Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines

Definitions

• the present invention relates to the co-administration, either simultaneously, separately or sequentially of a selective iKs antagonist and a beta-adrenergic receptor blocking agent for use in preventing, treating and terminating cardiac arrhythmias, such as atrial, supraventricular and ventricular ectopy, tachycardia, flutter or fibrillation, including atrial, supraventricular and ventricular arrhythmias resulting from myocardial ischemic injury in a patient in need thereof.
• This invention also relates to a pharmaceutical formulation which comprises a selective IKs antagonist and a beta- adrenergic receptor blocking agent along with a pharmaceutically acceptable carrier.
• arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In a serious case, arrhythmias give rise to ventricular fibrillation and can cause sudden death.
• antiarrhythmic agents are now available on the market, agents exhibiting both satisfactory effects and high safety profiles, are not yet available for patients.
• antiarrhythmic agents of Class I according to the classification of Vaughan-Williams, which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing ventricular fibrillation.
• Vmax maximum velocity of the upstroke of the action potential
• they have problems regarding safety, namely, they cause a depression of the myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of the impulse conduction.
• Beta-adrenergic receptor blocking agent which belong to Class II are of limited value since their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
• Antiarrhythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax.
• drugs in this class were limited to sotalol and amiodarone, both of which have been shown to possess Class IH properties.
• Sotalol also possesses Class II effects which may cause cardiac depression and be contraindicated in certain susceptible patients. Amiodarone is severely limited by side effects.
• Drugs of this class are expected to be effective in preventing ventricular fibrillations.
• Pure Class UI agents by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents.
• IKs antagonists In the treatment of arrhythmia, IKs antagonists have demonstrated effectiveness when delivered orally in amounts ranging from about 0.01 to about 1 mg per kg of body weight per day, in a single dose or in 2 to 4 divided doses.
• the activity of the compounds described herein as antiarrhythmic agents is measured by their ability to block the IKs and iKr currents as determined by the following test protocol.
• Outward potassium currents are measured in single guinea pig ventricular myocytes using a whole-cell voltage clamp technique described in detail elsewhere (Sanguinetti and Jurkiewicz, 1990, Two conn ents of cardiac delayed rectifier K + current: differential sensitivity to block by Class LU antiarrhythmic agents. J. Gen Physiol. 96: 195-215).
• Myocytes are isolated by enzymatic (collagenase and protease) digestion of Langandorf perfused hearts. Single cells are then voltage clamped using 1 mm square-bore pipettes filled with 0.5 M Kgluconate, 25 mM KC1, 5 mM K(2)ATP. Cells are bathed in a solution containing, in mN: 132 NaCl, 4KC1, 1.2 MgCl2, 10 HEPES, 10 glucose: pH 7.2, temp. 35°C.
• Test depolarizations are applied as voltage ramps from -85 to -50 mV, and as steps to -10 mV (0.5 s) and +50 mV (1.0 s).
• I ⁇ i is measured as peak outward current during the voltage ramp.
• iKr is measured as tail currents upon repolarization from -10 mV to -50 mV.
• IKs is measured as time-dependent current during the pulse to +50 mV. Currents are measured during control, then after exposure to drug at two different concentrations.
• the compounds described herein as selective IKs channel antagonists have an IC50 of less than 100 nM as IKs antagonists.
• the compounds of this invention are at least 10 times more potent in the blockade of IKs than of blockade of IKr-
• Beta-adrenergic receptor blocking agents are a class of pharmaceutically active compounds which decrease the positive chronotropic, positive inotropic, bronchodilator and vasodilator responses caused by beta-adrenergic receptor agonists. The magnitude of this decreased response is proportional to the existing sympathetic tone and the concentration of beta-blocker at the receptor sites. Beta-adrenergic receptor blockage is said to reduce cardiac output in both healthy subjects and patients with heart disease. While the mechanism of antihypertension effects of beta-adrenergic receptor blocking agents has not been established, possible mechanisms of action include reduction in cardiac output, reduction in plasma renin activity, and central nervous system sympatholytic action.
