EP0603314A1 - Composes chimiques - Google Patents

Composes chimiques

Info

Publication number
EP0603314A1
EP0603314A1 EP92920317A EP92920317A EP0603314A1 EP 0603314 A1 EP0603314 A1 EP 0603314A1 EP 92920317 A EP92920317 A EP 92920317A EP 92920317 A EP92920317 A EP 92920317A EP 0603314 A1 EP0603314 A1 EP 0603314A1
Authority
EP
European Patent Office
Prior art keywords
tetrahydro
chloro
methyl
benzazepine
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP92920317A
Other languages
German (de)
English (en)
Other versions
EP0603314A4 (en
Inventor
Robert Michael Demarinis
Francis Richard Pfeiffer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0603314A1 publication Critical patent/EP0603314A1/fr
Publication of EP0603314A4 publication Critical patent/EP0603314A4/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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

Definitions

  • This invention relates to novel substituted 2,3,4,5- tetrahydro-1H-3-benzazepine compounds having ⁇ -adrenergic receptor antagonist activity.
  • the autonomic nervous system is separated into the cholinergic and adrenergic nervous systems.
  • Norepinephrine the neurotransmitter of the adrenergic nervous system, exerts its activity by interaction with receptors (adrenoceptors) on the effector organs or on the nerve endings.
  • the adrenoceptors are of two primary types: ⁇ and ⁇ . Based upon selectivity of the receptors for a series of agonists and antagonists, the a
  • adrenoceptors have been subdivided into ⁇ 1 and ⁇ 2
  • SK&F 104078- insensitive and SK&F 104078-sensitive ⁇ 2 adrenoceptors variously are referred to as postjunctional ⁇ 2 adrenoceptors or, preferably, 0.3 adrenoceptors, United States Patent No. 4,683,229, July 28, 1987.
  • ⁇ adrenoceptors long have been the targets of efforts to develop agents effective in changing vascular tone for use in treating diseases, such as hypertension, in which alterations in vascular resistance produce therapeutic benefits.
  • Antihypertensive compounds presently in clinical use that function via interaction with a adrenoceptors include methyldopa, clonidine, and prazosin.
  • Efforts to modulate sympathetic tone through interactions with a adrenoceptors have resulted in several compounds that interact somewhat selectively with ⁇ 1 or ⁇ 2 adrenoreceptors.
  • Selective agonists include phenylephrine and methoxamine which preferentially activate ⁇ 1
  • adrenoceptors examples include prazosin which has high selectivity for ⁇ 1 adrenoceptors; and the ⁇ 2 -selective blockers yohimbine and rauwolscine.
  • the present invention resides in the discovery that certain substituted-2, 3,4,5,-tetrahydro-1H-3-benzazepine compounds are ⁇ -adrenoceptor antagonists.
  • Presently preferred compounds of the invention include:
  • the most preferred compound of the invention is 6- chloro-2,3,4,5-tetrahydro-3-methyl-9-(2-phenylethoxy)-1H- 3-benzazepine or a pharmaceutically acceptable salt thereof.
  • compositions comprising compounds useful in the method of the invention and a suitable pharmaceutical carrier .
  • compositions are used to produce a adrenoceptor antagonism and contain an effective amount of compounds useful in the methods of the invention.
  • X is H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 1 , CO 2 R 2 , CONR 2 R 2 , CN, NO 2 , NR 3 R 4 , OR 3 , SR 1 , SCF 3 , or any
  • R is H, C 1-6 alkyl, or C 3-5 alkenyl
  • B is absent or present as O or S
  • Z is O or S
  • each R 1 independently is C 1-6 alkyl or
  • each R 2 independently is H, C 1-6 alkyl, or
  • R 3 is H, C 1-6 alkyl, CHO, COR 1 , or SO 2 R 1 ;
  • R 4 is H or C 1-6 alkyl
  • X 1 is H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 1 , CO 2 R 2 , CONR 2 R 2 , CN, NO 2 , NR 3 R 4 , OR 3 , SR 1 , SCF 3 or any accessible combination thereof up to five substituents;
  • X is H taken three tames, Cl, Br, F, CF 3 , CH 3 , OCH 3 , di-OCH 3 , OH, di-OH, NO 2 , NH 2 , OC (O) C 1-6 alkyl, or di-CO(O)C 1-6 alkyl
  • B is absent, and A is S
