WO1996007411A1 - Novel antiarrhythmic agents - Google Patents

Novel antiarrhythmic agents Download PDF

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Publication number
WO1996007411A1
WO1996007411A1 PCT/US1995/011348 US9511348W WO9607411A1 WO 1996007411 A1 WO1996007411 A1 WO 1996007411A1 US 9511348 W US9511348 W US 9511348W WO 9607411 A1 WO9607411 A1 WO 9607411A1
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class
cyano
compound
mixture
stirred
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PCT/US1995/011348
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French (fr)
Inventor
Donald E. Slaughter
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Merck & Co., Inc.
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Priority to AU35852/95A priority Critical patent/AU3585295A/en
Publication of WO1996007411A1 publication Critical patent/WO1996007411A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10Spiro-condensed systems

Definitions

  • Arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In a serious case, arrhythmias give rise to a ventricular fibrillation and can cause sudden death.
  • antiarrythmic agents are now available on the market, those, having both satisfactory effects and high safety, have not been obtained.
  • antiarrythmic agents of Class I according to the classification of Vaughan -Williams which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing ventricular fibrillation.
  • Vmax maximum velocity of the upstroke of the action potential
  • they have problems regarding safety, namely, they cause a depression of the myocardial contractility and have a tendency to induce arrythmias due to an inhibition of the impulse conduction.
  • Beta- adrenoceptor Mockers and calcium antagonists which belong to Class II and IV respectively, have a defect that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
  • Antiarrythmic agents of Class III are dnigs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax. Drugs in this class are limited. Examples such as sotalol and amiodarone have been shown to possess Class HI properties. Sotalol also possesses Class II effects which may cause cardiac depression and be contraindicated in certain susceptible patients. Also, amiodarone is severely limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrillations. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents.
  • the invention is also concerned with pharmaceutical formulations comprising one of the novel compounds as an active ingredient.
  • the invention is also concerned with a method of treating arrhythmia by the administration of one of the novel compounds or formulation thereof to a patient in need of such treatment.
  • novel compounds of this invention have structural formula I
  • the pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quarternary ammonium salts of the compounds of Formulae 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, glucolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, aleic, 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.
  • Preferred compound of this invention are the individual diesteriomeric forms of (+)-N-[l'-(6-cyano-4-hydroxy-l ,2,3,4-tetrahydro- 2(R)-naphthaleneyl-3,4-dihydro-4(R)-hydroxyspiro[2H-l -benzopyran- 2,4'-piperidin]-6-yl]methanesulfonamide
  • the metabolite profile, reported above includes among the compounds produced, (+/-)-(4RS, l ",2"-trans)-l'-[r-(6-cyano- 4-hydroxy-l ,2,3-trihydro-2(R)-naphthaleneyl-3,4-dihydro-4(R)-hydroxy- spiro[2H- 1 -benzopyran-2,4'-piperidin]-6-yl]methanesulfonamide (also referred to as M2 in Scheme I and throughout portions of this specification) which may be separated by HPLC.
  • (+/-)-(4RS, l ",2"-trans)-[ l'-(6-cyano-4- hydroxy-l ,2,3-trihydro-2(R)-naphthaleneyl-3,4-dihydro-4(R)-hydroxy- spiro[2H-l-benzopyran-2,4'-piperidin]-6-yllmethanesulfonamide can undergo microsomal metabolism to hydroxylated analogs of M3.
  • novel compounds of the present invention will exhibit the pharmacological properties required for antiarrhythmic agents of Class HI, namely the prolongation of the myocardial action potential in vitro, without a significant depression of the Vmax, and the prolongation of QTc-interval in anesthetized dogs.
  • the compounds of the present invention are especially useful to control reentrant arrhythmias and prevent sudden death due to the ventricular fibrillation. These compounds are also effective in treating and preventing impaired cardiac pump functions.
  • one of the compounds or pharmaceutically acceptable salt thereof is administered in an amount ranging from about 0.0001 to about 20 mg per kg or body weight per day, preferably from about 0.001 to about 1.0 mg per kg of body weight per day and more preferably from about 0.001 to about .1 mg per kg of body weight per day, in a single dose or in 2 to 4 divided doses.
  • These compounds can be administered as the sole active ingredient or in combination with other antiarrhythmic agents or other cardiovascular agents.
  • these compounds may be administered along with class I, II or IV antiarrhythmic agents.
  • These compounds, or pharmaceutically acceptable salts thereof, in the described dosages are administered orally, intraperitoneally, subcutaneously, intramuscularly, transdermally, sublingually or intravenously. They are preferably administered intravenously or orally, for example in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, or the like prepared by art recognized procedures.
  • the amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
  • the activity of the compounds described herein as anti ⁇ arrhythmic agents is measured by their ability to block the DCs and IKr 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 actifier K + current: differential sensitivity to block by Class HI 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 KCl, 5 mM K(2)ATP. Cells are bathed in a solution containing, in mN: 132 NaCl, 4KC1, 1.2 MgCl[2], 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[KI] is measured as peak outward current during the voltage ramp.
  • I[Kr] is measured as tail currents upon repolarization from -10 mV to -50 mV.
  • I[KS] 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 have an IC5O of less then 1000 nM as an IKr blocker.