• beta-adrenergic receptor antagonists have been shown effective in reducing the incidence of mortality and sudden death in postinfarction patients (Yusaf et al., Prog Cardiovasc Dis 17: 335-371, 1985; Lau et al., N Eng J Med 327: 248-254, 1992).
• a method for use in preventing, treating and terminating cardiac arrhythmias such as atrial, supraventricular and ventricular ectopy, tachycardia, flutter or fibrillation, including atrial, supraventricular and ventricular arrhythmias resulting from myocardial ischemic injury in a patient in need thereof which comprises the co- administration, either simultaneously, separately or sequentially of a selective IKs antagonist and a beta-adrenergic receptor blocking agent.
• This invention also relates to a pharmaceutical formulation which comprises a selective IKs antagonist and a beta-adrenergic receptor blocking agent along with a pharmaceutically acceptable carrier.
• a method for use in preventing, treating and terminating cardiac arrhythmias such as atrial, supraventricular and ventricular ectopy, tachycardia, flutter or fibrillation, including atrial, supraventricular and ventricular arrhythmias resulting from myocardial ischemic injury in a patient in need thereof which comprises the co- administration, either simultaneously, separately or sequentially of a selective IKs antagonist and a beta-adrenergic receptor blocking agent.
• This invention also relates to a pharmaceutical formulation which comprises a selective IKs antagonist and a beta-adrenergic receptor blocking agent along with a pharmaceutically acceptable carrier.
• a “selective IKs antagonist” is meant those compounds which when studied in the test disclosed above have an IC50 of less than 100 nM as IKs blockers.
• the compounds of this invention are at least 10 times more potent in the blockade of IKs than of blockade of IKr-
• Beta-adrenergic receptor blocking agents are compounds which decrease the positive chronotropic, positive inotropic, bronch- odilator and vasodilator responses caused by beta-adrenergic receptor agonists. The magnitude of this decreased response is proportional to the existing sympathetic tone and the concentration of beta-adrenergic receptor blocking agent which reaches the receptor sites.
• Examples of compounds which fit the definition of beta- adrenergic receptor blocking agent include but are not limited to timolol, sotalol, esmolol, cateolol, propranolol, betaxolol, penbutolol, metoprolol, acebutolol, atenolol, metoprolol, pindolol, and bisoprolol, and their salts, hydrates, solvates and any crystal forms in which they may occur.
• Examples of compounds which fit the definition of selective IKs antagonists include, but are not limited to, the following:
• A is 1) thieno
• p is 0 or 1 ;
• Ri is 1) phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N02,
• R2 is 1 ) phenyl, either unsubstituted or substituted with Cl-3 alkoxy or 4,4-dimethyloxazolin-2-yl,
• Cl-6 alkyl either straight or branched chain, and either unsubstituted or substituted with Cl-3 alkoxy or Cl-3 alkoxy-Cl-3 alkoxy,
• R2 is phenyl
• the 2-position of the phenyl can be joined to the 4-position nitrogen of the diazepine ring through a carbonyl group and the double bond between the 4-nitrogen and the 5-carbon becomes a single bond
• R is 1 ) hydrogen or
• R4 is 1 ) hydrogen
• Cl-6 alkyl the chain of carbon atoms of which can be interrupted by one or two non-adjacent oxygen atoms and which is either unsubstituted or substituted with Cl-3 alkoxycarbonyl, -OH or
• R5 is hydrogen or oxygen or is joined to R2 to form the partial structure:
• This invention is meant to include the individual diastereomers where such exist and mixtures thereof and enantiomers and mixtures of the enantiomers.
• the pharmaceutically acceptable salts of the compounds of Formulas I include the conventional non-toxic salts or the quartemary ammonium salts of the compounds of Formula I formed, e.g., from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
• the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
• A is benzo
• X and Y are oxygen
• R3 is methyl
• R4 is hydrogen
• R2 is Cl-6 alkyl.
• X and Y are oxygen
• R is methyl
• R4 is hydrogen
• R2 is phenyl
• Z is Cl -6 alkylene or a bond
• Ri is phenyl, phenyl substituted with -CI, -Br, -I, -F, or -CF3, or R is cyclohexyl.
