WO1997049690A1 - A method for treating meniere's disease - Google Patents

A method for treating meniere's disease Download PDF

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Publication number
WO1997049690A1
WO1997049690A1 PCT/US1997/010561 US9710561W WO9749690A1 WO 1997049690 A1 WO1997049690 A1 WO 1997049690A1 US 9710561 W US9710561 W US 9710561W WO 9749690 A1 WO9749690 A1 WO 9749690A1
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phenyl
unsubstituted
substituted
alkyl
alkoxy
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PCT/US1997/010561
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French (fr)
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Peter K. S. Siegl
Allan I. Goldberg
Michael R. Goldberg
Paul I. Chang
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Merck & Co., Inc.
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Priority claimed from GBGB9617895.9A external-priority patent/GB9617895D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU34007/97A priority Critical patent/AU3400797A/en
Publication of WO1997049690A1 publication Critical patent/WO1997049690A1/en

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    • 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
    • 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
    • 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
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    • 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
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    • 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
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    • 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
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    • 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
    • C07D243/22—Sulfur atoms
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    • 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
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D495/04—Ortho-condensed systems

Definitions

  • Meniere's disease can be an incapacitating problem for patients with symptoms ranging from attacks of vertigo which appear suddenly and last from a few to 24 hours, nausea, vomiting, recurrent feeling of fullness or pressure in the affected ear, and fluctuating hearing which progressively worsens over the years. Tinnitus may be constant or intermittent and may be worse before, after or during the attack of vertigo.
  • the etiopatho- genesis of Meniere's disease has been studied since the early 1900's and has avoided definition. Generally the disease is said to result from distention of the endolymphatic compartment of the inner ear. The primary lesion appears to be in the endolymphatic sac, which is thought to be responsible for endolymph filtration and excretion. A precise cause of hydrops has not been established. Although usually only one ear is affected, both ears are involved in 10 to 15% of patients. (MERCK MANUAL, Vol. 16, 1992).
  • Meniere's disease has been subdivided into five stages. Stage one is primarily diagnosed by symptoms associated with unilateral cochlear pathology focused on signs, symptoms and pathology which are singularly cochlear. Patients in this stage often respond to treatment with diuretics and dexamethasone. Once in stage two, the hydrops extends to the vestibular labyrinth and the patient begins to experience vertigo. At this stage, surgery is recommended to insert a nylon tube in the lumen of the sac to relieve the endolymphatic pressure. Streptomycin perfusion of the membranous labyrinth is also recommended at this stage. In the third stage, hearing and balance are severely compromised, and comprehension fail.
  • Surgical treatment such as aminoglycoside destruction of the vestibular receptor or vestibular neurectomy are usually indicated.
  • the dizziness subsides, and the endolymphatic hydrops fills the vestibule so that the endolymph pressure cannot rise. Dizziness stops at this stage, but no known medical treatment is available.
  • the fifth stage widespread obstruction and ruptures in the membranous labyrinth occurs and all hearing is lost. Again no treatment is recognized once the patient has reached this stage. (REF. The America Journal of Otology, Volume 14, No. 3, May 1993, pp. 224 - 229).
  • I sK the protein which under lies the current I Ks
  • the I sK protein was present only on the endolymphatic surface of the marginal cell, consistent with involvement of I Ks in K + permeation in the luminal membrane of the marginal cell.
  • the K + conductance measured in vestibular dark cells and apical membranes of marginal cells was found to be comprised of a high density of I Ks channels(Sunose et al. Hearing Research 80:86-92, 1994; Marcus and Shen, Am. J. Physiol. 267: C857-C864, 1994; Wangemann et al. Hearing Research 84:19-29, 1995). Further, it has been determined that in its absence of the IKs channel, deftness results due to a lack of endolymph production. S. Heinemann and D. Vetter (Salk Institute), has determined that genetic knockout of IKs in mice results in vestibular dysfunction and deafness, secondary to the absence of endolymph. Recently, IKs message has been found in the ear. It is now believed that modulation of the IKs channel in the ear will affect endolymph production and mitigate the effects of this disease. OBJECTS OF THE INVENTION
  • an object of the present invention to provide methods of treating patients suffering from Meniere's disease with compounds not previously known to have activity for this condition. Another object is to provide new methods for treating Meniere's disease. A further object is to provide pharmaceutical formulations and methods for their preparation for use in treating Meniere's disease.
  • a method of treating Meniere's disease in mammals, including humans which comprises blocking the slowly activating delayed rectifier potassium (K + )current (IKs) in the ear is presented.
  • the compounds which exemplify this method of treatment are the 1 ,4-benzodiazepines or benzodiazepine derivatives that block the IKs current and are therefore effective in the treatment of Meniere's disease.
  • a method of treating Meniere's disease in mammals, including humans, which comprises blocking the slowly activating delayed rectifier potassium (K + )current (IKs) is presented. This method requires the addition of a compound which selectively blocks the IKs current and produces only minimal block of the IKr current.
  • Examples of compounds which are representative of selective IKs antagonists include, but are not limited to the following:
  • A is 1 ) thieno
  • Z is 1 ) C 1 -6 alkylene, either straight or branch chain and either unsubstituted or substituted with phenyl or spiro-piperidine, 2) C2-4 alkenylene, either straight or branch chain,
  • p is 0 or 1;
  • Rl is 1 ) phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N ⁇ 2, b) -Cl, Br, F, or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl-3 alkoxy, f) -CN, g) -methylenedioxy, 2) C5-7 cycloalkyl,
  • R2 is 1 ) phenyl, either unsubstituted or substituted with Cj -3 alkoxy or 4,4-dimethyloxazolin-2-yl, 2) Cl -6 alkyl, either straight or branched chain, and either unsubstituted or substituted with Cl-3 alkoxy or Cl-3 alkoxy-Cl-3 alkoxy,
  • R ⁇ 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
  • R3 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 R ⁇ 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.
  • One embodiment of this invention are novel compounds useful in the novel method of treatment of this invention wherein: A is benzo;
  • X and Y are oxygen
  • R3 is methyl
  • R4 is hydrogen
  • R 2 is Cl-6 alkyl.
  • X and Y are oxygen
  • R3 is methyl
  • R4 is hydrogen
  • R 2 is phenyl
  • Z is Cl -6 alkylene or a bond
  • Rl is phenyl, phenyl substituted with -Cl, -Br, -I, -F, or -CF3, or R l is cyclohexyl.
  • Z is C2-4 alkenylene and R 1 is phenyl or phenyl substituted with -Cl, -Br, -F, -I, -CF3, Cl -3 alkyl, Cl -3 alkoxy or methylenedioxy.
  • 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 effective in the treatment of Meniere's disease.
  • 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 1 and R 2 are independently
  • phenyl either unsubstituted or substituted with one or two substituents selected from a) -N02, OH, b) -Cl, Br, F, or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl -3 alkoxy, 0 -CN, g) -methylenedioxy, and
  • Z is 1 ) Cl-6 alkyl, either straight or branched chain ,
  • the IKs blockers or selective IKs antagonists 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.
  • the compounds of the present invention are especially useful for controlling and treating Meniere's disease via modulation of endolymph production.
  • 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 activity of the compounds described herein as agents which treat Meniere's disease 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 KCI, 5 mM K(2)ATP. Cells are bathed in a solution contaimng, 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 ⁇ Ks 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-
  • (+)-N-f (3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl-l H- 1 ,4- benzo-diazepin-3-yl l(trans-2-phenyl- 1 -cyclopropane )carboxamide m.p. 104-107°C, [ ⁇ ]D +328.2° (c 0.098, CH2CI2).
  • (+)-N-!(3R)-2,3-Dihydro- l -methyl-2-oxo-5-phenyl-l H- l ,4- benzodiazepin-3-yll- 1 H-indole-2-carboxamide m.p. 167-177°C, [ ⁇ ]D +1 13° (c 1.103, CH2CI2).
  • dH (CDCI3) 9.15 (IH, br s), 8.10 (I H, d, J 9.0 Hz), 7.75-7.10 (I4H, m),
  • (+)-N-f (3R)-2,3-Dihydro- 1 -methy l-2-oxo-5-pheny 1- 1 H- 1 ,4-benzo- diazepin-3- yl lheptanamide m.p. 49-54°C, [ ⁇ jD +69.5° (c 1.000, MeOH).
  • 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 tempera ⁇ ture for 40 min.
  • 3(R)- Amino- 1 ,3-dihydro- l -methyl-5-phenyl-2H- 1 ,4- benzodiazepin-2-one J. Ore. Chem. 1987, 52, 3232-3239
  • 400 mg, 1.51 mmol and triethylamine (252 mL.
  • (+)-N-l(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-3-(4-chlorophenyl)propanamide m.p. 203-205°C. f ⁇ lD +99.2° (c 0.300, CH2CI2).
  • (+)-N-[(3R)-2,3-Dihydro-l -methyI-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-2,2-diphenylethanamide m.p. 200-201°C, [ ⁇ ]D +97.0° (c 0.168, CH2CI2).
  • (+)-N-l(3R)-2,3-Dihydro- 1 -methy l-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-3-l2-(trifluoromethyl)phenyllpropana ⁇ ide m.p. 1 10-1 13°C, [ ⁇ ]D +79.2° (c 0.376, CH2CI2).
  • the benzylamine (2.07 g, 7.9 mmol) was dissolved in methanol (60 mL), BOC20 ( 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- 1 -methy l-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yl]- l '-(l ,l -dimethylethoxycarbony])spiro(cyclohexan-4,4'- piperidine)- 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 I-2-oxo-5-phenyl-l H- 1 ,4-benzodiazepin-3-yIl-2-bromo- acetamide 400 mg, 1.04 mmol was added and the mixture was stirred at room temperature for 18 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. Org. 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 tempera ⁇ ture for 18 h.
  • 2,4-DichlorophenyIisocyanate ( 188 mg, 1.0 mmol) was added to a solution of 3(R)-amino-l ,3-dihydro-l -methyl-5-phenyl-2H- 1 ,4-benzodiazepin-2-one (J. Org. Chem. 1987, 52, 3232-3239) (265 mg, 1.0 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 18 h. and the solvent was evaporated under reduced pressure.
  • 2,3-Dihydro-5-phenyl-l H- l ,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 mmol) was added to a mixture of 2, 3-dihydro-l -(2-dimethy laminoethyI)-3-hydroxyimino- 5-phenyl- l H-l ,4-benzodiazepin-2-one (0.91 g, 2.7 mmol) and triethyl ⁇ amine (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 (1 15 mg, 0.6 mmol) and 1 -hydroxy benzotriazole (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.
  • (+)-3(R)- ⁇ N-[3-(4-Chlorophenyl)prop- I -ylJamino ⁇ -l ,3-dihydro- l - methyl-5- phenyl-2H-l ,4-benzodiazepin-2-one hydrochloride m.p. 167-168°C. [ ⁇ ]D +20.8° (c 0.500, MeOH).
  • (+)-phenylmethyl N-[(3R)-2,3-dihydro-l - methyI-5-phenyI-2-oxo-l H-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 1 ,2-difhiane-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 (1M) and brine, dried (Na2S04) and the solvent was evaporated under reduced pressure.
  • 3-Methylphenylisocyanate 60 mL, 62 mg, 0.46 mmol was added to a solution of 3-amino-2,3-dihydro-l -methyl-5-phenyl-l H- 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 -methy l-5-phenyl- l H-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- ethylcarbodiimide hydro ⁇ chloride (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-l H-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-f(3R)-7-amino-2,3-dihydro-l -methyl-2- oxo-5-phenyl-l H- 1 ,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 HCl, water, saturated sodium bicarbonate solution, water, and brine (3 mL each), dried (Na2S ⁇ 4) and the solvent was evaporated under reduced pressure. The residue was dissolved in warm toluene, treated with charcoal, and filtered.
  • Step A To a solution of 2,3-dihydro- l -methyl-5-phenyl-l H-pyrido [4,3-e]-l ,4-diazepine-2-one (J. Med. Chem.. 1965, 8, 722-724) (1.63 g, 6.5 mmol) in toluene (32 mL) under argon cooled to -20°C (ice/methanol bath) was added potassium t-butoxide (1.83 g, 16.3 mmol). The resulting purple suspension was stirred 15 min. at -20°C and isoamyl nitrite (1.05 mL, 7.8 mmol) was added.
  • 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 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 (Na2S04), 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 (Na2S04) extracts gave 2.60 gms (97%).
  • the CBZ-amine-N -methyl amide (190 mg) was treated with 30% HBr/AcOH (0.8 mL) for 1 hour at room temperature.
  • the reaction mixture was poured into ether ( 10 mL) at 0°C and the solid filtered. Solid dissolved in 10% Aq. NaOH (5 mL) and CH2CI2 ( 10 mL) and organic layer separated, dried (Na2S04), filtered and concentrated to
  • Step B Preparation of N-(I ,3-dihydro- I -methyl-2-oxo-5-phenyl-
  • (+)-3-Cyclohexyl-N-[2,3-dihydro- 1 -methyl-2-oxo-5- phenyl-l H- 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- 1 H- 1 ,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)-lH-benzo[e][ l ,4]diazepine.
  • Step C Preparation of racemic 3-Amino-5-phenyl- 1 -(2,2,2- trifluoroethy 1)- 1 H-benzo[e] [ 1 ,4 jdiazepine.
  • Step D Preparation of 2-Amino-N-[2-oxo-5-phenyl- l -(2.2,2- trifluoroethyl)-2,3-dihydro- 1 H-benzo[eJ [ ! ,4]diazepin- 3-yl]-3-phenyIpropionamide
  • Step E Preparation of 3(R)-(+)-3-Amino-5- ⁇ henyl-l -(2,2,2- trifluoroefhyI)-lH-benzo[e]l 1 ,4J 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- ethylcarbodiimide hydro- chloride(4.44 g, 23.0 mmol), and 1 -hydroxybenztriazole hydrate (3.1 1 g, 23.0 mmol) and 3,5-Dichlorobenzoic acid (3.21 g, 16.8 mmol). This was stirred at ambient temperature for 2 hours.
  • the reaction was diluted with 500 mL satd. NaHC03 and extracted with 2 x 300 mL ethyl acetate. The combined organics were washed with 10% KHSO4 (200 mL) , brine (200 mL), dried over Na2S ⁇ 4, 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 .
  • 2,4-Bis(trifluoromethyl)benzonitrile (41.5mmol, 10.51 g) was taken up in lOOmL acetic acid, 50mL cone. H2SO4, and 20mL water. This was heated to 120°C for 3h. The reaction was then diluted with I L ice water, and extracted with 2x300mL ethyl acetate. The combined organics were washed with 2x200mL water, dried with brine and Na2S ⁇ 4, and evaporated under reduced pressure. The residue was taken up in a minimum of diethyl ether and crystallized by adding sufficient hexane to precipatate the product.

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Abstract

A method for the treatment of Meniere's disease comprising the administration of a medicament which modulates the IKs channel of the ear and thereby reduces endolymph production.

Description

TITLE OF THE INVENTION
A METHOD FOR TREATING MENIERE'S DISEASE
BACKGROUND OF THE INVENTION
A method of treating Meniere's disease through the modulation of the LKs channel is presented.
Meniere's disease can be an incapacitating problem for patients with symptoms ranging from attacks of vertigo which appear suddenly and last from a few to 24 hours, nausea, vomiting, recurrent feeling of fullness or pressure in the affected ear, and fluctuating hearing which progressively worsens over the years. Tinnitus may be constant or intermittent and may be worse before, after or during the attack of vertigo. The etiopatho- genesis of Meniere's disease has been studied since the early 1900's and has avoided definition. Generally the disease is said to result from distention of the endolymphatic compartment of the inner ear. The primary lesion appears to be in the endolymphatic sac, which is thought to be responsible for endolymph filtration and excretion. A precise cause of hydrops has not been established. Although usually only one ear is affected, both ears are involved in 10 to 15% of patients. (MERCK MANUAL, Vol. 16, 1992).
Meniere's disease has been subdivided into five stages. Stage one is primarily diagnosed by symptoms associated with unilateral cochlear pathology focused on signs, symptoms and pathology which are singularly cochlear. Patients in this stage often respond to treatment with diuretics and dexamethasone. Once in stage two, the hydrops extends to the vestibular labyrinth and the patient begins to experience vertigo. At this stage, surgery is recommended to insert a nylon tube in the lumen of the sac to relieve the endolymphatic pressure. Streptomycin perfusion of the membranous labyrinth is also recommended at this stage. In the third stage, hearing and balance are severely compromised, and comprehension fail. Surgical treatment such as aminoglycoside destruction of the vestibular receptor or vestibular neurectomy are usually indicated. In the fourth stage, the dizziness subsides, and the endolymphatic hydrops fills the vestibule so that the endolymph pressure cannot rise. Dizziness stops at this stage, but no known medical treatment is available. At the fifth stage, widespread obstruction and ruptures in the membranous labyrinth occurs and all hearing is lost. Again no treatment is recognized once the patient has reached this stage. (REF. The America Journal of Otology, Volume 14, No. 3, May 1993, pp. 224 - 229).
Since Meniere's disease primarily involves distention of the endolymphatic space, modulation of endolymph production will mitigate the progression of the disease and provide relief from the symptoms previously discussed.
The concept that the stria vascularis generates an endocochlear potential and secretes K+ is well accepted; however there is new information implicating an important role for IKs K+ channel in endolymph production and composition. Cellular localization of IsK ,the protein which under lies the current IKs, in the stria vascularis of the rat has been accomplished using immunohistochemistry (Sakagami et al. Hearing Research 56: 168-172, 1991). In these studies, the IsK protein was present only on the endolymphatic surface of the marginal cell, consistent with involvement of IKs in K+ permeation in the luminal membrane of the marginal cell. Furthermore, the K+ conductance measured in vestibular dark cells and apical membranes of marginal cells was found to be comprised of a high density of IKs channels(Sunose et al. Hearing Research 80:86-92, 1994; Marcus and Shen, Am. J. Physiol. 267: C857-C864, 1994; Wangemann et al. Hearing Research 84:19-29, 1995). Further, it has been determined that in its absence of the IKs channel, deftness results due to a lack of endolymph production. S. Heinemann and D. Vetter (Salk Institute), has determined that genetic knockout of IKs in mice results in vestibular dysfunction and deafness, secondary to the absence of endolymph. Recently, IKs message has been found in the ear. It is now believed that modulation of the IKs channel in the ear will affect endolymph production and mitigate the effects of this disease. OBJECTS OF THE INVENTION
It is, accordingly, an object of the present invention to provide methods of treating patients suffering from Meniere's disease with compounds not previously known to have activity for this condition. Another object is to provide new methods for treating Meniere's disease. A further object is to provide pharmaceutical formulations and methods for their preparation for use in treating Meniere's disease. These and other objects of the present invention will be apparent from the following description.
SUMMARY OF THE INVENTION
A method of treating Meniere's disease in mammals, including humans which comprises blocking the slowly activating delayed rectifier potassium (K+)current (IKs) in the ear is presented.
It has been found that compounds, which at a concentration of 1 μM or less (IC50), block 50% of the IKs current measured in isolated myocytes and exhibit a selectivity ratio equal to or greater than 10 times the block of the ΪKr, iK l currents, should result in treatment which is safe and effective.
Among the compounds which exemplify this method of treatment are the 1 ,4-benzodiazepines or benzodiazepine derivatives that block the IKs current and are therefore effective in the treatment of Meniere's disease.
DETAILED DESCRIPTION
A method of treating Meniere's disease in mammals, including humans, which comprises blocking the slowly activating delayed rectifier potassium (K+)current (IKs) is presented. This method requires the addition of a compound which selectively blocks the IKs current and produces only minimal block of the IKr current.
Among the compounds which exemplify this method of treatment are the 1 ,4-benzodiazepines or benzodiazepine derivatives that block the IKs current and are therefore effective in the treatment of Meniere's disease. Examples of compounds which are useful in this treatment of Meniere's disease can be found in United States Patent
Application Nos. 08/156,331; 08/516,467; and 08/516,226; which are hereby incoφorated by reference.
Examples of compounds which are representative of selective IKs antagonists include, but are not limited to the following:
Compounds represented by structural formula I
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof, wherein
A is 1 ) thieno,
2) pyrido, or
3) benzo either unsubstituted or substituted with -NH2 -NHS02 (Ci-3 alkyl), Ci -3 alkyl or C 1.3 alkoxy;
X is 1 ) =0,
2) =s, 3) =N-NH2, 4) =N-OH or 5) =H2;
Y is 1 ) =0,
2) =N-CN or 3) =H2;
Z is 1 ) C 1 -6 alkylene, either straight or branch chain and either unsubstituted or substituted with phenyl or spiro-piperidine, 2) C2-4 alkenylene, either straight or branch chain,
3) -(CH2)m-W-(CH2)n- wherein m and n are independently 0, 1 , 2, 3 or 4 and W is -0-, -S- or -NH,
4) 4-(5-methylisoxazole-3-yl),
5) C3-6 cycloalkylene, or
6) single bond;
p is 0 or 1;
Rl is 1 ) phenyl, either unsubstituted or substituted with one or two substituents selected from a) -Nθ2, b) -Cl, Br, F, or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl-3 alkoxy, f) -CN, g) -methylenedioxy, 2) C5-7 cycloalkyl,
3)
Figure imgf000007_0001
4) mono- or bicyclic heterocyclyl of 5 to 10 members one or two of which are sulfur, nitrogen or oxygen, the remaining being carbon, such as 2-thienyl, 2-furanyl, 2-indolyl, 2- quinoxolinyl, or 2-(2,3-dihydro benzofuranyl)
5) Cl -3 alkyl, or
6) indan-5-yl;
R2 is 1 ) phenyl, either unsubstituted or substituted with Cj -3 alkoxy or 4,4-dimethyloxazolin-2-yl, 2) Cl -6 alkyl, either straight or branched chain, and either unsubstituted or substituted with Cl-3 alkoxy or Cl-3 alkoxy-Cl-3 alkoxy,
3) C5-7 cycloalkyl,
4) 2- or 3-furyl,
5) l-methylpiperidin-2-yl, or
6) if R^ 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;
R3 is 1 ) hydrogen or
2) Cl-3 alkyl either unsubstituted or substituted with -N(CH3)2, -OH, -CF3, or
3) -CF3;
R4 is 1 ) hydrogen,
2) 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
Figure imgf000008_0001
3) tetrazol-5-yl;
R5 is hydrogen or oxygen or is joined to R^ to form the partial structure:
; and
Figure imgf000008_0002
the bond represented by is:
1 ) a double bond when p is zero or when p is 1 and R^ is oxygen, or
2) a single bond when R^ is hydrogen or R^ is joined to R^ to form the partial structure:
X
Figure imgf000009_0001
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. 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.
One embodiment of this invention are novel compounds useful in the novel method of treatment of this invention wherein: A is benzo;
X and Y are oxygen;
R3 is methyl;
R4 is hydrogen; and
R2 is Cl-6 alkyl.
Specific novel compounds representative of this embodiment are those of the following structure and specified in Table I:
TABLE I
Figure imgf000010_0001
Figure imgf000010_0002
Another embodiment of the compounds useful in the novel method of treatment of this invention is that wherein:
A is
Figure imgf000011_0001
X and Y are oxygen;
R3 is methyl;
R4 is hydrogen; and
R2 is phenyl.
A class of novel compounds within this embodiment is that with structural formula:
Figure imgf000011_0002
wherein
Z is Cl -6 alkylene or a bond and
Rl is phenyl, phenyl substituted with -Cl, -Br, -I, -F, or -CF3, or R l is cyclohexyl.
Specific novel compounds representative of this class are those depicted in the following Table II: TABLE II
Figure imgf000012_0001
Another class of novel compounds within this embodiment tructural formula:
Figure imgf000013_0001
wherein Z is C2-4 alkenylene and R 1 is phenyl or phenyl substituted with -Cl, -Br, -F, -I, -CF3, Cl -3 alkyl, Cl -3 alkoxy or methylenedioxy.
Specific novel compounds representative of this class are those depicted in the following Table III:
TABLE III
Figure imgf000013_0002
TABLE HI (Cont'd)
Figure imgf000015_0001
*This compound is disclosed in U.S. Patent 4,820,834
A third embodiment of the compounds useful in the novel method of treatment of this invention is that wherein: Z is -NH-.
Compounds representative of this embodiment are those disclosed in the following Table IV. TABLE IV
Figure imgf000016_0001
Figure imgf000016_0002
Other specific compounds included within the broadest genus but not included in one of the embodiments previously described are as shown in Table V. TABLE V
Figure imgf000017_0001
Representative of compounds wherein p is 1 is the compound of structural formula:
Figure imgf000017_0002
Representative of compounds wherein the bond between the and 5 positions is a single bond is the compound of structural formula:
Figure imgf000017_0003
Representative of compounds wherein the bond represents a single bond and R^ is joined to R2 is the compound of structural formula:
Figure imgf000018_0001
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.
Figure imgf000018_0002
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:
Figure imgf000019_0001
where
X and Y are independently hydrogen, chloro, fluoro, bromo, iodo, or trifluoromethyl and
n is 0, 1 or 2;
R is hydrogen, fluoro, chloro, bromo, iodo, or trifluoromethyl, methyl, or methoxy; and
the racemates, mixtures of enantiomers, individual diastereomers or individual enantiomers with all isomeric forms and pharmaceutically acceptable salts, hydrates or crystal forms thereof, which are effective in the treatment of Meniere's disease.
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:
Figure imgf000019_0002
R 1 and R2 are independently
1 ) phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N02, OH, b) -Cl, Br, F, or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl -3 alkoxy, 0 -CN, g) -methylenedioxy, and
Z is 1 ) Cl-6 alkyl, either straight or branched chain ,
2) substituted Cl -6 alkyl, either straight or branched chain, wherein the substituents are selected from F, OH, N02,
3) C2-4 alkenylene, either straight or branched chain,
4) -(CH2)m-W-(CH2)n- wherein m and n are independently 0, 1 , 2, 3 or 4 and W is -0-, -S- or -NH,
5) C3-6 cycloalkane,
6) C3-6 cycloalkylene, or
7) single bond;
The IKs blockers or selective IKs antagonists 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. The compounds of the present invention are especially useful for controlling and treating Meniere's disease via modulation of endolymph production.
In the novel method of this invention of treating Meniere's disease 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 activity of the compounds described herein as agents which treat Meniere's disease 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 KCI, 5 mM K(2)ATP. Cells are bathed in a solution contaimng, 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 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. Employing this test the compounds described herein as selective ΪKs 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-
The utility of the compounds of this invention to combat Meniere's disease via modulation of endolymph production is shown by the lack of endolymph production when there is an absence of functional IKs channels (i.e. IsK knockout mouse) and the effect of chronic administration of exemplified compounds on membranous structures in the ear of rats. Further evidence for this utility is obtained from experimentally induced of endolymphatic hydrops in animals.
Typical synthetic schemes employed in making the compounds herein are illustrated below.
