IE911532A1 - Novel compounds - Google Patents

Abstract

Tetrahydrobenzothienopyridines of formula (I) having pharmacological activity, processes for their preparation and their use as pharmaceuticals for the treatment and/or prophylaxis of CNS disorders.

Description

NOVEL COMPOUNDS 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 (Beecham Group pic) discloses a class of tetrahydrobenzothienopyridines which have anxiolytic and/or anti-depressant activity.

A class of compounds has now been discovered, which compounds have been found to have CNS activity, in particular anxiolytic and/or anti-depressant activity.

Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein : R^ is hydrogen, C_g alkyl, phenyl or phenyl C-j__4 alkyl wherein the phenyl moiety is optionally substituted by one or more C1_g alkyl, C-j__g alkoxy, alkylthio, hydroxy, C2_7 alkanoyl, halo, trifluoromethyl, nitro, amino B2981 -2optionally substituted by one or two C-j__g alkyl groups or by C2_7 alkanoyl, cyano, carbamoyl or carboxy groups; R2 and Rg are independently selected from hydrogen, C-[__g alkyl, Cg_7 cycloalkyl, Cg_7 cycloalkyl-C-]__4 alkyl, C2_g alkenyl, Cg_7 alkanoyl, C]__g alkylsulphonyl, di- (C1 — g alkyl)amino Cj_g alkyl, 3-oxobutyl, 3-hydroxybutyl, phenyl, phenyl alkyl, benzoyl, phenyl C2_7 alkanoyl or benzenesulphonyl any of which phenyl moieties are optionally substituted by one or two halogen, C_g alkyl, Cj_g alkoxy, CFg, amino or carboxy, or R2 and Rg together are C2_g polymethylene optionally interrupted by oxygen or NRg wherein Rg is hydrogen or Cg_g alkyl optionally substituted by hydroxy; Rg is hydrogen or C]__g alkyl and Rg is hydrogen or Rg and Rg together form a C-j__g alkylidene group at the 8-position; and -CO2R4 is a pharmaceutically acceptable ester group.

Alkyl moieties within the variables R^ to Rg are preferably C1_β alkyl, such as methyl, ethyl and n- and iso-propyl.

Values for R^ include hydrogen, methyl, ethyl, n- and iso-propyl, phenyl and benzyl. Preferably, is methyl.

It will be appreciated in selecting variables R2 and Rg that the nitrogen atom is not directly attached to unsaturated aliphatic carbon.

Values for R2 and Rg include hydrogen, methyl, ethyl, n- and iso-propyl, η-, sec-, iso- and tert-butyl, η-, sec, iso- and neo-pentyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentyl-C-]__4 alkyl, cyclohexyl-C^_4 alkyl and B2981 -3cycloheptyl-C^_4 alkyl, where values for 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 benzenesulphonyl, or R2 and Rg together form -(CH2)r~X-(CH2)s~ wherein r and s are independently 1, 2 or 3 and X is a bond, 0 or NRg, for example C4 or Cg polymethylene, -(CH2)2-0~ (CH2)2~ or -(CH2)2-NRg-(CH2)210 where Rg is preferably methyl.

Preferably R2 is hydrogen and Rg is hydrogen or C^_g alkyl, for example methyl.

Most preferably R2 and Rg are hydrogen.

Suitable examples of pharmaceutical esters of the compounds of formula (I) include C-]__g 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, η-, sec- and tert-butyl and 2,2,2-trifluoroethyl esters, C2_g alkenyl esters such as vinyl, prop-l-enyl, prop-2-enyl, 1-methylvinyl, but-l-enyl, but-3-enyl, 1-methylenepropyl and l-methylprop-2-enyl, (in both their E and Z forms where stereoisomerism exists), C2_g alkynyl esters such as prop-2-ynyl, but-2-ynyl and but-3ynyl, Cg_g cycloalkyl esters and Cg_g cycloalkyl-C]__4 alkyl esters such as cyclopropylmethyl. Preferably the pharmaceutically acceptable ester is the methyl, ethyl, 2,2,2-trifluoroethyl, propyl, prop-2-enyl, prop-2-ynyl, but3-enyl, but-2-ynyl, but-3-ynyl or cyclopropylmethyl ester, i.e. R^ 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.