• Z is C2-4 alkenylene and R 1 is phenyl or phenyl substituted with -CI, -Br, -F, -I, -CF3, Cl-3 alkyl, Cl -3 alkoxy or methy lenedioxy.
• a third embodiment of the compounds useful in the novel method of treatment of this invention is that wherein: Z is -NH-.
• Another embodiment of this invention is a group of compounds, active in the novel method of treatment of this invention, which are novel compounds per se. These novel compounds are depicted in the following Table VI.
• Another embodiment of this invention is a group of compounds which are active in the novel method of treatment of this invention. These compounds are depicted as follows:
• X and Y are independently hydrogen, chloro, fluoro, bromo, iodo, or trifluoromethyl and
• n 0, 1 or 2;
• R is hydrogen, fluoro, chloro, bromo, iodo, or trifluoromethyl, methyl, or methoxy;
• racemates mixtures of enantiomers, individual diastereomers or individual enantiomers with all isomeric forms and pharmaceutically acceptable salts, hydrates or crystal forms thereof, which are antiarrhythmic agents.
• Yet another embodiment of this invention is a group of compounds which are active in the novel method of treatment of this invention. These compounds are depicted as follows:
• R and R ⁇ are independently
• phenyl either unsubstituted or substituted with one or two substituents selected from a) -N02, OH, b) -CI, Br, F, or I, c) -CF3, d) -Cl-3 alkyl, e) -Cl-3 alkoxy, f) -CN, g) -methylenedioxy, and
• Z is 1) Cl-6 alkyl, either straight or branched chain ,
• the selective IKs blockers of the present invention have the pharmacological properties required for antiarrhythmic agents of Class III, namely they demonstrate prolongation of QTc-interval , and dose dependent increases in ventricular refractoriness. This is accomplished without effecting heart rate, mean arterial pressure and PR and QRS intervals. Modest increases in LV+dP/dt (left ventricular change in pressure with time) is observed. Further, these compounds suppress the induction of PVS (Programmed Ventricular Stimulation) induced ventricular tachy arrhythmias.
• PVS Programmed Ventricular Stimulation
• these compounds are effective in treating and preventing all types of arrhythmias including ventricular, atrial and supraventricular arrhythmias.
• the compounds of the present invention are especially useful for controlling reentrant arrhythmias and prevent sudden death due to ventricular fibrillation. These compounds are also effective in treating and preventing impaired cardiac pump functions.
• a selective IKs antagonist is administered in an amount ranging from about .0001 to about 10 mg per kg of body weight per day, preferably from about .0001 to about 2 mg per kg of body weight per day, and more preferably, when intravenous delivery of the compounds is employed, from about 0.0003 to about 0.3 mg per kg of body weight per day, or when given orally from about 0.01 to about 1 mg per kg of body weight per day, in a single dose or in 2 to 4 divided doses of each compound.
• the beta-adrenergic receptor blocking agent is administered in an amount ranging from about 1 mg per day to about 300 mg poer day and more preferably from about 2 mg/day to about 250 mg per day.
• the activity of the compounds described herein as antiarrhythmic agents is measured by their ability to block the IK and IKr currents as determined by the following test protocol.
• Outward potassium currents are measured in single guinea pig ventricular myocytes using a whole-cell voltage clamp technique described in detail elsewhere (Sanguinetti and Jurkiewicz, 1990, Two components of cardiac delayed rectifier K+ current: differential sensitivity to block by Class LII antiarrhythmic agents. J. Gen Physiol. 96: 195-215).
• Myocytes are isolated by enzymatic (collagenase and protease) digestion of Langandorf perfused hearts. Single cells are then voltage clamped using 1 mm square-bore pipettes filled with 0.5 M Kgluconate, 25 mM KC1, 5 mM K(2)ATP. Cells are bathed in a solution containing, in mN: 132 NaCl, 4KC1, 1.2 MgCl2, 10 HEPES, 10 glucose: pH 7.2, temp. 35°C.
