WO1993000094A2 - Utilisation de derives de tetrahydrobenzazepine pour le traitement de l'hypertension porte et de la migraine - Google Patents

Utilisation de derives de tetrahydrobenzazepine pour le traitement de l'hypertension porte et de la migraine Download PDF

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Publication number
WO1993000094A2
WO1993000094A2 PCT/GB1992/001083 GB9201083W WO9300094A2 WO 1993000094 A2 WO1993000094 A2 WO 1993000094A2 GB 9201083 W GB9201083 W GB 9201083W WO 9300094 A2 WO9300094 A2 WO 9300094A2
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WO
WIPO (PCT)
Prior art keywords
tetrahydro
benzazepine
hydroxy
compound
methoxy
Prior art date
Application number
PCT/GB1992/001083
Other languages
English (en)
Other versions
WO1993000094A3 (fr
Inventor
John Gerard Ward
Rodney Christopher Young
Alberto Julio Kaumann
Original Assignee
Smithkline Beecham Plc
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 GB919113379A external-priority patent/GB9113379D0/en
Priority claimed from GB919113377A external-priority patent/GB9113377D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to KR1019930703940A priority Critical patent/KR940701258A/ko
Priority to JP4511087A priority patent/JPH06508352A/ja
Priority to EP92912293A priority patent/EP0589973A1/fr
Publication of WO1993000094A2 publication Critical patent/WO1993000094A2/fr
Publication of WO1993000094A3 publication Critical patent/WO1993000094A3/fr

