CA2195973A1 - N-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1h-1,4-benzodiazepines - Google Patents

N-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1h-1,4-benzodiazepines

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Publication number
CA2195973A1
CA2195973A1 CA002195973A CA2195973A CA2195973A1 CA 2195973 A1 CA2195973 A1 CA 2195973A1 CA 002195973 A CA002195973 A CA 002195973A CA 2195973 A CA2195973 A CA 2195973A CA 2195973 A1 CA2195973 A1 CA 2195973A1
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CA
Canada
Prior art keywords
dihydro
phenyl
propyl
oxo
benzo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002195973A
Other languages
French (fr)
Inventor
David A. Claremon
Nigel Liverton
Harold G. Selnick
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Merck and Co Inc
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Individual
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Filing date
Publication date
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Publication of CA2195973A1 publication Critical patent/CA2195973A1/en
Abandoned legal-status Critical Current

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Classifications

    • 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
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61P9/06—Antiarrhythmics

Abstract

This invention is concerned with novel compounds represented by structural formula (I), where R1 is formula (II) or (III); X and Y are independently hydrogen, fluoro, chloro, bromo, iodo, or trifluoromethyl; n is 0, 1 or 2; and R2 is hydrogen, fluoro, chloro, bromo, iodo, or trifluoromethyl, methyl, or methoxy; as the racemates, mixtures of enantiomers, individual diastereomers or individual enantiomers, and pharmaceutically acceptable crystal forms, salts, or hydrates thereof.

Description

_ WO 96/05827 . PCT/US95/10501 ~ 2195973 TITLE OF THE INVENTION
N-2,3-DIHYDRO- 1 -(2-PROPYL)-2-OXO-5-PHENYL- 1 H- 1 ,4-BENZODL~ZEPINES

Arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In a serious case, ~hyll~ ias give rise to ventricular fibrillation and can cause sudden death.
Though various antia"yll",-ic agents are now available on the market, agents which exhibit both satisfactory effects and high safety profiles have not been obtained. For example, antiarrythmic agents of Class I, according to the cl~c~ific~ion of Vaughan-Williams, which cause a selective inhibition of the m~ximllm velocity of the upstroke of the 15 action potential (Vmax) are in:~tleqll~t~ for preventing ventricular fibril-lation. In addition, they have problems regardmg safety, namely, they cause a depression of the myocardial contractility and have a tendency to induce arrythmias due to an inhibition of the impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class Il 2 o and IV respectively, have a defect in that their effects are either limited to a certain type of al,hy~ "ia or are contr~3in~ tPd because of their cardiac de~ sal,i properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class 1.
Antiarrythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a ~ignific~nt depression of the Vmax. Drugs in this class are limited.
Examples such as sotalol and arniodarone have been shown to possess Class III properties. Sotalol also possesses Class II effects which may 3 o cause cardiac depression and be contraindicated in certain susceptible patients. Also, amiodarone is severely limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrilla-tions. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of a"l,y~ "ias due to the W096/05827 2 1 959 73 PCT/US95/10501 ~

inhibition of the action potential conduction as seen with Class I
a--iial-l-yll.---ic agents.

SUMMARY OF TH~ INVl~NTION
This invention is concerned with novel compounds ;s~nl~d by structural formula I

~N ~ ~
~:N H (cH2)n ~. , I

where Rl is ~y or ~

X and Y are independently hydrogen, fluoro, chloro, bromo, iodo, or trifluoromethyl;
nisO, l or2;and R2 is hydrogen, fluoro, chloro, bromo, iodo, or trifluoromethyl, methyl, or methoxy;
as the la~~lllal~s, mixtures of enantiomers, individual diastereomers or individual enantiomers, and ph~l " ,~. r~ll ically acceptable crystal forms, salts, or hydrates thereof, which are useful as antiarrhythmic agents.
The compounds of the present invention may have asymmetric centers and occur as r~r~rn:~Pc mixtures of enantiomers, individual diastereomers, or as individual enantiomers with all isomeric _ . . _ . . . . . _ . _ . . . . . _ .

~ WO 96/0582'1 2 ~ 9 5 9 7 3 PCT/US95/10501 forms being included in the present invention. The invention is also concerned with ph~rrn~entir~l formulations ~o~ )flsillg one of the novel compounds as an active ingredient.
The invention is also concerned with a method of treating 5 arrhythmia by the ad.~ ion of one of the novel compounds or formulation thereof to a patient in need of such treatment.

DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of this invention have structural 10 formula ~N ~ ~

~-cN H (CH2)n where Rl is ~y or ~

X and Y are in~PpP.n~ ntly hydrogen, fluoro, chloro, b}omo, iodo, or trifluoromethyl;
30 nisO, I or2;and R2 is hydrogen, fluoro, chloro, bromo, iodo, or trifluoromethyl, methyl, or methoxy;
as the r~rl~m~t~s, mixtures of en~ntiomPrs, individual diastereomers or individual enantiomers, and pl-," " ,;~,,1 ically acceptable crystal forms, wos6/oss27 2~ 95~73 PCIIUS95110501 ~

salts, or hydrates thereof. These compounds include pharm~rent~ ly acceptable crystal forms and hydrates of the compounds of Formula 1, which are ~llialflly~ llic agents.
The compounds of the present invention may have 5 asymmetric centers and occur as racemates, mixtures of enantiomers, individual diastereomers, or as individual ~n~ntiomf rs with all isomeric forms being included in the present invention.
One preferred embodiment of the present invention is (+)-2-[2,4-Bis(trifluoromethyl)phenyl]-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepin-3-yl]~et:~mide ~~ CF
N_~O ~ ~ 3 ~GN H CF3 Another embodiment of the novel compounds of this invention is ~+)-3,5-Dichloro-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][I ,4]diazepin-3-yl]ltrn7~lmi~

~ O Cl N~ ~ /=<
~5 N) H

A second embodirnent of the novel compounds of this invention is (+)-3-Cyclohexyl-N-[2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l,4]diazepin-3-yl]~ d"a",ide ~ WO 96/0S827 2 1 9 5 9 7 3 PCT/U595/lOSOI

s ~$ 1, 10Still another embodiment of the novel compounds of this invention is (+)-2-(3,4-Dichlorophenyl)-N-[2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][ I ,4]diazepin-3-yl]~ret~mi~

~0 ~ CI

Other examples of the cl ." ,l.""~c of this invention include:
(+)-2-(3,5-Dichlol~Jpllellyl)-N-[2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1 H-benzo[e] [ I ,4]diazepin-3-yl]~ret?rni-iP
~ Cll N--~~ ~0'C I
3 o \~5N H

WO 96/05827 PCT/US95/10501 ~

(+)-3-(2,4-Dichlorophenyl)-N-[2,3-dihydro- 1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepin-3-yl]lulù~Jdna~llide N H 1~ C I