• Test depolarizations are applied as voltage ramps from -85 to -50 mV, and as steps to -10 mV (0.5 s) and +50 mV (1.0 s).
• I ⁇ i is measured as peak outward current during the voltage ramp.
• IKr is measured as tail currents upon repolarization from -10 mV to -50 mV.
• IKs is measured as time-dependent current during the pulse to +50 mV. Currents are measured during control, then after exposure to drug at two different concentrations.
• the compounds described herein as selective IKs blockers have an IC50 of less than 100 nM as IKs blockers.
• the compounds of this invention are at least 10 times more potent in the blockade of IKs than of blockade of IKr-
• Oxalyl chloride (158 mL, 230 mg, 1.81 mmol) was added to a mixture of 3-phenylpropanoic acid (249 mg, 1.66 mmol) and DMF (1 drop) in THF (10 mL) and the mixture was stirred at room temperature for 40 min.
• 3(R)- Amino- 1 ,3-dihydro-l -methyl-5-phenyl-2H- 1 ,4- benzodiazepin-2-one J. Org. Chem. 1987, 52, 3232-3239
• triethylamine (252 mL, 183 mg, 1.81 mmol) were added and the mixture was stirred at room temperature for 18 h.
• (+)-N-[(3R)-2,3-Dihydro- 1 -methy l-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-v ⁇ -2.2-diphenylethanamide m.p. 200-201°C, [ ⁇ ]D +97.0° (c 0.168, CH2CI2).
• the benzylamine (2.07 g, 7.9 mmol) was dissolved in methanol (60 mL), BOC2O (1.72 g, 7.9 mmol) added and the mixture hydrogenated at 50 psi over 10% palladium hydroxide on charcoal (200 mg) for 18 hours.
• the reaction mixture was filtered through celite, washed with methanol and the filtrate evaporated to give 1 -t-butoxy- carbonylpiperidine-4,4-diethanol (2.0 g).
• (+)-N-[(3R)-2,3-Dihydro-l-methyl-2-oxo-5-phenyl-lH-l,4-benzo- diazepin-3-yl]-l '-(l ,1 -dimethylethoxycarbonyl)spiro(cyclohexan-4,4'- piperidineV 1 -carboxamide m.p. 135-138°C, [ ⁇ ]D +58.8° (C 0.925, CHCI3).
• Bromoacetyl bromide (165 mL, 383 mg, 1.9 mmol) was added to an ice cooled solution of 3(R)-amino-l ,3-dihydro-l-methyl-5- phenyl-2H-l ,4-benzodiazepin-2-one (J. Org. Chem. 1987, 52, 3232- 3239) (500 mg, 1.88 mmol) and triethylamine (264 mL, 192 mg, 1.9 mmol) in methylene chloride (10 mL) and the mixture was stirred at room temperature for 1 h.
• Phenol (104 mg, 1.1 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 44 mg, 1.1 mmol) in toluene (10 mL).
• sodium hydride 60% dispersion in mineral oil, 44 mg, 1.1 mmol
• toluene 10 mL
• N-[(3R)-2,3- dihydro- 1 -methy l-2-oxo-5-phenyl- 1 H- 1 ,4-benzodiazepin-3-yl] -2-bromo- acetamide 400 mg, 1.04 mmol was added and the mixture was stirred at room temperature for 1 h.
• the mixture was washed with water (3 x 15 mL), dried (MgS04) and the solvent was evaporated under reduced pressure.
• 3-Bromopropionyl chloride (2.01 mL, 3.428 g, 20 mmol) was added to an ice cooled solution of 3(R)-amino-l ,3-dihydro-l - methyl-5-phenyl-2H-l ,4-benzodiazepin-2-one (J. Orb. Chem. 1987, 52, 3232-3239) (5.0 g, 18.8 mmol) and triethylamine (2.79 mL, 2.02 mg, 20 mmol) in methylene chloride (85mL) and the mixture was stirred at room temperature for 18 h.
