WO1992015592A1 - DERIVES DE TETRAHYDROTHIENO(2,3-c)PYRIDINE, PROCEDE DE PREPARATION DE CEUX-CI ET APPLICATION PHARMACEUTIQUE - Google Patents

DERIVES DE TETRAHYDROTHIENO(2,3-c)PYRIDINE, PROCEDE DE PREPARATION DE CEUX-CI ET APPLICATION PHARMACEUTIQUE Download PDF

Info

Publication number
WO1992015592A1
WO1992015592A1 PCT/EP1992/000411 EP9200411W WO9215592A1 WO 1992015592 A1 WO1992015592 A1 WO 1992015592A1 EP 9200411 W EP9200411 W EP 9200411W WO 9215592 A1 WO9215592 A1 WO 9215592A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
solvate
tetrahydrothieno
Prior art date
Application number
PCT/EP1992/000411
Other languages
English (en)
Inventor
Giuseppe Giardina
Roberto Colle
Vittorio Vecchietti
Original Assignee
Smithkline Beecham Farmaceutici S.P.A.
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 Farmaceutici S.P.A. filed Critical Smithkline Beecham Farmaceutici S.P.A.
Priority to JP4504940A priority Critical patent/JPH06508348A/ja
Publication of WO1992015592A1 publication Critical patent/WO1992015592A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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

