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 50 ml of 1:1 tetrahydrofuran-methanol is heated at reflux for 18 hours. The volatiles are evaporated in vacuo and the residue is purified by chromatography on silica gel thick layer plates using a solvent system of 60:20:20:5 ethyl acetate-hexanes-chloroform-methanol to give 110 mg of the desired product. m.p. 118° C. 
     Examples 49-57 in Table III are prepared under substantially the same conditions as Example 48 from the appropriately substituted quinazolinone starting materials. 
     
                       TABLE III______________________________________ ##STR44##                          Ex. No.                                 m.p. °C.Ex.                            S..    or MassNo.  R.sup.6        X          Material                                 Spec.______________________________________49 ##STR45##     (CH.sub.2).sub.3 CH.sub.3                          41     126°50 ##STR46##     (CH.sub.2).sub.3 CH.sub.3                          39     562  (M + H)51 ##STR47##     (CH.sub.2).sub.3 CH.sub.3                          40      86°52 ##STR48##     (CH.sub.2).sub.3 CH.sub.3                          42     603 (M + H)53 ##STR49##     (CH.sub.2).sub.3 CH.sub.3                          38     160- 165°54 ##STR50##     (CH.sub.2).sub.3 CH.sub.3                          37     150°55 ##STR51##     (CH.sub.2).sub.3 CH.sub.3                          47      99°56 ##STR52##     (CH.sub.2).sub.3 CH.sub.3                          46     138°57 ##STR53##     (CH.sub.2).sub.3 CH.sub.3                          45     149°______________________________________ 
    
     Angiotensin II Antagonists In Vitro Tests 
     Materials and Methods 
     Beef adrenals are obtained from a local slaughter house (maxwell-Cohen). [ 125  I](Sar 1 ,Ile 8 )AngII, S.A. 2200 Ci/mmole, is purchased from Dupont (NEN®, Boston, Mass.). All unlabeled AngII analogs, Dimethylsulfoxide (DMSO), nucleotides, bovine serum albumin (BSA) are purchased from Sigma Chemical Co., St. Louis, Mo. U.S.A. 
     Preparation of Membranes 
     Approximately sixteen (16) to twenty (20) beef adrenal glands are processed as follows: fresh adrenal glands received on crushed ice are cleaned of fatty tissues and the tough membranes encapsulating the glands are removed and discarded. The brownish tissue forming the adrenal cortex is scraped off and finely minced with scissors before homogenization. Care is taken to avoid contamination with medullary tissue during dissection. The scraped cortices are suspended in twenty volumes of an ice-cold buffer medium consisting of 10 mM Tris.HCl (pH 7.4 at 22° C.) and containing 1.0 mM EDTA and 0.2M sucrose. Unless otherwise indicated, all subsequent operations are done at 4° C. The tissue is homogenized in a glass homogenizer with a motor-driven teflon pestle with a clearance of 1.0 mm. The homogenate is centrifuged first at low speed (3,000× g) for 10 min. The resulting pellet is discarded and the supernatant fluid recentrifuged at 10,000× g for 15 minutes to give a P 2  pellet. This P 2  pellet is discarded and the liquid phase is carefully decanted off in clean centrifuge tubes and recentrifuged at high speed (100,000× g) for 60 min. The translucent final pellet is harvested and combined in a small volume (20-50.0 ml) of 50.0 mM Tris.HCl buffer, pH 7.2. A 100 ul aliquot is withdrawn and the protein content of the preparation is determined by the Lowry&#39;s method (Lowry, O. H., Rosebrough, N. F., Parr, A. L. and Randall, R. J., Protein measurement with Folin phenol reagent. J. Biol. Chem., 48, 265-275; 1951). The pelleted membrane is reconstituted in 50.0 mM Tris.HCl buffer containing 0.1 mM of phenylmethylsulfonyl fluoride (PMSF) to give approximately a protein concentration of 2.5 mg per ml of tissue suspension. The membrane preparation is finally aliquoted in 1.0 ml volumes and stored at -70° C. until use in the binding assays. 
