EP0527964A1 - Tetrahydrobenzothienopyridines, leurs procedes de preparation et leur emploi en tant qu'agents pharmaceutiques - Google Patents

Tetrahydrobenzothienopyridines, leurs procedes de preparation et leur emploi en tant qu'agents pharmaceutiques

Info

Publication number
EP0527964A1
EP0527964A1 EP91920966A EP91920966A EP0527964A1 EP 0527964 A1 EP0527964 A1 EP 0527964A1 EP 91920966 A EP91920966 A EP 91920966A EP 91920966 A EP91920966 A EP 91920966A EP 0527964 A1 EP0527964 A1 EP 0527964A1
Authority
EP
European Patent Office
Prior art keywords
methyl
amino
thieno
pyridine
tetrahydrobenzo
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Withdrawn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
EP91920966A
Other languages
German (de)
English (en)
Inventor
D.Th. Smithkline Beecham Pharmaceuticals Davies
I.Th. Smithkline Beecham Pharmaceuticals Forbes
M. Smithkline Beecham Pharmaceuticals Thompson
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.)
Beecham Group PLC
Original Assignee
Beecham Group 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
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0527964A1 publication Critical patent/EP0527964A1/fr
Withdrawn legal-status Critical Current

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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

  • This invention relates to compounds having pharmacological activity, to a process for their preparation, to
  • compositions containing them and to their use in the treatment of mammals are provided.
  • EP-A-0 327 223 (Beecham Group pic) discloses a class of tetrahydrobenzothienopyridines which have anxiolytic and/or anti-depressant activity.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen, C 1-6 alkyl, phenyl or phenyl C 1-4 alkyl wherein the phenyl moiety is optionally substituted by one or more C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, hydroxy, C 2-7 alkanoyi, halo, trifluoromethyl, nitro, amino optionally substituted by one or two C 1-6 alkyl groups or by C 2-7 alkanoyl, cyano, carbamoyl or carboxy groups;
  • R 2 and R 3 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkyl, C 2-6 alkenyl, C 1-7 alkanoyl, C 1-6 alkylsulphonyl, di-(C 1-6 alkyl) amino C 1-6 alkyl, 3-oxobutyl, 3-hydroxybutyl, phenyl, phenyl C 1-4 alkyl, benzoyl, phenyl C 2-7 alkanoyl or
  • benzenesulphonyl any of which phenyl moieties are optionally substituted by one or two halogen, C 1-6 alkyl, C 1-6 alkoxy, CF 3 , amino or carboxy, or R 2 and R 3 together are C 2-6 polymethylene optionally interrupted by oxygen or NR 6 wherein R 6 is hydrogen or C 1-6 alkyl optionally substituted by hydroxy;
  • R 5 is hydrogen or C 1-6 alkyl and R 8 is hydrogen or R 5 and R 8 together form a C 1-6 alkylidene group at the 8-position; and -CO 2 R 4 is a pharmaceutically acceptable ester group.
  • Alkyl moieties within the variables R 1 to R 5 are preferably C 1-3 alkyl, such as methyl, ethyl and n- and iso-propyl. Values for R 1 include hydrogen, methyl, ethyl, n- and
  • R 1 is methyl.
  • R 2 and R 3 include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, n-, sec, iso- and neo-pentyl, cyclopentyl, cyclohexyi, cycloheptyl,
  • cyclopentyl-C 1-4 alkyl cyclohexyl-C 1-4 alkyl and cycloheptyl-C 1-4 alkyl, where values for C 1-4 alkyl include methylene and ethylene, but-2-enyl, but-3-enyl,
  • polymethylene - (CH 2 ) 2 -O-(CH 2 ) 2 - or - (CH 2 ) 2 -NR 6 - (CH 2 ) 2 - where R 6 is preferably methyl.
  • R 2 is hydrogen and R 3 is hydrogen or C 1-6 alkyl, for example methyl. Most preferably R 2 and R 3 are hydrogen.
  • Suitable examples of pharmaceutical esters of the compounds of formula (I) include C 1-6 alkyl esters wherein the alkyl moiety is optionally substituted by up to three halo atoms selected from chloro, fluoro and bromo, such as methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl and
  • C 2 , 2 ,2-trifluoroethyl esters C 2-6 alkenyl esters such as vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-3-enyl, 1-methylenepropyl and l-methylprop-2-enyl, (in both their E and Z forms where stereoisomerism exists), C 2-6 alkynyl esters such as prop-2-ynyl, but-2-ynyl and but-3- ynyl, C 3-6 cycloalkyl esters and C 3-6 cycloalkyl-C 1-4 alkyl esters such as cyclopropylmethyl.
  • C 2-6 alkenyl esters such as vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-3-enyl, 1-methylenepropyl and l-methylprop-2-enyl, (in both their E and Z forms where stereoisome
