Novel quinazolinone compounds of the formula: ##STR1## wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8, R and X are defined in the specification, which have angiotensin II (AII) antagonizing activity, intermediates useful in the preparation of the compounds, methods of producing and using the compounds to alleviate angiotensin induced hypertension and treat congestive heart failure in mammals.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to certain novel 2, 3, 6 substituted quinazolinone 
compounds which have demonstrated enhanced in vivo activity as angiotensin 
II (AII) antagonists and are therefore useful in alleviating angiotensin 
induced hypertension and for treating congestive heart failure. 
2. Description of the Prior Art 
The enzyme renin acts on a blood plasma .alpha..sub.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. 
Furukawa et al., in U.S. Pat. No. 4,340,598, issued Jul. 20, 1982, 
discloses hypotensive and angiotensin II receptor blocking imidazole 
derivatives of the formula: 
##STR2## 
wherein R.sup.1 is lower alkyl or phenyl C.sub.1-2 alkyl optionally 
substituted with halogen or nitro; R.sup.2 is lower alkyl, cycloalkyl or 
phenyl optionally substituted; one of R.sup.3 and R.sup.4 is 
--(CH.sub.2).sub.n COR.sup.5 where R.sup.5 is amino, lower alkoxyl or 
hydroxyl and n is 0, 1, 2 and the other of R.sup.3 and R.sup.4 is hydrogen 
or halogen; provided that R.sup.1 is lower alkyl or phenethyl when R.sup.3 
is hydrogen, n=1 and R.sup.5 is lower alkoxyl or hydroxyl; and salts 
thereof. 
Furukawa et al., in European Patent Application No. 103,647 discloses 
4-chloro-2-phenylimidazole-5-acetic acid derivatives useful for treating 
edema and hypertension and have angiotensin II receptor blocking activity 
of the formula: 
##STR3## 
where R represents lower alkyl and salts thereof. 
D. J. Carini, et al. in published European Patent Applications No. 
87109919.8, filed Sep. 7, 1987 and No. 89100144.8, filed May 1, 1989 
disclose angiotensin II receptor blocking imidazoles of the formula: 
##STR4## 
wherein the definitions of the substituents may be found within the 
applications. 
P. Aldrich et al., in U.S. Pat. No. 4,874,867, issued Oct. 17, 1989, 
describes tetrazole intermediates of the formula: 
##STR5## 
wherein X.sup.2 and X.sup.1 are defined therein. These intermediates are 
described as useful for producing compounds which are useful as inhibitors 
of the hormone angiotensin II (AII). 
D. J. Carini et al., in U.S. Pat. No. 4,880,804, issued Nov. 14, 1989, 
described substituted benzimidazoles useful as inhibitors of the hormone 
angiotensin II (AII) of the formula: 
##STR6## 
wherein R.sup.1 is --CO.sub.2 H, --NHSO.sub.2 CF.sub.3, or 
##STR7## 
R.sup.2 is H, halogen, NO.sub.2, methoxy, or alkyl of 1 to 4 carbon atoms; 
R.sup.3 is alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 
carbon atoms both of which may be optionally substituted with a halogen 
atom, --OR.sup.4 or up to two --CO.sub.2 R.sup.4 ; with the proviso that 
when R.sup.3 is methyl, it must be substituted with --OR.sup.4 or 
--CO.sub.2 R.sup.4 ; R.sup.4 is H, or alkyl of 1-4 carbon atoms; A is H, 
alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C.sub.6 
F.sub.5, halogen, alkoxy of 1 to 6 carbon atoms; 
##STR8## 
B is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, 
C.sub.6 F.sub.5, halogen or alkoxy of 1 to 6 carbon atoms; X is a 
carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH.sub.2 --. 
D. J. Carini et al. in published European Patent Application No. 
89100142.2, filed May 1, 1989, discloses angiotensin II receptor blocking 
pyrroles, pyrazoles and triazoles such as: 
##STR9## 
There has been no teaching or suggestion that the heretofore known 
antagonists of AII have the quinazolinone structure. 
SUMMARY OF THE INVENTION 
According to the present invention, there are provided novel compounds of 
Formula I which have enhanced in vivo angiotensin II-antagonizing 
properties and are useful as antihypertensives: 
##STR10## 
wherein: R is 
##STR11## 
X is straight or branched alkyl of 3 to 5 carbon atoms; n is 1 to 3; 
R.sup.5 is H; 
R.sup.6 is 
##STR12## 
where R.sup.9 is H, straight chain lower alkyl of 1 to 4 carbon atoms, 
phenyl, substituted phenyl (substitution selection from mono-lower alkyl 
of 1 to 3 carbon atoms, --CF.sub.3, nitro, O-alkyl of 1 to 3 carbon atoms, 
NH.sub.2), pyridine, thiophene, or furan; 
R.sup.10 is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl, 
substituted phenyl (substitution selection from mono-lower alkyl of 1 to 3 
carbon atoms, --CF.sub.3, nitro, O-alkyl of 1 to 3 carbon atoms, 
NH.sub.2), pyridine, thiophene, or furan; 
provided, however, that R.sup.9 and R.sup.10 cannot both be H, 
R.sup.11 is H, straight chain or branched lower alkyl of 1 to 4 carbon 
atoms; 
R.sup.12 is straight chain lower alkyl of 1 to 4 carbon atoms, phenyl, 
substituted phenyl (substitution selection from mono-lower alkyl of 1 to 3 
carbon atoms, --CF.sub.3, nitro, O-alkyl of 1 to 3 carbon atoms, 
NH.sub.2), pyridine, thiophene, or furan; 
R.sup.17 is straight or branched lower alkyl of 1 to 4 carbon atoms; 
R.sup.7 and R.sup.8 are H; and pharmaceutically acceptable salts of these 
compounds. 
The present invention also provides novel intermediate compounds, methods 
for making the novel 2, 3, 6 substituted quinazolinone angiotensin II 
antagonizing compounds, methods for making the novel intermediates, 
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 Method A, the quinazolinone intermediates of Formula 5, are 
prepared from the corresponding substituted anthranilic acids 2 wherein 
the substituents R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are described 
hereinabove except R.sup.6 may not be: 
##STR13## 
The corresponding anthranilic acid 2 is heated to reflux in alkyl acid 
anhydride 3 wherein X is 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. To prepare compounds for which R.sup.6, has been excluded 
from this method, refer to Schemes I to X herein. 
##STR14## 
Referring to Method B, the method of B. Baker, et al., J. Org. Chem. 17, 
157 (1952) is used to convert the appropriate substituted aniline 6 into 
quinazolinone 5 wherein the substituents R.sup.5, R.sup.6, R.sup.7 and 
R.sup.8 are described hereinabove except they may not be as follows: 
##STR15## 
The substituted aniline 6 is reacted with chloral and hydroxylamine 
hydrochloride to afford an oxime 7 which is cyclized to the isatin 8 in 
the presence of sulfuric acid. The isatin 8 is then hydrolyzed to the 
anthranilic acid 9 using 30% aqueous hydrogen peroxide and aqueous sodium 
hydroxide. Further reaction as in Method A yields the quinazolinone 
intermediate 5. To prepare compounds for which R.sup.6, has been excluded 
from this method, refer to Schemes I to X herein. 
##STR16## 
A general reference to the synthesis of 3,4-dihydro-4-oxo-quinazolines 5 is 
given in "The Chemistry of Heterocyclic Compounds, Fused Pyrimidines. Part 
I: Quinazolines", W. L. F. Armarego; Interscience Publishers (1967), pp. 
74-94. Additional references are described in "Heterocyclic Compounds", 
Vol. 6, p. 334, R. C. Elderfield (Editor), Wiley and Sons, 1957. 
Quinazolinone intermediates 5 are then modified according to the following 
schemes to obtain the novel 2, 3, 6 substituted quinazolinone Angiotensin 
II antagonizing compounds of the present invention. 
In Scheme I, 6-methylquinazolinone 10, as prepared by method A, is 
brominated with N-bromosuccinimide to give the bromomethyl compound 11. 
Hydrolysis of the bromide with aqueous potassium carbonate in 
dimethylsulfoxide yields the primary alcohol 12. 
The alcohol 12 is oxidized with pyridinium dichromate in 
N,N-dimethylformamide to afford aldehyde 13. The aldehyde 13 is reacted 
with a variety of Grignard Reagents R.sup.12 MgBr or lithium reagents 
R.sup.12 Li in tetrahydrofuran wherein R.sup.12 is selected from straight 
or branched alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl, 
pyridyl, thiophene and furan, to give the desired secondary alcohol 14. 
##STR17## 
In an alternate route to 13, as shown in Scheme II, 
2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 15, prepared by method A is 
reacted via a palladium catalyzed carbonylation to give aldehyde 13. 
Ester 16 is formed by palladium (II) catalyzed coupling of 
2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 15 with carbon monoxide and 
methanol. Further derivatization of 16 with an excess of Grignard R.sup.12 
MgX or R.sup.12 Li affords tertiary alcohol 17 where R.sup.12 is 
hereinbefore defined. 
##STR18## 
The synthetic pathway to tertiary alcohol substituted quinazolinones is 
shown in Scheme III. 
##STR19## 
As shown in Scheme III, the palladium (II) catalyzed coupling of 
(trimethylsilyl)acetylene with 
2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 15 yields the acetylenic 
quinazolinone 21. Desilylation of the acetylene with sodium hydroxide in 
water-methanol gives the terminal acetylene 22. Hydration with catalytic 
mercuric sulfate-sulfuric acid in acetic acid affords methyl ketone 23. 
