Abstract:
This disclosure describes novel 2,3,6-substituted quinazolinones of the formula: ##STR1## where R 6 , R 5  and R are 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 6-(bicyclic heterocyclic)-2-(lower alkyl)-3-(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 6-(bicyclic heterocyclic)-2-(lower alkyl)-3-(substituted) quinazolinone compounds of Formula I which have angiotensin II antagonizing properties and are useful as anti-hypertensives: ##STR2## wherein: 
     R 6  is ##STR3## 
     R 5  is lower alkyl of 3 to 5 carbon atoms; 
     R is: ##STR4## 
     R 1 , R 2 , and R 3  are independently selected from H and lower alkyl of 1 to 4 carbon atoms; n is one or two; or the 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, a novel pharmaceutical composition containing the novel 2,3,6-substituted quinazolinone 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 scheme: ##STR5## 
     Referring to Scheme I, aldehyde 1, reported in EPO0497150, where R 5  is hereinbefore defined is reacted with Grignard reagent 2 where R 1 , R 2 , and R 3  are hereinbefore defined and X is Br, I or Cl to give alcohol 3. 
     As described in EPO0497150, biphenyl 4 is attached to quinazolinone intermediate 3 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 at the first phenyl ring. Alternatively, the coupling of quinazolinone intermediate 3 where R 1 , R 2 , R 3  and R 5  are hereinbefore defined with biphenyl 4 where R 7  is a trityl protected tetrazole prepared by the methods of N. B. Mantlo, J. Med. Chem, 34, 2919-2922 (1991) or cyano prepared by the methods outlined in D. J. Carini, J. Med. Chem. 34, 2525-2547 (1991) and gives coupled product 5 by dissolving 3 and 4 in acetone or another suitable solvent such as N,N-dimethylformamide, N,N-dimethyl-acetamide, 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 intermediate 5 may be purified by chromatography or used as is in further transformations and/or deprotection. Quinazolinone intermediate 5 is then oxidized with pyridinium dichromate, manganese dioxide or other suitable oxidant to give ketone 6. Ketone 6 is reacted with commercially available cyclic trimethylsilyl enol ether reagent 7 in the presence of titanium tetrachloride to afford diketone quinazolinone intermediate 8. Reduction of 8 with sodium borohydride gives diol 9. Reaction of 9 with methanesulfonyl chloride and a base facilitates ring closure to afford 10. 
     Deprotection of the trityl group is accomplished by refluxing an aqueous acetone solution of the alkylated quinazolinone 10 with a catalytic amount of hydrochloric acid or other suitable acid such as sulfuric, trifluoroacetic or hydrogen chloride for 2-24 hours. Additionally, heating 10 in tetrahydrofuranmethanol removes the trityl protecting group and affords 11. Reaction of 10 where R 7  is cyano with sodium azide in the presence of tri-n-butyltin chloride in refluxing xylene affords the desired tetrazole 11 after acid work-up. Contemplated equivalents to tri-n-butyltin chloride include tri-(lower alkyl C 1  -C 4 )tin chlorides and bromides. Contemplated equivalents to sodium azide include potassium azide and lithium azide. 
     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, hydroscopicity 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 stereo-isomeric 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 nonlimiting examples. 
     EXAMPLE 1 
     2-Butyl-6-(1-hydroxy-2-propenyl)-4(1H)-quinazolinone 
     To a solution of 10.00 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 350 ml of tetrahydrofuran, cooled to 0° C. is added 130.43 ml of 1.0M vinylmagnesium bromide in tetrahydrofuran over 15 minutes. The reaction mixture is stirred at 0° C. for 30 minutes. The reaction mixture is quenched at 0° C. with 50 ml of saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried (Na 2  SO 4 ) and concentrated in vacuo to afford a residue which is purified by column chromatography on silica gel using 1:1 ethyl acetate-hexane to give 4.81 g of the desired product, as a white solid, MP 141° C. 
     EXAMPLE 2 
     2-Butyl-6-(1-hydroxy-2-propenyl)-3-[[2&#39;-[1-triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-4 (3H) -quinazolinone 
     A mixture of 4.81 g of the product of Example 1, 20.77 g of 5-[4&#39;-(bromomethyl)[1,1&#39;-biphenyl]-2-yl]-(triphenylmethyl)-1H-tetrazole, 0.850 g of lithium methoxide in 75 ml of tetrahydrofuran is refluxed for 48 hours and diluted with ethyl acetate. The mixture is washed with water and the organic layer dried (MgSO 4 ), and concentrated to a residue which is purified by column chromatography using ethyl acetate-hexane (1:4 to 1:1) to give 11.72 g of the desired product as a white solid.  1  H NMR(300MHz, CDCl 3 )δ 8.3(1H, s), 7.9(1H,dd), 7.8(1H,dd), 7.65(1H,dd) , 7.5-6.8(22H,n), 6.15(1H,m), 5.3(3H,m), 5.25(2H, br s), 2.65(2H, t), 1.7(2H,m), 1.4(2H,m), 0.9(3H, t). 