SCHEME I
Figure imgf000022_0001
SCHEME 2
Figure imgf000023_0001
SCHEME 3
Λ
Figure imgf000024_0001
SCHEME 4
Figure imgf000025_0001
SCHEME 5
Figure imgf000025_0002
SCHEME 6
V
Figure imgf000026_0001
SCHEME 7
Figure imgf000027_0001
SCHEME 8
W
Figure imgf000027_0002
SCHEME 9
Figure imgf000028_0001
SCHEME 10
Figure imgf000029_0001
SCHEMEll
Figure imgf000030_0001
SCHEME 12
Figure imgf000031_0001
SCHEME 13
W
Figure imgf000032_0001
SCHEME 14
Figure imgf000033_0001
SCHEME 15
Figure imgf000033_0002
SCHEME 16
Figure imgf000034_0001
Figure imgf000035_0001
EXAMPLES
EXAMPLE 1
Figure imgf000036_0001
(E)-(+)-N-[(3R)-2,3-Dihydro- 1 -methyI-2-oxo-5-phenyI- 1 H- 1 ,4-benzo- diazepin-3-yπ-3-phenyl-2-propenamide
A solution of (E)-3-phenyl-2-propenoyl chloride (367 mg,
2.2 mmol) in methylene chloride ( 1 mL) was added to a solution of 3(R)-amino- 1 ,3-dihydro- 1 -methyl-5-pheny 1-2H- 1 ,4-benzodiazepin-2- one (J. Org. Chem. 1987, 52, 3232-3239) (531 mg, 2.0 mmol) and triethylamine (307 mL, 225 mg, 2.2 mmol) in methylene chloride (10 mL). The mixture was stirred at room temperature for 25 min. and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/Et2θ (95:5) and the residue was triturated with Et2θ. The solid was collected and dried in vacuo at 70°C to give (E)-(+)-N-[(3R)-2,3-dihydro-l - methyl-2-oxo-5-phenyl-l H-l ,4-benzodiazepin-3-yl]-3-phenyl-2- propenamide as a colorless solid (170 mg, 21 %), m.p. 140-142°C, [αjD +86.7° (c=0.173. CH2Cl2). dH (CDC13) 7.70-7.26 (16H, m), 6.63 ( IH, d, J 15.6 Hz), 5.68 ( I H, d, J
8.3 Hz), and 3.50 (3H, s).
Anal. Calcd. for C25H21N3O2.O. I5 (C2H5)2θ:
C, 75.63; H, 5.58; N, 10.33. Found: C, 75.29; H, 5.57; N, 10.33%. Employing the procedure substantially as described above, but substituting an appropriate acid chloride for the (E)-3 -phenyl -2- propenoyl chloride, the following compounds were prepared:
EXAMPLE 2
Figure imgf000037_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yπbenzamide m.p. 224-225°C, [α]D +89.2° (c = 0.141 , CH2CI2). dH (CDCI3) 8.04 (I H, d, J 8.1 Hz), 7.96 (2H, d, J 6.8 Hz), 7.64-7.36
( 10H, m), 7.27 (2H, t, J 7.6 Hz), 5.74 ( I H, d, J 7.8 Hz), and 3.51 (3H, s).
Anal. Calcd. for C23H 19N3O2.O.2OH2O:
C, 74.06; H, 5.24; N, 11.26.
Found: C, 74.13; H, 5.12; N, 1 1.16%.
EXAMPLE 3
Figure imgf000037_0002
First diastereoisomer to elute:
(-)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4- benzo-diazepin-3-yll(trans-2-phenyl-l -cyclopropane)carboxamide m.p. 180-181 °C, lαJD -155.8° ( c = 0.434, CH2CI2). dH (CDCI3) 7.62-7.09 ( 15H, m). 5.59 ( I H, d, J 8.1 Hz), 3.47 (3H, s), 2.52-2.45 (IH, m), 1.90-1.84 ( I H, m).l .69-1.56 ( I H, m), and 1.38-1.32 (IH, m).
Anal. Calcd. for C26H23N3O2.O.25H2O: C, 75.43: H. 5.72; N. 10.15. Found: C, 75.38; H, 5.64; N, 9.94%.
Second diastereoisomer to elute:
(+)-N-f (3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl-l H- 1 ,4- benzo-diazepin-3-yl l(trans-2-phenyl- 1 -cyclopropane )carboxamide m.p. 104-107°C, [α]D +328.2° (c = 0.098, CH2CI2). dH (CDCI3) 7.62-7.13 (15H, m), 5.60 (I H, d, J 8.3 Hz), 3.48 (3H, s),
2.59-2.54 (I H, m), 1.93-1.87 (IH, m), 1.62-1.56 (I H, m, overlaps with water), and 1.33-1.25 (IH, m).
Anal. Calcd. for C26H23N3θ2.0.50H2θ.0.45PhCH3:
C, 76.13; H, 5.95; N. 9.14. Found: C, 76.10; H, 5.94; N, 9.17%.
EXAMPLE 4
Figure imgf000038_0001
(+)-N-!(3R)-2,3-Dihydro- l -methyl-2-oxo-5-phenyl-l H- l ,4- benzodiazepin-3-yll- 1 H-indole-2-carboxamide m.p. 167-177°C, [α]D +1 13° (c = 1.103, CH2CI2). dH (CDCI3) 9.15 (IH, br s), 8.10 (I H, d, J 9.0 Hz), 7.75-7.10 (I4H, m),
5.75 ( IH, d, J 9.0 Hz), and 3.50 (3H, s).
Anal. Calcd. for C25H20N4O2:
C, 73.51 ; H, 4.94; N, 13.72. Found: C, 73.31 : H, 4.80; N, 13.62%.
EXAMPLE 5
Figure imgf000039_0001
(+)-N-f (3R)-2,3-Dihydro- 1 -methy l-2-oxo-5-pheny 1- 1 H- 1 ,4-benzo- diazepin-3- yl lheptanamide m.p. 49-54°C, [αjD +69.5° (c=1.000, MeOH). Anal. Calcd. for C23H27N3O2.O.4OH2O: C, 71.81 ; H, 7.28; N, 10.92. Found: C, 71.90; H, 7.09; N, 10.85%.
EXAMPLE 6
Figure imgf000039_0002
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yllhexanamide
[α]D +72.6° (c=0.920, MeOH). Anal. Calcd. for C22H25N3O2:
C, 72.70; H, 6.93; N, 1 1.56. Found: C. 72.44: H, 6.75; N. 1 1.25%.
EXAMPLE 7
Figure imgf000040_0001
(+)-N-f(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yllpentanamide
(α]D +68.2° (c=1.310, MeOH).
Anal. Calcd. for C21 H23N3O2.O.25CHCI3:
C, 68.21 ; H, 6.26; N, 1 1.26. Found: C. 68.2: H, 6.29; N, 1 1.17%.
EXAMPLE 8
Figure imgf000041_0001
(+)-N-f(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yn-3-phenylpropanamide
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 tempera¬ ture for 40 min. 3(R)- Amino- 1 ,3-dihydro- l -methyl-5-phenyl-2H- 1 ,4- benzodiazepin-2-one (J. Ore. Chem. 1987, 52, 3232-3239) (400 mg, 1.51 mmol) and triethylamine (252 mL. 183 mg, 1.81 mmol) were added and the mixture was stirred at room temperature for 18 h. The mixture was poured into saturated aqueous sodium hydrogen carbonate (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were dried (Na2S04) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel. eluting with CH2Cl2/Et2θ (95:5) and the residue was recrystallized from toluene/hexane to give (+)-N-f(3R)-2,3- dihydro- 1 -methyl-2-oxo-5-pheny 1- 1 H- 1 ,4-benzodiazepin-3-yl]-3- phenylpropanamide as a colorless solid (380 mg, 63%), m.p. 179°C, [αlD +100.4° (c = 0.225, CH2CI2). dH (CDCI3) 7.62-7.57 (2H, m), 7.47-7.21 (13H, m), 5.54 ( I H, d, J 8.1 Hz), 3.47 (3H, s), 3.03 (2H, t, / 7.8 Hz), and 2.73-2.67 (2H, m). Anal. Calcd. for C25H23N3O2.O. I5H2O:
C. 75.04; H, 5.87; N. 10.50. Found: C, 75.06; H, 5.78; N, 10.55%. Employing the procedure substantially as described above, but substituting an appropriate carboxylic acid for the 3-phenyl- propanoic acid, the following compounds were prepared:
EXAMPLE 9
Figure imgf000042_0001
E-(+)-N-f (3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-pheny I- 1 H- 1 ,4-benzo- diazepin-3-vπ-3-(3,4-dichlorophenyl)-2-propenarnide m.p. 145-147°C, [cclD +77.8° (c=0.126, CH2CI2). dH (CDCI3) 7.64-7.25 (14H, m), 6.61 (IH, d, J 15.6 Hz), 5.65 (I H, d, J
8.0 Hz), and 3.50 (3H, s).
Anal. Calcd. for C25H 19N3O2CI2:
C, 64.67; H, 4.12; N, 9.05. Found: C, 64.57; H, 4.25; N, 9.01 %.
EXAMPLE 10
Figure imgf000042_0002
E-(+)-N-[(3R)-2.3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll3-(4-nitrophenvπ-2-propenamide m.p. 165-166 °C, [α]D +80.5° (c=0.126, CH2CI2). dH (CDCI3) 8.26 (I H, d, J 8.8 Hz), 7.74-7.28 (13H, m). 6.76 ( IH, d, J
15.6 Hz), 5.66 (IH, d, J 8.0 Hz), and 3.51 (3H, s).
Anal. Calcd. for C25H19N4O4:
C, 68.17; H, 4.58; N, 12.72. Found: C, 68.25; H, 4.65; N, 12.57%.
EXAMPLE 1 1
Figure imgf000043_0001
E-(+)-N-[(3R)-2,3-Dihydro- l -methyl-2-oxo-5-phenyl-l H- l ,4-benzo- diazepin-3-yll-3-(2.4-dichlorophenyl)-2-propenamide m.p. 137-139°C, [αjD +66.0° (c=0.144, CH2CI2). dH (CDCI3) 8.02 (I H, d, J 15.6 Hz), 7.73-7.26 ( 13H, m), 6.66 ( I H, d, J
15.6 Hz), 5.81 ( I H, d, J 8.8 Hz), and 3.53 (3H, s).
Anal. Calcd. for C25H19CI2N3O2:
C, 64.67; H, 4.12; N, 9.05. Found: C, 64.28; H, 4.24; N, 8.83%. EX AMPLE 12
Figure imgf000044_0001
E-(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyI- 1 H- 1 ,4- benzodiazepin-3-yl l-3-(4-methylphenyπ-2-propenamide m.p. 133-135°C, [α]D +90.4° (c=0.125, CH2CI2). dH (CDCI3) 7.68-7.19 (15H, m), 6.59 (I H, d, J 15.6 Hz), 5.70 (I H, d, J
8.0 Hz), 3.50 (3H, s), and 2.38 (3H, s).
Anal. Calcd. for C26H23N3O2:
C, 76.26; H, 5.66; N, 10.26. Found: C, 75.93; H, 5.82; N, 10.10%.
EXAMPLE 13
Figure imgf000044_0002
E-(+)-N-[(3R)-2,3-Dihydro-l -methyl-2-oxo-5-phenyl-lH-l ,4-benzo- diazepin-3-yl l-3-(4-methoxyphenyl)-2-propenamide m.p. 129-133°C. [α]D +89.9ϋ (c 0.188, CH2CI2). dH (CDC13) 7.65-7.24 ( 14H, m), 6.92 ( IH, d, J 8.8 Hz). 6.50 (I H, d, J 15.6 Hz), 5.69 (I H, d, J 8.0 Hz). 3.84 (3H, s). and 3.50 (3H, s). Anal. Calcd. for C26H23N3O3.O.3OH2O:
C, 72.48; H, 5.52; N, 9.75. Found: C, 72.75; H, 5.60; N, 9.36%.
EXAMPLE 14
Figure imgf000045_0001
(+)-N-l(3R)-2.3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-3-(2.4-dichlorophenyl)propanamide m.p. 92-95°C. [α]D 90.5° (c = 0.196, CH2CI2). dH (CDCI3) 7.62-7.15 (13H, m), 5.52 ( IH, d, J 8.1 Hz), 3.47 (3H, s),
3.10 (2H. t, J 7.6 Hz), and 2.68 (2H, dd, J 7.6, 2.8 Hz). Anal. Calcd. for C25H21CI2N3O2.O.2OH2O:
C, 63.89; H, 4.59: N, 8.94. Found: C, 63.86; H, 4.62: N, 8.87%.
EX AMPLE 15
Figure imgf000046_0001
E-(+)-N-[(3R)-2,3-Dihydro-l-methyl-2-oxo-5-phenyl- lH- l ,4-benzo- diazepin-3-yl l-3-(3-chlorophenyI)-2-propenamide m.p. 229-231°C, fα]D +86.2° (c = 0.225. CH2CI2). dH (CDCI3) 7.64-7.26 (15H, m), 6.62 (I H, d, J 15.6 Hz), 5.66 ( I H, d, J
8.1 Hz), and 3.50 (3H, s).
Anal. Calcd. for C25H2OCIN3O2:
C, 69.85; H, 4.69; N, 9.77. Found: C, 70.20; H, 4.83; N, 9.41 %.
EXAMPLE 16
Figure imgf000046_0002
E-(+)-N-[ (3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yl l-3-(2-chlorophenyI)-2-propenamide m.p. 128-131 °C, [αjD = +61.7° (c = 0.196, CH2CI2). dH (CDCI3) 8.06 ( IH, d, J 15.6 Hz), 7.65-7.28 (14H, m), 6.62, (I H, d, J 15.6 Hz), 5.68 (IH, d, J 8.3 Hz), and 3.50 (3H, s). Anal. Calcd. for C25H20CIN3O2.O.2OH2O:
C, 69.27; H, 4.74; N. 9.69. Found: C, 69.21 ; H, 4.68; N, 9.45%.
EXAMPLE 17
Figure imgf000047_0001
E-(+)-N-[(3R)-2.3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-3-(2,4-difluorophenyl)-2-propenamide m.p. 121 - 123°C, [α]D +76.8° (c = 0.1 1 1 , CH2CI2). dH (CDCI3) 7.71 ( IH, d, J 15.9 Hz), 7.64-7.24 ( 1 I H, m), 6.92-6.84 (2H, m), 6.69 (IH, d, J 15.9 Hz), 5.67 (IH, d, J 8.1 Hz), and 3.50 (3H, s). Anal. Calcd. for C25H 19F2N3O2.O. IOH2O:
C, 69.31 ; H, 4.47; N, 9.70. Found: C, 69.28; H, 4.57; N, 9.31 %.
EX AMPLE 18
Figure imgf000048_0001
(+)-N-l(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-3-(4-chlorophenyl)propanamide m.p. 203-205°C. fαlD +99.2° (c = 0.300, CH2CI2). dH (CDCI3) 7.62-7.16 (14H, m), 5.52 (I H, d, J 8.1 Hz), 3.47 (3H, s),
2.99 (2H, t, J 7.7 Hz), and 2.67 (2H, t, J 7.7 Hz).
Anal. Calcd. for C25H22CIN3O2:
C. 69.52; H, 5.13; N. 9.73. Found: C, 69.50; H, 5.15; N, 9.72%.
EXAMPLE 19
Figure imgf000048_0002
E-(+)-N-l(3R)-2.3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yl1-3-(2.6-dichlorophenyI)-2-propenamide m.p. 121 -124°C, | α]D +69.0° (c = 0.342, CH2CI2). dH (CDC13) 7.79 (I H, d, J 16.1 Hz), 7.64-7.15 (13H, m), 6.78 (I H, d, J 15.8 Hz), 5.69 (IH, d, J 8.1 Hz), and 3.50 (3H, s). Anal. Calcd. for C25Hl9Cl2N3θ2.0.15PhCH3:
C, 65.44; H, 4.23; N, 8.79. Found: C, 65.40: H, 4.38; N, 8.85%.
EXAMPLE 20
Figure imgf000049_0001
E-(+)-N-f (3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-3-[4-(trifluoromethyl)phenyl l-2-propenamide m.p. 133- 137°C, [α]D +68.7° (c = 0.1 15, CH2CI2). dH (CDCI3) 7.72-7.25 (15H, m), 6.71 (IH, d. J 15.6 Hz), 5.67 ( I H. d, J
8.1 Hz), and 3.51 (3H, s).
Anal. Calcd. for C26H20F3N3O2:
C, 67.38; H, 4.35; N, 9.07. Found: C, 67.38; H, 4.45; N, 8.95%.
EX AMPLE 21
Figure imgf000050_0001
(+)-5-Chloro-N-[(3R)-2,3-dihydro- 1 -methyl-2-oxo-5-pheny 1- 1 H- 1 ,4- benzodiazepin-3-yllindole-2-carboxamide m.p. 160- 164°C, [α]D +103.8° (c = 0.160, CH2CI2). dH (CDCI3) 9.71 (IH, br s), 8.13 ( I H, d, J 7.8 Hz), 7.68-7.09 (13H, m),
5.75 (IH, d, J 7.8 Hz), and 3.53 (3H, s).
Anal. Calcd. for C25Hi9ClN4θ2.0.25H2θ.0.15PhCH3:
C, 67.84; H, 4.49; N, 12.15. Found: C, 67.80; H, 4.41 ; N. 12.07%.
EXAMPLE 22
Figure imgf000050_0002
(+)-N-[(3R)-2,3-Dihydro-l -methyI-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-2,2-diphenylethanamide m.p. 200-201°C, [α]D +97.0° (c = 0.168, CH2CI2). dH (CDCI3) 7.60-7.22 (20H, m), 5.58 (I H, d, J 8.1 Hz), 5.08 (I H, s), and 3.44 (3H, s).
Anal. Calcd. for C30H25N3O2.O.I5PI1CH3:
C. 78.79; H, 5.55; N. 8.88. Found: C, 78.81 ; H, 5.63; N. 9.07%.
EXAMPLE 23
Figure imgf000051_0001
(+)-N-l(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-3-(2.4-difluorophenyl)propanamide m.p. 79-8 TC, [OC]D +92.9° (c = 0.105. CH2CI2). dH (CDCI3) 7.62-7.56 (3H, m), 7.50-7.19 (8H, m), 6.82-6.76 (2H, m),
5.52 (IH, d, J 8.1 Hz), 3.47 (3H, s), 3.01 (2H, t, J 7.6 Hz), and 2.69 (2H, m).
Anal. Calcd. for C25H21F2N3O2:
C, 69.27; H, 4.88; N, 9.69. Found: C, 68.96; H, 4.99; N, 9.47%. EXAMPLE 24
Figure imgf000052_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methy l-2-oxo-5-phenyl- 1 I I- 1 ,4-benzo- diazepin-3-yl l-2-phenylethanamide m.p. 241 -242°C (dec), [α]D +85.5° (c = 0.159, CH2CI2). dH (CDCI3) 7.59-7.55 (3H, m), 7.46-7.22 (12H, m), 5.51 (IH, d, J 8.1Hz), 3.72 (2H, s), and 3.44 (3H, s). Anal. Calcd. for C24H21 N3O2.O.55H2O: C. 73.28; H, 5.66; N, 10.68. Found: C, 73.25: H, 5.38: N, 10.47%.
EXAMPLE 25
Figure imgf000052_0002
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yl l-3-(2-chlorophenyl)propanamide m.p. 158.5-159.5°C, fαjD +95.8° (c = 0.224. CH2CI2). dH (CDC13) 7.62-7.57 (3H. m), 7.47-7.16 ( 1 1H, m), 5.55 ( I H, d, J 8. Hz), 3.47 (3H, s), 3.14 (2H, t, J 7.9 Hz), and 2.75-2.69 (2H, m). Anal. Calcd. for C25H22C1N3O2.0.15H2O:
C, 69.09; H, 5.17; N, 9.67. Found: C, 69.05; H, 5.12; N. 9.63%.
EXAMPLE 26
Figure imgf000053_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yl l-3-r4-(trifluoromethyl)phenyl1propanamide m.p. 175- 176°C, [α]D +86.5° (c = 0.141 , CH2CI2). dH (CDCI3) 7.62-7.54 (5H, m), 7.47-7.22 (9H, m), 5.52 ( I H, d, J 8. Hz), 3.47 (3H, m), 3.08 (2H, t, J 7.6Hz), and 2.72 (2H, m). Anal. Calcd. for C26H22F3N3O2.O.8OH2O:
C, 65.08; H, 4.93; N, 8.76. Found: C, 65.03; H, 4.63; N, 8.72%.
EXAMPLE 27
Figure imgf000054_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-vI l-2-r4-(trifluoromethyl)phenyllethanamide m.p. 224-226°C, lαjD +68.0° (c = 0.153, CH2CI2). dH (CDCI3) 7.63-7.55 (4H, m), 7.51 -7.33 (8H, m), 7.26-7.23 (2H, m),
5.51 (IH, d, J 8.1 Hz), 3.77 (2H, s), and 3.46 (3H, s).
Anal. Calcd. for C25H20F3N3O2:
C, 66.51 ; H, 4.47; N. 9.31. Found: C, 66.46; H, 4.36; N, 9.10%.
EXAMPLE 28
Figure imgf000054_0002
(+)-N-f(3R)-2,3-Dihydro-l -methyl-2-oxo-5-phenyl-lH- l ,4-benzo- diazepin-3-yl1-3-[3-(trifluoromethyl)phenyllpropanamide m.p. 135-136°C, (αjD +78.8° (c = 0.134, CH2CI2). dH (CDCI3) 7.62-7.56 (3H, m), 7.49-7.22 ( 1 I H, m), 5.53 ( IH, d, J 8. Hz), 3.47 (3H, s), 3.08 (2H, t, J 7.3 Hz), and 2.72 (2H, m). Anal. Calcd. for C26H22F3N3O2:
C, 67.09; H, 4.76; N, 9.03. Found: C, 67.03; H, 4.73; N, 9.13%.
EXAMPLE 29
Figure imgf000055_0001
(+)-3-Cyclohexy l-N-[(3R)-2,3-dihydro- 1 -methyI-2-oxo-5-phenyl- 1 H-
1 ,4-benzodiazepin-3-yllpropan amide m.p. 144.5- 145.5°C, [α]D +83.1 ° (c = 0.1 16, CH2CI2). dH (CDCI3) 7.62-7.56 (3H, m), 7.46-7.21 (7H, m), 5.55 (I H, d, J 8.3
Hz), 3.48 (3H, s), 2.41 -2.36 (2H, m), 1.77-1.58 (7H, m), 1.31 - 1.16 (4H, m), and 0.98-0.90 (2H, m).
Anal. Calcd. for C25H29N3O2:
C, 74.41 ; H, 7.24; N, 10.41. Found: C, 74.46; H, 7.27; N, 10.58%. EXAMPLE 30
Figure imgf000056_0001
(+)-N-l(3R)-2,3-Dihydro- 1 -methy l-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-3-l2-(trifluoromethyl)phenyllpropanaπιide m.p. 1 10-1 13°C, [α]D +79.2° (c = 0.376, CH2CI2). dH (CDCI3) 7.65-7.57 (4H, m), 7.50-7.22 ( 10H, m), 5.55 ( I H, d, J 8.0 Hz), 3.47 (3H, s), 3.20 (2H, t, J 7.9 Hz), and 2.70 (2H, dt, J 7.9, 3.3 Hz). Anal. Calcd. for C26H22F3N3O2:
C, 67.09; H, 4.76; N, 9.03. Found: C, 66.97: H, 4.76; N, 8.93%.
EXAMPLE 31
Figure imgf000056_0002
(+)-N-[(3R)-2,3-Dihydro-l -methyl-2-oxo-5-phenyl-lH-l ,4-benzo- diazepin-3-yl l-3-(4-cvanophenyl)propanamide m.p. 81-85°C, [OCJD +91.0° (c = 0.1 1 1. CH2CI2). dH (CDC13) 7.64-7.55 (4H, m), 7.48-7.16 (10H, m). 5.50 ( I H, d, J 8.3 Hz), 3.47 (3H, s), 3.08 (2H, t, J 7.6 Hz), and 2.74-2.69 (2H, m). Anal. Calcd. for C26H22N4θ2.0.60H2θ.0.50PhCH3:
C, 73.93; H. 5.62; N, 1 1.69. Found: C, 73.98; H, 5.61 ; N, 1 1 .71 %.
EXAMPLE 32
Figure imgf000057_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-vI1-3-(3-chlorophenyl)propanamide m.p. 157-159°C. [ OCJD +90.7° (c = 0.134, CH2CI2). dH (CDCI3) 7.62-7.57 (3H. m), 7.47-7.12 ( 1 I H, m), 5.53 ( I H, d, J 8.1 Hz), 3.47 (3H, s). 3.00 (2H, t, J 7.3 Hz), and 2.71 -2.66 (2H, m). Anal. Calcd. for C25H22CIN3O2.O.55H2O:
C, 67.96; H, 5.27; N, 9.51. Found: C, 67.99; H, 5.18; N, 9.26%.
EXAMPLE 33
Figure imgf000058_0001
E-(+)-N-l(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1.4-benzo- diazepin-3-yl]-3-(2-bromophenyl)-2-propenamide m.p. 1 13-1 16°C, fαjD +44.2° (c = 0.1 13, CH2CI2). dH (CDCI3) 8.03 (I H, d, J 15.6 Hz), 7.64-7.16 (14H, m), 6.57 (1 H, d, J
15.6 Hz), 5.68 (IH, d, J 8.1 Hz), and 3.50 (3H, s).
Anal. Calcd. for C25H2θBrN3θ2.0.60H2θ.0.30PhCH3:
C, 63.48; H, 4.58; N, 8.19. Found: C, 63.49; H, 4.38; N, 8.19%.
EXAMPLE 34
Figure imgf000058_0002
E-(+)-N-l(3R)-2,3-Dihydro- l-methyI-2-oxo-5-phenyl- lH-l ,4-benzo- diazepin-3-yl ]-3-(3-bromophenyl)-2-propenamide m.p. 221 -223 d°C, [α]D +65.5° (c = 0.206, CH2CI2). dH (CDC13) 7.69 (IH, br s), 7.64-7.57 (4H, m), 7.51 -7.37 (6H, m), 7.29-7.19 (4H, m), 6.62 (IH, d, J 15.6 Hz), 5.66 (IH, d, J 8.1 Hz), and 3.50 (3H, s). Anal. Calcd. for C25H2θBrN3θ2.0.35H2θ.0.20PhCH3:
C, 63.54; H, 4.46; N, 8.42. Found: C, 63.50; H. 4.39; N. 8.42%.
EXAMPLE 35
Figure imgf000059_0001
E-(+)-N-[ (3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyI- 1 H- 1 ,4-benzo- diazepin-3-yll-3-(4-iodophenyl)-2-propenamide m.p. I 37-I 40°C, [α]D +67.9° (c = 0.268, CH2CI2). dH (CDCI3) 7.75-7.72 (2H. m), 7.64-7.36 (8H, m), 7.29-7.16 (5H, m), 6.63 (I H, d, J 15.6 Hz), 5.66 (I H, d, J 8.1 Hz), and 3.50 (3H, m). Anal. Calcd. for C25H2θIN3θ2.0.30PhCH3:
C, 59.29; H, 4.06; N, 7.65. Found: C, 59.29; H, 3.90; N, 7.40%. EXAMPLE 36
Figure imgf000060_0001
E-(+)-N-[ (3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-vn-3-(4-bromophenyl)-2-propenamide m.p. 121 -I 24°C, [α]D +75.6° (c = 0.201 , CH2CI2). dH (CDCI3) 7.64-7.57 (3H, m), 7.55-7.35 ( 1 I H, m), 7.28-7.24 (I H, m), 6.62 (IH, d, J 15.6 Hz), 5.66 ( IH. d, J 8.1 Hz), and 3.50 (3H. s). Anal. Calcd. for C25H2θBrN3θ2:
C, 63.30; H, 4.25; N, 8.86. Found: C, 63.50; H, 4.20; N, 8.78%.
