US 5,064,825 AGrant
Angiotensin II Antagonists
Issue Date:1991-11-12
•9 Claims
Abstract
Novel substituted imidazo-fused 7-member ring heterocycles of the formulae (I) and (Ia), which are useful as angiotensin II antagonists, are disclosed. ##STR1##
Metadata
Assignee
- Merck & Co., Inc.
Inventors
- Prasun K. Chakravarty
- William J. Greenlee
- Nathan B. Mantlo
- Arthur A. Patchett
- William Schoen
- Thomas F. Walsh
Application Information
Application Number:US 5226627
Filing Date:1990-05-16
Priority Date:1989-06-01
Art Unit:129
Classifications
IPC:
A61K 3155C07D48722
Field of Search:
540514502;490;487221;211;81
Patent Drawings
This patent does not have any drawings.
Description
EXAMPLE 1
Preparation of 2-butyl-4-amino-5-carbomethoxy-1-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]im idaizole
Step A: Preparation of ethyl valeramidate
To 100 g (1.20mol) valeronitrile was added 71mL absolute ethanol (56 g 1.22 mol, 1.01 eq) and the mixture cooled to 0.degree. under nitrogen. Dry hydrogen chloride gas was bubbled through the solution for one hour and then the mixture was allowed to warm to room temperature and stir overnight.
The mixture was stripped of all volatiles in vacuo at 40.degree.; the residue slowly solidified to a pale yellow, low-melting solid. This solid was triturated with 500 mL of dry ether, filtered and washed with generous portions of dry ether. The titled compound was thus obtained as a hygroscopic white solid.
NMR 300MHz, CD.sub.3 OD): 1.02 (t,3H), 1.45 (m,2H), 1.53 (t,3H), 1.74 (m,2H), 2.69 (t,2H), 4.46 (q,2H).
Step B: Preparation of N-cyano-(ethylvaleramidate)
To a solution of 2.0g (12.1 mmol) of the product of Step 1(a) in 3mL absolute ethanol at room temperature was added 0.51g of cyanamide (12.1 mmol, 1.0 eq). After stirring overnight at room temperature, precipitated ammonium chloride was filtererd off and the filtrate stripped of solvent in vacuo. The residue was redissolved in ethyl acetate, filtered, and purified by medium pressure liquid chromatography on silica gel, eluting with ethyl acetate. In this manner, the titled compound was obtained as a colorless liquid.
NMR 200MHz, CDCl.sub.3): 0.95 (t,3H), 1.35 (t,3H), 1.4 (m,2H), 1.68 (m,2H), 2.68 (t,2H), 4.30 (q,2H).
Step C: Preparation of N'-cyano-N-(carbomethoxy) methyl)valeramidate
To a solution of 1.474 mg (9.56 mmol) N-cyano(ethyl valeramidate) (Example 1, Step B) in 3 mL absolute methanol at room temperature was added 1.44 g (11.5 mmol, 1.2 eq methyl glycinate hydrochlroide followed by 6.67 mL triethylamine (4.84 g. 47.9 mmol, 5 eq). The mixture was stirred at room temperature overnight then filtered and the filtrate concentrated in vacuo to a gummy residue The residue was taken up in 50 mL of ethyl acetate and washed with 5% aqueous citric acid (2.times.) and brine (1.times.). The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed in vacuo. The residue was purified by medium pressure liquid chromatography on silcia el, eluting with hexane/ethyl acetate (1:1). The title compound (0.998 g, 5.06 mmol, 53%) was thus obtained as a pale yellow oil that slowly solidified upon standing.
NMR (300 MHz, CDCl.sub.3 0.94 (t,3H). 1.41 (m,2H), 1.69 (m,2H), 2.62 (t,2H), 3.78 (s,3H), 4.06 (d,2H), 6.5 (br s, 1H).
EI-MS: 197 (.sup.+, 11%).
Step D: Preparation of 2-Cyano-4'-methyl-biphenyl
A solution of 4-bromotoluene (310 g, 1.81 moles) in 1500 ml of anhydrous ether was cooled to an internal temperature of -65.degree. C. (slurry forms at .about.-6.degree. C.) under nitrogen. A solution of t-butyllithium (1.7 M in pentane, 2.2 L, 3.74 moles) was added over a period of .about.90 minutes (internal temperature maintained below -55.degree. C.). The cooling bath was then replaced with water baths which brought the reaction mixture up to +20.degree. C. over 45 minutes and the white slurry was stirred an additional 2 hours at room temperature (most solids dissolved). The contents of this flask were then transferred under nitrogen pressure via a 1/8" plastic cannula to a stirred solution of ZnCl.sub.2 in ether (1M, 1.86 L) and THF (3.7 L) over 25 minutes (a cool water bath was used to maintain an internal temperature of 25.degree. C.). The reaction mixture was stirred at room temperature for 2 hours. The appearance may vary from a clear solution with white flocculent precipitate to a mixture with heavy white solids. The reaction mixture was then transferred via a 1/4" cannula under vacuum) to a solution of 2-bromobenzonitrile (220 g, 1.2 moles) and bis(triphenylphosphine) nickel (II) chloride (22 g, 0.0337 moles) in THF (3.1 L) at room temperature over 20 minutes. The internal temperature rose to 35.degree. C. during additions but subsided when complete. The dark red solution was stirred at room temperature overnight. The reaction mixture was then added carefully in portions to ice cold 1N HCl (.about.15 L) stirred rapidly in a large extractor. The organic layer was separated and the aqueous phase extracted with ether (3.times.2 L). The organic layers were combined and washed with water (2.times.2 L), brine, dried over MgSO.sub.4 and filtered through a plug of silica gel. The solution was concentrated to give the crude product as an oily solid (275 g). The material was then purified on a silica gel column (3 kg of E. Merck SiO.sub.2 60, 70-230 mesh) using methylene chloride-hexane (1:4 ) to give 196 g (85%) of the title compound as a low melting (46.degree.-49.5.degree. C.) solid. NMR (CDCl.sub.3): 2.22 (s, 3H), 7.24-7.78 (8H).
Step E: Preparation of trimethylstannyl azide
To a concentrated solution of sodium azide (1.2 kg, 18.5 moles) in water (3 L), a solution (required a little warming) of trimethyltin chloride (600 g, 3 moles) in dioxane (400 ml) was added in three portions with vigorous stirring. The immediate formation of a white precipitate was observed and no exotherm was recorded. The mixture was stirred overnight at room temperature. The solids were filtered, washed with water, dried under suction in the funnel and then over P.sub.2 O.sub.5 under vacuum. Yield 541 g (88%); mp 120.degree.-122.degree. C. The material was used without further purification.
Step F:
Preparation of 5-(4'-methylbiphen-2-yl)-tetrazole
To a solution of 390 g (2.02 moles) 2-cyano-4'-methylbiphenyl (Example 1, Step D) in toluene (2.3 1 was added trimethylstannyl azide (Example 1, Step E)(525g, 2.55 moles) at room temperature. The mixture was refluxed for 24 hours, cooled to room temperature, filtered, washed with toluene and sucked "dry" in a funnel. This gave the desired intermediate as a moist cake (1 kg). A small portion was dried further to give a white solid. mp 261.degree.-266.5.degree. C. (dec.) NMR (DMSO-d.sub.6): 0.35 (s, 9H), 2.23 (s, 3H), 6.96 (dd, 4H), 7.44 (m, 4H).
