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WO1994018205A1 - Tetrahydrobenzothienopyridines exerçant une activite sur le systeme nerveux central - Google Patents

Tetrahydrobenzothienopyridines exerçant une activite sur le systeme nerveux central Download PDF

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Publication number
WO1994018205A1
WO1994018205A1 PCT/EP1994/000350 EP9400350W WO9418205A1 WO 1994018205 A1 WO1994018205 A1 WO 1994018205A1 EP 9400350 W EP9400350 W EP 9400350W WO 9418205 A1 WO9418205 A1 WO 9418205A1
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WO
WIPO (PCT)
Prior art keywords
amino
methyl
pyridine
alkyl
ester
Prior art date
Application number
PCT/EP1994/000350
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English (en)
Inventor
Roger Thomas Martin
Mervyn Thompson
Robert William Ward
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 GB939302769A external-priority patent/GB9302769D0/en
Priority claimed from GB939309178A external-priority patent/GB9309178D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO1994018205A1 publication Critical patent/WO1994018205A1/fr

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    • 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

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.
  • EP-A-0 327 223 and WO 91/17165 disclose certain tetrahydrobenzothieno- pyridines which have CNS activity, in paticular anxiolytic and/or anti-depressant activity.
  • CNS activity in particular anxiolytic and/or antidepressant and/or anticonvulsant activity and/or activity useful in the treatment of sleep disorders.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R! is hydrogen, C ⁇ . ( . alkyl, phenyl or phenyl C ⁇ _ alkyl wherein the phenyl moiety is optionally substituted by one or more . alkyl, C ⁇ . ⁇ alkoxy, C ⁇ . ⁇ alkylthio, hydroxy, C2-7 alkanoyl, halo, trifluoromethyl, nitro, cyano, carbamoyl, carboxy or amino optionally substituted by one or two C g alkyl groups or by C2-7 alkanoyl;
  • R and R ⁇ are independently selected from hydrogen, Cj_6 alkyl, C3.7 cycloalkyl, C3.7 cycloalkyl-C ⁇ _4 alkyl, C3.6 alkenyl, C ⁇ . alkanoyl, C ⁇ .(. alkylsulphonyl, di-(Cj_6 alkyl)amino C ⁇ . ( , alkyl, 3-oxobutyl, 3-hydroxybutyl, phenyl, phenyl C1.4 alkyl, benzoyl, phenyl C2-7 alkanoyl and benzenesulphonyl any of which phenyl moieties are optionally substituted by one or two halogen, C ⁇ g alkyl, C ⁇ .(. alkoxy, CF3, amino or carboxy, or R ⁇ and R ⁇ together are C2-6 polymethylene optionally interrupted by oxygen or NR ⁇ wherein R ⁇ is hydrogen or C j.g alkyl optionally substituted by hydroxy;
  • R4 is an aryl or heteroaryl ring optionally substituted by one or more C ⁇ .(. alkyl, C ⁇ . alkoxy, C ⁇ alkylthio, hydroxy, C2-.7 alkanoyl, halo, trifluoromethyl, nitro, cyano, carbamoyl, carboxy, or amino optionally substituted by one or two C ⁇ . ⁇ alkyl groups or by C2-.7 alkanoyl;
  • R5 is hydrogen or C ⁇ . . alkyl and R ⁇ is hydrogen or R ⁇ and R ⁇ together form a C ⁇ .
  • Alkyl moieties within the variables R 1 to R ⁇ , R5 to R 7 , and R 9 to R 12 are preferably C]_4 alkyl, such as methyl, ethyl and n- and iso-propyl.
  • halo groups include fluoro, chloro, bromo or iodo, preferably chloro.
  • Values for R ⁇ include hydrogen, methyl, ethyl, n- and iso-propyl. phenyl and benzyl. Preferably, R is methyl. It will be appreciated in selecting variables R 2 and R ⁇ that the nitrogen atom is not directly attached to unsaturated aliphatic carbon.
  • R 2 and R ⁇ include hydrogen, methyl, ethyl, n- and i?o-propyl. n-, ⁇ ££-, iso- and lert-butyl, n-, ⁇ g ⁇ , i_Q- and neo-pentyl.