EXAMPLE 37
Figure imgf000060_0002
(+)-N-[(3R)-2,3-Dihydro- 1 -methy l-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-4-phenylbutanamide m.p. 65-74°C, [α]D +77.4° (c = 0.155. CH2CI2). dH (CDCI3) 7.62-7.56 (3H, m), 7.46-7.19 (12H, m), 5.55 ( I H, d. J 8.1 Hz), 3.47 (3H. s), 2.71 (2H, t, J 7.6 Hz), 2.42-2.37 (2H, m), and 2.09- 2.01 (2H, m).
Anal. Calcd. for C26H25N3O2.OJOH2O: C. 74.91 ; H, 6.19; N. 10.08. Found: C. 74.93; H, 6.05: N, 10.07%.
EXAMPLE 38
Figure imgf000061_0001
(+)-N-l(3R)-2.3-Dihydro- 1 -methyI-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yl]-5-methyl-3-phenylisoxazole-4-carboxamide m.p. 123-126:C, [αjD +122.0° (c = 0.199, CH2CI2). dH (CDCI3) 7.79-7.76 (2H, m), 7.62-7.32 (1 IH, m), 7.26-7.21 (2H, m), 5.61 (I H, d, J 7.9 Hz), 3.42 (3H, s), and 2.76 (3H, s). Anal. Calcd. for C27H22N4O3.O.4OH2O: C. 70.85; H, 5.02; N, 12.24. Found: C. 70.84; H, 4.91 ; N, 1 1.92%. EX AMPLE 39
Figure imgf000062_0001
(+)-N-[(3R)-2,3-Dihydro-l -methy l-2-oxo-5-phenyl-lH-l ,4-benzo- diazepin-3-yll-3-(3-cvanophenyl)propanamide m.p. 1 10-1 12°C, [αjD +84.2° (c = 0.202, CH2CI2). dH (CDCI3) 7.63-7.22 ( 14H, m), 5.51 (IH, d, J 8.1 Hz), 3.47 (3H, s), 3.06 (2H, t, J 7.8 Hz), and 2.74-2.68 (2H, m). Anal. Calcd. for C26H22N4O2.O.5OH2O: C, 72.37; H, 5.37; N, 12.98. Found: C, 72.52; H, 5.12; N, 12.59%.
EXAMPLE 40
Figure imgf000062_0002
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yllcyclohexanethanamide m.p. 144_146°C, |αlD +72.1 ° (c=1.000, MeOH). Anal. Calcd. for C24H27N3O2.O.2OH2O: C, 73.33; H, 7.03; N. 10.69.
Found: C, 73.27; H, 7.02; N, 10.76%.
EXAMPLE 41
C L
Figure imgf000063_0001
(+)-4-Cyclohexyl-N-[(3R)-2,3-dihydro- l -methyl-2-oxo-5-phenyl-lH- l ,4-benzodiazepin-3-yl]butanamide lαjD +57.7° (c=0.440, MeOH). Anal. Calcd. for C26H31 N3O2:
C, 74.79; H, 7.48; N, 10.06. Found: C, 74.8;0 H, 7.78; N, 10.05%.
EXAMPLE 42
Figure imgf000063_0002
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-4-methylpentanamide m.p. 123-125°C,. [αlD +66.8° (c=0.500, MeOH). Anal. Calcd. for C22H25N3O2-0.45H2O: C, 71.12; H, 7.03; N, 1 1.31. Found: C, 71.08; H, 6.81 ; N, 1 1.42%.
EXAMPLE 43
k ^ P
Figure imgf000064_0001
(+)-N-l(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-2,3-dihvdrobenzofuran-2-carboxamide
Diisopropylethylamine (0.3 mL, 223 mg, 1.72 mmol) was added to a stirred, cooled (0 °C) solution of 3(R)-amino-l ,3-dihydro- l - methyl-5-phenyl-2H- 1 .4-benzodiazepin-2-one (J. Org. Chem. 1987, 52, 3232-3239) (400 mg, 1.5 mmol), 2,3-dihydrobenzofuran-2-carboxylic acid (274 mg, 1.7 mmol), I -(3-dimethylaminopropyl)-3-ethylcarbodi- imide hydrochloride (583 mg, 3.0 mmol), and 1 -hydroxybenzotriazole (479 mg, 3.1 mmol) in DMF (4.5 mL). The mixture was stirred at room tempera¬ ture for 18 h., poured into aqueous hydrochloric acid (3M, 12 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (20 mL) and brine (20 mL), dried (MgSθ4) and evaporated under reduced pressure. The residue was crystallized from 2-chloro-2- methylpropane/ hexane to give (+)-N-l(3R)-2,3-dihydro-l -methyl-2-oxo-5-phenyl-lH- 1 ,4-benzodiazepin-3-yl]-2,3-dihydrobenzofuran-2-carboxamide as a colorless solid ( 156 mg. 25%). m.p. 141 - 180°C, [oc]D + 127.1 ° (c=0.425, CHC13). dH (CDCI3) (3: 1 Mixture of diastereoisomers) 8.44 ( I H, m), 7.65-6.91 ( 13H, m), 5.52 (IH, m), 5.28 (IH, m), and 3.70-3.40 (5H, m). Anal. Calcd. for C25H21N3O3.O.25 Hexane
C, 73.50; H, 5.70; N, 9.71. Found: C, 74.12; H, 5.57: N. 9.71 %.
EXAMPLE 44
(+)-N-[(3R)-2,3-dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yl]- 1 '-( 1 , 1 -dimethy lethoxycarbonyl)spiro(cyclohexan-4,4'- piperidine)- 1 -carboxamide
Step A:
Figure imgf000065_0001
Diethyl 1 -benzylpiperidine-4.4-diacetate
Ethanol (120 mL) was cooled in ice and ammonia bubbled through to give a saturated solution. l -Benzyl-4-piperidone (40.0g, 21 lmmol) and ethyl cyanoacetate (47.8g, 423 mmol) were added, the reaction vessel stoppered and stored at 0°C overnight. The solid was collected, washed with ethanol and ether and dried in vacuo to give a yellow solid (68.86g). The solid (58.86g) was dissolved in a mixture of sulfuric acid (70 mL, 98%) and water (60 mL) and heated under reflux for three days the mixture cooled and most of the water evaporated. The residue was azeotroped with ethanol (4x750 mL), further ethanol (500 mL) added and the mixture heated under reflux for 20h, cooled in ice and sodium carbonate (lOOg) added slowly with vigorous stirring. The ethanol was evaporated under reduced pressure, water (800 mL) added and the mixture extracted with methylene chloride (3x400 mL). The combined organic extracts were dried (Na2Sθ4) and the solvent evaporated to give diethyl l-benzylpiperidine-4,4-diacetate (37.5 lg). A small portion of this was purified by flash column chromatography.
NMR (300 MHz, CDCI3) d: 7.2-7.4 (m, 5H), 4.1 1 (q. J=7.3Hz,4H), 3.50 (s, 2H), 2.56 (s, 4H), 2.4 (m, 4H), 1.7 (m, 4H), 1.24 (t, J=7.3Hz, 6H).
Step B:
Figure imgf000066_0001
l-Benzylpiperidine-4,4-diethanol
A solution of the diester (12.2 g, 35 mmol) in ether (25 mL) was added to a cooled (-30°C) and stirred suspension of Li AIH4 (2.1 g, 55 mmol) in ether (400 mL), under argon. THF (60 mL) was added and the reaction mixture allowed to warm to room temperature. After recooling to 0°C, water (2.2 mL), 1 M NaOH (4.4 mL) and water (5 mL) were added, the reaction mixture stirred vigorously for 30 min and the solid filtered off. washing well with ether. The combined filtrates were evaporated to afford a white solid which was tritutrated with ether to give 8 g of l -benzylpiperidine-4,4-diethanol. m.p. 75-78°C
NMR (300 MHz, CDCI3) d: 7.2-7.4 (m, 5H), 3.7 (t, J = 6.8 Hz, 4H), 3.52 (s, 2H), 2.7 (brs, 2H), 2.43 (m, 4H), 1.66 (t, J = 6.8 Hz, 4H), 1.5 (m, 4H).
Step C:
Figure imgf000067_0001
l -t-Butoxycarbonylpiperidine-4,4-diethanol
The benzylamine (2.07 g, 7.9 mmol) was dissolved in methanol (60 mL), BOC20 ( 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).
NMR (300 MHz, CDCI3) d: 3.7 (m, 4H), d 3.3 (m, 6H), 1.65 (t, J = 6.8 Hz, 4H), 1.41 (s, 9H).
Step D:
Figure imgf000067_0002
l -t-Butoxycarbonylpiperidine-4,4-diethanol, bis(methanesulfonate) The diol (2.41 g. 8.9 mmol) was dissolved in dichloro- methene (50 mL), the solution cooled to -20°C under argon before addition of triethylamine (3.7 mL, 26 mmol) and methanesulfonyl chloride ( 1.6 mL, 20 mmol). After 30 min., the reaction mixture was poured into ice cold 10% citric acid and extracted with ether (X3). The combined extracts were washed with water, saturated NaHCθ3 and brine, dried (MgS04) and the solvent evaporated to afford 1 -t-butoxy- carbonylpiperidine-4,4-diethanol, bis(methanesulf onate) (3.2g). NMR (300 MHz, CDCI3) d: 4.32 (t, J = 7.1 Hz, 4H), 3.4 (m, 4H), 3.04 (s, 6H), 1.89 (t, J = 7.1 Hz, 4H). Step E:
Figure imgf000068_0001
Diethyl 3-t-butyloxycarbonyl-3-azaspirol5.5]undecane-9,9-dicarboxylate
To a slurry of 60% NaH (2.04 g, 0.51 mole) in toluene (160 mL), under argon, was slowly added diethyl malonate (3.72 mL, 24.3 mmol). The mixture was cooled to 0°C and the bis-mesylate 1 (7.0 g, 16.3 mmol) added as a solid and the mixture heated to reflux for 18 hours. The reaction was quenched into 10% citric acid (100 mL) and the product extracted with CH2CI2 (2x 150 mL). The extracts were dried (Na2S04), concentrated to an oil, and chromatographed on silica to give 3.83 g (60% ) of diethyl 3-t-butyloxycarbonyI-3-azaspiro- [5.5Jundecane-9,9-dicarboxylate.
I H NMR (CDCI3) d: 1.22 (t, 6H), 1.4 (s, 9H), 2.0 (m, 4H), 3.35 (m, 4H), 4.2 (q, 4H).
Step F
Figure imgf000069_0001
3-t-Butyloxycarbonyl-3-azaspiror5.51undecane-9-carboxylic acid
To a solution of the diester 2 (3.69 g, 0.0093 m) in THF (50 mL) was added IN LiOH (47 mL). The reaction was stirred for 3 days at 25 °C, diluted with water (50 mL) and pH adjusted to 2.2 with KHSO4. The product was extracted into ethyl acetate (2x75 mL), dried (Na2Sθ4), and concentrated to a foam (3.5 g). The solid was melted in a flask at 140°C for 2 hours, cooled and the oil dissolved in THF (15 mL), IN LiOH (10 mL) added and mixture stirred overnight at 30°C. The reaction was concentrated to remove THF, diluted with water (20 mL) and washed with diethyl ether (10 mL). The pH was adjusted to 2.5 with KHSO4 and product extracted (3x50 mL) with ethyl acetate. The extracts were dried (Na2Sθ4), filtered and concentrated to yield 3- t-butyloxycarbonyl-3-azaspiro[5.5]undecane-9-carboxyIic acid as a foam (2.48 g, 90%). I H NMR (CDCI3, partial) d: 1.45 (s, 9H), 3.4 (m, 4H).
Employing the procedure substantially as described in Example 43 but substituting an appropriate acid for the 2,3-dihydro- benzofuran-2-carboxylic acid, the following compounds were prepared: Step G:
Figure imgf000070_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methy l-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yl]- l '-(l ,l -dimethylethoxycarbony])spiro(cyclohexan-4,4'- piperidine)- 1 -carboxamide m.p. 135-138°C, [α]D +58.8° (C=0.925, CHCI3). dH (CDCI3) 7.61 -7.23 (10H, m), 5.54 (I H, d, J 9.0 Hz), 3.47 (3H, s),
3.37 (4H, m), 2.28 (IH, m), and 1.81 -1.18 (21H, s).
Anal. Calcd. for C32H40N4O4:
C, 70.56; H, 7.40; N, 10.29. Found: C, 70.21 ; H, 7.40; N, 10.16%.
EXAMPLE 45
Figure imgf000070_0002
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yl1-3-(furan-2-vπpropanamide m.p. 1 15-1 18°C, [α]D +65.8° (c=0.800, CHCI3). dH (CDCI3) 7.62-7.26 (1 I H, m), 6.28 ( IH, dd, J 3.2, 2.0 Hz), 6.08 ( IH, dd, J 3.2, 0.7 Hz), 5.58 (IH, d, J 8.1 Hz), 3.48 (3H, s), 3.04 (2H, t, J 7.6
Hz), and 2.75 (2H, m).
Anal. Calcd. for C23H2l N3θ3.0.3Hexane:
C, 72.07; H, 6.15; N, 10.17. Found: C, 71.78; H, 6.30: N, 9.77%.
EXAMPLE 46
Figure imgf000071_0001
(+)-N-[(3R)-2,3-Dihydro- l -methyl-2-oxo-5-phenyl-l H-l ,4-benzo- diazepin-3-yll-4-(2-thienyl)butanamide m.p. 170-180°C, [α]D +63.5° (c= 1.000, MeOH). Anal. Calcd. for C24H23N3O2S.O.95H2O:
C, 66.32; H, 5.77; N, 9.67. Found: C, 66.32; H, 5.34; N, 9.40%. EXAMPLE 47
Figure imgf000072_0001
(+)-N-| (3R)-2,3-Dihydro-l -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yπcyclohexylcarboxamide m.p. 213-214°C, [αjD +62.4° (c=1.000, MeOH). Anal. Calcd. for C23H24N3O2:
C, 73.77; H, 6.46; N, 1 1.22. Found: C, 73.86; H, 6.81 ; N, 11.15%.
EXAMPLE 48
Figure imgf000072_0002
(E)-(+)-N-l(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-3-(3.4-methylenedioxyphenyl)-2-propenamide m.p. 143-145°C, [α]D +62.3° (c=0.960, MeOH). Anal. Calcd. for C25H21 N3O4.O. IOH2O.O.2OE12O:
C, 69.78; H, 5.27; N, 9.46. Found: C, 69.78; H, 4.98: N, 9.28%. EXAMPLE 49
Figure imgf000073_0001
(+)-N-l(3R)-2,3-dihydro- 1 -methyl-2-oxo-5-pheny 1- 1 H- 1 ,4-benzo- diazepin-3-yn-2-quinoxalinecarboxamide lα]D +85.8° (c=0.360, MeOH). Anal. Calcd. for C25H 19N5O2:
C, 69.96; H, 4.90; N, 15.33. Found: C, 69.95; H, 4.72; N, 15.25%.
EXAMPLE 50
(+)-N-[(3R)-2,3-Dihydro-2-methyl-2-oxo-5-pheny 1- 1 H- 1 ,4-benzo- diazepin-3-yll-2-(phenylamino)acetamide
Step A:
Figure imgf000074_0001
N-f (3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzodiazepin-
3-yl 1-2-bromoacetamide
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. The mixture was washed with water (3 x 10 mL), dried (MgS04) and the solvent was evaporated under reduced pressure to give N-l(3R)-2.3-dihydro-l -methyl-2-oxo-5-phenyI-l H-l ,4- benzodiazepin-3-yl]-2-bromoacetamide as a colorless foam (760 mg, 100%). dH (CDC13) 8.24 (IH, d, J 7.8 Hz), 7.64-7.24 (9H, m), 5.48 ( I H, d, J 7.8 Hz), 4.00 (2H, m), and 3.50 (3H, s).
Step B:
Figure imgf000075_0001
(+)-N-[(3R)-2,3-Dihydro-l-methyl-2-oxo-5-phenyl-l H-l ,4-benzo- diazepin-3-yll-2-(phenylamino)acetamide
Aniline (297 mL, 304 mg, 3.26 mmol) was added to a solution of N-[(3R)-2,3-dihydro- 1 -methyl-2-oxo-5-pheny 1- 1 H- 1 ,4- benzodiazepin-3-yl]-2-bromoacetamide (600 mg, 1.55 mmol) in ethanol (25 mL) and the mixture was heated under reflux for 24 h. The mixture was cooled and the solid was collected and recrystallized from ethanol (20 mL) to give (+)-N-l(3R)-2,3-dihydro-l-methyl-2-oxo-5- phenyl-lH-l ,4-benzodiazepin-3-yl]-2-(phenylamino)acetamide as a colorless solid (500 mg, 81 %), m.p. 245-246°C, [α]D + 1 19° (C=0.850, CHCI3). dH (CDCI3) 8.26 ( I H, d, J 8.3 Hz). 7.63-7.20 ( 12H, m), 6.81 (I H, t, J 7.3 Hz). 6.72 (2H, d, J 7.6 Hz). 5.56 ( I H, d, J 8.3 Hs > 3.95 (2H, d, J 1.5 Hz), and 3.45 (3H, s). Anal. Calcd. for C24H22N4O2:
C, 72.34; H, 5.57; N, 14.06. Found: C, 72.37; H, 5.59; N, 14.32%.
Employing the procedure substantially as described above, but substituting 2-chloroaniline or 4-(trifluoromethyl)aniline for the aniline, the following compounds were prepared: EX AMPLE 51
Figure imgf000076_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H-l ,4-benzo- diazepin-3-yll-2-(2-chlorophenylamino)acetamide m.p. 222-224°C, [OCJD +1 1 1 ° (c=0.973, CHCI3). dH (CDCI3) 8.15 (IH, d, J 8.3 Hz), 7.60-7.16 ( 12H, m), 6.71 (2H, m), 5.57 ( I H, d, J 8.3 Hz), 4.01 (2H, d, J 2.7 Hz), and 3.45 (3H, s). Anal. Calcd. for C24H21 CIN4O2:
C, 66.59; H, 4.89; N, 12.94. Found: C, 66.40; H, 4.94; N, 12.92%.
EXAMPLE 52
Figure imgf000076_0002
(+)-N-[(3R)-2,3-Dihydro-l-methyI-2-oxo-5-phenyl- lH-l ,4-benzo- diazepin-3-yll-2-[4-(trifluoromethyl)phenylamino1acttamide m.p. 218-219°C, [α]D +91.9° (c = 0.419, CHCI3). dH (CDCI3) 8.13 (IH, d, J 9.0 Hz), 7.70-7.25 (12H, m), 6.72 (2H, d, J 8.7 Hz), 5.60 (IH, d, J 9.0 Hz), 4.05 (2H, m). and 3.50 (3H, s). Anal. Calcd. for C25H21F3N4O2.O.7H2O:
C, 62.68; H, 4.71 : N, 1 1.69. Found: C, 62.47; H, 4.32; N, 1 1.44%.
EXAMPLE 53
Figure imgf000077_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyI- 1 H- 1 ,4-benzo- diazepin-3-yll-2-(phenoxy)acetamide
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). When hydrogen evolution had stopped, N-[(3R)-2,3- dihydro- 1 -methy I-2-oxo-5-phenyl-l H- 1 ,4-benzodiazepin-3-yIl-2-bromo- acetamide (400 mg, 1.04 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was washed with water (3 x 15 mL), dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was triturated with 2-propanol and the solid was collected and recrystallized from 2-propanol (5 mL) to give (+)-N- f (3R)-2,3-dihydro- 1 -methyI-2-oxo-5-phenyl- 1 H- 1 ,4-υenzodiazepin-3- yl ]-2-(phenoxy)acetamide as a colorless solid (1 12 mg, 27%), m.p. 126- 128°C, LαjD +81.6 (C=0.692, CHCI3). dH (CDC13) 8.49 (IH, d, J 8.2 Hz), 7.64-7.01 (14H, m), 5.61 (IH, d, J 8.2 Hz), 4.65 (IH, d, J 14.6 Hz), 4.58 (IH, d, J 14.6 Hz), and 3.50 (3H, s). Anal. Calcd. for C24H21N3O3:
C, 72.17; H, 5.30: N, 10.52. Found: C, 71.84; H, 5.25: N, 10.41 %.
Employing the procedure substantially as described above, but substituting 2,4-dichlorophenol, thiophenol or 2,4-dichloro- thiophenol for the phenol, the following compounds were prepared:
EXAMPLE 54
Figure imgf000078_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yl l-2-(2,4-dichlorophenoxy)acetamide m.p. 206°C, [α]D +31.1 ° (c=0.289, CHCI3). dH (CDC13) 8.75 ( IH, d, J 9.0 Hz), 7.65-7.20 (1 I H, m), 6.90 (I H, d, J 8.7 Hz), 5.60 (IH, d, J 9.0 Hz), 4.65 (2H, m), and 3.50 (3H, s). Anal. Calcd. for C24H19CI2N3O3.O.3H2O:
C, 60.85; H, 4.17; N. 8.87. Found: C, 60.80; H, 4.04; N, 8.87%. EXAMPLE 55
Figure imgf000079_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-2-(phenylthio)acetamide
[αJD +104.9° (c=0.316, CHC13). dH (CDCI3) 8.50 (I H, d, J 9.0 Hz), 7.60-7.20 ( 14H, m), 5.50 ( I H, d, J
9.0 Hz), 3.75 (2H, m), and 3.45 (3H, s).
Anal. Calcd. for C24H21N3O2S:
C, 69.37; H, 5.10; N, 10.1 1. Found: C, 68.98; H, 5.06; N, 9.76%.
EXAMPLE 56
Figure imgf000079_0002
(+)-N-[(3R)-2,3-Dihydro- 1 -methy l-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yll-2-(2,4-dichlorophenvIthio)acetamide
[α]D +97.4° (c=0.286, CHCI3). dH (CDCI3) 8.35 (IH, d. J 9.0 Hz), 7.70-7.20 ( 12H, rn), 5.50 ( I H, d, J 9.0 Hz), 3.70 (2H, m), and 3.50 (3H, s). Anal. Calcd. for C24H19CI2N3O2S:
C, 59.51 ; H, 3.95; N, 8.67. Found: C, 59.32; H, 3.95: N, 8.65%.
EXAMPLE 57
Figure imgf000080_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methy l-2-oxo-5-phenyl- 1 H- 1 ,4-benzo- diazepin-3-yπ-3-(phenylamino)propanarnide
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. Org. 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 tempera¬ ture for 18 h. The mixture was washed with saturated aqueous sodium hydrogen carbonate (85 mL), water (2 x 85 mL), and brine (85 mL), dried (MgS04) and the solvent was evaporated under reduced pressure. A sample (0.5 g, 1.25 mmol) was dissolved in ethanol (25 mL), aniline (230 mL, 233 mg, 2.5 mmol) was added and the mixture was heated under reflux for 70 h. The mixture was cooled and the solid was collected and recrystallized from ethanol to give (+)-N-[(3R)-2,3- dihydro- l -methyl-2-oxo-5-phenyl-lH-l ,4-benzodiazepin-3-ylJ-3- (phenylamino)propanamide as a colorless solid, m.p. 218-221°C, [α]D +58.2° (c=0.585, CHCI3). dH (CDCI3) 7.60-6.71 (16H, m), 5.54 (IH, d, J 8.1 Hz), 3.54 (2H, t, J 6.1 Hz), 3.52 (3H, s), and 2.70 (2H, m). Anal. Calcd. for C25H24N4O2.O.5EUOH: C, 71.70; H, 6.25; N, 12.87. Found: C, 71.42; H, 5.98; N, 12.84%.
EXAMPLE 58
Figure imgf000081_0001
(+)-l -[(3R)-2,3-Dihydro-l -methyl-2-oxo-5-phenyl- 1 H-l ,4-benzo- diazepin-3-yll-3-(2.4-dichIorophenyl)urea
2,4-DichlorophenyIisocyanate ( 188 mg, 1.0 mmol) was added to a solution of 3(R)-amino-l ,3-dihydro-l -methyl-5-phenyl-2H- 1 ,4-benzodiazepin-2-one (J. Org. Chem. 1987, 52, 3232-3239) (265 mg, 1.0 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 18 h. and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH (99.5:0.5) and the residue was crystallized from CH2θ2/hexane to give (+)-l - [(3R)-2,3-dihydro- 1 -methyl-2-oxo-5-pheny 1- 1 H- 1 ,4-benzodiazepin-3- yl]-3-(2,4-dichlorophenyl) urea as a colorless solid, m.p. 215-216.5°C, [αlD +76.2° (c=0.261 , CHCI3). dH (CDCI3) 8.10 (IH, d. J 9.0 Hz), 7.65-6.95 ( 13H, m), 5.50 (IH, d, J 9.0 Hz), and 3.50 (3H, s). Anal. Calcd. for C23H I 8CI2N4O2.O.3H2O:
C, 60.22; H, 4.09; N, 12.21. Found: C, 60.28; H, 3.89; N, 12.10%.
EXAMPLE 59
Figure imgf000082_0001
(-)-3-Cyclohexyl-N-[(3R)-2,3-dihydro- l -methyl-2-oxo-4-oxido-5- phenyl-lH-l ,4-benzodiazepin-3-yπpropanamide
3-Chloroperoxybenzoic acid (80%, 0.32 g, 1.5 mmol) was added to a solution of (+)-3-cyclohexyl-N-[(3R)-2,3-dihydro- l -mefhyl- 2-oxo-5-phenyl-lH-l ,4-benzodiazepin-3-yI]propanamide (0.60 g, 1.5 mmol) in dichloromethane (25 mL) and the mixture was stirred at room tempera¬ ture for 18 h. Further 3-chloroperoxybenzoic acid (80%, 0.1 g, 0.5 mmol) was added and the mixture was stirred for 24 h. The mixture was washed with saturated aqueous sodium hydrogen carbonate (4 x 25 mL), water (2 x 25 mL) and brine (25 mL), dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was recrystallized from toluene/hexane (65:35) to give (-)-3-cyclohexyl-N- [(3R)-2,3-dihydro- 1 -methy l-2-oxo-4-oxido-5-phenyl- 1 H-l ,4- benzodiazepin-3-yl]propanamide as colorless prisms, m.p. 222-224°C, [OC]D -80.7° (c=1.15, CHCI3). dH (CDCI3) 7.71 -7.23 (10H, m), 6.01 (I H, d, J 9.3 Hz), 3.54 (3H, s), 2.48 (2H, m), and 1.76-0.89 (13H, m). Anal. Calcd. for C25H29N3O3.O.5H2O:
C, 70.06; H, 7.06; N, 9.81. Found: C, 70.10; H, 6.80; N, 9.79%. EXAMPLE 60
N-l2,3-Dihydro- 1 -(2-dimethy laminoethyl)-2-oxo-5-phenyl- 1 H- 1 ,4- benzodiazepin-3-yl)-3-(2.4-dichlorophenyl)propanamide
Step A:
Figure imgf000083_0001
2,3-Dihydro- 1 -(2-dimethylaminoethyl)-5-phenyl- 1 H- 1 ,4-benzodiazepin-
2-one
2,3-Dihydro-5-phenyl-l H- l ,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. Potassium iodide (1 crystal) was added and the mixture was stirred at 1 10°C for 30 min. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water (2 x), dried (MgS04) and the solvent was evaporated under reduced pressure to give 2,3-dihydro- l -(2-dimethy laminoethyl)-5-phenyl-l H-l , 4- benzodiazepin-2-one ( 1.21 g, 93%). dH (CDC13) 7.63-7.16 (9H, m), 4.77 (I H, d, J 10.6 Hz), 4.41 (I H, m), 3.80 (IH, m), 3.78 (IH, d, J 10.6 Hz), 2.49 (2H, m), and 2.13 (6H, s).