The intermediate was re-suspended in toluene (3.5 L) and THF (250 ml) was added. Anhydrous HCl was bubbled in at a moderate rate at room temperature to give a clear solution (.about.45 minutes). Addition of HCI gas was continued for another 20 minutes with stirring whereupon a white precipitate appeared. The HCl bubbler was removed and the mixture stirred at room temperature overnight (convenient). The solid product was filtered, washed with toluene followed by ether and then dried under vacuum. This produced 250 g of the title compound. mp 152.degree.-154C.; NMR (CDCl.sub.3): 2.4 (s, 3H), 7.19 (dd, 4H), 7.4 (dd, 1H), 7.55 (m, 2H), 8.25 (dd, 1H). May be crystallized from toluene.
Step G: Preparation of N-triphenylmethyl-5-(4'-methylbiohen-2-yl)tetrazole
To a cloudy solution of 250 g (1.06 moles) of the product from Step F in methylene chloride (4 L) was added triphenylmethyl chloride (310 g, 1.11 moles) at room temperature. The reaction mixture was stirred and triethylamine (190 ml, 138 g, 1.36 moles) was added in portions. After addition, the mixture was stirred at reflux (.about.40.degree. for 90 minutes. The solution was cooled to room temperature, washed with water 2.times.1 L), dried over MgSO.sub.4, filtered through a silica gel plug and concentrated on the rotovap to a solid. This was crystallized from toluene to give the title compound as an off-white solid (425 g, 84%);mP 166.degree.-168.degree. C.;NMR (CDCl.sub.3):2.28 (s,3H). 6.9-7.05 (m,.about.10H), 7.2-7.5 (m,.about.12H), 7.9 (dd,1H),
Step H: Preparation of N-triphenylmethyl-5-(4'-bromomethylbiohen-2-yl)tetrazole
To a solution of 425 g (0 89 moles) of N-triphenylmethyl-5-[2-(4'-methylbiphenylyl)]tetrazole in CCl.sub.4 (4.0 L) were added freshly opened N-bromosuccinimide (159 g, 0.89 moles) and dibenzoyl peroxide (22 g, 0.089 moles). The mixture was refluxed for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a thick oil. The addition of ether (.about.2.0 L) to this oil resulted in a clear solution followed by crystallization, filtration gave the title compound as a white solid (367 g, 74%). mp 137.degree.-139.5.degree. C.; NMR (CDCl.sub.3):4.38(s.2H)'6.9-8.0(m..about.23H). There is a trace of starting material still present.
Step I: Preparation of 4-amino-2 butyl 5 carbomethoxy-1-[(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl]imi dazole
To a solution of 137 mg (0.69 mmol) (N'-cyano-N-(carbomethoxy)methylvaleramidate (Step C) in 1 mL dry dimethyl formamide at room temperature was added 33 mg of sodium hydride (60% oil dispersion; 0.83 mmol, 1.2 eq). After 15 minutes, a solution of 386 mg (0.69 mmol, 1.0 eq) N-triphenylmethyl-5(4'-bromomethylbiphen-2-yl)tetrazole (Step H) was 14 added and the mixture stirred at room temperature for hours. The mixture was treated with one drop of glacial acetic acid then added to 30 mL ethyl acetate and washed once with 5% aqueous citric acid and once with brine. The organic layer was removed, dried over MgSO.sub.4, filtered and solvents removed in vacuo. The residue was purified by medium pressure liquid chromatography on silica gel, eluting with ethyl acetate to afford 172 mg (0.26 mmol, 37%) of the title compound as a pale yellow foam.
NMR (300 MHz, CDCl.sub.3): 0.83 (t,3H), 1.25(m,2H),1.58 (m,2H), 2.40 (t,2H), 3.67 (s,3H), 4.9 (br s, 2H), 5.29 (s,2H), 6.80 (d,2H), 6.90 (d,6H), 7.05 (d,2H), 7.2-7.5 (m,12H), 7.88 (d,1H).
FAB-MS: 674 (M+H, 8%), 243 (trityl+, 100%).
Step J: Preparation of 4-amino-2-butyl-5-carbomethoxy-1-(2'-(tetrazol-5-yl)biphen 4 yl)methylimidazole
To a solution of 47 mg (0.070 mmol) 4-amino-2-butyl-5-carbomethoxy-1-(2'-(N-triphenylmethyltetrazol-5-yl)biphe n-4-yl)methylimidazole (Example 1, Step I) in 1 mL glacial acetic acid was added 1 mL distilled water and the mixture stirred at room temperature for 14 hours. All volatiles were removed in vacuo and the residue purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/acetonitrile/methanol (9:1:.5), to afford 24 mg (0.056 mmol, 79%) of the title compound as a pale yellow powder.
NMR (300 MHz, CDl.sub.3 OD): 0.92 (t,3H), 1.37 (m,2H), 1.58 (m,2H), 2.66 (t,2H), 3.77 (s,3H), 5.51 (s,2H), 7.03 (d,2H), 7.13 (d,2H), 7.6 (m,2H), 7.7 (m,2H).
FAB-MS: 432 (M+H,100%).
EXAMPLE 2
2-Butyl-5-carbomethoxy-4-(methylamino)-1-(2'(tetra-zol-5-yl)biphen-4-yl)met hylimidazole
Step A: Preparation of 2-butyl-5-carbomethoxy-4(methyamino)-1-(2'-(N-triphenylmethyltetra-zol-5-y l)biphen-4-yl)methylimidazole and
2-butyl-5-carbomethoxy-4-(dimethylamino)-1-(2'-(N-triphenylmethyltetrazol-5 -yl)biphen-4-yl)methylimidazole
To a solution of 103 mg (0.15 mmol) 2-butyl-4-amino-5-carbomethoxy-1-(2'-(N-triphenylmethyltetra-zol-5-yl)-bip hen-4-yl)methylimidazole (Example 1, Step I) in 1 mL dry DMF at room temperature was added 7 mg sodium hydride/oil dispersion (60% dispersion; 0.18 mmol, 1.1 eq). After 15 minutes at room temperature, two drops of methyl iodide were added and the mixture capped tightly and stirred at room temperature for 16 hours. Two drops of glacial acetic acid were added and the mixture diluted into 20 mL ethyl acetate and washed with pH 7.0 phosphate buffer (2.times.) and brine (1.times.). The organic layer was removed, dried over magnesium sulfate, filtered and stripped; the residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (2:1) to afford 65 mg of a 2:1 mixture of mono- and di-methylated products in addition to 23 mg of recovered starting material.
Step B: Preparation of 2 -butyl-5-carbomethoxy-4-(methylamino)-1-(2'-tetrazol-5-yl)biphenyl]-4-yl)m ethylimidazole and 2-butyl-5-carbomethoxy-4-(dimethylamino)-1-(2'-(tetrazol-5-yl)biphen-4-yl) methylimidazole
65 mg of the mixture of intermediates described in Step A above was dissolved in 2 mL glacial acetic acid and treated with 2 mL distilled water for 18 hours at room temperature. All volatiles were removed in vacuo and the residue purified by reverse phase HPLC on C18 eluting with methanol/0.1% aqueous trifluoroacetic acid (gradient: 65% MeOH to 75% MeOH linearly over 10 minutes). In this manner, 27 mg 0.061 mmol'40%) of the title compound, 2-butyl-5-carbomethoxy-4-(methylamino)-1-(2'-(tetrazol-5-yl)biphen-4-yl)me thylimidazole in addition to 12 mg of the dimethyl compound (Example 3) were isolated.
