WO1999020281A1 - Nouveaux derives de benzodiazepine s'utilisant comme agents anti-arythmisants - Google Patents

Nouveaux derives de benzodiazepine s'utilisant comme agents anti-arythmisants Download PDF

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Publication number
WO1999020281A1
WO1999020281A1 PCT/US1998/021597 US9821597W WO9920281A1 WO 1999020281 A1 WO1999020281 A1 WO 1999020281A1 US 9821597 W US9821597 W US 9821597W WO 9920281 A1 WO9920281 A1 WO 9920281A1
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WIPO (PCT)
Prior art keywords
compounds
phenyl
compound
pharmaceutically acceptable
hydrogen
Prior art date
Application number
PCT/US1998/021597
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English (en)
Inventor
Nigel J. Liverton
John W. Butcher
David A. Claremon
Harold G. Selnick
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9806686.3A external-priority patent/GB9806686D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP2000516678A priority Critical patent/JP2001520197A/ja
Priority to CA002306960A priority patent/CA2306960A1/fr
Priority to EP98953453A priority patent/EP1024811A4/fr
Priority to AU10827/99A priority patent/AU1082799A/en
Publication of WO1999020281A1 publication Critical patent/WO1999020281A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms

Definitions

  • Class I antiarrhythmic agents are those agents which provide for sodium channel blockade, including those compounds which exert a membrane stabilizing effect. Exemplary of this class of compounds are quinidine, procainamide, disopyramide, lidocane, tocainide, flecainide and propafenone.
  • Class II antiarrhythmic compounds are agents which block sympathetic activity. Exemplary of this class of compounds are propranolol and acebutolol.
  • Class III antiarrhythmic agents are compounds which prolong the effective refractory period without altering the resting membrane potential or rate of depolarization.
  • Class IV antiarrhythmic agents are effective in calcium channel blockade.
  • Exemplary of this class of compounds are diltiazem and verapamil. Further definition of these classes can be found in Pharma Projects, section C1B, May 1993.
  • antiarrythmic agents 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 as they cause a depression of the myocardial contractility and have a tendency to induce arrythmias due to an inhibition of the impulse conduction.
  • Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV, respectively, have a defect in 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 drugs 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. Drugs such as sotalol and amiodarone have been shown to possess Class III properties. Sotalol also possesses Class II effects which can cause cardiac depression and is therefore contraindicated in certain susceptible patients. Amiodarone is also 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.
  • U.S. Patent No. 5,658,901 discloses novel 2-oxo-l,4- benzodiazepines which are potent Class III agents. Compounds in this patent, while extremely potent, display extended half lives in animals, resulting in a high potential for toxicity. The compounds of the present invention show a decreased half-life in animals.
  • U.S. Patent Nos. 5,595,900 and 5,631,251 disclose additional antiarrhythmic benzodiazepines.
  • This invention relates to compounds of the general formula
  • phenyl 2) substituted phenyl, with one or two substituents, selected from the group consisting of a) -hydrogen, b) -Cl, Br, F, or I, c) -CF 3 , d) -Ci-3 alkyl, e) -Ci-3 alkoxy, and
  • n 0, 1 or 2;
  • the invention also relates to pharmaceutical compositions containing said compounds for use in mammals and methods of treating arrhythmia by the administration of one or a combination of the novel compounds of the invention.
  • This invention relates to compounds of the general formula
  • Rl is 1) phenyl
  • the compounds of the present invention may have asymmetric centers and occur as racemates, mixtures of enantiomers, individual diastereomers, or as individual enantiomers with all isomeric forms being included in the present invention.
  • R 2 is 1) substituted phenyl, with one or two substituents, selected from the group consisting of a) -hydrogen, b) -Cl, Br, F, or I, c) -CF 3 , d) -Cl-3 alkyl, and
  • n 0, 1 or 2.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.