B2981 -4Suitable values of Rg include hydrogen, methyl, ethyl and n and iso propyl, preferably hydrogen. Alternatively, Rg and Rg together may represent an 8-(1-methylethylidene) group.

There is a preferred group of compounds within formula (I) of formula (II) or a pharmaceutically acceptable salt thereof: wherein Rg^ is hydrogen or C-j__g alkyl and R-j_ and R^ are as defined in formula (I).

Preferred values for Rg and Rg1 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, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.

It will be appreciated that the compounds of formula (I) in which R2 or Rg is hydrogen may exist tautomerically in more than one form. The invention extends to each of these forms and to mixtures thereof.

Compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms.

B2981 -5When referred to herein, it is understood that the term '' compound of formula (I)'' also includes solvates thereof.

It should be appreciated that compounds of formula (I) in 5 which Rg is hydrogen and is other than hydrogen have a chiral centre on the carbon atom adjacent to the Rg moiety. In addition, compounds in which Rg and Rg represent an alkylidene group may exist in E and Z forms, while substituents Rj, R2, R3, R4, and Rg 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) : or imine tautomer thereof, wherein R1f is R-j_ as defined in formula (I) or a group convertible thereto, R4' is -CO2R4 as defined in formula (I) or an electron-withdrawing group convertible to -CO2R4, R5 and Rg are as defined as in formula (I) , R-y 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^, wherein is a leaving group and M is hydrogen, or Y is hydrogen and M is a group CN or COL2, wherein L2 is a leaving group; and thereafter, B2981 -6optionally or as necessary, and in any appropriate order, converting R·? when hydrogen to an N-protecting group, when Y or M is a group COLj_ or COL2, converting the resulting hydroxy group to a leaving group and reacting the latter with a compound HNR^'F^' wherein R2' and Rg' are R2 and Rg or N-protecting groups, removing any R7 N-protecting group, converting any electron-withdrawing group R^' to CO2R4, converting R^' when other than to Rp interconverting R2, Rg, R4, R5 and Rg, converting J and K to a keto group, separating any stereoisomers such as enantiomers and/or forming a pharmaceutically acceptable salt of a compound of formula (I).

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 ZnC^, SnCl4 or CuOCOCHg 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 R4' is CO2R4.

Preferably J and K together represent a group convertible to a keto group such as a protected hydroxy group or a protected keto group. A protected hydroxy such as trimethylsilyl or tetrahydropyranyl may be de-protected conventionally to give a hydroxy group which may be oxidised conventionally for example using oxalylchloride/ dimethylsulphoxide or pyridinium chlorochromate to give the ketone.

!E 911532 B2981 -7Protected keto groups J and K are exemplified by compounds of formula (III) wherein J is XR^g and K is ZR^4, X and Z are independently oxygen or sulphur and R·^ and R14 are independently Cq-g alkyl or together are C2_4 polymethylene optionally substituted with one or more C-j__g alkyl groups.

When X and Z are both oxygen, the group "X-R13 and -Z-R44 may be conventionally converted to a keto group for example by treatment with aqueous hydrochloric acid.

When one of X or Z is an oxygen atom and the other is a sulphur atom, the group "Χ-Κχβ and -Z-R^ 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 alkylhalide followed by water.

When X and Z are both sulphur the group _X~Ri3 and -Z-R14 may be conventionally converted to a keto group by reacting one of the sulphur atoms with; (i) a heavy metal cation such as silver (ii) a quaternising agent such as an alkylhalide or 25 (iii) 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.

Preferably X and Z are oxygen. and Rg hydrogen may be converted to an alkylidene group in the 8-position by an aldol condensation with an B2981 -8appropriate aldehyde or ketone, such as acetone. The alkylidene group may then be hydrogenated to the corresponding Rg alkyl group conventionally using, for example, a palladium on charcoal catalyst.

Examples of R7 N-protecting groups include trimethylsilyl and 2-(trimethylsilyl)ethoxymethyl, which may be removed conventionally, for example using tetra-n-butylammonium fluoride .

Preferably R-y is hydrogen.