NMR (300 MHz, CD.sub.3 OD): 0.94 (t,3H), 1.41 (m,2H), 1.46 (m,2H), 2.92 (t,2H), 3.08 (s,3H), 3.81 (s,3H), 5.72 (s,2H), 7.16 (m,4H), 7.6 7.8 (m,4H).
FAB-MS: 446 (M+H,100%)
EXAMPLE 3
2-Butyl-5-carbomethoxy-4-(dimethylamino)-1-(2'-tetrazol-5-yl)biphen-4yl)met hylimidazole
As described in Example 2 Step B), 12 mg (0.026 mmol, 17%) of the title compound was obtained from HPLC separation of a mixture of mono and dimethylated compounds.
NMR (300 MHz, CD.sub.3 OD): 0.95 (t,3H), 1.42 (m,2H), 1.60 (m,2H), 2.92 (t,2H), 3.12 (s,6H), 3.80 (s,3H), 5.70 (s,2H), 7.11 (d,2H), 7.18 (d,2H), 7.55-7.75 (m,4H).
FAB-MS: 460 (M+H,100%).
EXAMPLE 4
2-Butyl-5-carbomethoxy 4-(pyrrolidin 1-yl) 1 (2'-(tetrazol-5-yl-binpen-4-yl)methylimidazole
Step A: Preparation of 2-butyl-5-carbomethoxy-4-(pyrrolidin-1-yl)-1-(2'-(N-triphenylmethyl-tetraz ol-5-yl-biphen-4-yl)methylimidazole
To a solution of 65 mg (0 096 mmol) 4-amino-2-butyl-5-carbomethoxy-1-(2'-(N-triphenylmethyl-tetrazol-5-yl)biph en-4-yl)methylimidazole (Example 1, Step I) in 0.25 mL dry DMF at room temperature was added 9 mg of sodium hydride/oil dispersion (60% dispersion. 0.23 mmol. 2.3 eq). After 15 minutes at room temperature. 20 uL of 1,4-dibromobutane was added and the mixture stirred at room temperature for three days. The mixture was diluted with 10 mL ethyl acetate and washed with pH 7.0 phosphate buffer and brine. The organic layer was removed, dried (MgSO.sub.4), filtered and solvents removed in vacuo. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexanes (2:1) to afford 42 mg (0.058 mmol, 60%) of the title compound as a colorless oil.
NMR (300 MHz, CDCl.sub.3): 0.82 (t,3H), 1.25 (m,2H), 1.55 (m,2H), 1.88 (m,4H), 2.46 (t,2H), 3.46 (m,4H), 3.60 (s,3H), 5.32 (s,2H), 6.77 (d,2H), 6.91 (d,6H), 7.04 (d,2H), 7.2-7.5 (m,12H), 7.85 (d,1H).
Step B: Preparation of 2-butyl 5-carbomethoxy-4-(pyrrolidin-1-yl) 1-(2'(tetrazol-5-yl)-biphen-4-yl)methylimidazole
The intermediate described in Step A above (42 mg, 0.058 mmol) was dissolved in 0.5 mL glacial acetic acid and treated with 0.5 mL water for 12 hours at room temperature. All volatiles were removed in vacuo and the residue purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/acetonitrile/methanol (9:1:.25) to afford 23 mg (0.047 mmol, 49% overall) of the title compound as a pale yellow solid.
NMR (300 MHz, CDl.sub.3 OD): 0.92 (t,3H), 1.39 (m,2H), 1.57 (m,2H), 1.95 (m,4H), 2.70 (t,2H), 3.46 (m,4H), 3.65 (s,3H), 5.52 (s,2H), 7.00 (d,2H), 7.12 (d,2H), 7.55-7.70 (m,4H).
FAB-MS: 486 (M+H,100%).
EXAMPLE 5
4-Acetamido-2-butyl-5-carbomethoxy-1-(2'-(tetrazol-5-yl)biphen-biphen-4-yl) methylimidazole
Step A: Preparation of 4-acetamido-2-butyl-5-carbomethoxy-1-(2'-(N-triphenylmethyltetrazol-5yl)bi phen-4-yl)methylimidazole
To a solution of 86 mg (0.13 mmol) of the intermediate described in Example 1 (Step I) in 2 mL methylene chloride at 0.degree. under nitrogen was added 110 uL of diisopropylethyl amine (82 mg, 0.63 mmol, 5 eq) followed by 14 uL of acetyl chloride (15 m . 0.20 mmol, 1.5 eq . The mixture was stirred at 0.degree. for one hour then allowed to warm to room temperature slowly. The mixture was diluted with 5 mL ethyl acetate and washed once with 5% aqueous citric acid and once with brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvent removed. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate to afford 72 mg (0.10 mmol, 79%) of the title compound as a colorless oil.
NMR (300 MHz, CDC13): 0.83 (t,3H), 1.24 (m,2H), 1.63 (m,2H), 2.20 (s,3H), 2.52 (t,2H), 3.66 (s,3H), 5.46 (s,2H), 6.76 (d,2H), 6.92 (d,6H), 7.08 (d,2H), 7.2-7.4 (m,10H), 7.45 (m,2H), 7.88 (m,1H).
Step B: Preparation of 4-acetamido-2-butyl-5-carbomethoxy-1-(2'-(tetrazol-5-yl)biphen-4-yl) methylimidazole
65 mg (0.09 mmol) of the intermediate described in Step A above was dissolved in 0.5 mL glacial acetic acid at room temperature and treated with 0.5 mL distilled water for fourteen hours. All volatiles were removed in vacuo and the residue purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/acetonitrile/ methanol (9:1:0.25) to afford 32 mg 0.068 mmol, 74%) of the title compound as a white powder. NMR (300 MHz, CDCl.sub.3): 0.88 (t,3H), 1.32 (m,2H), 1.68 (m,2H), 2.26 (s,3H), 2.62 (t,2H), 3.71 (s,3H), 5.05 (s,2H), 6.95 (d,2H), 7.11 (d,2H), 7.39 (d,1H), 7.55 (m,2H), 7.98 (d,1H).
FAB-MS: 474 (M+H,28%)
EXAMPLE 6
4-Acetoxyacetamido-2-butyl 5-carbomethoxy-1-(2'-(tetrazol-5-yl)biphen-4-yl)methylimidazole
Step A: Preparation of 4-acetoxyacetamido-2-butyl-5-carbomethoxy-1-(2'-(N triphenylmethyl-tetrazol-5-yl)bipen-4-yl)methylimidazole
To a solution of 110 mg (0.16 mmol) of the intermediate described in Example 1 (Step I) in 1 mL methylene chloride at 0 under nitrogen was added 85 uL of diisopropylethyl amine (63 mg, 0.49 mmol, 3 eq) followed by 26 uL of acetoxyacetyl chloride (33 mg, 0.24 mmol, 1.5 eq). The mixture was stirred at 0.degree. for one hour then diluted with 10 mL ethyl acetate and washed once with 5% aqueous citric acid and once with brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (2:1) to afford 115 mg (0.15 mmol, 91%) of the title Compound as a colorless glass.
