WO1997049690A1 - Procede de traitement de la maladie de meniere - Google Patents

Procede de traitement de la maladie de meniere Download PDF

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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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English (en)
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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/fr

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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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    • C07D243/06—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
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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
    • C07D243/20—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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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
    • C07D243/22—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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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
    • C07D243/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
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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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • 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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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • 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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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • 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

La présente invention concerne un procédé de traitement de la maladie de ménière comprenant l'administration d'un médicament qui module le canal de courant redresseur retardé de potassium (IKS) de l'oreille, réduisant ainsi la production d'endolymphe.
PCT/US1997/010561 1996-06-27 1997-06-23 Procede de traitement de la maladie de meniere WO1997049690A1 (fr)

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GBGB9617895.9A GB9617895D0 (en) 1996-08-28 1996-08-28 A method for treating meniere's disease
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8955512B2 (en) 2001-06-05 2015-02-17 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
JP2019527724A (ja) * 2016-08-15 2019-10-03 ザ・ユニバーシティ・オブ・ダラム 抗微生物化合物
US11642473B2 (en) 2007-03-09 2023-05-09 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5426185A (en) * 1993-11-22 1995-06-20 Merck & Co., Inc. Antiarrhythmic benzodiazepines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5426185A (en) * 1993-11-22 1995-06-20 Merck & Co., Inc. Antiarrhythmic benzodiazepines

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US9440034B2 (en) 2001-05-24 2016-09-13 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
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 (ja) * 2016-08-15 2019-10-03 ザ・ユニバーシティ・オブ・ダラム 抗微生物化合物

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