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to certain tetrahydrobenzazepine derivatives for use in the treatment of disorder characterised by excessive vasodilatation, in particular the treatment of portal hypertension and the treatment and prophylaxis of migraine, and more generally to the use of 5-HT 2 and 5-HT 1 -like receptor agonists in the treatment of portal hypertension and to the use of 5-HT 2 agonists in the treatment and prophylaxis of migraine.
  • Portal hypertension which is commonly associated with cirrhosis of the liver is characterised by increased portal venous blood flow, (which is caused by dilatation of
  • gastrointestinal motility disorders are agonists at 5-HT 2 and/or 5-HT 1 -like-receptors and are expected to have utility in the treatment of portal hypertension.
  • Migraine is a non-lethal disease suffered by one in ten individuals.
  • the main symptom is headache; other symptoms include vomiting and photophobia.
  • ergotamine, dihydroergotamine or methysergide are inter alia agonists of 5HT 1 -like receptors but also have other actions; treatment with them is associated with a number of adverse side effects.
  • some patients experience a "withdrawal headache" following the cessation of treatment with an ergot product, such as ergotamine, causing them to repeat the treatment and resulting in a form of addiction.
  • an ergot product such as ergotamine
  • gastrointestinal motility disorders are agonists at 5HT 1 -like and/or 5HT 2 -receptors and are expected to have utility in the treatment of migraine.
  • the present invention therefore provides compounds of structure (I):
  • R is hydrogen, C 1-6 alkyl or C 3-5 alkenyl
  • R 1 is NO 2 , cyano, halo, COR 3 , SO n R 4 or
  • R 2 is hydrogen, hydroxy or C 1-4 alkoxy
  • R 3 is hydrogen, C 1-4 alkyl, OR 5 or NR 5 R 6 ;
  • R 4 is C 1-6 alkyl or halo C 1-6 alkyl
  • R 5 and R 6 are hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; and n is 1 or 2;
  • R is hydrogen, C 1-6 alkyl or C 3-5 alkenyl
  • R is hydrogen.
  • R 1 is nitro, cyano, halo, COR 3 , SO n R 4 or
  • n NR 5 R 6 preferably R 1 is SO n R 4 , nitro or halo; most preferably R 1 is SO n R 4 .
  • n is 1 or 2; preferably n is 2.
  • R 2 is hydrogen, hydroxy or C 1-4 alkoxy
  • R 2 is C 1-4 alkoxy or hydroxy.
  • R 3 is hydrogen, C 1-4 alkyl, OR 5 or NR 5 R 6 ;
  • R 3 is C 1-4 alkyl, in particular methyl.
  • the group R 1 is at the 8-position and the group R 2 is at the 7-position of the ring of the compound of structure (I).
  • R 4 is C 1-6 alkyl or halo C 1-6 alkyl
  • R 4 is C 1-6 alkyl, or C 1-6 alkyl substituted by 1 to 6 halogen atoms (eg. CF 3 ) and most preferably R 4 is methyl.
  • R 5 and R 6 are hydrogen or C 1-6 alkyl, or C 3-6 cycloalkyl.
  • both groups represent C 1-6 alkyl, they are the same.
  • C 1-6 alkyl groups either alone or as part of another group, can be straight or branched.
  • Suitable salts will be apparent to those skilled in th art, and include, for example, acid addition salts such as the hydrochloride, or the oxalate.
  • Suitable examples of compounds for use in the present invention are as described in EP-0229510-B, for example : 7-hydroxy-8-sulphamoyl-2,3,4,5-tetrahydro-1H-benzazepine, an 7-hydroxy-8-(N,N-dimethylsulphamoyl)-2,3,4,5-tetrahydro-1H-benzazepine.
  • the present invention relates to the use of a compound in which R is hydrogen, R 1 is methylsulphonyl and R 2 is hydroxy, namely, 7-hydroxy-8- methylsulphonyl-2,3,4,5-tetrahydro-1H-benzazepine, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of migraine.
  • Compounds of structure (I) may be prepared by the methods described in EP 0229510-B, or by the following methods : a) to prepare a compound of structure (I) where R 1 represents -SO n R 4 , the reaction of a compound of structure (II) :
  • N-protecting groups R 7 are well known in the art and include acyl groups such as acetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, and benzyloxycarbonyl. N-deprotection may be carried out by conventional methods.
  • the oxidising agent may be for example hydrogen peroxide or a peracid such as 3-chloroperbenzoic acid, in a solvent such as acetic acid.
  • the acylating agent may be for example an acid chloride or acid anhydride corresponding to the group R 3 CO-.
  • the reaction is desirably effected in the presence of tin tetrachloride. Nitration may be effected using
  • Halogenation may be carried out with an acidic solution of halogen e.g. Br 2 in acetic acid, followed by neutralisation with e.g. sodium bicarbonate.
  • halogen e.g. Br 2 in acetic acid
  • neutralisation e.g. sodium bicarbonate
  • the nitration and halogenation reactions will result in a mixture of isomeric compounds, substituted respectively at the 7,8 and 6,7 positions of the benzazepine ring, which may be separated for example by chromatography, or crystallisation.
  • the compounds of structure (I) have been found to be agonists at 5-HT 2 and/or 5-HT ⁇ -like receptors and are
  • 5-HT 1 -like agonists and 5-HT 2 -agonists are effective in portal hypertension through constriction of mesenteric arterioles, and partial constriction of paraesophageal collaterals with consequent reduction of portal flow and portal pressure.
  • Preferred compounds for use according to the present invention are partial agonists at 5-HT 2 receptors and/or 5-HT 1 -like
  • the present invention provides 5-HT 2 receptor agonists and 5-HT 1 -like-agonists for use in the treatment of portal hypertension.
  • the invention also provides the use of 5-HT 2 receptor agonists and 5-HT 1 -like-agonists in the
  • a method of treating portal hypertension which comprises administering to a subject in need thereof an effective amount of a 5-HT 2 -agonist or 5-HT 1 -like-agonist.
  • a 5-HT 2 -agonist or 5-HT 1 -like-agonist is preferably a partial agonist at the said receptor.
  • a compound for use according to this invention is a partial agonist at both 5-HT 2 and 5-HT 1 -like receptors.
  • the compounds of structure (I) have been found to be agonists at 5HT 1 -like and/or 5HT2 receptors and are expected to have utility in medicine in the treatment or prophylaxis of migraine. Whilst not wishing to be bound by theory, it is believed that 5HT 1 -like agonists are effective in migrain through constriction of cerebral arteries and that 5HT 2 agonists constrict the superficial temporal artery.