  • X 1 is not H taken five times, Cl, di-Cl, F, OH, NO 2 , CH 3 , CF 3 , or OCH 3 .
  • C 1-6 alkyl means straight or branched alkyl of one to six carbon atoms
  • C 3-5 alkenyl means a straight or branched chain alkenyl having from 3 to 5 carbon atoms
  • any accessible combination thereof means any combination of up to three substituents on the phenyl moiety that is available by chemical synthesis and is stable.
  • Formula (la) includes presently preferred Formula (I) compounds:
  • X is H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 1 , CO 2 R 2 ,
  • R is H, C 1-6 alkyl, or C 3-5 alkenyl
  • B is absent or present as O or S
  • Z is O or S
  • each R 1 independently is C 1-6 alkyl or
  • each R 2 independently is H, C 1-6 alkyl, or
  • R 3 is H, C 1-6 alkyl, CHO, COR 1 , or SO 2 R 1 ;
  • R 4 is H or C 1-6 alkyl
  • X 1 is H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 1 , CO 2 R 2 , CONR 2 R 2 , CN, NO 2 , NR 3 R 4 , OR 3 , SR 1 , SF 3 , or any accessible combination thereof up to five substituents;
  • X is H, Cl, Br, F, CF 3 , CH 3 , OCH 3 , OH, NO 2 , NH 2 , or OC(O) C 1-6 alkyl
  • B is absent, and A is S
  • X 1 is not H taken five times, Cl, di-Cl, F, OH, NO 2 , CH 3 , CF 3 , or OCH 3 .
  • Preferred compounds are represented by Formula (la) when:
  • X is Cl, Br, F, or I; and R is CH 3 .
  • a suitable base such as an alkali metal hydride, for example, sodium hydride
  • a suitable organic solvent such as
  • -OCH 2 CH CH- and B is absent or present as O or S.
  • Formula (I) compounds wherein B is absent and A is -O- are prepared by reacting formula (I) compounds with a X 1 -substituted diphenyliodonium halide, such as
  • diphenyliodonium chloride in the presence of copper and a suitable base, such as triethylamine, in a suitalbe solvent, such as methanol.
  • Formula (I) compounds wherein A is -OCO (CH 2 ) 1-4 - are prepared also from formula (I) compounds.
  • the starting alcohol compounds are reacted with a (X 1 -substituted-phenyl) alkanoyl halide, such as 4-(4- nitrobenzene)butanoyl chloride, in the presence of a base, such as triethylamine, in a suitable solvent, such as methylene chloride.
  • a base such as triethylamine
  • the benzazepines of formula (2) are known to the art (J. Med. Chem., 27:918-921 (1984)) or are synthesized by known procedures.
  • the primary amine of formula (2) compounds is diazotized using, for example, sodium nitrite in acetic acid, water, and sulfuric acid.
  • Conversion to the corresponding cyano compounds of formula (3) is accomplished by reacting the diazonium salt with cyanide, for example, potassium cyanide.
  • the carboxylic acid compounds of formula (4) are prepared by reacting the cyano of the formula (3) compounds in the presence of barium hydroxide, in a suitable solvent, such as a mixture of ethanol and water.
  • the resulting acids are reacted with a suitable base, such as an alkali metal hydride, such as sodium hydride, in an appropriate solvent, such as dimethylformamide.
  • Scheme III illustrates the preparation of additional Formula (I) compounds.
  • formula (3) cyano compounds are converted to the corresponding aldehyde derivatives of formula (6), for example using Raney® nickel in a suitable solvent, such as formic acid, at a temperature of about 35°C to about 100°C, preferably at about 100°C.
  • a suitable solvent such as formic acid
  • benzazepines are prepared from the formula (6) aldehyde compounds by reductive methods, for example, using sodium borohydride in a suitable solvent, such as methanol, at a temperature from about 0°C to about 35°C, preferably from about 5°C to about 24°C.
  • Formula (8) benzazepines, which are Formula (I) compounds, are prepared from formula (7) benzazepines, using the methods described in Scheme I.
  • Scheme III also shows the preparation of Formula (I) compounds wherein A is -(CH 2 ) 3-5 - and B is absent.