Step B:
Figure imgf000084_0001
2,3-Dihydro-l -(2-dimethy laminoethyl)-3-hydroxyimino-5-phenyl-lH- 1 ,4-benzodiazepin-2-one
2,3-Dihydro- 1 -(2-dimethylaminoethy I)-5 -phenyl- 1 H- 1 ,4- benzodiazepin-2-one (1.21 g, 3.9 mmol) was dissolved in toluene (20 mL). The mixture was cooled to -78 °C and potassium t-butoxide (1.0M solution in /-butanol, 4.72 mL, 4.72 mmol) was added. The mixture was stirred at -78 °C for 20 min., then isoamyl nitrite (0.63 mL, 0.55 g, 4.72 mmol) was added. The mixture was stirred at -78°C for 90 min. then allowed to warm to room temperature and poured into aqueous citric acid ( 1 M, 10 mL). The pH was adjusted to 5.0 with aqueous sodium hydroxide then to 7.0 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (50 mL) and the organic layer was aged at room temperature. The solid which formed was collected and dried in vacuo to give 2,3-dihydro-l - (2-dimethylaminoethyl)-3-hydroxyimino-5-phenyl- 1 H- 1 ,4- benzodiazepin-2-one (0.876 g, 66%) as a solid, m.p. 232-234°C. dH (d6-DMSO) 10.90 (IH, s), 7.72-7.25 (9H, m), 4.40 (IH, m), 3.80 (IH, m), 2.50 (2H, m), and 1.85 (6H, s). Step C:
Figure imgf000085_0001
3-Amino-2,3-dihydro- 1 -(2-dimethylaminoethyl)-5-phenyl- 1 H- 1 ,4- benzodiazepin-2-one
Ethyl isocyanate (320 mL, 287 mg, 4.0 mmol) was added to a mixture of 2, 3-dihydro-l -(2-dimethy laminoethyI)-3-hydroxyimino- 5-phenyl- l H-l ,4-benzodiazepin-2-one (0.91 g, 2.7 mmol) and triethyl¬ amine (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. The mixture was cooled, the solvent was evaporated under reduced pressure and ethyl acetate (75 mL) and water (25 mL; were added. The organic phase was washed with water (4 x 25 mL), dried (MgSθ4) and evaporated under reduced pressure. The residue was dissolved in ethanol (100 mL), palladium on carbon (10%, 100 mg) was added and the mixture was shaken under hydrogen (50 p.s.i.) for 4.5 h. Further palladium on carbon (10%, 100 mg) was added and the mixture was shaken under hydrogen (50 p.s.i.) for 1.5 h. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2d2/MeOH to give 3-amino-2,3-dihydro-l -(2-dimethylaminoethyl)- 5-phenyl- lH-l ,4-benzodiazepin-2-one (180 mg, 17%). dH (CDCI3) 7.75-7.17 (9H, m), 4.45 (IH, s), 4.40 (I H, m), 3.82 (IH, m), 2.47 (4H, m), and 2.08 (6H. s). Step E:
Figure imgf000086_0001
N-[2,3-Dihydro- 1 -(2-dimethylaminoethyl)-2-oxo-5-ρhenyl- 1 H- 1 ,4- benzodiazepin-3-yl1-3-(2.4-dichlorophenyl)ρropanamide
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 (1 15 mg, 0.6 mmol) and 1 -hydroxy benzotriazole (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 solvent was evaporated under reduced pressure and ethyl acetate was added. The mixture was was washed with water, saturated aqueous sodium hydrogen carbonate and water, dried (MgS04) and evaporated under reduced pressure. The residue was triturated with acetone and recrystallized from i- PrOH/MeOH to give N-[2,3-dihydro- l -(2-dimethylaminoethyl)-2-oxo-5- pheny 1- 1 H- 1 ,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)-propanamide as a solid, m.p. 199-201 °C. dH (CDC13) 7.60-7.15 (13H, m), 5.50 (IH, d, J 8.0 Hz), 4.40 (IH, m), 3.80 (IH, m), 3.10 (2H, t, J 7.5 Hz), 2.70 (2H, t, J 7.5 Hz), 2.40 (2H, m), and 2.05 (6H, s). Anal. Calcd. for C28H28CI2N4O2:
C, 64.25; H, 5.39: N. 10.70. Found: C, 64.23; H, 5.40; N, 10.61 %. EXAMPLE 61
Figure imgf000087_0001
(+)-3(R)- { N-l3-(4-chlorophenyl)prop- 1 -en-3-yl]amino } - 1 ,3-dihydro-
1 -methyl-5-pheny I-2H- 1.4-benzodiazepin-2-one hydrochloride
A mixture of 3(R)-amino- l ,3-dihydro- l -methyl-5-phenyl- 2H- l ,4-benzodiazepin-2-one (J. Org. Chem. 1987, 52, 3232-3239) (265 mg, 1 mmol), £-l -chloro-4-(3-chloro- l -propenyl)benzene (281 mg, 1.5 mmol), potassium carbonate (276 mg, 2 mmol) and potassium iodide (25 mg, 0.15 mmol) in acetonitrile (2 mL) was heated under reflux for 4 h. The mixture was cooled and poured into ethyl acetate ( 10 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic fractions were washed with brine, dried (Na2Sθ4) 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 HCl (6 M, 0.1 1 mL) was added. The mixture was stirred, then the solvent was evaporated under reduced pressure. The residue was triturated with ether and the solid was collected and dried in vacuo to give (+)-3(R)-{N,N-bi.i[ l -(4- chlorophenyl)propen-3-yl]amino } - 1 ,3-dihydro- 1 -methy l-5-phenyl-2H- 1 ,4-benzodiazepin-2-one hydrochloride (235 mg, 39%) as a tan solid, m.p. 138- 145°C, [αjD +9.2° (c=0.500, MeOH). dH (d6-DMSO) 1 1.2 (I H. br s), 7.77-7.31 (17H, m), 6.85 (2H, br m), 6.54 (2H, m), 5.20 (lH. br s), 4.60-4.00 (4H, m), and 3.46 (3H, s). Anal. Calcd. for C34H29CI2N3O.HCI.O. IOE1OH:
C, 67.60; H, 5.08; N, 6.92. Found: C, 67.60; H, 5.03; N, 7.03%.
The second compound to elute was suspended in ethanol (0.5 mL) and ethanolic HCl (6 M, 0.035 mL) was added. The mixture was stirred, then the solvent was evaporated under reduced pressure. The residue was triturated with ether and the solid was collected and dried in vacuo to give (+)-3(R)-{ N-[3-(4-chlorophenyl)propen-3- yljamino } -1 ,3-dihydro- 1 -methyl-5-phenyl-2H- 1 ,4-benzodiazepin-2-one hydro-chloride (56 mg, 12%) as a yellow solid, m.p. 156-162°C, |αjD +35° (c=0.100, MeOH). dH (d6-DMSO) 10.3 (IH, br s), 10.0 ( I H, br s), 7.79-7.34 (13H, m), 6.78 (IH, d, J 15.9 Hz), 6.40 (I H, dt, Jd 15.9, Jt 9.0 Hz), 5.13 (I H, s), 4.00 (2H, m), and 3.46 (3H, s). Anal. Calcd. for C25H22ClN3θ.HC1.0.10EtOH.0.40H2θ:
C, 65.20; H, 5.30; N, 9.05. Found: C, 65.14; H, 5.09; N, 9.33%.
Employing the procedure substantially as described above, but substituting l-(2-bromoefhoxy)-4-nitrobenzene or 4-chlorobenzene- propanol methanesulfonate for the E- l -chloro-4-(3-chloro- l -propenyl)- benzene, the following compounds were prepared:
EXAMPLE 62
Figure imgf000089_0001
(+)-3(S)- { N,N-Bisf 2-(4-nitrophenoxy)ethyI]amino } - 1 ,3-dihydro- 1 -methyl-5-phenyl-2H- 1 ,4-benzodiazepin-2-one hydrochloride m.p. 126- 145°C. Iain +5.0°(0.100. CHCh). dH (d6-DMSO) 8.20 (4H, d, J 9.2 Hz), 7.75-7.36 (9H, m), 7.08 (4H, d, J 9.2 Hz), 4.90 (IH, br s), 4.50 (4H, br s), 4.30-3.60 (5H, br m), and 3.34 (3H, s). Anal. Calcd. for C32H29N5θ7.HC1.0.15EtOH:
C, 60.71 ; H, 4.87; N, 10.96. Found: C, 60.70; H, 4.87; N, 10.70%.
EXAMPLE 63
Figure imgf000089_0002
(+)-3(R)- { N-[3-(4-Nitrophenoxy)ethyI]amino } - 1 ,3-dihydro- 1 -methyl-
5-phenyl-2H-l .4-benzodiazepin-2-one hydrochloride m.p. I54-160°C, [α]D +84.6°(0.500, MeOH). dH (d6-DMSO) 10.2 (IH, br s), 8.25 (2H, d, J 9.0 Hz), 7.83-7.41 (9H, m), 7.09 (2H, d. J 9.0 Hz), 5.21 (IH, s), 4.57 (2H, m), 3.70 (2H, m),
3.47 (3H, s), and 3.40 (1 H, m).
Anal. Calcd. for C24H22N4θ4.HCI.0.15EtOH.0.20H2θ:
C. 61.13; H, 5.13: N, 1 1.74. Found: C. 61.12; H, 4.92; N, 1 1.64%.
EXAMPLE 64
Figure imgf000090_0001
(+)-3(R)-{ N-[3-(4-Chlorophenyl)prop- I -ylJamino }-l ,3-dihydro- l - methyl-5- phenyl-2H-l ,4-benzodiazepin-2-one hydrochloride m.p. 167-168°C. [α]D +20.8° (c=0.500, MeOH). dH (d6-DMSO) 9.9 (2H, br m), 7.78-7.26 (13H, m), 5.08 (IH, s), 3.45
(3H, s), 3.20 (IH. m), 3.00 ( IH, m). 2.70 (2H, t, J 7.4 Hz), and 2.05
(2H, m).
Anal. Calcd. for C25H24CIN3O.HCI:
C, 66.08; H, 5.55; N, 9.25. Found: C, 65.81; H, 5.49; N, 9.30%. EXAMPLE 65
S λ o
Figure imgf000091_0001
(+)-Phenylmethyl N-f (3R)-2,3-dihydro- 1 -methyl-5-phenyl-2-fhioxo- 1 H- 1 ,4-benzodiazepin-3-yllcarbamate
A mixture of (+)-phenylmethyl N-[(3R)-2,3-dihydro-l - methyI-5-phenyI-2-oxo-l H-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. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (75:25) to give (+)-phenylmethyl N-[(3R)-2,3-dihydro- l -methyl-5-phenyl-2-thioxo-lH- l ,4-benzodiazepin-3-yl]carbamate as a solid, m.p. 128-131 °C, [α]D +22.5° (c=0.656, CHCI3). dH (CDCI3) 7.65-7.26 (15H, m), 5.50 (I H, d, J 8.8 Hz), 5.14 (2H, s), and 3.86 (3H, s). Anal. Calcd. for C24H21 N3O2S.O.25H2O:
C, 68.63; H, 5.16; N, 10.01. Found: C, 68.28; H, 5.21; N, 10.06%.
Employing the procedure substantially as described above, but substituting phenylmethyl N-[2,3-dihydro-5-phenyl-2-oxo-lH-l ,4- benzodiazepin-3-yl] carbamate for the (-t-)-phenylmethyl N-[(3R)-2,3- dihydro- 1 -methyl-5-pheny 1-2-oxo- 1 H- 1 ,4-benzodiazepin- 3-yl]carbamate, the following compound was prepared: EXAMPLE 66
Figure imgf000092_0001
Phenylmethyl N-[2,3-dihydro-5-phenyl-2-thioxo- 1 H- 1 ,4-benzodiazepin-
3-yllcarbamate dH (d6-DMSO) 10.85 (IH, s), 8.42 (IH, d, J 8.6 Hz), 7.65-7.10 (14H, m), 5.10 (2H, s), and 5.05 (IH, d, J 8.6 Hz).
EXAMPLE 67
Figure imgf000092_0002
3-Cyclohexyl-N-(2,3-dihydro-l-methyl-5-phenyl-2-thioxo-lH-l ,4- benzodiazepin-3-yl)propanamide
Hydrogen bromide was bubbled at room temperature through a solution of (+)-phenylmethyl N-f(3R)-2,3-dihydro-l-methyl- 5-phenyl-2-thioxo-lH-l ,4-benzodiazepin-3-ylJcarbamate (0.9 g, 2.1 mmol), acetic acid (5 mL) and dichloromethane (5 mL). After 2 h., the solvent was evaporated under reduced pressure, ether was added and the solid was collected and dried in vacuo. A sample (0.58 g, 1.8 mmol) was suspended in THF (10 mL), triethylamine (0.24 mL, 0.18 g, 1.8 mmol) was added and the mixture was stirred at room temperature for 3 h. In a separate flask, oxalyl chloride (0.20 mL, 0.29 g, 2.3 mmol) was added to a solution of cyclohexanepropionic acid (0.33 mL, 0.30 g, 1.9 mmol) and DMF (1 drop) in THF (10 mL) and the mixture was stirred at room temperature for 3 h. The two mixtures were combined, triethylamine (0.32 mL, 0.23 g, 2.3 mmol) was added and the mixture was stirred at room temperature for 2.5 h. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water, saturated aqueous sodium hydrogen carbonate, water (2 x) and brine, dried (Na2S04) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH (99.5:0.5) and the residue was recrystallized from EtOAc/Hexane to give 3-cyclohexyl-N-(2,3- dihydro-l -methyl-5-phenyl-2-thioxo-lH- l ,4-benzodiazepin-3- yOpropan amide as a solid, m.p. 219-221 °C. dH (CDC13) 7.95 (IH, br d, J 8.6 Hz), 7.65-7.30 (9H, m), 5.72 (I H, d, J 8.6 Hz), 3.87 (3H, s), 2.41 (2H, t, J 7.6 Hz), and 1.80-0.85 (13H, m). Anal. Calcd. for C25H29N3OS.0.25H2O:
C, 70.81 ; H, 7.01 ; N, 9.91. Found: C, 70.80; H, 6.91 ; N, 9.95%.
Employing the procedure substantially as described above, but substituting phenylmethyl N-[2,3-dihydro-5-phenyl-2-fhioxo- lH- l ,4-benzodiazepin-3-yl]carbamate for the (+)-phenylmethyl N-[(3R)- 2,3-dihydro- 1 -methyl-5-phenyl-2-thioxo- 1 H- 1 ,4-benzodiazepin-3- yljcarbamate and an appropriate acid for the cyclohexanepropionic acid, the following compounds were prepared: EXAMPLE 68
Figure imgf000094_0001
3-Cyclohexyl-N-(2,3-dihydro-5-phenyl-2-thioxo- 1 H- 1 ,4-benzodiazepin-
3-yl)propanamide m.p. 1 13-1 19°C. dH (CDC13) 9.8 (IH, br s), 7.75-7.25 ( 10H, m), 5.75 ( I H, d, J 8.1 Hz),
2.41 (2H, m), and 1.80-0.85 (13H, m).
Anal. Calcd. for C24H27N3OS.O.8CH2CI2:
C, 62.91 ; H, 6.09; N, 8.87. Found: C, 62.88; H, 5.70; N. 9.12%.
EXAMPLE 69
Figure imgf000094_0002
3-Cyclohexyl-N-(2,3-dihydro-2-hydrazono-5-pheny 1- 1 H- 1 ,4- benzodiazepin-3yl)propanamide
Hydrazine (53 mL, 56 mg, 1.8 mmol) was added to a solution of 3-cyclohexyl-N-(2,3-dihydro- l -methyl-5-phenyl-2-thioxo- lH-1.4-benzodiazepin-3-yl)propanamide (120 mg, 0.25 mmol) in methanol (3 mL). The mixture was stirred at room temperature for 3 h. and the solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with water an J brine, dried (Na2Sθ4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH (99.5:0.5 increasing to 98:2) to give 3- cyclohexyl-N-(2,3-dihydro-2-hydrazono-5-phenyl-lH-l ,4-benzodiaze- pin-3yl)propanamide as a foam. dH (CDC13) 7.55-7.00 (1 IH, m), 5.75 (IH, d, J 7.6 Hz), 3.50 (2H, br s), 2.37 (2H, t, J 8.0 Hz), and 1.80-0.85 ( 13H, m). Anal. Calcd. for C24H29N5O.O.8CH3OH.O. I 5CH2CI2:
C, 67.82; H, 7.41 ; N, 15.85. Found: C, 67.79; H, 7.46; N, 16.05%.
EXAMPLE 70
Figure imgf000095_0001
(E)- and (Z)-3-Cyclohexyl-N-(2,3-dihydro-2-hydroxyimino-5-phenyl- lH-1.4-benzodiazepin-3-yl)propanamide
A mixture of 3-cyclohexyl-N-(2,3-dihydro-l-methyl-5- phenyl-2-thioxo-lH-l ,4-benzodiazepin-3-yl)propanamide (740 mg, 1.83 mmol). hydroxy lamine hydrochloride (140 mg, 2 mmol) and triethyl¬ amine (280 mL, 203 mg, 2 mmol) in methanol ( 15 mL)/THF ( 15 mL) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue was purified by flash column chroma¬ tography on silica gel, eluting with CH2θ2/MeOH (98:2). The residue recrystallized from ethyl acetate. The first isomer to crystallize was recrystallized from ethyl acetate to give(E)-3-cyclohexyl-N-(2,3- dihydro-2-hydroxyimino-5-pheny 1- 1 H- 1 ,4-benzodiazepin-3- yl)propanamide as a solid, m.p. 196°C. dH (d6-DMSO) 12.20 (IH, s), 9.00 (IH, d, J 8.0 Hz). 7.70-7.30 (10H, m), 5.45 (IH, d, J 8.0 Hz), 2.30 (2H, m), and 1.80-0.75 (13H, m).
The second isomer to crystallize was recrystallized from methanol to give (Z)-3-cyclohexyl-N-(2,3-dihydro-2-hydroxyimino-5- phenyl- I H-l ,4-benzodiazepin-3-yI)propanamide as a solid, m.p. 219°C. dH (d6-DMSO) 9.95 (I H, s), 8.95 (IH, s), 8.75 (I H, d, J 8.0 Hz), 7.50- 7.00 (9H, m), 5.70 (IH, d, J 8.0 Hz), 2.25 (2H, m), and 1.75-0.75 (13H, m). Anal. Calcd. for C24H28N4O2:
C, 71.26; H, 6.98; N, 13.85. Found: C, 70.89; H, 6.99; N, 13.55%.
EXAMPLE 71
Figure imgf000096_0001
3-Cyclohexyl-N-(2,3-dihydro-l -methyl-5-phenyl-lH-l ,4-benzodiazepin-
3yl) propanamide
Freshly prepared Raney nickel (400 mg) was added to a solution of 3-cyclohexyl-N-(2,3-dihydro-l -methyl-5-phenyl-2-thioxo- l H-l ,4-benzodiazepin-3-yI)propanamide (200 mg, 0.5 mmol) in ethanol
(20 mL) and the mixture was stirred at room temperature for 2 h. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH (99.75:0.25) to give 3-cyclo- hexyl-N-(2,3-dihydro- 1 -methyl-5-phenyl- 1 H- 1 ,4-benzodiazepin-3y 1) propanamide as a foam. dH (CDC13) 7.60-6.80 (9H, m), 6.37 (IH, br d, J 6.6 Hz), 5.53 (IH, m),
3.60 (2H, m), 2.77 (3H, s), 2.21 (2H, t, J 8.0 Hz), and 1.85-0.80
(13H, m).
Anal. Calcd. for C25H31 N3O.O.2CH2CI2:
C, 74.45; H, 7.79; N, 10.34. Found: C, 74.68; H, 7.87; N, 10.23%.
EXAMPLE 72
1 -(2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H-thieno-f 2,3-e]- 1.4- diazepin-3-yl)-3-(3-methyl-phenvDurea
Step A:
Figure imgf000097_0001
(2-Amino-3-thienyl)phenylmethanone
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 1 ,2-difhiane-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 (1M) and brine, dried (Na2S04) and the solvent was evaporated under reduced pressure. The residue was recrystallized from acetonitrile (150 mL) to give (2- amino-3-thienyl)-phenylmethanone as an orange solid (5.7 g, 44%). dH (CDC13) 7.70-7.35 (5H, m), 6.95 (2H, br s), 6.90 (I H, d, J 6.3 Hz), and 6.15 (IH, d, J 6.3 Hz).
Step B:
Figure imgf000098_0001
2.3-Dihvdro-5-phenyl- lH-thienor2,3-e l-l ,4-diazepin-2-one
A solution of l ,3-dihydro-l ,3-dioxo-2H-isoindoIe-2-acetyl chloride (8.6 g, 38 mmol) in dichloromethane (20 mL) was added slowly to a cooled (0°C) mixture of (2-amino-3-thienyl)phenyl- methanone (6.8 g, 33 mmol), pyridine (6.34 mL, 6.20 g, 78 mmol) and 4-dimethylamino-pyridine (0.79 g, 6.5 mmol) in dichloromethane (130 mL). The mixture was stirred at 0°C for 30 min., diluted with dichloromethane (80 mL) and washed with aqueous hydrochloric acid (1 M), saturated aqueous sodium hydrogen carbonate and brine. The mixture was dried (Na2Sθ4) and the solvent was evaporated under reduced pressure. The residue was triturated with ethanol and the solid was collected and dried in vacuo to give N-(3-benzoyIthien-2-yl)-l ,3- dihydro-l ,3-dioxo-2H-isoindole-2-acetamide as a solid (9.8 g, 76%). A mixture of N-(3-benzoylthien-2-yl)-l ,3-dihydro-l ,3- dioxo-2H-isoindole-2-acetamide (10.9 g, 28 mmol) and hydrazine (1.9 mL, 1.94 g, 60 mmol) in THF (500 mL) was heated under reflux for 4 h. The mixture was cooled, filtered and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2Sθ4) and the solvent was evaporated under reduced pressure. Acetic acid (300 mL) was added and the mixture was heated under reflux for 15 min. The mixture was cooled and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2S04) and the solvent was evaporated under reduced pressure to give 2,3-dihydro-5- phenyl-l H-thieno[2,3-e]-l ,4-diazepin-2-one as a foam (3.5 g, 52%). dH (CDC13) 9.75 (IH, br s), 7.90-7.30 (5H, m), 6.87 (IH, d, J 6.0 Hz), 6.82 (I H, d, J 6.0 Hz), and 4.45 (2H, s).
Step C:
Figure imgf000099_0001
2,3-Dihydro-l -methyl-5-phenyl-lH-thienoI2.3-el-l ,4-diazepin-2-one Sodium hydride (60% dispersion in mineral oil, 757 mg, 1 1.3 mmol) was added to a cooled (0°C) solution of 2,3-dihydro-5- phenyl- lH-thieno!2,3-eJ-l ,4-diazepin-2-one (2.61 g, 10.8 mmol) in DMF (1 mL). Further DMF (10 mL) was added and the mixture was stirred for 30 min. A solution of iodomethane (0.67 mL, 1.53 g, 10.8 mmol) in ether (20 mL) was added and the mixture was stirred for 1 h. The mixture was poured into water and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2Sθ4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH (95:5) to give 2,3-dihydro-l -methyl-5-phenyl-lH- thieno[2,3-e]-l,4-diazepin-2-one (1.5 g, 54%). dH (CDC13) 7.67-7.35 (5H, m), 7.00 (IH, d, J 6.0 Hz), 6.85 (I H, d, J 6.0 Hz), 4.45 (2H, br s), and 3.50 (3H, s).
Step D:
Figure imgf000100_0001
3-Amino-2,3-dihydro- 1 -methyl-5-phenyl- 1 H-thienof 2,3-eJ- 1 ,4-diazepin- 2-one
2,3-Dihydro- 1 -methyl-5-ρhenyl- 1 H-thieno[ 2,3-el- 1 ,4- diazepin-2-one (1.5 g, 5.8 mmol) was dissolved in toluene (30 mL). The mixture was cooled to -10°C and potassium t-butoxide ( 1.7 g, 15.1 mmol) was added. The mixture was stirred at -10°C for 15 min., then isoamyl nitrite (1.0 mL, 0.87 g, 7.4 mmol) was added. The mixture was stirred at -10°C for 1 h. then allowed to warm to room temperature and poured into water (50 mL) and acetic acid (3 mL). The mixture was extracted with ethyl acetate and the combined organic fractions were washed with brine, dried (Na2Sθ4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane to give 2,3- dihydro- 1 -methyl-3-hydroxyirnino-5-pheny 1- 1 H-thieno[2,3-e]- 1 ,4- diazepin-2-one (0.80 g, 48%).
2,3-Dihydro-l -methyl-3-hydroxyimino-5-phenyl-lH-thieno [2,3-e]-l ,4-diazepin-2-one (0.80 g, 2.8 mmol) was dissolved in ethanol (40 mL) and Raney nickel (2 g) was added. The mixture was shaken under hydrogen (50 p.s.i.) for 5 days, adding further Raney nickel (10 g) in portions. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chroma¬ tography on silica gel, eluting with CH2θ2/MeOH to give 3-amino-2,3- dihydro- 1 -methy 1-5-phenyl- 1 H-thieno[2,3-e]- 1 ,4-diazepin-2-one (248 mg, 33%). dH (CDC13) 7.50-7.30 (5H, m). 7.05 (IH, d, J 6.0 Hz), 6.85 (I H, d, J 6.0 Hz), 4.57 (IH, s), 3.55 (3H, s), and 1.70 (2H, br s).
Step E:
Figure imgf000101_0001
1 -(2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H-thieno[2,3-e]- 1 ,4-diazepin- 3-yl)-3-(3-methylphenyl)urea
3-Methylphenylisocyanate (60 mL, 62 mg, 0.46 mmol) was added to a solution of 3-amino-2,3-dihydro-l -methyl-5-phenyl-l H- 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. The residue was crystallized from EtOAc (4 mL) to give 1 -(2,3 -dihydro-1 -methy 1- 2-oxo-5-phenyl- 1 H-thieno[2,3-eJ- 1 ,4-diazepin-3-yl)-3-(3-methyl- phenyl)urea as a solid (94 mg, 50%). m.p. 128-130°C. dH (CDCI3) 8.70 (IH, s), 7.65-6.75 (12H, m), 5.55 (I H, d, J 9.0 Hz), 3.55 (3H, s), and 2.30 (3H, s). Anal. Calcd. for C22H20N4O2S.O.25H2O:
C, 64.62; H, 4.99; N, 13.70. Found: C, 64.68; H, 4.96; N, 13.70%.
EXAMPLE 73
Figure imgf000102_0001
3-Cyclohexyl-N-(2.3-dihydro- 1 -methyl-2-oxo-5-phenyI- 1 H-thieno[2,3- el- 1 ,4-diazepin-3-yl)propanamide
Triethylamine (75 mL, 54 mg, 0.54 mmol) was added to a mixture of 3-amino-2,3-dihydro-l -methy l-5-phenyl- l H-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- ethylcarbodiimide hydro¬ chloride (58 mg, 0.3 mmol) and 1 -hydroxybenzotriazole (42 mg, 0.3 mmol) in DMF (1.5 mL). The mixture was stirred at room temperature for 18 h. and ethyl acetate (60 mL) was added. The mixture was washed with aqueous citric acid (10%), saturated aqueous sodium hydrogen carbonate and brine, dried (Na2S04) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane to give 3- cyclohexyl-N-(2,3-dihydro-l -methyl-2-oxo-5-phenyI-lH-thieno[2,3-e]- l ,4-diazepin-3-yI)propanamide as a solid (56 mg, 46%). m.p. 189-190°C. dH (CDC13) 7.65-6.85 (8H, m), 5.65 (IH, d, J 8.0 Hz), 3.55 (3H, s), 2.40 (2H, t, J 7.0 Hz), and 1.80-0.85 (13H, m). Anal. Calcd. for C23H27N3O2S.O.5H2O: C, 66.00; H, 6.74; N. 10.04. Found: C, 66.25; H, 6.76; N, 9.83%.