  • halogen or halo is intended to include fluorine, chlorine, bromine and iodine.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • optical isomeric forms that is mixtures of enantiomers, e.g., racemates, or diastereomers as well as individual enantiomers or diastereomers of the instant compound are included.
  • These individual enantiomers are commonly designated according to the optical rotation they effect by the symbols (+) and (-), (L) and (D), (1) and (d) or combinations thereof.
  • These isomers may also be designated according to their absolute spatial configuration by (S) and (R), which stands for sinister and rectus, respectively.
  • the individual optical isomers may be prepared using conventional resolution procedures, e.g., treatment with an appropriate optically active acid, separating the diastereomers and then recovering the desired isomer.
  • the individual optical isomers may be prepared by asymmetric synthesis.
  • a given chemical formula or name shall encompass pharmaceutically acceptable addition salts thereof and solvates thereof, such as hydrates.
  • the compounds of the present invention while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility and other desirable properties.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts.
  • acid salts are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or prodrug formulations.
  • salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethyl- ammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminome
  • esters can be employed, e.g. methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the compounds of the present invention may have chiral centers other than those centers whose stereochemistry is depicted in formula I, and therefore may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers, with all such isomeric forms being included in the present invention as well as mixtures thereof.
  • crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • novel compounds of the present invention have the pharmacological properties required for antiarrhythmic agents of Class III, 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 of body weight per day, preferably from about 0.001 to about 5.0 mg per kg of body weight per day in a single dose or in 2 to 4 divided doses.
  • These compounds, or pharmaceutically acceptable salts thereof, in the described dosages are administered orally, intraperitone- ally, subcutaneously, intramuscularly, transdermally, sublingually or intravenously. They are preferably administered intravenously or orally, for example in the form of tablets, troches, capsules, elixirs, suspensions, emulsions, 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.
  • These compounds can be administered as the sole active ingredient or in combination with other antiarrhythmic agents or other cardiovascular agents, such as Class I, Class II or Class IV antiarrhythmic agents, vasodilators, angiotensin converting enzyme inhibitors, angiotensin II antagonists, diuretics or digitalis.
  • other antiarrhythmic agents or other cardiovascular agents such as Class I, Class II or Class IV antiarrhythmic agents, vasodilators, angiotensin converting enzyme inhibitors, angiotensin II antagonists, diuretics or digitalis.
  • vasodilators are compounds such as papaverine and isosorbide dinitrat.
  • angiotensin converting enzyme inhibitors include enalapril, lisinopril and captopril.
  • diuretics include hydrochlorothiazide and acetazolamide.
  • the pharmaceutical agents listed herein are examples and do not represent a complete listing of the many compounds in these classes which are contemplated by this invention.
  • the activity of the compounds described herein as antiarrhythmic agents is measured by their ability to block the IKs 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 M KC1, 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).
  • IKI is measured as peak outward current during the voltage ramp.
  • IKr is measured as tail currents upon repolarization from -10 mV to -50 mV.
  • IKs is measured as time-dependent current during the pulse to +50 mV. Currents are measured during control, then after exposure to drug at two different concentrations.
  • the compounds described herein have an IC50 of less than 1,000 nM as IKs blockers.
  • the compounds of this invention are at least 10 times more potent in the blockade of IKs than the blockade of IKr.
  • Step A Preparation of 2.3-dihydro-l-ethyl-2-oxo-5-phenyl-lH-1.4- benzole! ri.41diazepine