  • C]_4 alkyl include methylene and ethylene, but-2-enyl, but-3-enyl, l-methylprop-2-enyl, formyl, acetyl, propionyl, methylsulphonyl, 3-dimethylaminobutyl, 3-oxobutyl, 3-hydroxybutyl, phenyl, benzyl, benzoyl, benzylcarbonyl and benzene- sulphonyl, or R 2 and R ⁇ together form -(CH2) r -X "-(CH2)s- wherein r and s are independently 1, 2 or 3 and X" is a bond, O or NR 9 , for example C4 or
  • Suitable examples of aryl rings for R ⁇ include any carbocyclic aromatic ring such as phenyl.
  • heteroaryl rings for R ⁇ include any five or six membered aromatic ring containing at least one heteroatom selected from O, S or N, preferably 2- or 3- thienyl or 2-, 3- or 4-pyridyl.
  • R ⁇ is unsubstituted or is monosubstituted or disubstituted by halo, trifluoromethyl, or C j.g alkoxy e.g. methoxy.
  • R ⁇ examples include hydrogen, methyl, ethyl and n and __Q propyl, preferably hydrogen.
  • R ⁇ and R ⁇ together may represent an 8-(l- methylethylidene) group.
  • R ⁇ and R 7 are both hydrogen or C ⁇ g alkyl, for example methyl, preferably R > and R 7 are both hydrogen.
  • n is 1 or 2, preferably n is 1.
  • J is hydrogen and K is OR 1 .
  • Values for R 12 include hydrogen and methyl, preferably R 12 is methyl.
  • J and K together are a keto group.
  • J is X'R 10 and K is Z R 1 1.
  • X and Z are preferably the same and RlO and R! 1, when C . ⁇ alkyl, are preferably the same, most preferably methyl or ethyl.
  • RlO and R ⁇ is suitably polymethylene optionally substituted by one or two C ⁇ .(. alkyl groups or by C j.g alkylidene, more preferably C1-.4 alkyl or C1-.4 alkylidene, and most preferably is unsubstituted.
  • linked J and K examples include ethylenedioxy, ethylenedithio, propylenedioxy, 2,2-dimethyl propylenedioxy and 2-methylene propylenedioxy.
  • R ⁇ & is hydrogen or C ⁇ .
  • ⁇ alkyl, Rl, R ⁇ to R ⁇ and n are as defined in formula (I) and J and K are X'R 10 and Z R 1 in which X ' and Z are both oxygen and R 10 and R 1 1 together represent an ethylene group, or J is hydrogen and K is OR 12 or J and K together are a keto group.
  • J, K, R , R ⁇ a , R4 to R , Rl2 anc j n are as described for the corresponding variables 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, hydrobromic, phosphoric, trifluoroacetic, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, methanesulphonic and oxalic acid.
  • This invention covers all tautomeric and optical isomeric forms of compounds of formula (I) including single stereoisomers such as enantiomers or diastereomers, or mixtures thereof including racemates.
  • compounds in which R ⁇ and R° represent an alkylidene group may exist in E and Z forms.
  • the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof which comprises the cyclisation of a compound of formula (III):
  • Rl a is R as defined in formula (I) or a group convertible thereto
  • R ⁇ a is -CO2(CR6R7)
  • ⁇ R4 as defined in formula (I) or an electron-withdrawing group convertible to -CO2(CR ⁇ R ⁇ ) n R ⁇
  • R ⁇ and R ⁇ are as defined as in formula (I)
  • Rl3 is hydrogen or an N-protecting group
  • J and K' represent J and K as defined in formula (I) or a group or groups convertible thereto
  • Y is a group CN or COL , wherein l is a leaving group and M is hydrogen, or Y is hydrogen and M is a group CN or COL , wherein L2 is a leaving group; and thereafter, optionally or as necessary, and in any appropriate order, converting Rl3 when hydrogen to an N-protecting group, when Y or M is a group COLl or COI- converting the resulting hydroxy group to a leaving group and reacting
  • 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 or sodium ethoxide in a suitable solvent such as methanol or ethanol, at elevated temperature, or in the presence of a Lewis acid such as ZnCl2, SnCl4 or CUOCOCH3 in a suitable solvent such as n-butyl acetate at elevated temperature.
  • Lewis acid catalysed cyclisation using copper (I) acetate is preferred especially when cyclising to give compounds of formula (I) directly i.e. where R ⁇ a is CO (CR 6 R 7 ) n R 4 .
  • j' and K' represent J and K or together represent a group convertible to a keto group such as a protected hydroxy group.