  • the compounds of Table LVIII were prepared according to the method described in Example 556 by reducing the appropriate ketone with (R)- or (S)-tetrahydro-l-methyl-3,3- diphenyl- lH,3H-pyrrolo-[ 1 ,2,c] [ 1 ,3,2]oxazaborole-borane complex as indicated.
  • Step 2 Preparation of (+)-l ⁇ -dioxa-S- ⁇ '-bromo-l' S' ⁇ '- tetrahydronaphth-2'- yl -8-azaspiro[4.51decane
  • Para- toluenesulfonic acid (0.50 g) and l ,4-dioxa-8-azaspiro[4,5]- decane (81.5 g, 489 mmol) were added and the sti ⁇ ed mixture heated to reflux and the water removed (4.5 hrs).
  • the mixture was cooled, and concentrated to an oil in vacuo.
  • the oil was dissolved in anhydrous tetrahydrofuran (1.5 L) and cooled to 0°C under argon. Dry HC1 gas was introduced (at below 5°C) and a solid precipitate formed.
  • Sodium cyanoborohydride (36.3 g, 578 mmol) was added in four portions. The reaction was allowed to warm gradually to room temperature and stirred 16 hrs.
  • the title compound was prepared by a modification of the procedure described in Organic Syntheses, 61, 35 (1983).
  • Cyanogen bromide (189J g, 1.78 mol) was added and the mixture was stirred for 5 min.
  • Phenol (160.0 g., 1.7 mol) in carbon tetrachloride (535 ml) was added in one portion.
  • THF 600 ml, distilled from Na benzo-phenone
  • Phenyl cyanate (26.06 ml, 28.5 g, 0.24 mol) dissolved in anhydrous THF (400 ml) under nitrogen in a 2 L R.B. flask equipped with a digital_the ⁇ mometer was cooled to -75°C.
  • n-Butyl lithium (1.6M in hexane, 137.5 mL, 0.22 mmol) was added over 5 min. to the bromide solution. Further n-butyl lithium (12.5 mL, 0.02 mmol) was added to the phenyl cyanate solution.
  • Step 4 Resolution of l,4-dioxa-8-(6'- tetrahydronaphth-2'-yl -8-azaspiro[4.51decane
  • Step 5 Preparation of N-(6'-Cyano-l , ,2',3 , ,4'- tetrahvdronaphth-2'-v piperidin-4-one
  • a solution of (+)-l,4-dioxa-8-(6'-cyano-l',2 ⁇ 3',4 , - tetrahydronaphth-2'yl)-8-azaspiro[4.5]-decane (10.0 g, 33.5 mmol) was dissolved in IN HCl (100 mL). This was stirred and heated to 100°C under an argon atmosphere for 1.5 hrs.
  • Step 6 Methanesulfonamide, N-[l'-(6-cyano-l , 2,3,4- tetrahydro-2-naphthalenyl)-3,4- dihydro-4- oxospiro[2H- 1 -benzopyran-2,4'-piperidin]-6-yl]-, monohydrochloride
  • the title compound was generated as a metabolite of (+)-N- [l '-(6-cyano- 1 ,2,3, 4Jrihydro-2(R)-naphthaleneyl-3, 4-dihydro-4(R)- hydroxyspiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]methanesulfon- amide, both radio labeled ( ⁇ H labeled) and unlabled, by incubation in a broth which comprises non-induced rat liver microsomes.
  • the broth was composed of 2 mg microsomal protein/mL; in the presence of a solution containing 10 mM glucose-6-phosphate; 1 mM NADP; 2 I.U.
  • glucose- 6-phosphate dehydrogenase/mL used as the NADPH generating system; 0.1 M potassium phosphate buffer, pH 7.4; and 3 mM MgCl2-
  • the incubation conditions were 1 hr incubation at 37°C. Protein was precipitated from incubations by the addition of 0.3 volumes of 15% acetic acid.
  • the title compound was purified first by passage through aromatic sulfonic acid solid phase extraction column which had been pre-washed with 75% acetonitrile and water, followed by 0.1% trifluroracetic acid and water. After sample loading, the column was washed sequentially with 0.5M NaCl and water. The starting material and metabolites were eluted with 75% aqueous acetonitrile containing 0.1 % trifluroacetic acid.
  • the collected fractions were dried under vacuum, redissolved in 0.1 % trifluroracetic acid and purified by HPLC on a Thomson Spherisorb )DS-2 column, using a linear gradient mobile phase of acetonitrile/ 0.1 % aqueous trifluroracetic acid as follows: 0- 35% acetonitrile in 8 minutes, 35-45% acetonitrile in 1 minutes, stepped to 90% acetonitrile and held 5 minutes. Eluate was monitored by radioflow and or UV detection. Metabolite peaks were hand collected and dried under vacuum. Following repurification using the same chromatographic conditions, the compound was dried under vacuum and stored at -20°C.
  • sample aliquot was dissolved in 50% acetonitrile containing 0.1 % aqueous trifluroracetic acid and passed into a Sciex API HI mass spectrometer without chromatography through a heated nebulier ionization inlet.
  • the apparent molecular ion (m/z 484) was elucidated by Ql scanning with mass spectra derived from m/z 484 daughter ion scans.