  • triphenylphosphoranylideneacetaldehyde in a suitable solvent, such as toluene, at a temperature of about 80°C to about 110°C, preferably at 110°C, or with an
  • -CH CHCO 2 ethyl, respectively.
  • the vinyl intermediates thus generated are reduced to the corresponding saturated analogs, for example by hydrogenation in the presence of a suitable catalyst, such as platinum oxide, in a suitable solvent, such as ethanol.
  • a suitable catalyst such as platinum oxide
  • the terminal ester or formyl groups are reduced to the corresponding alcohol derivatives using standard reagents, for example, an ester-reducing agent, such as lithium aluminum hydride, or a formyl- reducing agent, such as sodium borohydride.
  • the alcohols are reacted with a halogenating agent, such as thionyl chloride, to give - (CH 2 ) 3-5 halo benzazepines.
  • the pharmaceutically acceptable, nontoxic, acid addition salts having the utility of the free bases of Formula (I), are formed with inorganic or organic acids, by methods well known in the art.
  • suitable acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
  • the compounds of Formula (I) are ⁇ - adrenoceptor antagonists they are useful in treating cardiovascular diseases in which changes in vascular resistance are desirable, including hypertension,
  • Formula (I) compounds also are useful in treating benign prostatic hypertrophy, diabetes, glaucoma, ocular hypertension, obesity, disorders of
  • gastrointestinal motility including colonic spasm, irritable bowel syndrome, and constipation, impotence, and central nervous system disorders such as depression and senile dementia. Additionally, the invented compounds are useful in treating diseases resulting from inappropriate platelet aggregation.
  • ⁇ -adrenoceptor activity of certain compounds of the present invention was determined using the following in vitro systems.
  • Tissue segments were equilibrated for 2 hours prior to drug testing, during which time basal tension was maintained at 2 gm. Tissues were washed at 30 minute intervals during this equilibration period.
  • the Krebs- Hensleit solution contained cocaine (6mM) to block
  • Tissues were usually challenged once with norepinephrine (0.1mM) during the equilibration period to check for viability.
  • norepinephrine was obtained in each aortic segment.
  • the a adrenoceptor antagonist to be tested was added to the bath. After the tissue had been in contact with the antagonist for 30-60 minutes, the norepinephrine concentration response-curve was repeated in the presence of antagonist. The tissue was then washed again, and a tenfold higher concentration of antagonist added. Following equilibration (30-60 minutes), a third norepinephrine concentration-response curve was determined in the presence of the antagonist.
  • the receptor dissociation constant (K ⁇ ) for the antagonist was determined using the relationship
  • Alpha 2 adrenoceptor antagonist activity of the compounds was determined using the isolated, superfused guinea pig left atrium. Briefly, the heart is removed from a pentobarbital-anesthetized male guinea pig. The left atrium is separated, dissected free of extraneous tissue and mounted in a 2 ml superfusion chamber. The tissue is paced at 30 pulse/minute and the sympathetic nerves excited at 6 minute intervals by field stimulation. The response to nerve stimulation is measured as the difference in contractile force between the basal
  • a concentration-response curve for B-HT 920 (a known ⁇ 2 agonist) is prepared by administering increasing concentrations of B-HT 920 following each successive stimulation. The tissue then is superfused for thirty minutes with the ⁇ -adrenoceptor antagonist to be tested and the B-HT 920 concentration-effect curve is repeated in the presence of antagonist. Data are reported as K B , defined above. Additional details of this test system are found in Hieble, J. P. and R. G. Pendleton, Arch. Pharmacol., 309 :217-224 (1979).