     Receptor Binding Assay 
     Binding of [ 125  I](Sar 1 ,Ile 8 )AngII 
     The binding of [ 125  I](Sar 1 ,Ile 8 )AngII to microsomal membranes is initiated by the addition of reconstituted membranes (1:10 vols.) in freshly made 50.0 mM Tris.HCl buffer, pH 7.4 containing 0.25% heat inactivated bovine serum albumin (BSA): 80 ul membrane protein (10 to 20 ug/assay) to wells already containing 100 ul of incubation buffer (as described above) and 20 ul [ 125  I](Sar 1 ,ILE 8 )AngII (Specific Activity, 2200 Ci/mmole). Non-specific binding is measured in the presence of 1.0 uM unlabeled (Sar 1 ,ILE 8 )AngII, added in 20 ul volume. Specific binding for [ 125  I](Sar 1 ,Ile 8 ) AngII is greater than 90%. In competition studies, experimental compounds are diluted in dimethylsulfoxide (DMSO) and added in 20 ul to wells before the introduction of tissue membranes. This concentration of DMSO is found to have no negative effects on the binding of [ 125  I] (Sar 1 ,Ile 8 ) AngII to the membranes. Assays are performed in triplicate. The wells are left undisturbed for 60 min. at room temperature. Following incubation, all wells are harvested at once with a Brandel® Harvester especially designed for a 96 well plate (Brandel® Biomedical Research &amp; Development Labs. Inc., Gaithersburg, Md., U.S.A.). The filter discs are washed with 10×1.0 ml of cold 0.9% NaCl to remove unbound ligand. Presoaking the filter sheet in 0.1% polyethyleneimine in normal saline (PEI/Saline) greatly reduces the radioactivity retained by the filter blanks. This method is routinely used. The filters are removed from the filter grid and counted in a Parkard® Cobra Gamma Counter for 1 min. (Packard Instrument Co., Downers Grove, Ill., U.S.A.). The binding data are analyzed by the non-linear interactive &#34;LUNDON-1&#34; program (LUNDON SOFTWARE Inc., Cleveland, Ohio U.S.A.). Compounds that displace 50% of the labelled angiotensin II at the screening dose of 50 μM are considered active compounds and are then evaluated in concentration-response experiments to determine their IC 50  values. The results are shown in Table IV. 
     
                       TABLE IV______________________________________ ##STR54##                           Angiotensin IIEx.                             ReceptorNo.  R.sup.6         X          Binding IC.sub.50 (M)______________________________________18 ##STR55##      (CH.sub.2).sub.3 CH.sub.3                            4.2 × 10.sup.-821 ##STR56##      (CH.sub.2).sub.3 CH.sub.3                            1.6 × 10.sup.-848 ##STR57##      (CH.sub.2).sub.3 CH.sub.3                            5.7 × 10.sup.-849 ##STR58##      (CH.sub.2).sub.3 CH.sub.3                           88.0 × 10.sup.-850 ##STR59##      (CH.sub.2).sub.3 CH.sub.3                            9.9 × 10.sup.-851 ##STR60##      (CH.sub.2).sub.3 CH.sub.3                           15.0 × 10.sup.-852 ##STR61##      (CH.sub.2).sub.3 CH.sub.3                           18.0 × 10.sup.-853 ##STR62##      (CH.sub.2).sub.3 CH.sub.3                            7.1 × 10.sup.-854 ##STR63##      (CH.sub.2).sub.3 CH.sub.3                           16.0 × 10.sup.-855 ##STR64##      (CH.sub.2).sub.3 CH.sub.3                            7.8 × 10.sup.-856 ##STR65##      (CH.sub.2).sub.3 CH.sub.3                            9.4 × 10.sup.-857 ##STR66##      (CH.sub.2).sub.3 CH.sub.3                           18.0 × 10.sup.-8______________________________________ 
    
     As can be seen from Table IV, the compounds demonstrate excellent Angiotensin II Receptor Binding activity. 
     The enzyme renin acts on a blood plasma α 2  -globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin converting enzyme to AII. The substance AII is a powerful vasopressor agent which is implicated as a causative agent for producing high blood pressure in mammals. Therefore, compounds which inhibit the action of the hormone angiotensin II (AII) are useful in alleviating angiotensin induced hypertension. 