Abstract

This invention is concerned with novel compounds represented by structural formulae (I) or a pharmaceutically acceptable salt, hydrate or crystal form thereof, which are useful as antiarrhythmic agents.

Description

TITLE OF THE INVENTION
NOVEL ANTIARRHYTHMIC AGENTS
BACKGROUND OF THE INVENTION
Arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In a serious case, arrhythmias give rise to a ventricular fibrillation and can cause sudden death.
Though various antiarrythmic agents are now available on the market, those, having both satisfactory effects and high safety, have not been obtained. For example, antiarrythmic agents of Class I according to the classification of Vaughan -Williams which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of the myocardial contractility and have a tendency to induce arrythmias due to an inhibition of the impulse conduction. Beta- adrenoceptor Mockers and calcium antagonists which belong to Class II and IV respectively, have a defect that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
Antiarrythmic agents of Class III are dnigs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax. Drugs in this class are limited. Examples such as sotalol and amiodarone have been shown to possess Class HI properties. Sotalol also possesses Class II effects which may cause cardiac depression and be contraindicated in certain susceptible patients. Also, amiodarone is severely limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrillations. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents.
SUMMARY OF THE INVENTION
This invention is concerned with novel compounds represented by structural formula I
Figure imgf000004_0001
or a pharmaceutically acceptable salt , hydrate or crystal form thereof, which are useful as antiarrhythmic agents. The invention is also concerned with pharmaceutical formulations comprising one of the novel compounds as an active ingredient. The invention is also concerned with a method of treating arrhythmia by the administration of one of the novel compounds or formulation thereof to a patient in need of such treatment.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of this invention have structural formula I
Figure imgf000004_0002
OH or a pharmaceutically acceptable salt, hydrate or crystal form thereof.
The pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quarternary ammonium salts of the compounds of Formulae 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, glucolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, aleic, 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.
Preferred compound of this invention are the individual diesteriomeric forms of (+)-N-[l'-(6-cyano-4-hydroxy-l ,2,3,4-tetrahydro- 2(R)-naphthaleneyl-3,4-dihydro-4(R)-hydroxyspiro[2H-l -benzopyran- 2,4'-piperidin]-6-yl]methanesulfonamide
Figure imgf000005_0001
and
Figure imgf000006_0001
The preparation of compounds of this invention is represented schematically in Scheme I.
SCHEME I
Figure imgf000007_0001
The synthesis outlined in Scheme I are further defined as follows: (+)-N-[l'-(6-cyano-l,2,3,zl tetrahydro-2(R)-naphthaleneyl- 3,4-dihydro-4(R)-hydroxyspiro[2H- ' -benzopyran-2,4'-piperidin]-6- yljmethanesulfonamide is treated with liver microsomes. Studies have shown that mouse, rat, dog or human liver microsomes all produce the desired metabolite. The metabolite profile, reported above includes among the compounds produced, (+/-)-(4RS, l ",2"-trans)-l'-[r-(6-cyano- 4-hydroxy-l ,2,3-trihydro-2(R)-naphthaleneyl-3,4-dihydro-4(R)-hydroxy- spiro[2H- 1 -benzopyran-2,4'-piperidin]-6-yl]methanesulfonamide (also referred to as M2 in Scheme I and throughout portions of this specification) which may be separated by HPLC.
The most abundant metabolites in rat and mouse are M3 and Ml , respectively, while M2, M3 and M4 are created at about the same level when microsomes from dog and human are used. A comparison of rat microsomal and biliary metabolite data suggests that glutathione mediated events represent the major metabolism of (+)-N-[l'-(6-cyano- l ,2,3,4-tetrahydro-2(R)-naphthaleneyl-3,4-dihydro-4(R)-hydroxyspiro [2H-l-benzopyran-2,4'-piperidin]-6-yl]methanesulfonamide. Purified M4 and to a lesser extent, (+/-)-(4RS, l ",2"-trans)-[ l'-(6-cyano-4- hydroxy-l ,2,3-trihydro-2(R)-naphthaleneyl-3,4-dihydro-4(R)-hydroxy- spiro[2H-l-benzopyran-2,4'-piperidin]-6-yllmethanesulfonamide can undergo microsomal metabolism to hydroxylated analogs of M3. Additionally, when rats are fed (+)-N-[ l'-(6-cyano- 1 ,2,3 ,4-tetrahydro- 2(R)-naphthaleneyl-3,4-dihydro-4(R)-hydroxyspiro[2H-l-benzopyran- 2,4'-piperidin]-6-yl]methanesulfonamide, the metabolite (+)-N-[l'-(6- cyano-4-hydroxy-l,2,3-trihydro-2(R)-naphthaleneyl-3,4-dihydro-4(R)- hydroxyspiro[2H-l-benzopyran-2,4'-piperidinl-6-yl]methanesulfonamide is clearly more abundant than the Ml , M3 or M4 metabolites found in the bile.
The novel compounds of the present invention will exhibit the pharmacological properties required for antiarrhythmic agents of Class HI, namely the prolongation of the myocardial action potential in vitro, without a significant depression of the Vmax, and the prolongation of QTc-interval in anesthetized dogs.
