WO2001010216A1

WO2001010216A1 - Antiarrhythmic compounds

Info

Publication number: WO2001010216A1
Application number: PCT/US2000/021538
Authority: WO
Inventors: John W. Butcher; David A. Claremon; Nigel J. Liverton
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1999-08-09
Filing date: 2000-08-07
Publication date: 2001-02-15
Anticipated expiration: 2002-02-09
Also published as: AU6895000A

Abstract

1H-Benzo[e][1,4]diazepin-2-one compounds of Formula (I) which are selective IKs antagonists useful for the treatment and prevention of cardiac arrhythmias are disclosed. Also claimed herein is the method of treatment or prevention of cardiac arrhythmias, such as atrial, supraventricular and ventricular ectopy, tachycardia, flutter or fibrillation, including atrial, supraventricular and ventricular arrhythmias resulting from myocardial ischemic injury, and pharmaceutical compositions containing the compounds of Formula (I) useful for the same.

Description

TITLE OF THE INVENTION ANTIARRHYTHMIC COMPOUNDS

BACKGROUND OF THE INVENTION 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.

Though various antiarrhythmic agents are now available on the market, agents exhibiting both satisfactory effects and high safety profiles, are not yet available for patients. For example, 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. In addition, 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. Until recently, drugs in this class were limited to sotalol and amiodarone, both of which have been shown to possess Class III properties. However, 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 III 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.

Recently, a novel group of Class III agents have been disclosed which antagonize the IKs channel found in heart muscle. These compounds IKs channel antagonists are effective in treating and preventing all types of arrhythmias including ventricular and atrial (supraventricular) arrhythmias. These novel compounds are disclosed and claimed in U.S. Patent Application, Serial Nos. 08/411,240; 08/516,467; and 08/516,226 which are hereby incorporated by reference. These novel compounds are especially useful for controlling reentrant arrhythmias and preventing sudden death due to ventricular fibrillation. These compounds are also effective in treating and preventing impaired cardiac pump functions.

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 components of cardiac delayed rectifier K+ current: differential sensitivity to block by Class III 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.

Each cell is maintained at a holding potential of -50 mV. 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). Iκi s measured as peak outward current during the voltage ramp. iRr 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. Employing this test 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, or "beta-blockers", 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. The administration of beta-adrenergic receptor antagonists has 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). While both selective IKs channel blockers and beta- adrenergic receptor blocking agents have been proven effective when administered separately, it is considered to be in the best interest of the patient to reduce the amount of these compounds provided to the patient. Any reduction of one or the other compound would be considered helpful, but this is particularly true of beta-adrenergic receptor blocking agents which are known to have significant side effects in some humans.

lH-Benzo[e] [l,4]diazepin-2-one compounds of Formula I, which are selective IKs antagonists useful for the treatment and prevention of cardiac arrhythmias, are presented. Also claimed herein is the method of treatment and prevention of cardiac arrhythmias, such as atrial, supraventricular and ventricular ectopy, tachycardia, flutter or fibrillation, including atrial, supraventricular and ventricular arrhythmias resulting from myocardial ischemic injury, and pharmaceutical compositions containing the compounds of Formula I useful for the same.

DETAILED DESCRIPTION OF THE INVENTION

A compound of formula I

or a pharmaceutically acceptable salt, crystal form or hydrate thereof, wherein:

R¹ is: C₃-C₄-alkyl, straight or branched;

R is: C₃-C₆-cycloalkyl, or phenyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Cι-C₄-alkyl, trifluoromethyl, and halo;

R³ is: optionally substituted (CH₂)_n-phenyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: C C₄-alkyl, trifluoromethyl, and halo; and

n is: 0, 1 or 2. 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 quarternary ammonium salts of the compounds of Formula I formed, e.g., from non- toxic inorganic or organic acids. For example, 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 compound of formula I

or a pharmaceutically acceptable salt, crystal form or hydrate thereof, wherein: R .1 i ^•s: C₃-C₄-alkyl, straight or branched;

R is: Ca-Cβ-cycloalkyl, or phenyl, unsubstituted or substituted with one two or three substituents selected from the group consisting of: C₁-C₄-alkyl, trifluoromethyl, and halo;

R³ is: optionally substituted (CH₂)_n-phenyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: C C -alkyl, trifluoromethyl, and halo; and

n is: 0, 1 or 2.