     The compounds of this invention inhibit the action of AII. By administering a compound of this invention to a rat, and then challenging with angiotensin II, a blockage of the vasopressor response is realized. The results of this test on representative compounds of this invention are shown in Table II. 
     AII Challenge 
     Conscious Male okamoto-Aoki SHR, 16-20 weeks old, weighing approximately 330 g are purchased from Charles River Labs (Wilmington, Mass.). Conscious rats are restrained in a supine position with elastic tape. The area at the base of the tail is locally anesthetized by subcutaneous infiltration with 2% procaine. The ventral caudal artery and vein are isolated, and a cannula made of polyethylene (PE) 10-20 tubing (fused together by heat) is passed into the lower abdominal aorta and vena cava, respectively. The cannula is secured, heparinized (1,000 I.U./ml), sealed and the wound is closed. The animals are placed in plastic restraining cages in an upright position. The cannula is attached to a Statham P23Db pressure transducer, and pulsatile blood pressure is recorded to 10-15 minutes with a Gould Brush recorder. (Chan et al., (Drug Development Res., 18:75-94, 1989). Angiotensin II (human sequence, Sigma Chem. Co., St. Louis, Mo.) of 0.05 and 0.1 ug/kg i.v. is injected into all rats (predosing response). Then a test compound, vehicle or a known angiotensin II antagonist is administered i.v., i.p. or orally to each set of rats. The two doses of angiotensin II are given to each rat again at 30, 60, 90, 120, 180, 240 and 300 minutes post dosing the compound or vehicle. The vasopressor response of angiotensin II is measured for the increase in systolic blood pressure in mmHg. The percentage of antagonism or blockade of the vasopressor response of angiotensin II by a compound is calculated using the vasopressor response (increase in systolic blood pressure) of angiotensin II of each rat predosing the compound as 100%. A compound is considered active if at 30 mg/kg i.v. it antagonized at least 50% of the response. 
     
         __________________________________________________________________________ANGIOTENSIN II (AII) VASOPRESSOR RESPONSE  Dose AII Dose             Min Post                  Control                        Response   Average                                        &amp;  (mg/kg)       mcg/kg IV             Dose Before AII                        After AII                              Change                                   Change                                        Inhibition__________________________________________________________________________SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body Weight(s): 355, 340 gramsCONTROL     0.05   0   220   275   55   47.5                  190   230   40       0.1        215   275   60   50                  190   230   40Ex. No.   3 I.V.       0.05   30  185   210   25   15   6818                     230   235    5       0.1        230   245   15   12.5 75                  190   200   10       0.05   60  220   250   30   22.5 53                  190   205   15       0.1        220   250   30   20   60                  190   200   10       0.05   90  230   260   30   25   47                  190   210   20       0.1        250   280   30   27.5 45                  190   215   25       0.05  120  200   220   20   45    5                  190   260   70       0.1        200   225   25   50    0                  190   265   75       0.05  180  230   255   25   20   58                  180   195   15       0.1        230   260   30   25   50                  220   240   20SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 330, 340 grams       0.05  240  220   240   20   17.5 63                  185   200   15       0.1        220   270   50   45   10                  180   220   40       0.05  300  210   250   40   42.5 11                  165   210   45       0.1        230   270   40   27.5 45                  180   195   15CONTROL     0.05   0   255   315   60   47.5                  230   265   35       0.1        260   322   62   57Ex. No.   1 I.V.       0.05   30  250   270   20   22.5 5321                     200   225   25       0.1        260   290   30   27   53                  220   244   24       0.05   60  250   265   15   15   68                  220   235   15       0.1        250   285   35   25   56                  225   240   15       0.05   90  260   285   25   17.5 63                  225   235   10       0.1        255   295   40   27.5 52                  225   240   15SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 360, 330 grams       0.05  120  255   275   20   17.5 63                  215   230   15       0.1        250   270   20   22.5 61                  220   245   25       0.05  180  245   265   20   17.5 63                  215   230   15       0.1        240   275   35   30   47                  215   240   25       0.05  240  240   270   30   27.5 42                  225   250   25       0.1        245   270   25   22.5 61                  225   245   20       0.05  300  235   265   30   30   37                  215   245   30       0.1        245   280   35   37.5 34                  