(-)-3-(2,4-Dichlorophenyl)-N-[3S-2,3-dihydro- 1 -(2-propyl)-2-oxo-5 -phenyl-lH-benzo[e][1,4]diazepin-3-yl]l,-u~ ide ~$H

(-)-3-(3,4-Dichloro)-N-[3S-2,3-dihydro- 1 -(2-propyl)-2-oxû-5-phenyl- 1 H-benzo[e][ I ,4]diazepin-3-yl]bPn7~mi-1.o I~H J~

~ WO 96/05827 21 9 5 9 7 3 PCT0S95110501 (+)-2-Afi,qm,qnt,qn-l-yl-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-~ lH-benzo[e][1,4]diazepin-3 yl1qretqmi(le ~N H

(+)-4-Cyclohexyl-N-[3R-2,3 -dihydro- I -(2-propyl)-2-oxo-S-phenyl- I H-benzo[e][l ,4]diazepin-3-yl]bntqnqmi(l-~

_~0 ~~0 (+)-A~qmqntqn- I -yl-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-25 IH-benZO[e][l,4]diaZepill-3-yl]CarbOXalllide 3 0 ~N H

WO 96/0582~ 2 1 ~ 5 9 7 3 PCT/US9~/10~01 (+)-2-[3,5-Bis(trifluoromethyl)phenyl] -N-[3R-2,3-dihydro- 1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l ,4]diazepin-3-yl]~et~mitl~
N H

(+)-2-(2,4-Dichlorophenyl)-N-[3R-2,3-dihydro-l -(2-propyl)-2-oxo-5-phenyl-lH-benzo~e][l ,4]diazepin-3-yl]acetamide ~lal N

(+)-3-Chloro-N-[3R-2,3 -dihydro- I -(2-propyl)-2-oxo-5-phenyl-1 H- 1,4-25 benzodiazepin-3-yl]b~on7~m~

~--~'n'HN)~CI
/CI\ .

~ WO 96/05827 . 2 1 9 5 9 7 3 PCT/US95/10501 (+)-4-Chloro-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH- 1,4-benzodiazepin-3-yl]benzamide .

~0 ~3 (+)-2-(3-Chlorophenyl)-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1 ,4]diazepin-3-yl]~ret:~mi(lt~

~ ~0 ~

(+)-3-Bromo~-chloro-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l ,4]dia~epin-3-yl]ben7slmi~1~

~~ ~

W O 96/05827 2 1 q 5 q 7 3 PC~rAUS95/10501 3,4-Dichloro-N-[2,3-dihydro-1 -(2-propyl)-2-oxo-5-(2-fluorophenyl)-1 H-benzo[e][ I ,4~diazepin-3-yl]k~n7.~mide ~~ O

H

o ~F

(+)-3-Bromo-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l74]diazepin-3-yl]b n7.~mi~1~

N ~ Br 2 5 3-Cyclohexyl-N-L2,3-dihydro- 1 -(2-propyl)-2-oxo-5-(2-fluorophenyl)- 1 H-benzo[e][1,4]diazepin-3-yl]p,~ all-ide 3 o ~5~N~O
g~F

~ W0 96/05827 . 2 l 9 5 9 7 3 PCr/USg5ll050l 3-(3,5-Dichloro)-N-[3S-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l ,4]diazepin-3-yl]ben7.~mi~

~ N H~

(+)-N-[3R-2,3-dihydro- 1 -(2-propyl)-2-oxo-5-phenyl- I H- 1,4-b~n70~ 7.f~pin-3-yl]bl~n7.~mi,l,-~ N ~3 g~

(+)-2-(3-Trifluorome~ylphenyl)-N-[3R-2,3-dihydro-1 -(2-propyl)-2-25 oxo-5-phenyl-lH-benzole][1,4]diazepin-3-yl]~e~lmi-~N H CF3 g~

WO 96/05827 2 1 9 5 9 7 3 PCT/US9511050~ ~

(+)-3,5-Bis(trifluoromethyl)-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-S-phenyl- I H-benzo[e] [ I ,4]diazepin-3 -yl]bPn7.~mide N J~c F3 (+)-2-(2-Trifluoromethylphenyl)-N-[3R-2,3-dihydro- l -(2-propyl)-2-oxo-~-phenyl-lH-benzo[e][l~4]diazepin-3-yl]~ret~ dp N ~3 (+)-2-(4-TrifluululllelllyllJhenyl)-N-~3R-2,3-dihydro-1 -(2-propyl)-2-25 oxo-~-phenyl- 1 H-benzo~e]l I ,4]diazepin-3-yl]~et~mi,l.o ~ ~o ~ ~CF3 ~ WO 96/05827 2 1 9 5 9 7 3 PCT/US95110501 (+)-2-Phenyl-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[E] [ 1 ,4]diazepin-3-yl]acetamide (-)-2-(3,5-Dichlorophenyl)-N-[3S-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][ I ,4]diazepin-3-yl]acetarnide Cl ¢~=$ N ~ J~C I
~

(-)-2-Hydroxy-2-(4-trifluoromethylphenyl)-N-[3R-2,3-dihydro- 1 -(2-2s propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepin-3-yl]~,~et:~mitllo ~sN H OH CF3 ~ ,~

WO 96105827 2 1 9 5 9 7 3 PCTIUSgSlloSol (+)--2-Hydroxy-2-(4-trifluoromethylphenyl)-N-[3R- I -(2-propyl)-2-oxo-5-phenyl-2,3-dihydro-lH-ben~o[e][l ,4]diazepin-3-yl]:~ret:~mifie .

¢~N O H CF3 ~

(+)-3-Cyclohexyl-N-[2,3-dihydro- 1 -(2-propyl)-2-oxo-5-(4-fluoprophenyl)-lH-benzo[e][1,4]diazepin-3-yl]l~lup~lalllide < ~N'~I--'O

(+)-3 ,S-Dichloro-N-[2,3-dihydro- 1 -(2-propyl)-2-oxo-5-(4-fluorophenyl)-25 lH-benzo[e][1,4]diazepin-3-yl]h~n7~mi~

~, wo 96/0s827 2 1 9 5 9 7 3 PcTrusg5rlo501 ~ O

~ Cl F

A novel process for preparing the compounds of this invention is srhPm:~rir~lly exemplified below im scheme, and these steps are well known in the art and/or described in the Examples that follow.

W096/05827 . ~1 95~73 PCWS95110501 Scheme 1 HN~O iPr-l ~N~
~ N Cs2CO3 ~ N

~,N KHMDS
i o ~.~N~ N~
~J~ NH2 P(Ph)3 ~/ ~N3 ~N . \~N

\ D-Boc-Phe-OH, EDC, HOBT

~N
¢~N H NHBoc HCI (9) ~ WO 96/05827 2 1 9 5 9 7 3 PCT/US95/lOSOI

Scheme 1 cont'd.