  • Tetrahydroth1eno(2,3-c)pyr1d1ne derivatives process for their preparation their pharmaceutical appl ication.
  • This invention is concerned with novel heterocyclic derivatives, processes for their preparation, and their use in medicine.
  • kappa-receptor agonists act as analgesics through interaction with kappa opioid receptors.
  • EP-A-333427 and 370732 disclose groups of heterocyclic derivatives which exhibit kappa-receptor agonism without some of the behavioural effects of morphine and morphine analogues, and which are thus of potential therapeutic utility as analgesics.
  • a small class of heterocyclic derivatives falling within the scope of one or other of the above European Applications, but not specifically disclosed therein, has now been discovered which also exhibit potent kappa receptor agonism without some of the undesirable behavioural effects of morphine and morphine analogues, and are therefore of potential use in the treatment of pain.
  • This novel class of derivatives also possess diuretic activity which indicates that they are of potential use in the treatment of hyponatraemic disease states in mammals.
  • the novel class of derivatives are also of potential use in the treatment of other conditions which respond to administration of kappa agonists, in particular convulsions, cough, asthma, inflammation (including inflammation pain), pancreatitis, arrhythmias and cerebral ischaemia.
  • X and Y which may be the same or different, are each hydrogen, halogen, trifluoromethyl or together form a -CO(CH2)3- or -(CH.2 n - .group, in which n is 3 or 4;
  • Rj and R2 are each independently hydrogen, linear or branched C ⁇ _ ⁇ alkyl, C3.6 cycloalkyl or C4.12 cycloalkyl alkyl or together form a C2-8 polymethylene group; and R3 is hydrogen or methyl.
  • Examples of X and Y are, respectively, chlorine and chlorine, trifluoromethyl and hydrogen, and -CO(CB_2)3-.
  • Rj and R2 are -(CH2)4- and methyl.
  • 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 the 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.
  • the additional ionic and solvent moieties must also be non-toxic.
  • Examples of pharmaceutically acceptable salt of a compound 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 pharmaceutically acceptable solvates of a compound of formula (I) include hydrates.
  • the compounds of formula (I) have an 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 a compound of formula (ID:
  • Suitable active derivatives of the compound of formula (III) are the acid chloride or acid anhydride.
  • Another suitable derivative is a mixed anhydride formed between the acid and an alkyl chloroformate.
  • 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.
  • hydrates may be formed by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.
  • salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.
  • the compounds of formula (I) exist in more than one stereoisomeric form and the processes of the invention produces 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 would offer a route to the individual form.
  • the activity of the compounds of formula (I) in standard tests indicates that they are of potential therapeutic utility in the treatment of pain, cerebral ischaemia, hyponatraemic disease states, convulsions, cough, asthma, inflammation (including inflammation pain) pancreatitis and arrythmias (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
  • 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, (hereinafter referred to as the Compounds) in the manufacture of a medicament for the treatment of the Conditions.
  • 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 the Compound.
  • Medicaments and compositions containing the Compounds may be prepared by admixture of a Compound with an appropriate carrier, which may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • an appropriate carrier which may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • a medicament or 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 for the treatment of each of the Conditions.
  • the suitable dosage range for a Compound depends on the Compound to be employed, the Condition to be treated, 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 may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, 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 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, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • 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, polyvinylpyrrolidone, sodium
  • 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 quantities of fillers.
  • 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 capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • 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, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include 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; and if desired conventional flavouring or colour
  • compositions may be formulated, for example, for rectal administration as a suppository or for topical administration as a cream or lotion. 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 pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • a pharmaceutically acceptable liquid e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • 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 pharmaceutically acceptable additives.
  • 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 inject
  • the Compounds may also be administered by inhalation, via the nasal or oral routes.
  • administration can be carried out with a spray formulation comprising a Compound 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 comprises transdermal delivery utilising a skin-patch formulation.
  • a preferred formulation comprises a Compound 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.
  • pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.
  • the effective dose of Compound depends on the particular Compound employed, the Condition to be treated, the condition of the patient and on the frequency and route of administration.
  • 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 20mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • Example No. 1 Prepared as described in Example No. 1, from 1.7 g (7.65 mmoles) of 7-(p ⁇ rrolidin-l-yl)methyl-4,5,6,7-tetrahydrothieno [2,3-c] yridine, 2.12 g (15.36 mmoles) of anhydrous potassium carbonate and 1.88 g (8.40 mmoles) of distilled 4-trifluoro- methylphenylacetyl chloride in 50 ml of dry chloroform- The crude product was dissolved in 30 ml of ethyl acetate and the solution brought to acidic pH with HCl/Et2 ⁇ .
  • Example No. 1 Prepared as described in Example No. 1, from 1.1 g (5.60 mmoles) of 7-dimethylaminomethyl-4,5,6,7-tetrahydrothieno[2,3-c] pyridine, 1.8 g (13.04 mmoles) of anhydrous potassium carbonate and 1.6 g (7.19 mmoles) of distilled 3,4-dichlorophenylacetyl chloride in 30 ml of dry chloroform.
  • the crude product was purified by silica gel flash column chromatography, eluting with a mixture of CH2CI2 , MeOH, 28% NH4OH , 95:5:0.5 respectively, to afford the pure free base which was dissolved in 40 ml of ethyl acetate and the .solution was brought to acidic pH with HCl/Et2 ⁇ .
  • Example No. 1 Prepared as described in Example No. 1, from 1.1 g (5.60 mmoles) of 7-diraethylaminomethyl-4,5,6,7-tetrahydrothieno[2, 3-c] pyridine, 1.0 g (7.24 mmoles) of anhydrous potassium carbonate and 1.48 g (6.61 mmoles) of crude l-oxo.-3,4-dihydro-(2H)-napht-
  • the crude product was purified by silica gel flash column chromatography, eluting with ethyl acetate containing 1.5% of methanol and 0.5% of 28% NH4OH.
  • 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 experimentation. 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 20 min., 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 contraction of the abdomen associated with hind leg extension.
  • 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:
  • mice Male Charles River mice (Swiss Strain) , 22-34g body weight were used. Animals were allowed food and water ad libitum and were randomized into groups of 10 prior to experimentation. Before administration of the test compound, 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.
  • Radio receptor binding to kappa site is performed on fresh guinea pig brain homogenates prepared according to Kosterlitz (1981).
  • the pellet is then resuspended in the same buffer, incubated at 37°C for 45 min and centrifuged again.
  • the binding to the kappa sites is performed using a tritiated kappa selective compound.
  • Final homogenate with solutions of the cold ligand and of the labelled ligand is incubated for 40 min at 25°C, filtered through Whatman GF/C glass filter discs and washed.
  • the radioactivity bound to the filters is counted by liquid scintillation spectrophotometry.
  • the non-specific binding is determined in the presence of 500 nM of the benzomorphan non-selective compound Mr 2266.
  • Enkephalin 3H[D-Ala2, MePhe ⁇ , Gly-ol 5 ]
  • Enkephalin 3H-DAGO
  • an enkephalin analogue that binds selectively to mu receptor is added to the biological substrate and incubated at 25°C for 40 min, filtered through Whatman GF-C and washed with ice-cold Tris-buffer.
  • H-DADLE which binds to mu and delta sites, is used in the presence of 30 nM of unlabelled DAGO to prevent mu binding.
  • a concentration of radioligand near KD is used in the binding assays evaluating compounds of the invention.
  • Non-specific binding is determined by addition of Mr 2266 2.5 u .
  • the tubes are incubated for 40 min at 25°C and bound ligand is separated from free by filtration through Whatman GF/C filters.
  • the level of bound radioactivity of the filters is measured by liquid scintillation after solubilization in Filtercount.