  • the reaction was stirred at -70°C for 10 minutes and then treated with acetic acid (1 mL in 5 mL of THF) and warmed to room temperature over one hour.
  • the reaction mixture was then poured into water (500 mL) and extracted with ethyl acetate (3 X 250 mL) The combined ethyl acetate fractions were washed with water (200 mL), and brine (200 mL).
  • the ethyl acetate solution was then dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to afford 9.3 g of the product.
  • Step C Preparation of racemic 3-Amino-2.3-dihydro-l- ethyl-2- oxo-5-phenyl- IH- 1.4-benzo Tel f 1.41 diazepine
  • Step E Preparation of (+)-3-Amino-2,3-dihydro-l- ethyl-2-oxo-5- phenyl- IH- 1.4-benzo fe f 1.41 diazepine
  • (2R)-2-amino-3-phenyl-N-[2,3- dihydro-1 ethyl 2-oxo-5-phenyl-lH-l,4-benzo[e] [l,4]diazepin-3-yl] propionamide 5 g, 11.7 mmol
  • phenyl isothiocyanate 1.5 mL, 1.66 g, 12.3 mmol
  • Step F Preparation of (+)-2-(2.4-bis trifluoromethylphenyl)-N-[2.3- dihydro-1- ethyl -2-oxo-5-phenyl-lH-1.4- benzofe1 [1.41diazepin-3-yllacetamide
  • (+)-3-amino-2,3-dihydro-l- ethyl- 2-oxo-5-phenyl-lH-l,4-benzo[e] [l,4]diazepine 200 mg, 0.71 mmol
  • dimethylformamide 4 mL
  • EDC 150 mg, 0.783 mmol
  • HOBT 95 mg, 0.71 mmol
  • 2,4-bis trifluoromethylphenylacetic acid 215 mg, 0.78 mmol.
  • THF 1.0 L
  • a 1.6 M solution of cyclopropyl magnesium bromide in THF (1.55 L, 2.48 mole).
  • the reaction was allowed to stir overnite at room temperature then slowly quenched into a -10°C solution of 4N HCL (1.2 L).
  • the mixture was stirred for 1 hour at room temperature and the pH adjusted to 7.5 with ION sodium hydroxide.
  • the THF layer was removed, the aqueous layer washed with ethyl acetate (800 mL), and the organic extracts concentrated in vacuo to an oil.
  • the oil was dissolved in methylene chloride (1.2 L), washed with water (500 mL), dried over sodium sulfate, and filtered.
  • reaction mixture was concen- trated in ⁇ acuo to 2.7 L and the pH adjusted to 12.0 with 50% sodium hydroxide. After stirring at pH 12 for 1 hour, the reaction pH was adjusted to 8.5 with concentrated hydrochloric acid and the solids were filtered. The cake was washed with water (1.0 L), sucked dry and dried in ⁇ acuo at 40°C to give 102.2 g of 5-cyclopropyl-l,4- benzo[e] [l,4]diazepine-2-one. MP- 192-193 °C
  • Step B Preparation of 2.3-dihydro-l-ethyl-2-oxo-5-cyclopropyl- lH-1.4-benzo[el [1.41diazepine
  • a solution of 5-cyclopropyl-l,4-benzodiazepine-2-one (50 g, 0.250 mole) in DMF (250 mL) was treated with cesium carbonate (122 g, 0.375 mole) , cooled to 0° C and iodoethane (47.2 g, 0.30 mole) added. The mixture was stirred at 25°C overnight. The reaction was cooled to room temperature and filtered.
  • Step C Preparation of 3-azido-5-cvclopropyl-l-ethyl-lH- benzo[e1 [1.41diazepine
  • 5-cyclopropyl-l-ethyl-lHbenzo[e] [1,4] diazepine (6.4 g, 0.028 mol) in THF (125 ml) cooled to -78°C was added potassium tert-butoxide (2.05 eq, 0.057 mol, 57.2 ml of a 1 M solution in THF) dropwise over 15 min.
  • Step E Preparation of:(+.-)-2-(2.4-bis-trifluoromethylphenyl) -N-
  • the solution was stirred at ambient temperature for 2 hours.
  • the reaction was diluted with 10% citric acid (20 mL) and extracted with ethyl acetate (2 x 40 mL) .
  • the combined organics were washed with 10% sodium bicarbonate (20 mL) dried over Na2S04, and evaporated to a foam.
  • the foam was chromatographed using a Chiralpak AD® preparative HPLC column (Chiral Technology, 25x2 cm) eluting with ethanol/hexane(l/l, 6 mL/min).
  • the pure fractions were collected and evaporated under reduced pressure to give 95 mg of the (+) enantiomer and 95 mg of the (-) enantiomer as foams.
  • the enantiomers were crystallized from ether/hexane to give 80 mg (+) enantiomer and 80 mg (-) enantiomer as solids.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne de nouveaux composés de la formule structurale (I) qui sont efficaces dans le traitement de l'arythmie.
PCT/US1998/021597 1997-10-17 1998-10-13 Nouveaux derives de benzodiazepine s'utilisant comme agents anti-arythmisants WO1999020281A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000516678A JP2001520197A (ja) 1997-10-17 1998-10-13 抗不整脈薬として有効な新規なベンゾジアゼピン誘導体
CA002306960A CA2306960A1 (fr) 1997-10-17 1998-10-13 Nouveaux derives de benzodiazepine s'utilisant comme agents anti-arythmisants
EP98953453A EP1024811A4 (fr) 1997-10-17 1998-10-13 Nouveaux derives de benzodiazepine s'utilisant comme agents anti-arythmisants
AU10827/99A AU1082799A (en) 1997-10-17 1998-10-13 Novel benzodiazepine derivatives as antiarrhythmic agents