Suitable examples of groups R^' include the groups hereinbefore described for -CO2R4, CORa where Ra is hydrogen, Cg_g alkyl, Cg_7 cycloalkyl Cg_4 alkyl or Cg_7 cycloalkyl, CH=NOH, CC^H, CO2Q where Q is a protecting group such as benzyl wherein the benzyl moiety is optionally substituted in the phenyl ring by one or two of halogen, CFg, Cg_g alkoxy, Cg_g alkyl or nitro, cyano and -CONRgRgQ where Rg and Rgg are independently selected from hydrogen, Cg_g alkyl, Cg_g alkoxy and phenyl or phenyl Cg_4 alkyl optionally substituted as described above for optional substituents in the phenyl ring of a benzyl ester, or together form a C2_g polymethylene chain optionally interrupted by oxygen or NRgg wherein Rgg is hydrogen or Cg_g alkyl, e.g. morpholino or piperazino.

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 R4OH, 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 R4X where X is a leaving group such as chloro, bromo or iodo, in the presence B2981 -9of a suitable base such as potassium carbonate in an inert solvent such as dimethylformamide.

An intermediate amide may be hydrolysed to the free acid which can then be esterified as described above.

An R4' cyano group may be converted under anhydrous acidic conditions to an imino ester by reaction with the appropriate alcohol R^OH and then hydrolysed to the group -co2r4.

An R4' CH=NOH group may be converted to cyano by dehydration with a suitable dehydrating agent such as formic acid at elevated temperature, and the resulting cyano group converted to CO2R4 as just described. Alternatively the CH=NOH group may be converted to formyl by hydrolysis, oxidised to the free acid using a suitable oxidising agent such as CrOg and esterified as above.

R4' CORa groups may be converted to CO2R4 via the acid by a haloform reaction and esterification.

Suitable examples of a leaving groups L-[_ and L2 when Y or M is COLt. or COL2 include hydroxy and, more preferably, alkoxy such as C4_g 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 HNR2'R3' under conventional conditions for nucleophilic aromatic displacements, at elevated temperatures in an inert solvent such as toluene, methanol, ethanol, pyridine, dimethylformamide or dioxan.

B2981 -10Alternatively, the reaction may be carried out in neat which functions as the solvent.

An R2' or Rg' protecting group such as p-methoxybenzyl may 5 be removed conventionally.

Conversion of R2 and R-j 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-j· or COL2 in the compound of formula (III), by displacement of the leaving group with the compound HNR2'R3' as discussed above.

Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or derivative .

Compounds of formula (III) may be prepared by the reaction of a compound of formula (IV): with a compound of formula (V): (IV) B2981 (V) wherein R^', R4', R5, R7/ Rg/ Y/ 3, and 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.

Intermediates of formula (III) and (IV) are novel and form a further aspect to the present invention.

Suitable examples of the leaving group L include halogens, such as chloro and bromo, hydroxy, C-j__g acyloxy such as acetoxy, C-]__g alkoxy, such as methoxy or ethoxy, preferably methoxy or NRaRb where Ra and are independently hydrogen or C4_4 alkyl or together form a C2_g polymethylene chain optionally interrupted by oxygen or NRQ where Rc is hydrogen or Cj__g alkyl optionally substituted by hydroxy. When L is hydroxy, it will be appreciated that the compound of formula (V) exists in more than one tautomeric form.

The 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, ethanol, pyridine, dimethylformamide or dioxan, optionally in the presence of a catalyst such as para-toluene sulphonic acid or 10-camphorsulphonic acid, with water separation if appropriate . -12B2981 For the preparation of compounds of formula (I) in which Rj is hydrogen, the compound of formula (V) may be used in which: (i) L and M together represent a bond or L is hydroxy and M is hydrogen, and is a C]__g alkoxycarbonyl group. The reaction with the compound of formula (IV) may then be followed by a decarboxylation step to give Rj hydrogen; (ii) L is a leaving group and R^' is hydroxy. In the resulting compound, the R^' 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-j. 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 R4' are both C4_g alkoxycarbonyl, and Rj' is hydrogen.

Compounds of formula (IV) are prepared analogously to the methods described in K. Gewald et al, Chem. Ber. 94 (1966) by reacting compounds of formula (VI): (VI) B2981 -13wherein R^, Rg, J and K are as defined in formula (III), with NCCHgY and sulphur in the presence of a base such as diethylamine in an inert solvent such as methanol or ethanol.

Compounds of formula (VI) are either known compounds or can be prepared analogously to known compounds.