  • inventions are partial agonists at 5HT 1 -like and/or 5HT 2 receptors.
  • a 5-HT 2 -receptor agonist for use in the treatment of migraine.
  • the invention also provides the use of 5-HT 2 -receptor agonists in the manufacture of a medicamen for the treatment of migraine.
  • a method of treating migraine which comprises administering to a subject in need thereof an effective amount of a 5-HT 2 agonist.
  • a 5-HT 2 -agonist is preferably a partial agonist at this receptor.
  • the compounds are incorporated into standard pharmaceutical compositions. They can be
  • pharmaceutically acceptable salts which are active when give orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for
  • ethanol for exampl polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • glycerine for exampl polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier (s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • suitable pharmaceutical carrier for example aqueous gums, celluloses, silicates or oils
  • pharmaceutically acceptable salts which are active when administered parenterally (i.e. by injection or infusion) can be formulated as solutions or suspensions.
  • a composition for parenteral administration will generally consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, for example polyethyleneglycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethyleneglycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to
  • a typical suppository composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • a typical transdermal formulation comprises a
  • aqueous or non-aqueous vehicle for example, a cream, ointment lotion or paste or in the form of a
  • each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 150 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 400 mg, for example between 10 and 400 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 30 mg, for example between 1 and 30 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compounds will be
  • Helicoids of dog saphenous vein were set up at 37°C in modified Krebs solution at a resting force of 10 mN.
  • the solution also contained 1 ⁇ mol/1 each of ketanserin prazosin, atropine and mepyramine, 6 ⁇ mol/1 cocaine and 200 ⁇ mol/1 ascorbate.
  • Nearly isomeric contractions were measured with force transducers on a polygraph.
  • the tissues were exposed twice to 5-hydroxytryptamine (5-HT) 2 ⁇ mol/1 followed by washes.
  • a cumulative concentration-effect curve to the test compound was determined, followed by a curve to 5-HT in the presence of the highest used concentration of test compound. Contractions caused by the test compound were compared with those caused by 5-HT.
  • the intrinsic activity of the test compound was calculated as the ratio of the maximum test compound-induced effect over the effect caused by 2 ⁇ mol/1 5-HT.
  • the EC 50 of the test compound was estimated from the corresponding effect curve.
  • Kp were estimated by the method of Marano & Kaumann (1976, J. Pharmacol. Exp. Ther. 198, 518-525).
  • the whole brain was quickly removed and immersed in ice cold modified Kreb's solution and the basilar artery removed with the aid of a dissecting microscope.
  • the Krebs solution was of the following composition (mM) Na + (120); K + (5); Ca 2+ (2.25); Mg 2+ (0.5); Cl- (98.5); SO 4 2- (1); EDTA (0.04), equilibrated with 95% 02/5% CO 2 .
  • the endothelium was removed by a gentle rubbing of the lumen with a fine metal wire. Arteries were then cut into ring segments (ca 4-5 mm wide) and set up for recording of isometric tension in 50 ml tissue baths in modified Krebs solution with the additional supplement of
  • concentration-effect curves to the test compounds or 5-HT were constructed in the presence of ascorbate, indomethacin, cocaine, ketanserin and prazosin.
  • the ventral caudal artery was used from rats pretreate with reserpine 7mg/kg ip (20 h).
  • Five interconnected arterial rings were prepared and set up to contract in modified Krebs solution at 32.5°C as follows. Resting for of the rings was set to be 4 mN and the rings allowed to relax thereafter without further readjustment.
  • Three cumulative concentration-effect curves were determined, the first to 5-HT followed by washout, the second to the test compound and the third to 5-HT in the presence of the highe used concentration of test compound.
  • the intrinsic activi of the test compound was calculated as the ratio of the maximum test compound-induced effect over maximum 5-HT- induced effect.
  • the EC 50 of the test compound was estimat from the corresponding concentration-effect curve.
  • the compounds of structure (I) have been found to demonstrate activity in this screen, for example, 7-hydroxy- 8-methylsulphonyl-2,3,4,5-tetrahydro-1H- benzazepine was found to have an EC 50 of 2 ⁇ M, and the compound of Example 2 an EC 50 of 1 ⁇ M.
  • a toxicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added.
  • 3-Acetyl-7-methoxy-8-methylthio-2,3,4,5-tetrahydro-1H-benzazepine (3.04g) was dissolved in methanol (500 ml) a treated with a 15% solution of titanium trichloride (11.8g), followed by 6% hydrogen peroxide solution (18.0g), dropwise, with stirring, over 10 minutes at room temperature. After stirring for a further 30 minutes, the reaction mixture was filtered, diluted with water and extracted with chloroform.
  • Aluminium chloride (1.71 g) was added to
  • dichloromethane (50 ml) at room temperature, and a solution of 3-acetyl-7-methoxy-8-methylsulphinyl-2,3,4,5-tetrahydro- 1H-benzazepine (0.90 g) in dichloromethane was added dropwis with stirring over 3h. After leaving the mixture to stir overnight at room temperature, the dichloromethane solution was decanted from the precipitated gum. The latter was digested with IM sodium hydroxide solution, and the resultin aqueous solution was washed with dichloromethane, acidified to pH2 with cone. HCl and extracted (3x) with chloroform.
  • the aqueous phase was separated and heated at 100°C for 40 h, cooled, and passed down an ion exchange column