¢~H ~'z ¦ Separate Diaste~omers ~5~NH-D-Phe-H 1~ IH-D-Phe-H
~ ' 1 . 1) PhNCS
~ 2) TFA _~

NH2 [~ ~ NH2 ~N ~N

R(CH2)nCOCI or R(CH2)nCO2H, EDC, HOBT , /

N~ (CH2)n~R ¢~ N~ (CH2)n-R

R = O ; ~ X X~Y= H, Cl, CF3, Br WO 96/05827 2 1 ~ 5 9 7 3 PCT/US95110501 The novel compounds of the present invention have the pharmacological properties required for antiarrhythmic agents of C~lass III, namely they demonstrate prolongation of QTc-interval, and dose dependent increases im ventricular refractoriness. This is accom-plished without effecting heart rate, mean arterial pressure and PR and QRS intervals. Modest increases in LV+dPldt (left ventricular change im pressure with time) is observed. Further, these compounds suppress the induction of PVS (Programmed Ventricular Stimulation) induced o ventricular tachyarrhythmias.
These compounds are effective in treating and preventing all types of a-lllyll~--ias including ventricular and atrial (supraventricular) arrhythmias. The compounds of the present invention are especially useful to control reentrant arrhythmias and prevent sudden death due to the ventricular fihrill~tinn These compounds are also effective in treating and preventing impaired cardiac pump functions.
In the novel method of this invention of treating arrhythmia, one of the compounds or pl~ c~ icsllly acceptable salt thereof, is ~.l,,,;,,i~l~,c~d 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 by iu~ wus delivery of from about 0.0003 to about 0.3 mg per kg of body weight per day, or when given orally from about 0.03 to about I mg per kg of body weight per day, in a single dose or in 2 to 4 divided doses.
These compounds, orpl~ ",;~.~elll;r~lly acceptable salts thereof, in the described dosages, are ~ cd orally, iullldlue,ilu"e-ally, ,suh.~ l.Pously, intr~mll~clll~rly, transdermally, sublingually or intravenously. They are preferably ~lmini~ti~red intravenously or orally, for example in the form of tablets, troches, capsules, elixirs, ~u~)en~iùns, 3 0 ~mnl~ion~ syrups, wafers, chewing gum, or the like prepared by art recognized procedures. The amount of active compound in such thera-peutically useful compositions or preparations is such that a suitable dosage will be obtained.

~ WO 96/05827 2 1 9 5 ~ 7 3 PCT/US95110501 These compounds can be ~mini~t~red as the sole active ingredient or in combination with other antiarrhythmic agents or other ~ cardiovascular agents, such as Class 1, Class Il or Class IV antiarrhythmic agents, vasodilators, angiotensin converting enzyme inhibitors, 5 angiotensin II antagonists, diuretics or digitalis.
These compoumds can be :~(iminist~red as a method of treat-ing arrhythmia and impaired cardiac pump functions in conjunction with defibrillators, including implantable defibrillators. These compounds reduce the frequency of defibrillator firing.
By Class I ~l~iallhyllllllic agents is meant those agents which provide for sodium channel blockade, mcluding those compounds which exert a ~llellJl,ldlle stabilizing effect. Exemplary of this class of compounds are qlliniriin~ l,lu':Ai~ ie, disopyramide, lidocane, tocainide, flt-r~ini(1~- and plulJdrt;llolle. By Class Il ~lliallhyllllllic compounds is meant those agents which block symp~thf~ti~ activity.
Exemplary of this class of compounds are propranolol and acebutolol.
By Class m antiarrhythmic agents is meant those compounds which prolong the effective refractory period without altering the resting membrane potential or rate of depolarization. In addition to the novel 20 compounds of this invention, compounds such as amiodarone, bretylium and sotalol are considered to be in this class. Class IV allliallhyllllllic agents are effective in calcium channel blockade. Exemplary of this class of compounds are diltiazem and verapamil. Further definition of these classes can be found in Pharma Projects, section CIB, May 1993, which 25 is hereby incul~,uldl~d by reference.
Exemplary of vasodilators are compounds such as papaverine and isosorbide dinitrat. Examples of :~ngiot~n~in converting enzyme inhibitors include enalapril, lisinopril and captopril. Examples of diuretics include hydrochlorothiazide and acetazolamide. The pharma-3 0 ceutical agents listed herein are examples and do not represent a completelisting of the many compounds in these classes which are contemplated by this invention.
The activity of the compounds described herein as antiarrhythmic agents is measured by their ability to block the IKS

27 95~3 and IKr currents as .1~ t~rminf~d 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 (~qn~in~tti and Jurkiewicz, 1990, Two 5 components of cardiac delayed rectifier K+ current: differential se~ ivily to block by Class m ~lliallhy~ llic agents. J. Gen Physiol.
96: 195-215). Myocytes are isolated by enzymatic (collagenase and protease) digestion of T ~ng~ndorf perfused hearts. Single cells are then voltage clamped using I mm square-bore pipettes filled with 0.5 M
gluconate, 25 mM KCI, 5 mM K(2)ATP. Cells are bathed in a solution containing,inmM: 132NaCI,4KCI, 1.2MgC12, 10HEPES, 10glucose:
pH 7.2, temp. 35~C.
Each cell is m~int~inPd at a holding potential of -50 mV.
Test depolarizations are applied as voltage rarnps from -85 to -50 mV, and as steps to -10 mV (0.5 s) and +50 mV (1.0 s). IKI 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 2 o ~nn(~ntrzltion~
Employing this test the compounds described herein have an ICso of less than 100 nM as IKS blockers. The comounds of this invention are at least 10 times more potent in the blockade of IKS than the blockade of IKr-2s Fxample 1 (+)-3,5-Dichloro-N- [3R-2,3-dihydro- 1 -(2-propyl)-2-oxo-5-phenyl - 1 H-benzo[e][l ,4]diazepin-3-y]]bPn7~mi~

~ WO 96105827 PCTIUS95110501 2l ~5973 ~ N H ~
~ Cl Step A: Preparation of 2,3-dihydro-1-(2-propyl)-2-oxo-S-phenyl-o lH-benzo[e][1,4]diazepine A solution of S-phenyl-l ,4-ben70~ 7f pine-2-one (J. Org.
Che~r., 1962, 27, 3788)(50 g, 0.21 lmole) in DMF (100 mL) was treated with Cesium carbonate (82.8 g, 0.254mole) and 2-iodup.upd.lf (43.2 g, 5 0.254 mole). The mixture was stirred at room L~ alul~ for five hours.
The reaction mixture was then poured into water (2L) and extracted with ethyl acetate (3 X IL). The combined ethyl acetate fractions were dried over anhydrous m~gnf ~inm sulfate, filtered and concentrated at reduced pressure. The residue was crystallized from ethyl ether to give 45 g (77 20 %) of the product. MP = 153 - 155~C
IH NMR (CDC13) o 7.65-7.6(m, 2H), 7.60-7.35 (m, SH), 7.35-7.20 (m, 2H),4.72(d, J = 10 Hz, lH), 4.58 (hep, J = 6.8 Hz, lH), 3.75 (d,J=lOHz, lH), 1.5(d,J=6.8Hz,3H),1.2(d,J=6.8Hz,3H).