     EXAMPLE 3 
     2-Butyl-6-(1-oxo- 2-propenyl)-3-[[2&#39;-[1-(triphenylmethyl) -1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
     A mixture of 1.00 g of the product of Example and 10.0 g of manganese dioxide in 25 ml of methylene chloride is stirred at room temperature for 2 hours then filtered through diatomaceous earth. The cake is washed with methylene chloride and the filtrate concentrated in vacuo to a residue which is purified by column chromatography on silica gel using 1:3 ethyl acetate-hexane to give 0.389 g of the desired product as a white solid. 
       1  H NMR(300 MHz, CDCl 3 )δ 8.9(1H, s), 8.4(1H,dd), 7.95(1H,dd), 7.75(1H, d), 7.5-6.9(22H,m), 6.55(1H,dd), 6.0(1H, dd), 5.3(1H,br s), 2.7(2H,t), 1.7(2H,m), 1.35(2H,m), 0.9(3H, t). 
     EXAMPLE 4 
     2-Butyl-6-[1-oxo-3-(2-oxocyclopentyl)propyl]-3-[[2&#39;-[1-(triphenylmethyl) -1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
     To a solution of 0.201 g of the product of Example 3 in 4.5 ml of methylene chloride, cooled to -78° C., is added dropwise 0.549 ml of 1.0M TiCl 4  in methylene chloride. The reaction mixture is stirred at -78° C. for 30 minutes and 0.098 ml of 1-(trimethylsilyloxy)-cyclopentene added dropwise. The reaction mixture is stirred at -78° C., for 0.5 hours and quenched with saturated potassium carbonate, diluted with chloroform, filtered through magnesium sulfate and concentrated in vacuo to give a residue which is purified by chromatography on silica gel by elution with 1:3 ethyl acetatehexane to give 0.079 g of the desired product as a white solid. 
     MS (FAB): m/z 839(M+Na). 
     EXAMPLE 5 
     2-Butyl-6-[1-oxo-3-(2-oxocyclohexyl)propyl]-3-[[2&#39;-[1-(triphenylmethyl) -1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl-4(3H)-quinazolinone 
     To a solution of 2.50 g of the product of Example 3 in 10.0 ml of methylene chloride, cooled to -78° C., is added dropwise 6.831 ml of 1.0M TICl 4  in methylene chloride. The reaction mixture is stirred at -78° C. for 30 minutes and 1.33 ml of 1-cyclohexenyloxytrimethylsilane added dropwise. The reaction mixture is stirred at -78° C., for 0.5 hours and quenched with saturated potassium carbonate diluted with chloroform, filtered through magnesium sulfate and concentrated in vacuo to give a residue which is purified by chromatography on silica gel by elution with 1:2 ethyl acetatehexane to give 0.979 g of the desired product as a white solid. 
     MS (FAB): m/z 853(M+Na). 
     EXAMPLE 6 
     2-Butyl-6-[1-hydroxy-3-(2-hydroxycyclopentyl)propyl]-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl-4(3H)-quinazolinone 
     To a solution of 0.950 g of the product of Example 4 in 25 ml of ethyl alcohol and 50 ml of tetrahydrofuran is added in one portion at room temperature 0.111 g of sodium borohydride. The reaction mixture is stirred at room temperature for one hour then poured into water and extracted with chloroform. The organic layer is dried with magnesium sulfate and concentrated in vacuo to give a residue which is purified by chromatography on silica gel by elution with 3:2 ethyl acetate-hexane to give 0.507 g of the desired product as a white solid. 
     MS (FAB): m/z 843(M+Na). 
     EXAMPLE 7 
     2-Butyl-6-[1-hydroxy-3-(2-hydroxycyclohexyl)propyl]-3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
     To a solution of 0.950 g of the product of Example 5 in 25 ml of ethyl alcohol and 50 ml of tetrahydrofuran is added in one portion at room temperature 0.109 g of sodium borohydride. The reaction mixture is stirred at room temperature for one hour then poured into water and extracted with chloroform. The organic layer is dried with magnesium sulfate and concentrated in vacuo to give a residue which is purified by chromatography on silica gel by elution with 2:1 ethyl acetate-hexane to give 0.147 g of the desired product as a white solid. 
     MS(FAB): m/z 857(M+Na). 