EXAMPLE 74
Figure imgf000103_0001
3-Cyclohexyl-N-(5-cyclohexyl-2,3-dihydro-2-oxo- lH-l ,4- benzodiazepin-3-y0 propanamide
Phenylmethyl N-[5-cyclohexyl-2,3-dihydro-2-oxo-l H-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. In a separate flask, oxalyl chloride (38 mL, 56 mg, 0.44 mmol) was added to a solution of cyclohexanepropionic acid (61 mL, 56 mg, 0.36 mmol) and DMF (1 drop) in THF (2 mL) and the mixture was stirred al room temperature for 3 h. The two mixtures were combined, triethylamine (61 mL, 44 mg, 0.44 mmol) was added and the mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and ethyl acetate was added. The mixture was washed with water (2 x), saturated aqueous sodium hydrogen carbonate, water and brine, dried (Na2S04) and the solvent was evaporated under reduced pressure. The residue was recrystallized from i-PrOH to give 3- cyclohexy l-N-(5-cyc!ohexyl-2,3-dihydro-2-oxo- 1 H- 1 ,4-benzodiazepin- 3-yl)propanamide as a solid, m.p. 133-138°C. dH (CDCI3) 7.85 (IH, br s), 7.62-6.95 (5H, m), 5.40 (IH, d, J 8.7 Hz), 2.77 (IH, m), 2.34 (2H, m), and 2.05-0.75 (23H, m). Anal. Calcd. for C24H33N3O2.O.7C3H7OH:
C, 71.64; H, 8.89; N, 9.60. Found: C, 71.28; H, 8.70; N, 9.82%.
EXAMPLE 75
Figure imgf000104_0001
(+)-N-[(3R)-7-Amino-2,3-dihydro-l -methyl-2-oxo-5-phenyl-lH-l ,4- benzodiazepin-3-yll-3-(2.4-dichlorophenyl)propanamide
Step A:
To a mixture of 3(R)-amino- l ,3-dihydro- l -methyI-5- phenyl-2H-l ,4-benzodiazepin-2-one (J. Org. Chem. 1987, 52, 3232- 3239) (3.98 g, 15.0 mmol) in concentrated sulfuric acid (15 mL) cooled in an ice- bath was added dropwise a solution of potassium nitrate (2.12 g, 21.0 mmol) in concentrated sulfuric acid (6 mL). The mixture was stirred with cooling for 2 h., then stirred at ambient temperature for 1.5 h. Ice (80 g) was added and the mixture was basified with concentrated ammonium hydroxide to pH 9. The resulting mixture was extracted with ethyl acetate (3 x 220 mL). The combined organic fractions were washed with brine, dried (Na2S04) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with chloroform/methanol (97:3). The material which eluted was further purified by flash column chromatography on silica gel, eluting with ethyl acetete/methanol (95:5). The material which eluted was stirred under /7-butyl chloride (30 mL) and the solvent was evaporated under reduced pressure to give an inseparable mixture of 3(R)-amino-l ,3-dihydro-l -methy 1-7 -nitro-5- phenyl-2H-l ,4-benzodiazepin-2-one and 3(R)-amino-l ,3-dihydro-l - methyl-7-nitro-5-(2-nitrophenyl)-2H-l .4-benzodiazepin-2-one (3.81 g) in a 3: 1 ratio as a yellow solid. dH (CDC13) (mononitro compound) 8.43 (IH, dd, J 9, 3 Hz), 8.23 (IH, d, J 3 Hz), 7.59 (2H, m), 7.52 (2H,m), 7.44 (2H,m), 4.47 ( l H,s), 3.53 (3H,s), and 2.42 (2H, br s); (dinitro compound) 8.49 ( I H, dd, J 9, 3), 8.42 (IH, m), 8.18 (IH, d, J 3 Hz), 8.01 (IH, m), 7.67 (IH, t, J 6 Hz), 7.6-7.4 (2H, m), 4.52 (lH,s), 3.56 (3H,s), and 2.42 (2H, br s).
Step B:
A solution of 3-(2,4-dichlorophenyl)propionic acid (482 mg, 2.2 mmol), DMF (0.017 mL, 0.22 mmol), and thionyl chloride (0.24 mL, 3.3 mmol) in chloroform (2.5 mL) was heated at reflux for 1 h. The solvent was evaporated under reduced pressure to give 3-(2,4- dichloro- phenyl)propionyl chloride (520 mg, 100%). To a solution of mixed 3(R)-amino- 1 ,3-dihydro- 1 -methyl-7-nitro-5-phenyl-2H- 1 ,4- benzodiazepin-2-one and 3(R)-amino-l ,3-dihydro- 1 -methy l-7-nitro-5- (2-nitrophenyI)-2H- l ,4-benzodiazepin-2-one (3: 1 ) (621 mg, 2 mmol) and triethylamine (0.305 mL, 2.2 mmol) in methylene chloride (10 mL), was added a solution of 3-(2.4-dichlorophenyl)propionyl chloride (520 mg, 2.2 mmol) in methylene chloride (1.5 mL). The mixture was stirred for 30 min., the solvent was partially evaporated under reduced pressure, and the reaction mixture was purified by flash column chromatography on silica gel, eluting with methylene chloride/ether (90: 10) to give a mixture of (+)-N-[(3R)-2,3-dihydro-l -methyl-7-nitro- 2-oxo-5-phenyI- lH-l ,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)- propanamide and (+)-N-[(3R)-2,3-dihydro- l -methyl 7-nitro-2-oxo-5- (2-nitrophenyl)- 1 H- 1 ,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)- propanamide (850 mg, 84%) in a 3: 1 ratio as a solid white foam. dH (CDC13) (mononitro compound) 8.45 (I H, dd, J 9, 3 Hz), 8.25 (IH, d J 3 Hz), 7.54 (3H, m), 7.45 (2H, m), 7.38 (IH, d, J 2 Hz), 7.26-7.18 (4H, m), 5.50 (IH, d, J 8 Hz), 3.52 (3H, s), 3.10 (2H, m), and 2.70 (2H, m); (dinitro compound) 8.51 (I H, dd, J 9, 3 Hz), 8.40 (I H, m), 8.21 (IH, d J 3 Hz), 7.98 (IH, m), 7.68 (IH, t, J 6 Hz), 7.60 (IH, m), 7.44 ( IH, m), 7.26-7.15 (4H, m), 5.52 ( I H, d, J 8 Hz), 3.55 (3H, s), 3.10 (2H, m), and 2.70 (2H, m).
Step C:
To a solution of mixed N-f(3R)-2,3-dihydro-l -methyl- 7-nitro-2-oxo-5-phenyl-l H-l ,4-benzodiazepin-3-yl]-3-(2,4-dichloro- phenyl)propanamide and (+)-N-[(3R)-2,3-dihydro- l-methyl-7-nitro-2- oxo-5-(2-nitrophenyl)-lH- l ,4-benzodiazepin-3-yl j-3-(2,4-dichloro- phenyl) propanamide (3:1) (770 mg, 1.5 mmol) in acetic acid (6 mL) was added dropwise in portions over 1.5 h. a solution of 15% titanium (III) chloride in 20-30% hydrochloric acid (7.8 mL, 9.0 mmol). The resulting solution was stirred 30 min., basified with 20% sodium hydroxide solution (pH 9). diluted with water (80 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic fractions were washed with brine, dried (Na2Sθ4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (75:25 increasing to 100:0). The first compound to elute was crystallized from ethyl acetate to give (+)-N-f(3R)-7-amino-2,3-dihydro-l -methyl-2-oxo- 5-phenyl-lH-l,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyI)- propanamide (413 mg, 57%) as a pale yellow solid, m.p. 179-180°C, [α]D +60.2° (c= 0.500, CHCI3). dH (CDCI3) 7.60 (2H, d, J 7 Hz), 7.49-7.36 (5H, m) 7.24 (I H, d, J 9 Hz), 7.17 (2H, m), 6.99 (IH, dd, J 9, 3 Hz), 6.64 (l H,d, J 3 Hz), 5.54 (IH, d, J 8 Hz), 4.80-3.50 (2H, br s), 3.39 (3H, s), 3.09 (2H, t, J 8 Hz), and 2.68 (2H, dt, Jd 3, Jt 8 Hz). Anal. Calcd. for C25H22CI2N4O2:
C, 62.38; H, 4.61 ; N, 1 1.64. Found: C, 62.58; H, 4.68; N, 11.65%.
The second compound to elute was crystallized from ethyl acetate to give (+)-N-[(3R)-7-amino-2,3-dihydro-l -methyl-2-oxo-5- (2-aminophenyl)- 1 H- 1 ,4-benzodiazepin-3-yl]-3-(2.4-dichlorophenyl)- propanamide ( 114 mg, 15%) as a pale yellow solid, m.p. 188-189°C, [α]D +50.0° (c=0.100, MeOH). dH (CDCI3) 7.36 (2H, m), 7.25 (IH, d. J 9 Hz), 7.15 (3H, m), 7.00 (IH, m), 6.88 (2H, m), 6.79 ( IH, m), 6.60 ( IH, bs), 5.52 ( I H, d, J 8 Hz), 4.10-2.80 (4H br s), 3.40 (3H, m), 3.09 (2H, t, J 8 Hz), and 2.69 (2H, m). Anal. Calcd. for C25H23Cl2N5θ2-0.05EtOAc:
C, 60.43; H, 4.71 ; N, 13.99. Found: C, 60.79; H, 4.74; N, 13.83%.
EXAMPLE 76
Figure imgf000107_0001
(+)-N-[(3R)-2,3-Dihydro- 1 -methyl-2-oxo-5-phenyI-7-methane- sulfonamido-lH-l ,4-benzodiazepin-3-ylj-3-(2,4-dichlorophenyl)- propanamide
Methanesulfonyl chloride (0.040 mL, 0.52 mmol) was added to a solution of (+)-N-f(3R)-7-amino-2,3-dihydro-l -methyl-2- oxo-5-phenyl-l H- 1 ,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 HCl, water, saturated sodium bicarbonate solution, water, and brine (3 mL each), dried (Na2Sθ4) and the solvent was evaporated under reduced pressure. The residue was dissolved in warm toluene, treated with charcoal, and filtered. The filtrate was diluted with hexane, the mixture was cooled, and the resulting precipitate was collected and dried in vacuo to give (+)-N-f(3R)-2,3-dihydro-l -methyl-2-oxo-5- phenyl-7-methanesulfonamido-lH-1.4-benzodiazepin-3-yl]-3-(2,4- dichlorophenyl)propanamide ( 152 mg, 68%) as a white solid, m.p. 130-148°C, [α]D +11 1.6° (c=0.500, CHC13). dH (CDCI3) 7.55-7.32 (9H, m), 7.24 (2H, dd, J 10, 2 Hz), 7.17 (IH, dd, J 9, 2 Hz), 7.05 (IH, d, J 3 Hz), 5.49 (IH, d, J 8 Hz), 3.41 (3H, s), 3.08 (2H, t, J 8 Hz), 2.97 (3H. s), and 2.71 (2H, dt, Jd 3, Jt 8 Hz). Anal. Calcd. for C26H24CI2N4O4S:
C, 55.82; H, 4.32; N, 10.01. Found: C, 56.12; H, 4.47; N, 9.89%.
EXAMPLE 77
Figure imgf000108_0001
N-(2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H-pyrido(4,3-eJ- 1 ,4- diazepin-3-yI)-3-(2,4-dichlorophenyl)propanamide hydrochloride
Step A: To a solution of 2,3-dihydro- l -methyl-5-phenyl-l H-pyrido [4,3-e]-l ,4-diazepine-2-one (J. Med. Chem.. 1965, 8, 722-724) (1.63 g, 6.5 mmol) in toluene (32 mL) under argon cooled to -20°C (ice/methanol bath) was added potassium t-butoxide (1.83 g, 16.3 mmol). The resulting purple suspension was stirred 15 min. at -20°C and isoamyl nitrite (1.05 mL, 7.8 mmol) was added. 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 triturated with cold toluene and the solid was collected and dried in vacuo to give 2,3-dihydro-3-hydroxyimino-l -methyI-5-phenyl-lH- pyrido[4,3-e]-l ,4-diazepine-2-one (1.22 g, 67%) as a yellow solid, m.p. 223-224°C. dH (CDC13) 8.92 (IH, bs), 8.73 (I H, d, J 7 Hz), 8.62 (IH, s), 7.80 (2H, dd, J 7, 1 Hz), 7.59 (IH, m), 7.48 (2H, m), 7.26 (I H, d, J 7 Hz), and 3.50 (3H,s).
Step B:
A mixture of 2,3-dihydro-3-hydroxyimino-l-methyl-5- phenyl-lH-pyrido[4,3-e]-l ,4-diazepine-2-one (1.77 g, 6.3 mmol) and freshly prepared Raney nickel (3.2 g) in 1 : 1 ethanol/methanol ( 190 mL) was shaken on a Parr hydrogenation apparatus under hydrogen (50 psi) for 4 h. The mixture was filtered through filter aid and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/chloroform/ acetic acid (5:95: 1 increasing to 10:90: 1). The material which eluted was stirred under chloroform (30 mL) with potassium carbonate (0.3 g) and water (0.2 mL) for 5 min. The mixture was dried (Na2S04) and the solvent was evaporated under reduced pressure to give 3-amino-2,3- dihydro-l -methyl-5-phenyl- lH-pyridol4,3-e]- l ,4-diazepine-2-one (276 mg, 16%), as a yellow solid, m.p. 109-123°C. dH (CDC13) 8.72 (IH, d, J 6 Hz), 8.58 (IH, s), 7.61 (2H, m), 7.51 (IH, m), 7.43 (2H, m), 7.26 (IH, m), 4.47 (I H ,s), 3.50 (3H, s), and 2.1
(2H, bs).
High res. mass spectrum: Theoretical mass for C15H14N4O (M+l ):
267.124586. Measured mass (M+l): 267.123654.
Step C:
A solution of dicyclohexylcarbodiimide (87 mg, 0.42 mmol) in methylene chloride (0.17 mL) was added to a solution of 3- amino-2,3-dihydro- 1 -methyl-5-phenyl- 1 H-pyrido[4,3-e]- 1 ,4-diazepine- 2-one (93 mg, 0.35 mmol) and 3-(2,4-dichlorophenyl)propionic acid (83 mg, 0.38 mmol) in tetrahydrofuran (0.5 mL) under argon. The resulting mixture was stirred for 5 h.. filtered, and the filtrate 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 (Na2S04) and the solvent was evaporated under reduced pressure. The residue was suspended in ethanol (2 mL) and ethanolic HCl (6.8 M, 0.147 mL) was added. The mixture was stirred, the resulting precipitate was collected and dried in vacuo to give N-(2,3-dihydro- l-methyI-.)-oxo-5-phenyl- 1 H-pyrido[4,3-e]- 1 ,4-diazepin-3-yl)-3-(2,4-dichlorophenyl) propanamide hydrochloride (32 mg, 18%) as a white solid, m.p. 218- 219°C. dH (d6-DMSO) 9.38 (IH, d, J 8 Hz), 8.86 (IH, bs), 8.59 (IH bs), 7.79 (IH, d, J 6 Hz), 7.56 (3H, m), 7.51 (2H, m), 7.39 (2H, m), 7.25 (IH, m), 7.16 (I H, m), 5.37 (IH, d, J 8 Hz), 3.44 (3H, s) 2.94 (2H, t, J 7 Hz), and 2.64 (2H, t, J 7 Hz). Anal. Calcd. for C24H20CI2N4O2.HCI:
C, 57.22; H. 4.20; N. 1 1.12. Found: C, 56.87; H, 4.18; N, 1 1.09%.
EXAMPLE 78
Figure imgf000111_0001
N-(2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H-pyrido| 4,3-e]- 1 ,4- diazepin-3-vπ-3-(cvclohexyπpropanamide
A solution of dicyclohexylcarbodiimide (87 mg, 0.42 mmol) in methylene chloride (0.17 mL) was added to a solution of 3- amino-2,3-dihydro-l -methyl-5-phenyl-l H-pyrido[4,3-eJ-l ,4-diazepine- 2-one (93 mg, 0.35 mmol) and cyclohexanepropionic acid (0.065 mL, 0.38 mmol) in tetrahydrofuran (0.5 mL) under argon. The resulting mixture was stirred for 5 h., filtered, and the filtrate 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 (Na2Sθ4) and the solvent was evaporated under reduced pressure. The residue was crystallized from toluene to give N- (2,3-dihydro-l -methyl-2-oxo-5-phenyl-lH-pyrido[4,3-e]-l ,4-diazepin-3- yl)-3-(cyclohexyl)-propanamide (47 mg, 33%) as a white crystalline solid, m.p. 170-173°C. dH (CDC13) 8.75 (I H, d, J 6 Hz), 8.61 (IH, s), 7.58 (2H, m), 7.52 ( I H, m), 7.45 (2H, m), 7.31 (IH, d, J 6 Hz), 7.21 (IH, d, J 8 Hz), 5.54 (IH, d, J 8 Hz), 3.51 (3H, s), 2.39 (2H, m), 1.73 (4H, m), 1.63 (3H, m), 1.85- 1.12 (4H, m), and 0.94 (2H, m). Anal. Calcd. for C24H28N4O2.0.10PhCH3:
C, 71.70; H, 7.02; N, 13.54. Found: C, 71.78; H, 7.01 ; N, 13.57%.
Employing the procedure substantially as described above, but substituting 3-(4-trifluoromethyIphenyI)-propionic acid for the cyclohexanepropionic acid, the following compound was prepared:
EXAMPLE 79
Figure imgf000112_0001
N-(2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl- 1 H-ρyrido[4,3-e J- 1 ,4- diazepin-3-yl)-3-(4-trifluoromethylphenyl)propan amide m.p. 191 -192°C. dH (CDC13) 8.76 (IH, d, J 6 Hz), 8.61 (IH, s), 7.56 (4H, m), 7.52 (IH, m), 7.42 (2H, d, J 7 Hz), 7.38 (2H, m), 7.30 (IH, d, J 6 Hz), 7.22 (IH, d, J 8 Hz), 5.51 (IH, d, J 8 Hz), 3.50 (3H. s), 3.09 (2H, t, J 8 Hz), and
2.73 (2H, t, J 8 Hz).
Anal. Calcd. for C25H2lF3N4θ2.0.20PhCH3:
C, 65.39; H, 4.70; N, 1 1.56. Found: C, 65.69; H, 4.64; N. 1 1.95%. EXAMPLE 80
Figure imgf000113_0001
N-(2,3-Dihydro- 1 -methyl-2-oxo-5-phenyl-l H-pyridof 3,4-e]- 1 ,4- diazepin-3-yl)-3-(2.4-dichlorophenyDpropanamide
Step A:
To a solution of 2,3-dihydro-l -methy 1-5-phenyl-l H- pyrido[3,4-e]-l ,4-diazepine-2-one (Can. J. Chem. 1987, 65, 1 158- 1 161) (1.43 g, 5.7mmol) in toluene (28 mL) under argon cooled to -20°C (ice/methanol bath) was added potassium t-butoxide (1.59 g, 14.2 mmol). The resulting purple suspension was stirred 15 min. at -20 °C and isoamyl nitrite (0.92 mL, 6.8 mmol) 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 (Na2S04), and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried in vacuo to give 2,3-dihydro-3-hydroxyimino-l-methyl-5-phenyl-lH- pyrido[3,4-e]-l ,4-diazepine-2-one (1.60 g, 100%) as a tan foam. dH (CDCI3) 8.77 (IH, s), 8.50 (I H, d, J 4 Hz), 7.81 (2H, dd, J 8, 1 Hz), 7.60 (IH, m), 7.49 (3H, m), 7.32 (I H, d, J 5 Hz), and 3.55 (3H,s). Step B:
A solution of stannous chloride dihydrate (3.72 g, 16.5 mmol) in concentrated hydrochloric acid (11 mL) was added dropwise to 2,3-dihydro-3-hydroxyimino- 1 -methy 1-5-phenyl-l H-pyrido[3,4-e]- 1 ,4-diazepine-2-one (1.54 g, 5.5 mmol) cooled in an ice bath. The resulting solution was stirred at ambient temperature for 3 h. The solution was diluted with water (20mL), basified with concentrated ammonium hydroxide (18 mL), and extracted with ether (4 x 75 mL). The combined organic fractions were washed with brine (30 mL), dried (Na2S04), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol/chloroform/acetic acid (5:95: 1 increasing to 10:90: 1 ). The material which eluted was stirred under chloroform (20 mL) with potassium carbonate (0.3 g) and water (2 drops) for 5 min. The mixture was dried (Na2S04) and the solvent was evaporated under reduced pressure. The residue was stirred under hexane, and the resulting solid was collected to give 3-amino-2,3-dihydro-l -methyl-5- phenyl-l H-pyrido[3,4-eJ-l ,4-diazepine-2-one (241 mg, 16%) as a yellow solid, m.p. 94-1 18°C. dH (CDC13) 8.79 (IH, s), 8.48 (IH, d, J 5 Hz), 7.62 (2H, dd, J 8, 1 Hz), 7.51 (IH, m), 7.45 (2H, m), 7.24 (IH, dd, J 5, 1 Hz), 4.47 (IH ,s), 3.55 (3H, s), and 2.2 (2H, bs). Anal. Calcd. for Cl 5H ] 4N4θ.0.25(C2H5)2θ:
C, 67.46; H, 5.84; N, 19.67. Found: C, 67.28; H, 5.66; N, 19.53%.
High res. mass spectrum: Theoretical mass for C15H14N4O (M+l): 267.124586. Measured mass (M+l ): 267.123093.
Step C:
A solution of oxalyl chloride (0.023 mL, 0.26 mmol) in methylene chloride (0.2 mL) was added dropwise to a solution of 3- (2,4-dichlorophenyl)propionic acid (48 mg, 0.22 mmol) and DMF (1 drop) in methylene chloride (0.5 mL) cooled in an ice-bath. The resulting solution was stirred 1 h. with cooling. The solvent was evaporated under reduced pressure to give 3-(2,4-dichlorophenyl)- propionyl chloride (52 mg, 100%). To a solution ot *-amino-2,3- dihydro-l -methyl-5-phenyl- lH-pyrido[3,4-e]-l ,4-diazepine-2-one (53 mg, 0.20 mmol) and pyridine (0.021 mL, 0.22 mmol) in methylene chloride (3 mL), was added a solution of 3-(2,4-dichlorophenyl)- propionyl chloride (52 mg, 0.22 mmol) in methylene chloride (0.5 mL). The mixture was stirred for 1 h., the solvent was partially evaporated under reduced pressure, and the reaction mixture was purified by flash column chromatography on silica gel. eluting with methanol/ether (5:95 increasing to 7.5:92.5). The material which eluted was crystallized from toluene/hexane to give N-(2,3-dihydro- l -methyl- 2-oxo-5-phenyl- lH-pyrido[3,4-eJ-l ,4-diazepin-3-yl)-3-(2,4-dichloro- phenyl)propanamide (38 mg, 38%) as a white crystalline solid, m.p. 220-221 °C. dH (CDC13) 8.81 (IH, s), 8.52 (I H, d, J 5 Hz), 7.56 (2H, dd, J 7, 2 Hz), 7.51 (IH, m), 7.44 (2H, d, J 6 Hz), 7.40 ( I H, m), 7.27 (2H, m), 7.18 (2H, dd, J 8. 2 Hz), 5.48 (IH ,d, J 8 Hz), 3.55 (3H, s;. 3.10 (2H, t, J 7 Hz), and 2.71 (2H, dt, Jd 2 Jt 8 Hz). Anal. Calcd. for C24H20Cl2N4θ2-0.25PhCH3:
C, 63.06; H, 4.52; N, 1 1.43. Found: C, 63.03; H, 4.48; N, 1 1.25%.
EXAMPLE 81
N-[2,3-Dihydro-l -methyl-2-oxo-5-isopropyl-lH-l ,4-benzodiazepin-3- vπ-3-(2.4-dichlorophenyl)propanamide
Step A:
Figure imgf000116_0001
To a solution of the benzodiazepine (1.0 g, 5.3 mmol) in THF (20 mL) at -78°C under argon was added 60% (NaH, 2.52 g, 6.3 mmol) Boc anhydride (1.27 g, 5.8 mmol) and the mixture stirred at -78°C for 1/2 hour. The reaction was then allowed to warm to 25°C and stirred for 2 hours before quenching into cold aq. NH4CI (10%) and extracting the product into ethyl acetate (3x50 mL). Concentration of the dried (Na2Sθ4) extracts gave an oil which was passed through silica (EtOAc/hexane) to give 1.35 g product (89%). lH NMR (CDC13) d: 1.60 (s, 9H), 3.40 (s, 3H), 3.95 (brd, IH), 4.80 (brd, IH), 7.20 (d, IH), 7.30 (q, I H), 7.60 (t, I H), 7.92 (d, IH).
Step B:
Figure imgf000117_0001
To a solution of the BOC-benzodiazepine (4.0 g, 13.8 mmol) in THF (80 mL) under argon was rapidly added a solution of isopropyl- magnesium chloride (2.0 M) in THF (7.66 mL, 15.3 mmol). The reaction was stirred for 1/2 hour, quenched into aq NH4CI (50 mL), and extracted with ethyl acetate (2x200 mL). The organic extracts were concentrated and chromatographed on silica (1 :1 , EtOAC/hexane) to give 1.55 g (34%) of product. l H NMR (CDCI3) d: 1.14 (d, 3H), 1.19 (d, 3H), 1.40 (s, 9H), 3.13 (s, 3H), 3.2-3.8 (m, 3H), 5.45 (brs, I H), 7.28 (dt, IH), 7.48 (dt. IH), 7.56 (dt, IH), 7.72 (dd, IH).
Step C:
Figure imgf000117_0002
To a 0°C solution of the isopropylphenone (1.55 g) in ethyl acetate was added anhydrous HCl gas over 90 min. The reaction was then concentrated in vacuo to give a solid which was dissolved in H2O (40 mL) and the pH adjusted to 11.0 with IN LiOH. After 30 min. at pH = 11.0 the pH was adjusted to 7.0 with IN HCl and product extracted into ethyl acetate. The organic extracts were dried (Na2Sθ4), filtered and concentrated to give a solid 1.22 g, 100%.
! H NMR (CDC13) d: 0.95 (d, 3H), 1.30 (d, 3H), 3.16 (septet, I H), 3.36
(s, 3H), 3.60 (d, IH), 4.60 (d, IH), 7.2-7.3 (m, 2H), 7.45-7.55 (m, 2H).
Step D:
The benzodiazepine obtained in Step C was converted to the oxime as described in Example 80 Step A.
Step E:
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 (Na2S04) 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.
! H NMR (CDCI3) d: 0.92 (d, 3H), 1.25 (d, 3H), 2.65 (dt, 2H), 3.05 (t, 2H), 3.15 (SepT, IH), 3.40 (s, 3H), 5.38 (d, IH), 7.0 7.6 (m, 8H).