Compounds of formula (V) are known compounds or can be prepared analogously to known compounds. For example, compounds of formula (V) wherein M is hydrogen, L is OH and Rg is CHg may be prepared by reacting diketene with the appropriate alcohol R4OH using a method similar to that of R.J. Clemens and J.A. Hyatt, J. Org. Chem., 1985 50 2431.

The compound of formula (V) in which Rg' is phenyl, M is hydrogen, L is ethoxy and R4' is ethoxycarbonyl is described by V.L. Leighton, Amer. Chem. Journal (1898), 20 , 133.

A class of intermediates comprises compounds of formula (VII) or a salt ester or amide thereof: (VII) wherein R4'' is R4' as defined in formula (III) or a group convertible to CO2R4, X is NRg'Rg', OH or chloro, Rg', Rg'/ Rg', J and K are as defined in formula (III) and R4, Rg and Rg are as defined in formula (I), provided that when X is NRgRg, J and K together represent a keto group and Rg' is Rg, R4'' is other than CO2R4- Novel compounds of formula B2981 -14(VII) also form part of the invention.

Examples of R4'' when other than CO2R4 include CO2H.

In a further aspect, 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 NR2Rg, R4'' is CO2R4 and R^' is Rj_, and J and K together represent a group convertible to a keto group and thereafter optionally separating any stereoisomers such as enantiomers and/or forming a pharmaceutically acceptable salt of a compound of formula (I).

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 B2981 -15elixirs, 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 .

For parenteral administration, fluid unit dosage forms are io 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. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, 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. Advantageously, 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 or depression will vary in the usual way with the seriousness of the disorders, the w B2981 -16of the sufferer, and other similar factors. However, as a general guide 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 10 for use in the treatment of CNS disorders, in particular anxiety or depression 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 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 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 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 following examples illustrate the preparation of compounds of the invention.

B2981 -17Description 1 2-Amino-6,6-ethylenedioxy-4,5,6, 7-tetrahydrobenzo[bi thiophene-3-carbonitrile (DI) CN (DI) The title compound was prepared from 1,4-cyclohexandione mono-ethylene ketal using a procedure similar to that of K Gewald et al., Chem. Ber. 1966, 94 (49% yield).

NMR (CDClg) δ: 1.95 (2H, t), 2.72 (4H, m), 4.02 (4H, s) , 4.72 (2H, bs) .

Description 2 N-3- (2- (3-Cyano-6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo [b]thienyl)amino)-2-butenoic acid, ethyl ester (D2) (D2) B2981 -18A mixture of aminonitrile (DI) (13.16g; 55.7mmol) and ethyl β-ethoxycrotonate (26g; 164mmol) in mesitylene (400ml) was heated at reflux for 1.5h then evaporated to dryness. The residue was chromatographed on Kieselgel 60 eluting with a 0-2% methanol in dichloromethane gradient. Trituration of the product with petrol (bpt:40 - 60°C) and filtration afforded the title compound as a yellow solid (11.9g, 61%) m.p. 115-118°C.

NMR (CDClg) δ: 1.30 (3H, t), 1.95 <2H, t), 2.10 (3H, s), 2.85 (4H, m) , 4.02 (4H, s), 4.20 (2H, q), 4.90 (IH, s).