220   260   40CONTROL  0.05  0    200  245   45    37.5                  180   210   30       0.1        205   250   45   42.5                  175   215   40Ex. No.   3 I.V.       0.05   30  200   205    5   2.5  9348                     170   170    0       0.1        205   210    5   2.5  94                  160   160    0SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 360, 330 grams       0.05   60  200   200    0   0    100                  165   165    0       0.1        195   202    7   6    86                  160   165    5       0.05   90  190   195    5   5    87                  165   170    5       0.1        190   205   15   10   76                  180   185    5       0.05  120  210   215    5   4    89                  170   173    3       0.1        205   215   10   7.5  82                  170   175    5       0.05  180  190   205   15   15   60                  160   175   15       0.1        185   215   30   22.5 47                  170   185   15       0.05  240  195   210   15   15   60                  170   185   15       0.1        200   215   15   22.5 47                  160   190   30       0.05  300  185   210   25   20   47                  165   180   15       0.1        200   215   15   27.5 35                  150   190   40SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 270, 280 gramsCONTROL     0.05   0   205   242   37   41                  190   235   45       0.1        210   255   45   47.5                  190   240   50Ex. No.   5 P.O.       0.05   30  205   210    5   10   7648                     195   210   15       0.1        195   210   15   16   66                  190   207   17       0.05   60  200   205    5   10   76                  185   200   15       0.1        195   205   10   12.5 74                  185   200   15       0.05   90  185   202   17   8.5  79                  195   195    0       0.1        190   202   12   7    85                  195   197    2       0.05  120  205   205    0   4    90                  190   198    8       0.1        207   207    0   5    89                  185   195   10       0.05  180  185   185    0   7.5  82                  185   200   15       0.1   185  190    5    12.5 74                  180   200   20SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 280, 290 grams       0.05  240  185   185    0   2.5  94                  180   185    5       0.1        180   190   10   10   79                  180   190   10       0.05  300  200   205    5   3    93                  175   176    1       0.1        190   200   10   10   79                  175   185   10CONTROL     0.05   0   152   200   48   44                  190   230   40       0.1        160   215   55   52.5                  190   240   50Ex. No.   1 I.V.       0.05   30  165   180   15   15   6648                     195   210   15       0.1        165   190   25   25   52                  190   215   25       0.05   60  160   180   20   20   55                  190   210   20       0.1        170   185   15   15   71                  195   210   15       0.05   90  157   185   28   26.5 40                  190   215   25       0.1        175   195   20   25   52                  195   225   30SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 350, 330 grams       0.05  120  170   195   25   22.5 49                  195   215   20       0.1        175   205   30   36   31                  183   225   42       0.05  180  165   200   35   27.5 38                  175   195   20       0.1        175   215   40   32.5 38                  175   200   25       0.05  240  175   215   40   32.5 26                  175   200   25       0.1        175   218   43   35.5 32                  175   203   28       0.05  300  170   217   47   36   18                  175   200   25       0.1        172   210   38   36.5 30                  175   210   35CONTROL     0.05   0   196   232   36   38                  195   235   40       0.1        182   235   53   54                  170   225   55Ex. No.  10 I.V.       0.05   30  200   200    0   0    10049                     155   155    0       0.1        192   205   13   6.5  88                  160   160    0       0.05   60  185   185    0   1    97                  175   177    2       0.01       175   185   10   7.5  86                  165   170    5       0.05   90  170   175    5   5    87                  160   165    5       0.1        170   175    5   7.5  86                  150   160   10       0.05  120  174   180    6   5.5  86                  175   180    5                  170   180   10   10   81                  165   175   10       0.05  180  180   190   10   12.5 67                  165   180   15       0.1        175   195   20   20   63                  170   190   20SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 330, 330 gramsCONTROL     0.05   0   207   250   43   34                  205   230   25       0.1        200   250   50   42.5                  205   250   35Ex. No.   5 P.O.       0.05   30  200   233   33   21.5 3749                     200   210   10       0.1        203   236   33   26.5 38                  195   215   20       0.05   60  