NMR (300MHz, CDCl.sub.3): 0.84 (t,3H), 1.29 (m,2H), 1.64 (m,2H), 2.23 (s,3H), 2.55 (br t,2H), 3.69 (s,3H), 4.8 (br s, 2H), 5.35 (s,2H), 6.76 (d,2H), 6.93 (d,6H), 7.09 (d,2H), 7.2-7.4 (m,10H), 7.47 (m,2H), 7.89 (m,1H).
FAB-MS: 773 (M.sup.+, 6%), 243 (Tr.sup.+, 100%).
Step B: Preparation of 4-acetoxyacetamido-2-butyl-5-carbomethoxy-1-(2'-(tetrazol-5-yl)biphen 4-yl)methylimidazole
110 mg (0.14 mmol) of the intermediate described in Step A above was dissolved in 1 mL glacial acetic acid at room temperature and treated with 1 mL distilled water for fourteen hours. All volatiles were removed in vacuo and the residue purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/acetonitrile/methanol (9:1:0.25) to afford 62 mg (0.12 mmol, 82%) of the title compound as a colorless glass.
NMR (300MHz, CDCl.sub.3 : 0.80 (br t,3H), 1.25 (br m,2H), 1.54 (br m,2H), 2.20 (s,3H), 2.46 (br m,2H), 3.73 (s,3H), 4.55 (br s,2H), 5.38 (s,2H), 6.84 (d,2H), 7.09 (d,2H), 7.37 (d,1H), 7.50 (m,2H), 7.85 (d,1H).
FAB-MS: 532 (M+H,100%)
EXAMPLE 7
4-(Aminoacetyl)amino-2-butyl-5-carbomethoxy-1-(2'-(tetrazol-5-yl)biphen-4-y l)methylimidazole
Step A: Preparation of 2-butyl-4-chloroacetamido 5-carbomethoxy-1-(2'-(N-triphenylmethyl-tetrazol-5-yl)biphen-4-yl)methylim idazole
To a solution of 142 mg (0.21 mmol) of the intermediate described in Example 1 (Step I) in 2 mL methylene chloride at 0.degree. under nitrogen was added 60 uL of triethyl amine (44 mg, 0.43 mmol, 2 eq) followed by 20 uL of chloroacetyl chloride (28 mg, 0.25 mmol, 1.2 eq . The mixture was stirred at 0.degree. for one hour then warmed to room temperature and stirred an additional hour. The mixture was diluted with 30 mL ethyl acetate and washed with 5% aqueous citric acid (2.times.) and brine (1.times.). The organic layer was removed, dried over magnesium sulfate, filtered and solvent removed. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexanes (2:1) to afford 129 mg (0.17 mmol, 82%) of the title compound as a white, crusty foam.
NMR 300MHz, DMSO-d.sub.6): 0.76 (t,3H), 1.18 (m,2H), 1.48 (m,2H), 2.45 (s,3H), 3.61 (s,3H), 4.30 (s, 2H), 5.48 (s,2H), 6.9 (m,8H), 7.05 (d,2H), 7.3-7.6 (m,12H), 7.79 (d,1H).
FAB-MS: 750 (M+H,5%), 243 (Tr.sup.+, 100%).
Sep B: Preparation of 4-(t-butoxycarbonylamino) acetyl-2-butyl-5-carbomethoxy-1-(2'(N-tri-phenylmethyltetrazol-5-yl)biphen -4-yl) methylimidazole
Ammonia was slowly bubbled through a solution of 82 mg (0.11 mmol) of the intermediate described in Step A above in 2 mL dry DMF at 60.degree. for three hours. All volatiles were removed in vacuo, the residue re-dissolved in 2 mL methylene chloride and treated with excess (ca. 0.5 mL) di-t-butyl-dicarbonate. After 30 minutes at room temperature, all volatiles were removed in vacuo and the gummy residue extracted with several small portions of ethyl acetate. The combined extracts were concentrated to dryness and purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexanes (2:1) to afford 72 mg (0.087 mmol, 79%) of the title compound as a white foam.
NMR 300MHz, CDCl.sub.3): 0.83 (t,3H), 1.26 (m,2H), 1.46 s'9H), 1.62 (m,2H), 2.52 (t,2H), 3.69 (s'3H), 5.34 s.2H), 6.75 d.2H), 6.91 (d.6H), 7.07 (d,2H), 7.2-7.5 (m,12H), 7 88 (d,1H),
FAB-MS: 831 (M+H,38%)
Step C: Preparation of 4-(aminoacetyl)amino-2-butyl-5-carbomethoxy-1-(2'-(tetrazol-5 yl)biphen-4-yl)methylimidazole
To a solution of 70 mg (0.084 mmol) of the intermediate described in Step B above in 1 mL glacial acetic acid at room temperature was added 0.5 mL 6N HCI and the mixture stirred for two days. All volatiles were removed in vacuo and the residue purified by reverse phase HPLC on C-18, eluting with methanol/0.1% aqueous trifluoroacetic acid (gradient: 70% methanol increased linearly to 80% methanol over ten minutes). The title compound, as its trifluoroacetate salt (46 mg, 0.076 mmol, 91%) was thus obtained as a white powder.
NMR (300MHz, CD.sub.3 OD): 0.95 (t,3H), 1.30 (m,2H), 1.65 (m,2H), 2.78 (m,2H), 3.83 (s,3H), 4.1 (br s,2H), 5.66 (s,2H), 7.05 (d,2H), 7.16 (d,2H), 7.6-7.8 (m,4H).
FAB-MS: 489 (M+H,100%).
EXAMPLE 8
2-Butyl-4-[N-methyl N-[(benzyloxycarbonyl)acetyl]] amino-5-carbomethoxy-1-((tetrazol-5-yl)biphen-4-yl) methylimidazole
Step A: Preparation of 2-butyl-4-(methylamino) 5-carbomethoxy-1-(2'-(N-triphenylmethyl) tetrazol-5-yl)biphen-4-yl)methylimidazole
To a solution of 217 mg (0.322 mmol) 4-amino-2-butyl-5-carbomethoxy-1-((2'(N-triphenylmethyl)tetrazol-5-yl)biph en-4-yl) (Example 1, Step I) in 2 mL dry dimethylformamide at room temperature under nitrogen was added 17 mg of 60% sodium hydride/oil dispersion (10 mg NaH, 0.43mmol, 1.3 eq). After 15 minutes at room temperature, two drops of methyl iodide were added; the flask was stoppered tightly and the mixture stirred overnight.
The mixture was added to 50 mL ethyl acetate nd washed once with pH 7 phosphate buffer and once with brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed in vacuo. The residue was purified by medium pressure liquid chromatography on silica gel, eluting with ethyl acetate/hexane (2:1) to afford 180 mg (0.262 mmol, 81%) of the title compound which was contaminated with approximately 15% of dimethylated material.
NMR (200MHz, CDCl.sub.3 : 0.83 (t,3H), 1.22 (m,2H), 1.58 (m,2H), 2.46 (t,2H), 3.06 (d,3H), 3.63 (s,3H), 5.29 (s,2H), 5.5 (br s,1H), 6.78 (d,2H), 6.92 (d,6H), 7.15 (d,2H), 7.2-7.5 (m,12H), 7.88 (m,1H).