These compounds are effective in treating and preventing all types of arrhythmias including ventricular and atrial (supraventricular) arrhythmias. The compounds of the present invention are especially useful to control reentrant arrhythmias and prevent sudden death due to the ventricular fibrillation. These compounds are also effective in treating and preventing impaired cardiac pump functions.
In the novel method of this invention of treating arrhythmia, one of the compounds or pharmaceutically acceptable salt thereof, is administered in an amount ranging from about 0.0001 to about 20 mg per kg or body weight per day, preferably from about 0.001 to about 1.0 mg per kg of body weight per day and more preferably from about 0.001 to about .1 mg per kg of body weight per day, in a single dose or in 2 to 4 divided doses.
These compounds can be administered as the sole active ingredient or in combination with other antiarrhythmic agents or other cardiovascular agents. For example, these compounds may be administered along with class I, II or IV antiarrhythmic agents.
These compounds, or pharmaceutically acceptable salts thereof, in the described dosages, are administered orally, intraperitoneally, subcutaneously, intramuscularly, transdermally, sublingually or intravenously. They are preferably administered intravenously or orally, for example in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, or the like prepared by art recognized procedures. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
The activity of the compounds described herein as anti¬ arrhythmic agents is measured by their ability to block the DCs and IKr 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 actifier K+ current: differential sensitivity to block by Class HI 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 KCl, 5 mM K(2)ATP. Cells are bathed in a solution containing, in mN: 132 NaCl, 4KC1, 1.2 MgCl[2], 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). I[KI] is measured as peak outward current during the voltage ramp. I[Kr] is measured as tail currents upon repolarization from -10 mV to -50 mV. I[KS] 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 have an IC5O of less then 1000 nM as an IKr blocker.
EXAMPLE I
(+)-N-f 1 '-(6-cyano-l .2.3.4-tetrahvdro-2(R)-naphthaleneyl-
3.4-dihvdro-4fRVhvdroxyspiror2H- 1 -benzopyran-2.4'- piperidinl-6-yllmethanesulfonamide
The title material can be synthesized using the procedure described in United States Patent 5,206,240, which issued to Baldwin et al. on April 27, 1993, which is hereby incorporated by reference. This synthesis is reproduced herein for convenience. (+)-N-[ 1 '-(6-Cyano-l ,2,3,4-tetrahydro-2-napthalenyl)-
3,4-dihydro-4-hydroxyspiro[2H-l-benzopyran-2,4'- piperidin]yl]methanesulfonamide hydrochloride was prepared as follows, (+)-N-[ 1 '-(6-Cyano-l ,2,3,4-tetrahydro-2-napthalenyl)-
3,4-dihydro-4-oxospiro[2H- 1 -benzopyran-2,4'- piperidin]yl]methanesulfonamide (581 mg, 1.25 mmol) was dissolved with warming in methylene chloride (20 ml) and cooled to -20°C. A solution of (S)-tetrahydro-l-methyl-3,3- diphenyl- 1 H,3H-pyrrolo[ 1 ,2,c][ 1 ,3,2]oxazaborole-borane complex (400 mg, 1.38 mmol) in methylene chloride (4 ml) was added dropwise and the mixture was stirred under argon at -20 to -15°C for 1 h, then at ambient temperature for 30 min. Methanol (20 ml) was added, followed after 10 min. by HC1-
H2O (1M, 10 ml). The mixture was stirred for 1 h., diluted with aqueous sodium hydrogen carbonate (Saturated, 20 ml) and extracted with methylene chloride (3 x 20 ml). The combined organic fractions were dried (Na2S04) and.evaporated under reduced pressure to give a white foam (981 mg). This was dissolved in methylene chloride (25 ml) and cooled in ice. Four portions of acetic anhydride (132 ml, 142 mg, 1.4 mmol) were added at hourly intervals. After 4 h. at 0 °C, the mixture was stiπed at ambient temperature for a further 20 h. Methanol (10 ml) and aqueous sodium hydrogen carbonate (Saturated, 10 ml) were added and the mixture was stirred vigorously for 1 h. Aqueous sodium hydrogen carbonate (Saturated, 20 ml) was added and the mixture was extracted with methylene chloride (3 x 20 ml). The combined organic fractions were dried (Na2Sθ4) and evaporated under reduced pressure to give a white foam (1.05 g). The residue was purified by flash column chroma- tography on silica gel, eluting with CH2Cl2/MeOH/NH3-H20 (94:6:0.6 increasing to 90:10:1), re-chromatographing impure fractions. Pure fractions were evaporated under reduced pressure, redissolved in CH2CI2 (20 ml), filtered through anhydrous Na2Sθ4 and evaporated under reduced pressure to give a white foam (369 mg, 63%). The residue was dissolved in ethanol (4 ml) and HCl-EtOH (6M, 0.5 ml) was added dropwise with stirring. The mixture was stirred at ambient temperature for 1 h., then refrigerated over night. The solid was collected by filtration under argon, then dried in vacuo at ambient temperature for 48 h. and at 35 °C for 24 h to give the hydrochloride as a white solid (321 mg), m.p. 211-213°C,
Figure imgf000011_0001
+30.5° (c = 0.102, MeOH). HPLC analysis [Ultron ES OVM column; 0.3% n- propanol/ammonium foramate-water (12 g/1)] showed this to be the faster eluting diastereoisomer. Elementary analysis Calc'd for C25H30CIN3O4S:
C 59.57; H 6.00; N 8.34%. Found: C 59.45; H 5.76; N 8.40%.