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  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention se rapporte à des dérivés de tétrahydrobenzazépine utilisés comme médicaments.
PCT/GB1992/001083 1991-06-21 1992-06-17 Utilisation de derives de tetrahydrobenzazepine pour le traitement de l'hypertension porte et de la migraine WO1993000094A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
KR1019930703940A KR940701258A (ko) 1991-06-21 1992-06-17 문맥압 항진증 및 편두통의 치료를 위한 테트라하이드로벤즈아제핀 유도체의 용도
JP4511087A JPH06508352A (ja) 1991-06-21 1992-06-17 門脈圧亢進症および片頭痛の治療用のテトラヒドロベンズアゼピン誘導体の使用
EP92912293A EP0589973A1 (fr) 1991-06-21 1992-06-17 Medicaments

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9113379.3 1991-06-21
GB919113379A GB9113379D0 (en) 1991-06-21 1991-06-21 Medicaments
GB9113377.7 1991-06-21
GB919113377A GB9113377D0 (en) 1991-06-21 1991-06-21 Medicaments

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WO1993000094A2 true WO1993000094A2 (fr) 1993-01-07
WO1993000094A3 WO1993000094A3 (fr) 1993-03-04

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PCT/GB1992/001083 WO1993000094A2 (fr) 1991-06-21 1992-06-17 Utilisation de derives de tetrahydrobenzazepine pour le traitement de l'hypertension porte et de la migraine

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EP (1) EP0589973A1 (fr)
JP (1) JPH06508352A (fr)
KR (1) KR940701258A (fr)
AU (1) AU1927992A (fr)
CA (1) CA2110575A1 (fr)
IE (1) IE921990A1 (fr)
MX (1) MX9203012A (fr)
PT (1) PT100602A (fr)
WO (1) WO1993000094A2 (fr)

Cited By (18)