Description 3 4-Amino-7,7-ethylenedioxy-2-methyl-5, 6,7,8-tetrahydrobenzo[bithieno[2,3-b]pyridine-3-carboxylic acid, ethyl ester (D3) (D3) A solution of enaminoester D2 (11.7g, 33.6 mmol) in toluene 30 (400ml) was treated with a IM solution of sodium ethoxide in ethanol (40ml) and heated to reflux for 2.5h. The reaction mixture was cooled and added to ethyl acetate and B2981 -19half-saturated aqueous ammonium chloride. The mixture was filtered, the organic phase separated, dried (Na2SO4) and evaporation in vacuo gave a brown oil. Chromatography on TLC alumina, eluting with a 0-2% methanol in dichloromethane gradient, afforded the title compound as a yellow gum (7g 60%) . NMR (CDCl3 ) δ: 1.40 (3H, t), 2.05 (2H, t), 2.70 (3H, s), 3.00 (2H, s), 3.23 (2H, t), 4.05 (4H, s) , 4.38 (2H, q), 6.60 (2H, bs) Example 1 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b] thienof2,3-blpyridine-3-carboxylic acid, ethyl ester (El, R4 = C2H5) A solution of ketal D3 (4.62g, 13.3mmol) in acetone (200ml) was treated with water (10ml) and concentrated hydrochloric acid (2ml) then heated to reflux under nitrogen for 24h. Additional concentrated hydrochloric acid (2ml) was added, and the mixture heated to reflux for 8h, then stored at ca 5°C for 12h. Filtration afforded a white crystalline solid (3.5g) which was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4) and concentrated in B2981 -20vacuo whereupon crystallisation occured. After storing at ca. 5°C for 12h, filtration afforded the title compound as a white crystalline solid (2.37g, 59%). m.p. 159-161°C Found: C, 59.32; H, 5.19; N, 9.17 C15H16N2°3S requires C, 59.19; H, 5.30; N, 9.20 NMR (CDClg) δ: 1.42 <3H, t), 2.71 (3H, s) , 2.80 (2H, t), 3.45 (2H, t), 3.78 (2H, s) , 4.40 (2H, q), 6.55 (2H, bs) .

Example 2 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[blthieno f2,3-b]pyridine-3-carboxylic acid, cyclopropylmethyl ester (E2, R4 = CH2-c-C3H5) The title compound was prepared from DI and 3-oxo-butyric 20 acid, cyclopropylmethyl ester via the intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5, 6, 7, 8-tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylie acid, cyclopropylmethyl ester using a procedure similar to that described in Description 2, Description 3 and Example 1. m.p. 168° (from ethyl acetate) Found: C, 61.89; H, 5.51; N, 8.53 ^17^18^2^3^ requires C, 61.80; H, 5.49, N, 8.48% B2981 -21Example 3 4-Amino-2-methyl-7-oxo-5,6,7, 8-tetrahydrobenzo[b]thieno [2,3-b]pyridine-3-carboxylic acid, methyl ester (E3, R4 = CHg) The title compound was prepared from DI and methyl acetoacetate via the intermediate 4-amino7,7-ethylenedioxy-2-methyl-5,6,7, 8-tetrahydro10 benzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, methyl ester using a procedure similar to that of Example 2. m.p. 202-6° (from ethyl acetate) Found: C, 57.95; H, 4.86; N, 9.65 C14H14N2O3S requires C, 57.92; H, 4.86; N, 9.65%.

Example 4 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b]thieno [2,3-b]pvridine-3-carboxylic acid, propyl ester (E4, R4 = CHoCHoCHg) The title compound was prepared in 11% overall yield from 25 DI and 3-oxo-butyric acid, propyl 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, propyl ester using a procedure similar to that of Example 2. m.p. 141-2° (from ethyl acetate / 60:80 petroleum ether) B2981 -22NMR (dg DMSO) δ: 0.95 (3H, t, J=7Hz), 1.75 (2H, sx, J=7Hz), 2.55 (3H, s), 2.70 (2H, t, J=6Hz), 3.40 (2H, t, J=6Hz), 3.70 (2H, s), 4.25 (2H, t, J=7Hz), 6.75 (2H, bs) .

Example 5 4-Amino-2-methyl-7-oxo-5/6,7,8-tetrahydrobenzo[b] thieno[2,3-b]pyrldine-3-carboxylic acid, prop-2-enyl ester (E5, R4 = CH2CH=CH2) The title compound was prepared in 8% overall yield from DI and 3-oxo-butyric acid, prop-2-enyl ester via the intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5,6,7,815 tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, prop-2-enyl ester using a procedure similar to that described in Example 2. m.p. 148-150° (from ethyl acetate).

NMR (CDClg) δ: 2.74 (3H,s), 2.80 (2H, t, J=8.5Hz), 3.45 (2H, m,), 3.70 (2H, s), 4.85 <2H, m), 5.30 - 5.50 (2H, bm), 5.95-6.18 (IH, bm), 6.60 (2H, broad).

Example 6 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b]thieno [2,3-b]pyridine-3-carboxylic acid, but-2-ynyl ester (E6, R^ = CH2C=CCHg) The title compound was prepared in 5% overall yield from DI and 3-oxo-butyric acid, 2-but-2-ynyl ester via the B2981 -23intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5,6,7,8tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylie acid, but-2-ynyl ester using a procedure similar to that described in Example 2. m.p. 190-2° (from ethyl acetate).