The compounds of Table LVIII were prepared according to the method described in Example 556 by reducing the appropriate ketone with (R)- or (S)-tetrahydro-l-methyl-3,3- diphenyl- lH,3H-pyrrolo-[ 1 ,2,c] [ 1 ,3,2]oxazaborole-borane complex as indicated.
The preparation of N-[l'-(6-cyano- 1,2,3, 4-tetrahydro-2- naphthalenyl)-3,4-dihydro-4-oxospiro-[2H-l-benzopyran-2,4'- piperidin]-6-yl]methanesulfonamide, its monohydrochloride and separation into its enantiomers was accomplished as follows:
Step 1: Preparation of 6-Bromo-2-tetralone
A single neck 3 liter round bottom flask under an Ar atmosphere was charged with 4-bromo-phenyl acetic acid (250.0 g± 1.15 m), methylene chloride (1.5 L), and dimethylformamide (0.5 mL). This magnetically stirred solution was cooled to 0°C and treated dropwise with oxalyl chloride (156 mL, 1.74 m). The reaction was allowed to reach room temperature and stirred 16 hrs. The reaction was concentrated on a rotary evaporator to approximately 1 L of volume. A separate dry 5 liter 3 neck round bottom flask under Ar, fitted with gas inlet tube, overhead stiπer, and digital thermometer was charged with methylene chloride (1.5 L) and AICI3 (312.0 g, 2.34 m). This suspension was cooled to 0°C and stirred while the above solution of acid chloride was added to it slowly via cannula. When the addition was complete, ethylene gas was introduced for 1 -2 hrs to the vigorously stirred suspension while maintaining the internal temperature at 15°C. Upon completion by HPLC, the reaction was warmed to room temperature and stirred for 0.5 hrs. The mixture was recooled to 0°C and cautiously quenched slowly with water (1.5L). The layers were separated, and the aqueous one washed with 500 mL of methylene chloride. The organic portion was washed with 2N aqueous HC1 (2 X 800 mL), brine (400 mL), and saturated aqueous NaHCθ3 (2 X 800 mL). Each aqueous extract was washed with the same 500 mL methylene chloride extract from above. The methylene chloride extracts were combined, dried (Na2Sθ4), filtered, and concentrated to approximately 500 mL of volume. This was then added to 5.0 L of hexane warmed to 50°C. The methylene chloride was distilled off and the hot solution decanted from an insoluble brown tar. The solution was allowed to cool to 25°C and placed in the freezer overnight. The precipitate was collected and washed with hexane (200 mL), and dried in vacuo to give 229.0 g of the compound as a pale yellow solid (88%).
Step 2: Preparation of (+)-l ^-dioxa-S- ό'-bromo-l' S'^'- tetrahydronaphth-2'- yl -8-azaspiro[4.51decane A 3 L round bottom flask fitted with an argon inlet, and Deak-Stark apparatus was charged with a solution of 6- bromo-2-tetralone (100.0 g, 445 mmol) in toluene (2.0 L). Para- toluenesulfonic acid (0.50 g) and l ,4-dioxa-8-azaspiro[4,5]- decane (81.5 g, 489 mmol) were added and the stiπed mixture heated to reflux and the water removed (4.5 hrs). The mixture was cooled, and concentrated to an oil in vacuo. The oil was dissolved in anhydrous tetrahydrofuran (1.5 L) and cooled to 0°C under argon. Dry HC1 gas was introduced (at below 5°C) and a solid precipitate formed. Sodium cyanoborohydride (36.3 g, 578 mmol) was added in four portions. The reaction was allowed to warm gradually to room temperature and stirred 16 hrs. This was quenched with I N aqueous sodium hydroxide (500 mL) and stirred for 0.5 hr (pH=13.5). The mixture was concentrated on a rotary evaporator to remove THF, and diluted with IN NaOH (1.1 L) and diethyl ether (1.5 L). This mixture was stirred 15 min and the layers were separated and the aqueous layer was washed with diethyl ether (2 X 200 mL). The organic layers were combined, washed with water (2 X 500 mL) and saturated aqueous NaCl (2 X 250 mL) and then with IN HC1 (1 X 1.0 L, 2 X 500 mL). The acid extracts were combined, stirred with methylene chloride (1.0L), and basified with 40% aq. NaOH (pH=10). The layers were separated, and the aqueous extracted with methylene chloride (500 mL). The methylene chloride extracts were combined, dried (Na2Sθ4), and concentrated to an oil. The oil was flushed with toluene (2 X 400 mL) and dried in vacuo to give the title compound as a solid on standing (128.8 g, 87%) which was greater than 98% pure by HPLC and used in the next step without purification. Note: The amount of of excess HCl gas present (pH=3-4, THF suspension on wet pH paper) critically determines the yield free amine. Additional HCl may be added during the introduction of the cyano borohydride. In runs in which the pH was not adjusted properly the yield was reduced to 50%; the balance being a borane complex which was isolated from the ether layers. This borane complex could be quantitatively converted to the free amino by heating in 40% aq NaOH/ethylene glycol (l :l) at lOO°C.