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WO1993024116A1 (fr) 1992-05-28 1993-12-09 Glaxo Canada Inc. Compositions pharmaceutiques comprenant des agonistes des recepteurs 5-ht1 et des stimulateurs d'absorption
EP0932407A1 (fr) * 1996-03-25 1999-08-04 Eli Lilly And Company Technique de traitement de la douleur due a la migraine
WO2002074746A1 (fr) * 2001-03-16 2002-09-26 Yamanouchi Pharmaceutical Co., Ltd. Derives de benzazepine
WO2005019180A1 (fr) * 2003-08-11 2005-03-03 Eli Lilly And Company 6-(2,2,2-trifluoroethylamino)-7-chloro-2,3,4,5-tetrahydro-1h-benzo[d]azepine utilisee comme agoniste du recepteur 5-ht2c
US6953787B2 (en) 2002-04-12 2005-10-11 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
US7696193B2 (en) 2002-12-20 2010-04-13 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
US7704993B2 (en) 2003-06-17 2010-04-27 Arena Pharmaceuticals, Inc. Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases
US8153621B2 (en) 2004-12-23 2012-04-10 Arena Pharmaceuticals, Inc. 5ht2C receptor modulator compositions
US8168624B2 (en) 2004-12-21 2012-05-01 Arena Pharmaceuticals, Inc. Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
US8168782B2 (en) 2006-04-03 2012-05-01 Arena Pharmaceuticals, Inc. Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
US8299241B2 (en) 2006-12-05 2012-10-30 Arena Pharmaceuticals, Inc. Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof
US8367657B2 (en) 2003-06-17 2013-02-05 Arena Pharmaceuticals, Inc. Processes for preparing 3-benzazepines
US8822727B2 (en) 2008-03-04 2014-09-02 Arena Pharmaceuticals, Inc. Processes for the preparation of intermediates related to the 5-HT2C agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
US8999970B2 (en) 2010-09-01 2015-04-07 Arena Pharmaceuticals, Inc. Administration of an anti-obesity compound to individuals with renal impairment
US9169213B2 (en) 2012-10-09 2015-10-27 Arena Pharmaceuticals, Inc. Method of weight management
US9248133B2 (en) 2010-09-01 2016-02-02 Arena Pharmaceuticals, Inc. Salts of lorcaserin with optically active acids
US9365521B2 (en) 2010-09-01 2016-06-14 Arena Pharmaceuticals, Inc. Non-hygroscopic salts of 5-HT2C agonists
US10226471B2 (en) 2010-09-01 2019-03-12 Arena Pharmaceuticals, Inc. Modified-release dosage forms of 5-HT2C agonists useful for weight management

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WO2010148207A2 (fr) 2009-06-18 2010-12-23 Arena Pharmaceuticals, Inc. Procédés pour la préparation d'agonistes du récepteur 5-ht2c
KR20130112848A (ko) 2010-06-02 2013-10-14 아레나 파마슈티칼스, 인크. 5-ｈｔ2ｃ 수용체 아고니스트의 제조 방법
CA2808900A1 (fr) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Formes posologiques a dissolution rapide d'agonistes de 5-ht2c

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La Revue du Praticien, vol. 40, no. 5, 11 February 1990, (Paris, FR), P.-J. GOADSBY et al.: "Physiopathologie de la migraine", pages 389-393, see page 391, column 1 *
Recenti Progressi in Medicina, vol. 80, no. 12, December 1989, J.W. LANCE: "Headache: classification, mechanism and principles of therapy, with particular reference to migraine", pages 673-680, see page 673: "Summary"; page 676, column 2 - page 677, column 1; page 678, column 2 *
The American Journal of Surgery, vol. 160, no. 1, July 1990, (US), D. LEBREC: "Current status and future goals of the pharmacologic reduction of portal hypertension", pages 19-25, see the whole article *

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CA2110575A1 (fr) 1993-01-07
JPH06508352A (ja) 1994-09-22
AU1927992A (en) 1993-01-25
IE921990A1 (en) 1992-12-30
MX9203012A (es) 1993-07-01
WO1993000094A3 (fr) 1993-03-04
EP0589973A1 (fr) 1994-04-06
PT100602A (pt) 1993-09-30
KR940701258A (ko) 1994-05-28

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