Landscapes

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

Abstract

Dérivés de tetrahydrothionopyridine de formule (I) présentant une activité d'agoniste de récepteurs-kappa sont potentiellement utiles pour le traitement entre autres de la douleur et de l'ischémie cérébrale. X et Y, qui peuvent être identiques ou différents, représentent chacun hydrogène, halogène, trifluorométhyle ou bien forment ensemble un groupe -CO(CH2)3- ou -(CH2)n-, dans lequel n est égal à 3 ou 4; R1 et R2 représentent chacun indépendamment hydrogène, un alkyle C1-6 linéaire ou ramifié, un cycloalkyle C3-6 ou un cycloalkylalkyle C4-12 ou forment ensemble un groupe polyméthylène C2-8; et R3 représente hydrogène ou méthyle.
PCT/EP1992/000411 1991-03-07 1992-02-22 DERIVES DE TETRAHYDROTHIENO(2,3-c)PYRIDINE, PROCEDE DE PREPARATION DE CEUX-CI ET APPLICATION PHARMACEUTIQUE WO1992015592A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4504940A JPH06508348A (ja) 1991-03-07 1992-02-22 テトラヒドロチエノ（２，３−ｃ）ピリジン誘導体、その製造方法およびその医薬用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919104839A GB9104839D0 (en) 1991-03-07 1991-03-07 Novel compounds
GB9104839.7 1991-03-07

Publications (1)

Publication Number Publication Date
WO1992015592A1 true WO1992015592A1 (fr) 1992-09-17

Family

ID=10691165

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/000411 WO1992015592A1 (fr) 1991-03-07 1992-02-22 DERIVES DE TETRAHYDROTHIENO(2,3-c)PYRIDINE, PROCEDE DE PREPARATION DE CEUX-CI ET APPLICATION PHARMACEUTIQUE

Country Status (5)

Country Link
EP (1) EP0575362A1 (fr)
JP (1) JPH06508348A (fr)
AU (1) AU1277092A (fr)
GB (1) GB9104839D0 (fr)
WO (1) WO1992015592A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5366981A (en) * 1989-11-24 1994-11-22 Dr Lo Zambeletti S.P.A. N-acyl-substituted azacyclic compounds, processes for their preparaion, and their use as pharmaceuticals
US5428042A (en) * 1990-04-28 1995-06-27 Dr Lo Zambeletti S.P.A. 1-(2H-1-oxo-3,4-dihydronaphtyl-6-yl)-acetyl-piperidines as kappa agonists
WO2000014090A1 (fr) * 1998-09-02 2000-03-16 Novo Nordisk A/S Derives de 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine
US6090797A (en) * 1998-09-02 2000-07-18 Novo Nordisk A/S 4,5,6,7-tetrahydro-thieno(2,3-C)pyridine derivatives
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0333427A1 (fr) * 1988-03-16 1989-09-20 Smithkline Beecham Farmaceutici S.p.A. Dérivés d'hétérocycles
EP0366327A1 (fr) * 1988-10-18 1990-05-02 Glaxo Group Limited Furo- et thiéno[3,2-c]pyridines et compositions pharmaceutiques les contenant
EP0370732A2 (fr) * 1988-11-24 1990-05-30 SmithKline Beecham Farmaceutici S.p.A. Composés hétérocycliques azotés

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0333427A1 (fr) * 1988-03-16 1989-09-20 Smithkline Beecham Farmaceutici S.p.A. Dérivés d'hétérocycles
EP0366327A1 (fr) * 1988-10-18 1990-05-02 Glaxo Group Limited Furo- et thiéno[3,2-c]pyridines et compositions pharmaceutiques les contenant
EP0370732A2 (fr) * 1988-11-24 1990-05-30 SmithKline Beecham Farmaceutici S.p.A. Composés hétérocycliques azotés

