EP0585296A1 - Derives de 2-(pyrrolidinyle-1-methyle)-piperidine et leur utilisation comme agonistes de recepteurs kappa - Google Patents

Derives de 2-(pyrrolidinyle-1-methyle)-piperidine et leur utilisation comme agonistes de recepteurs kappa

Info

Publication number
EP0585296A1
EP0585296A1 EP92910424A EP92910424A EP0585296A1 EP 0585296 A1 EP0585296 A1 EP 0585296A1 EP 92910424 A EP92910424 A EP 92910424A EP 92910424 A EP92910424 A EP 92910424A EP 0585296 A1 EP0585296 A1 EP 0585296A1
Authority
EP
European Patent Office
Prior art keywords
methyl
compound
formula
trifluoromethylphenyl
acetyl
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.)
Withdrawn
Application number
EP92910424A
Other languages
German (de)
English (en)
Inventor
Giuseppe Giardina
Roberto Colle
Geoffrey Douglas Clarke
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.)
GlaxoSmithKline SpA
Original Assignee
Smithkline Beecham Farmaceutici SpA
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 GB919110951A external-priority patent/GB9110951D0/en
Priority claimed from GB919114772A external-priority patent/GB9114772D0/en
Application filed by Smithkline Beecham Farmaceutici SpA filed Critical Smithkline Beecham Farmaceutici SpA
Publication of EP0585296A1 publication Critical patent/EP0585296A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention is concerned with novel substituted azacyclic derivatives, processes for their preparation, and their use in medicine, particularly, but not exclusively, as
  • kappa-receptor agonists through interaction with kappa opioid receptors.
  • EP-A-330461, 330467 and 330469 (Glaxo Group Ltd).
  • EP-A-361791 and WO 91/08206 disclose groups of azacyclic derivatives which are stated to exhibit kappa-receptor agonism, and which are said to be of
  • the new derivatives are also of potential use in other therapeutic treatments which are associated with kappa agonists, in particular the treatment of convulsions, cough, asthma, inflammation (including inflammation pain),
  • pancreatitis pancreatitis, arrhythmias, hyponatraemic disease states and cerebral ischaemia.
  • a compound of formula (I) or a solvate or salt thereof.
  • the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of a compound of formula (I) or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.
  • crystalline form including such form in a pharmaceutical composition.
  • a pharmaceutically acceptable salt of the compounds of formula (I) include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • Examples of a pharmaceutically acceptable solvate of the compounds of formula (I) include hydrates.
  • the compounds of formula (I) have at least one asymmetric centre and therefore exist in more than one stereoisomeric form.
  • the invention extends to all such forms and to mixtures thereof, including racemates.
  • the present invention also provides a process for the preparation of a compound of formula (I) which comprises reacting 4-trifluoromethylphenylacetic acid, or an active derivative thereof, with a compound of formula I (a)
  • R 1 , R 2 , R 3 , R 4 and X are as defined in formula (I), and then optionally forming a salt and/or solvate of the obtained compound of formula (I).
  • a suitable active derivative of 4-trifluoromethylphenylacetic acid is the acid chloride.
  • the compounds of formula (I) may be converted into their pharmaceutically acceptable acid addition salts by reaction with the appropriate organic or mineral acids.
  • Solvates of the compounds of formula (I) may be formed by crystallization or recrystallization from the appropriate solvent. For example hydrates may be formed by
  • the compounds of formula (I) exist in more than one stereoisomeric form and the processes of the invention produce mixtures thereof.
  • the individual isomers may be separated one from another by resolution using an optically active acid such as tartaric acid.
  • an asymmetric synthesis may be used.
  • Compounds of formula (I(a)) may be prepared from known compounds by known methods, such as those described in WO 91/08206.
  • the (R,S;R,S) compound of formula I(a) in which X is hydroxy, R 1 is hydrogen, R 2 and R 3 are both methyl, and R 4 is hydrogen may be prepared according to the method described in Descriptions 1(a) and 1(b) of WO 91/08206, but starting from N-ethoxycarbonyl-4,4-dimethyl pippecolic acid instead of 1-ethoxycarbonylpipecolic acid.
  • N-ethoxycarbonyl-4,4-dimethylpipecolic acid is treated firstly with thionylchloride in dry methylene chloride, and the reaction mixture is then treated with
  • the activity of the compounds of formula (I) in standard tests indicates that they are of potential therapeutic utility in the treatment of pain, hyponatraemic disease states, cerebral ischaemia, convulsions, cough, asthma, inflammation (including inflammation pain), arrhythmias, and pancreatitis (hereinafter referred to as the 'Conditions').
  • the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.
  • the present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Conditions.
  • a medicament, and a composition of this invention may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the Conditions.
  • the suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • the compound or composition of the invention may be
  • composition is suitable for oral, rectal, topical, inhalation, parenteral, intravenous or intramuscular administration.
  • Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges. reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin,
  • sorbitol tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinyl- pyrrolidone, sodium starch glycollate or
  • microcrystalline cellulose or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large
  • compositions When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
  • edible oils for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline
  • preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid
  • flavouring or colouring agents for example almond oil,
  • compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an