The compound of Formula la

la or a pharmaceutically acceptable salt, crystal form or hydrate thereof, wherein the substituents are as recited above.

The compound of Formula la, as recited above, or a pharmaceutically acceptable salt, crystal form or hydrate thereof, wherein:

R¹ is: n-propyl, or sec-butyl;

R is: cyclopropyl, or phenyl;

R is: -CH₂-phenyl substituted with two substituents selected from the group consisting of: methyl and trifluoromethyl. The compound of Formula lb

lb or a pharmaceutically acceptable salt, crystal form or hydrate thereof, wherein the substituents are as recited above.

The compound of Formula lb, as recited above, or a pharmaceutically acceptable salt, crystal form or hydrate thereof, wherein:

R¹ is: n-propyl, or sec-butyl;

R is: cyclopropyl, or phenyl;

R is: -CH₂-phenyl substituted with two substituents selected from the group consisting of: methyl and trifluoromethyl.

A compound of Formula I, or a pharmaceutically acceptable salt, crystal form or hydrate thereof, selected from the group consisting of:

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((R)-2-butyl)-2-oxo-5- cyclopropyl-lH-benzo[e] [l,4]diazepin-3-yl]acetamide;

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((S)-2-butyl)-2-oxo-5- cyclopropyl-lH-benzo[e] [l,4]diazepin-3-yl]acetamide;

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((S)-2-butyl)-2-oxo-5- cyclopropyl-lH-benzo [e] [1,4] diazepin-3-yl] acetamide; (+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((R)-2-butyl)-2-oxo-5- phenyl- lH-benzo [e] [1,4] diazepin-3-yl] acetamide ;

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((R)-2-butyl)-2-oxo-5- phenyl- lH-benzo[e] [l,4]diazepin-3-yl]acetamide;

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((S)-2-butyl)-2-oxo-5- phen l-lH-benzo [e] [1,4] diazepin-3-yl] acetamide;

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((S)-2-butyl)-2-oxo-5- phenyl- lH-benzo [e] [1,4] diazepin-3-yl] acetamide;

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5-propyl- lH-benzo [e] [1,4] diazepin-3-yl] acetamide;

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5-propyl- lH-benzo[e] [l,4]diazepin-3-yl]acetamide;

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5-phenyl- lH-benzo[e] [l,4]diazepin-3-yl]acetamide; and

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5-phenyl- lH-benzo[e] [l,4]diazepin-3-yl]acetamide.

A method of treating cardiac arrhythmia which comprises the administration to a patient in need of such treatment of an effective amount of a selective Ij^_g antagonist of Formula I as recited above.

A method of preventing cardiac arrhythmia which comprises the administration to a patient in need of such treatment of an effective amount of a selective Ij _s antagonist of Formula I as recited above.

A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of Formula I, as recited above, or a pharmaceutically acceptable salt, crystal form or hydrate thereof.

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 tachyarrhythmias.

Individually, 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.

In the novel method of this invention of treating arrhythmia, 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 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 components of cardiac delayed rectifier K⁺ current: differential sensitivity to block by Class III 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.

Each cell is maintained at a holding potential of -50 mV. 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). IjQ 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 s 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.

Employing this test 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-

Typical synthetic schemes employed in making the compounds disclosed herein are illustrated below.

SCHEME 1

t>- MqBr

THF

1 )Bromoacetyl bromide CH₂CI₂, 3N NaOH

2)1:1 Ethanol/Aq. NH₄OH 3) NaOH, pH=12.0

SCHEME 2

K-tOBu,Trisyl azide, THF, AcOH -78°C

(R,S) 5

SCHEME 3

(R.S) 8

SCHEME 4

EXAMPLE 1

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((R)-2-butyl)-2-oxo-5- cvclopropyl- IH- 1 ,4-benzodiazepin-3-yl] acetamide

Step A S-(+)-Methanesulfonic acid sec-butyl ester

To a solution of S-(+)-2-butyl alcohol (5.0 gm, 0.0675 mole) in methylene chloride (100 ml) at 0c and under argon was added triethylamine (16.9 ml, 0.121 mole) followed by a slow addition of methanesulfonyl chloride (6.3 ml, 0.081 mole). The reaction was aged for 30 minutes quenched into a mixture of 10 % sodium bicarbonate and let stir for 15 minutes. The product was extracted with ethyl acetate (2X 200 ml), dried over sodium sulfate, filtered and concentrated to an oil. Yield 10.1 gm (98%). !H NMR (CDCI3, 300 Mhz) 4.75(m,lH), 3.0(S,3H), 1.7(m,2H), 1.4(d,3H),

0.98(t,3H).