195   215   20   14   59                  202   210    8       0.1        195   235   40   30   29                  195   215   20       0.05   90  195   210   15   15   56                  190   205   15       0.1        190   205   15   17.5 59                  200   220   20       0.05  120  185   210   25   20   41                  190   205   15       0.1        195   218   23   19   55                  195   210   15       0.05  180  200   215   15   12.5 63                  200   210   10       0.1        195   235   40   27.5 35                  195   210   15SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 310, 305 grams       0.05  240  200   230   30   22.5 34                  185   200   15       0.1        200   235   35   27   36                  186   205   19CONTROL     0.05   0   200   270   70   55                  240   280   40       0.1        200   265   65   55                  235   280   45Ex. No.   3 I.V.       0.05   30  200   235   35   20   6450                     225   230    5       0.1        210   235   25   18.5 66                  218   230   12       0.05  60   195   218   23   16.5 70                  210   220   10       0.1        200   225   25   19   65                  220   233   13       0.05   90  190   202   12   11   80                  215   225   10       0.1        190   225   35   26.5 52                  220   238   18       0.05  120  185   207   22   18.5 66                  210   225   15       0.1        185   210   25   14   75                  210   213    3       0.05  180  200   225   25   22.5 59                  200   220   20       0.1        190   220   30   17.5 68                  220   225    5SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 315, 370 gramsCONTROL     0.05   0   195   235   40   42.5                  185   230   45       0.1        200   240   40   42.5                  190   235   45Ex. No.   5 P.O.       0.05   30  200   215   15   22.5 4750                     195   225   30       0.1        198   227   29   32   25                  185   220   35       0.05   60  205   225   20   22.5 47                  185   210   25       0.1        210   228   18   29   32                  185   225   40       0.05   90  200   230   30   20   53                  180   190   10       0.1        200   230   30   20.5 52                  185   196   11       0.05  120  203   220   17   13.5 68                  190   200   10       0.1        205   240   35   22.5                  185   195   10       0.05  180  185   220   35   27.5 35                  160   180   20       0.1        205   240   35   35   18                  160   195   35SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 300, 320 gramsCONTROL     0.05   0   215   240   25   30                  200   235   35       0.1        205   237   32   41Ex. No.   1 I.V.       0.05   30  190   220   30   25   1750                     190   210   20       0.1   185  215   30    25   39                  190   210   20       0.05   60  190   220   30   25   17                  180   200   20       0.1        185   220   35   30   27                  185   210   25       0.05   990 190   225   35   24   20                  180   193   13       0.1        190   230   40   37.5  9                  180   215   35       0.05  120  190   225   35   25   17                  180   195   15       0.1        207   240   33   26.5 35                  180   200   20       0.05  180  220   245   25   22.5 25                  195   215   20       0.1        225   250   25   27.5 33                  185   215   30SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 340, 340 grams       0.05  240  185   230   45   32.5 -8                  185   205   20       0.1        195   250   55   47.5 -16                  175   215   40       0.05  300  185   240   55   37.5 -25                  190   210   20       0.1        191   244   53   45.5 -11                  180   218   38CONTROL     0.05   0   160   198   38   45                  170   222   52       0.1        165   232   67   61                  185   240   55Ex. No.   3 I.V.       0.05   30  185   185    0   5    8951                     175   185   10       0.1        170   183   13   8    87                  180   183    3       0.05   60  165   195   30   16.5 63                  170   173    3       0.1        175   195   20   11   82                  175   177    2       0.05   90  165   177   12   10   78                  175   183    8       0.1        185   205   20   12.5 80                  180   185    5SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 300, 290 grams       0.05  120  165   175   10   7.5  83                  165   170    5       0.1        165   186   21   15.5 75                  180   190   10       0.05  180  165   180   15   15   67                  170   185   15       0.1        165   190   25   22.5 63                  165   185   20CONTROL     0.05   0   220   265   45   37.5                  210   240   30       0.1        220   265   45   42.5                  200   240   40Ex. No.   3 I.V.       0.05   30  220   225    5   4    8952                     200   203    3       0.1        