The following compounds were prepared in a similar manner as described in Example 81 , using the appropriate Grignard reagent in place of isopropyl magnesium chloride. EXAMPLE 82
N-[2,3-dihydro-l-memyl-2-oxo-5-isopropyl-lH-l ,4-benzodiazepin-3- yl]-3-cyclohexylpropanamide m.p. 164- 165°C
CHN: Anal. Calcd. for C22H31N3O2:
C, 71.51 ; H, 8.46; N, 11.37 Observed: C, 71.72; H, 8.39; N, 1 1.32
EXAMPLE 83
N-[2,3-dihydro-l -methyl-2-oxo-5-isopropyl-lH- l ,4-benzodiazepin-3- yll-3-(4-trifluoromethylphenyl)propanamide m.p. 187-188°C l H NMR (CDCI3) d: 0.92 (d, 3H), 1.25 (d, 3H), 2.66 (dt, 2H), 3.04 (t, 2H), 3,15 (SepT, IH), 3.40 (S, 3H), 5.38 (d, I H), 7.14 (brd, IH), 7.25- 7.6 (m, 8H).
Employing substantially the same methods described in Example 80, but replacing Step E with the reduction method described below, the following compounds were prepared:
Figure imgf000119_0001
£ To a solution of the oxime i (1.28 g, 0.0048 mole) in H2θ (130 ml) and THF (65 ml) was added sodium dithionite (Na2S2θ4) (13.0 g, 0.075 mole). The mixture was stirred for 2 hours then diluted with saturated aqueous sodium bicarbonate (50 ml) and product extracted into ethyl acetate (2 x 150 ml). The organic extracts were combined, dried over Na2Sθ4, filtered, and concentrated to give an oil ( 1.0 g). The oil was chromatographed on silica using ethyl acetate, followed by 10% methanol/methylene chloride to give pure amine 0.778g (64%). lH NMR (DMSO) d 3.32 (s, 3H), 4.30 (s, I H), 6.64 (d, d, I H), 6.76 (d, IH), 7.35 (dl, IH), 7.58-7.74 (m. 3H), 7.88 (m, I H).
EXAMPLE 84
N-[2,3-dihydro- 1 -methyl-2-oxo-5-(2-furany 1)- 1 H- 1 ,4-benzodiazepin-3- yl l-3-cyclohexylpropanamide m.p. 168-169°C
CHN: Anal. Calcd. for C23H27N3O3:
C, 70.21 ; H, 6.92; N, 10.68 Observed: C. 70.15: H, 6.67: N, 10.64
EXAMPLE 85
N-l2,3-dihydro- 1 -methyl-2-oxo-5-(2-furany 1)- 1 H- 1 ,4-benxodiazepin-3- yll-3-(4-trifluoromethylphenyl)propanamide m.p. 155-157°C
CHN: Anal. Calcd. for C24H20N3O3F3:
C, 63.29; H, 4.432; N, 9.23 Observed: C, 63.22; H, 4.44; N, 9.07
EXAMPLE 86
N-[2,3-dihydro-l -methyl-2-oxo-5-(2-furanyl)-lH-l ,4-benzodiazepin-3- yll-3-(2.4-dichlorophenyDpropanamide m.p. 132- 133°C
CHN: Anal. Calcd. for C23H19N3O3CI2
C, 60.54; H, 4.20; N, 9.21 Found: C, 60.62; H, 4.07; N, 9.07
EXAMPLE 87
N-l2,3-dihydro-l -methyl-2-oxo-5-(3-furanyl)-lH-l ,4-benzodiazepin-3- yll-3-cyclohexylpropanamide m.p. 199-200°C
! H NMR (CDCI3) d: 0.9-1.8 (brm, 3H), 2.38 (t, 2H), 3.42 (S, 3H), 5.55
(brd, IH), 6.90 (S, I H), 7.2-7.77 (m, 7H)
EXAMPLE 88
N-[2,3-Dihydro- 1 -methyl-2-oxo-5-(3-furanyl)- 1 H- 1 ,4-benzodiazepin-3- yl l-3-(4-trifluoromethylphenyl)propanamide m.p. 213-214°C l H NMR (CDCI3) d: 2.71 (dt, 2H), 3.05 (t, 2H), 3.42 (S, 3H), 5.72 (d,
IH), 6.82 (brS. I H), 7.2-7.7 (m, 1 1 H)
EXAMPLE 89
N-[ 2,3-Dihydro- 1 -methy l-2-oxo-5-[2'-(4,4-dimethyl-2-oxazolinyl)- phenyl]-l H- l ,4-benzodiazepin-3-yll-3-(2.4-dichlorophenvD- propanamide
The subject compound was prepared substantially as described in Example 81. m.p. 194- 195°C CHN: Anal. Calcd. for C30H28N4O3CI2
C, 63.95; H, 5.01 ; N, 9.94 Found: C, 63.70; H, 5.01 ; N, 9.96 EXAMPLE 90
N-f 2,3,4,5-Tetrahydro- 1 -methy!-2-oxo-5-isopropyl- 1 H- 1 ^-benzo¬ diazepine yll-3-cvclohexylpropanamide
Figure imgf000122_0001
A solution of N-[2,3-dihydro-l -methyl-2-oxo-5-isopropyl- lH-l ,4-benzodiazepin-3-yl l-3-cyclohexylpropanamide (50 mg) in methanol (10 mL), containing 10% Pd/C (50 mg) was stirred under 1 atmosphere of hydrogen for 18 hours. Filtration of the reaction, concentration and crystallization ffrom diethyl ether gave 21 mg N-[2,3,4,5-tetrahydro-l - methyl-2-oxo-5-isopropyl-l H-l ,4-benzodiazepin-3-yl]-3- cyclohexylpropanamide. CHN: Anal. Calcd. for C22H33N3O2
C. 71.12; H. 8.95: N, 1 1.31 Observed: C, 70.98; H, 8.97: N. 1 1.15 m.p. 1 14- 1 15°C EXAMPLE 91
N-[2,3-dihydro- 1 -methyl-2-oxo-5-methyl- 1 H- 1 ,4-benzodiazepin-3-y 1]- 3-(2,4-dichlorophenyl)propanamide
Step A:
Figure imgf000123_0001
To CBZ-benzodiazepine (250 mg, 0.776 mmol) in toluene (25 mL) at reflux was added dropwise a solution of DMF dimethylacetal (1.09 mL) in toluene (10 mL). The reaction was refluxed for 5 hours, cooled and concentrated to an oil. The oil was triturated with ether to give a white solid ( 124 mg). l H NMR (CDCI3) d: 2.50 (s. 3H), 3.42 (s. 3H), 5.12-5.20 (m, 3H), 6.62 (d, I H), 7.25-6.4 (m, 7H), 7.5-7.6 (m, 2H).
Step B:
Figure imgf000123_0002
The CBZ-amine-N -methyl amide (190 mg) was treated with 30% HBr/AcOH (0.8 mL) for 1 hour at room temperature. The reaction mixture was poured into ether ( 10 mL) at 0°C and the solid filtered. Solid dissolved in 10% Aq. NaOH (5 mL) and CH2CI2 ( 10 mL) and organic layer separated, dried (Na2S04), filtered and concentrated to
an oil (172 mg, 1 10%).
I H NMR (CDCI3) d: 2.42 (s. 3H), 3.05 (brs, 2H), 3.40 (s. 3H), 4.40 (s,
I H), 7.2-7.6 (m. 4H).
Step C:
Figure imgf000124_0001
N-[2,3-dihydro- 1 -methyl-2-oxo-5-methyl- 1 H- 1 ,4-benzodiazepin-3-yl j-3-
(2,4-dichlorophenyl)propanamide was prepared in a similar manner as described previously in Example 43. m.p. 194-195°C
CHN: Anal. Calcd. for C20H 19N3O2CI2
C, 59.42; H, 4.74; N, 10.39 Observed: C, 59.50; H, 4.74; N, 10.44 l H NMR (CDCI3) d: 2.49 (brs, 3H), 2.65 (dt, 2H), 3.05 (t, 2H), 3.42 (s, 3H), 5.35 (d, IH), 71 -7.6 (m, 8H).
EXAMPLE 92
N-[2,3-Dihydro- 1 -methyl-2-oxo-[4,5-a]-( 1 -oxo- 1 ,3-dihydro-2H- isoindole)- 1 H- 1 ,4-benzodiazepin-3-yll-3-(2,4-dichlorophenyl )- propanamide
Figure imgf000125_0001
To a solution of N-[2,3-dihydro- l -methyl-2-oxo-5-[2'- (4,4-dimethyl-2-oxazolinyl)phenyI]-l H-l ,4-benzodiazepin-3-yl]-3-(2,4- dichlorophenyl)propanamide ( 100 mg, 0.178 mmol) in methylene chloride was slowly added methyl trifluoromethanesulfonate (22 mL, 0.198 mmol). After stirring 5 minutes, sodium borohydride (7.6 mg, 0.20 mmol) in asolute ethanol (0.5 mL) was added and reaction stirred 30 min. the product was extracted into ethyl acetate and purified by column chromatography on silica (60% ethyl acetate/hexane) to give 30 mg N-[2,3-dihydro-l -methyl-2-oxo-[4,5-a|-( l -oxo- l ,3-dihydro-2H- isoindole)- 1 H- 1 ,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)- propanamide.
*H NMR (CDC13) d: 2.70 (m, 2H), 3.12 (t, 2H), 3.55 (s, 3H), 5.68 (s,
IH), 5.90 (d, IH), 6.85 (dd, IH), 7.05 (brd, IH), 7.1 -7.5 (m, 9H), 7.85
(d, IH).
MS M+l -494.
EXAMPLE 93
Figure imgf000126_0001
3R-(+)-3-(Phenylthio)-N-f 2,3-dihydro- 1 -methyI-2-oxo-5-phenyI- 1 H- 1 ,4-benzodiazepin-3-yl lpropanamide
To a stirred solution of 3-bromopropionic acid (l .Og, 6.5mmol) in DMF (20 mL) was added K2CO3 (1.8 g, 13 mmol) and thiophenol (0.72 g, 6.5 mmol). This was heated to 50°C for lh. The mixture was then diluted with 200 mL H2O and extracted with 2 x 100 mL EtOAc. The combined organics were washed with 100 mL H2O and dried with Na2Sθ4. This was evaporated to give 1.52g of a colorless oil, 1.18g corrected for residual DMF by NMR.
The above oil was taken up in 30 mL DMF and l -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.45g, 12.8mmol) and 1 -hydroxybenztriazole hydrate ( 1.73g, 12.8mmol) were added. This was stirred for 5 min at rt. 3-(R)-Amino-l ,3-dihydro-l - methyI-5-phenyl-2H-l ,4-benzodiazepin-2-one (0.66g, 2.6mmol) was then added and the reaction was stirred at rt overnight. The reaction was diluted with 200 mL H2O and extracted with 2x l50mL EtOAc. The combined organics were washed with l xlOOmL H2O, dried with Na2Sθ4 and evaporated. The residue was chromatographed over silica eluting with 2% MeOH:CHCl3. Collected pure fractions, evaporated. Evaporated from diethyl ether to give 770mg of a white foam. Anal. Calcd for C25H23N3θ2S-0.05Hexane:
C, 70.04; H, 5.51 ; N, 9.69. Found: C 69.91 , H 5.40, N 9.78.
EXAMPLE 94
Figure imgf000127_0001
3R-(+)-5-(Methylthio)-N-[2,3-dihydro- l -methyl-2-oxo-5-phenyl-l H- l ,4-benzodiazepin-3-ynpropanamide
To an aqueous solution of K2CO3 (0.76g, 5.5mmol) was added 5-bromopentanoic acid and sodium thiomethoxide. This was stirred at rt overnight. The reaction was diluted with 50 mL H2O and acidified to pH=0 with 6N HCl. Extracted with 2 x 50 mL EtOAc. Dried with Na2S04, evaporated to give 0.55g of a yellow oil.
The above oil was taken up in 10 mL DMF and l -(3- dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride ( 1.30g, 6.8mmol) and 1 -hydroxybenztriazole hydrate (0.92g, 6.8mmol) were added. 3-(R)- Amino- 1 ,3-dihydro- 1 -methyl-5-phenyl-2H- 1 ,4- benzodaizepin-2-one (0.85g, 3.4 mmol) was then added and the reaction was stirred overnight at rt. The reaction was diluted with 100 mL H2O and extracted with 2 x 50 mL EtOAc. Combined organics were dried with brine and Na2Sθ4. and evaporated to give yellow oil. The residue was chromatographed over silica eluting with 50:50 EtOAc:Hex to 100% EtOAc. Pure fractions were collected to give 1 .33g of a colorless oil, 0.4g of which was chroma-tographed over silica eluting with 2% MeOH:CH2Cl2- Pure fractions were collected, and evaporated from ethyl etheπhexane to give a white powder mp. 61-65°C. Anal. Calcd for C22H25N3θ2S»0.35H2θ:
C, 65.76; H, 6.45; N, 10.46. Found: C, 65.81 : H, 6.21 ; N. 10.57.
EXAMPLE 95
Figure imgf000128_0001
N-cyano-N'-cyclohexylmethyl-N"-(l ,3-dihydro- l -methyl-2-oxo-5- phenyl-2H- 1 ,4-benzodiazepin-3-yl)guanidine
A solution of 3-(R)-amino- l ,3-dihydro-l-methyl-5-phenyl- 2H-l ,4-benzodiazepin-2-one ( lg, 3.7 mmole) in acetonitrile (20 mL) was treated with diphenylcyanocarbonimidate (0.9 g, 3.7 mmole) and stirred at room temperature for thirty minutes. Cyclohexylmethyl¬ amine (0.84 g, 7.4 mmole) was then added and the reaction stirred at room temperature for two hours. The reaction was poured into 100 mL of 0.1 N HCl and extracted with 3 x 100 mL portions of ethyl acetate. The organic layers were combined and washed once with saturated sodium bicarbonate (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 50% ethyl acetate/hexane to give 0.875 g of the product. The analytical sample was crystallized from ethyl acetate. m.p. 158-161 °C.
Anal. Calcd. for C25H28N60:
C. 70.07; H, 6.59; N, 19.61. Found: C. 70.05; H, 6.59; N, 19.64%.
EXAMPLE 96
Figure imgf000129_0001
N-( 1 ,3-Dihydro- 1 -methyl-2-oxo-5-phenyl-2H- 1 ,4-benzodiazepin-3-yl)- 4-(4-chlorobenzyl)-4-piperidinecarboxamide dihydrochloride
Step A: Preparation of N-tert-butyloxycarbonyl-4-
(4-chlorobenzyl)-4-piperidinecarboxylic acid
A solution of N-Boc-ethylisonipecotate (51 .4 g, 200 mmole) in THF (IL) 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. The organic layers were combined and washed once with saturated sodium bicarbonate (500 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 10%-20% ethyl acetate/hexane to give the product ester which was used directly. The material thus obtained was dissolved in THF ( 100 mL) and IPA (100 mL) and treated with 350 mL of 10 N NaOH. The mixture was heated to reflux for 30 hours. The reaction was cooled to room temperature and poured over a mixture of crushed ice (2 L), 6 N HCl (500 mL) and saturated potassium hydrogen sulfate (1 L). The mixture was extracted with two 1 L portions of ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure to give 52 g of the product, m.p. 179-180°C,
! H NMR CDC13 d 7.26 (d, J = 8 Hz, 2 H), 7.03 (d, J = 8 Hz, 2 H), 3.98 (m, 2H), 3.0-2.8 (m, 2H), 2.84 (s, 2H), 2.10-2.00 ( m, 2H), 1.55- 1.40 (m, 2H), 1.45 (s, 9H)
Step B : Preparation of N-(I ,3-dihydro- I -methyl-2-oxo-5-phenyl-
2H- 1 ,4-benzodiazepin-3-yl)-4-(4-chlorobenzyl)-4-piper- idinecarboxamide dihydrochloride
A mixture consisting of N-tert-butyloxycarbonyl-4-(4- chlorobenzyl)-4-piperidinecarboxylic acid (1.48 g, 4.18 mmole), 3-(R)- amino- 1 ,3-dihydro- 1 -methyl-5-pheny 1-2H- 1 ,4-benzodiazepin-2-one ( 1 g, 3.7 mmole), hydroxybenzotriazole (1.17 g. 8.66 mmole), l -(3-dim- ethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.49 g, 7.70 mmole), diisopropylethyl amine (0.53 g, 4.13 mmole), and DMF (10 mL) was stirred at room temperature for 18 hours. The reaction was poured into 1 N HCl and extracted with ethyl acetate (4 X 50 mL). The organic layers were combined and washed once with saturated sodium bicarbonate (50 mL), once with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 25%-50% ethyl acetate/hexane to give 2.34 g of the product amide which was used directly. The material thus obtained was dissolved in ethyl acetate (50 mL) and HCl (g) was bubbled into the reaction for 5 minutes. The reaction was concentrated at reduced pressure and the residue recrystallized from ethyl acetate to give 1 .13 g of the product as a pale yellow solid, m.p. 190 - 195°C.
Anal. Calcd. for C29H29C1N402-2 HCl: C, 60.68; H, 5.44; N, 9.76. Found: C, 60.47; H, 5.5; N, 9.42%.
Utilizing the procedures substantially as desribed above except substituting N-Boc-ethylnipecotate for N-Boc-ethyl isonipecotate there were obtained the following compounds
EXAMPLE 97
Figure imgf000131_0001
N-( l ,3-dihydro-l -methyl-2-oxo-5-phenyl-2H-l ,4-benzodiazepin-3-yl)- 3-(4-chlorobenzyl)-3-piperidinecarboxamide hydrochloride A + B isomers
Isomer A m.p. 205 - 210°C.
Anal. Calcd. for C29H28C1N4O2-HC1-0.5 CH3CH2OHO.8 H2O:
C, 62.67; H, 6.07; N, 9.75. Found: C, 62.69; H, 5.94; N, 9.42%.
Isomer B m.p. 200 - 205°C. Anal. Calcd. for C29H28ClN4θ2«HCl.«0.1 CH3CH2θCOCH3«l .6 H2θ:
C, 61.39; H, 5.96; N, 9.74. Found: C, 61.39; H, 5.66; N, 9.56%.
EXAMPLE 98
Figure imgf000132_0001
(+)-3-CycIohexyl-N-[2,3-dihydro- 1 -methy l-2-oxo-5-phenyl- 1 H- 1 ,4- benzodiazepin-3-yll-N-(ethoxycarbonylmethyl)propanamide
3-(R)- Amino- 1 ,3-dihydro- 1 -methyl-5-phenyI-2H- 1 ,4- benzodiazepin-2-one (5.0 g, 18.8 mmol) in acetonitrile (100 mL) was mixed with ethyl bromoacetate (2.1 mL, 18.8 mmol) and sodium hydrogen carbonate (4.0 g) was suspended in the mixture. The mixture was stirred and heated at reflux for 2 h. After that time, the reaction was cooled to room temperature, diluted with 150 mL water, and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried with magnesium sulfate, gravity filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed over silica in 3: 1 ethyl acetate: hexane, yielding the mono-alkylated product (2.58 g, 39%) as well as the starting 1 ,4-benzodiazepin-2-one and bis-alkylated material. To a solution of 3-cyclohexylpropionic acid ( 1.0 g, 6.40 mmol) ih methylene chloride (30 mL) was added oxalyl chloride (0.56 mL, 6.40 mmol) and catalytic (N.N)-dimethyl formamide ( 2 drops). After 0.5 h. a solution of the acetate (2.25 g, 6.40 mmol) in methylene chloride ( 10 mL) was added and the reaction was stirred for 0.25 h. The reaction was then diluted with methylene chloride (150 mL) and saturated aqueous sodium hydrogen carbonate (150 mL ) was added. The aqueous portion was extracted again with methylene chloride (2 x 100 mL) and the organics were combined, dried with magnesium sulfate, gravity filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed over silica with 1 : 1 ethyl acetate:hexane, yielding a foam that was crystallized with ether, giving 2.0 g (64%) of the product, m.p. 120-122°C, [α]D +^0.63° (c=0.79; MeOH). Anal. Calcd. for C29H35N3O4:
C, 71.14; H, 7.21 ; N. 8.58. Found: C, 71.13; H. 7.13; N, 8.75%.
The following compound was prepared in a manner substantially as desribed above except substituting ethyl bromobutyrate for ethyl bromoacetate.
EXAMPLE 99
Figure imgf000133_0001
3-Cyclohexyl-N-[2,3-dihydro- 1 -methyl-2-oxo-5-ρheny 1- 1 H- 1 ,4- benzodiazepin-3-vn-N-ιethoxycarbonylpropyl)propan amide m.p. 103-105°C, [α]D 0.00°; c=0.85; MeOH. Anal. Calcd. for C31 H39N3O4.O.4O mol H2O:
C, 70.94; H, 7.64; N, 8.01. Found: C, 70.91 ; H, 7.44; N, 8.12%.
EXAMPLE 100
Figure imgf000134_0001
N-f2,3-Dihydro-l -methyl-2-oxo-5-phenyl-l H- l ,4-benzodiazepin-3-ylJ-
N-[2-(2-methoxyethoxy)ethynhexanamide
3-(R)-Amino- 1 ,3-dihydro- 1 -methyl-5-phenyl-2H- 1 ,4- benzodiazepin-2-one (1.33 g, 5.0 mmol) in N, N-dimethyl formamide (30 mL ) was mixed with l-bromo-2-(2-methoxyethoxy)ethane ( 1.35 mL , 5.0 mmol) and triethylamine (1.0 mL ). The mixture was stirred and heated at reflux for 4 h. After that time, the reaction was cooled to room tempera¬ ture, diluted with 150 mL water, and extracted with ethyl acetate (3 x 100 mL ). The organic layers were combined, dried with magnesium sulfate, gravity filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed over silica in 1 : 1 ethyl acetate:hexane, yielding the mono-alkylated product (1.2 g, 65%) as well as the starting 1 ,4-benzo- diazepin-2-one and bis-alkylated material. To a solution of the mono- alkylated material ( 1.2 g, 3.27 mmol) in methylene chloride (20 mL) was added hexanoyl chloride (0.96 mL, 3.27 mmol) and the reaction was stirred for 0.25 h. The reaction was then diluted with methylene chloride (150 mL) and saturated aqueous sodium hydrogen carbonate ( 150 mL) was added. The aqueous portion was extracted again with methylene chloride (2 x 100 mL) and the organics were combined, dried with magnesium sulfate, gravity filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed over silica with 1 : 1 ethyl acetate: hexane, yielding an oil, giving 580 mg (38%) of the product. [α]D 0.00°; c=0.27; MeOH. Anal. Calcd. for C27H35N3O4.O.8O mol H2O:
C, 67.56; H, 7.69; N, 8.75. Found: C, 67.56; H, 7.39; N, 8.85%.
EXAMPLE 101
Figure imgf000136_0001
(+)-N-[2,3-Dihydro- 1 -methyI-2-oxo-5-pheny I- 1 H- 1 ,4-benzodiazepin-3- yl l-N-(5-hydroxypentyl)hexanamide
3-(R)-Amino- 1 ,3-dihydro- 1 -methyl-5-pheny 1-2H- 1 ,4- benzodiazepin-2-one (1.33 g, 5.0 mmol) in acetonitrile (40 mL ) was mixed with 5-chloropentan-l -ol (0.61 g, 5.0 mmol) and sodium hydrogen carbonate (2.0 g) was suspended in the mixture. The mixture was stirred and heated at reflux for 12 h. After that time, the reaction was cooled to room temperature, diluted with 100 mL water, and extracted with ethyl acetate (3 x 75 mL ). The organic layers were combined, dried with magnesium sulfate, gravity filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed over silica in 1 :49 methanol: chloroform yielding the mono-alkylated product ( 1.1 g, 62%) as well as the starting 1 ,4-benzodiazepin-2-one and bis-alkylated material. To a solution of the monoalkylated material (0.50 g, 1.42 mmol) in methylene chloride (30 mL ) was added hexanoyl chloride (0.20 mL, 1.42 mmol) and the reaction was stirred for 0.25 h. The reaction was then diluted with methylene chloride ( 100 mL) and saturated aqueous sodium hydrogen carbonate (100 mL ) was added. The aqueous portion was extracted with methylene chloride (2x75 mL ) and the organics were combined, dried with magnesium sulfate, gravity filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed over silica with 1 : 1 ethyl acetate:hexane, yielding a foam, giving 360 mg (64%) of the product. foam . [ocjd + 8.36° (c=0.61 , MeOH). Anal. Calcd. for C27H35N3O2.O.25 mol H2O:
C, 71.42; H, 7.88; N, 9.25. Found: C, 71.47; H, 7.89; N, 9.12%.
EXAMPLE 102
Figure imgf000138_0001
(+)-N-[2,3-Dihydro- 1 -methyI-2-oxo-5-phenyl- 1 H- 1 ,4-benzodiazepin-3- yll-N-(ethoxycarbonylpentyl)hexanamide
3-(R)-Amino-l ,3-dihydro- l -methyl-5-phenyl-2H- l ,4- benzodiazepin-2-one (1.33 g, 5.0 mmol) in acetonitrile (40 mL ) was mixed with ethyl-6-bromohexanoate (0.89 mL , 5.0 mmol) and sodium hydrogen carbonate (2.0 g) was suspended in the mixture. The mixture was stirred and heated at reflux for 10 h. After that time, the reaction was cooled to room temperature, diluted with 100 mL water, and extracted with ethyl acetate (3x75 mL ). The organic layers were combined, dried with magnesium sulfate, gravity filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed in 1 :49 methanol: chloroform, yielding the mono-alkylated product (0.56 g, 28%) as well as the starting 1 ,4-benzodiazepin-2-one and bis-alkylated material. To a solution of the mono-alkylated material (0.56 g, 1.37 mmol) in methylene chloride (20 mL) was added hexanoyl chloride (0.19 mL, 1.37 mmol) and the reaction was stirred for 0.25 h. The reaction was then diluted with methylene chloride ( 100 mL) and saturated aqueous sodium hydrogen carbonate (100 mL) was added. The aqueous portion was extracted again with methylene chloride (2x75 mL) and the organics were combined, dried with magnesium sulfate, gravity filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed over silica with 1 : 1 ethyl acetate:hexane, yielding a foam, giving 0.40 g (58%) of the product, m.p. 59-65°C, [α]d (+)52.7° (c=0.48,MeOH). Anal. Calcd. for C30H39N3O4.-O.2O mol CH2CI2:
C, 69.4; H, 7.6; N. 8.04. Found: C, 69.44; H, 7.68; N, 7.71 %.
The following compound was prepared in a manner substantially as described above except substituting ethyl bromoacetate for ethyl 6-bromohexanoate.
EXAMPLE 103
Figure imgf000139_0001
(+)-N-[2,3-Dihydro- 1 -methyI-2-oxo-5-phenyl- 1 H- 1 ,4-benzodiazepin-3- yll-N-(ethoxycarbonylmethyl)hexanamide foam, [αJd + 2.04° (c=0.98; MeOH). Anal. Calcd. for C26H31 N3O4:
C, 69.47; H, 6.95; N, 9.35. Found: C, 69.41 ; H, 7.03: N, 9.26%.
EXAMPLE 104
Figure imgf000140_0001
(+)-3-Cyclohexyl-N-[2,3-dihydro- 1 -methy l-2-oxo-5-pheny I- 1 H- 1 ,4- benzodiazepin-3-yll-N-(hvdroxymethyl)propanamide
(+)-3-Cyclohexyl-N-[2,3-dihydro- 1 -methyl-2-oxo-5- phenyl-l H- 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. The aqueous portion was extracted again with ethyl acetate (2 x 100 mL) and the organics were combined, dried with magnesium sulfate, gravity filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed over silica with 1 : 1 ethyl acetate :hexane, yielding a foam (0.80 g, 37%). foam, J oc]d + 124° (c=0.69, MeOH). Anal. Calcd. for C26H31 N3O3:
C, 72.03; H, 7.21 ; N, 9.69. Found: C, 71.66; H, 7.08; N, 9.78%.