Step B: Preparation of 2-butyl-4-[N methyl-N-[(benzyloxycarbonylamino)acetyl]]amino-5carbomethoxy-1-[(2'-(N-tr iphenylmethyl)tetrazol-zol-5-yl)biphen-4-yl]methylimidazole
370 mg (1.77 mmol, 10 eq.) of N-carbobenzyloxy glycine was dissolved in 2mL dry methylene chloride at 0.degree. under nitrogen and treated with 184 mg (0.89 mmol, 5 eq.) dicyclohexylcarbodiimide. The mixture was stirred at 0.degree. for 30 minutes then a solution of 123 mg (0.18 mmol, 1.0 eq.) of the product of Step A in 1 mL methylene chloride was added and the mixture allowed to warm to room temperature and stir overnight.
The mixture was added to 50 mL ethyl acetate, filtered and the filtrate washed twice with saturated aqueous sodium bicarbonate and once with brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed in vacuo. The residue was purified by medium pressure liquid chromatography on silica gel, eluting with ethyl acetate/hexane (2:1) to afford 180 mg (0.262 mmol, 81%) of the title compound which was contaminated with approximately 15% of dimethylated material.
NMR (200 MHz, CDCl.sub.3 0.83 (t,3H), 1.22 (m,2H), 1.58 (m,2H), 2.46 (t,2H), 3.06 (d,3H), 3.63 (s,3H), 5.29 (s,2H), 5.5 (br s,1H), 6.78 (d,2H), 6.92 (d,6H), 7.15 (d,2H), 7.2-7.5 (m,12H), 7.88 (m,1H).
Step C: Preparation of 2-butyl-4-[N methyl-N [(benzyloxycarbonylamino)acetyl]]amino-5-carbomethoxy-1-(2'-(tetrazol 5-yl)biphen-4 yl)-methylimidazole
124 mg (0.14 mmol) of the product of Step B in 4 mL glacial acetic acid was treated with 4 mL distilled water and the resulting mixture stirred 18 hours at room temperature.
All volatiles were removed in vacuo and the residue purified by medium pressure liquid chromatography on silica gel, eluting with ethyl acetate/acetonitrile/methanol (9:1:0.5)) to afford 85 mg (0.13 mmol, 95%) of the title compound as a pale yellow foam.
NMR (200MHz, CDCl.sub.3 : 0.94 (t,3H), 1.42 (m,2H), 1.78 (m,2H), 2.81 (t,2H), 3.21 (s,3H), 3.68 (d,2H), 3.73 (s,3H), 4.88 (s,2H), 5.46 (s,2H), 5.76 (br t,1H), 6.92 (d,2H), 7.0-7.6 (m,10H), 7.86 (d,1H).
FAB-MS: 637 (M+H,100%).
EXAMPLE 9
2-Butyl-4-[N-methyl-N-aminoacetyl]amino-5-carbomethoxy-1-(2'-(tetrazol-5-yl )biphen-4-yl)methylimidazole
A solution of 72 mg (0.11 mmol) of the compound described in Example 8 (Step C) was dissolved in 2 mL methanol and hydrogenated at 1 atmosphere over 15 mg of 10% Pd(OH).sub.2 /C for one hour. The reaction mixture was filtered through Celite and solvent removed under vacuum to afford 55 mg (0.10 mmol, 91%) of the title compound as a colorless glass.
NMR (200MHz, CD.sub.3 OD): 0.88 (t,3H), 1.34 (m,2H), 1.62 (m,2H), 2.72 (t,2H),3.20 (s,3H), 3.52 (s,2H), 3.76 (s,3H), 5.60 (s,2H), 6.98 (d,2H), 7.08 (d,2H), 7.52 (m,2H), 7.60 (m,2H).
FAB-MS: 503 (M+H,100%).
EXAMPLE 10
2-Butyl-4-methyl-1-(2'-(tetrazol-5-yl)biphen-4-yl) methyl-1,4,6,7-tetrahydroimidazo[4,5-e]-[1,4]-diazepine-5,8-dione
A solution of 50 mg (0.099 mmol) of the compound described in Example 9 dissolved in 5 mL dry DMF was treated with 5 mg (0.04 mmol, 0.4 eq) 4-(dimethylamino)pyridine and the resulting solution heated at 140.degree. under nitrogen for one hour. All volatiles were removed under vacuum nd the residue purified by reverse phase HPLC on C-18 eluting with methanol/0.1% aqueous trifluoroacetic acid (gradient: 75% methanol to 85% methanol linearly over ten minutes). In this manner, 19 mg (0.040 mmol, 41%) of the title compound was obtained as a colorless glass. In addition, 25 mg (0.047 mmol, 47%) of the more mobile N-formyl derivative of the starting material was obtained as a by-product.
NMR (200MHz, CD.sub.3 OD): 0.87 (t,3H), 1.34 (m,2H), 1.58 (m,2H), 2.66 (t,2H), 3.39 (s,3H), 3.80 (s,2H), 5.55 (s,2H), 7.05 (s,4H), 7.5-7.7 (m,4H).
FAB-MS: 471 (M+H,60%).
EXAMPLE 11
2-Butyl-4-[N-methyl-N-[N'-formyl]aminoacetyl]amino-5-carbomethoxy-1-((tetra zol-5-yl)biphen-4-yl)methyl-imidazole
The title compound was isolated as a colorless glass as described in Example 10.
NMR (200MHz, CD.sub.3 OD): 0.87 (t,3H), 1.33 (m,2H), 1.60 (m,2H), 2.69 (t,2H),3 18 (s,3H), 3.73 (s,3H), 3 85 s,2H), 5.53 (s,2H), 7.00 (d,2H), 7.11 (d,2H), 7.5-7.7 (m,4H), 8.07 (br s,1H).
FAB-MS: 531 (M+H,100%).
EXAMPLE 12
4-Amino-2-butyl-5-carboethoxy-1 (2'carboxybiphen-4-yl)methylimidazole
Step A: Preparation of N'-cyano-N-[(carboethoxy) methyl]-valeramidine
To a solution of 100 mg (0.65 mmol) N-cyano-(ethylvaleramidate) (Example 1, Step B , in 2 mL absolute ethanol at room temperature was added 100 mg (0.72 mmol, 1.1 leq) ethyl glycinate hydrochloride followed by 0.30 mL triethylamine (220 mg, 2.16 mmol, 3.3 eq). The mixture was stirred at room temperature overnight then concentrated in vacuo to a gummy residue. The residue was treated with 20 mL of hexane/ethyl acetate (1:1), stirred vigorously, filtered, and the filtrate purified by medium pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (1:1). The title compound (119 mg, 0.56 mmol, 87%) was thus obtained as a pale yellow oil that slowly solidified upon standing.
NMR(200MHz,CDCl.sub.3): 0.95(t,3H),1.28(t,3H),1.42(m,2H),1.72(m,2H),2.65 (t,2H),4.05(d,2H),4.25(q,2H),6.7(br s,1H).
B: Preparation of N'-Cyano-N-(carboethoxymethyl)-N-(2'-t-butoxycarbonylbiphen 4-yl) methylvaleramidine
To a solution of 119 mg (0.56 mmol of the product of Step A in 1 mL dry DMF at room temperature (under N.sub.2) was added 23 mg of 60% sodium hydride-oil dispersion (14 mg NaH, 0.58 mmol, 1.05 eq). After 15min., a solution of 195 mg (.56 mmol, 1.0 eq) 4'-bromomethyl-2-t-butoxycarbonylbiphenyl in 1 mL dry DMF was added and the mixture stirred at room temperature for 6 hours. [The bromide was synthesized by the method of Carini, et al, European Patent Application 253,310 (to DuPont), 1988.]