  • a protected hydroxy such as a silyl ether, for example is ⁇ -butyldimethylsilyl or trimethylsilyl ether, tetrahydropyranyl ether or C ⁇ .
  • alkyl or benzyl ester optionally substituted as described hereinafter for the protecting group Q when benzyl may be de-protected conventionally to give a hydroxy group which if desired may be oxidised conventionally for example using oxalyl chloride/dimethyl- sulphoxide or pyridinium chlorochromate or tetrapropyl ammonium pemithenate to give the ketone.
  • the hydroxy group may be converted to other OR 2 groups by conventional etherification reactions for example by treatment with a strong base such as sodium hydride in an inert solvent such as dimethylformamide followed by reaction with an appropriate alkyl halide, preferably the iodide, bromide or chloride. Protection of the remaining substituents, particularly the 4-amino group may be required.
  • tercon version of J and K may be carried out using conventional methods.
  • a compound wherein J and K together are a keto group may be converted to the corresponding compound wherein J is X RIO and K is Z Rl 1 by reacting with the appropriate alcohol or thiol Rl ⁇ X H and Rl lZ H under acid conditions such as anhydrous hydrochloric acid, para-toluenesulphonic acid or 10-camphorsulphonic acid or in the presence of a Lewis acid such as FeCl3 or BF3 in an inert solvent such as toluene or the alcohol/thiol itself.
  • acid conditions such as anhydrous hydrochloric acid, para-toluenesulphonic acid or 10-camphorsulphonic acid or in the presence of a Lewis acid such as FeCl3 or BF3 in an inert solvent such as toluene or the alcohol/thiol itself.
  • J and K When J and K are X'RIO and Z Rl 1 these groups may be converted to a keto group which may then be converted to other values of X'RIO and ZRl 1.
  • X RIO and Z Rl 1 may be directly interconverted, for example a compound wherein J and K together represent an ethylenedioxy group may be converted to a compound wherein J and K together represent an ethylenedithio group by reaction with ethane dithiol in the presence of an acid catalyst such as BF3 in an inert solvent such as chloroform.
  • the group X'RIO and Z Rl 1 may be conventionally converted to a keto group for example by treatment with aqueous hydrochloric, formic or trifluoroacetic acid.
  • the group X RIO and Z Rl 1 may be 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 alkyl halide followed by water.
  • the group X'RIO and Z Rl 1 may be conventionally converted to a keto group by reacting one of the sulphur atoms with: a heavy metal cation such as silver; or a quaternising agent such as an alkyl halide; 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.
  • a heavy metal cation such as silver
  • a quaternising agent such as an alkyl halide
  • an oxidising agent such as a peracetic acid
  • R ⁇ and R ⁇ hydrogen may be converted to an alkylidene group in the 8-position by an aldol type condensation with an appropriate aldehyde or ketone, such as acetone.
  • the alkylidene group may then be hydrogenated to the corresponding R ⁇ alkyl group conventionally using, for example, a palladium on charcoal catalyst.
  • J and K together represent a keto group this group may be reduced to hydroxy (i.e. J is H and K is OH) using a suitable reducing agent such as sodium borohydride.
  • a suitable reducing agent such as sodium borohydride.
  • Rl3 N-protecting groups include trimethylsilyl and 2-(trimethylsilyl)ethoxymethyl, which may be removed conventionally, for example using tetra-n-butylammonium fluoride.
  • Rl3 is hydrogen
  • a protecting group Q may be removed by conventional hydrolysis or hydrogenolysis to yield the free acid which can then be esterified under conventional conditions by reaction with the appropriate alcohol R 4 (CR6R 7 ) n OH, optionally with prior conversion of the acid to the acid chloride by reaction with a suitable chlorinating agent such as thionyl chloride, or with an alkylating agent R 4 (CR6R 7 ) n X where X is a leaving group such as chloro, bro o or iodo, in the presence of a suitable base such as potassium hydroxide or carbonate in an inert solvent such as dimethylformamide.
  • Q may be converted directly to (CR ⁇ R 7 ) n R 4 by transesterification under basic conditions, suitably when Q is Cj.galkyl such as ethyl.
  • R2 and/or R ⁇ are hydrogen it may be necessary to conventionally protect the nitrogen atom to which R and R ⁇ are attached.
  • An intermediate amide may be hydrolysed to the free acid which can then be esterified as described above.