Step B 5-cyclopropyl-l,4-benzodiazepine-2-one

To a solution of anthranilonitrile (85 g, 0.720 mole) in THF (1.0 L) at -10° C was slowly added a 1.6 M solution of cyclopropyl magnesium bromide in THF (1.55 L, 2.48 mole). The reaction was allowed to stir overnite at room temperature then slowly quenched into a -10°C solution of 4N HCL (1.2 L). The mixture was stirred for 1 hour at room temperature and the pH adjusted to 7.5 with ION sodium hydroxide. The THF layer was removed, the aqueous layer washed with ethyl acetate (800 mL), and the organic extracts concentrated in υacuo to a dark oil. The oil was dissolved in methylene chloride (1.2 L), washed with water (500 mL), dried over sodium sulfate, and filtered. To the methylene chloride filtrate at 0°C was slowly added bromoacetyl bromide (168.0 g, 0.836 mole) followed by 3N sodium hydroxide (800mL). The reaction was allowed to stir for 1 hour and the pH of the mixture adjusted to 7.5 with concentrated hydrochloric acid. The methylene chloride layer was removed and the aqueous layer washed with methylene chloride (1.0 L). The methylene chloride extracts were washed with 5% aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to an oil. The oil was dissolved in ethanol (1.5 L) added to a 50% solution of ethanol/ aqueous ammonium hydroxide (6.3 L) and allowed to stir for 48 hours. The reaction mixture was concentrated in υacuo to 2.7 L and the pH adjusted to 12.0 with 50% sodium hydroxide. After stirring at pH=12 for 1 hour the reaction pH was adjusted to 8.5 with concentrated hydrochloric acid and solids filtered. The cake was washed with water (1.0 L), sucked dry and dried in υacuo at 40°C to give 102.2 g, (71%). MP- 192-193 °C. !H NMR (CDCI3, 300 MHz) d 9.45 (s, IH) 7.84 (dd, J=8.0 and 1.6 Hz,lH), 7.45 (dt, J=8.0 and 1.6 Hz, IH), 7.24 (dt, J=8.0 and 1.6 Hz,lH), 7.12 (dd, J=8.0 and 1.6 Hz, 1H),4.04 (br s. 2H), 1.95 (m,lH), 0.9-1.2 (m, 4H).

Step C Preparation of 2,3-dihydro-l-2-(R)-butyl)-2-oxo-5-cyclopropyl- IH- 1 ,4-benzodiazepine

A solution of 5-cyclopropyl-l,4-benzodiazepine-2-one (2.0 g, 0.01 mole) in DMF (10 mL) was treated with cesium carbonate (10.0 g, 0.03 mole) , cooled to 0° c and S-(+)-Methanesulfonic acid sec-butyl ester (3.0 g, 0.02 mole) added. The mixture was stirred at 50°C for 2 hours. The reaction was diluted with water (100 ml) and ethyl acetate (250 ml). The pH was adjusted to 7.6 with 10% aqueous potassium hydrogen sulfate and the organic layer removed. The aqueous layer was washed with ethyl acetate (100 ml) and combined ethyl acetate extracts washed with water (lOOmL). The ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in υacuo to an oil. (1.9 g ) The oil was chromatographed on silica using 30 % ethyl acetate / hexane to give upon concentration 1.69 gm. (66%). MS- M⁺¹=257

Step D Preparation of 3-Azido-5-cyclopropyl-l-(2-(R)-butyl)-lH- benzofel [1.4]diazepine

To a stirring solution of 5-cyclopropyl-l-(2-(R)-butyl)-lH- benzo[e] [l,4]diazepine (1.7 g, 0.0066 mol) in THF (34 ml) cooled to -78°C was added potassium tert-butoxide (2.05 eq, 0.0145 mol, 14.5 ml of a 1 M solution in THF) dropwise over 15 min. A solution of 2,4,6-