25 Step B: Preparation of 3-Azido-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl- 1 H-benzo[e] [1,4]diazepine To a solution of 2,3-dihydro-1-(2,propyl)-2-oxo-5-phenyl-~ 1 H- 1,4-benzodiazepine (50 g, 0.179 mole) in THF (1200 mL) at -70~C
30 was added a solution of potassium bis(trimethylsilyl) amide in toluene (400 mL of a 0.5 N solution, 0.20 mole). The deep orange solution was then treated with a solution of lliisul,lu~,yll,r"~f .~f~,llfonyl azide (61.1 g,0.197 mole) in THF (200 mL). The reaction was stirred at -70~C for 10 minutes and then treated with acetic acid (4 mL in 20 mL of THF) and WO 96/05827 2 1 9 ~ 9 7 3 PCT/US95110501 warmed to room le-l-peldlul~ over one hour. The reaction mixture was then poured into water (1.5 L) and extracted with ethyl acetate (3 X 500 mL) The combined ethyl acetate fractions were washed with a solution of sodium bicarbonate (300 mL), then water (2 X 500 mL), and then brine 5 (500 mL). The ethyl acetate solution was then dried over anhydrous m~gn~sillm sulfate, filtered and concentrated at reduced pressure. The residue was crystallized from ethyl ether to give 48 g (84 ~o) of the product. MP= 178 - 179~C;
H NMR (CDCI3) o 7.75-7.65(m, 2H), 7.60-7.20 (m, 7H), 4.58 (hep, o J = 6.8 Hz, IH),4.45(s, lH), 1.51 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H)-~: Preparation of racemic 3-Amino-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepine To a solution of 3-azido-2,3-dihydro-1-(2,propyl)-2-oxo-5-phenyl-lH-1,4-benzodiazepine (48 g, 0.15 mole) in THF (500 mL) at room l~ ulc; was added water (40 mL) and triphenyl phosphine (90 g, 0.343 mole). The reaction was stirred at room Lt;lll~ iUI~ for 24 hours 20 and conr~nt-~rl-d at reduced pressure. The residue was partitioned between lN H~l (1.5 L) and ether (500 mL). The ether layer was discarded and the aqueous phase was extracted with ethyl acetate ( I X
100 mL) which was also discarded. The aqueous phase was basified to pH 8 by careful addition of 6 N sodium hydroxide solution and extracted 25 with ethyl acetate (3 X 500 mL). The combined ethyl acetate phases were dried over anhydrous m~nf~sillm sulfate, filtered, and cu~). r~ ed at reduced pressure. The residue was crystallized from ethyl ether to give 41.7 g (94 %) of the product. MP = 130-135~C;
lH NMR (CDC13) ~ 7.75-7.65 (m, 2H), 7.60-7.20 (m, 7H), 4.65 (hep, 30 J = 6.8 Hz, lH),4.43 (s~ lH), 2.5 (br s, 2H,-NH2),1.51 (d, J = 6.8 Hz, 3H), 1.26(d,J=6.8Hz,3H).

_ WO 96/05827 PCT/US95/10501 2l 95973 ~ ~ Preparation of (2R)-2-Amino-3-phenyl-N-[2,3-dihydro-1-(2-propyl)-2-oxo-S-phenyl-lH-benzo[e][1,4]diazepin-3-yl]
propionamide To a stirring solution of ( )-3-amino-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-1,4-b~n7O~ 7l~pine (40.8 g, 139 mmol) in dimethylformamide (140 mL) was added EDC (32.0 g, 167 mmol), HOBT (22.6 g, 167 mmol) and N-BOC-D-phenylalanine (44.3 g, 167 mmol). This was stirred at ambient l~ eld~u~c for 2 h. The reaction was diluted with saturated aqueous sodium hydrogen carbonate (1.5 L) and extracted with ethyl acetate (3 x I L). The organic layers were combined, dried with brine, anhydrous m~gn~ lm sulfate, filtered, and evaporated under reduced pressure to give a yellow oil which was dissolved in ethyl acetate (700 mL), cooled in an ice/water bath.
15 Hydrogen chloride gas was bubbled into the solution for 3 h. The reaction mixture was cullcelllldl~d under reduced pressure and the resulting foam was dissolved in ethyl acetate (1 L) and saturated aqueous sodium hydrogen carbonate (I L). The layers were separated and the aqueous layer was extracted with ethyl acetate again (2xl L). The 20 organic layers were combined, dried with brine, dnhy(huus m~gnPcillm sulfate, filtered, and evaporated under reduced pressure to give a white solid, which was chromatographed over silica (2.5 kg) with ethyl acetate.
The faster running diastereomer was recovered as a white solid (22.0 g, 72%). IH NMR, CDC13, o 9.02 (d, J=8.6 Hz, lH), 7.64-7.25 (m, 14H), 25 5-50 (d, J=8.6 Hz, lH), 4.54 (septet, J=7.0 Hz, lH), 3.70 (dd, J=3.9, 9.8 Hz, lH), 3.34 (dd, J= 3.9, 13.8 Hz, lH), 2.82 (dd, J=9.8, 13.8 Hz, lH), 1.51-1.40 (m, 5H), 1.27 (d, J=7.0 Hz, lH).

The absolute stereochemistry at C-3 of the b~n7o~li7~pine rulg was 30 determined to be "R" by single crystal X-Ray analysis The slower running diastereomer was recovered as a white solid (5.0 g, 16%). 1H NMR, CDC13, o 9.05 (d, J=8.5 Hz, lH), 7.63-7.20 (m, 14H), 5.48 (d, J=8.5 Hz~ lH), 4.56 (septet, J=7.0 Hz, IH), 3.74 (dd, J=4.3, 10.0 WO 96/05827 PCT/IJS95/lOSOI
21 959~73 Hz, lH), 3.37 (dd, J= 4.3, 13.8 Hz, lH), 2.68 (dd, J=10.0, 13.8 Hz, IH), 1.55-1.39 (m, SH), 1.29 (d, J=7.0 Hz, IH).