  • R 4a cyano group may be converted under anhydrous acidic conditions to an imino ester by reaction with the appropriate alcohol R 4 (CR"R ') n OH and then hydrolysed to the group -CO2(CR 6 R 7 ) n R 4 .
  • R 4a COR a ⁇ -methylene keto groups may be converted to CO2(CR°R 7 ) n R4 via the acid by a haloform reaction and esterification.
  • R 4 groups may be interconverted via the intermediate acid or directly by transesterification as described above.
  • Suitable examples of a leaving groups Ll and L2 when Y or M is COLl or COL2 include hydroxy and, more preferably, alkoxy such as C 1.5 alkoxy, for example ethoxy or methoxy.
  • the cyclisation of the compound of formula (HI) 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 hydroxy group can be converted to a triflate leaving group by reaction with triflic anhydride in pyridine.
  • the leaving group may be displaced by the compound HNR aR3a un der conventional conditions for nucleophilic aromatic displacements, at elevated temperatures in an inert solvent such as toluene, methanol, ethanol, dimethylformamide or dioxan.
  • the reaction may be carried out in neat HNR2 R3a which functions as the solvent.
  • R2 a or R ⁇ a protecting group such as p-methoxybenzyl may be removed conventionally.
  • R2/R3 Conversion of R2 and R ⁇ hydrogen to other R2/R3 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, R2/R3 other than hydrogen or acyl groups are preferably introduced via the route in which Y or M is COL or COL2 in the compound of formula (III), by displacement of the leaving group with the compound HNR a R a as discussed above. An R a group such as hydroxy or chloro may be converted to alkyl or phenyl C ⁇ .
  • R , R 4 , R5 ? R8 ? R13 ; ⁇ ? anc j K' are as defined as in formula (III)
  • L is a leaving group and M is as defined in formula (III) or L and M together represent a bond.
  • Suitable examples of the leaving group L include halogens, such as chloro and bro o, hydroxy, Cj.g acyloxy such as acetoxy, C j .g alkoxy, such as methoxy or ethoxy, preferably methoxy or NR ⁇ R C where R ⁇ and R c are independently hydrogen or Cj_4 alkyl or together form a C2-6 polymethylene chain optionally interrupted by oxygen or NR" where R ⁇ is hydrogen or C].
  • reaction of a compound of formula (IV) with a compound of formula (V) may be carried out under conditions conventional for condensation reactions, at elevated temperatures in an inert solvent such as toluene, benzene, pyridine, dimethylformamide, mesitylene or dioxan, optionally in the presence of a catalyst such as para-toluene sulphonic acid or 10-camphorsulphonic acid, with water separation if appropriate, e.g. in the presence of powdered molecular sieves.
  • an inert solvent such as toluene, benzene, pyridine, dimethylformamide, mesitylene or dioxan
  • a catalyst such as para-toluene sulphonic acid or 10-camphorsulphonic acid
  • L is a leaving group and Rl a is hydroxy.
  • the R a 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 Rl hydrogen may be carried out before or, more preferably, after cyclisation of the compound of formula (III);
  • (iii) L is a leaving group, M and R 4a are both C . alkoxycarbonyl, and Rl a is hydrogen.
  • Compounds of formula (VI) are either known compounds or can be prepared analogously to known compounds.
  • a class of intermediates comprises compounds of formula (VII) or a salt, ester or amide thereof:
  • Novel compounds of formula (VII), for example where R 4a is CO2(CR ⁇ R 7 ) n R hereinafter referred to as compounds of formula (Vila), also form part of the invention. Examples of R 4a when other than CO2(CR 6 R 7 ) n R 4 include CO2H.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • 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.
  • 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 reconstitution with water or other suitable vehicle before use.
  • Such 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 pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and 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.
  • the dose of the compound used in the treatment of CNS disorders such as anxiety, sleep disorders, depression or diseases treatable with anti-convulsant agents such as epilepsy, will vary in the usual way with the seriousness of the disorder and the disorder itself, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, for anxiety more suitably 0.05 to 20.0 g, for example 0.2 to 10 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, sleep disorders, depression or disorders treatable with anti-convulsant agents such as epilepsy, which composition comprises an effective, non-toxic amount of compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention further provides a method for the treatment and/or prophylaxis of CNS disorders, in particular anxiety, sleep disorders, depression or disorders treatable with anticonvulsant agents such as epilepsy in mammals, including humans, which comprises administering to the sufferer an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • 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, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy.