  • ester is the methyl, ethyl, 2,2,2-trifluoroethyl, propyl, prop-2-enyl, prop-2-ynyl, but- 3-enyl, but-2-ynyl, but-3-ynyl or cyclopropylmethyl ester, i.e.
  • R 4 is methyl, ethyl, 2,2,2-trifluoroethyl, propyl, prop-2-enyl, prop-2-ynyl, but-3-enyl, but-2-ynyl, but-3-ynyl or cyclopropylmethyl.
  • Suitable values of R 5 include hydrogen, methyl, ethyl and n and iso propyl, preferably hydrogen.
  • R 5 and R 8 together may represent an 8-(1-methylethylidene) group.
  • R 3 1 is hydrogen or C 1-6 alkyl and R 1 and R 4 are as defined in formula (I).
  • the compounds of the formula (I) can form acid addition salts with acids, such as the conventional pharmaceutically acceptable acids, for example, maleic, hydrochloric,
  • substituents R 1 , R 2 , R 3 , R 4 , and R 5 may contain asymmetric carbon atoms.
  • the present invention extends to any single stereoisomers such as enantiomers, or mixtures thereof including racemates, of compounds of formula (I).
  • the invention also provides a process for the preparation of a compound of formula (I) , or a pharmaceutically acceptable salt thereof which process comprises the cyclisation of a compound of formula (III):
  • R 1 ' is R 1 as defined in formula (I) or a group convertible thereto
  • R 4 ' is -CO 2 R 4 as defined in formula (I) or an electron-withdrawing group convertible to -CO 2 R 4
  • R 5 and R 8 are as defined as in formula (I)
  • R 7 is hydrogen or an N-protecting group
  • J and K together represent a keto group or a group convertible thereto
  • Y is a group CN or COL 1 , wherein L 1 is a leaving group and M is hydrogen, or Y is hydrogen and M is a group CN or COL 2 , wherein L 2 is a leaving group; and thereafter, optionally or as necessary, and in any appropriate order, converting R 7 when hydrogen to an N-protecting group, when Y or M is a group COL 1 or COL 2 , converting the resulting hydroxy group to a leaving group and reacting the latter with a compound HNR 2 'R 3 ' wherein R 2 ' and R
  • the cyclisation of the enamine of formula (III) or imine tautomer thereof may be carried out under conventional conditions, in the presence of a strong base such as an alkali metal alkoxide, for example sodium methoxide in a suitable solvent such as methanol, at elevated temperature, or in the presence of a Lewis acid such as ZnCl 2 , SnCl 4 or CuOCOCH 3 in a suitable solvent such as n-butyl acetate at elevated temperature.
  • a strong base such as an alkali metal alkoxide, for example sodium methoxide in a suitable solvent such as methanol
  • a Lewis acid such as ZnCl 2 , SnCl 4 or CuOCOCH 3 in a suitable solvent such as n-butyl acetate at elevated temperature.
  • Lewis acid catalysed cyclisation using copper (I) acetate or tin (IV) chloride is preferred especially when cyclising to. give compounds of formula (I) directly i.e. where R 4 ' is CO 2 R 4 .
  • J and K together represent a group convertible to a keto group such as a protected hydroxy group or a
  • trimethylsilyl or tetrahydropyranyl may be de-protected conventionally to give a hydroxy group which may be oxidised conventionally for example using oxalylchloride/
  • keto groups J and K are exemplified by compounds of formula (III) wherein J is XR 13 and K is ZR 14 , X and Z are independently oxygen or sulphur and R 13 and R 14 are independently C 1-6 alkyl or together are C 2-4 polymethylene optionally substituted with one or more C 1-6 alkyl groups.
  • the group -X-R 13 and -Z-R 14 may be conventionally converted to a keto group for example by treatment with aqueous hydrochloric acid.
  • keto group conventionally converted to a keto group, for example by treatment with aqueous hydrochloric acid or quaternisation of the sulphur atom followed by hydrolysis, for example using an alkylhalide followed by water.
  • the group -X-R 13 and -Z-R 14 may be conventionally converted to a keto group by reacting one of the sulphur atoms with;
  • quaternising agent such as an alkylhalide or
  • an oxidising agent such as a peracetic acid and thereafter, hydrolysing off the protecting group to afford a keto group, for example using aqueous acetone or aqueous acetonitrile.
  • X and Z are oxygen.
  • R 5 and R 8 hydrogen may be converted to an alkylidene group in the 8-position by an aldol condensation with an appropriate aldehyde or ketone, such as acetone.