Reduction of ketone 23 with sodium borohydride in ethanol gives secondary 
alcohol 24. Alternatively, methyl ketone 23 is reacted with Grignard 
reagents R.sup.12 MgBr or lithium reagent R.sup.12 Li where R.sup.12 is as 
defined before to yield tertiary alcohols 25. The palladium (II) catalyzed 
coupling of substituted acetylenes where R.sup.17 is defined as straight 
or branched lower alkyl of 1 to 4 carbon atoms with 
2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 15 yields the acetylenic 
quinazolinone 26. Hydration of 26 with catalytic mercuric sulfate-sulfuric 
acid in acetic acid gives ketone 27. Reduction of ketone 27 with sodium 
borohydride in ethanol gives secondary alcohol 28. Reaction of ketone 27 
with Grignard reagent R.sup.12 MgBr or lithium reagent R.sup.12 Li where 
R.sup.12 is as defined before yields alcohol 29. 
Carboxylic acid 77, prepared by Method A, as presented in Scheme IV, is 
converted to the ethyl ester 78 by reaction with ethyl alcohol containing 
a catalytic amount of sulfuric acid. Reduction of 78 with lithium aluminum 
hydride in tetrahydrofuran affords alcohol 79. Alcohol 79 is oxidized with 
pyridinium dichromate to yield aldehyde 80. 
##STR20## 
Reaction of aldehyde 80 with Grignard reagent R.sup.12 MgBr or lithium 
reagent R.sup.12 Li, where R.sup.12 is hereinbefore defined, affords 
alcohol 81. Also, ethyl ester 78 is reacted with Grignard reagent R.sup.12 
MgBr or lithium reagent R.sup.12 Li to give alcohol 82. 
The coupling of a quinazolinone intermediate 5 to a biphenyl tetrazole 84 
where R is as defined before, which are prepared by the methods of P. E. 
Aldrich et al., U.S. Pat. No. 4,874,867, issued Oct. 17, 1989, is 
illustrated in Scheme V. 
##STR21## 
The quinazolinone 5 and the biphenyl 84 are dissolved 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, sodium t-butoxide or potassium t-butoxide for 2-24 hours, at 
20.degree.-60.degree.. The obtained alkylated quinazolinones 85 may be 
purified by chromatography or used as is in further transformations and/or 
deprotection. 
In those cases where the R in the alkylated quinazolinones 85 is a trityl 
tetrazole, deprotection of the trityl group, as outlined in Scheme VI, is 
accomplished by refluxing an aqueous acetone solution of the alkylated 
quinazolinone 86 with a catalytic amount of hydrochloric acid or other 
suitable acid such as sulfuric, trifluoroacetic or hydrogen chloride for 
2-24 hours. The resulting tetrazoles 87 are isolated by flash 
chromatography or by trituration with ether and collection by filtration. 
##STR22## 
As shown in Scheme VII, alcohol 93 is reacted with an alkylating agent 
R.sup.17 I, wherein R.sup.17 is alkyl of 1 to 4 carbon atoms, n is 0 to 3 
and I is iodide, in the presence of a base, such as sodium hydride, to 
afford ethers 98. The intermediate ethers 98 are deblocked via dilute acid 
in acetone to give tetrazoles 99. 
##STR23## 
Alcohol 100, as shown in Scheme VIII, is prepared from 93 by dilute acid 
hydrolysis to remove the trityl protecting group, is reacted with the 
desired acid anhydride, (R.sup.17 CO).sub.2 O wherein R.sup.17 is defined 
as straight or branched lower alkyl of 1 to 4 carbon atoms or an acid 
chloride R.sup.17 COCl where n is 0 to 3 in the presence of a base such as 
pyridine to afford ester 101. 
Alcohol 93, is prepared via methods of Schemes I, II and XV. 
An alternate synthetic method of preparing 87 from 5 is illustrated in 
Scheme IX. 
##STR24## 
Quinazolinone 5 is alkylated in a solvent such as acetone in the presence 
of potassium carbonate with 
##STR25## 
wherein R.sup.40 is selected from I, Br or --OSO.sub.2 CF.sub.3 and B is 
selected from appropriate leaving groups such as I, Br, Cl, --OMs, --OTs 
or --OSO.sub.2 CF.sub.3 to give 108. Palladium or nickel catalyzed 
coupling of 108 with 109 where M can be --MgBr, --Sn(lower alkyl of 1 to 4 
carbon atoms or phenyl), Li or --Zn complex, affords 110 which is 
deprotected to give 87. 
Scheme X illustrates the method of preparing 109. Reaction of 
o-bromobenzonitrile with tri-n-butyltin azide affords 111. Further 
reaction of 111 with hydrogen chloride and trityl chloride gives 112. 
Reaction of 112 with a metal M such as magnesium, or n-BuLi or s-BuLi 
followed by ZnCl.sub.2 or (Me).sub.3 SnCl affords 109. 
##STR26## 
It will be appreciated that the chemical manipulations of R.sup.5, R.sup.6, 
R.sup.7 and R.sup.8 as outlined in Schemes I-X can be accomplished after 
alkylation as outlined in Scheme V. Additionally, it will also be 
appreciated that the chemical manipulations of R.sup.5, R.sup.6, R.sup.7 
and R.sup.8 as outlined in Schemes VII-VIII can be accomplished before 
alkylation as outlined in Scheme V. The reactions are performed in a 
solvent appropriate to the reagents and materials em-ployed 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 will frequently 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'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, hygroscopicity 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 
four 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 cyrstallography. 
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 can be understood 
further by the following examples, but should not constitute a limitation 
thereof. 
EXAMPLE 1 
2-Butyl-6-(methyl)-4(1H)-quinazolinone 
Method A 
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 quinazolone as a white 
solid. 
Method B: 
The procedure described by B. Baker et. al., J. Org. Chem. 17 157(1952) and 
Sandmeyer, Helv. Chim. Acta 2, 234(1919) is used. 
Examples 2-34 in Table 1 are prepared by using the appropriately 
substituted anthranilic acids by using synthetic method A or B described 
hereinabove. 
TABLE I 
______________________________________ 
##STR27## 
Ex. Synthesis 
No. R.sup.5 
R.sup.6 R.sup.7 
R.sup.8 
X Method MP .degree.C. 
______________________________________ 
2 H Br H H (CH.sub.2).sub.3 CH.sub.3 
A 111 
3 H H H H (CH.sub.2).sub.3 CH.sub.3 
A 129 
4 H Cl H H (CH.sub.2).sub.3 CH.sub.3 
A 194 
5 H I H H (CH.sub.2).sub.3 CH.sub.3 
A 257-258 
6 H I H I (CH.sub.2).sub.3 CH.sub.3 
A 267-268 
7 H CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
A 231-232 
8 H Cl H H (CH.sub.2).sub.3 CH.sub.3 
A 255-256 
9 H H H H (CH.sub. 2).sub.3 CH.sub.3 
A 185-187 
10 H CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
A * 
11 H OCH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
B 181-182.degree. C. 
12 H Cl H H (CH.sub.2).sub.3 CH.sub.3 
A 194.degree. C. 
______________________________________ 
*CI MASS SPEC MH.sup.+ 217 
EXAMPLE 13 
2-Butyl-7-carboethoxy-4(1H)-quinazolinone 
A mixture of 5.0 g of 2-butyl-7-carboxy-4(1H)-quinazolinone in 100 ml of 
absolute ethanol containing 2 ml of sulfuric acid is refluxed for 48 
hours. The solvent is evaporated in vacuo and the residue partitioned 
between water and chloroform. The organic layer is washed with aqueous 
saturated sodium bicarbonate, dried with anhydrous sodium sulfate, 
filtered and evaporated to a residue which crystallizes from ethyl 
acetate-hexane to afford 4.5 g of the desired product, mp 145.degree. C. 
EXAMPLE 14 
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 the next step 
without further purification. 
EXAMPLE 15 
2-Butyl-6-(hydroxymethyl)-4(1H)-quinazolinone 
To a suspension of 2.0 g of impure 
2-butyl-6-(bromomethyl)-4(1H)-quinazolinone 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 16 
2-Butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde 
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 17 
2-Butyl-6-(1-hydroxyethyl)-4(1H)-quinazolinone 
To a solution of 0.60 g of 
2-butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde in 30 ml of dry 
tetrahydrofuran, cooled to 0.degree. C. is added dropwise, 2.61 ml of a 
3.0M solution of methylmagnesium bromide in diethyl ether. The reaction is 
stirred at 0.degree. 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.sup.+). 
EXAMPLE 18 
2-Butyl-6-(1-hydroxypropyl)-4(1H)-quinazolinone 
To a solution of 0.25 g of 
2-butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde in 10 ml of dry 
tetrahydrofuran, cooled to 0.degree. C., is added 1.63 ml of 2.0M ethyl 
magnesium bromide in tetrahydrofuran. The reaction mixture is stirred for 
30 minutes at 0.degree. 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.sup.+). 
EXAMPLE 19 
2-Butyl-1,4dihydro-4-oxo-6-quinazoline-carboxaldehyde 
To a solution of 1.0 g of 2-butyl-1,4-dihydro-4-oxo-6-iodo-quinazoline and 
0.355 g of tetrakis(triphenylphosphine)palladium in 15 ml of 
tetrahydrofuran and 5 ml of N,N-dimethylformamide, heated to 55.degree. 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.degree.-244.degree. C. 