  • the compounds of this invention may also be administered by inhalation, via the nasal or oral routes.
  • inhalation via the nasal or oral routes.
  • administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
  • Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles.
  • the compound particle size is from about 2 to 10 microns.
  • a further mode of administration of the compounds of the invention comprises transdermal delivery utilising a skin-patch formulation.
  • a preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient. For a constant rate of
  • a unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • the composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • the present invention also provides a method for the treatment and/or prophylaxis of the Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of a compound of formula (I) or a
  • the reaction mixture was allowed to reach room temperature and left overnight.
  • the reaction mixture was allowed to reach room temperature and left overnight.
  • the compound was prepared according to the method described in
  • the compound was prepared following Description 2 of WO 91 / 08206 and starting from 4 g (18.51 mmoles) of 1-chloromethyl-3,4-dihydroisoquinoline hydrochloride [J. Am. Chem. Soc. 59, 2555 (1933)] and 4.9 g (39.65 mmoles) of (3S)-3-fluoropyrrolidine hydrochloride.
  • the compound was prepared following Description 2 o WO 91 / 08206 and starting from 4 g (16.38 mmoles) of 1 chloromethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline
  • the compound was prepared following Descriptions 1a and 1b of WO 91 / 08206 and starting from 2.75 g (12.00 mmoles) of (RS)-N- ethoxycarbony1-4,4-dimethyl pipecolic acid and 2.61 g (29.9 mmoles) of (3S)-3-hydroxypyrrolidine.
  • reaction mixture was allowed to reach room temperature and stirred overnight, washed with water , 5% NaHCO 3 and the organic solution dried over Na 2 SO 4 ; the solvent was evaporated in vacuo to dryness and the residue purified by 230-400 mesh silica gel flash column chromatography, eluting with ethyl acetate containing 0.6% of 28% NH 4 OH.
  • the crude product was purified by silica gel flash column chromatography, eluting with a mixture of EtOAc/n-hexane/28% NH 4 OH, 40:10:0.3 respectively to yield 800 mg of the pure free base which was dissolved in EtOAc and the solution brought to acidic pH with HCl/Et 2 O.
  • the crude product was purified by silica gel flash column chromatography, eluting with a mixture of EtOAc/n-hexane/28% NH 4 OH, 40:10:0.2 respectively to yield 1.8 g of the pure free base which was dissolved in ethyl acetate and the solution brought to acidic pH with HCl/Et 2 O.
  • the crude product was purified by silica gel flash column chromatography, eluting with a mixture of EtOAc/n-hexane/28% NH4OH, 25:25:0.2 respectively to yield 1.7 g of the pure free base which was recrystallized from n-hexane to yield 1.6 g of the title compound.
  • the crude product was purified by silica gel flash column chromatography, eluting with a mixture of CH 2 Cl 2 /MeOH/28% NH 4 OH, 94.5:5:0.5 respectively to obtain 1.8 g of the pure free base which was dissolved in ethyl acetate and the solution brought to acidic pH with HCl/Et 2 O.
  • the pharmacological activity of the compounds of this invention is illustrated by various in vitro and in vivo models, using the following test procedures, in which the mousetail flick test demonstrates analgesic activity.
  • mice Male Charles. River mice (Swiss Strain), 25-36g body weight, were used. Animals were allowed food and water ad libitum and were randomized into groups of 10 prior to
  • Test compounds were dissolved in either distilled water or distilled water plus 0.1 M AMS, and administered by the subcutaneous route in a final volume of 10 ml/Kg. Control animals received 10 ml/Kg of the
  • mice were injected intraperitoneally with p-phenylquinone, 2 mg/Kg at 37°C in a final volume of 10 mg/Kg.
  • mice were placed, in groups of 3, in a compartmented perspex box maintained at room temperature and were observed for a period of 8 min. During this period the number of abdominal writhing responses per animal were recorded where writhing consists of an intermittent
  • the degree of antinociceptive protection afforded by the test compound was determined as the mean number of writhing responses observed in the treated group (T) expressed as a percentage of the mean number of writhing responses in the control group (C) according to the following formula:
  • the reaction time of each animal was determined by focusing a beam of light onto the tail, eliciting a reflex withdrawal after a certain latency; only mice exhibiting a latency between 3-8 sec. were used subsequently in the evaluation of drug effects.
  • Test compounds were dissolved in either distilled water or distilled water plus 0.1 M AMS and administered by the subcutaneous route in a final volume of 10 ml/Kg. Control animals received 10 ml/kg of the appropriate vehicle alone. Following a pretreatment period of 30 min., the mice were again placed under the heat source and the reaction tine re-determined.
  • Percentage quantal protection was determined as the number of mice in which the reaction time was doubled compared to pretreatment values, expressed as a percentage of the total number of mice in the group.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Des dérivés azacycliques ayant la formule (I) sont des agonistes de récepteurs-kappa et peuvent être utilisés pour le traitement des convulsions, de la toux, de l'asthme, des inflammations, de la pancréatite, des arythmies, des états hyponatrémiques et de l'ischémie cérébrale.
EP92910424A 1991-05-21 1992-05-15 Derives de 2-(pyrrolidinyle-1-methyle)-piperidine et leur utilisation comme agonistes de recepteurs kappa Withdrawn EP0585296A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB919110951A GB9110951D0 (en) 1991-05-21 1991-05-21 Azacyclic derivatives
GB9110951 1991-05-21
GB919114772A GB9114772D0 (en) 1991-07-09 1991-07-09 Azacyclic derivatives
GB9114772 1991-07-09