  • alkylidene group may then be hydrogenated to the
  • R 5 alkyl group conventionally using, for example, a palladium on charcoal catalyst.
  • R 7 N-protecting groups include trimethylsilyl and 2-(trimethylsilyl)ethoxymethyl, which may be removed conventionally, for example using tetra-n-butylammonium fluoride.
  • R 7 is hydrogen
  • Suitable examples of groups R 4 ' include the groups
  • R 11 is hydrogen or C 1-6 alkyl, e.g. morpholino or piperazino.
  • a protecting group Q may be removed by conventional
  • reaction with a suitable chlorinating agent such as thionyl chloride, or with an alkylating agent R 4 X where X is a leaving group such as chloro, bromo or iodo, in the presence of a suitable base such as potassium carbonate in an inert solvent such as dimethylformamide.
  • a suitable chlorinating agent such as thionyl chloride
  • R 4 X where X is a leaving group such as chloro, bromo or iodo
  • An intermediate amide may be hydrolysed to the free acid which can then be esterified as described above.
  • R 4 ' cyano group may be converted under anhydrous acidic conditions to an imino ester by reaction with the
  • R 4 ' COR a groups may be converted to CO 2 R 4 via the acid by a haloform reaction and esterification.
  • Suitable examples of a leaving groups L 1 and L 2 when Y or M is COL 1 or COL 2 include hydroxy and, more preferably, alkoxy such as C 1-6 alkoxy, for example ethoxy or methoxy.
  • the cyclisation of the compound of formula (III) or imine tautomer thereof gives a resulting compound having an hydroxy group in the 4-position of the pyridine ring.
  • the hydroxy group may be converted to a leaving group such as those defined below for L, preferably halo such as chloro, by reaction with a halogenating agent such as phosphorus oxychloride or phosphorus oxybromide.
  • the leaving group may be displaced by the compound HNR 2 'R 3 ' under conventional conditions for nucleophilic aromatic displacements, at elevated temperatures in an inert solvent such as toluene, methanol, ethanol, ine, dimethylformamide or dioxan.
  • an inert solvent such as toluene, methanol, ethanol, ine, dimethylformamide or dioxan.
  • reaction may be carried out in neat
  • R 2 ' or R 3 ' protecting group such as p-methoxybenzyl may be removed conventionally.
  • R 2 and R 3 hydrogen to other R 2 /R 3 may be carried out in accordance with conventional procedures for the alkylation or acylation of a primary amine. Acylation may be carried out by reaction with the appropriate acyl halide. However, R 2 /R 3 other than hydrogen or acyl groups are preferably introduced via the route in which Y or M is COL 1 or COL 2 in the compound of formula (III), by
  • Suitable examples of the leaving group L include halogens, such as chloro and bromo, hydroxy, C 1-6 acyloxy such as acetoxy, C 1-6 alkoxy, such as methoxy or ethoxy, preferably methoxy or NR a R b where R a and R b are independently hydrogen or C 1-4 alkyl or together form a C 2-6 polymethylene chain optionally interrupted by oxygen or NR C where R c is hydrogen or C 1-6 alkyl optionally substituted by hydroxy.
  • L is hydroxy, it will be appreciated that the compound of formula (V) exists in more than one tautomeric form.
  • reaction of a compound of formula (IV) with a compound of formula (V) may be carried out under conditions
  • L is a leaving group and R 1 ' is hydroxy.
  • the R 1 ' hydroxy may be converted to hydrogen by first replacing it by chloro by conventional chlorination with a chlorinating agent such as phosphorus oxychloride followed by reductive dehalogenation under conventional conditions, for example zinc in acetic acid.
  • the conversion to R 1 hydrogen may be carried out before or, more preferably, after cyclisation of the compound of formula (III);
  • L is a leaving group
  • M and R 4 ' are both C 1-6 alkoxycarbonyl
  • R 1 ' is hydrogen
  • Compounds of formula (VI) are either known compounds or car. be prepared analogously to known compounds.
  • a class of intermediates comprises compounds of formula (VII) or a salt ester or amide thereof:
  • R 4 '' is R 4 ' as defined in formula (III) or a group convertible to CO 2 R 4
  • X is NR 2 /R 3 ', OH or chloro
  • R 1 ', R 2 ', R 3 ', J and K are as defined in formula (III)
  • R 4 , R 5 and R 8 are as defined in formula (I), provided that when X is NR 2 R 3 , J and K together represent a keto group and R 1 ' is R 1 , R 4 '' is other than CO 2 R 4 .