EXAMPLE 20 
2-Butyl-6-[(trimethylsilyl)ethylnyl]-4(1H)-quinazolinone 
To a solution of 1.0 g of 2-butyl-1,4-dihydro-4-oxo-6-iodo-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.degree. C. for 1 hour and them 65.degree. 
C. for 5 hours. Upon cooling, the reation mixture is concentrated in vacuo 
and the residue is 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(M.sup.+). 
EXAMPLE 21 
2-Butyl-6-[(trimethylsilyl)ethylnyl]-7-fluoro-4(1H)-quinazolinone 
The compound is prepared using the experimental conditions of Example 20 
starting from 7-fluoro-6-bromo-2-butyl-4(1H)-quinazolinone, m.p 
192.degree. C. 
EXAMPLE 22 
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.sup.+). 
EXAMPLE 23 
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.sup.+). 
EXAMPLE 24 
2-Butyl-6-(1-hydroxy-1-methylethyl)-4(1H)-quinazolinone 
To a solution of 4.00 g 6-acetyl-2-butyl-4(1H)-quinazolinone in 250 ml of 
dry tetrahydrofuran, cooled to 0.degree. C., is added dropwise 16.4 ml of 
3.0M methylmagnesium bromide in diethyl ether. The reaction is stirred at 
0.degree. C. for 0.5 hours and then allowed to warm to room temperature 
followed by quenching with 100 ml of saturated ammonium chloride solution. 
The mixture is diluted with 50 ml of water and extracted with ethyl 
acetate. The combined organic layers are washed with brine, dried over 
anhydrous magnesium sulfate, filtered and concentrated in vacuo. The 
residue is purified by flash chromatography on silica gel, eluting with 
100:0.25 chloroform-methanol to give 2.75 g of the desired product as a 
white solid. CI MASS SPEC 261(MH.sup.+). 
EXAMPLE 25 
2-Butyl-6-(1-hydroxyethyl)-4(1H)-quinazolinone 
To a suspension of 0.102 g of 6-acetyl-2-butyl-4(1H)quinazolinone in 10.0 
ml of ethanol is added 0.015 g of sodium borohydride. The reaction mixture 
is stirred for 1.5 hours at room temperature and then diluted with 50 ml 
of water. The aqueous layer is extracted with 5:1 chloroform-methanol and 
the combined organics dried over magnesium sulfate, filtered and 
concentrated in vacuo to yield 0.103 g of the desired product. CI MASS 
SPEC 247(MH.sup.+). 
EXAMPLE 26 
2-Butyl-6-ethyl-4(1H)-quinazolinone 
To a suspension of 0.278 g of 2-butyl-6-ethynyl-4(1H)quinazolinone in 8 ml 
of pyridine is added 0.080 g of 5% palladium-on-barium sulfate. The 
reaction is stirred under a hydrogen atmosphere for 48 hours, filtered, 
concentrated in vacuo and the residue purified by flash chromatography on 
silica gel eluting with ethyl acetate-hexanes to give 0.179 g of the 
desired product. CI MASS SPEC 231(MH.sup.+). 
EXAMPLE 27 
Methyl 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate 
To a solution of 1.00 g of 2-butyl-1,4-dihydro-4-oxo-6-iodoquinazoline 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.sup.+). 
EXAMPLE 28 
2-Butyl-6-(1-hydroxy-1-methylethyl)-4(1H)-quinazolinone 
To a solution of 0.075 g of methyl 
2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate in 5 ml of dry 
tetrahydrofuran, cooled to 0.degree. C., is added dropwise 0.51 ml of a 
solution of 3.0M methylmagnesium bromide in diethyl ether. The reaction is 
stirred at 0.degree. C. for 0.5 hours and then at room temperature for 1 
hour followed by quenching with 10 ml of saturated ammonium chloride 
solution. The resulting reaction mixture is diluted with 10 ml of water 
and extracted with ethyl acetate. 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 100:0.25 
chloroform-methanol to yield 0.055 g of the desired product as a white 
solid, m.p. 190.degree.-192.degree. C. 
EXAMPLE 29 
2-Butyl-6-(1-methylethenyl)-4(1H)-quinazolinone 
To a suspension of 3.66 g of methyltriphenylphosphonium bromide in 30 ml of 
dry tetrahydrofuran, cooled to -78.degree. C., is added dropwise 5.9 ml of 
a 1.73M solution of n-butyllithium in hexanes. Following complete 
addition, the reaction mixture is allowed to warm to room temperature and 
stirred for 15 minutes, until all the phosphonium bromide is dissolved. 
The reaction mixture is then recooled to -78.degree. C. and a suspension 
of 6-acetyl-2-butyl-4(1H)-quinazolinone in 15 ml of dry tetrahydrofuran is 
added. The reaction is allowed to warm to room temperature and stirred for 
24 hours followed by quenching with saturated ammonium chloride solution. 
After diluting with 10 ml of water, the aqueous layer is extracted with 
chloroform and the combined organics dried over magnesium sulfate, 
filtered and concentrated in vacuo. The residue is purified by flash 
chromatography on silica gel, eluting with 1:2 ethyl acetate-hexanes to 
give 0.23 g of the desired product as a white solid. CI MASS SPEC 
243(MH.sup.+ ). 
EXAMPLE 30 
2-Butyl-6-(hydroxyphenylmethyl)-4(1H)-quinazolinone 
To a stirred solution of 2.00 g of 
2-butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde in 100 ml of 
tetrahydrofuran, cooled at 0.degree. C., is added 13.0 ml of 2.0M 
phenyllithium and stirring continued 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.sup.+). 
EXAMPLE 31 
2-Butyl-6-(1-hydroxyethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1, 
1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
A suspension of 2.50 g of 2-butyl-6-(1-hydroxyethyl)-4(1H)-quinazolinone, 
6.79 g of 
5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole 
and 4.20 g of anhydrous potassium carbonate in 225 ml of dry acetone is 
heated at reflux for 16 hours. The reaction mixture is allowed to cool to 
room temperature, filtered and the filtrate evaporated in vacuo. The 
residue is purified by high pressure liquid chromatography on silica gel 
by eluting with 1:2 ethyl acetate-hexanes to afford 4.25 g of the desired 
product as a white solid, FAB M+H 723. 
Examples 32-48 in Table II are prepared under substantially the same 
alkylation conditions as Example 31 from the appropriately substituted 
quinazolinone starting materials. 
TABLE II 
__________________________________________________________________________ 
##STR28## 
Ex. FAB Low Resolution 
No. 
R.sup.5 
R.sup.6 R.sup.7 
R.sup.8 
X Mass Spectrum 
__________________________________________________________________________ 
32 H CH(OH)CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
723(M + H) 
33 H CH.sub.3 H H (CH.sub.2).sub.3 CH.sub.3 
693(M + H) 
34 H CH.sub.2 CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
707(M + H) 
35 H CH.sub.2 OH 
H H (CH.sub.2).sub.3 CH.sub.3 
709(M + H) 
36 H H H H (CH.sub.2).sub.3 CH.sub.3 
665(M + H) 
37 H CH(OH)CH.sub.2 CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
737(M + H) 
38 H (CH.sub.3).sub.2 OH 
H H (CH.sub.2).sub.3 CH.sub.3 
737(M + H) 
39 H CH.sub.3 H H (CH.sub.2).sub.3 CH.sub.3 
693(M + H) 
40 H H H H (CH.sub.2).sub.3 CH.sub.3 
665(M + H) 
41 H CO.sub.2 CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
737(M + H) 
42 H 
##STR29## 
H H (CH.sub.2).sub.3 CH.sub.3 
721(M + H) 
43 H CH(OCH.sub.3)CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
737(M + H) 
44 H CH(OCH.sub.3)C.sub.6 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
799(M + H) 
45 H CH(OH)C.sub.6 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
807(M + Na) 
46 H CH(OCH.sub.3)C.sub.2 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
751(M + H) 
47 H C(CH.sub.3).sub.2 OCH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
751(M + H) 
48 H Cl H H (CH.sub.2).sub.3 CH.sub.3 
609(M + H) 
__________________________________________________________________________ 
EXAMPLE 49 
2-Butyl-6-(1-hydroxyethyl)-3-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]m 
ethyl]-4(3H)-quinazolinone 
To a suspension of 2.00 g of 
2-butyl-6-(1-hydroxyethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1 
,1'biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 70 ml of 3:1 acetone-water 
is added one drop of 5% aqueous hydrochloric acid solution. The mixture is 
then heated at reflux for 16 hours. After cooling, the reaction mixture is 
concentrated in vacuo and the residue purified by flash chromatography on 
silica gel by elution with 9:1 chloroform-methanol to afford 0.915 g of 
the desired product as a white solid, m.p. 146.degree.-147.degree. C. 
Examples 50-57 in Table III are prepared under substantially the same 
conditions as Example 49 from the appropriately substituted quinazolinone 
starting materials. 
TABLE III 
__________________________________________________________________________ 
##STR30## 
Ex. 
No. 
R.sup.5 
R.sup.6 R.sup.7 
R.sup.8 
X MP .degree.C. 