Step 3(a): Preparation of Phenyl Cyanate
The title compound was prepared by a modification of the procedure described in Organic Syntheses, 61, 35 (1983). A 3-necked, 2 L R.B. flask, equipped with a 500 ml pressure equalized dropping funnel, a mechanical stirrer and a thermometer, was charged with water and coled in an ice-salt bath. Cyanogen bromide (189J g, 1.78 mol) was added and the mixture was stirred for 5 min. Phenol (160.0 g., 1.7 mol) in carbon tetrachloride (535 ml) was added in one portion. The mixture was stirred vigorously while triethylamine (236.9 ml, 172.0 g, 1.7 mol) was added dropwise at a rate such that the reaction temperature did not exceed 5°C (total addition time = 45 min.). The mixture was stirred for a further 15 min. then transferred to a 2 L separator^ funnel. The organic layer was separated and the aqueous layer was extracted with carbon tetrachloride (2 X 90 ml). The combined organic layers were washed with water (3 X 90 ml) then dried by stirring with phosphorus pentoxide (10 g) for 15 min. The mixture was filtered and the solvent was evaporated under reduced pressure (water aspirator) at 20°C to give a yellow oil. Polyphosphate ester (Y. Kanaoka, et al., Chem. Phar . Bull., 13, 1065-1072
(1965)) (0.2 ml) was added and the mixture was distilled under reduced pressure through a 15 cm vigreux column to give phenyl cyanate (165.8 g, 82%) as a colorless oil, b.p. 79-82°C
(16 mmHg)l . The product was stored under nitrogen at -10°C
(freezes).
1H NMR (300 MHz, CDCI 3) d: 7.49-7.30 (5H, m).
Step 3 (b): Preparation of(+)- 1 ,4-Dioxa-8-(6'- cyano- 1 ',2,,3',4'- tetrahydronapath-2yl)-8-azaspiror4.51decane (+)-! ,4-Dioxa-8-(6'-bromo-l ',2',3',4-tetrahydronaphth- 2-yl)-8-azaspiro[4.5]decane (70.4 g, 0.2 mol) under nitrogen in a 1 L R.B. flask was dissolved in anhydrous THF (600 ml, distilled from Na benzo-phenone) and cooled to -75°C. Phenyl cyanate (26.06 ml, 28.5 g, 0.24 mol) dissolved in anhydrous THF (400 ml) under nitrogen in a 2 L R.B. flask equipped with a digital_theιmometer was cooled to -75°C. n-Butyl lithium (1.6M in hexane, 137.5 mL, 0.22 mmol) was added over 5 min. to the bromide solution. Further n-butyl lithium (12.5 mL, 0.02 mmol) was added to the phenyl cyanate solution. After 5 min., the lithiated bromide solution was added over 5 min., via cannual, to the phenyl cyanate solution (reaction temperature rises to -35°C). The mixture was stirred and cooled to -75°C for 30 min. then the cooling bath was removed and HCI-H2O (IM, 200 mL) was added with vigorous stirring. The mixture was warmed to room temperature, diluted with HCI-H2O (IM, 1800 mL) and washed with ether (2 X 1000 mL.). Methylene chloride (1000 mL) was added and the mixture was stirred and cooled in ice during the addition of aqueous sodium hydroxide 10 M, 180 mL). The layers were separated, and the aqueous layer was extracted withjnethylene chloride (500 mL). The combined organic layers were dried (Na2S04), and the solvent was evaporated under reduced pressure to give crude (+) 1 ,4-dioxa- 8-(6,-cyano-l',2,,3',4'Jetrahydro-naphth-2'yl)-8-azaspiro[4.5] decane as a tan solid (56.2g). Crude (+)l ,4-dioxa-8-(6'-cyano- 1 ,,2',3',4,-tetrahydronaphth-2'yl)-8-azaspiro-[4.5]-decane in three batches (56.4 g, 56.2 g, 27.7 g; total 140.3g) were separately dissolved in refluxing methyl-cyclo-hexane (1000 mL each) and combined by decanting into a 5 L, 4-necked flask equipped with a mechanical stiπer, thermometer, reflux condenser and a stopper. The mixture was heated to reflux (clear solution formed), then allowed to cool with stirring to room temperature, then to 5°C. The mixture was stored at -15°C for 15 hr. The solid was collected by filtration, washed with cold methylcyclo- hexane (2 X 150 ml) and dried in vacuo at room temperature to give the spirodecane as a pale yellow solid (121.3 g), .m.p. 136- 138°C. Purity = 99.3%
Step 4: Resolution of l,4-dioxa-8-(6'-
Figure imgf000016_0001