  • Alpha 3 adrenoceptor antagonist receptor activity was determined using the dog saphenous vein (DSV) as the test system. This test system has been shown a suitable preparation in which to characterize postsynaptic ⁇ 2 ( ⁇ 3 ) adrenoceptors, Sullivan, A. T. and G. M. Drew, Arch.
  • This test system is prepared by removing the lateral saphenous vein from an anesthetized dog and cutting the vein into segments of 4 mm in length. Segments are mounted as described for the isolated rabbit aorta.
  • the ⁇ 3 adrenoceptor antagonist activity of the compounds of interest is determined by measuring shifts in the dose-response curve of a specific agonist induced by the tested compounds.
  • the ⁇ 2 , ⁇ 3 agonist, B-HT 920, was used in testing the compounds listed in Table I.
  • Novel pharmaceutical compositions are obtained when the compounds are incorporated with pharmaceutical
  • Solid or liquid pharmaceutical carriers into convenient dosage forms such as capsules, tablets, or injectable preparations.
  • Solid or liquid pharmaceutical carriers can be employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any suitable carrier or diluent.
  • the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid, or an aqueous or nonaqueous liquid suspension or solution.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating and compressing, when necessary, for tablet forms, or mixing, filling, and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
  • Doses of the present compounds in pharmaceutical dosage units will be an efficacious, nontoxic quantity selected from the range of 0.03-100 mg/kg of active compound, preferably 0.1-50 mg/kg.
  • the selected dose is administered to a human patient in need of treatment from 1-6 times daily, orally, rectally, topically, by
  • inhalation or injection, or continuously by infusion.
  • Oral administration is preferred because it is more convenient for the patient.
  • Example 2 Using the general procedure of Example 2 , replacing4-methoxybenzyl chloride with 2, 6-dimethoxybenzyl chloride, 4-chlorobenzyl chloride, 2-phenylethyl bromide, 2- (2-methoxyphenyl) ethyl 4-methylbenzenesulfonate, 2-(3- methoxyphenyl) ethyl 4-methylber ⁇ zenesulfonate, 2-(3,4- dimethoxyphenyl) ethyl chloride, cinnamyl chloride, 2- (phenoxy) ethyl bromide, 2-(2,6-dimethoxyphenyl) ethyl bromide and 2, 3-dihydrobenzodioxin-2-methanol
  • Example 14 Using the general procedure of Example 14, replacing 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[4-(4- nitrophenyl)-butoxy]-1H-3-benzazepine with 6-chloro- 2,3,4,5-tetrahydro-3-methyl-9-[((3-(4-nitrophenyl)- propyl) carbonyl) oxy] -1H-3-benzaze ⁇ ine gave 9-[((3-(4- aminophenyl) propyl) carbonyl) oxy] -6-chloro-2,3,4,5- tetrahydro-3-methyl-1H-3-benzazepine hydrochloride.
  • An oral dosage form for administering the presently invented compounds is produced by screening, mixing, and filling into a hard gelatin capsule ingredients in the proportions shown in Table II, below.
  • sucrose, calcium sulfcite dihydrate and Formula (I) compound shown in Table III below are mixed and granulated with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
  • 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(2- phenylethoxy)-1H-3-benzazepine 75 mg, is dispersed in 25 ml of normal saline to prepare an injectable preparation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à des agents antagonistes des récepteurs alpha-adrénergiques, ayant la formule (I), qui servent à produire une action antagoniste sur les récepteurs alpha-adrénergiques, à des compositions pharmaceutiques contenant ces agents antagonistes, ainsi qu'à des procédés d'utilisation de ces agents antagonistes dans le but de produire une action antagoniste sur les récepteurs $(a)-adrénergiques chez les mammifères.
EP9292920317A 1991-09-12 1992-09-11 Chemical compounds. Ceased EP0603314A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB919119467A GB9119467D0 (en) 1991-09-12 1991-09-12 Chemical compounds
GB9119467 1991-09-12
PCT/US1992/007694 WO1993004686A1 (fr) 1991-09-12 1992-09-11 Composes chimiques