FAB MS 
__________________________________________________________________________ 
50 H H H H (CH.sub.2).sub.3 CH.sub.3 
92 
51 H C(CH.sub.3).sub.2 OH 
H H (CH.sub.2).sub.3 CH.sub.3 
156-158 
52 H CH(OH)CH.sub.2 CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
138-140 
53 H CH.sub.2 OH 
H H (CH.sub.2).sub.3 CH.sub.3 
126-128 
54 H CH(OH)C.sub.6 H.sub.5 
H H (CH.sub.2).sub. 3 CH.sub.3 
543(M + H) 
55 H CH(OCH.sub.3)C.sub.2 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
509(M + H) 
56 H C(C.sub.6 H.sub.5)OCH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
557(M + H) 
57 H C(CH.sub.3).sub.2 OCH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
509(M + H) 
__________________________________________________________________________ 
EXAMPLE 58 
6-[1-(Acetyloxy)ethyl]-2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-y 
l]methyl]-4(3H)-quinazolinone 
To a solution of 1.00 g of 
2-butyl-6-(1-hydroxyethyl)-3-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]4-yl]m 
ethyl-4(3H)-quinazolinone in 2.0 ml of acetic anhydride at room temperature 
is added 2 drops of dry pyridine. The reaction is stirred at room 
temperature for 16 hours then evaporated in vacuo. The residue is purified 
by flash chromatography on silica gel eluting with 95:5 
chloroform-methanol to yield 0.059 g of the desired product as a white 
solid. FAB MASS SPEC 523(M+H). 
EXAMPLE 59 
2-Butyl-6-(1-methoxyethyl)-4-[[2'-(1H-tetrazol)-5-yl)[1,1'-biphenyl]-4-yl]m 
ethyl]-4(3H)-quinazolinone 
A mixture of 0.300 g of 
2-butyl-6-(1-methoxyethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-[ 
1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone in 20 ml of 3:1 
acetone-water containing 1 drop of 5% hydrochloric acid is heated at 
reflux for 16 hours and evaporated to a residue. The residue is purified 
on silica gel eluting with 95.5 chloroform-methanol to provide 0.171 g of 
the product as a white solid, mp 154.degree.-156.degree. C. 
EXAMPLE 60 
2-Butyl-6-(1-methoxyethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol)-5-yl][1 
,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone 
To a suspension of 0.044 g of a 60% dispersion of sodium hydride in mineral 
oil and 0.345 ml of methyl iodide in 5.0 ml of dry tetrahydrofuran at room 
temperature is added 0.400 g of 
2-butyl-6-(1-hydroxyethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-[ 
1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in one portion. The 
reaction is stirred at room temperature for 18 hours and then poured onto 
a pad of silica gel. Elution with 1:3 ethyl acetate-hexanes and fractions 
containing the desired product evaporated to provide 0.356 g of a white 
solid. FAB MASS SPEC 737(M+H). 
EXAMPLE 61 
2-Butyl-6-(1-hydroxy-1-methylethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl 
]-4-yl]methyl]-4(3H)-quinazolinone monosodium salt 
A mixture of 0.400 g of 
2-Butyl-6-(1-hydroxy-1-methylethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-bipheny 
l]-4-yl]methyl]-4(3H)-quinazolinone monosodium salt, 10 ml of methanol and 
0.810 ml of 1N sodium hydroxide is stirred at room temperature for 1 hour 
and evaporated in vacuo to a residue which is triturated with ether, 
filtered and the cake air dried to give the desired product as a solid. 
FAB MASS SPEC 517(M+H). 
EXAMPLE 62 
2-Butyl-6-(hydroxymethyl)-3-[[2'-(1H-tetrazol-5-yl) 
[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone monosodium salt 
Following the procedure of Example 182 and using 
2-Butyl-6-(1-hydroxy-1-methylethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-bipheny 
l]-4-yl]methyl]-4(3H)-quinazolinone affords the product of the Example. 
EXAMPLE 63 
2-Butyl-6-(1-methoxy-1-methylethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol 
-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone 
To a suspension of 0.049 g of a 60% oil dispersion of sodium hydride in 4.5 
ml of THF is added 0.76 ml of methyl iodide followed by 0.45 g of 
2-butyl-6-(1-hydroxy-1-methylethyl)-3-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphen 
yl]-4-yl]methyl]-4(3H)-quinazolinone. The reaction mixture is stirred at 
room temperature for 24 hours and then an additional 0.05 g of 60% sodium 
hydride and 0.80 ml of methyl iodide are added. The reaction is stirred at 
room temperature for another 24 hours and then quenched with saturated 
ammonium chloride solution and extracted with ether. The organics are 
dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue is 
purified by flash chromatography on silica gel, eluting with 1:5 ethyl 
acetate/hexanes to provide 0.397 g of the desired product as a white 
solid. FAB MASS SPEC 751(M+H). 
EXAMPLE 64 
2-Butyl-6-(1-methoxy-1-methylethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl 
]-4-yl]methyl]-4(3H)-quinazolinone 
The product of the Example is prepared using the conditions of Example 111 
and 0.397 g of 
2-Butyl-6-(1-methoxy-1-methylethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazo 
l-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone to give 0.188 g of 
the desired product as a white solid following chromatography on silica 
gel by elution with 50:50:5:0.1 ethyl acetate/hexanes/methyl 
alcohol/acetic acid. FAB MASS SPEC 509(M+H). 
EXAMPLE 65 
2-Butyl-6-(methoxyphenylmethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-y 
l][1,1'-biphenyl]-4-yl]methyl]-(3H)-quinazolinone 
To a solution of 0.398 ml of methyl iodide in 5.0 ml of THF is added 0.851 
g of 60% sodium hydride followed by 0.500 g of 
2-butyl-6-(hydroxyphenylmethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5- 
yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone. The reaction mixture 
is stirred for 16 hours at room temperature, then quenched with saturated 
NH.sub.4 Cl solution and extracted with ether. The organics are dried over 
MgSO.sub.4, filtered and concentrated in vacuo. The residue is purified by 
flash chromatography on silica gel, eluting with ethyl acetate/hexanes 
(1:5) to provide 0.434 g of FAB MASS SPEC 799(M+H). 
EXAMPLE 66 
2-Butyl-6-(methoxyphenylmethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- 
yl]methyl]-4(3H)-quinazolinone 
The product of the Example is prepared using the conditions of Example 49 
and 0.413 g of 
2-Butyl-6-(methoxyphenylmethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5- 
yl][1,1'-biphenyl]-4-yl]methyl]-(3H)-quinazolinone to give 0.192 g of the 
desired product as a white solid following chromatography on silica gel by 
elution with 50:50:5:0.1 ethyl acetate/hexanes/methyl alcohol/acetic acid. 
FAB MASS SPEC 557(M+H). 
EXAMPLE 67 
2-Butyl-6-(1-methoxypropyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1 
,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
To a solution of 0.556 ml of methyl iodide in 5.0 ml of THF is added 0.071 
g of 60% sodium hydride followed by 0.657 g of 
2-butyl-6-(1-hydroxypropyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][ 
1,1'-biphenyl]-4-yl]methyl]4(3H)-quinazolinone. The reaction is stirred for 
16 hours at room temperature, then quenched with saturated NH.sub.4 Cl 
solution and extracted with ether. The organics are dried over MgSO.sub.4, 
filtered and concentrated in vacuo. The residue is purified by flash 
chromatography on silica gel, eluting with 1:5 ethyl acetate/hexanes to 
provide 0.59 g of the desired product as a white solid. FAB MASS SPEC 
751(M+H). 
EXAMPLE 68 
2-Butyl-6-(1-methoxypropyl)-3-[[2'-(1H-tetrazol-5-yl) 
[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
The product of the Example is prepared using the conditions of Example 111 
and 0.58 g of 
2-Butyl-6-(1-methoxypropyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][ 
1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone to give 0.326 g of the 
desired product as a white solid following chromatography on silica gel by 
elution with 50:50:5:0.1 ethyl acetate/hexanes/methyl alcohol/acetic acid. 
FAB MASS SPEC 509(M+H). 
EXAMPLE 69 
1-Amino-3-fluoro-4-bromo-benzoic acid 
To a solution of 3.0 g of 4-fluoroanthranilic acid in 250 ml of glacial 
acetic acid is slowly added a solution of 3.2 g of bromine in 10 ml of 
acetic acid. The reaction mixture is stirred at room temperature for 8 
hours and poured into 500 ml of water. The resulting precipitate is 
filtered off and the cake crystallized from methyl alcohol to give 3.4 g 
of the desired product, m.p. 180.degree.. 
EXAMPLE 70 
6-Bromo-2-butyl-7-fluoro-4(1H)-quinazolinone 
Following the procedure of Example 1 and using 3.0 g of 
1-amino-3-fluoro-4-bromo-benzoic acid, 100 ml of valeric anhydride and 200 
ml of ammonium hydroxide affords the product of the Example, m.p. 
225.degree. C. 
EXAMPLE 71 
2-Butyl-7-fluoro-6-[(trimethylsilyl)ethynyl]-4(1H)-quinazolinone 
Using the procedure of Example 20 and 
6-bromo-2-butyl-7-fluoro-4(1H)-quinazolinone, the product of the Example 
is obtained, m.p. 192.degree. C. 