• 2,3-Dihydro-5 -phenyl- 1 H- 1 ,4-benzodiazepin-2-one (1.00 g, 4.23 mmol) was added to hexane washed sodium hydride (60% dispersion in mineral oil, 186 mg, 4.65 mmol) in DMF (5 mL). Further DMF (10 mL) was added and the mixture was stirred at room temperature. 2-(Dimethylamino)ethyl chloride hydrochloride (0.73 g, 5 mmol) was added to hexane washed sodium hydride (60% dispersion in mineral oil, 200 mg, 5.0 mmol) in DMF (5 mL) and the mixtures were combined.
• Ethyl isocyanate (320 mL, 287 mg, 4.0 ⁇ unol) was added to a mixture of 2,3-dihydro-l -(2-dimethy laminoethy l)-3-hydroxyimino-5- phenyl-lH-l ,4-benzodiazepin-2-one (0.91 g, 2.7 mmol) and triethylamine (0.56 mL, 0.41 g, 4.0 mmol) in THF (30 mL). The mixture was heated under reflux for 7 h., further ethyl isocyanate (167 mL, 150 mg, 2.1 mmol) was added and the mixture was heated under reflux for 12 h.
• Triethylamine was added to a mixture of 3-amino-2,3- dihydro- 1 -(2-dimethylaminoethyl)-5-phenyl- 1 H- 1 ,4-benzodiazepin-2- one (180 mg, 0.6 mmol), 3-(2,4-dichlorophenyl)propanoic acid (131 mg, 0.6 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg, 0.6 mmol) and 1 -hydroxyberzotriazole (81 mg, 0.6 mmol) in DMF (15 mL) until the pH was 9.0. The mixture was stirred at room temperature for 72 h.
• the layers were separated and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic fractions were washed with brine, dried (Na2S ⁇ 4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chroma-tography on silica gel, eluting with EtOAc/Hexane (65:35 increasing to 100:0). The first compound to elute was suspended in ethanol (1 mL) and ethanolic HC1 (6 M, 0.11 mL) was added. The mixture was stirred, then the solvent was evaporated under reduced pressure.
• (+)-3(R)- ⁇ N-[3-(4-Chlorophenyl)prop- 1 -yl]amino ⁇ - 1 ,3-dihydro- 1 - methyl-5- phenyl-2H- 1.4-benzodiazepin-2-one hydrochloride m.p. 167-168°C, [ ⁇ ]D +20.8° (c 0.500, MeOH).
• (+)-pheny Imethy 1 N-[(3R)-2,3-dihydro-l- methyl-5-phenyl-2-oxo-lH-l ,4-benzodiazepin-3-yl]carbamate (4.0 g, 10 mmol) and 2,4-bis(4-methoxyphenyl)-l ,3-dithia-2,4-diphosphetane-2,4- disulfide (4.5 g, 1 1 mmol) in toluene (100 mL) was heated under reflux for 75 min. The mixture was cooled and the volume was reduced to 30 mL by evaporation under reduced pressure.
• Triethylamine (6.8 mL, 4.94 g, 49 mmol) was added to a heated (33°C) mixture of b-oxobenzenepropanenitrile (18.6 g, 128 mmol) and l,2-dithiane-2,5-diol (9.8 g, 64 mmol) in ethanol (120 mL) and the mixture was stirred at 50C° for 18 h. The mixture was cooled and the solvent was evaporated under reduced pressure. Dichloromethane was added, the mixture was washed with aqueous hydrochloric acid (0.5M), aqueous sodium hydroxide (IM) and brine, dried (Na2S ⁇ 4) and the solvent was evaporated under reduced pressure.
• aqueous hydrochloric acid 0.5M
• IM aqueous sodium hydroxide
• brine dried (Na2S ⁇ 4)
• 3-Methylphenylisocyanate 60 mL, 62 mg, 0.46 mmol was added to a solution of 3-amino-2,3-dihydro-l-methyl-5-phenyl-lH- thieno[2,3-e]-l,4-diazepin-2-one (124 mg, 0.46 mmol) in tetrahydro- furan (5 mL). The mixture was stirred at room temperature for 2 h. and the solvent was evaporated under reduced pressure.