Triisopropylphenylsulfonylazide (2.27 g, 0.0073 mol) in THF (20 ml) was added over 5 min. This was stirred for 10 min, acetic acid (1.9 ml, 0.032 mol) was added and the reaction warmed to 30°C for 2 hour. The reaction was concentrated the residue dissolved in dichloromethane (200 mL) and washed with satd. NaHCOβ (200 ml). The aqueous layer was back extracted with dichloromethane (100ml). The organic layers were combined, dried with Na2SO and evaporated to a brown foam. This was chromatographed over silica eluting with 20% ethyl acetate :hexane. The appropriate fractions were collected and evaporated under reduced pressure to give 1.65 g (79%) of a solid. MS- M⁺¹=298.

Step E Preparation of 3-Amino-5-cyclopropyl-l-(2-(R)-butyl)-lH- benzo[e] fl.4]diazepine To a stirred solution of 3-Azido-5-cyclopropyl-l-(2-(R)-butyl)- lH-benzo[e] [l,4]diazepine (0.60 g, 2.0 mmol) in ethanol (60 mL) under argon was added 10 % palladium on charcoal (0.2 gm). The argon was displaced with hydrogen and the mixture was vigorously stirred for 45min (latm hydrogen). The reaction was filtered and the filtrate concentrated in υacuo to an oil 0.58 gm, 100 %)

IH NMR (CDCI3, 300 MHz) d 7.70-7.78(m, IH), 7.42-7.5 (m, 1 H),7.24-

7.37 (m, 2H), 4.32(m, IH), 4.22 (s, 0.5 H), 4.18 (s, 0.5 H), 4.05 (m, IH), 2.20 (br s, 2 H), 1.94 (m, 1 H), 1.54-1.72 (m, IH), 1.47 (d, J=7.8 Hz, 1.5 H), 1.41 (d, J=7.8 Hz, 1.5 H), 0.8-1.3 (m, 4 H), 0.83 (t, J=7.8 Hz, 1.5 H), 0.74 (t, J=7.8 Hz, 1.5 H).

Step F Preparation of:(+,-)-(2,4-Bistrifluoromethylphenyl)-N-[2,3- dihydro-l-(2-(R)-butyl)-2-oxo-5-cyclopropyl-lH-l,4- benzodiazepin-3-yn acetamide To a stirring solution of 3-amino-5-cyclopropyl-l-(2-(R)- butyl)-lH-benzo[e] [l,4] diazepine (0.25 g, 0.92 mmole) in DMF (4 mL) was added 1-hydroxybenztriazole hydrate (197 mg, 1.29 mmol), 2,4- Bistrifluoromethylphenylacetic acid (256 mg, 0.92 mmol), triethylamine (180 u L, 1.29 mmole), and (l-(3-dimethylaminopropyl-3- ethylcarbodiimide (246 mg, 1.29 mmol). This was stirred at ambient temperature for 2 hours. The reaction was diluted with 10% citric acid (20 mL) and extracted with ethyl acetate (2 x 40 mL) . The combined organics were washed with 10% sodium bicarbonate (20 mL) dried over Na2Sθ4, and evaporated to a white foam. This was chromatographed using a Chiralpak AD preparative HPLC column (Chiral Technology, 25x2 cm) eluting with ethanol/hexane(0.1% diethylamine) (1/1, 7 mL/min), . The pure fractions were collected and evaporated under reduced pressure to give 150 mg (+)enantiomer and 140 mg (-) enantiomer as foams. The enantiomers were crystallized from ether/hexane to give white solids 120 mg. (+)enantiomer and 80 (-) enantiomer. (+)enantiomer lH NMR (CDCI3, 300 MHz) d 7.90 (brs, IH), 7.64-7.8 (m, 3 H),7.40-7.50 (m, IH), 7.18-7.38(m, 3H), 5.24 (d, J=8.6 Hz,l H), 4.28 (m, IH), 3.89 (s, 2H), 1.95 (m, 1 H), 1.50-1.7 (m, 3H), 0.8-1.1 (m, 3H), 1.42 (d, J=6.9 Hz, 3H), 0.73 (t, J=7.2 Hz, 3H). Analysis Calcd. for C26H25F6N3O2 0.5 H₂O: C, 58.42; H, 4.90; N, 7.86;

Found: C, 58.42; H, 4.81; N, 7.75. mp=108-109°C. [α]D= +30.3° (MeOH).