EXAMPLE 72 
2-Butyl-6-ethynyl-7-fluoro-4(1H)-quinazolinone 
A mixture of 1.0 g of 
2-butyl-7-fluoro-6-[(trimethylsilyl)ethynyl]-4(1H)-quinazolinone, 20 ml of 
1N sodium hydroxide and 25 ml of methyl alcohol is heated at 60.degree. C. 
for 5 hours then evaporated in vacuo. The residue is dissolved in 100 ml 
of water and acidified. The resulting solid is collected and dried to 
afford 700 mg of the desired product as a yellow solid, m.p. 218.degree. 
C. 
EXAMPLE 73 
3-[(4-Bromophenyl)methyl]-2-butyl-6-(1-hydroxy-1-methylethyl)-4(3H)-quinazo 
linone 
To a solution of 1.37 g of 
2-butyl-6-(1-hydroxy-1-methylethyl)-4(1H)-quinazolinone in 115 ml of 
acetone is added 1.58 g of 4-bromobenzyl bromide and 2.18 g of anhydrous 
potassium carbonate. The resulting suspension is heated to reflux for 16 
hours. The reaction mixture is then allowed to cool to room temperature, 
filtered and the filtrate is concentrated vacuo. The residue is purified 
by HPLC eluting with ethyl acetate/hexanes (1:3) to provide the desired 
product. 
Examples 74-84 in Table VI are prepared under substantially the same 
alkylation conditions as Example 73 from the appropriately substituted 
quinazolinone starting materials. 
TABLE VI 
______________________________________ 
##STR31## 
Ex. 
No. R.sup.5 R.sup.6 R.sup.7 
R.sup.8 
X 
______________________________________ 
74 H I H H (CH.sub.2).sub.3 CH.sub.3 
75 H CH(OH)CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
76 H CH.sub.3 H H (CH.sub.2).sub.3 CH.sub.3 
77 H CH.sub.2 OH H H (CH.sub.2).sub.3 CH.sub.3 
78 H H H H (CH.sub.2).sub.3 CH.sub.3 
79 H CH(OH)CH.sub.2 CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
80 H C(CH.sub.3).sub.2 OH 
H H (CH.sub.2).sub.3 CH.sub.3 
81 H CH.sub.3 H H (CH.sub.2).sub.3 CH.sub. 3 
82 H H H H (CH.sub.2).sub.3 CH.sub.3 
83 H CH(OH)C.sub.6 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
84 H Cl H H (CH.sub.2).sub.3 CH.sub.3 
______________________________________ 
EXAMPLE 85 
3-[(4-Bromophenyl)methyl]-2-butyl-6-(1-methoxy-1-methylethyl)-4(3H)-quinazo 
linone 
To a solution of 0.186 g of 60% sodium hydride and 2.90 ml of iodomethane 
in THF at room temperature is added 1.00 g of 
3-[(4-bromophenyl)methyl]-2-butyl-6-(1-hydroxy-1-methylethyl)-4(3H)-quinaz 
olinone. The reaction mixture is stirred overnight at room temperature and 
then quenched with ammonium chloride solution and diluted with water. The 
aqueous layer is extracted with ether and the combined organics are dried 
over MgSO.sub.4, filtered and concentrated in vacuo. The residue is 
purified by flash chrmoatography eluting with ethyl acetate/hexanes (1:3) 
to provide the desired product. 
Examples 86-89 in Table VII are prepared under substantially the same 
alkylation conditions as Example 85 from the appropriately substituted 
quinazolinone starting materials. 
TABLE VII 
______________________________________ 
##STR32## 
Ex. 
No. R.sup.5 
R.sup.6 R.sup.7 
R.sup.8 
X 
______________________________________ 
86 H CH(OCH.sub.3)CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
87 H CH(OCH.sub.3)C.sub.6 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
88 H CH(OCH.sub.3)C.sub.2 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
89 H C(CH.sub.3).sub.2 OCH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
______________________________________ 
EXAMPLE 90 
2-Butyl-6-(1-methoxy-1-methylethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol 
-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
To a suspension of 0.41 g of magnesium turnings in 50 ml of THF is added a 
catalytic amount of iodine followed by 1.00 g of the 
5-(2-bromophenyl)-1-(triphenylmethyl)-1H-tetrazole in 10 ml of THF. The 
reaction mixture is heated to reflux until the Grignard formation is 
initiated as indicated by the disappearance of the iodine color. The 
remaining 6.94 g of the bromide in 70 ml of THF is then added to the 
reaction at a rate sufficient to maintain a gentle reflux. The reaction is 
then stirred at room temperature for 4 hours following the completion of 
the bromide addition. 
To a solution of 4.08 g of the 
3-[(4-bromophenyl)methyl]-2-butyl-6-(1-methoxy-1-methylethyl)-4(3H)-quinaz 
olinone and 71 mg of 1,4-bis(diphenylphosphino)butane palladium (II) 
chloride in 100 ml of THF is added the Grignard solution described above 
and the resulting solution is heated to reflux for 2 hours, following the 
method of Kumada (Tet. Letters, 52, 5319 (1981) . After cooling to room 
temperature, the reaction is quenched with water and dilute sodium 
hydroxide solution and then extracted with ether. The combined organics 
are dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue 
is purified by flash chromatography on silica gel eluting with ethyl 
acetate/hexanes (1:3) to provide the desired product. 
EXAMPLES 91-94 in Table VIII are prepared under substantially the same 
coupling conditions as Example 90 from the appropriately substituted 
quinazolinone starting materials. 
TABLE VIII 
______________________________________ 
##STR33## 
Ex. 
No. R.sup.5 R.sup.6 R.sup.7 
R.sup.8 
X 
______________________________________ 
91 H CH(OCH.sub.3)CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
92 H CH(OCH.sub.3)C.sub.6 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
93 H CH(OCH.sub.3)C.sub.2 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
94 H C(CH.sub.3).sub.2 OCH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
______________________________________ 
EXAMPLE 95 
3-[(4-Bromophenyl)methyl]-2-butyl-6-[1-[[(1,1-dimethylethyl)dimethylsilyl]o 
xy]-1-methylethyl]-4(3H)-quinazolinone 
To a solution of 1.00 g of 3-[(4-bromophenyl) 
methyl]-2-butyl-6-(1-hydroxy-1-methylethyl)-4(3H)-quinazolinone in 2.0 ml 
of DMF is added 0.438 g of t-butyldimethylsilyl chloride followed by 0.4 g 
of imidazole. The reaction mixture is stirred at room temperature for 18 
hours and then diluted with water and extracted with ether. The combined 
ether extracts are dried over MgSO.sub.4, filtered and concentrated in 
vacuo. The residue was purified by flash chromatography eluting with ethyl 
acetate/hexanes (1:5) to provide the desired product as a white solid. 
Examples 96-100 in Table IX are prepared under substantially the same 
conditions as Example 95 from the appropriately substituted quinazolinone 
starting materials. 
TABLE IX 
______________________________________ 
##STR34## 
Ex. 
No. R.sup.5 
R.sup.6 R.sup.7 
R.sup.8 
X 
______________________________________ 
96 H CH(OTBDMS)CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
97 H CH.sub.2 OTBDMS H H (CH.sub.2).sub.3 CH.sub.3 
98 H CH(OTBDMS)CH.sub.2 CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
99 H C(CH.sub.3).sub.2 OTBDMS 
H H (CH.sub.2).sub.3 CH.sub.3 
100 H CH(OTBDMS)C.sub.6 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
______________________________________ 
*TBDMS = tbutyldimethylsilyl 
EXAMPLE 101 
2-Butyl-6-[1-[[(1,1-dimethylethyl]dimethylsilyl]oxy]-1-methylethyl]-3-[[2'- 
[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-qu 
inazolinone 
To a suspension of 0.41 g of magnesium turnings in 50 ml of THF is added a 
catalytic amount of iodine followed by 1.00 g of the 
5-(2-bromophenyl)-1-(triphenylmethyl)-1H-tetrazole in 10 ml of THF. The 
reaction mixture is heated to reflux until the Grignard formation is 
initiated as indicated by the disappearance of the iodine color. The 
remaining 6.94 g of the bromide in 70 ml of THF is then added to the 
reaction at a rate sufficient to maintain a gentle reflux. The reaction is 
then stirred at room temperature for 4 hours following the completion of 
the bromide addition. 
To a solution of 5.00 g of 3-[(4-bromophenyl) 
methyl]-2-butyl-6-[1-[[(1,1-di-methylethyl)dimethylsilyl]oxy]-1-methylethy 
l]-4(3H)-quinazolinone and 71 mg of 1,4-bis(diphenylphosphino)butane 
palladium (II) chloride in 100 ml of THF is added the Grignard solution 
described above and the resulting solution is heated to reflux for 2 
hours, fillowing the method of Kumada (Tet. Letters, 52, 5319 (1981)). 
After cooling to room temperature, the reaction is quenched with water and 
dilute sodium hydroxide solution and then extracted with ether. The 
combined organics are dried over MgSO.sub.4, filtered and concentrated in 
vacuo. The residue is purified by flash chromatography on silica gel 
eluting with ethyl acetate/hexanes (1:3) to provide the desired product. 
Examples 102-106 in Table X are prepared under substantially the same 
conditions as Example 101 from the appropriately substituted quinazolinone 
starting materials. 
TABLE X 
______________________________________ 
##STR35## 
Ex. 