Step E: Preparation of 3R-(+) and 3S-(-) 3-Amino-2,3-dihydro-1-(2-propyl)-2-oxo-5 -phenyl- 1 H-benzo [e] [1,4]diazepine To a stirring solution of (2R)-2-amino-3-phenyl-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepin-3-yl]
propionarnide (the faster running diastereomer from step D)(22 g, 49.9 mmol) in methylene chloride (100 mL) was added phenylisothiocyanate (7.17 mL~ 59.9 rnmol) and the resulting solution was stirred for 16 h.
The reaction mixture was cun.;ell~ d under reduced pressure to yield a yellowish oil which was cooled im an ice/water bath. Trifluoroacetic acid (40 mL, 500 rnmol) was added dropwise to the oil and the resulting solution was allowed to warm to ambient l~ elalu~ over 2.5 h. The reaction mixture was concentrated under reduced pressure to yield a yellowish oil which was chromatographed over silica (I kg) with 90:10:1:1 methylene chloride: methanol: acetic acid: water. The resulting white foam was crystallized from ethyl acetate/hexane to give The 3R-(+) enantiomer as a white solid (9.5 g, 65%). MP = 155 - 157~C;
2 IH NMR, CDC13, o 7.63-7.20 (m, 9H), 4.58 (septet, J=7.0 Hz, lH), 4.41 (s, IH), 2.43 (s, 2H), l.SO (d, J=7.0 Hz, 3H), 1.23 (d, J=7.0 Hz, 3H).
[a]D = +150~ (c=0.63; MeOH) The 3S-(-) en~nl~nmPr was prepared in the same fashion by starting with the slower running diastereomer from step D.
MP = 155 - 157~C;
IH NMR, CDC13, o 7.63-7.20 (m, 9H), 4.58 (septet, J=7.0 Hz, IH), 4.41 (s, IH), 2.43 (s, 2H), 1.50 (d, J=7.0 Hz, 3H), 1.23 (d, J=7.0 Hz, 3H).
[a]D = -159~ (c=0.83, MeOH) Step F: Preparation of (+)-3-(3,5-Dichloro)-N-[2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l ,4]diazepin-3-yl]
~?~on7:~mide ~ W096/05827 . 2 1 9 5 9 7 3 PCT/US95/10501 To a stirring solution of (+)3R-3-ammo-2,3-dihydro-1-(2-~ propyl)-2-oxo-5-phenyl-lH-1,4-bPn7n~i,q.7epine (5.2 g, 17.7 mmol) in dimethylformamide (20 mL) was added EDC (4.08 g, 21.3 mmol), HOBT (2.87 g, 21.3 mmol) and 3,5-dichlorobenzoic acid (4.06 g, 213 mmol). This was stirred at ambient temperature for 2 h. The reaction was diluted with saturated aqueous sodium hydrogen carbonate (700 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layers were combined, dried with brine, anhydrous m,qgT~ lm sulfate, filtered, and evaporated under reduced pressure to give a colorless oil which was chromatographed over silica with 10 to 30% ethyl acetate/hexane. The resulting foam was crystallized from ethyl acetate/hexane to give a white solid (6.7 g, 81 %). mp=141-142~C, [c~]D=+80.6~ (c=0.74; MeOH), I H NMR, CDC13, ~ 8.03 (d, J=7.8 Hz, lH), 7.80-7.20 (m, 12H), 5.61 (d, J=7.8 Hz, lH), 4.58 (septet, J=7.0 Hz, IH), 1.52 (d, J=7.0 Hz, 3H), 1.32 (d, J=7.0 Hz, 3H).
Anal. Calcd. for C25H2lN3o2cl2:
C, 63.89; H, 4.59; N, 8.94. Found: C, 63.87; H, 4.70; N, 8.88%.

The following examples were prepared by a procedure AIII;AIIY as describedforExample I step Ffrom eitherthe 3R-(+) or the 3S-(-) amine ~nq~ltinmf-r obtained in step E.

Example 2 (+)-3-Cyclohexyl-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepin-3-yl]~ ide WO 96/05827 2 ~ 9 5 9 7 3 PCT0595/lOSOI

H

mp=154-155~C
[a]D=+58.7~ (c=0.77; MeOH) lH NMR, CDC13, o 7.60-7.13 (m, 10H), 5.48 (d, J=8.3 Hz, lH), 4.53 (septet, J=6.9 Hz, lH), 2.40-2.34 (m, 2H), 1.80-1.43 (m, 10H), 1.39-1.10 (m, 7H), 1.01-0.92 (m, 2H).
Anal. Calcd. for C27H33N302:
5 C,75.14;H,7.71;N,9.74.Found:C,75.28;H,7.71;N,9.86Yo.
l~xarnple 3 (+)-2-(3,4-Dichlorophenyl)-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-20 phenyl-lH-benzo[e][1,4]diazepin-3-yl];~et:~mi(l~

l~N H
.

30 mp=l7l-l72t~c [a]D =+37.0~ (c=0.61; MeOH) lH NMR, CDC13, o 7.59-7.19 (m, 10H), 5.44 (d, J=8.3 Hz, lH), 4.54 (septet, J=6.9 Hz, IH), 3.54 (s, 2H), 1.49 (d, J=6.9 Hz, 3H), 1.25 (d, J=6.9 Hz, 3H).

- =

WO 96/05827 . PCT/US95J10501 ~ 21 9~7~

- Anal. Calcd. for C26H23N3o2cl2: -C, 65.01; H, 4.83; N, 8.75. Found: C, 65.00; H, 4.89; N, 8.71%.

Example 4 (+)-2-(3,5-Dichlorophenyl)-N-[3R-2,3-dihydro- 1 -(2-propyl)-2-oxo-5-phenyl- I H-benzo[e] [1,4]diazepin-3 -yl]~ e~midP

N~C

mp=90-96~C
[a]D = +42.7~ (c=0.71; MeOH) lH NMR, CDC13, ~ 7.59-7.19 (m, 10H), 5.44 (d, J=8.3 Hz, IH), 20 4 54 (septet, J=6.9 Hz, lH), 3.54 (s, 2H), 1.49 (d, J=6.9 Hz, 3H), 1.25 (d, J=6.9 Hz, 3H).
Anal. Calcd. for C26H23N3O2C12-0.20 H20:
C, 64.52; H, 4.87; N, 8.68. Found: C, 64.55; H, 5.00; N, 8.54~o.
Fx~ ?le5 (+)-3-(2,4-Dichlorophenyl)-N-[3R-2,3-dihydro- 1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l ,4]diazepin-3-yl]~..,pdlldlllide WO 96/05827 . 2 ~ 9 5 9 7 3 PCTNS95/10501 ~

N Y ~

¢~cN H Cl 10 m.p. 138-139 ~C, [a]D = +70.9" (c=0.79; MeOH).
Anal. Calcd. for C27H25N302C12:
C,65.59;H,5.1;N,8.5.Found:C,65.21;H,5.1;N,8.6%.

Examyle 6 (-)-3-(2,4-Dichlorophenyl)-N-[3S-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepin-3-yl]~ an~llide -~ , m.p. 142-143 ~C, [a]D = -66.3~ (c=0.64; MeOH).
Anal. Calcd. for C27H25N3o2cl2.:
C, 65.59; H, 5.1; N, 8.5. Found: C, 65.51; H, 5.04; N, 8.65%.