• Triethylamine (75 mL, 54 mg, 0.54 mmol) was added to a mixture of 3-amino-2,3-dihydro-l-methyl-5-phenyl lH-thieno[2,3-e]- 1 ,4-diazepin-2-one (82 mg, 0.3 mmol), cyclohexanepropanoic acid (52 mL, 47 mg, 0.3 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodi- imide hydrochloride (58 mg, 0.3 mmol) and 1-hydroxybenzotriazole (42 mg, 0.3 mmol) in DMF (1.5 mL).
• Phenylmethyl N-[5-cyclohexyl-2,3-dihydro-2-oxo-lH-l ,4- benzodiazepin-3-yl]carbamate (150 mg, 0.38 mmol) was dissolved in hydrogen bromide in acetic acid (30%, 0.5 mL). After 2 h., ether was added and the solid was collected and dried in vacuo. THF (3 mL) and triethylamine (0.45 mL, 33 mg, 0.32 mmol) were added and the mixture was stirred at room temperature for 3 h.
• Methanesulfonyl chloride (0.040 mL, 0.52 mmol) was added to a solution of (+)-N-[(3R)-7-amino-2,3-dihydro-l-methyl-2- oxo-5-phenyl-lH-l,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)- propanamide (193 mg, 0.40 mmol) and pyridine (0.065 mL, 0.80 mmol) in methylene chloride (1.6 mL). The resulting solution was stirred 2 h.
• the solution was diluted with ethyl acetate (12 mL), washed with IN HC1, water, saturated sodium bicarbonate solution, water, and brine (3 mL each), dried (Na2S04) and the solvent was evaporated under reduced pressure. The residue was dissolved in warm toluene, treated with charcoal, and filtered.
• the mixture was stirred at -20°C for 30 min., then poured into a mixture of water (50 mL), acetic acid (3 mL), and ethyl acetate (65 mL). The mixture was stirred to dissolve all solids and the layers were separated. The aqueous layer was extracted with ethyl acetate (65 mL). The combined organic fractions were washed with saturated sodium bicarbonate solution and brine (20 mL each), dried (Na2S04), and the solvent was evaporated under reduced pressure.
• the residue was purified by preparative plate chromatography on silica gel eluting with methanol/ chloroform/acetic acid (5:95:1).
• the purified material was stirred under chloroform (5 mL) with potassium carbonate (0.1 g) and water (2 drops) for 5 min.
• the mixture was dried (Na2S ⁇ 4) and the solvent was evaporated under reduced pressure.
• the residue was suspended in ethanol (2 mL) and ethanolic HC1 (6.8 M, 0.147 mL) was added.
• the mixture was stirred at -20°C for 30 min., then poured into a mixture of water (25 mL), acetic acid (2.5 mL), and ethyl acetate (55 mL). The mixture was stirred to dissolve all solids and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 55 mL). The combined organic fractions were washed with saturated sodium bicarbonate solution and brine (20 mL each), dried (Na2S ⁇ 4), and the solvent was evaporated under reduced pressure.
• the benzodiazepine obtained in Step C was converted to the oxime as described in Example 80 Step A.
• the oxime (2 gms) was dissolved in acetic acid (150 mL) and 10% Pd/C (1 gm) added. The mixture was stirred rapidly under an atmosphere of hydrogen for 90 min or until complete by HPLC. The reaction was filtered, the catalyst washed with methylene chloride (200 mL) and the filtrates concentrated in vacuo to an oil. The oil was dissolved in saturated aqueous sodium bicarbonate (100 mL) and product extracted with ethyl acetate (3 x 150 mLs). Concentration of the dried (Na2S ⁇ 4) extracts gave 2.60 gms (97%).
• Step F The anine was coupled with 3-(2,4-dichlorophenyl)- propionic acid as described in Example 43 to yield N-(2,3-dihydro-l- methyl-2-oxo-5-isopropyl-lH-l ,4-benzodiazepin-3-yl)-3-(2,4- dichlorophenyl)propanamide.