No. R.sup.5 
R.sup.6 R.sup.7 
R.sup.8 
X 
______________________________________ 
102 H CH(OTBDMS)CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
103 H CH.sub.2 OTBDMS H H (CH.sub.2).sub.3 CH.sub.3 
104 H CH(OTBDMS)CH.sub.2 CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
105 H C(CH.sub.3).sub.2 OTBDMS 
H H (CH.sub.2).sub.3 CH.sub.3 
106 H CH(OTBDMS)C.sub.6 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
______________________________________ 
*TBDMS = tbutyldimethylsilyl 
EXAMPLE 107 
2-Butyl-6-(1-hydroxy-1-methylethyl)-3-[[2'-[1-triphenylmethyl)-1H-tetrazol- 
5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
To a solution of 0.50 g of 
2-butyl-6-[1-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-methylethyl]-3-[[2' 
-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-q 
uinazolinone in 15.0 ml of THF is added 0.88 ml of a 1.0M solution of 
tetrabutylammonium fluoride in THF. The reaction is stirred at room 
temperature for 1 hour and then poured into 100 ml of water. The aqueous 
layer is extracted with ether and the combined organics are washed with 
brine, dried over MgSO.sub.4, filtered and concentrated in vacuo. The 
residue is purified by flash chromatography on silica gel eluting with 
ethyl acetate/hexanes (1:3) to provide the desired product. 
EXAMPLES 108-112 in Table XI are prepared under substantially the same 
conditions as Example 107 from the appropriately substituted quinazolinone 
starting materials. 
TABLE XI 
______________________________________ 
##STR36## 
Ex. 
No. R.sup.5 R.sup.6 R.sup.7 
R.sup.8 
X 
______________________________________ 
108 H CH(OH)CH.sub.3 H H (CH.sub.2).sub.3 CH.sub.3 
109 H CH.sub.2 OH H H (CH.sub.2).sub.3 CH.sub.3 
110 H CH(OH)CH.sub.2 CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
111 H C(CH.sub.3).sub.2 OH 
H H (CH.sub.2).sub.3 CH.sub.3 
112 H CH(OH)C.sub.6 H.sub.5 
H H (CH.sub.2).sub.3 CH.sub.3 
______________________________________ 
EXAMPLE 113 
5-(2-Bromophenyl)-1-(trimethylstannyl)-1H-tetrazole 
To a solution of 1.50 g of o-bromobenzonitrile in 8.0 ml of toluene is 
added 1.70 g of trimethyltin azide. The reaction mixture is heated to 
reflux for 18 hours and then allowed to cool to room temperature. The 
resulting white precipitate is isolated by filtration and used without 
purification in the next step. 
EXAMPLE 114 
5-(2-Bromophenyl)-1H-tetrazole 
To a solution of 1.0 g of 
5-(2-bromophenyl)-1-(trimethylstannyl)-1H-tetrazole in toluene/THF (10:1) 
at room temperature is added HCl gas, via a bubbler. Gas addition is 
continued for 5 minutes after the appearance of a precipitate and the 
solid is then isolated by filtration and washed with hexanes. 
EXAMPLE 115 
5-(2-Bromophenyl)-1-(triphenylmethyl)-1H-tetrazole 
To a solution of 0.50 g of 5-(2-bromophenyl)-1H-tetrazole in 20 ml of 
CH.sub.2 Cl.sub.2 is added 0.65 g of triphenylmethyl chloride followed by 
0.37 ml of triethylamine. The solution is refluxed for 2.5 hours, cooled 
to room temperature and then washed with water, dried over MgSO.sub.4 and 
concentrated in vacuo. The residue is purified by flash chromatography 
eluting with ethyl acetate/hexanes (1:5) to provide the desired product. 
EXAMPLE 116 
2-butyl-6-(1-methoxy-1-methylethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl 
]-4-yl]methyl]-4(3H)-quinazolinone, sodium salt 
To a solution of 2.488 g of the free tetrazole from Example 57 in 60 ml of 
methanol is added 5.036 ml of 1.0N sodium hydroxide solution. The mixture 
is stirred at room temperature for 1 hour and then concentrated in vacuo. 
The residue is titrated with hexanes, filtered and dried in vacuo to 
provide 2.29 g of the product as a white solid. 
EXAMPLE 117 
2-Butyl-6-(1-methoxyethyl)-4-[[2'-(1H-tetrazol)-5-yl)[1,1'-biphenyl]-4-yl]m 
ethyl-4(3H)-quinazolinone, sodium salt 
To a solution of 2.156 g of the free tetrazole from Example 59 in 60 ml of 
methanol is added 4.359 ml of 1.0N Sodium Hydroxide solution. The mixture 
is stirred at room temperature for 1 hour and then concentrated in vacuo. 
The residue is titrated with hexanes, filtered and dried in vacuo to 
provide 2.09 g of the product as a white solid. 
EXAMPLE 118 
2-Butyl-6-(methoxymethyl)-4-[[2'-(1H-tetrazol)-5-yl)[1,1'-biphenyl]-4-yl]me 
thyl-4(3H)-quinazolinone 
To a stirred solution of NaH (500 mg) and primary alcohol from Example 53 
in dry THF (35 ml) at 0.degree. C., is added CH.sub.3 I (1 ml). The 
reaction mixture is stirred at room temperature for 4 hours. The reaction 
mixture is then carefully poured over crushed ice and extracted with 
chloroform. The organic layer is washed well with water; dried and 
concentrated. The spongy solid obtained is dissolved in acetone (25 ml) 
and 5N HCL (3 ml) is added. The reaction mixture is stirred at room 
temperature for 3 hours. The reaction mixture is then concentrated and the 
product is purified by column chromatography. Yield: 8.5 mg; m.p: 
85.degree. C. 
Utility 
The performance of the novel compounds of the present invention are shown 
in the following In Vitro test. The results of this test for 
representative compounds of the present invention are shown in Table IV. 
Angiotensin II Antagonists In Vitro Tests 
The source of the angiotensin II receptors utilized in the screen is from 
rat adrenocortical microsomes. The cortices are placed in ice cold sucrose 
buffer (0.2 m sucrose, 1 mm EDTA, 10 mm Trizma base, pH 7.4) and 
homogenized in a chilled ground glass tissue grinder. The homogenate is 
centrifuged at 3000.times.g for 10 min. and the resultant supernatant is 
decanted through cheesecloth and centrifuged at 12,000.times.g for 3 min. 
The resulting supernatant is then centrifuged at 1000,000.times.g for 60 
min. and the pellet resuspended in assay buffer (0.25% bovine serum 
albumin, 5 mm MgCl.sub.2, 50 mm Trizma base, pH 7.2). Binding assays are 
performed by incubating aliquots of freshly prepared microsomes in the 
absence or presence of compound (40 uM final concentration). Ten minutes 
later, .sup.3 H-angiotensin II is added to each tube (2 nM final 
concentration) and incubated for 60 minutes at 27.degree. C. The reaction 
is terminated by the addition of 3 ml of cold assay buffer without 
albumin and the bound and free radioactivity is separated rapidly through 
glass-fiber filters prewetted with assay buffer. After two additional 3 ml 
rinses, the filters are placed in scintillation fluid and counted in a 
scintillation counter to determine trapped radioactivity. Compounds that 
displace 50% of the labelled angiotensin are considered active compounds 
and are then evaluated in concentration-response experiments to determine 
IC.sub.50 values. The results ar shown in Table IV. 
TABLE IV 
__________________________________________________________________________ 
##STR37## 
Angiotensin II 
Receptor 
Ex. No. 
R.sup.5 
R.sup.6 R.sup.7 
R.sup.8 
X Binding IC.sub.50 (M) 
__________________________________________________________________________ 
49 H CH(OH)CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
8.8 .times. 10.sup.-9 
51 H C(CH.sub.3).sub.2 OH 
H H (CH.sub.2).sub.3 CH.sub.3 
9.4 .times. 10.sup.-9 
52 H CH(OH)CH.sub.2 CH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
1.2 .times. 10.sup.-8 
54 H (C.sub.6 H.sub.5)CHOH 
H H (CH.sub. 2).sub.3 CH.sub.3 
&gt;1.0 .times. 10.sup.-5 
55 H CH.sub.3 CH.sub.2 CHOCH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
5.0 .times. 10.sup.-9 
56 H (C.sub.6 H.sub.5)CHOCH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
8.6 .times. 10.sup.-9 
57 H (CH.sub.3).sub.2 COCH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
6.4 .times. 10.sup.-9 
58 H CH.sub.3 CHOOCCH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
1.1 .times. 10.sup.-8 
60 H CH.sub.3 (CH.sub.3 O)CH 
H H (CH.sub.2).sub.3 CH.sub.3 
8.4 .times. 10.sup.-8 
64 H (CH.sub.3).sub.2 COCH.sub.3 
H H (CH.sub.2).sub.3 CH.sub.3 
6.4 .times. 10.sup.-9 
H 
66 H (C.sub.6 H.sub.5)C(OCH.sub.3) 
H H (CH.sub.2).sub.3 CH.sub.3 
8.6 .times. 10.sup.-9 
H 
68 H (C.sub.2 H.sub.5)C(OCH.sub.3) 
H H (CH.sub.2).sub.3 CH.sub.3 
5.0 .times. 10.sup.-9 
__________________________________________________________________________ 
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 blackage of the vasopressor response is realized. The 
results of this test on representative compounds of this invention are 
shown in Table V. 
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, 90 and 150 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. 
The results are shown in Table V and FIG. 1. 