Publications (2)

Publication Number Publication Date
EP0603314A1 true EP0603314A1 (fr) 1994-06-29
EP0603314A4 EP0603314A4 (en) 1994-08-24

Family

ID=10701273

Family Applications (1)

Application Number Title Priority Date Filing Date
EP9292920317A Ceased EP0603314A4 (en) 1991-09-12 1992-09-11 Chemical compounds.

Country Status (5)

Country Link
EP (1) EP0603314A4 (fr)
JP (1) JPH06510545A (fr)
AU (1) AU2654792A (fr)
GB (1) GB9119467D0 (fr)
WO (1) WO1993004686A1 (fr)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999007353A1 (fr) * 1997-08-05 1999-02-18 The Mount Sinai School Of Medicine Of The City University Of New York UTILISATION D'ANTAGONISTES DE RECEPTEUR α1A-ADRENERGIQUE DANS LA THERAPIE DU GLAUCOME
JP2002542147A (ja) * 1998-12-14 2002-12-10 セレジィ ファーマシューティカルス， インコーポレイテッド 肛門直腸障害の処置のための組成物および方法
WO2003042190A1 (fr) 2001-11-12 2003-05-22 Pfizer Products Inc. Derives de n-adamantylalkyle benzamide en tant qu'antagonistes du recepteur p2x7
PA8557501A1 (es) 2001-11-12 2003-06-30 Pfizer Prod Inc Benzamida, heteroarilamida y amidas inversas
EP2133340B1 (fr) 2002-12-20 2013-01-16 Glaxo Group Limited Nouveaux dérivés de benzazépine
US7071223B1 (en) 2002-12-31 2006-07-04 Pfizer, Inc. Benzamide inhibitors of the P2X7 receptor
PA8591801A1 (es) 2002-12-31 2004-07-26 Pfizer Prod Inc Inhibidores benzamidicos del receptor p2x7.
MXPA05012086A (es) 2003-05-12 2006-02-22 Pfizer Prod Inc Inhibidores de benzamida del receptor p2x7.
BRPI0415842A (pt) * 2003-10-23 2007-01-02 Hoffmann La Roche derivativos de benzapepina como inibidores de mao-b
CN102329267A (zh) 2004-02-25 2012-01-25 伊莱利利公司 作为5-HT2C受体激动剂的6-取代的2,3,4,5-四氢-1H-苯并［d］氮杂䓬
WO2006003500A1 (fr) 2004-06-29 2006-01-12 Pfizer Products Inc. Procedes permettant de preparer des derives de 5-[4-(2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3h-[1,2,4]triazin-2-yl]-benzamides par deprotection des precurseurs proteges par hydroxyle
WO2007028131A1 (fr) 2005-09-01 2007-03-08 Eli Lilly And Company 2,3,4,5-TÉTRAHYDRO-1H-BENZO[d]AZÉPINES SUBSTITUÉS EN POSITION 6 EN TANT QU’AGONISTES DU RÉCEPTEUR DE 5-HT2C
JP5249031B2 (ja) * 2005-09-01 2013-07-31 イーライ リリー アンド カンパニー ５−ＨＴ２Ｃ受容体アゴニストとしての６−Ｎ結合型へテロ環置換された２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｄ］アゼピン
WO2007028082A1 (fr) * 2005-09-01 2007-03-08 Eli Lilly And Company 2,3,4,5-tetrahydro-1h-benzo[d]azepines 6-substituees en tant qu'antagonistes du recepteur 5-ht2c
BRPI0615048A2 (pt) 2005-09-01 2010-03-30 Lilly Co Eli composto, composição farmacêutica, e, uso de um composto

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3483185A (en) * 1966-08-16 1969-12-09 American Home Prod N-substituted 2,3,4,5-tetrahydro-1h-3-benzazepines
ZA792785B (en) * 1978-07-07 1980-08-27 Smithkline Corp Mercapto substituted-2,3,4,5-tetrahydro-1h-3-benzazepines
US4469634A (en) * 1982-07-29 1984-09-04 Smithkline Beckman Corporation Allyloxy- and allylthio-2,3,4,5-tetrahydro-1H-3-benzazepines
US4683229A (en) * 1986-03-17 1987-07-28 Smithkline Beckman Corporation 6-halo-9-alkenyleneoxy-3-alkyl-2,3,4,5-tetrahydro-(1H-3)-benzazepines and their use as selective alpha-adrenergic receptor antagonists
EP0285287A3 (fr) * 1987-03-23 1990-08-16 Smithkline Beecham Corporation Emploi de 3-benzazépines pour le traitement des troubles de la mobilité gastro-intestinale

Also Published As

Publication number Publication date
WO1993004686A1 (fr) 1993-03-18
GB9119467D0 (en) 1991-10-23
EP0603314A4 (en) 1994-08-24
AU2654792A (en) 1993-04-05
JPH06510545A (ja) 1994-11-24

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