The mixture was diluted with 30 mL ethyl acetate, washed twice with 5% aqueous citric acid, twice with 5% aqueous sodium bicarbonate and once with brine. The organic layer was separated, dried over MgSO.sub.4, filtered and stripped of solvent in vacuo. The crude product was purified by medium pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (2:1) to afford the title compound as a colorless oil.
NMR (300MHz, CDCl.sub.3 : The .sup.1 H NMR spectrum indicates that the product exists as a mixture of rotamers in a ratio of approximately 80:20. 0.95 (t,3H), 1.25 (t,3H), 1.28 (s,9H), 1.48 (m,2H), 1.74 (m,2H), 2.70 (t,.2.times.3H), 2.82 (t,.8.times.3H)], [4.02 (s,2.times.2H), 4.10 (s,.8.times.2H)], 4.2 (q,2H), [4.70 (s,8.times.2H), 4.80 (s,.2.times.2H) , 7.1-7.8 (m,8H).
Step C: Preparation of 4 amino-2-butyl-5 carboethoxy-1-(2'-t-butoxycarbonylbiphen-4-yl) methylimidazole
To a solution of 98 mg (0.21 mmol) of the product of Step B in 2 mL absolute ethanol at room temperature was added a solution made from 3 mg of sodium hydride (60% oil dispersion; 0.07 mmol. 0.3 eq) in 1 mL absolute ethanol. The mixture was stirred at room temperature for 3 hours then treated with several drops of glacial acetic acid. The mixture was added to 30 mL ethyl acetate and washed once with saturated aqueous sodium bicarbonate and once with brine. The organic layer was separated, dried over MgSO.sub.4, filtered and solvents removed in vacuo. The residue was purified by medium pressure liquid chromatography on silica gel, eluting with ethyl acetate to afford the title compound as a pale yellow oil.
NMR (300MHz, CDCl.sub.3 : 0.85 (t.3H)'1.20 (s,9H)'1.26 (t'3H)'1.32 (m'2H). 2.59 (t.2H). 4.20 (q'2H), 5.0 (variable, br s.1H), 5.46 (s'2H)'7.03 (d,2H), 7.25 (m,3H), 7.36 (t,1H), 7.45 (t,1H), 7.75 (d,1H).
Step D: 4-Amino-2-butyl-5-carboethoxy-1-(2'-carboxy-biphen-4-yl)methylimidazol
To a solution of 32 mg (0.067 mmol of the intermediate described in Step C in 1 mL methylene chloride at room temperature was added several drops of anisole followed by 1 mL anhydrous trifluroacetic acid. After 3 hours, all volatiles were removed in vacuo and the residue Purified by reverse phase HPLC on C18 eluting with methanol/0.1% aqueous trifluoroacetic acid (linear gradient: 70% methanol to 80% methanol over 10 minutes). The title compound (22 mg, 0.052 mmol, 78%) was thus obtained as a light yellow powder.
NMR (300MHz, CD.sub.3 OD): 0.94 (t,3H), 1.30 (t,3H), 1.40 (m.2H). 1.61 (m.2H). 2.94 (t,2H). 4.35 (q.2H), 5.76 (s'2H). 7.22 (d,2H). 7.38 (m.3H). 7.47 (t,1H)'7.59 (t,1H). 7.86 (d.1H).
FAB-MS: 422 (M+H, 100%).
EXAMPLE 13
2-Butyl-4-methylamino-5-carboethoxy-1-(2-carboxybiphen-4-yl)methylimidazole
Step A: Preparation of 2-butyl-4-methylamino-5-carboethoxy-1-(2'-t-butoxycarbonylbiphen-4-yl)meth ylimidazole and 2 butyl 4-dimethyl-amino-5-carboethoxy-1-(2'-t-butoxycarbonyl-biphen-4-yl)methylim idazole
To a solution of 92 mg (0.19 mmol) of the intermediate described in Example 12 (Step C) in 1 mL dry dimethyl formamide at room temperature was added 9 mg of sodium hydride oil dispersion (60% dispersion; 5.4 mg NaH, 0.23 mmol, 1.2 eq). After 30 minutes, a solution of two drops (excess) methyl iodide in 0.5 mL DMF was added and the mixture stirred at room temperature overnight. The mixture was added to 20 mL ethyl acetate and washed with 5% aqueous citric acid and brine. The organic layer was separated, dried over magnesium sulfate, filtered and solvents removed in vacuo. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (2:1) to afford 56 mg of product in addition to 22 mg (0.05 mmol, 24%) recovered starting material. NMR analysis reveals the product to be a mixture of 85% mono methyl and 15% dimethyl derivatives.
NMR 300MHz, CDCl.sub.3 : 0.87 (t,3h , 1.20 (s,,9H), 1.21 (t,3h), 1.33 (m,2H), 1.62 (m,2H), 2.59 (t,2HO, 2.04 (d,3H), 4.17 (q,2H), 5.43 s,2H , 5.55 (br s, 1H), 7.02 (d,2H), 7.23 (d,2H), 7.24 (d,1H), 7.36 (t,1H), 7.45 (t,1H), 7.74 (d,1H).
FAB-MSS: 492 (M+H, 48%): monomethyl, 505 (M+, 22%): dimethyl
Step B: Preparation of 2-butyl-4-methylamino-5-carboethoxy-1-(2'-carboxybiphen-4-yl)methyl-imidaz ole
To a solution of 56 mg (ca. 0.11 mmol) of the mixture of intermediates described in Step A above in 2 mL methylene chloride at room temperature was added two drops of anisole followed by 2 mL anhydrous trifluoroacetic acid. After three hours, all volatiles were removed in vacuo and the residue purified by reverse phase HPLC on C18 eluting with methanol/0.1% aqueous trifluoroacetic acid (linear gradient: 80% methanol to 85% methanol over 10 minutes). In this manner, 33 mg (0.080 mmol, 66%) of the title compound was obtained in addition to 9 mg (0.02 mmol, 17%) of the dimethyl derivative.
NMR (300MHz, CD.sub.3 OD): 0.95 (t,3H), 1.26 (t,3H), 1.41 (m,2H), 1.59 (m,2H), 2.93 (t,2H), 3.08 (s,3H), 4.30 (q,2H), 5.73 (s,2H), 7.20 (d,2H), 7.38 (d,3H), 7.48 (t,1H), 7.59 (t,1H), 7.85 (d,1H).
FAB-MS: 436 (+H, 100%).
EXAMPLE 14
2-Butyl-4-dimethylamino-5-carboethoxy-1-(2-carboxy-biphen-4-yl)methylimidaz ole
The title compound (9 mg, 13%) was obtained by the procedures described in Example 13 (Step B).
NMR (300MHz, CDCl.sub.3 : 0.94 (t,3H), 1.26 (t,3H), 1.42 (m,2H), 1.61 (m,2H), 2.95 (t,2H), 3.14 (s,6H), 4.29 (q,2H), 5.77 (s,2H), 7.19 (d,2H), 7.38 (d,3H), 7.48 (t,1H), 7.60 (t,1H), 7.86 (d,1H).
FAB-MS: 450 (M+H, 100%).