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US6283397P 1997-10-17 1997-10-17
US60/062,833 1997-10-17
GB9806686.3 1998-03-27
GBGB9806686.3A GB9806686D0 (en) 1998-03-27 1998-03-27 Novel benzodiazepine derivatives as antiarrhythmic agents

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WO (1) WO1999020281A1 (fr)

Citations (9)

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Publication number Priority date Publication date Assignee Title
US4628084A (en) * 1986-01-02 1986-12-09 Merck & Co., Inc. Process for 3-acylamino benzodiazepines
US4994258A (en) * 1990-03-05 1991-02-19 Merck & Co., Inc. Gamma emitting, CCK-A antagonists for pancreatic imaging
US5004741A (en) * 1984-06-26 1991-04-02 Merck & Co., Inc. Methods of antagonizing CCK or gastrin with benzodiazepine analogs
US5426185A (en) * 1993-11-22 1995-06-20 Merck & Co., Inc. Antiarrhythmic benzodiazepines
US5597818A (en) * 1991-12-03 1997-01-28 Merck & Co., Inc. Methods of treating cardiac arrhythmia
US5633251A (en) * 1994-08-18 1997-05-27 Merck & Co., Inc. N-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1h-1,4-benzodiazepines
WO1997048686A1 (fr) * 1996-06-21 1997-12-24 Merck & Co., Inc. Nouveaux n-1 alkyl-2-oxo-2,3,4,5-tetrahydro-1h-1,5-benzodiazepin-3-yl)-3-amides
US5776930A (en) * 1996-06-28 1998-07-07 Merck & Company, Inc. Pharmaceutical preparation
US5817658A (en) * 1997-03-14 1998-10-06 Merck & Company, Inc. Method for treating Meniere's disease

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5004741A (en) * 1984-06-26 1991-04-02 Merck & Co., Inc. Methods of antagonizing CCK or gastrin with benzodiazepine analogs
US4628084A (en) * 1986-01-02 1986-12-09 Merck & Co., Inc. Process for 3-acylamino benzodiazepines
US4994258A (en) * 1990-03-05 1991-02-19 Merck & Co., Inc. Gamma emitting, CCK-A antagonists for pancreatic imaging
US5597818A (en) * 1991-12-03 1997-01-28 Merck & Co., Inc. Methods of treating cardiac arrhythmia
US5426185A (en) * 1993-11-22 1995-06-20 Merck & Co., Inc. Antiarrhythmic benzodiazepines
US5633251A (en) * 1994-08-18 1997-05-27 Merck & Co., Inc. N-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1h-1,4-benzodiazepines
WO1997048686A1 (fr) * 1996-06-21 1997-12-24 Merck & Co., Inc. Nouveaux n-1 alkyl-2-oxo-2,3,4,5-tetrahydro-1h-1,5-benzodiazepin-3-yl)-3-amides
US5776930A (en) * 1996-06-28 1998-07-07 Merck & Company, Inc. Pharmaceutical preparation
US5817658A (en) * 1997-03-14 1998-10-06 Merck & Company, Inc. Method for treating Meniere's disease

Non-Patent Citations (4)

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Title
BUREAU R, RAULT S, ROBBA M: "COMPARATIVE MOLECULAR FIELD ANALYSIS OF CCK-B ANTAGONISTS", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY., EDITIONS SCIENTIFIQUE ELSEVIER, PARIS., FR, vol. 29, no. 06, 1 January 1994 (1994-01-01), FR, pages 487 - 494, XP002916245, ISSN: 0223-5234, DOI: 10.1016/0223-5234(94)90076-0 *
See also references of EP1024811A4 *
SELNICK H G, ET AL.: "CLASS III ANTIARRHYTHMIC ACTIVITY IN VIVO BY SELECTIVE BLOCKADE OF THE SLOWLY ACTIVATING CARDIAC DELAYED RECTIFIER POTASSIUM CURRENT IKS BY (R)-2-(2,4-TRIFLUOROMETHYL)-N-¬2-OXO-5-PHENYL- 1-(2,2,2-TRIFLUOROETHYL)-2,3-DIHYDRO-1H-BENZO¬E¾¬1,4¾DIAZEPIN-3-YL¾ACETAMIDE", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 40, no. 23, 7 November 1997 (1997-11-07), US, pages 3865 - 3868, XP002916243, ISSN: 0022-2623, DOI: 10.1021/jm970517u *
TOKARSKI J S, HOPFINGER A J: "THREE-DIMENSIONAL MOLECULAR SHAPE ANALYSIS-QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF A SERIES OF CHOLECYSTOKININ-A RECEPTOR ANTAGONISTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 37, no. 21, 14 October 1994 (1994-10-14), US, pages 3639 - 3654, XP002916244, ISSN: 0022-2623, DOI: 10.1021/jm00047a021 *

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EP1024811A1 (fr) 2000-08-09
EP1024811A4 (fr) 2002-11-13
JP2001520197A (ja) 2001-10-30
CA2306960A1 (fr) 1999-04-29
AU1082799A (en) 1999-05-10

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