  • 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, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy.
  • the title compound was prepared from D3 and 3-thiophene-ethanol using the procedure of El. m.p. 128-30°C.
  • the title compound was prepared from E8 by sequential treatment with aqueous TFA by the method of El 6 and then reduction of the resulting ketone with sodium borohydride in ethanol by the method El 7. m.p. 224-6°C (dec) after recrystallization from MeOH.
  • the title compound was prepared in 30% overall yield from ester D3 and 4-nitrobenzyl bromide using a procedure similar to that of E5. m.p. 210- 1 1 °C (from dichloromethane) / z : 455 (M+; 65%), 369 (50), 302 (48), 215 (70), 121 (95), 98 (100).
  • 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.
  • the results are expressed as the percentage increase in square root of the total number of lever presses in the FR5 'conflict' session. Square root transformation is necessary to normalise the data for statistical analysis using parametric methods (ANOVA).
  • rat cerebral cortices are homogenised in 20 volumes of 0.32M sucrose and centrifuged at lOOOg for 20 minutes (4°C). The supernatant is removed and recentrifuged at 50,000g (4°C, 20 mins). The P2 pellet is then suspended in 20 volumes of Tris citrate buffer (pH 7.1) and centrifuged at 50,000g (4°C, 20 mins). This washing step is repeated three times and the pellet finally resuspended in 20 volumes of buffer and stored at -70 C prior to use.
  • the tissue suspension (50 ⁇ l) is incubated (25°C, 120 mins) with [35s]-TBPS (2nM) in Tris citrate buffer (pH 7.1 ) containing 0.2M NaCl and 1 x 10" 6 M GAB A. Non-specific binding is measured in the presence of 10" M picrotoxin. Varying concentrations of test drugs (10" 7 , 10" ⁇ , 10" ⁇ and 10' 4 M final concentration) are added in a volume of 50 ⁇ l. The total assay volume is 500 ⁇ l. Incubation is stopped by rapid filtration using a Skatron cell harvester and radioactivity measured by liquid scintillation spectrometry. ICSQ'S are calculated as the concentration of test drug to inhibit 50% of specific binding.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne des tétrahydrobenzothiénopyridines de la formule (I), exerçant une activité sur le système nerveux central.
PCT/EP1994/000350 1993-02-11 1994-02-07 Tetrahydrobenzothienopyridines exerçant une activite sur le systeme nerveux central WO1994018205A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB939302769A GB9302769D0 (en) 1993-02-11 1993-02-11 Novel compounds
GB9302769.6 1993-02-11
GB939309178A GB9309178D0 (en) 1993-05-05 1993-05-05 Novel compounds
GB9309178.3 1993-05-05

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WO1994018205A1 true WO1994018205A1 (fr) 1994-08-18

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0327223A1 (fr) * 1988-01-22 1989-08-09 Beecham Group Plc Dérivés de la tetrahydrobenzothienopyridine avec une activité anxiolytique et antidepressive
WO1991017165A1 (fr) * 1990-05-08 1991-11-14 Beecham Group Plc Tetrahydrobenzothienopyridines, leurs procedes de preparation et leur emploi en tant qu'agents pharmaceutiques
WO1993004068A1 (fr) * 1991-08-13 1993-03-04 Smithkline Beecham Plc Tetrahydrobenzothienopyridines agissant sur le systeme nerveux central
WO1993009122A1 (fr) * 1991-11-07 1993-05-13 Smithkline Beecham Plc Tetrahydrobenzothienopyridines agissant sur le systeme nerveux central

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0327223A1 (fr) * 1988-01-22 1989-08-09 Beecham Group Plc Dérivés de la tetrahydrobenzothienopyridine avec une activité anxiolytique et antidepressive
WO1991017165A1 (fr) * 1990-05-08 1991-11-14 Beecham Group Plc Tetrahydrobenzothienopyridines, leurs procedes de preparation et leur emploi en tant qu'agents pharmaceutiques
WO1993004068A1 (fr) * 1991-08-13 1993-03-04 Smithkline Beecham Plc Tetrahydrobenzothienopyridines agissant sur le systeme nerveux central
WO1993009122A1 (fr) * 1991-11-07 1993-05-13 Smithkline Beecham Plc Tetrahydrobenzothienopyridines agissant sur le systeme nerveux central

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