NMR (CDC13) δ:1.90 (3H, t, J=3Hz), 2.74 (3H, s), 2.80 (2H, t, J=8Hz), 3.45 (2H, m), 3.70 (2H, s), 4.90 (2H, q, J=3Hz), 6.55 (2H, broad s).

Example 7 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b]thieno Γ2,3-b]pyridine-3-carboxylic acid, 2,2,2-trifluoroethyl ester (E7, R4 = CH2CF3) The title compound was prepared in 1% overall yield from 2,2,2-trifluoroethyl acetoacetate and Dl via the intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5,6,7,8tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylie acid, 2,2,2-trifluoroethyl ester using a procedure similar to that of Example 2. m.p. 140-6° NMR (CDCI3) δ: 2.55(3H, s) , 2.80 (2H, t, J=6Hz), 3.40 (2H, t, J=6Hz), 3.65 (2H, s) , 4.70 (2H, q, J=8Hz), 6.70 (2H, broad s). m/z = 358 (M+).

B2981 -24Example 8 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b]thieno [2,3-b]pyridine-3-carboxylic acid, but-3-enyl ester (E8, r4 = (ch2)2 ch=ch2) The title compound was prepared from DI and 3-oxo-butyric acid, but-3-enyl ester via the intermediate 4-amino10 7,7-ethylenedioxy-2-methyl-5,6, 7,8-tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, but-3-enyl ester using copper (I) acetate following a procedure similar to that of Example 2. m.p. 130-2° (from ethyl acetate).

NMR (CDCI3) δ: 2.55 (2H, m) , 2.70 (3H, s), 2.85 (2H, t, J=8.5 Hz), 3.45 (2H, t, J=8.5 Hz), 3.70 (2H, s), 4.45 (2H, t, J=8.5 Hz), 5.10-5.25 (2H, br, m), 5.80-5.95 (IH, br, m) , 6.60 (2H, br, s) .

Example 9 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b]thieno [2,3-b]pyridine-3-carboxylic acid, but-3-ynyl ester (E9, R4 = (CH2}_2CaCH) .

The title compound was prepared in 5% overall yield from DI and 3-oxo-butyric acid, but-3-ynyl ester via the intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5,6, 7,8-tetrahydrobenzo[b]thieno[2,3-b]pyridine3-carboxylic acid, but-3-ynyl ester using a procedure similar to that of Example 2, but in which the cyclisation B2981 -25step was carried out in n-butyl acetate using SnCl^. m.p. 167-8°C NMR (CDClg) 5: 2.05 (IH, t, J = 2.8Hz), 2.70 (2H, dt, J = 2.8, 8.5 Hz), 2.75 (3H, s), 2.80 (2H, t, J = 8.5Hz), 3.45 (2H, m), 3.70 (2H, s), 4.45 (2H, t, J = 8.5 Hz), 6.60 (2H, broad s).

Example 10 4-Amino-2-methyl-8-(1-methyl-l-ethylidene)-7-oxo-5,6,7,8tetrahydrobenzo[bithieno[2,3-b1pyridine-3-carboxylie acid, but-3-enyl ester (E10) The amine DI and 3-oxobutyric acid, but-3-enyl ester were converted into the cyclised product using copper (I) acetate in 39% yield by the method of Description 2 and Description 3. Treatment with aqueous hydrochloric acid/acetone at reflux for 48h, similar to the method of Example 1, gave a crude product in 93% yield. Chromatography on silica, using 30% ethyl acetate/n-pentane, afforded a pure sample of the title compound which was recrystallised from ethyl acetate as yellow crystals.

B2981 m.p. 136-8° NMR (CDC13) δ: 2.74 (3H, J=8.5Hz), broad m), -26.25 <3H, s), 2.27 (3H, s), 2.55 (2H, m), s), 2.80 (2H, t, J = 8.5Hz), 3.40 (2H, t, 4.42 (2H, t, J=8.5Hz), 5.10-5.25 (2H, 5.75-5.98 (IH, broad m), 6.70 (2H, broad s) B2981 -27Pharmacological Data 1. 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 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).