(-)enantiomer lH NMR (CDCI3, 300 MHz) d 7.90 (brs, IH), 7.64-7.8 (m, 3 H),7.40-7.50 (m, IH), 7.18-7. 34(m, 3H), 5.21 (d, J=8.6 Hz,l H), 4.02 (m, IH), 3.88 (s, 2H), 2.12 (m, 1 H), 1.95 (m, 1 H), 0.8-1.7 (m, 5H), 1.42 (d, J=6.9 Hz, 3H), 0.84 (t, J=7.2 Hz, 3H). Analysis Calcd. for C26H25F6N3O2 0.5 H₂O: C, 58.42; H, 4.90; N, 7.86;

Found: C, 58.38; H, 4.87; N, 7.93 . mp=119-120°C. [α]D= -43.1° (MeOH).

The following compounds were prepared by procedures similar to those described above for the preparation of Example 1 utilizing the appropriate 5- substituted benzodiazapine and alkylation reagent.

EXAMPLE 2

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((S)-2-butyl)-2-oxo-5- cyclopropyl-lH- 1 ,4-benzodiazepin-3-yl] acetamide

Analysis Calcd. for C26H25F6N3O2 0.80 H2O: C, 57.84; H, 4.97; N, 7.78; Found: C, 57.80; H, 4.70; N, 7.59. mp=109-110°C. [α]D= +32.9° (MeOH).

EXAMPLE 3

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((S)-2-butyl)-2-oxo-5- cyclopropyl-lH-1.4-benzodiazepin-3-yl]acetamide

Analysis Calcd. for C26H25F6N3O2 0.80 H₂0: C, 57.84; H, 4.97; N, 7.78; Found: C, 57.95; H, 4.59; N, 7.66. mp=118-120°C. [α]D= -27.2° (MeOH). EXAMPLE 4

(+)-2,4-Bistriπuoromethylphenyl-N-[2,3-dihydro-l-((R)-2-butyl)-2- oxo-5-phenyl-lH-1.4-benzodiazepin-3-yl]acetamide

Analysis Calcd. for C29H2δF6N3θ2»0.25 H20: C,61.53; H,4.54; N,7.42; Found: C, 61.51; H, 4.31; N, 7.43. mp=125-126°C. [ ]D= +38. 1° (MeOH).

EXAMPLE 5

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((R)-2-butyl)-2- oxo-5-phenyl- IH- 1 ,4-benzodiazepin-3-yl] acetamide

Analysis Calcd. for C29H25F6N3O2 0.25 H₂O: C, 61.53; H, 4.54; N, 7.42;

Found: C, 61.53; H, 4.42; N, 7.39. mp=124-126°C. [α)D= -38.4° (MeOH).

EXAMPLE 6

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((S)-2-butyl)-2-oxo-5- phenyl-lH-1.4-benzodiazepin-3-yllacetamide

Analysis Calcd. for C29H25F6N3O2 0.70 H₂O: : C,60.66; H,4.63; N,7.32; Found: C,60.64; H,4.39; N,7.70. mp=119-120°C.

[α]D= -+41.90° (MeOH).

EXAMPLE 7

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((S)-2-butyl)-2-oxo-5- phenyl- IH- 1 ,4-benzodiazepin-3-vπ acetamide

Analysis Calcd. for C29H25F6N3O2 0.70 H₂0: C,60.66; H,4.63; N,7.32; Found: C,60.81; H,4.42; N,7.55. mp=120-121°C. [α]D= --31.8° (MeOH).

EXAMPLE 8

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5- cyclopropyl- IH- 1 ,4-benzodiazepin-3-yn acetamide

Analysis Calcd. for C25H23F6N3O2 0.85 H₂O: C, 57.00; H, 4.73; N, 7.98;

Found: C, 57.01; H, 4.57; N, 8.13. mp=94-95°C.

[cc]D= +22.7° (MeOH).