  • Novel compounds of formula (VII) also form part of the invention.
  • R4 '' when other than CO 2 R 4 include CO 2 H.
  • the invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof which process comprises deprotecting a compound of formula (VII) in which X is NR 2 R 3 , R 4 '' is CO 2 R 4 and R 1 ' is R 1 , and J and K
  • the present invention also provides a pharmaceutically acceptable salt of a compound of formula (I).
  • composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral or
  • parenteral administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, or injectable or infusable solutions or suspensions.
  • Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants,
  • disintegrants and acceptable wetting agents are disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for
  • liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or
  • concentration used can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a number of weeks or months.
  • the invention further provides a pharmaceutical composition for use in the treatment of CNS disorders, in particular anxiety or depression which composition comprises an
  • the invention further provides a method for the treatment and/or prophylaxis of CNS disorders, in particular anxiety or depression in mammals, including humans, which comprises administering to the sufferer an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof for the use in the treatment and/or prophylaxis of CNS disorders, in particular anxiety or depression.
  • the invention yet further provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment and/or prophylaxis of CNS disorders, in particular anxiety or depression.
  • the title compound was prepared in 5% overall yield from D1 and 3-oxo-butyric acid, 2-but-2-ynyl ester via the intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, but-2-ynyl ester using a procedure similar to that described in Example 2. m.p. 190-2° (from ethyl acetate).
  • the title compound was prepared in 1% overall yield from 2,2,2-trifluoroethyl acetoacetate and D1 via the
  • the title compound was prepared in 5% overall yield from D1 and 3-oxo-butyric acid, but-3-ynyl ester via the
  • Geller-Seifter Procedure Potential anxiolytic properties have been evaluated using the Geller-Seifter procedure based on that originally described by Geller and Seifter, (1960) Psychopharmacologia, 1, 482-492. This procedure has been shown to be selective for drugs with anxiolytic properties (Cook and Sepinwall, (1975) ''Mechanism of Action of Benzodiazepines'' ed. Costa, E. and Greengard, P., Raven Press, New York, pp. 1-28).
  • Rats are trained on a variable interval 30 sec schedule (VI30) to press a lever in order to obtain food reward.
  • the 5 min sessions of the VI30 schedule alternate with 2-5 min of a schedule (FR5) in which every 5th lever press is followed by presentation of a food pellet paired with a 0.5 sec mild footshock.
  • the total study lasts approximately 30 mins .
  • Rats typically respond with high rates of lever pressing under the VI30 schedule and low response rates under the FR5 'conflict' session.
  • Anxiolytic drugs increase the suppressed response rates of rats in 'conflict' session.
  • Drugs are administered intraperitoneally or orally to groups of 3-8 rats 30 min before testing.
  • tissue suspension 50 ⁇ l is incubated (25°C, 120 mins) with [ 35 S]-TBPS (2nM) in Tris citrate buffer (pH 7.1) containing 0.2M NaCl and 5 x 10 -6 M GABA. Non-specific binding is measured in the presence of 10 M picrotoxin.
  • IC 50 'S are calculated as the concentration of test drug to inhibit 50% of specific binding.
  • Example 1 20 p. o. + 52% Compound E2 also showed a significant increase in responding in the 'conflict' session at a dose of 20mg/kg p.o.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Public Health (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Tétrahydrobenzothiénopyridines possédant une efficacité pharmacologique, procédés de préparation et d'utilisation de ces composés en tant que produits pharmaceutiques.
EP91920966A 1990-05-08 1991-05-01 Tetrahydrobenzothienopyridines, leurs procedes de preparation et leur emploi en tant qu'agents pharmaceutiques Withdrawn EP0527964A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909010296A GB9010296D0 (en) 1990-05-08 1990-05-08 Novel compounds
GB9010296 1990-05-08