B2981 -282. [SI-TBPS binding to rat cerebral cortex membranes in vitro Pooled 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 (50μ1) is incubated (25°C, 120 mins) with [35s]-TBPS (2nM) in Tris citrate buffer (pH 7.1) containing 0.2M NaCl and 5 x 10-^M GABA. Non-specific binding is measured in the presence of 10-4M picrotoxin. Varying concentrations of test drugs (10-10-^, 10-^ and -^M final concentration) are added in a volume of 50μ1.

The total assay volume is 500μ1. Incubation is stopped by rapid filtration using a Skatron cell harvester and radioactivity measured by liquid scintillation spectrometry. IC^q's are calculated as the concentration of test drug to inhibit 50% of specific binding.

Testing Results 1. Geller-Seifter procedure Compound Dose Increase in responding (mg/kg) in the 'conflict' session Example 1 20 p.o. + 52% B2981 -29Compound E2 also showed a significant increase in responding in the 'conflict' session at a dose of 20mg/kg p.o. 2. [3^3]-TBPS binding procedure Compound IC^q Example 1 13μΜ, 17μπι (2 determinations) Compounds of Examples 2, 6, 7 and 10 showed an IC^q of less than 20μΜ. -301. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

Claims (10)

1. \ / N o R (I) 15 wherein: R 4 is hydrogen, C-j__g alkyl, phenyl or phenyl Cj_ 4 alkyl wherein the phenyl moiety is optionally substituted by one or more C]__g alkyl, C-]__g alkoxy, C-^g alkylthio, hydroxy,

2. A compound according to claim 1 wherein R4 is C-j__g alkyl optionally substituted by up to three halo atoms, C2_g alkenyl, C 2 _g alkynyl, Cg_g cycloalkyl or Cg_g cycloalkyl-C-j__4 alkyl. 2° C 2 _7 alkanoyl, halo, trifluoromethyl, nitro, amino optionally substituted by one or two C]__g alkyl groups or by C 2 _7 alkanoyl, cyano, carbamoyl or carboxy groups; R 2 and R 3 are independently selected from hydrogen, C-j__g 25 alkyl, C 3 _7 cycloalkyl, C 3 _7 cycloalkyl-Cj_ 4 alkyl, C 2 -g alkenyl, C 4 _ 7 alkanoyl, C 4 _g alkylsulphonyl, di- (C-j__g alkyl)amino C 4 _g alkyl, 3-oxobutyl, 3-hydroxybutyl, phenyl, phenyl C 4 _ 4 alkyl, benzoyl, phenyl C 2 _ 7 alkanoyl or benzenesulphonyl any of which phenyl moieties are optionally 30 substituted by one or two halogen, C^_g alkyl, C^_g alkoxy, CF 3 , amino or carboxy, or R 2 and R 3 together are C 2 _g polymethylene optionally interrupted by oxygen or NRg wherein Rg is hydrogen or C 4 _g alkyl optionally substituted by hydroxy; B2981/A -31is hydrogen or C-^_g alkyl and Rg is hydrogen or Rq, and Rg together form a C^_g alkylidene group at the 8-position; and -CO2R4 is a pharmaceutically acceptable ester group.

3. A compound according to claim 1 or 2 wherein R^ is hydrogen, C_3 alkyl, phenyl or benzyl.

4. . A compound according to any preceding claim wherein R2 15 and R3 are independently hydrogen or C-j__g alkyl. 5. Manufacture of a medicament for the treatment or prophylaxis of CNS disorders. 36. A method for the treatment and/or prophylaxis of CNS disorders in mammals including humans which comprises 5 27. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, 2,2,2-trifluoroethyl ester. 28. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,βίο tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, but3-enyl ester. 29. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylie acid, 15 but-3-ynyl ester. 30. A salt of a compound according to any one of claims 21 to 29 . 20 31. A process for the preparation of a compound as defined in claim 1 which process comprises deprotecting a compound of formula (VII) as defined in claim 20 in which X is NRgRg, R^'is COgR^ and Rg' is Rg and J and K together represent a group convertible to a keto group and thereafter optionally 25 separating any stereoisomers such as enantiomers and/or forming a pharmaceutically acceptable salt of a compound of formula (I). 32. A pharmaceutical composition which comprises a 30 compound according to claim 1 and a pharmaceutically acceptable carrier. 33. A compound according to claim 1 for use an an active therapeutic substance. -36B2981/A 34. A compound according to claim 1 for use in the treatment and/or prophylaxis of CNS disorders. 35. Use of a compound according to claim 1 in the

5. A compound according to any preceding claim wherein Rg is hydrogen. 20

6. A compound according to claim 5 wherein Rc, and Rg are both hydrogen.

7. . 4-Amino-2-methyl-7-oxo-5, 6, 7,8-tetrahydrobenzo[b] thieno[2,3-b]pyridine-3-carboxylic acid, ethyl ester.