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of Medicinal Chemistry, vol. 34, no. 8, August 1991, (Washington, DC, US), V. VECCHIETTI et al.: "(1S)-1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinoline and heterocycle-condensed tetrahydropyridine derivatives: Members of a novel class of very potent k opioid analgesics", pages 2624-2633, see abstract; page 2627, table IV, compound 51, scheme III, compound 24 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5366981A (en) * 1989-11-24 1994-11-22 Dr Lo Zambeletti S.P.A. N-acyl-substituted azacyclic compounds, processes for their preparaion, and their use as pharmaceuticals
US5428042A (en) * 1990-04-28 1995-06-27 Dr Lo Zambeletti S.P.A. 1-(2H-1-oxo-3,4-dihydronaphtyl-6-yl)-acetyl-piperidines as kappa agonists
WO2000014090A1 (fr) * 1998-09-02 2000-03-16 Novo Nordisk A/S Derives de 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine
US6090797A (en) * 1998-09-02 2000-07-18 Novo Nordisk A/S 4,5,6,7-tetrahydro-thieno(2,3-C)pyridine derivatives
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10085968B2 (en) 2009-12-04 2018-10-02 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10894033B2 (en) 2009-12-04 2021-01-19 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11958862B2 (en) 2016-07-29 2024-04-16 Sumitomo Pharma America, Inc. Compounds and compositions and uses thereof
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11440921B2 (en) 2018-02-16 2022-09-13 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11987591B2 (en) 2018-02-16 2024-05-21 Sumitomo Pharma America, Inc. Salts, crystal forms, and production methods thereof
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders

Also Published As

Publication number Publication date
EP0575362A1 (fr) 1993-12-29
JPH06508348A (ja) 1994-09-22
GB9104839D0 (en) 1991-04-17
AU1277092A (en) 1992-10-06

Similar Documents

Publication Publication Date Title
US5366981A (en) N-acyl-substituted azacyclic compounds, processes for their preparaion, and their use as pharmaceuticals
US4999359A (en) Heterocyclic ethylene diamine compounds and their pharmaceutical compositions and methods
US4826819A (en) Piperidine analgesics
US5030649A (en) 2-aminoethylamine derivatives, compositions of the same and use of said compounds in medicine
US5041451A (en) Tetrahydroisoquinoline and tetrahydrothieno derivatives
EP0330360B1 (fr) 1,2,3,4-Tetrahydroisoquinolines, procédé pour leur préparation et leur utilisation comme agoniste de Kappa-récepteur
WO1992017467A1 (fr) Composes azacycliques substitues, leur procede de preparation et leur utilisation a titre d'analgesiques
WO1992015592A1 (fr) DERIVES DE TETRAHYDROTHIENO(2,3-c)PYRIDINE, PROCEDE DE PREPARATION DE CEUX-CI ET APPLICATION PHARMACEUTIQUE
EP0333315B1 (fr) Composés azacycliques, procédés pour leur préparation et leur application comme médicaments
EP0409489B1 (fr) Médicaments
EP0228246B1 (fr) Composés de l'isoquinoléine
US5968949A (en) Substituted hydroisoquinoline derivatives and their use as pharmaceuticals
US5441956A (en) Hydroisoquinoline derivatives
EP0873330B1 (fr) Derives de diarylalcenylamine
US5981540A (en) Heterocycle-condensed morphinoid derivatives
EP0585296A1 (fr) Derives de 2-(pyrrolidinyle-1-methyle)-piperidine et leur utilisation comme agonistes de recepteurs kappa
WO1990007502A1 (fr) Composes de decahydroisoquinoline
US5428042A (en) 1-(2H-1-oxo-3,4-dihydronaphtyl-6-yl)-acetyl-piperidines as kappa agonists
KAPPA Vecchietti et al.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)

Free format text: AU,CA,KR

WWE Wipo information: entry into national phase

Ref document number: 1992905359

Country of ref document: EP

ENP Entry into the national phase

Ref country code: US

Ref document number: 1993 117001

Date of ref document: 19930907

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1992905359

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1992905359

Country of ref document: EP