F~mrle 7 (-)-3-(3,4-Dichloro)-N-[3S-2,3-dihydro- 1 -(2-propyl)-2-oxo-5-phenyl- 1 H-benzo[e][1,4]diazepin-3-yl]bPn7~mi~

~ WO 96/05827 . PCT/US95/10501 -- 21 9~9~3 H J~

10 m.p. 143-144 ~C, [a]D = -72.2~ (c=0.45; MeOH).
Anal. Calcd. for C25H21N3O2C12-0.55 mol cyclohexane:
C, 66.3; H, 5.43; N, 8.2. Found: C, 66.31; H, 5.49; N, 8.19%.

Example 8 (+)-2-(A-i~m:lnt~n-1 -yl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l ,4]diazepin-3-yl]~ret:~mi~1r ¢~, m.p. 176-177 ~C, [oc]D = +63.5~ (c=0.51; MeOH).
Anal. Calcd. for C30H3sN3o2:
C, 76.73; H, 7.51; N, 8.95. Found: C, 76.39; H, 7.46; N, 8.86~o.

Fx~mple 9 (+)4-Cyclohexyl-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepin-3-yl]bnt~n~mi(li~

WO 96/05827 . PCTIUS95/10501 2 ~ 95973 s ~ H

m.p. foam ~C, [~c]D = +59.1 ~ (c=0.43; MeOH)..
Anal. Calcd. for C2gH35N3O2-0.20 mol H20:
C, 74.87; H, 7.94, N, 9.35. Found: C? 74.92; H, 7.88; N, 9.35%.

Example 10 (+)-~lqm:~nt~n- I -yl-N-[3R-2,3-dihydro- 1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepin-3-yl]carboxamide N
N

m.p. 206-207 ~C, [oc]D = +38.5~ (c=0.52; MeOH).
Anal. Calcd. for C29H33N302-0.30 mol H20:
C, 75.56; H, 7.35; N, 9.11. Found: C, 75.62; H, 7.33; N, 8.91%.
Example 11 (+)-2-[3,5-Bis(trifluoromethyl)phenyl]-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][ l ,4]diazepin-3-yl]~et~mi(lP

~ WO 96/05827 . 2 l 9 5 9 7 3 PCTrusg5rl0sol --~ C F3 ~5N H CF3 m.p. 152-153 ~C, [a]D = +37.5~ (c=0.65; MeOH).
Anal. Calcd. for C28H23N3o2F6:
C, 61.43; H, 4.23; N, 7.67. Found: C, 61.47; H, 4.22; N, 7.7~O.

Fx~n~le 12 (+)-2-(2,4-Dichlol uphcllyl)-N-[3R-2,3-dihydro- 1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l ,4]diazepin-3-yllf~.ç~t~mide 2 0 ~ N

m.p. 78-84 ~C, [a]D = +26.3~ (c=0.67; MeOH).
Anal. Calcd. for C26H23N3O2C12-0.20 mol cyclohexane:
C, 65.7; H, 5.15; N, 8.45. Found: C, 65.53; H, 5.25; N, 8.35%.

- Example 13 (+)-3-Chloro-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-S-phenyl-lH-benzo[e][1,4]diazepin-3-yl]kPn7~mi~P

WO 96/05827 ' PCT/USgS/10501 21 95~73 N~CI

m.p. 79-86 ~C, [oc]D = +50.5~ (c=0.55; MeOH).
Anal. Calcd. for C25H22N3O2CI-0.35 mole cyclohexane:
C, 70.55; H, 5.72; N, 9.11. Found: C, 70.63; H, 5.79; N, 9.18%.

Fx~mRle 14 (+)-4-Chloro-N-[3R-2,3 -dihydro-l -(2-propyl)-2-oxo-5-phenyl- I H-benzo[e][l ,4]diazepin-3-yllbPn7s,mi~
-;~

m.p. 168-169 ~C, [a]D = +79.7" (c=0.96; MeOH).
Anal. Calcd. for C25H22N3O2CI.:
C, 69.52; H, 5.13; N, 9.73. Found: C, 69.75; H, 5.19; N, 9.9%.
Fx:~m,l?le 15 (+)-2-(3-Chlo~ h~llyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-ben_o[e][l,4]diazepin-3-yl]~ çr~mi-lP

~ WO 961058:~7 PCTIUS95/10501 ~N H

m-p- 137-139~C, [a]D= +44.2~ (c=0.60; MeOH).
Anal. Calcd. for C26H24N302CI.:
C, 70.03; H, 5.42; N, 9.42. Found: C. 70.23; H, 5.43; N, 9.45%.

Fx~mQle 16 (+)-3-Bromo-4-chloro-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l ,4]diazepin-3-yl]benzamide ~ N~[~Br ~

m.p. 173-175 ~C, [a]D = +58.6~ ~c=0.36; MeOH).
Anal. Calcd. for C25H20N3o2Brcl-o.4o mol H20:
C, 58.08; H, 4.06; N, 8.13. Found: C, 58.1; H, 4.14; N, 8.11%.
Example 17 (+)-3-Bromo-N-[3R-2,3-dihydro- 1 -(2-propyl)-2-oxo-5-phenyl- 1 H -benzo[e][1 ,4]diazepin-3-yl]hen7:~,mi~P

N~Br m.p. 78-85 ~C, [a]D = +50.4~ (c=0.76; MeOH).
Anal. Calcd. for C25H22N302Br 0.85 mol H20 0.30 mol cy~lnh!~x~n~:
C, 62.27; H, 5.32; N, 8.13. Found: C, 62.27; H, 5.16; N, 8.03%.

Example 18 (-)-3,5-Dichloro-N-[3S-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepin-3-yl]b.on7~mi(1~o ~ H~

Cl m.p. 140-141 ~C, [a]D = -83.7~ (c=0.52; MeOH).
Anal. Calcd. for C25H2lN3o2cl2-C, 64.39; H, 4.54; N, 9.01. Found: C, 64.36; H, 4.76; N, 8.62%.
Example 19 (+)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l ,4]diazepin-3-yl]ben7~mi~1to ~ WO 96/05827 . PCT/US9S/10501 21 95973 ~

m.p. 216-219 ~C, [a]D +53.9~ (c=0.36; CHC13).
Anal. Calcd. for C25H23N3o2:
C, 75.55; H, 5.83; N, 10.57. Found: C, 75.9; H, 5.87; N, 10.69%.

Example 20 (+)-2-(3-Trifluoromethylphenyl)-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepin-3-yl]sl~ et:lmi(le -20 ¢~~ ~--~'CF3 [a]D+35.9~(c--0.41; MeOH).
Anal. Calcd. for C27H24N3o2F3:
C, 67.63; H, 5.05; N, 8.76. Found: C, 67.96; H, 5.27; N, 8.37%.
Fx:~ml?le 21 (+)-3,5-Bis(trifluoromethyl) -N- [3R-2,3 -dihydro- I -(2-propyl)-2-oxo-S-phenyl-lH-benzo[e][l ,4]diazepin-3-yl]bPn7~mi(ie W096/05827 . 2195973 PCI/US95110501 ~

N ~c F3 10 m.p. 198-199 ~C, [a]D +39.2~ (c=0.53; MeOH).
Anal. Calcd. for C27H21N3O2F6-0.40 mol EtOAc:
C, 60.4; H, 4.29; N, 7.39. Found: C, 60.4; H, 4.28; N, 7.42%.