EXAMPLE 15
4-Acetamido-2-butyl-1-(2'-(tetrazol-5-yl)biphen-4-yl)-methylimidazole-5-car boxylic acid
Step 1 4-Amino-2-butyl-1-[(2'-(N-triphenylmethyl-tetrazol-5-yl)biphen-4-yl)methyl ]-5-(tert-butoxycarbonyl)imidazole
The title compound was prepared by using the procedures outlined in Example 1 substituting t-butylglycinate hydrochloride for the corresponding methyl ester in Step C. .sup.1 H NMR (300 MHz, CDCl.sub.3 .delta. 7.85 (d, 1H), 7.63-7.58 (m, 2H), 7.44 (d, 1H), 7.05 (d, 2H), 6.72 (d, 2H), 5.22 (s, 2H), 2.22 (t, 2H), 1.48-1.35 (m, 2H), 1.34 (s, 9H), 1.22-1.09 (m, 2H), 0.73 (t, 3H).
Step 2 4-Acetamido-2-butyl-1-[(2'-(N-triphenyl-methyltetrazol-5-yl)biphen-4-yl)me thyl]-5-(tert-butoxycarbonyl)imidazole
The title compound was prepared by using the procedures outlined in Example 5, Step A. 1H NMR (300 MHz, CDCl.sub.3 .delta. 7.86 (d. 1H). 7.52-7.40 (m, 2H), 7.36-7.22 (m, 10H), 7.10 (d, 2H), 6.96 (d, 2H), 5.38 (s, 2H), 2.52 (s(b), 3H), 2.32 (t'2H), 1.70-1.56 (m, 2H), 1.42 (s, 9H), 1.35-1.20 (m, 2H), 0.86 (t, 3H).
Step 3 4-Acetamido-2-butyl-1-(2'-(tetrazol-5-yl)-biphen-4-yl)methylimidazole-5-ca rboxylic acid
A mixture of the Step 2 material (51 mg) and 85% formic acid (2 mL) was stirred at room temperature for 36 hours. Concentration (in vacuo at room temperature) and purification (SiO.sub.2, 35:65:1 CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH) gave the title compound (10 mg) as a solid. FAB MS (M.sup.+ +1)=460, (M++Na)=482; 1H NMR (300 MHz, CDCl.sub.3 .delta. 7.63-7.35 (m, 4H), 7.06-6.86 (ABq, 4H), 5.73 (s, 2H), 2.74-2.60 (m, 2H), 2.02 (s(b), 3H), 1.48-1.22 (m, 4H), 0.83 (t, 3H).
EXAMPLE 16
2-Butyl-4-(N-methylacetamido)-1-(2'-(tetrazol-5-yl)-biphen-4-yl)methylimida zole-5-carboxylic acid
Step 1 5-(tert-Butoxycarbonyl)-2-butyl 4-(methylamino)-1-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methylim idazole
The title compound was prepared by using the procedures outline in Example 2, Step A starting from 4-amino-(5-tert-butoxycarbonyl)-2-butyl-1-(2'-(N-tri-phenylmethyltetrazol- 5-yl)biphen-4-yl)methylimidazole.
Step 2 2-Butyl-4-(N-methylacetamido)-1-(2'-(tetrazol-5-yl)biphen-4-yl)methylimida zole-5-carboxylic acid
The title compound was prepared by using the procedures outlined in Example 15, Steps 2 and 3.
FAB MS (M.sup.+ +1)=474, (M.sup.+ +Na)=496;
.sup.1 H NMR (300 MHz, CDCl.sub.3 .delta. 7.58-7.48 (m, 4H), 7.12-6.88 (ABq, 4H), 5.69 (s, 2H), 3.18 (s, 3H), 2.62 (t, 2H), 1.90 (s, 3H), 1.65-1.50 (m, 2H), 1.40-1.28 (m, 2H), 0.89 (t, 3H).
EXAMPLE 17
2-Butyl-4-(methylamino)-1-(2'-(tetrazol-5-yl)biphen-4-yl)methylimidazole-5- carboxylic acid
The title compound can be prepared from 2-butyl-4-(N-methylacetamido)-1-(2'-(tetrazol-5-yl)-biphen-4-yl)methylimid azole-5-carboxylic acid by reaction with 3 molar equivalents of diisobutyl-aluminum hydride in THF at room temperature followed by aqueous workup (extraction from 0.1% aqueous HOAc with EtOAc and isolation (SiO.sub.2, 35:65:1 CH.sub.2 Cl.sub.2 /MeOH/ NH.sub.4 OH). Alternatively' the title compound could be prepared from 4-methylamino-5-benzyloxycarbonyl-2-butyl-1-(2'-(N-triphenylmethyltetrazol -5-yl-biphen-4-yl)methylimidazole (mentioned in Example 18, Step 2) by reaction as outlined in Example 18, Step 3.
EXAMPLE 18
2-Butyl-4-(dimethylamino)-1-(2'-(tetrazol 5-yl)biphen-4-yl)methylimidazole-5-carboxylic acid
Step 1 4-Amino-5-benzyloxycarbonyl-2-butyl-1-(2'-(N-triphenylmethyltetrazol-5-yl) biphen-4-yl)methylimidazole
The title compound can be prepared by using the procedures outlined in Example 1 substituting benzylglycinate hydrochloride for the corresponding methyl ester in Step C.
Step 2 4-(Dimethylamino)-5-benzyloxycarbonyl-2-butyl-1-(2'-(N-triphenylmethyltetr azol-5-yl)biphen-4-yl)methylimidazole
The title compound can be prepared by using the procedures outlined in Example 3 starting from 4-amino-5-benzyloxycarbonyl-2-butyl-1-(2'-(N-tri-phenylmethyltetrazol-5-yl )biphen-4-yl)methylimidazole. A side product in this reaction would be 4-methyl-amino-5-benzyloxycarbonyl-2-butyl-1-(2'(N-triphenyl-methyltetrazo l-5-yl)biphen-4-yl)methylimidazole.
Step 3 4-(Dimethylamino)-2-butyl-1-(2'-(tetrazol-5-yl)biphen-4-yl)methylimidazole -5-carboxylic acid
The title material can be prepared by treating a mixture of 4-(dimethylamino)-2 butyl 5-benzyloxycarbonyl-1-(2'-(N-triphenylmethyltetrazol-5-yl)biphen 4-yl)methylimidazole and 5 weight % of 10% Pd-C with H.sub.2 (at 40 psi) in EtOH for 16 hours, followed by filtration (Celite) and purification (SiO.sub.2 '35:65:1 CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH).
EXAMPLE 19
2-Butyl-4-(pyrrilidin-1-yl)-1-(2'-(tetrazol-5-yl)-biphen-4-yl)methylimidazo le-5-carboxylic acid
Step 1 5-Benzyloxycarbonyl-2-butyl-4-(pyrrolidin-1-yl)-1-(2'-(N-triphenylmethylte trazol-5-yl)biphen-4-yl)methylimidazole
The title compound could be prepared by using the procedure outlined in Example 4, Step A starting from 4-amino-5-benzyloxycarbonyl-2-butyl-1-(2'-(N-triphenylmethyltetrazol-5-yl) biphen-4-yl) methylimidazole.
Step 2 2 Butyl-4-(pyrrolidin-1-yl)-1-(2'-(tetrazol-5-yl)biphen-4-yl)methylimidazole -5-carboxylic acid
The title compound could be prepared by using the procedure outlined in Example 18, Step 3.