tetrahydronaphth-2'-yl -8-azaspiro[4.51decane A 12 L round bottom flask fitted with a reflux condenser, digital thermometer, and overhead stirrer was charged with absolute ethanol (10.6 L) and 1 ,4-dioxa-8-(6'- cyano-r,2',3',4'-tetrahy-dronaphth-2'yl)-8-azaspiro[4.5]decane 120.0 g, 402 mmol). The mixture was warmed to 65°C to give a clear solution, and 97% di-p-toluoyl-L-tartaric acid monohydrate (167.7 g, 402 mmol) was added. The resulting clear solution was seeded with this salt and allowed to cool to room tempera¬ ture with stirring overnight. The precipitate was collected by filtration and washed with absolute ethanol (600 mL). The solid was dried in vacuo to a solid and converted to free base in a stirred mixture of ethyl acetate (2.0 L) and saturated aqueous NaHCO3(3.0L). The layers were separated, and the aqueous one washed with ethyl acetate (2 X 500 mL). The organic layers were combined, washed with brine (2 X 200 mL), dried (Na2S04), and concentrated to 69.4 g of a solid (59% yield). The solid free base (69.4 g, 233 mmol) was dissolved in absolute ethanol (4.25 L) at 60°C and 97% di-p-toluoyl-D-tartaric acid (92.64 g, 233 mmol) was added. The resulting clear solution was seeded with a sample of this salt and allowed to cool to room temperature overnight. The precipitate which formed was collected, washed with absolute ethanol (800 mL), and dried in vacuo at 40°C to give 122.5 g (44.5%). This + D salt was completely dissolved in absolute ethanol (8.0L) at reflux and concentrated to approximately 7.0 L of volume by distillation at 1 atmosphere. The solution was seeded and cooled to room temperature overnight. The solid was collected, washed with absolute ethanol (800 mL) dried in vacuo to give 100.9 g [a]D=+104.7° (c= 1.0 pyridine)) (36.7%). This salt was dissolved in hot absolute ethanol (8.3L), concentrate. J 1 atmosphere to 3.1 L of total volume, seeded and cooled to room temperature overnight. This solid was collected, washed with absolute ethanol (900 mL)_and dried in vacuo to give 89.7 g [a]D=105.4° (c=1.0 pyridine)) (32.6%). A further crystallization from 7.0 L hot ethanol concentrated to 2.9 L volume gave 74.3 g ([aJD=+105.4° (c=1.0 pyridine)) (32.6%). A further recrystallization from 7.0 L hot ethanol concentrated to 2.9 L volume gave 74.3 g [a]o= 104.9° (c=1.0 pyridine)) (27% yield). The free base was obtained by treating a stirred mixture of saturated aq. NaHCθ3 (250 mL) and methylene chloride (250 mL) with 1 ,4-dioxa-8-(6'-cyano ,2',3',4'-tetrahydronaphth- 2'yl)-8-azaspiro]4.5]decane di-p-toluoyl-D-tartaric acid salt (10.0 g, 33.5 mmol). After 15 min the layers were separated, the aqueous washed with methylene chloride (100 mL), and the combined organics washed with saturated aq. NaHC03 (100 mL), dried Na2Sθ4) and concentrated to give 4.30 g (99%) of a solid. A sample of free base was analyzed by chiral shift reagent proton NMR to be 99.8% pure (+) enantiomer.
Step 5: Preparation of N-(6'-Cyano-l ,,2',3,,4'- tetrahvdronaphth-2'-v piperidin-4-one A solution of (+)-l,4-dioxa-8-(6'-cyano-l',2\3',4,- tetrahydronaphth-2'yl)-8-azaspiro[4.5]-decane (10.0 g, 33.5 mmol) was dissolved in IN HCl (100 mL). This was stirred and heated to 100°C under an argon atmosphere for 1.5 hrs. the solution was cooled in an ice bath to 25°C and methylene chloride added (200 mL). The mixture was stiπed and basified to pH=9.0 with saturated aqueous sodium carbonate. The organic layer was separated and the aqueous extracted with methylene chloride(2X 50 mL). The combined organic extract was dried (Na2Sθ4), and concentrated to a foam to give 7.5g(99%) of N-(6'-cyano-l,,2',3,,4,Jetrahydronaphth-2,-yl)- piperdin-4-one (98% by HPLC).
Step 6: Methanesulfonamide, N-[l'-(6-cyano-l , 2,3,4- tetrahydro-2-naphthalenyl)-3,4- dihydro-4- oxospiro[2H- 1 -benzopyran-2,4'-piperidin]-6-yl]-, monohydrochloride
A solution of 2-hydroxy-5-methanesulfonamido- acetophenone (26.98 g, 117.7 mmol), and pyrrolidine (9.8 mL, 1 17.7 mmol) in methanol (480 mL) was stirred at 25 °C for 10 min. (+)-N-(6-Cyano-l,2,3,,4,- tetrahydronaphth-2'-yl)- piperidin-4-one (20.0 g, 78.4 mmol) was added in one portion and the mixture stirred for 24 hrs at 25 °C. The reaction was concentrated to an oil in vacuo and flash chromato-graphed (silica gel, ethyl acetate) to afford the product in appropriate fractions which were combined and concentrated to a foam. This was crystallized from isopropyl alcohol (525 mL) to give a solid which was collected by filtration, washed with IPA (50 mL) and dried in vacuo (30.8 g). This was dissolved in ethyl acetate (1.5L) and treated with 1.3N HCl in IPA (55 mL). The precipitate was stirred 20 hrs, filtered and dried in vacuo (60°C, 0J ton) to give 32.3 g (84%) of (+) Methanesulfonamide, N-[l'- (6-cyano-l ,2,3,4-tetrahydro-2-naphthalenyl) -3,4-dihydro-4- oxospiro[2H-l-benzopyran-2,4'-piperidinl-6-yl]-,_[ ]£) = +40.7 (c=0J7, MeOH).