8. . 4-Amino-2-methyl-7'-oxo-5, 6, 7, 8-tetrahydrobenzo [b] thieno[2,3-b]pyridine-3-carboxylic acid, cyclopropylmethyl ester . 30

9. 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b] thieno[2,3-b]pyridine-3-carboxylic acid, methyl ester. 10. 4-Amino-2-methyl-7-oxo-5,6, 7, 8-tetrahydrobenzo[b] thieno[2,3-b]pyridine-3-carboxylic acid, propyl ester. B2981/A -3211. 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b] thieno[2,3-b]pyridine-3-carboxylic acid, prop-2-enyl ester . 12. 4-Amino-2-methyl-7-oxo-5, 6, 7,8-tetrahydrobenzo[b] thieno[2,3-b]pyridine-3-carboxylic acid, but-2-ynyl ester. 13. 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b] thieno[2,3-b]pyridine-3-carboxylic acid, 2,2,2-trifluoroethyl ester. 14. 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b] thieno[2,3-b]pyridine-3-carboxylic acid, but-3-enyl ester. 15. 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b] thieno[2,3-b]pyridine-3-carboxylic acid, but-3-ynyl ester. 16. 4-Amino-2-methyl-8-(1-methyl-l-ethylidene)-7-oxo5,6,7,8-tetrahydrobenzo[b]thieno[2,3-b]pyridine-3carboxylic acid, but-3-enyl ester. 17. A pharmaceutically acceptable salt of a compound according to any one of claims 7 to 16. 18. A compound according to claim 1 as hereinbefore described in any one of Examples 1 to 10. 19. A process for the preparation of a compound as defined in claim 1 which process comprises the cyclisation of a compound of formula (III) : B2981/A -33R M R (III) or imine tautomer thereof, wherein R-^' is R^ as defined in 10 formula (I) or a group convertible thereto, R^' is -CO2R4 as defined in formula (I) or an electron-withdrawing group convertible to -CO2R4, R5 and Rq are as defined as in formula (I), R7 is hydrogen or an N-protecting group, J and K together represent a keto group or a group convertible 15 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 2 , wherein L 2 is a leaving group; and thereafter, optionally or as necessary, and in any appropriate order, converting R7 when hydrogen to an N-protecting group, when Y 20 or M is a group COL-^ or COL 2 , converting the resulting hydroxy group to a leaving group and reacting the latter with a compound HNR 2 'R 2 ' wherein R 2 ' and R3' are R 2 and R 2 or N-protecting groups, removing any R7 N-protecting group, converting any electron-withdrawing group R 4 ' to CO 2 R 4 , 25 converting R^' when other than Rj to R-p interconverting R 2 , Rg,’R4, R5 and Rg, converting J and K to a keto group, separating any stereoisomers such as enantiomers and/or forming a pharmaceutically acceptable salt of a compound of formula (I) . 20. A compound of formula (VII) or a salt, ester or amide thereof: -34IE 914532 B2981/A (VII) 10 wherein R4'' is R4' as defined in claim 19 or a group convertible to CO2R4, X is NRg'Rg', OH or chloro, Rg'/ Rg't Rg', J and K are as defined in claim 19 and R4, Rg and Rg are as defined in claim 1, provided that when X is NRgRg, J and K together represent a keto group and Rg' is Rg, R4'' is 15 other than CO2R4· 21. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylie acid, ethyl ester. 22. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylie acid, cyclopropylmethyl ester. 25 23. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylie acid, methyl ester. 24. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,830 tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, propyl ester. 25. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylie acid, 35 prop-2-enyl ester. B2981/A -3526. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, but-2-ynyl ester.

10. Administering to the sufferer an effective, non-toxic amount of a compound according to claim 1.