Publications (1)

Publication Number Publication Date
EP0527964A1 true EP0527964A1 (fr) 1993-02-24

Family

ID=10675638

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91920966A Withdrawn EP0527964A1 (fr) 1990-05-08 1991-05-01 Tetrahydrobenzothienopyridines, leurs procedes de preparation et leur emploi en tant qu'agents pharmaceutiques

Country Status (10)

Country Link
EP (1) EP0527964A1 (fr)
JP (1) JPH06505698A (fr)
AU (1) AU641504B2 (fr)
CA (1) CA2082392A1 (fr)
GB (1) GB9010296D0 (fr)
IE (1) IE911532A1 (fr)
NZ (1) NZ238055A (fr)
PT (1) PT97570A (fr)
WO (1) WO1991017165A1 (fr)
ZA (1) ZA913394B (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9117459D0 (en) * 1991-08-13 1991-09-25 Smithkline Beecham Plc Novel compounds
MX9206365A (es) * 1991-11-07 1994-02-28 Smithkline Beecham Plc Tetrahidrobenzotienopiridinas,proceso para su preparacion y composicion farmaceutica que las contiene
GB9127188D0 (en) * 1991-12-21 1992-02-19 Smithkline Beecham Plc Novel compounds
GR920100421A (el) * 1992-10-08 1994-06-30 Smithkline Beecham Plc Τετραυδροβενζοθειενοπυριδινες εχουσα δραση κ.ν.ς.
WO1994018205A1 (fr) * 1993-02-11 1994-08-18 Smithkline Beecham Plc Tetrahydrobenzothienopyridines exerçant une activite sur le systeme nerveux central
GB9309179D0 (en) * 1993-05-05 1993-06-16 Smithkline Beecham Plc New use

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8600651D0 (en) * 1986-01-11 1986-02-19 Beecham Group Plc Compounds
IL87861A0 (en) * 1987-10-05 1989-03-31 Pfizer 4-aminopyridine derivatives
GB8801491D0 (en) * 1988-01-22 1988-02-24 Beecham Group Plc Novel compounds
GB8804448D0 (en) * 1988-02-25 1988-03-23 Smithkline Beckman Intercredit Compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9117165A1 *

Also Published As

Publication number Publication date
CA2082392A1 (fr) 1991-11-14
PT97570A (pt) 1992-01-31
JPH06505698A (ja) 1994-06-30
ZA913394B (en) 1992-07-29
WO1991017165A1 (fr) 1991-11-14
NZ238055A (en) 1993-08-26
AU641504B2 (en) 1993-09-23
AU7772191A (en) 1991-11-27
GB9010296D0 (en) 1990-06-27
IE911532A1 (en) 1991-11-20

Similar Documents

Publication Publication Date Title
KR900007780B1 (ko) 축합된 피롤리논 유도체의 제조방법
US5656629A (en) 6-substituted pyrazolo (3,4-d)pyrimidin-4-ones and compositions and methods of use thereof
JPH047746B2 (fr)
IE912224A1 (en) "New 4-aminobutyric acid compounds, process for the preparation thereof and pharmaceutical preparations containing them"
US5093493A (en) 4-amino-benzo[b]thieno[2,3-b]pyridines useful in the treatment of CNS disorders
AU641504B2 (en) Tetrahydrobenzothienopyridines, processes for their preparation and their use as pharmaceuticals
FI75344B (fi) Foerfarande foer framstaellning av terapeutiskt verkande n-substituerade 2-pyridylindoler.
WO1993013104A1 (fr) Derives tricycliques de la thienopyridine ayant une activite sur le systeme nerveux central
US4833136A (en) Pharmaceutically useful pyrazolo[4,3-b]pyridines
AU617489B2 (en) Pyridazinone derivatives
US5447937A (en) CNS active tetrahydrobenzothienopyridines
CZ322492A3 (en) Triazaspirodecanone-methyl chromans
IE42626B1 (en) 6-aryl-2,3,6,7-tetrahydro-5h-pyrrolo (1,2- )-imidazole derivatives, processes for their manufacture and compositions containing them
US4837238A (en) Pharmacologically useful pyrazolopyridines
JP2939280B2 (ja) フッ素置換メトキシキノロンカルボン酸誘導体
EP0426018B1 (fr) Dérivés du thiophène et leurs applications pharmaceutiques
SK99894A3 (en) Pyrazolopyrimidine derivatives, method of their preparation pharmaceutical agent and use
GB2209336A (en) Germinally substituted cyclic ether carboxylic acids
IE910365A1 (en) Therapeutic agents
EP0612323A1 (fr) Tetrahydrobenzothienopyridines agissant sur le systeme nerveux central
FI71149B (fi) Foerfarande foer framstaellning av nya terapeutiskt anvaendbara pyrrolo/3,4-d//2/bensazepinderivat
US3681365A (en) Derivatives of acetic acid
EP0168181A1 (fr) Amides cycliques
WO1994018205A1 (fr) Tetrahydrobenzothienopyridines exerçant une activite sur le systeme nerveux central
EP0088575A2 (fr) Composés pentacycliques

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19920919

AK Designated contracting states

Kind code of ref document: A1

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

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19951201