Example 22 (+)-2-(2-Trifluorornethylphenyl)-N-[3R-2.3-dihydro- 1 -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l ,4]diazepin-3-yl]S~et:lmi~l~
-~sN H CF3 m.p. 160-162 ~C, [oc]D +32.3~ (c=0.39; MeOH).
Anal. Calcd. for C27H24N3o2F3:
C, 67.63; H, 5.05; N, 8.76. Found: C, 67.58; H, 5.1; N, 8.85%.

Example 23 (+)-2-(4-Tlinuululll~ ylluh~;llyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-S-phenyl-lH-benzo[e][1,4]diazepin-3-yl]~ref~mi~l~

~ WO 96105827 . PCT/US95/10501 s ~ N ~C F3 m.p. 227-228 ~C, [a]D +38.0~ (c=0.30; MeOH).
Anal. Calcd. for C27H24N3o2F3:
C, 67.63; H, 5.05; N, 8.76. Found: C, 67.93; H, 5.06; N, 8.98%.

lS Example 24 (+)-2-Phenyl-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][l ,4]diazepin-3-yl]~ret~mi~l.q ~ N~3 ~_Y

m.p. 154-156 ~C, [a]d +40.3~ (c=0.38; MeOH).
Anal. Calcd. for C26H25N3O2-0.45 mol H20:
30 C, 74.42; H, 6.22; N, 10.01. Found: C, 74.45; H, 6; N, 9.96%.

WO 96/05827 . PCT/US95/10501 Fx;~rnple 25 (-)-2-(3,5-Dichlorophenyl)-N-[3S-2,3-dihydro-1 -(2-propyl)-2-oxo-5-phenyl-lH-benzoLe][1,4]diazepin-3-yl]acetamide ~ Cl ~ H
~

m.p. foam ~C, [a]D = -39.1~ (c=0.46; MeOH).
Anal. Calcd. for C26H23N3o2cl2:
C, 65.01; H, 4.83; N, 8.75. Found: C, 64.69; H, 4.85; N, 8.559'o.
Fx~ rle 26 20 (-)-2-Hydroxy-2-(4-trifluoromethylphenyl)-N-[1 -(2-propyl)-2-oxo-5-phenyl-2,3-dihydro-lH-benzo[e][l ,4]diazepin-3-yl]~ret~mirl~

~--~'~ N~CF3 m.p. 195-6 ~C, [a]D = -33~ (c=0.49; MeOH).
Anal. Calcd. for C27H24N303F3:
C, 65.45; H, 4.88; N, 8.48. Found: C, 65.19; H, 4.83; N, 8.35%.

~ WO 96105827 2 1 9 5 9 7 3 PCT/US95~10501 Example 27 (+)-2-Hydroxy-2-(4-trifluoromethylphenyl)-N-[1 -(2-propyl)-2-oxo-S-phenyl-2,3-dihydro-lH-benzoLe][ l ,4]diazepin-3-yl]~et~mi~

~~ ~CF3 m.p. 227-8 ~C, [oc]D = +53~ (c=0.89; MeOH).
Anal. Calcd. for C27H24N303F3:
C, 65.45; H, 4.88; N, 8.48. Found: C, 65.26; H, 4.82; N, 8.55%.

F~lmrlç 28 20 (+)-2-[2,4-Bis(trifluoromethyl)phenyl]-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-S-phenyl-lH-benzo[e][l ,4]diazepim-3-yl]~re~:~mi~
/

~N H ~F
~ ' W096/05827 2 ~ 9 5 9 73 PCTIUS95/10501 ~

Step A. 2,4-Bis(trifluoromethyl)benzonitrile To a stirring biphasic mixture of 100mL ethanol and 250mL of pho~rh~t~
buffer (Ig of NaH2PO4-H2O per 5 mL H2O adjusted to pH=7.0 with 50%
NaOH) and NaCN (81.3mmol,4.0g) heated to 60~C was added 2,4-bis(trifluoromethyl) benzyl bromide (32.5rnmol,10g) in 50mL EtOH
dropwise over 30min. The reaction was heated at 60~C for 24h. The reaction was then evaporated under reduced pressure. The remaining aqueous was extracted with 2xl50mL EtOAc. The organic layers were combined, dried with brine and Na2SO4. The organic phase was evaporated under reduced pressure and the residue chromatographed over silica eluting with 10% EtOAc:Hexanes. The pure fractions were collected and evaporated to give 7.0g of a pale yellow oil, 85.1 % NMR
H (CDCI3) o 8.0-7.85 (m,3H), 4.03 (s,2H) Step B. 2,4-Bis(trifluoromethyl)phenyl acetic acid 2,4-Bis(trifluolu~ Ll.yl)benzonitrile (41.5mmol,10.51g) was taken up in 100mL acetic acid, 50mL conc. H2SO4, and 20mL water. This was heated to 120~Cfor 3h. The reaction was then diluted with IL ice water, and extracted with 2x300mL ethyl acetate. The ct-mhin~d organics were washed with 2x200mL water, dried with brine and Na2SO4, and evaporated under reduoed pressure. The residue was taken up in a minimnm of diethyl ether and crystallized by adding sufficient hexane to precipatate the product. The solid was collected to give 7.74g of 2,4-bis(trifluoromethyl) phenyl acetic acid as white crystals, 68.5%.NMR IH
(CDCI3) ~ 7.93 ~s,lH), 7.80 (d, J=7.9Hz,lH), 7.55 (d, J=7.9Hz,lH), 3.94 (s,2H).

Step C: (+)-2-[2,4-Bis(trifluoromethyl)phenyl]-N-[3R-2,3-dihydro-I -(2-propyl)-2-oxo-5-phenyl-lH-benzo[e][1,4]diazepin-3-yl] ~ oet~mi(l~

The 2,4-Bis-(trifluoromethyl) phenyl acetic acid obtained in step B

Wo 96/05827 . PCI/US95/10501 ~ was coupled with 3R-3-Amino-2,3-dihydro- 1- (2-propyl)-2-oxo-5-phenyl-lH-benzo[e][ 1 ,4]diazepine from step E example I by a procedure suh~t~nti~lly as desribed for step F example I to give (+)-2-[2,4-Bis(trifluoromethyl)phenyl]-N-[3R-2,3-dihydro-1 -(2-propyl)-2-oxo-5-5 phenyl-lH-benzo[e][1,4]diazepin-3-yl]-:~ret~,mi~P
m.p. 134-136 ~C, [a]D = +22~ (c=0.39; MeOH).
Anal. Calcd. for C28H23N3o2F3:
C,61.43;H,4.23;N,7.67.Found:C,61.61;H,4.24;N,7.75%.