220   230   10   10   76                  195   205   10       0.05   60  220   225    5   7.5  80                  190   200   10       0.1        205   225   20   17.5 59                  185   200   15       0.05   90  200   242   42   28.5 24                  190   205   15       0.1        210   240   30   20   53                  185   195   10SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 300, 330 grams       0.05  120  225   250   25   14   63                  190   193    3       0.1        225   250   24   17.5 59                  195   205   10       0.05  180  200   230   30   30   20                  190   220   30       0.1        225   265   40   37.5 12                  190   225   35       0.05  240  225   255   30   27.5 27                  180   205   25       0.1        235   260   25   22.5 47                  180   200   20       0.05  300  225   250   25   33                  180   205   25       0.1        225   260   35   36   15                  183   220   37CONTROL     0.05   0   195   232   37   40                  192   235   43       0.1        185   235   50   42.5                  200   235   35Ex. No.   5 P.O.       0.05   30  195   200    5   10   7553                     195   210   15       0.1        195   200    5   17.5 59                  185   215   30SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 300, 330 grams       0.05   60  175   175    0   7.5  81                  185   200   15       0.1        175   190   15   20   53                  185   210   25       0.05   90  170   170    0   5    88                  180   190   10       0.1        170   175    5   10   76                  175   190   15       0.05  120  165   165    0   1    98                  175   185   10       0.1        165   177   12   11   74                  175   185   10       0.05  180  165   165    0   1.5  96                  175   178    3       0.1        165   170    5   9    79                  170   183   13       0.05  240  160   170   10   12.5 69                  160   175   15       0.1        165   180   15   12.5 71                  175   185   10       0.05  300  155   165   10   6.5  84                  170   173    3       0.1        155   175   20   20   53                  155   175   20SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 340, 335 gramsCONTROL     0.05   0   180   218   38   39                  185   225   40       0.1        175   225   50   49Ex. No.    3 I.V.       0.05   30  185   190    5   10   7453                     185   200   15       0.1        180   190   10   9.5  81                  183   192    9       0.05   60  175   175    0   0.5  99                  184   185    1       0.1        200   200    0   2.5  95                  200   205    5       0.05   90  170   185   15   12.5 68                  180   190   10       0.1        180   198   18   16.5 66                  183   198   15       0.05  120  175   190   15   22.5 42                  180   210   30       0.1        180   205   25   17.5 64                  190   200   10       0.05  180  185   190    5   9    77                  185   198   13       0.1        195   210   15   17.5 64                  180   200   20SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 330, 380 grams       0.05  240  175   200   25   25   36                  185   210   25       0.1        175   210   35   27.5 44                  190   210   20       0.05  300  178   198   20   49                  175   195   20       0.1        175   205   30   30   39                  175   205   30CONTROL     0.05   0   230   275   45   45                  240   285   45       0.1        220   280   60   55                  240   290   50Ex. No.   3 I.V.       0.05   30  235   235    0   1.5  9755                     235   238    3       0.1        225   230    5   2.5  95                  240   240    0       0.05   60  230   230    0   0    100                  240   240    0       0.1        225   230   5    2.5  95                  240   240    0       0.05   90  230   235    5   5    89                  237   242   5       0.1        220   225    5   5    91                  235   240    5SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 330, 345 grams       0.05  120  225   225    0   1.5  97                  232   235    3       0.1        215   222    7   3.5  94                  235   235    0       0.05  180  220   225    5   2.5                  240   240    0       0.1        215   225   10   12.5 77                  230   245   15       0.05  240  220   225    5   5    89                  240   245   5       0.1        220   230   10   10   82                  240   250   10       0.05  300  210   230   20   17.5 61                  225   240   15       0.1        220   240   20   27.5 50                  215   250   35CONTROL     0.05   0   230   260   30   35                  200   240   40       0.1        220   260   40   45                  200   250   50Ex. No.   3 P.O.       0.05   30  225   240   15   27.5 2155                     195   235   40       0.1        220   250   30   37.5 17                  195   240   45SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 