EXAMPLE 20
Typical Pharmaceutical Compositions Containing a Compound of the Invention
A: Dry Filled Capsules Containing 50 mg of Active Ingredient Per Capsule
The 2-butyl-4-methyl-1-(2'-(tetrazol-5-yl) biphenyl]-4-yl)methyl-1,4,6,7-tetrahydroimidazo[4,5-e]-[1,4]-diazepine-5,8 -dione can be reduced to a No. 60 powder and the lactose and magnesium stearate can then be passed through a No. 60 blotting cloth onto the powder. The combined ingredients can then be mixed for about 10 minutes and filled into a No. 1 dry gelatin capsule.
B: Tablet
A typical tablet would contain 2-butyl-4-methyl-1 (2'(tetrazol-5-yl)biphen-4-yl) methyl-1,4,6,7-tetrahydroimidazo[4'5-e]-[1.4]diazepine 5,8-dione (25 mg), pregelatinized starch USP (82 mg), microcrystaline cellulose 82 mg and magnesium stearate (1 mg).
C: Combination Tablet
A typical combination tablet would contain, for example, a diuretic such as hydrochlorothiazide and consist of 2-butyl-4-methyl-1-(2'-(tetrazol-5-yl) biphen-4-yl)methyl-1,4'6,7-tetrahydroimidazo[4,5-e]-[1,4]-diazepine-5,8-di one hydrochlorothiazide (50 mg), pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).
D: Suppository
Typical suppository formulations for rectal administration can contain 2-butyl-4-methyl-1-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-1.4.6.7-tetrahydr o-imidazo[4,5-e]-[1,4]-diazepine-5,8-dione butylated hydroxyanisol (0.08-1.0 mg), disodium calcium edetate (0.25-0.5 mg), and polyethylene glycol (775-1600 mg). Other suppository formulations can be made by substituting, for example butylated hydroxytoluene (0.04-0.08 mg) for the disodium calcium edetate and a hydrogenated vegetable oil (675-1400 mg) such as Suppocire L, Wecobee FS, Wecobee M, Witepsols, and the like, for the polyethylene glycol. Further, these suppository formulations can also include another active ingredient such as another antihypertensive and/or a diuretic and/or an angiotensin converting enzyme and/or a calcium channel blocker in pharmaceutically effective amounts as described, for example, in C above.
E: Injection
A typical injectible formulation would contain 2-butyl-4-methyl-1-(2'-(tetrazol-5-yl) biphen-4-yl)methyl-1,4,6,7-tetrahydroimidazo[4,5-e]-[1,4]diazepine-5,8-dio ne sodium phosphate dibasic anhydrous (11.4 mg) benzylalcohol (0.01 ml) and water for injection (1.0 ml). Such an injectible formulation can also include a pharmaceutically effective amount of another active ingredient such as another antihypertensive and/or a diuretic and/or an angiotensin converting enzyme inhibitor and/or a calcium channel blocker.
Claims
What is claimed is:
1. A compound of formula (II): ##STR45## wherein: R.sup.1 is (a) carboxy, (b) C.sub.1 -C.sub.4 -alkoxycarbonyl, (c) --NHSO.sub.2 CF.sub.3, or ##STR46## (e) --PO(OR.sup.9)R.sup.9, (f) --PO(OR.sup.9).sub.2, (g) --SO.sub.2 NH-heteroaryl, (h) --CH.sub.2 CO.sub.2 NH-heteroaryl, (i) --SO.sub.2 NH--CO--R.sup.25, (j) --CH.sub.2 SO.sub.2 NH--CO--R.sup.25, (k) --CONH--SO.sub.2 R.sup.25, (l) --CH.sub.2 CONH--SO.sub.2 R.sup.25, (m) --NHSO.sub.2 NCHO--R.sup.25, (n) --NHCONHSO.sub.2 R.sup.25, (o) --SO.sub.2 NHCONHR.sup.25 ; R.sup.2 and R.sup.3 are independently (a) hydrogen, (b) C.sub.1 -C.sub.4 -alkyl, or (c) halo; R.sup.4 and R.sup.5 are independently (a) hydrogen, (b) C.sub.1 -C.sub.6 -alkyl, (c) C.sub.1 -C.sub.6 -alkoxy, or (d) halo; R.sup.6 is (a) C.sub.1 -C.sub.6 -alkyl, (b) C.sub.1 -C.sub.6 -alkenyl, (c) C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.6 -alkyl, (d) C.sub.1 -C.sub.4 -alkylthio-C.sub.1 -C.sub.6 -alkyl, (e) C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.6 -alkenyl, or (f) C.sub.1 -C.sub.4 -alkylthio-C.sub.1 -C.sub.6 -alkenyl; E is --S--; p is 0 or 1; X is ##STR47## (b) --S--or (c) --OCH.sub.2 --; q is 0 or 1; R.sup.14 is H; R.sup.15 is (a) H, (b) C.sub.1 -C.sub.6 -alkyl, (c) substituted C.sub.1 -C.sub.6 -alkyl wherein the substituent is selected from the group consisting of (i) hydroxy, (ii) amino, (iii) guanidino, (iv) C.sub.1 -C.sub.4 -alkylthio, (v) carboxy, (vi) carboxamido, (vii) C.sub.1 -C.sub.4 -alkoxycarbonyl, or ##STR48## (d) benzyl, (e) 4-hydroxybenzyl, (f) 3-indolylmethyl, (g) 4-imidazolylmethyl, or (h) phenyl; and R.sup.16 is H or C.sub.1 -C.sub.4 -alkyl Y is (a) --O--, ##STR49##
2. A compound of claim 1 wherein: R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are hydrogen; and p and q are zero.
3. A compound of claim 2 wherein: R.sup.1 is (a) carboxy, (b) C.sub.1 -C.sub.4 -alkoxycarbonyl, ##STR50##
4. A compound of claim 3 wherein: R.sup.6 is C.sub.1 -C.sub.6 -alkyl, R.sup.15 and R.sup.16 are each hydrogen; Y is --NH--.
5. A compound of claim 4 selected from the group consisting of: (1) 2-butyl-1-(2'-carboxybiphen-4-yl)-methyl-1,4,6,7-tetrahydroimidazo[4,5-e]- [1,4]diazepine-5,8-dione; and, (2) 2-butyl-1-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-1,4,6,7-tetrahydroimidazo[ 4,5-e]-[1,4]diazepine-4-methyl-5,8-dione.
6. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier an a pharmaceutically effective amount of a compound of claim 1.
7. A method of treating hypertension which comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of claim 1.
8. An ophthalmalogical formulation for the treatment of ocular hypertension comprising an ophthalamologically acceptable carrier and an effective ocular antihypertensive amount of a compound of claim 1.
9. A method of treating ocular hypertension comprising administering to a patient in need of such treatment an effective ocular antihypertensive amount of a compound of claim 1.
Patent Citations (8)
Non-Patent Literature (2)
- P. G. Wong et al., J. Pharmcol. Exp. Ther., "Nonpeptide Angiotension II Receptor Antagonists", 247(1), pp. 1-(1988).
- P. K. Bridson et al., Journal of Heterocyclic Chemistry, "Cyclic Homologs of Xanthins", 25(4), pp. 1179-1182 (1988).