The following examples were prepared by procedures ~ub~ lially as described in example I except sl-hstihltin~ the ~ -vpri~-te fluoro suh~titllt~d aminobenzophenone in step A.

Example 29 (+)-3-Cyclohexyl-N-[2,3-dihydrol -(2-propyl)-2-oxo-5-(4-fluoprophenyl)-lH-benzo[e][l,4]diazepim-3-yl]~"v~u~ lide ~

F
mp=179-181~C
[a]D=+45.1~ (c=0.55; MeOH) Anal. Calcd. for C27H32FN302:
C, 72.14; H, 7.17; N, 9.35. Found: C, 71.98; H, 7.10; N, 9.43%.

WO 96/05827 2 ~ 9 5 9 7 3 PCTIUS95/10501 ~

Example 30 (+)-3-S-Dichloro-N-[2,3-dihydro- 1 -(2-propyl)-2-oxo-5-(4-fluorophenyl)-I H-benzo[e] [ I ,4]diazepin-3-yl]benzamide o ~ Cl m.p. 174-176 ~C, [a]D +53.9~ (c=0.36; CHC13).
Anal. Calcd. for C25H2ocl2FN3o2:
C, 61.54; H, 4.21; N, 8.61. Found: C, 61.54; H, 4.22; N, 8.72 Example 31 3-Cyclohexyl -N-r2,3-dihydro- 1 -(2-propyl)-2-oxo-5-(2-fluorophenyl)- I H -benzo[e] [ l ,4]diazepin-3-yl]~ ,pallal-lide ~~ O
25 ~ Jl o /~F

m.p. 165-167 ~C.
Anal. Calcd. for C27H32N302F:
C,72.14;H,7.17;N,9.35.Found:C,71.71;H,7.11;N,9.33%.

~59;,73 ~xample 32 3,4-Dichloro-N-[2,3-dihydro- 1 -(2-propyl)-2-oxo-5-(2-fluorophenyl)- I H-benzo[e][l ,4]diazepin-3-yl]b.on7~mi~1e '~ J~c F

m.p. l 88-189 ~C.
15 Anal. Calcd. for C25H2oN3o2cl2F~:
C,61.99; H,4.16; N, 8.68. Found: C, 61.7; H,4.22; N,8.59%.

Claims (15)

WHAT IS CLAIMED IS:
1. A compound of the structural formula I

FORMULA I

where R1 is or ;

X and Y are independently hydrogen, fluoro, chloro, bromo, iodo, or trifluoromethyl;
n is 0, 1 or 2; and R2 is hydrogen, fluoro, chloro, bromo, iodo, or trifluoromethyl, methyl, or methoxy;
as the racemates, mixtures of enantiomers, individual diastereomers or individual enantiomers, and pharmaceutically acceptable crystal forms, salts, or hydrates thereof.
2. The compound of Claim 1 selected from the group consisting of (+)-3,5-Dichloro-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]benzamide.

;

(+)-3-Cyclohexyl-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]propanamide ;

(+)-2-(3,4-Dichlorophenyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-2-(3,5-Dichlorophenyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-2-[2,4-Bis(trifluoromethyl)phenyl]-N-[1-(2-propyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-3-(2,4-Dichlorophenyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]propanamide ;

(-)-3-(2,4-Dichlorophenyl)-N-[3S-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]propanamide ;

(-)-3,4-Dichloro-N-[3S-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]benzamide ;

(+)-2-Adamantan-1-yl-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-4-Cyclohexyl-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]butanamide ;

(+)-Adamantan-1-yl-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]carboxamide ;

(+)-2-[3,5-Bis(trifluoromethyl)phenyl]-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-2-(2,4-Dichlorophenyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-3-Chloro-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]benzamide ;

(+)-4-Chloro-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]benzamide ;

(+)-2-(3-Chlorophenyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-3-Bromo-4-chloro-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]benzamide ;

3,4-Dichloro-N-[2,3-dihydro-1-(2-propyl)-2-oxo-5-(2-fluorophenyl)-1H-benzo[e][1,4]diazepin-3-yl]benzamide ;

(+)-3-Bromo-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]benzamide ;

3-(Cyclohexyl)-N-[2,3-dihydro-1-(2-propyl)-2-oxo-5-(2-fluorophenyl)-1H-benzo[e][1,4]diazepin-3-yl]propanamide ;

(-)-3,5-Dichloro-N-[3S-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]benzamide ;

(+)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]benzamide ;

(+)-2-(3-Trifluoromethylphenyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-3,5-Bis(trifluoromethyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]benzamide ;

(+)-2-(2-Trifluoromethylphenyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-2-(4-Trifluoromethylphenyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-2-Phenyl-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(-)-2-(3,5-Dichlorophenyl)-N-[3S-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(-)-3R-2-Hydroxy-2-(4-trifluoromethylphenyl)-N-[1-(2-propyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-3R-2-Hydroxy-2-(4-trifluoromethylphenyl)-N-[1-(2-propyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide ;

(+)-3-Cyclohexyl-N-[2,3-dihydro-1-(2-propyl)-2-oxo-5-(4-fluoprophenyl)1H-benzo[e][1,4]diazepin-3-yl]propanamide ; and (+)-3-5-(Dichloro)-N-[2,3-dihydro-1-(2-propyl)-2-oxo-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-3-yl]benzamide
3. The compound of Claim 1 which is (+)-3,5-Dichloro-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]benzamide.

.
4. The compound of Claim 1 which is (+)-3-Cyclohexyl-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]propanamide .
5. The compound of Claim 1 which is (+)-2-(3,4-Dichlorophenyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide
6. The compound of Claim 1 which is (+)-2-(3,5-Dichlorophenyl)-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-benzo[e][1,4]diazepin-3-yl]acetamide
7. The compound of Claim 1 which is (+)-2-[2,4-Bis-(trifluoromethyl)phenyl]-N-[3R-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide
8. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of Claim 1 or a pharmaceutically acceptable salt, crystal form or hydrate thereof.
9. The pharmaceutical formulation of Claim 8 comprising in addition another antiarrhythmic agent or other cardiovascular agent.
10. A method of preventing or treating arrhythmia which comprises the administration to a patient in need of such treatment of an antiarrhythmically effective amount of the compound of Claim 1.
11. The method of Claim 10 comprising the concomitant administration of another antiarrhythimic agent or other cardiovascular agent.
12. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of Claim 7 or a pharmaceutically acceptable salt, crystal form or hydrate thereof.
13. The pharmaceutical formulation of Claim 7 comprising in addition another antiarrhythmic agent or other cardiovascular agent.
14. A method of preventing or treating arrhythmia which comprises the administration to a patient in need of such treatment of an antiarrhythmically effective amount of the compound of Claim 7.
15. The method of Claim 14 comprising the concomitant administration of another antiarrhythimic agent or other cardiovascular agent.
CA002195973A 1994-08-18 1995-08-17 N-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1h-1,4-benzodiazepines Abandoned CA2195973A1 (en)

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