The following compound was prepared in a manner substantially as described above starting from (+)-N-[2,3-dihydro- l -methyl-2-oxo-5-phenyl-l H-1 .4-benzodiazepin-3-yllhexanamide.
EXAMPLE 105
Figure imgf000141_0001
(+)-N-[2,3-Dihydro- 1 -mefhyl-2-oxo-5-phenyl- 1 H- 1 ,4-benzodiazepin-3- yll-N-(hydroxymethyl)hexanamide m.p. 154-156°C, [α]d + 190.8° (c=0.24 , MeOH). Anal. Calcd. for C23H27N3O3O.30 mol H2O:
C, 69.26; H, 6.97; N, 10.53. Found: C, 69.29; H, 6.81 ; N, 10.6%.
EXAMPLE 106
Figure imgf000141_0002
(+)-3-Cyclohexyl-N-[2,3-dihydro-l-methyI-2-oxo-5-phenyl-l H-l ,4- benzodiazepin-3-yll-N-(tetrazolylmethyl)propanamide
(+)-3-Cyclohexyl-N-[2,3-dihydro- 1 -methyl-2-oxo-5- phenyl- 1 H- 1 ,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). The organic layers were combined, dried with magnesium sulfate, gravity filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed twice over silica with 1 : 1 ethyl acetate :hexane, yielding two constitutional isomers. a (65 mg, 9%) and b (56 mg, 7.5%).
Isomer A: m.p. 96-98°C, [α]d +188.9° (c=0.19, MeOH).
Anal. Calcd. for C27H3 l N7θ2*0.30 mol TFA:
C, 63.78; H, 6.07; N, 18.86. Found: C, 63.7; H. 6.12; N, 18.76%.
Isomer B: m.p. 92-95°C, [α]d +81.3° (c=0.31 , MeOH).
Anal. Calcd. for C27H31N7O2O.35 mol TFA:
C, 63.31 ; H, 6.01; N, 18.66. Found: C, 63.35; H, 6.02; N, 18.74%. EXAMPLE 107
Figure imgf000143_0001
3R-(+)-3-(Benzyloxycarbonylamino)-2,3-dihydro- l -methy l-2-oxo-5- phenyl- 1 H- 1 ,4-benzodiazepine
To a stirring solution of 3-(R)-amino- l ,3-dihydro- l - methyl-
5-phenyl-2H- l ,4-benzodiazepin-2-one (2.0 g, 7.5 mmol) in methylene chloride (45 mL ) at 0°C was added benzyl chloroformate (1.2 mL, 8.3 mmol) and the reaction was allowed to warm to room temperature. The reaction mixture was diluted with methylene chloride ( 150 mL ), and extracted with saturated aqueous sodium hydrogen carbonate ( 150 mL ). The aqueous portion was extracted with methylene chloride (2 x 100 mL ) and the organics were combined, dried with magnesium sulfate, gravity filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed over silica with 1 : 1 ethyl acetate:hexane, yielding a white foam (3.0 g, 99.7%) [aid +57.5° (c= 1.17; MeOH). Anal. Calcd. for C24H20N3O3-- 0.70 mol H2θ -0.15 mol CHCI3:
C, 67.62; H, 5.06; N. 9.8. Found: C, 67.6; H, 5.02; N, 9.75%.
The following compounds were prepared substantially as described in Example 81. EXAMPLE 108
N-f 2,3-Dihydro- 1 -methyl-2-oxo-5-ethy 1- 1 H- 1 ,4-benzodiazepin-3-yl]-3-
(2.4-dichlorophenyl)propanamide m.p. 156-158°C.
CHN: Anal. Calcd. for C21 H21 CI2N3O2O.5 H2O:
C, 59.02; H. 5.19; N, 9.83. Found: C, 58.99; H, 4.89; N, 9.88.
EXAMPLE 109
N-[2,3-Dihydro- 1 -methyl-2-oxo-5-t-butyl- 1 H- 1 ,4-benzodiazepin-3-yl]-
3-(2,4-dichIorophenyl)propanamide m.p. 170-171 °C.
CHN: Anal. Calcd. for C23H25CI2N3O2O.7 H2O:
C, 60.18; H, 5.80; N, 9.16. Found: C, 60.17; H, 5.30; N, 9.30.
EXAMPLE 1 10
N-[2,3-Dihydro-l -methyl-2-oxo[4'-(4,4-dimethyl-2-oxazolinyl)phenylj-
1 H- 1 .4-benzodiazepin-3-yn-3-(2.4-dichlorophenyl)prχ)panamide m.p. 188-190°C.
CHN: Anal. Calcd. for C30H28N4O3CI2:
C, 63.95; H, 5.01 ; N, 9.94. Found: C, 63.96; H. 5.02; N, 10.08.
EXAMPLE 1 1 1
N-[2,3-Dihydro- 1 -methyl-2-oxo-5-(4-methoxyphenyl)- 1 H-1 ,4- benzodiazepin-3-vH-3-(2.4-dichlorophenyl)propanamide m.p. 188-189°C.
CHN: Anal. Calcd. for C26H23CI2N3O3O.45 H2O: C, 62.91 ; H, 4.67; N, 8.47. Found: C, 61.89; H, 4.78; N, 8.33.
EXAMPLE 1 12
(+)-3,5-Dichloro-N-[3R-2,3-dihydro-2-oxo-5-pheny I- 1 -(2,2,2- trifluoroethyl)-lH-benzo[e]f 1 ,41dιazepιn-3-yllbenzamιde.
Figure imgf000145_0001
Step A: Preparation of 2,3-dihydro-2-oxo-5-phenyl-l -(2,2,2- trifluoroethyl)-lH-benzo[e][ l ,4]diazepine.
A solution of 5-phenyl-1.4-benzodiazepine-2-one (J. Org. Chem.. 1962, 27. 3788)(50 g, 0.21 1 mole) in DMF (100 mL) was treated with cesium carbonate (103.5 g, 0.317 mole) and trifluoroethyl iodide (109.7 g, 0.525 mole). The mixture was stirred at 50°C overnight. The reaction mixture was then poured into water (2 L) and extracted with ethyl acetate (3 X I L). The combined ethyl acetate fractions were dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The residue was crystallized from ethyl ether to give 45 g (68 %) of the product. MP = 130 - 131 °C; l H NMR (CDC13, 300 MHz) d 7.65-7.60 (m, 2H), 7.60-7.45 (m, 5H), 7.40-7.20(m, 2H), 5.25 (dq, .1 = 14, 8.6 Hz, I H), 4.82(d, J = 10.5 Hz, IH), 4.15 (app sextet, J = 8.6 Hz, IH), 3.81 (d, J = 10.5 Hz, IH) Step B: Preparation of 3-Azido-5-phenyl- l -(2,2.2-trifluoroethyl)-
1 H-benzo[eJ[ 1 ,4]diazepine.
To a stirring solution of 5-phenyl-l -(2,2,2-trifluoroethyI)- lH-benzole]f 1 ,4]diazepine (70 g,0.22 mol) in THF ( 1500 mL) cooled to -70°C was added potassium tert-butoxide(l .l eq, 0.24 mol. 240 mL of a 1 N solution in THF) dropwise over 15 min. A solution of 2,4,6- triisopropylbenzenesulfonylazide (74.8 g, 0.24 mol) in THF (250 ml) was added over 5 min. This was stirred for 10 minutes and acetic acid (40 mL, 0.63 mol) was added and the reaction allowed to warm to ambient temperature. The reaction was poured into satd. NaHC03 ( 1500 mL) and ethyl acetate ( IL). The phases were separated and the aqueous phase was extracted with ethyl acetate(500 mL). The combined organic layers were washed with water (500 mL) then brine (300mL). The organic layers were dried with Na2Sθ4 and evaporated to a brown foam. This was triturated with ethyl ether to give 65 g of a white powder. The filtrate was concentrated and chromatographed over silica gel eluting with 30% ethyl acetate/hexane to give another 8.9 g. The combined yield was 74 g( 93%). MP = 159 - 160°C; l H NMR (CDC13, 300 MHz) d 7.70-7.26 (m,9H), 5.28-5.12 (m,lH), 4.63 (s.l H), 4.35-4.10 (m. lH).
Step C: Preparation of racemic 3-Amino-5-phenyl- 1 -(2,2,2- trifluoroethy 1)- 1 H-benzo[e] [ 1 ,4 jdiazepine.
To a stirring solution of 3-Azido-2-oxo-5-phenyl-l -(2,2,2- trifluoroethyl)-2,3-dihydro-lH-benzole]l l ,4]diazepine (83.4mmol,30g) in 300mL ethanol and 150mL THF was added 10%Pd/C (10 wt%, 3.0g). Hydrogen gas was bubbled through the solution for 8h. The reaction was filtered and evaporated under reduced pressure. The residue was crystallized from ethyl ether to give 20.0g of white crystals. Another 4g was recovered from evaporation and recrystallization of the filtrates. Combined yeild, 86.7%. MP = 141 - 143°C; l H NMR (CDC13,300 MHz) d 7.70-7.26 (m,9H), 5.28-5.12 (m,lH), 4.57 (s,lH), 4.35-4.10 (m, l H).
Step D: Preparation of 2-Amino-N-[2-oxo-5-phenyl- l -(2.2,2- trifluoroethyl)-2,3-dihydro- 1 H-benzo[eJ [ ! ,4]diazepin- 3-yl]-3-phenyIpropionamide
To a stirring solution of 3-Amino-2-oxo-5-phenyl- l -(2,2,2- trifluoroethyl)-2,3-dihydro-l H-benzo[e]f l ,4]diazepine (92.2 mmol, 30.74g) in DMF (300mL) was added N-Benzyloxy-D-Phenylalanine (92.2 mmol, 27.6g), l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12mol,22.95g) and 1 -hydroxybenztriazole hydrate (46.1mmol,6.23g). This was stirred at room temperature for 2h. The reaction was then diluted with I L of 10% KHSO4 and extracted with ethyl acetate (2x600 mL). The organic layers were combined and washed with saturated sodium hydrogen carbonate (600mL). They were dried with brine and sodium sulfate and evaporated under reduced pressure. 66.58g of an orange foam, which contained ethyl acetate by NMR. NMR 1 H (CDCI3) d 7.75-7.18 (m, 20H). 5.62-5.55 (m, lH), 5.48-5.00 (m, 4H), 4.72-4.60 (m, I H), 4.25-4.05 (m, i H) 3.32-3.05 (m, 2H). This material was carried on without further purification.
To a stirring solution of 2-(N-Benzyloxyamino)-N-[2-oxo- 5-pheny 1- 1 -(2,2,2-trifluoroethyl)-2,3-dihydro- 1 H-benzo[e] [ 1 ,4]diazepin- 3-yl]-3-phenyl propionamide in I L ethanol was added 10% Pd/C (15 wt%) and hydrogen was bubbled through the reaction for 2h and then left stirring under 1 atm. hydrogen overnight. Hydrogen was bubbled through the reaction for an additional three hours the following morning. The reaction was then filtered, the catalyst was rinsed with I L methylene chloride and evaporated under reduced pressure. The resulting solid was dried under vacuum overnight to give 44.46g of a white solid. This was chomatographed over silica, eluting with 1 % MeOH:EtOAc. The pure upper Rf fractions were collected and evaporated under reduced pressure. The mixed fractions were collected, evaporated and rechromatographed. The pure fractions were collected and combined with the above pure fractions to get a combined yield of 18.1 lg, 83.5% of the upper Rf diastereomer. ]H NMR (CDCl3,300 MHz) d 8.94 (d, J=8.6Hz, I H), 7.65-7.10 (m, 9H), 5.64 (d, J=8.6 Hz, IH), 5.28-5.12 (m. IH), 4.57 (s. IH), 4.35-4.10 (m. IH) 3.71 (dd, J=9.8 and 3.9 Hz. IH), 3.34 ( dd, .1= 13.9 and 3.9 Hz.l H), 2.79 (dd. J=13.9 and 10.0 Hz, I H). The Absolute stereochemistry at C-3 of the benzodiazepine ring was determined to be (R) by X-Ray analysis.
The lower Rf material corresponding to C-3(S) was isolated as well.
Step E: Preparation of 3(R)-(+)-3-Amino-5-ρhenyl-l -(2,2,2- trifluoroefhyI)-lH-benzo[e]l 1 ,4J diazepine.
To a stirring solution of 2-Amino-N-[2-oxo-5-phenyl-l - (2,2,2-trifluoroethyl)-2,3-dihydro- 1 H-benzoleJ[ 1 ,4Jdiazepin-3-yl]-3- phenylpropionamide (13.6 g, 28.3 mmol) in methylene chloride ( 136 mL) was added phenyl isothiocynate (3.87 mL, 34.0 mmol). This was stirred overnight at ambient temperature. The reaction was then cooled in ice, trifluoroacetic acid (2.73 mL, 0.283 mol) added and the reaction allowed to warm to ambient temperature. After stirring at ambient temperature for 2.5 hours the reaction was evaporated under reduced pressure, chromatographed with 90: 10: 1 : 1 methylene chloride:methanol:acetic acid:water. The low Rf spot was collected and evaporated under reduced pressure with no heat. The residue was taken up in 600 mL methylene chloride and washed with 300 mL saturated NaHC03 and 300 mL water. The solution was dried over Na2S04 and evaporated under reduced pressure. The residue was crystallized from ethyl acetate: hexanes to give 6.65 g of a white powder . MP = 162 - 164°C;
! H NMR (CDCl3,300 MHz) d 7.70-7.26 (m,9H), 5.28-5.12 (m, I H), 4.57 (s, lH), 4.35-4.10 (m. l H). l<x]D = +72.9° (c=0.7, MeOH) The (-)-3S enantiomer was prepared in the same fashion from the Lower Rf product of Step D. MP = 156 - 158°C; l H NMR (CDCl3,300 MHz) d 7.70-7.26 (m,9H), 5.28-5.12 (m,lH), 4.57 (s, lH), 4.35-4.10 (m,lH). [αlD = -71.2° (c=0.66, MeOH)
Step F: Preparation of (+)-3,5-Dichloro-N-[3R-2,3-dihydro-2-oxo-
5- phenyl- 1 -(2,2.2-trifluoroethyl)- 1 H-benzo[e][ 1 ,4]diazepin-3- yljbenzamide:
To a stirring solution of (+)-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- ethylcarbodiimide hydro- chloride(4.44 g, 23.0 mmol), and 1 -hydroxybenztriazole hydrate (3.1 1 g, 23.0 mmol) and 3,5-Dichlorobenzoic acid (3.21 g, 16.8 mmol). This was stirred at ambient temperature for 2 hours. The reaction was diluted with 500 mL satd. NaHC03 and extracted with 2 x 300 mL ethyl acetate. The combined organics were washed with 10% KHSO4 (200 mL) , brine (200 mL), dried over Na2Sθ4, 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 . mp=140- 143°C, [αlD=+47.9°; l H NMR (CDCI3, 300 MHz) d 7.85-7.75 (m, 2 H), 7.70-7.20 (m, 9 H), 5.78 (d, J=8.1 Hz, l H), 5.30-5.15 (m, I H), 4.30-4.15 (m, I H) Analysis Calcd. for C24H16CI2F3N3O2:
C, 56.93; H, 3.19; N, 8.30; Found: C, 56.81 ; H, 3.17; N, 8.17.
The following examples were prepared by a procedure substantially as described for Example 1 , Step F. EXAMPLE 1 13
(-)-2-(3,4-Dichlorophenyl)-N-[3R-2,3-dihydro-2-oxι--5-phenyl- 1 -(2.2.2-trifluoroefhyl)-l H-benzofell 1 ,41diazepin-3-yl lacetamide.
Figure imgf000150_0001
mp=219-221°C; [α]D=-10.8°: l H NMR (CDC13.300 MHz) d 7.65-7.15 (m, 12H), 5.78 (d, J=8.1 Hz,
IH), 5.25-5.10 (m. IH), 4.25-4.05 (m, I H), 3.56 (s, 2H);
Analysis Calcd. for C25H 18CI2F3N3O2O.85 H2O:
C, 56.06; H, 3.71 ; N, 7.84. Found: C, 56.03; H, 3.53; N, 7.82.
EXAMPLE 1 14
(-)-2-(3.5-Dichlorophenyl)-N-[3R-2,3-dihydro-2-oxo-5-phenyI- 1 -(2,2.2-trifluoroethyl)- 1 H-benzoleU l ,41diazepin-3-yl lacetamide
Figure imgf000150_0002
mp=93-100°C, [α]D = -5.770c . i H NMR (CDCl3,300 MHz) d 7.65-7.15 (m, 12H), 5.78 (d, J=8.1 Hz, IH), 5.25-5.10 (m, IH), 4.25-4.05 (m, IH), 3.65 (s, 2H); Analysis Calcd. for C25HI 8CI2F3N3O2 : C, 57.71 ; H, 3.49; N, 8.08; Found : C, 57.41 ; H, 3.48; N, 8.12.
EXAMPLE 1 15
(-)-2-f3,5-Bis(trifluoromethyl)phenyl l-N-[3R-2.3-dihydro-2-oxo-5- phenvl- 1 -(2.2.2-trifluoroethvπ- 1 H-benzolelf 1 ,4]diazepin-3-yllacetamide
Figure imgf000151_0001
m.p. foam °C, [α]D = -9.7° (c=0.59.MeOH). Anal. Calcd. for C27H 18F9N3O2-0.75 H20:
C, 53.96; H, 3.27; N, 6.99. Found: C, 53.96; H, 3.1 ; N, 6.98%.
EXAMPLE 1 16
(-)-2-(4-TrifIuoromethylphenyl)-N-[3R-2,3-dihydro-2-oxo-5- phenyl- 1 -(2.2.2-trifluoroethyl V 1 H-benzol e 111 .4 ldiazepin-3- yllacetamide
Figure imgf000152_0001
m.p. 253-255 °C. [α]D =-9.2c (c=0.25. MeOH).
Anal. Calcd. for C26H19F6N3O2O.O5 ethyl etherθ.55 H20:
C, 59.03; H, 3.9; N, 7.88. Found: C, 59.05; H, 3.82; N, 7.78%.
EXAMPLE 1 17
2-(3-Trifluoromethylphenyl)-N-[3R-2,3-dihydro-2-oxo-5-phenyl- 1 -(2,2,2-trifluoroethyl )- 1 H-benzolelD ,4 ldiazepin-3-yl lacetamide
Figure imgf000152_0002
m.p. 172-173 °C, [α]D = +5.9° (c=0.56, CHCI3). Anal. Calcd. for C26H 19F6N3O2O.6O H20:
C, 58.89; H, 3.84; N, 7.92. Found: C, 58.92; H, 3.71 ; N, 7.98%. EXAMPLE 1 18
(+)-2-(2-Trifluoromethylphenyl)-N-[3R-2,3-dihydro-2-oxo-5- phenyl- l -(2.2.2-trifluoroethylVl H-benzol e II 1.41diazepin-3-yllacetamide
Figure imgf000153_0001
m.p. 170-171 °C, [α]D = +9.0° (c=0.48, CHC13). Anal. Calcd. for C26H 19F6N3O2-0.25 H20:
C, 59.6; H. 3.75: N, 8.02. Found: C, 59.64; H, 3.68; N, 7.97%.
EXAMPLE 1 19
(-)-2-(2,4-Dichlorophenyl)-N-13R-2,3-dihydro-2-oxo-5-phenyl- l -(2,2,2-trifluoroethyl)- l H-benzol ell l ,41diazepin-3-yl lacetamide
Figure imgf000153_0002
m.p. 143-145 °C. [α]D = -22.6° (c=0.73; MeOH). Anal. Calcd. for C25H 18N3O2CI2F3: C, 57.71 ; H, 3.49; N, 8.08. Found: C, 57.75; H, 3.52; N. 8.09%.
EXAMPLE 120
(-)-2-(3-Chlorophenyl)-N-f3R-2,3-dihydro-2-oxo-5-phenyl- 1 - (2.2.2-trifluoroethyl)-l H-benzofeiπ .41diazepin-3-yl lacetamide
Figure imgf000154_0001
m.p. 188-189 °C, [α]D = -5.4° (c=1.03,MeOH). Anal. Calcd. for C25H19CIF3N3O2O.IO ethyl ether:
C, 61.84; H, 4.09; N, 8.52. Found: C, 61.84; H, 4.05; N, 8.5%.
EXAMPLE 121
(-)-2-(4-Chlorophenyl)-N-l3R-2,3-dihydro-2-oxo-5-phenyl- l -(2,2,2-trifluoroethyl)-l H-benzole ll l ,41diazepin-3-yl lacetamide
Figure imgf000154_0002
m.p. 246-247 °C, |α]D =- 10.1 ° (c=0.45,MeOH). Anal. Calcd. for C25H19CIF3N3O2O.2O H20 0.15 ethyl ether:
C, 61.42; H, 4.21 ; N, 8.39. Found: C, 61.46; H, 4.15; N, 8.39%.
Example 122
(-)-2-[2,4-Bis(trifluoromethyl)phenyl]-N-[3R-2,3-dihydro-2-oxo-5- phenyl- 1 -(2,2,2-trifluoroethyl)- 1 H-benzolelf l ,41diazepin-3-yl lacetamide
Figure imgf000155_0001
Step A. 2,4-Bis(trifluoromefhyI)benzonitrile
To a stirring biphasic mixture of lOOmL ethanol and 250 mL of phosphate buffer (lg of NaH2Pθ4-H2θ per 5 mL H2θ 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 (32.5mmol,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 2xl 50mL EtOAc. The organic layers were combined, dried with brine and Na2S04. 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) d 8.0-7.85 (m,3H), 4.03 (s,2H) Step B. 2,4-Bis(trifluoromethyl)phenyl acetic acid
2,4-Bis(trifluoromethyl)benzonitrile (41.5mmol, 10.51 g) was taken up in lOOmL acetic acid, 50mL cone. H2SO4, and 20mL water. This was heated to 120°C for 3h. The reaction was then diluted with I L ice water, and extracted with 2x300mL ethyl acetate. The combined organics were washed with 2x200mL water, dried with brine and Na2Sθ4, and evaporated under reduced pressure. The residue was taken up in a minimum 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 J H (CDCI3) d 7.93 (s,l H), 7.80 (d, J=7.9Hz, l H), 7.55 (d, J=7.9Hz, l H), 3.94 (s,2H).
Step C. Preparation of (-)-2-[2.4-Bis(trifluoromethyl)phenyl]-N-
13R-2,3-dihydro-2-oxo-5-phenyl- 1 -(2,2,2-trifluoroethyl)- 1 H-benzo[e][ 1 ,4]diazepin-3-yl lacetamide
To a stirring solution the 3R-3-Amino-2-oxo-5-phenyl-l - (2,2,2-trifluoroethyl)-2,3-dihydro-J H-benzo|el[ l ,4]diazepine (28.4 mmol, 9.47g) in DMF (lOOmL) was added 2,4- Bis(trifluoromethyl)phenyl acetic acid (28.4mmol.7.74g), l-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42.6mmol,8.16g) and 1 -Hydroxybenztriazole hydrate ( 14.2mmol, 1.92g). This was stirred for l h at room temperature. The reaction was then diluted with 750mL of 10% KHSO4 and extracted with ethyl acetate (2x300mL). The organic layers were combined and washed with saturated sodium hydrogen carbonate ( l x600mL). The organics were then dried with brine, and sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica eluting with 20% EtOAc:Hexane. Pure fractions were collected and evaporated. The residue was taken up in 100 mL of warm 75% isopropanol: water. This was allowed to cool slowly and stirred overnight ( 16 hr) at room temperature. The suspension was cooled briefly to @5°C and filtered. The white solid was dried overnight at
60°C to give 10.5 g of material that melted at 132- 134°C. X-Ray diffraction confirms crystal linity.
NMR i H (CDC13) d 7.95-7.25 (m,13H), 5.60 (dj=« 1 HZ, 1 H), 5.30-
5.10 (m,lH), 4.25-4.06 (m, lH), 3.96 (s,2H)
Anal. Calcd. for C27HI 8F9N3O2:
C, 55.20; H, 3.09: N, 7.15. Found: C, 55.03; H, 3.14: N. 7.10%.
EXAMPLE 123
(+)-2-(3,5-DichlorophenyI)-N-[2,3-dihydro-2-oxo-5-phenyl- l -(2.2.2-trifluoroethyl)-lH-benzo[elf l .41diazepin-3-yll acetamide
Figure imgf000157_0001
m.p. 219-220 °C. racemic
Anal. Calcd. for C25HI 8N3O2CI2F3:
C, 57.71 : H, 3.49: N, 8.08. Found: C, 57.94; H, 3.48; N, 8.02%.
EXAMPLE 124
2-(3,5-dichloro-4-methoxyphenyI)-N-[3R-2,3-dihydro-2-oxo-5- phenyl- l -(2,2,2-trifluoroethyl)-lH-benzolell l ,41diazepin-3-yliacetamide
Figure imgf000158_0001
m.p. 100-104 °C, fα]D = -8.9° (c=0.55,MeOH). Anal. Calcd. for C26H20CJ2F3N3O3:
C, 56.74; H, 3.66; N, 7.63. Found: C, 55.67; H, 3.47; N, 7.41 %.
The following examples were prepared by procedures substantially as described in example 1 except substituting the appropriate fluoro substituted aminobenzophenone in step A.
EXAMPLE 125
(+)-2-(3,5-Dichlorophenyl)-N-f2,3-dihydro-5-(4-fluorophenyl)-2- oxo-l -(2.2.2-trifluoroethyl)-l H-benzolell l ,41diazepin -3-yllacetamide
Figure imgf000158_0002
m.p. foam °C, fα)D = +3.4° (c=0.55; MeOH). Anal. Calcd. for C25H17N3O2CI2F4:
C, 55.78; H, 3.18; N, 7.81. Found: C, 55.73; H, 3.25; N, 7.72%.
EXAMPLE 126
(-)-2-(2,4-Dichlorophenyl)-N-[2.3-dihydro-5-(4-fluorophenyl)-2- oxo- 1 -(2.2.2-trifluoroethylVl H-benzolell 1.4ldiazepin-3-vnacetamide
Figure imgf000159_0001
m.p. foam °C, [αlD = - H ° (c=0.68: MeOH). Anal. Calcd. for C25H17N3O2F4:
C, 55.78; H, 3.18; N, 7.81. Found: C, 55.82; H, 3.41 ; N, 7.42%.
EXAMPLE 127
(+)-2-(3,5-Bis(trifluoromethyl)phenyl)-N-f 2,3-dihydro-5-(4- fluorophenyl)-2-oxo- l -(2,2,2-trifluoiOethyI)- l H-benzo|el 1 1.41diazepin-3-yll-acetamide
Figure imgf000160_0001
m.p. foam °C, [ajD = +2.8° (c=0.67; MeOH). Anal. Calcd. for C27H17N3O2F10:
C, 53.56; H, 2.83; N, 6.94. Found: C, 53.56; H, 2.93; N, 6.91 %.
EXAMPLE 128
(-)-2-12,4-Bis(trifluoromethyl)phenyI]-N-[2,3-dihydro-5-(4- fluorophenyl)-
2-oxo I -(2,2,2-trifluoroethyl)- 1 H-benzolel 1 1 ,4 ldiazepin-3-yl lacetamide
Figure imgf000160_0002
fαjD = -14° (c=0.63; MeOH). Anal. Calcd. for C27H 17N3O2F1O:
C, 53.56; H, 2.83; N, 6.94. Found: C, 53.3; H, 2.89; N. 7.05%.