EXAMPLE fl
(+)-N-π '-(,6-cvano-4-hvdroxy-1.2.3.4-tetrahvdro-2(R)-naphthaleneyl-3.4- dihydro-4(R -hydroxyspiror2H- 1 -benzopyran-2.4'-piperidin1-6- yllmethanesulfonamide
The title compound was generated as a metabolite of (+)-N- [l '-(6-cyano- 1 ,2,3, 4Jrihydro-2(R)-naphthaleneyl-3, 4-dihydro-4(R)- hydroxyspiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]methanesulfon- amide, both radio labeled (^H labeled) and unlabled, by incubation in a broth which comprises non-induced rat liver microsomes. The broth was composed of 2 mg microsomal protein/mL; in the presence of a solution containing 10 mM glucose-6-phosphate; 1 mM NADP; 2 I.U. glucose- 6-phosphate dehydrogenase/mL used as the NADPH generating system; 0.1 M potassium phosphate buffer, pH 7.4; and 3 mM MgCl2- The incubation conditions were 1 hr incubation at 37°C. Protein was precipitated from incubations by the addition of 0.3 volumes of 15% acetic acid.
The title compound was purified first by passage through aromatic sulfonic acid solid phase extraction column which had been pre-washed with 75% acetonitrile and water, followed by 0.1% trifluroracetic acid and water. After sample loading, the column was washed sequentially with 0.5M NaCl and water. The starting material and metabolites were eluted with 75% aqueous acetonitrile containing 0.1 % trifluroacetic acid. The collected fractions were dried under vacuum, redissolved in 0.1 % trifluroracetic acid and purified by HPLC on a Thomson Spherisorb )DS-2 column, using a linear gradient mobile phase of acetonitrile/ 0.1 % aqueous trifluroracetic acid as follows: 0- 35% acetonitrile in 8 minutes, 35-45% acetonitrile in 1 minutes, stepped to 90% acetonitrile and held 5 minutes. Eluate was monitored by radioflow and or UV detection. Metabolite peaks were hand collected and dried under vacuum. Following repurification using the same chromatographic conditions, the compound was dried under vacuum and stored at -20°C.
For mass spectral analysis, sample aliquot was dissolved in 50% acetonitrile containing 0.1 % aqueous trifluroracetic acid and passed into a Sciex API HI mass spectrometer without chromatography through a heated nebulier ionization inlet. The apparent molecular ion (m/z 484) was elucidated by Ql scanning with mass spectra derived from m/z 484 daughter ion scans.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula I
Figure imgf000021_0001
I
(+)-N-[l '-(6-cyano-4-hydroxy-l ,2,3,4-tetrahydro-2(R)-naphthaleneyl- 3,4-dihydro-4(R)-hydroxyspiro[2H- 1 -benzopyran-2,4'-piperidin]-6- yljmethanesulfonamide, or a pharmaceutically acceptable salt , hydrate or crystal form thereof.
2. A compound of formula 1 selected from the group consisting of
and
Figure imgf000021_0002
OH
3. A pharmaceutical formulation comprising a carrier and a therapeutically effective amount of a compound of Claim 1.
4. The pharmaceutical formulation of Claim 3, comprising, in addition, a pharmaceutically effective amount of one or more of a Class I, Class II or Class IV antiarrhythmic agent.
5. A method of preparing the compound of Claim 1 comprising the step of incubating (+)-N-[ l '-(6-cyano-l,2,3,4-tetrahydro- 2(R)-naphthaleneyl-3,4-dihydro-4(R)-hydroxyspiro[2H-l-benzopyran- 2,4'-piperidin]-6-yl]methanesulfonamide with liver microsomes.
6. The method of Claim 5 wherein the liver microsomes are selected from the liver microsomes of mouse, rat, dog or human.
7. A method of treating arrhythmia or impaired cardiac pump function in a patient in need of such treatment which comprises administering to such patient a therapeutically effective amount of the compound of Claim 1.
8. The method of Claim 7, comprising, the administration of one or more of a class I, class II or Class IV antiarrhythmic agent in addition to a compound of Claim I.
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Citations (3)

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Publication number Priority date Publication date Assignee Title
US4173654A (en) * 1977-01-03 1979-11-06 California Institute Of Technology Novel fluorohydrocarbons
US5206240A (en) * 1989-12-08 1993-04-27 Merck & Co., Inc. Nitrogen-containing spirocycles
US5413915A (en) * 1988-07-12 1995-05-09 Resource Technologies Group, Inc. Method and sensor for detecting toxic chemical exposure effects and metabolic activation of carcinogenic chemical agents

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US4173654A (en) * 1977-01-03 1979-11-06 California Institute Of Technology Novel fluorohydrocarbons
US5413915A (en) * 1988-07-12 1995-05-09 Resource Technologies Group, Inc. Method and sensor for detecting toxic chemical exposure effects and metabolic activation of carcinogenic chemical agents
US5206240A (en) * 1989-12-08 1993-04-27 Merck & Co., Inc. Nitrogen-containing spirocycles

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Title
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Volume 35, issued April 1993, T. EBNER et al., "The Metabolism of Aprindine in Relation to the Sparteine/Debrisoquine Polymorphism", pages 426-430. *

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