TABLE V 
__________________________________________________________________________ 
% INHIBITION (ANGIOTENSIN BLOCKAGE) OF ANGIOTENSIN II (AII) 
VASOPRESSOR RESPONSE 
AII Control 
Response 
Min. After Percent 
Dose Dose 
Before 
After 
Dosing Inhibition 
Ex. No. 
mg/kg iv 
g/kg iv 
AII AII Compound 
Change 
(Average) 
__________________________________________________________________________ 
.05 195 240 0 45 
.1 185 240 55 
49 1 .05 190 217 30 27 40 
.1 185 225 40 27 
49 1 .05 170 195 45 25 45 
.1 185 210 25 55 
.05 170 210 90 40 11 
.1 185 225 40 27 
49 2 .05 190 200 120 10 78 
.1 185 220 35 36 
.05 190 225 150 35 23 
.1 190 230 40 27 
.05 175 225 180 50 11 
.1 175 230 55 0 
.05 220 254 0 26 
.05 205 235 0 30 
0.1 223 272 0 44 
0.1 205 250 0 45 
49 .05 253 253 30 0 
10 .05 190 190 30 0 100 
0.1 243 243 30 0 
0.1 190 190 30 0 100 
.05 228 228 90 0 
.05 185 185 90 0 100 
.05 185 230 0 45 
185 225 40 
1. 180 235 55 
185 235 50 
50 30 .05 175 190 30 15 82 
190 190 0 
1. 170 195 25 76 
190 190 0 
.05 170 200 90 30 29 
180 215 30 
1. 180 210 30 52 
185 205 20 
.05 170 200 150 30 41 
170 190 20 
1. 185 220 35 48 
170 190 20 
.05 220 260 0 40 
.05 200 232 0 32 
0.1 215 265 0 50 
0.1 200 240 0 40 
51 5* .05 205 235 30 30 
.05 185 210 30 25 30 
0.1 200 240 30 40 
0.1 190 215 30 25 26 
.05 205 210 90 5 
.05 180 193 90 13 75 
0.1 200 225 90 25 
0.1 180 195 90 15 55 
.05 190 205 150 15 
.05 180 190 150 10 63 
0.1 190 217 150 27 
0.1 180 200 150 20 46 
.05 235 285 0 50 
.1 225 285 60 
*51 1 .05 220 260 30 40 20 
.1 220 275 55 8 
*51 1 .05 220 245 45 25 50 
.1 220 260 40 33 
.05 220 265 90 45 10 
.1 210 275 65 8 
*51 2 .05 225 250 120 25 50 
*sodium salt 
.1 215 265 50 17 
.05 225 260 150 35 30 
.1 225 270 45 25 
.05 225 265 180 40 20 
.1 235 280 45 25 
.05 210 265 0 55 
.05 205 255 0 50 
0.1 215 275 0 60 
0.1 210 265 0 55 
52 5 oral 
.05 205 230 30 25 
.05 190 215 30 25 52 
0.1 205 240 30 35 
0.1 190 220 30 30 43 
.05 185 205 90 20 
.05 185 200 90 15 66 
0.1 185 205 90 20 
0.1 185 206 90 21 63 
.05 180 195 150 15 
.05 175 180 150 15 71 
0.1 175 201 150 26 
0.1 180 200 150 20 60 
.05 165 220 0 55 
185 230 45 
.1 175 220 45 
190 240 50 
53 10 .05 155 157 10 2 83 
140 155 15 
.1 155 165 10 90 
130 130 0 
.05 155 160 30 5 85 
135 145 10 
.1 160 165 5 84 
155 165 10 
.05 160 175 60 15 65 
140 160 20 
.1 165 180 15 68 
150 165 15 
.05 200 245 0 45 
175 222 47 
185 230 45 
.1 200 252 47 
170 217 55 
180 235 55 
53 10 30 
.05 210 245 35 17 
175 215 40 
185 225 40 
.1 205 250 45 19 
175 220 45 
195 232 37 
60 
53 .05 192 237 45 27 
170 190 20 
175 210 35 
.1 195 245 50 4 
170 220 50 
175 225 50 
90 
.05 205 245 40 41 
175 195 20 
185 207 22 
.1 200 250 50 56 
175 210 35 
177 225 48 
30 
.05 207 225 18 76 
167 190 23 
180 210 30 
.1 200 255 55 60 
175 197 22 
180 223 43 
60 
.05 200 240 40 46 
170 180 10 
200 225 25 
53 .1 207 250 43 44 
170 190 20 
190 230 40 
90 
.05 195 235 40 35 
165 180 15 
180 215 35 
.1 200 250 50 26 
175 190 15 
180 230 50 
.05 210 275 0 65 
230 270 40 
.1 210 280 70 
235 280 45 
53 6 .05 200 220 30 20 67 
210 225 15 
.1 205 220 15 70 
210 230 20 
.05 205 225 90 20 48 
200 235 35 
.1 205 240 35 30 
205 250 45 
53 6 .025 
235 265 0 30 
.05 235 265 30 
.1 235 265 30 
53 6 .025 
210 225 30 15 50 
.05 210 235 25 17 
.1 215 250 35 17 
.025 
200 210 90 10 
.05 190 225 35 17 
.1 200 235 35 17 
.05 187 240 0 53 
213 260 47 
.1 187 240 53 
215 265 50 
53 3 .05 175 205 10 30 62 
207 215 8 
.1 175 215 40 42 
205 225 20 
.05 175 210 30 35 45 
210 2340 20 
.1 190 220 30 47 
215 235 20 
.05 175 215 60 40 30 
210 240 30 
.1 180 235 55 13 
220 255 35 
.05 210 270 0 60 
225 265 40 
.1 205 275 70 
235 290 55 
53 3 .05 200 215 30 15 55 
230 260 30 
.1 195 215 20 44 
220 270 50 
.05 200 225 90 25 25 
225 275 50 
.1 200 235 35 13 
225 277 52 
53 3 .05 175 190 30 15 60 
225 250 25 
.1 180 210 30 36 
225 250 50 
.05 200 250 0 50 
210 265 55 
.1 200 255 55 
200 265 65 
53 3 .05 185 210 30 25 67 
190 200 10 
.1 185 205 20 67 
190 210 20 
.05 185 235 90 50 10 
195 260 65 
.1 190 235 45 17 
200 255 55 
.025 
220 260 40 
210 255 45 
.05 220 265 45 
210 260 50 
.1 220 275 55 
215 265 50 
53 3 .025 
210 225 30 15 53 
195 220 25 
53 .05 207 220 13 65 
190 210 20 
.1 210 235 25 52 
190 215 25 
.025 
210 230 90 20 47 
185 210 25 
.05 210 240 30 35 
190 222 32 
.1 210 250 40 
195 235 40 24 
.05 190 235 0 45 
210 255 65 
.1 190 245 55 
210 255 45 
54 1 .05 190 215 30 25 47 
205 227 32 
.1 195 230 35 30 
210 245 35 
54 1 .05 190 207 45 17 75 
205 215 10 
.1 185 230 45 28 
200 227 27 
.05 190 217 90 27 49 
210 240 30 
.1 200 240 40 34 
210 235 25 
54 2 .05 220 220 120 0 85 
200 215 15 
.1 202 222 20 64 
200 215 15 
.05 185 205 150 20 67 
195 210 15 
.1 190 215 25 54 
195 215 20 
.05 190 207 180 17 69 
190 207 17 
.1 190 220 30 50 
190 210 20 
54 5 P.O.* 
0.05 
210 235 180 25 55 
0.1 197 245 48 26 
*oral dosage 
.05 200 255 0 55 
.1 200 255 55 
55 30 .05 180 190 30 10 82 
.1 180 195 15 73 
.05 170 185 90 15 73 
.1 170 175 5 91 
.05 185 205 150 20 64 
.1 190 195 5 91 
.025 
230 260 0 30 
.05 225 270 45 
.1 235 283 48 
57 1 .025 
205 220 15 15 50 
.05 220 225 5 89 
.1 217 242 25 48 
.025 
215 230 30 15 50 
.05 225 235 10 78 
.1 225 260 35 27 
.025 
240 245 60 5 83 
.05 240 255 15 67 
.1 240 275 35 27 
57 2 .025 
230 255 90 25 17 
.05 225 235 10 78 
.1 225 255 30 37 
.025 
205 265 120 60 100 
.05 225 255 30 33 
.1 235 255 20 58 
57 3 .025 
210 225 150 15 50 
.05 215 230 15 67 
.1 215 240 25 48 
.025 
207 250 0 43 
210 260 50 
.05 215 253 38 
210 265 55 
.1 220 265 45 
220 265 45 
57 *5 .025 
205 210 30 5 94 
205 205 0 
.05 200 207 7 77 
200 215 15 
.1 198 215 17 64 
200 215 15 
.025 
205 215 60 10 89 
195 195 0 
.05 215 215 0 87 
193 205 12 
.1 200 217 17 58 
190 210 20 
.025 
195 200 120 5 94 
200 200 0 
.05 195 210 15 72 
200 210 10 
.1 192 220 28 40 
200 225 25 
.025 
195 210 180 15 72 
200 210 10 
.05 200 215 15 68 
200 215 15 
*oral dosage 
.1 200 215 15 56 
200 225 25 
.025 
220 220 240 0 100 
190 190 0 
.05 195 210 15 62 
180 200 20 
.1 220 235 15 49 
185 215 30 
.05 200 260 0 60 
210 257 47 
.1 205 260 55 
200 260 60 
58 30 .05 195 205 30 10 87 
222 225 3 
.1 205 205 0 98 
205 206 2 
.05 190 190 90 0 85 
210 225 15 
.1 195 195 0 95 
210 215 5 
.05 180 190 150 10 85 
200 205 5 
.1 190 207 17 81 
205 210 5 
.05 235 285 0 50 
230 290 60 
.1 225 285 60 
230 285 55 
60 1 .05 207 232 30 25 55 
215 240 25 
.1 215 260 45 17 
210 260 50 
60 1 .05 195 205 45 10 82 
215 225 10 
.1 190 215 25 43 
210 250 40 
.05 210 230 90 20 58 
210 235 25 
.1 215 245 30 43 
210 245 35 
60 2 .05 215 215 120 0 100 
220 220 0 
.1 210 220 10 86 
220 225 5 
.05 220 225 150 5 82 
205 220 15 
.1 215 225 10 52 
205 250 45 
.05 215 240 180 25 45 
210 245 35 
60 .1 215 250 35 31 
205 250 45 
.025 
195 209 0 14 
.025 
200 218 0 18 
.05 200 215 0 15 
.05 195 228 0 33 
0.1 200 220 0 20 
0.1 200 250 0 50 
61 2 .025 
195 195 30 0 
.025 
200 200 30 0 100 
.05 190 190 30 0 
.05 180 180 30 0 100 
0.1 165 165 30 0 
0.1 220 220 30 0 100 
.025 
190 190 90 0 
.025 
197 197 90 0 100 
.05 185 185 90 0 
.05 200 200 90 0 100 
0.1 185 185 90 0 
0.1 205 205 90 0 100 
.025 
180 180 140 0 
.025 
200 200 150 0 100 
.05 180 180 150 0 
.05 195 195 150 0 100 
0.1 185 185 150 0 
0.1 180 194 150 14 80 
180 200 20 
.025 
200 210 0 10 
.025 
215 225 0 10 
.05 200 220 0 20 
.05 215 235 0 20 
0.1 210 235 0 25 