EXAMPLE 9

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5- cyclopropyl- IH- 1.4-benzodiazepin-3-yl] acetamide

Analysis Calcd. for C25H23F6N3O2 0.35 H₂O: C, 57.99; H, 4.61; N, 8.12;

Found: C, 57.94; H, 4.65; N, 8.28. mp=78-80°C

[α]D= -24.4° (MeOH).

EXAMPLE 10

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5- phenyl- IH- 1.4-benzodiazepin-3-yl1 acetamide

Analysis Calcd. for C28H23F6N3O2 0.2 diethyl ether: C, 61.51; H, 4.48; N, 7.47; Found: C, 61.19; H, 4.48; N, 7.18. mp=127-129°C. [α]D= +40.0° (MeOH).

EXAMPLE 11

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5- phenyl- IH- 1 ,4-benzodiazepin-3-yl] acetamide

Analysis Calcd. for C28H23F6N3O2 0.9 H₂O: C, 59.65; H, 4.43; N, 7.45; Found: C, 59.95; H, 4.29; N, 7.06. mp=136-138°C. [α]D= -34.6° (MeOH).

Claims

WHAT IS CLAIMED IS:

1. A compound of formula I

R¹ is: C₃-C₄-alkyl, straight or branched;

R is: C₃-C₆-cycloalkyl, or phenyl, unsubstituted or substituted with one two or three substituents selected from the group consisting of: Cι-C₄-alkyl, trifluoromethyl, and halo;

R is: optionally substituted (CH₂)_n-phenyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Cι-C₄-alkyl, trifluoromethyl, and halo; and

n is: 0, 1 or 2.

2. The compound of Formula I

or a pharmaceutically acceptable salt, crystal form or hydrate thereof, wherein the substituents are as defined in Claim 1.

3. The compound of Formula la, as recited in claim 2, or a pharmaceutically acceptable salt, crystal form or hydrate thereof, wherein:

R¹ is: n-propyl, or sec-butyl;

R is: cvclopropyl, or phenyl;

The compound of Formula I

lb or a pharmaceutically acceptable salt, crystal form or hydrate thereof, wherein the substituents are as defined in Claim 1.

5. The compound of Formula lb, as recited in claim 4, or a pharmaceutically acceptable salt, crystal form or hydrate thereof, wherein:

R is: n-propyl, or sec-butyl;

R is: cyclopropyl, or phenyl;

6. A compound or a pharmaceutically acceptable salt, crystal form or hydrate thereof, selected from the group consisting of:

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((R)-2-butyl)-2-oxo-5- cvclopropyl- lH-benzo[e] [l,4]diazepin-3-yl]acetamide;

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((S)-2-butyl)-2-oxo-5- cyclopropyl-lH-benzo[e] [l,4]diazepin-3-yl]acetamide;

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((R)-2-butyl)-2-oxo-5- phenyl- lH-benzo [e] [1,4] diazepin-3-yl] acetamide ;

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((R)-2-butyl)-2-oxo-5- phenyl-lH-benzo[e] [l,4]diazepin-3-yl]acetamide;

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((S)-2-butyl)-2-oxo-5- phenyl- lH-benzo[e] [l,4]diazepin-3-yl]acetamide;

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-((S)-2-butyl)-2-oxo-5- phenyl-lH-benzo [e] [1 ,4] diazepin-3-yl] acetamide;

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5-propyl- lH-benzo [e] [1 ,4] diazepin-3-yl] acetamide;

(-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5-propyl- lH-benzo [e] [1,4] diazepin-3-yl] acetamide;

(+)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5-phenyl- lH-benzo[e] [l,4]diazepin-3-yl]acetamide; and (-)-2,4-Bistrifluoromethylphenyl-N-[2,3-dihydro-l-propyl-2-oxo-5-phenyl- lH-benzo[e] [l,4]diazepin-3-yl]acetamide.

7. A method of treating cardiac arrhythmia which comprises the administration to a patient in need of such treatment of an effective amount of a selective Ijζ_g antagonist of Formula I as recited in

Claim 1.

8. A method of preventing cardiac arrhythmia which comprises the administration to a patient in need of such treatment of an effective amount of a selective Ijζ_g antagonist of Formula I as recited in

Claim 1.

9. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of Formula I, as recited in Claim 1, or a pharmaceutically acceptable salt, crystal form or hydrate thereof.