     EXAMPLE 8 
     2-Butyl-6-(octahydro-2H-1-benzopyran-2-yl)-3-[[2&#39;-[1-triphenylmethyl) -1H-tetrazol-5-yl][1,1&#39;-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
     To a solution of 0.498 g of the product of Example 7 in 5.0 ml of pyridine is added 0.051 ml of methanesulfonylchloride followed by stirring at room temperature for 48 hours and heating at reflux for 5 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:3 ethyl acetate-hexane to give 0.080 g of the desired product as a white solid. 
     MS(FAB): m/z 839(M+Na). 
     EXAMPLE 9 
     2-Butyl-6-(octahydrocyclopenta[b]pyran-2-yl) -3-[[2&#39;-[1-(triphenylmethyl)-1H-tetrazol-5-yl][[1,1&#39;-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone 
     To a solution of 0.491 g of the product of Example 6 in 5.0 ml of pyridine is added 0.051 ml of methanesulfonylchloride followed by stirring at room temperature for 48 hours and heating at reflux for 5 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:3 ethyl acetate-hexane to give 0.044 g of the desired product as a white solid. 
     MS(FAB): m/z 825(M+Na). 
     EXAMPLE 10 
     2-Butyl-6-(octahydrocyclopenta[b]pyran-2-yl)-3-[[2&#39;-(1H) -tetrazol-5-yl)[1,1&#39;-biphenyl]-4-yl]methyl]-4(4H)-quinazolinone 
     A solution of 0.040 g of the product of Example 9 in 0.5 ml of tetrahydrofuran and 2.5 ml of methyl alcohol is heated at reflux for 18 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 9:1 chloroform-methyl alcohol to give 0.017 g of the desired product as a white solid. 
     MS (FAB): m/z 561(M+H). 
     EXAMPLE 11 
     2-Butyl-6-(octahydro-2H-1-benzopyran-2-yl) -3-[[2&#39;-(1H)-tetrazol-5-yl)[1,1&#39;-biphenyl]-4yl]methyl]-4-(3H)-quinazolinone 
     A solution of 0.071 g of the product of Example 8 in 0.5 ml of tetrahydrofuran and 2.5 ml of methyl alcohol is heated at reflux for 18 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 9:1 chloroform-methyl alcohol to give 0.035 g of the desired product as a white solid. 
     MS(FAB): m/z 575 (M+H) 
     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 (1000,000× 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 μl aliquot is withdrawn and the protein content of the preparation is determined by the Lowry&#39;s method (Lowry, O. H., Rosebrough, N. F., Farr, 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 μl membrane protein (10 to 20 μg/assay) to wells already containing 100 μl of incubation buffer (as described above) and 20 μl [ 125  I](Sar 1 , Ile 8 )AngII (Specific Activity, 2200 Ci/mmole). Non-specific binding is measured in the presence of 1.0 μM unlabeled (Sar 1 , Ile 8 )AngII, added in 20 μl 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 μl 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® 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 I. 
     
                       TABLE I______________________________________ ##STR6##                          Angiotensin II                          ReceptorEx. No.  R            R.sup.5    Binding IC.sub.50 (M)______________________________________10   ##STR7##    (CH.sub.2).sub.3 CH.sub.3                          105 × 10.sup.-911   ##STR8##    (CH.sub.2).sub.3 CH.sub.3                          132 × 10.sup.-9______________________________________ 
    
     The enzyme renin acts on a blood plasma alpha 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 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. 
     As can be seen from Table I, the compounds demonstrate excellent Angiotensin II Receptor Binding activity. 
     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 μg/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. 
     
                                           TABLE II__________________________________________________________________________ANGIOTENSIN II (AII) VASOPRESSOR RESPONSE         AII Dose              Min Post                   Control                         Response   AverageDose (mg/Kg)  mcg/Kg              Dose Before AII                         After AII                               Change                                    Change                                         % Inhibition__________________________________________________________________________Control       0.05  0   255   295   40   42.5                   250   295   45         0.1       250   310   60   57.5                   260   315   55Ex. No 11 3 iv    0.05  30  245   260   15   17.5 59                   245   265   20         0.1       250   260   10   20   65                   250   280   30         0.05  60  230   260   30   22.5 47                   240   255   15         0.1       240   260   20   15   74                   245   255   10         0.05  90  235   265   30   20   53                   235   245   10         0.1       255   285   30   27.5 52                   235   260   25         0.05 120  245   255   10   10   76                   230   240   10         0.1       240   255   15   20   65                   225   250   25         0.05 180  235   265   30   32.5 24                   225   260   35         0.1       235   270   35   27.5 52                   235   255   20         0.05 240  230   250   20   13.5 68                   233   240    7         0.1       250   285   35   32.5 43                   225   255   30         0.05 300  245   275   30   22.5 47                   240   255   15         0.1       240   275   35   32.5 43                   245   275   30__________________________________________________________________________ SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weights(s): 400, 400 grams 
    
     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 1E, 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 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 micro-organisms 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.