Publications (1)

Publication Number Publication Date
EP0585296A1 true EP0585296A1 (fr) 1994-03-09

Family

ID=26298933

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92910424A Withdrawn EP0585296A1 (fr) 1991-05-21 1992-05-15 Derives de 2-(pyrrolidinyle-1-methyle)-piperidine et leur utilisation comme agonistes de recepteurs kappa

Country Status (7)

Country Link
EP (1) EP0585296A1 (fr)
JP (1) JPH06511231A (fr)
AU (1) AU1760992A (fr)
IE (1) IE921620A1 (fr)
MX (1) MX9202352A (fr)
PT (1) PT100499A (fr)
WO (1) WO1992020657A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6239154B1 (en) 1996-03-08 2001-05-29 Adolor Corporation Kappa agonist compounds pharmaceutical formulations and method of prevention and treatment of pruritus therewith
US5763445A (en) 1996-03-08 1998-06-09 Adolor Corporation Kappa agonist compounds pharmaceutical formulations and method of prevention and treatment of pruritus therewith
USRE38133E1 (en) * 1996-03-08 2003-06-03 Adolor Corporation Kappa agonist compounds and pharmaceutical formulations thereof
US6057323A (en) * 1996-03-08 2000-05-02 Adolor Corporation Kappa agonist compounds pharmaceutical formulations and method of prevention and treatment of pruritus therewith
US6303611B1 (en) * 1996-03-08 2001-10-16 Adolor Corporation Kappa agonist compounds and pharmaceutical formulations thereof
US5688955A (en) * 1996-03-08 1997-11-18 Adolor Corporation Kappa agonist compounds and pharmaceutical formulations thereof
US5646151A (en) * 1996-03-08 1997-07-08 Adolor Corporation Kappa agonist compounds and pharmaceutical formulations thereof
US6750216B2 (en) 1996-03-08 2004-06-15 Adolor Corporation Kappa agonist compounds and pharmaceutical formulations thereof
US5760023A (en) * 1997-07-14 1998-06-02 Adolor Corporation Kappa agonist anti-pruritic pharmaceutical formulations and method of treating pruritus therewith
JP2003526594A (ja) * 1997-07-14 2003-09-09 アドラー コーポレーション カッパ・アゴニスト抗掻痒薬学的製剤およびそれにより掻痒を治療する方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8804104D0 (en) * 1988-02-23 1988-03-23 Glaxo Group Ltd Chemical compounds
EP0330467A1 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Composés hétérocycliques
PT89780A (pt) * 1988-02-23 1989-10-04 Glaxo Group Ltd Processo para a preparacao de derivados da tetrahidroisoquinolina
DE68924751T2 (de) * 1988-09-26 1996-04-11 Smithkline Beecham Farma Azacyclische Verbindungen, verwendbar als Arzneimittel.
WO1991008206A1 (fr) * 1989-11-24 1991-06-13 Dr. Lo. Zambeletti S.P.A. Composes azacycliques a substitution n-acyle, procedes de preparation de ces composes et utilisation de ces composes comme pharmaceutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9220657A1 *

Also Published As

Publication number Publication date
PT100499A (pt) 1994-05-31
WO1992020657A1 (fr) 1992-11-26
MX9202352A (es) 1992-11-01
IE921620A1 (en) 1992-12-02
AU1760992A (en) 1992-12-30
JPH06511231A (ja) 1994-12-15

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