• Step A Preparation of N-tert-butyloxycarbonyl-4-(4-chloro- benzyl)-4-piperidinecarboxylic acid
• N-Boc-ethylisonipecotate (51.4 g, 200 mmole) in THF (1L) at -60° C was treated with a solution of lithium bistrimethylsilyl amide (220 mL of a 1 N solution in THF, 220 mmole). After stirring at -60°C for 5 minutes, a solution of 4-chlorobenzyl chloride (33.8 g, 210 mmole) in THF (200 mL) was added and the reaction allowed to warm to room temperature. Most of the THF (about 800 mL) was removed by evaporation at reduced pressure. The remainder was poured into 1 L of 1 N HCl and extracted with two 800 mL portions of ethyl acetate.
• Step B Preparation of N-( 1 ,3-dihydro- 1 -methyl-2-oxo-5-phenyl- 2H- 1 ,4-benzodiazepin-3-yl)-4-(4-chlorobenzyl)-4-piper- idinecarboxamide dihydrochloride
• (+)-3-Cyclohexyl-N-[2,3-dihydro- 1 -methyl-2-oxo-5- phenyl-lH-l ,4-benzodiazepin-3-yl]propanamide (2.0 g, 5.0 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0°C and methyl magnesium chloride (3M, 2.0 mL) was added. After 0.25 h, paraformadehyde (0.15 g, 10 mmol) was added, and the mixture was allowed to warm to room temperature. The reaction was then diluted with ethyl acetate (150 mL) and saturated aqueous sodium hydrogen carbonate (150 mL) was added.
• (+)-3-Cyclohexyl-N-[2,3-dihydro- 1 -methyl-2-oxo-5- phenyl-lH-l ,4-benzodiazepin-3-yl]-N-(hydroxymethyl)propanamide (0.67 g, 1.56 mmol) was dissolved in methylene chloride(100 mL), along with tetrazole (0.33 g, 4.7 mmol), and then N,N-diisopropyl- dibenzyl-phosphoramidite (1.07 g, 3.1 mmol). After 2 h, the mixture was diluted with methylene choride (150 mL), and extracted with saturated aqueous sodium hydrogen carbonate (3 x 100 mL).
• Step A Preparation of 2,3-dihydro-2-oxo-5-phenyl-l -(2,2,2- trifluoroethyl)- 1 H-benzo[e] [ 1 ,4]diazepine.
• Step C Preparation of racemic 3-Amino-5-phenyl-l -(2,2,2- trifluoroethyl)- 1 H-benzo[e] [ 1 ,4]diazepine.
• Step D Preparation of 2-Amino-N-[2-oxo-5-phenyl- 1 -(2,2,2- trifluoroethyl)-2,3 -dihydro- 1 H-benzo[e] [ 1 ,4]diaze ⁇ in- 3-yl]-3-phenylpropionamide
• Step E Preparation of 3(R)-(+)-3-Amino-5-phenyl- 1 -(2,2,2- trifluoroethyl)-l H-benzo[e] [1 ,4] diazepine.
• Step F Preparation of (+)-3,5-Dichloro-N-[3R-2,3-dihydro-2-oxo-
• (+)-3R-3-amino-5-phenyl-l- (2,2,2-trifluoroethyl)-lH-benzo[e][ l,4] diazepine (5.6 g, 16.8 mmol) in DMF (50 mL) was added l-(3-Dimethylaminopropyl-3-ethylcarbodi- imide hydrochloride(4.44 g, 23.0 mmol), and 1-hydroxybenztriazole hydrate (3.11 g, 23.0 mmol) and 3,5-Dichlorobenzoic acid (3.21 g, 16.8 mmol). This was stined at ambient temperature for 2 hours.
• the reaction was diluted with 500 mL satd. NaHC ⁇ 3 and extracted with 2 x 300 mL ethyl acetate. The combined organics were washed with 10% KHSO4 (200 mL) , brine (200 mL), dried over Na2S04, and evaporated to a white foam. This was chromatographed over a 75 x 200 mm silica column eluting with 20% ethyl acetate:hexane. The pure fractions were collected and evaporated under reduced pressure to give 8.5 g of a white foam which was crystallized from 15% ethyl acetate :hexane to give 5.3 g of a white powder .

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