310, 330 grams       0.05   60  210   240   30   32.5  7                  215   250   35       0.1        215   255   40   40   11                  205   245   40       0.05   90  205   230   25   30   14                  210   245   35       0.1        215   245   30   37.5 17                  205   250   45       0.05  120  205   220   15   27.5 21                  205   245   40       0.1        205   230   25   27.5 39                  210   240   30       0.05  180  205   240   35   30   14                  205   230   25       0.1        210   240   30   32.5 28                  205   240   35CONTROL     0.05   0   210   245   35   27.5                  220   240   20       0.1        220   255   35   31                  230   257   27Ex. No.   3 P.O.       0.05   30  215   238   23   19   3156                     215   230   15       0.1        220   245   25   27.5 11                  210   240   30SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 300, 310 grams       0.05   60  215   230   15   22.5 18                  200   230   30       0.1        210   240   30   25   19                  210   230   20       0.05   90  205   225   20   17.5 36                  215   230   15       0.1        200   230   30   25   19                  215   235   20       0.05  120  205   230   25   17.5 36                  210   220   10       0.1        200   230   30   22.5 27                  220   235   15       0.05  180  195   235   40   30   -9                  220   240   20       0.1        200   230   30   30    3                  215   245   30CONTROL     0.05   0   245   280   35   32.5                  225   255   30       0.1        240   285   45   45                  220   265   45Ex. No.   3 I.V.       0.05   30  245   245    0   0    10056                     220   220    0       0.1        240   240    0   0    100                  220   220    0CONTROL     0.05   60  240   240    0   0    100                  190   190    0       0.1        230   235    5   5    89                  185   190    5       0.05   90  230   230    0   0    100                  190   190    0       0.1        235   240    5   5    89                  180   185    5       0.05  120  225   240   15   7.5  77                  195   195    0       0.1        235   245   10   10   78                  195   205   10       0.05  180  225   235   10   7.5  77                  195   200    5       0.1        230   242   12   11   76                  195   205   10       0.05  240  235   245   10   9    72                  185 193                         8       0.1        235   260   25   20   56                  195   210   15       0.05  300  230   240   10   11.5 65                  195   208   13       0.1        240   245    5   15   67                  190   215   25SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 320, 320 gramsCONTROL     0.05   0   220   265   45   35                  220   245   25       0.1        215   270   55   40                  225   250   25Ex. No.   3 I.V.       0.05   30  210   210    0   0    10057                     220   220    0       0.1        210   211    1   0.5  99                  215   215    0       0.05   60  230   230    0   0    100                  215   215    0       0.1        220   230   10   5    88                  215   215    0       0.05   90  230   235    5   2.5  93                  215   215    0       0.1        205   225   20   10   75                  215   215    0       0.05  120  208   215    7   3.5  90                  210   210    0       0.1        205   220   15   7.5  81                  220   220    0       0.05  180  195   220   25   13.5 61                  210   212    2       0.1        210   230   20   10   75                  215   215    0SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 310, 325 grams       0.05  240  230   240   10   8    77                  214   220    6       0.1        220   240   20   17.5 56                  210   225   15       0.05  300  210   225   15   10   71                  215   220    5       0.1        210   235   25   25   38                  210   235   25CONTROL     0.05   0   214   250   36   38                  215   255   40       0.1        210   260   50   47.5                  220   265   45Ex. No.   3 P.O.       0.05   30  210   235   25   25   3457                     210   235   25       0.1        210   240   30   30   37                  210   240   30       0.05   60  215   230   15   12.5 67                  225   235   10       0.1        210   240   30   22.5 53                  220   235   15       0.05   90  205   220   15   20   47                  205   230   25       0.1        210   230   20   25   47                  210   240   30SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 310, 325 grams       0.05  120  210   240   30   22.5 41                  205   220   15       0.1        215   240   25   17.5 63                  210   220   10       0.05  180  195   238   43   34   11                  215   240   25       0.1        210   240   30   22.5 53                  225   240   15__________________________________________________________________________