0.1 215 245 0 30 
64 2 .025 
195 195 30 0 
.025 
190 190 30 0 100 
.05 195 195 30 0 
.05 190 190 30 0 100 
0.1 195 195 30 0 
0.1 195 195 30 0 100 
.025 
185 185 90 0 
.025 
185 185 90 0 100 
.05 190 190 90 0 
.05 185 185 90 0 100 
0.1 190 190 90 0 
0.1 190 190 90 0 100 
.025 
190 190 150 0 
.025 
185 185 150 0 100 
.05 185 185 150 0 
.05 185 185 150 0 100 
0.1 185 185 150 0 
0.1 185 195 150 10 82 
185 215 30 
180 213 33 
.05 220 255 0 35 
210 250 40 
.1 215 255 40 
210 257 47 
64 5 P.O.* 
.05 195 217 30 22 45 
200 220 20 
.1 200 225 25 32 
200 235 35 
.05 197 215 60 18 50 
190 210 20 
.1 195 225 30 25 
195 230 35 
.05 190 200 90 10 61 
185 205 20 
.1 185 210 25 36 
190 220 30 
.05 185 205 120 20 47 
200 220 20 
.1 185 210 25 41 
200 227 27 
.05 185 195 180 10 49 
195 220 25 
.1 190 207 17 41 
195 230 35 
oral dosage 
64 .05 190 200 240 10 49 
195 220 25 
.1 190 205 15 48 
195 225 30 
.025 
215 245 0 30 
.05 220 255 35 
.1 220 255 35 
66 1 .025 
207 225 15 18 40 
.05 210 225 15 57 
.1 215 230 15 57 
.025 
205 227 30 27 27 
.05 215 230 15 57 
.1 215 235 20 43 
.025 
210 230 60 20 33 
.05 210 230 20 43 
.1 210 240 30 14 
66 2 .025 
195 205 90 10 67 
.05 205 220 15 57 
.1 205 210 5 86 
.025 
200 220 120 20 33 
.05 200 215 15 57 
.1 190 205 15 57 
.025 
180 195 150 15 50 
.05 190 200 10 71 
.1 185 205 20 43 
.05 200 255 0 55 
.1 200 255 55 
68 30 .05 180 190 30 10 82 
.1 180 195 15 73 
.05 170 185 90 15 73 
.1 170 175 5 91 
.05 185 205 150 20 64 
.1 190 195 5 91 
__________________________________________________________________________ 
Antihypertensive Effects in Conscious Aorta-Coarcted Renin/Angiotensin 
II-Dependent Renal Hypertensive Rats 
Following the method reported by Chan et al., Drug Development Res. 18: 
75-94, 1989, hypertension is induced by complete ligation of the aorta 
between the origin of the renal arteries according to the method of 
Rojo-Ortega and Genest (Can. J. Physio Pharmacol 46: 883-885, 1968.) and 
Fernandes et al., (J. Lab. Clin. Med. 87: 561-567, 1976) with 
modifications of the surgery procedures. Male Sprague-Dawley rats (Charles 
River Labs., Inc., Wilmington, Mass.) of 350 to 400 gm body weight are 
anesthetized with methohexital sodium (Brevital sodium, Eli Lilly and Co.) 
60 mg/kg i.p. An incision is made in the left flank parallel to the rib 
cage. Using No. 3-0 silk suture(Davis & Geck, Pearl River, NY), the aorta 
is completely ligated between the origins of the renal arteries. The wound 
is closed, and the animals returned to their individual cages. On the 7th 
day after aortic coarctation, the rats are used. The rats are restrained 
in a supine position with elastic tape, and the heads are immobilized by 
gentle restraining. The ventral portion of the neck is locally 
anesthetized by subcutaneous infiltration with 2% lidocaine. The left 
carotid artery is isolated and cannulated with a length of PE50 tubing, 
which is in turn, connected to a Statham P23Db pressure transducer - 
Beckman Dynagraph recording system. In some studies, the cannular is 
exteriorized through the back of the neck for long period of blood 
pressure monitoring. Recordings are taken over a 15-20 minute period, and 
the rats are dosed with the test compounds or vehicle (saline). After 
dosing, the blood pressure is monitored continuously. The results are 
shown in FIGS. 2 to 7. 
When the compounds are employed for the above utility, they may be combined 
with one or more pharmaceutically acceptable carriers, for example, 
solvents, diluents and the like, and may be administered orally in such 
forms as tablets, capsules, dispersible powders, granules, or suspensions 
containing, for example, from about 0.05 to 5% of suspending agent, syrups 
containing, for example, from about 10 to 50% of sugar, and elixirs 
containing, for example, from about 20 to 50% ethanol, and the like, or 
parenterally in the form of sterile injectable solutions or suspension 
containing from about 0.05 to 5% suspending agent in an isotonic medium. 
Such pharmaceutical preparations may contain, for example, from about 0.05 
up to about 90% of the active ingredient in combination with the carrier, 
more usually between about 5% and 60% by weight. 
The effective dosage of active ingredient employed may vary depending on 
the particular compound employed, the mode of administration and the 
severity of the condition being treated. However, in general, satisfactory 
results are obtained when the compounds of the invention are administered 
at a daily dosage of from about 0.5 to about 500 mg/kg of animal body 
weight, preferably given in divided doses two to four times a day, or in 
sustained release form. For most large mammals the total daily dosage is 
from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms 
suitable for internal use comprise from about 0.5 to 500 mg of the active 
compound in intimate admixture with a solid or liquid pharmaceutically 
acceptable carrier. This dosage regimen may be adjusted to provide the 
optimal therapeutic response. for example, several divided doses may be 
administered daily or the dose may be proportionally reduced as indicated 
by the exigencies of the therapeutic situation. 
These active compounds may be administered orally as well as by 
intravenous, intramuscular, or subcutaneous routes. Solid carriers include 
starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose 
and kaolin, while liquid carriers include sterile water, polyethylene 
glycols, non-ionic surfactants and edible oils such as corn, peanut and 
sesame oils, as are appropriate to the nature of the active ingredient and 
the particular form of administration desired. Adjuvants customarily 
employed in the preparation of pharmaceutical compositions may be 
advantageously included, such as flavoring agents, coloring agents, 
preserving agents, and antioxidants, for example, vitamin E, ascorbic 
acid, BHT and BHA. 
The preferred pharmaceutical compositions from the standpoint of ease of 
preparation and administration are solid compositions, particularly 
tablets and hard-filled or liquid-filled capsules. Oral administration of 
the compounds is preferred. 
These active compounds may also be administered parenterally or 
intraperitoneally. Solutions or suspensions of these active compounds as a 
free base or pharmacologically acceptable salt can be prepared in water 
suitably mixed with a surfactant such as hydroxypropylcellulose. 
Dispersions can also be prepared in glycerol, liquid polyethylene glycols 
and mixtures thereof in oils. Under ordinary conditions of storage and 
use, these preparations contain a preservative to prevent the growth of 
microorganisms. 
The pharmaceutical forms suitable for injectable use include sterile 
aqueous solutions or dispersions and sterile powders for the 
extemporaneous preparation of sterile injectable solutions or dispersions. 
In all cases, the form must be sterile and must be fluid to the extent 
that easy syringability exists. It must be stable under the conditions of 
manufacture and storage and must be preserved against the contaminating 
action of microorganisms such as bacteria and fungi. The carrier can be a 
solvent or dispersion medium containing, for example, water, ethanol, 
polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), 
suitable mixtures thereof, and vegetable oils.