EXAMPLE 129
3-Cyclohexyl-N-[2,3-dihydro-5-(2-fluorophenyl)-2-oxo- 1 - (2.2.2-trifluoroethyl- lH-benzolelf 1.41diazepin-3-yllpropionamide
Figure imgf000161_0001
m.p. 202-204 °C. i H NMR d (CDC13) 7.72 (m.8H). 5.65 (d,J=8.3Hz, I H), 5.35-5.08 (m,l H), 4.32-4.15 (m, l H), 2.37 (t.J=7.8Hz.2H), 1.80- 1.55 (m.7H), 1.45-Anal. Calcd. for C26H27F4N3O2:
C, 63.8; H, 5.56; N, 8.58. Found: C, 63.82; H, 5.54; N, 8.56%.
EXAMPLE 130
3,4-Dichloro-N-[2,3-dihydro-5-(2-fluorophenyl)-2-oxo- 1 - (2,2,2 -trifluoroethyl)- 1 H-benzolell l ,41diazepin-3-yllbenzamide
Figure imgf000162_0001
m.p.168-170 °C. iHNMR d (CDC13) 8.03 (d,J=2.0,lH), 7.86 (d,J=7.8Hz,lH), 7.78-7.05 (m,9H), 5.80 (d,J=7.8Hz,lH), 5.27-5.15 (m,lH), 4.35-4.20 (m,lH) Anal. Calcd. for C24H15CI2F4N3O2:
C, 54.98; H, 2.88; N, 8.01. Found: C, 54.96; H, 2.89; N, 8.12%.

Claims

WHAT IS CLAIMED IS:
1. A method of treating Meniere's disease in mammals, including humans, comprising modulation of the slowly activating delayed rectifier potassium (K+) current (ΪKs)-
2. The method of Claim 1 wherein the slowly activating delayed rectifier potassium (K+) current (IKs) in isolated myocytes is blocked by a compound at a concentration of lμM or less (IC50) and the concentration that blocks IKs by 50% is at least 10 fold lower than the concentration required to cause 50% block of IKr and/or Iκ i -
3. The method of Claim 1 wherein the blockade is induced through the use of a 1 ,4-benzidiazepine or benzidiazepine derivative.
4. The method of Claim 3, wherein the benzodiazepine or benzodiazepine derivatives block the slowly activating delayed rectifier potassium (K+) current (IKs)-
5. The method of Claim 4, wherein the 1 ,4- benzodiazepines or benzodiazepine derivatives are selective IKs antagonists consisting of those compounds which block the IKs current measured in isolated myocytes by 50% at a concentration of 1 uM or less and exhibit a selectivity ratio of greater than 10 over blockade of iKn ΪK 1 and ICa-
6. The method of Claim 5 wherein the selective Ij^s antagonist is a compound of structural formula:
Figure imgf000164_0001
individual diastereomers. enantiomers and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein
A is
1 ) thieno,
2) pyrido, or
3) benzo either unsubstituted or substituted with -NH2, -NHSθ2(Ci-3 alkyl), Cl-3 alkyl or Cl-3 alkoxy;
Xis
1) = 0,
2) = S,
3) = N-NH2,
4) = N-OH or
5) = H2;
Yis
1) = 0,
2) = N-CN or
3) = H2; Z is
1 ) Cl -6 alkylene, either straight or branch chain and either unsubstituted or substituted with phenyl or spiropiperidine,
2) C2-4 alkenylene, either straight or branch chain,
3) -(CH2)m-W-(CH2)n- wherein m and n are independently 0, 1. 2, 3 or 4 and W is -0-. -S- or -NH.
4) 4-(5-methylisoxazole-3-yl).
5) C3-6 cycloalkylene, or
6) single bond;
p is 0 or 1 ;
Rl is
1 ) phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N02, b) -Cl, Br, F, or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl -3 alkoxy. f) -CN, g) -methylenedioxy.
2) C5-7 cycloalkyl.
3)
Figure imgf000165_0001
4) mono- or bicyclic heterocyclyl of 5 to 10 members one or two of which are sulfur, nitrogen or oxygen, the remaining being carbon, such as 2-thienyl, 2-furanyl, 2-indolyl, 2- quinoxolinyl, or 2-(2,3-dihydro benzofuranyl)
5) methyl, or
6) indan-5-yl; R2 is
1 ) phenyl, either unsubstituted or substituted with Cj -3 alkoxy or 4,4-dimethyloxazolin-2-yl,
2) Cj -4 alkyl, either straight or branched chain and either unsubstituted or substituted with Cι _3 alkoxy or
Cl -3 alkoxy-Cl -3 alkoxy.
3) C5-7 cycloalkyl,
4) 2- or 3-furyI,
5) l -methylpiperidin-2-yl, or
6) if R^ 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;
R3 is
1 ) hydrogen or
2) Cl -6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3)2, -OH, -CF3, or
3) -CF3;
R4
1 ) hydrogen,
2) 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
Figure imgf000166_0001
3) tetrazoI-5-yl; and
R5 is hydrogen or oxygen or is joined to R^ to form the partial structure:
Figure imgf000167_0001
and the bond represented by ___: is:
1 ) a double bond when p is zero or when p is 1 and R is oxygen, or
2) a single bond when R^ is hydrogen or R$ is joined to R2 to form the partial structure:
Figure imgf000167_0002
7. The selective Ij^s compound of Claim 6 wherein
A is benzo either unsubstituted or substituted with -NH2, -NHS02(Cl -3 alkyl), Cl -3 alkyl or Cl -3 alkoxy;
X and Y are O,
Z is
1 ) Cl -6 alkylene, either straight or branch chain and either unsubstituted or substituted with phenyl or spiropiperidine,
2) C2-4 alkenylene, either straight or branch chain,
3) -(CH2)m-W-(CH2)n- wherein m and n are independently 0, 1 , 2, 3 or 4 and W is -0-. -S- or -NH,
4) 4-(5-methylisoxazole-3-yl),
5) C3-6 cycloalkylene, or
6) single bond; R1 is
1 ) phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N02, b) -Cl, Br, F, or 1, c) -CF3, d) -Cl -3 alkyl, e) -Cl -3 alkoxy, f) -CN, g) -methylenedioxy.
2) C5-7 cycloalkyl.
3)
Figure imgf000168_0001
4) mono- or bicyclic heterocyclyl of 5 to 10 members one or two of which are sulfur, nitrogen or oxygen, the remaining being carbon, such as 2-thienyl. 2-furanyl. 2-indolyl, 2- quinoxolinyl. or 2-(2.3-dihydro benzofuranyl)
5) methyl, or
6) indan-5-yl;
R2 IS
1 ) phenyl, either unsubstituted or substituted with Cl -3 alkoxy or 4,4-dimethyloxazolin-2-yl,
2) Cl -4 alkyl, either straight or branched chain and either unsubstituted or substituted with Cl -3 alkoxy or
C] -3 alkoxy-Cl -3 alkoxy,
3) C5-7 cycloalkyl,
4) 2- or 3-furyl,
5) l-methylpiperidin-2-yl, or
6) if 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;
R3 i IS<
1 ) hydrogen or
2) Cl-6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3)2, -OH, -CF3, or
3) -CF3;
R4 is
1 ) hydrogen,
2) C l -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
Figure imgf000169_0001
3) tetrazol-5-yl; and
R5 is hydrogen or oxygen or is joined to R 2 to form the partial structure:
Figure imgf000169_0002
and the bond represented by ___: is:
1 ) a double bond when p is zero or when p is 1 and R^ is oxygen, or
2) a single bond when R^ is hydrogen or R5 is joined to R2 to form the partial structure:
Figure imgf000170_0001
including individual diastereomers, enantiomers and mixtures thereof, or a pharmaceutically acceptable salt.
8. The selective Ijςs compound of Claim 7 wherein
A is benzo either unsubstituted or substituted with -NH2, -NHS02(Cl -3 alkyl), Cl -3 alkyl or C] -3 alkoxy;
X and Y are O,
Z is
1 ) Cl -6 alkylane, either straight or branch chain and either unsubstituted or substituted with phenyl or spiropiperidine,
2) C2-4 alkenylene, either straight or branch chain,
3) -(CH2)m-W-(CH2)n- wherein m and n are independently 0, 1 , 2. 3 or 4 and W is -0-. -S- or -NH.
4) 4-(5-methylisoxazole-3-yl),
5) C3-6 cycloalkylene, or
6) single bond;
Rl is phenyl. either unsubstituted or substituted with one or two substituents selected from a) -N02, b) -Cl, Br, F, or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl -3 alkoxy, f) -CN, g ) -methylenedioxy. R2 is phenyl, either unsubstituted or substituted with Cl -3 alkoxy or
4,4-dimethyloxazolin-2-yl, R3 is -CF3 or Cl -6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3)2, -OH, -CF3;
R4 and R5 are hydrogen;
including individual diastereomers, enantiomers and mixtures thereof, or a pharmaceutically acceptable salt.
9. The selective Ij^s compound of Claim 8 wherein A is unsubstituted benzo;
Rl is phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N02, b) -Cl, Br, F. or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl -3 alkoxy, f) -CN, g) -methylenedioxy,
R2 is phenyl, either unsubstituted or substituted with Cl -3 alkoxy or 4,4-dimethyloxazolin-2-yl,
R3 is -CF3 or C l -6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3)2, -OH, -CF3;
R4 and R5 are hydrogen;
including individual diastereomers, enantiomers and mixtures thereof, or a pharmaceutically acceptable salt.
10. The selective I^s compound of Claim 9 which is (-)-2- [2,4-Bis(trifluoromethyl)phenyl]-N-f3R-2,3-dihydro-2-oxo-5-phenyl-l (2,2,2 -trifluoroethyl)-! H-benzofelf l ,41diazepin-3-yllacetamide
Figure imgf000172_0001
1 1. The selective Ijζs compound of Claim 9 which is 3,4-
Dichloro-N-f2,3-dihydro-5-(2-fluorophenyI)-2-oxo-l -(2,2,2-trifluoro- ethyl)- 1 H-benzo[el[ 1 ,41diazepin-3-yllbenzamide
Figure imgf000172_0002
12. The selective Ij^s compound of Claim 9 which is (-)-2-(2,4-Dichlorophenyl)-N-[3R-2,3-dihydro-2-oxo-5-phenyl- l - (2,2,2-trifluoroethyl)-I H-benzo[e]f l ,41diazepin-3-yllacetamide
Figure imgf000173_0001
13. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a beta-adrenergic receptor blocking agent and a selective Ipςs antagonist.
14. The selective Ij«ςs antagonist of Claim 13 which is a compound of structural formula:
^
Figure imgf000173_0002
individual diastereomers, enantiomers and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein
A is
1 ) thieno,
2) pyrido, or
3) benzo either unsubstituted or substituted with -NH2, -NHS02(C l -3 alkyl). Cl -3 alkyl or Cl -3 alkoxy; X is
1) = 0,
2) = s,
3) = N-NH2,
4) = N-OH or
5) = H2:
Y is
1 ) = 0,
2) = N-CN or
3) = H2;
Z is
1 ) Cl -6 alkylene, either straight or branch chain and either unsubstituted or substituted with phenyl or spiropiperidine,
2) C2-4 alkenylene, either straight or branch chain.
3) -(CH2)m-W-(CH2)n- wherein m and n are independently 0, 1 , 2, 3 or 4 and W is -0-, -S- or -NH,
4) 4-(5-methylisoxazole-3-yl),
5) C3-6 cycloalkylene, or
6) simile bond;
p is 0 or 1 ;
Ms
1 ) phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N02, b) -Cl. Br, F. or I,
0 -CF3, d) -Ci -3 alkyl, e) -Cl -3 alkoxy, f) -CN, g) -methylenedioxy, 2) C5-7 cycloalkyl,
3)
Figure imgf000175_0001
4) mono- or bicyclic heterocyclyl of 5 to 10 members one or two of which are sulfur, nitrogen or oxygen, the remaining being carbon, such as 2-thienyl, 2-furanyl, 2-indolyl, 2- quinoxolinyl, or 2-(2,3-dihydro benzofuranyl)
5) methyl, or
6) indan-5-yl;
R2 is
1 ) phenyl, either unsubstituted or substituted with Cl -3 alkoxy or 4,4-dimethyloxazolin-2-yl,
2) C i -4 alkyl, either straight or branched chain and either unsubstituted or substituted with C}-3 alkoxy or
Cl -3 alkoxy-Cl -3 alkoxy,
3) C5.7 cycloalkyl,
4) 2- or 3-furyl,
5) l -methylpiperidin-2-yl, or
6) if 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;
R3 is
1 ) hydrogen or
2) C l -6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3)2, -OH, -CF3, or
3) -CF3;
R4 j is
1 ) hydrogen, 2) 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 alkoxy carbonyl, -OH or
Figure imgf000176_0001
3) tetrazol-5-yl; and
R is hydrogen or oxygen or is joined to R2 to form the partial structure:
Figure imgf000176_0002
the bond represented by zzzz is:
1 ) a double bond when p is zero or when p is 1 and R^ is oxygen, or
2) a single bond when R^ is hydrogen or R^ is joined to R2 to form the partial structure:
Figure imgf000176_0003
15. The selective I^s compound of Claim 14 wherein
A is benzo either unsubstituted or substituted with -NH2, -NHSO2 (Cl -3 alkyl), Cl -3 alkyl or Cl -3 alkoxy;
X and Y are O, Z is
1 ) Cl -6 alkylene, either straight or branch chain and either unsubstituted or substituted with phenyl or spiropiperidine,
2) C2-4 alkenylene. either straight or branch chain,
3) -(CH2)m-W-(CH2)n- wherein m and n are independently 0, 1 , 2, 3 or 4 and W is -0-. -S- or -NH,
4) 4-(5-methylisoxazole-3-yl),
5) C3-6 cycloalkylene, or
6) single bond;
1 ) phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N02, b) -Cl. Br, F. or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl -3 alkoxy, f) -CN, g) -methylenedioxy,
2) C5-7 cycloalkyl.
3 ) J ^
Figure imgf000177_0001
<
4) mono- or bicyclic heterocyclyl of 5 to 10 members one or two of which are sulfur, nitrogen or oxygen, the remaining being carbon, such as 2-thienyl, 2-furanyl, 2-indolyl, 2- quinoxolinyl, or 2-(2,3-dihydro benzofuranyl)
5) methyl, or
6) indan-5-vl; R2 is
1 ) phenyl, either unsubstituted or substituted with Cl -3 alkoxy or 4,4-dimethyloxazolin-2-yl,
2) Cl -4 alkyl, either straight or branched chain and either unsubstituted or substituted with Cl -3 alkoxy or
Cl -3 alkoxy-Ci -3 alkoxy.
3) C5-7 cycloalkyl,
4) 2- or 3-furyl,
5) l -methylpiperidin-2-yl, or
6) if 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;
R3 is
1 ) hydrogen or
2) Cl-6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3)2, -OH, -CF3, or
3) -CF3;
R4 is
1 ) hydrogen,
2) 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 alkoxy carbonyl, -OH or
Figure imgf000178_0001
3) tetrazol-5-yl; and
R^ is hydrogen or oxygen or is joined to R2 to form the partial structure:
Figure imgf000179_0001
and the bond represented by ;___ is:
1 ) a double bond when p is zero or when p is 1 and R^ is oxygen, or
2) a single bond when R$ is hydrogen or R^ is joined to R2 to form the partial structure:
Figure imgf000179_0002
including individual diastereomers, enantiomers and mixtures thereof, or a pharmaceutically acceptable salt.
16. The selective Ij^s compound of Claim 15 wherein A is benzo either unsubstituted or substituted with -NH2, -NHSθ2(Cl -3 alkyl), Cl -3 alkyl or C 1 -3 alkoxy;
X and Y are O,
Z is
1 ) Cl -6 alkylane, either straight or branch chain and either unsubstituted or substituted with phenyl or spiropiperidine,
2) C2-4 alkenylene, either straight or branch chain,
3) -(CH2)m-W-(CH2)n- wherein m and n are independently 0, 1 , 2, 3 or 4 and W is -0-. -S- or -NH,
4) 4-(5-methylisoxazole-3-yl),
5) C3-6 cycloalkylene, or
6) single bond; R 1 is phenyl, either unsubstituted or substituted with one or two substituents selected from a) -Nθ2, b) -Cl, Br, F, or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl -3 alkoxy, f) -CN, g) -methylenedioxy.
R2 is phenyl, either unsubstituted or substituted with Cl -3 alkoxy or 4,4-dimethyloxazolin-2-yl,
R3 is -CF3 or Cl -6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3)2, -OH, -CF3;
R4 and R^ are hydrogen;
including individual diastereomers, enantiomers and mixtures thereof, or a pharmaceutically acceptable salt.
17. The selective I^s compound of Claim 16 wherein A is unsubstituted benzo;
R l is phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N02, b) -Cl, Br, F, or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl -3 alkoxy, f) -CN, g) -methylenedioxy.
R2 is phenyl, either unsubstituted or substituted with Cl -3 alkoxy or 4,4-dimethyloxazolin-2-yl,
R3 is -CF3 or Cl -6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3)2. -OH, -CF3;
R4 and R^ are hydrogen;
including individual diastereomers, enantiomers and mixtures thereof, or a pharmaceutically acceptable salt.
18. The selective I^s compound of Claim 14 which is
(-)-2-[ 2,4-Bis(trifluoromethyl)phenyl]-N-[ 3R-2,3-dihydro-2-oxo-5- phenyl- l -(2,2,2-trifluoroethy I)- lH-benzo[e 11 l ,41diazcpin-3-yI lacetamide
Figure imgf000181_0001
19. The selective Ij^s compound of Claim 14 which is 3,4-Dichloro-N-f 2.3-dihydro-5-(2-fluorophenyI)-2-oxo- 1 -(2,2,2- trifluoroethyl)-l H-benzofe][l ,4]diazepin-3-yllbenzamide
Figure imgf000182_0001
20. The selective Iκs compound of Claim 14 which is (-)-2-(2,4-Dichlorophenyl)-N-f3R-2,3-dihydro-2-oxo-5-phenyl- l - (2,2,2-trifluoroethyl)- 1 H-benzofe] [ 1 ,41diazepin-3-yllacetamide
Figure imgf000182_0002
21. A method of preventing Meniere's disease which comprises the administration to a patient in need of such treatment of an effective amount of a selective l^s antagonist.
22. The method of Claim 21 wherein the selective Ij^s antagonist is a compound of structural formula:
Figure imgf000183_0001
individual diastereomers, enantiomers and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein
A is
1 ) thieno,
2) pyrido, or
3) benzo either unsubstituted or substituted with -NH2, -NHS02(Cι_3 alkyl). Cl-3 alkyl or C 1-3 alkoxy;
Xis
1) = 0,
2) = s,
3) = N-NH2,
4) = N-OH or
5) = H2:
Yis
1) = 0,
2) = N-CN or
3) = H2; Z is
1 ) Cl -6 alkylene, either straight or branch chain and either unsubstituted or substituted with phenyl or spiropiperidine,
2) C2-4 alkenylene, either straight or branch chain,
3) -(CH2)m-W-(CH2)n- wherein m and n are independently 0, 1 , 2, 3 or 4 and W is -0-, -S- or -NH,
4) 4-(5-methylisoxazole-3-yl).
5) C3-6 cycloalkylene, or
6) single bond;
p is 0 or 1 ;
R l is
1 ) phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N02, b) -Cl, Br, F, or I, c) -CF3, d) -Cj -3 alkyl, e) -Cl -3 alkoxy, f) -CN, g) -methylenedioxy.
2) C5-7 c :ycloalkyl,
3)
Figure imgf000184_0001
<
4) mono- or bicyclic heterocyclyl of 5 to 10 members one or two of which are sulfur, nitrogen or ox v gen, the remaining being carbon, such as 2-thienyl, 2-furanyl, 2-indolyl, 2- quinoxolinyl, or 2-(2,3-dihydro benzofuranyl)
5) methyl, or
6) indan-5-yl; R2 is
1 ) phenyl, either unsubstituted or substituted with Cl .3 alkoxy or 4,4-dimethyIoxazolin-2-yl,
2) Cl -4 alkyl, either straight or branched chain and either unsubstituted or substituted with Cl -3 alkoxy or
Cl -3 alkoxy-Ci -3 alkoxy,
3) C5-7 cycloalkyl,
4) 2- or 3-furyl.
5) l -methylpiperidin-2-yl. or
6) if 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;
R3 is
1 ) hydrogen or
2) C l -6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3 »2, -OH, -CF3, or
3) -CF3;
R4 i IS
1 ) hydrogen,
2) C l -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
Figure imgf000185_0001
3) tetrazol-5-yl; and
R5 is hydrogen or oxygen or is joined to R2 to form the partial structure:
Figure imgf000186_0001
and the bond represented by ___: is:
1 ) a double bond when p is zero or when p is 1 and R^ is oxygen, or
2) a single bond when R^ is hydrogen or R5 is joined to R2 to form the partial structure:
Figure imgf000186_0002
23. The selective Ijςs compound of Claim 22 wherein
A is benzo either unsubstituted or substituted with -NH2, -NHSθ2(Cl -3 alkyl), Cl-3 alkyl or Cl -3 alkoxy;
X and Y are O,
Z is
1 ) Cl -6 alkylene, either straight or branch chain and either unsubstituted or substituted with phenyl or spiropiperidine,
2) C2-4 alkenylene, either straight or branch chain,
3) -(CH2)m-W-(CH2)n- wherein m and n are independently 0, 1 , 2, 3 or 4 and W is -0-, -S- or -NH,
4) 4-(5-methylisoxazole-3-yl),
5) C3-6 cycloalkylene, or
6) single bond; Rl is
1 ) phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N02, b) -Cl, Br, F, or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl -3 alkoxy, f) -CN, g) -methylenedioxy,
2) C5-7 cycloalkyl,
3)
Figure imgf000187_0001
4) mono- or bicyclic heterocyclyl of 5 to 10 members one or two of which are sulfur, nitrogen or oxygen, the remaining being carbon, such as 2-thienyl, 2-furanyl, 2-indolyl, 2- quinoxolinyl, or 2-(2,3-dihydro benzofuranyl)
5) methyl, or
6) indan-5-yl;
R2 IS
1 ) phenyl, either unsubstituted or substituted with Cl -3 alkoxy or 4,4-dimethyloxazolin-2-yl,
2) Cl -4 alkyl, either straight or branched chain and either unsubstituted or substituted with Cl -3 alkoxy or
Cl -3 alkoxy-Cl -3 alkoxy,
3) C5-7 cycloalkyl,
4) 2- or 3-furyl,
5) l -methylpiperidin-2-yl, or
6) if 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: R3 is
1 ) hydrogen or
2) Cl -6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3)2, -OH, -CF3, or
3) -CF3;
R4 is
1 ) hydrogen,
2) C l -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
Figure imgf000188_0001
3) tetrazol-5-yl; and
R5 is hydrogen or oxygen or is joined to R2 to form the partial structure:
Figure imgf000188_0002
the bond represented by zzzz is:
1 ) a double bond when p is zero or when p is 1 and R^ is oxygen, or
2) a single bond when R is hydrogen or R^ is joined to R2 to form the partial structure:
Figure imgf000189_0001
including individual diastereomers, enantiomers and mixtures thereof, or a pharmaceutically acceptable salt.
24. The selective Ij,ςs compound of Claim 23 wherein
A is benzo either unsubstituted or substituted with -NH2, -NHS02 (C l -3 alkyl), Cl -3 alkyl or Cl -3 alkoxy;
X and Y are O,
Z is
1 ) Cl -6 alkylane, either straight or branch chain and either unsubstituted or substituted with phenyl or spiropiperidine,
2) C2-4 alkenylene. either straight or branch chain,
3) -(CH2)m-W-(CH2)ιr wherein m and n are independently 0, 1 , 2, 3 or 4 and W is -0-, -S- or -NH,
4) 4-(5-methylisoxazole-3-yl),
5) C3-6 cycloalkylene, or
6) single bond;
Rl is phenyl, either unsubstituted or substituted with one or two substituents selected from a) -NO2. b) -Cl, Br, F, or I, c) -CF3. d) -Cl -3 alkyl, e) -Cl -3 alkoxy, f) -CN. g) -methylenedioxy, R2 is phenyl, either unsubstituted or substituted with Cj -3 alkoxy or 4,4-dimethyloxazolin-2-yl.
R3 is -CF3 or Cl -6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3)2, -OH, -CF3;
R4 and R5 are hydrogen;
including individual diastereomers. enantiomers and mixtures thereof, or a pharmaceutically acceptable salt.
25. The selective iKsCompound of Claim 24 wherein A is unsubstituted benzo;
R l is phenyl, either unsubstituted or substituted with one or two substituents selected from a) -N02, b) -Cl, Br. F, or I, c) -CF3, d) -Cl -3 alkyl, e) -Cl -3 alkoxy, f) -CN, g) -methylenedioxy,
R2 is phenyl, either unsubstituted or substituted with Cl -3 alkoxy or 4,4-dimethyloxazoIin-2-yl,
R3 is -CF3 or Cl -6 alkyl, either straight or branched chain and either unsubstituted or substituted with -N(CH3)2, -OH, -CF3;
R4 and R5 are hydrogen;
including individual diastereomers, enantiomers and mixtures thereof, or a pharmaceutically acceptable salt.
26. The selective Ij,ςs compound of Claim 25 which is (-)-2-[2,4-Bis(trifluoromethyl)phenyll-N-I3R-2,3-dihydro-2-oxo-5- phenyl- 1 -(2,2,2-trifluoroethyl)- 1 H-benzo[e] f 1 ,4]diazepin-3-yllacetamide
Figure imgf000191_0001
27. The selective lj^s compound of Claim 26 which is 3,4-Dichloro-N-[2,3-dihydro-5-(2-fluorophenyl)-2-oxo- 1 -(2,2,2- trifluoroethyl)- 1 H-benzo[e] f 1 ,4]diazepin-3-yl jbenzamide
Figure imgf000191_0002
28. The selective Ij^s compound of Claim 27 which is
(-)-2-(2,4-Dichlorophenyl)-N-[3R-2,3-dihydro-2-oxo-5-phenyl-l - (2,2,2-trifIuoroethyl)- 1 H-benzo[e][ 1 ,4]diazepin-3-yl lacetamide
Figure imgf000192_0001
29. A composition useful in the treatment of Meniere's disease in mammals comprising a pharmaceutical compound and a suitable pharmaceutical carrier wherein the compound provides selective block of the slowly activating delayed rectifier potassium (K+) current (IKs)-
PCT/US1997/010561 1996-06-27 1997-06-23 A method for treating meniere's disease WO1997049690A1 (en)

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US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
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US10350157B2 (en) 2001-05-24 2019-07-16 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US8955512B2 (en) 2001-06-05 2015-02-17 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US9308208B2 (en) 2001-06-05 2016-04-12 Alexza Pharmaceuticals, Inc. Aerosol generating method and device
US9439907B2 (en) 2001-06-05 2016-09-13 Alexza Pharmaceutical, Inc. Method of forming an aerosol for inhalation delivery
US9687487B2 (en) 2001-06-05 2017-06-27 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US11065400B2 (en) 2001-06-05 2021-07-20 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US11642473B2 (en) 2007-03-09 2023-05-09 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
JP2019527724A (en) * 2016-08-15 2019-10-03 ザ・ユニバーシティ・オブ・ダラム Antimicrobial compounds

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