AU7772191A

AU7772191A - Tetrahydrobenzothienopyridines, processes for their preparation and their use as pharmaceuticals

Info

Publication number: AU7772191A
Application number: AU77721/91A
Authority: AU
Inventors: David Thomas Davies; Ian Thomson Forbes; Mervyn Thompson
Original assignee: Beecham Group PLC
Current assignee: Beecham Group PLC
Priority date: 1990-05-08
Filing date: 1991-05-01
Publication date: 1991-11-27
Anticipated expiration: 2011-05-01
Also published as: AU641504B2; IE911532A1; NZ238055A; ZA913394B; GB9010296D0; JPH06505698A; CA2082392A1; PT97570A; EP0527964A1; WO1991017165A1

Description

TETRAHYDROBENZOTHIENOPYRIDINES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS PHARMACEUTICALS

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: R₁ 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;

R₂ and R₃ 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, CF₃, amino or carboxy, or R₂ and R₃ together are C_2-6 polymethylene optionally interrupted by oxygen or NR₆ wherein R₆ is hydrogen or C_1-6 alkyl optionally substituted by hydroxy;

R₅ is hydrogen or C_1-6 alkyl and R₈ is hydrogen or R₅ and R₈ together form a C_1-6 alkylidene group at the 8-position; and -CO₂R₄ is a pharmaceutically acceptable ester group.

Alkyl moieties within the variables R₁ to R₅ are preferably C_1-3 alkyl, such as methyl, ethyl and n- and iso-propyl. Values for R₁ include hydrogen, methyl, ethyl, n- and

iso-propyl, phenyl and benzyl. Preferably, R₁ is methyl.

It will be appreciated in selecting variables R₂ and R₃ that the nitrogen atom is not directly attached to unsaturated aliphatic carbon.

Values for R₂ and R₃ 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,

1-methylprop-2-enyl, formyl, acetyl, propionyl,

methylsulphonyl, 3-dimethylaminobutyl, 3-oxobutyl,

3-hydroxybutyl, phenyl, benzyl, benzoyl, benzylcarbonyl and benzenesulphonyl, or R₂ and R₃ together form

- (CH₂)_r-X- (CH₂)_s- wherein r and s are independently 1, 2 or 3 and X is a bond, 0 or NR₆, for example C₄ or C₅

polymethylene, - (CH₂)₂-O-(CH₂)₂- or - (CH₂)₂-NR₆- (CH₂)₂- where R₆ is preferably methyl.

Preferably R₂ is hydrogen and R₃ is hydrogen or C_1-6 alkyl, for example methyl. Most preferably R₂ and R₃ 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

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. Preferably the

pharmaceutically acceptable 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. R₄ 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 R₅ include hydrogen, methyl, ethyl and n and iso propyl, preferably hydrogen. Alternatively, R₅ and R₈ 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 R₃ ¹ is hydrogen or C_1-6 alkyl and R₁ and R₄ are as defined in formula (I).

Preferred values for R₁ and R₃ ¹ 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 R₃ 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. When 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 which R₈ is hydrogen and R₅ is other than hydrogen have a chiral centre on the carbon atom adjacent to the R₅ moiety. In addition, compounds in which R₅ and R₈ represent an alkylidene group may exist in E and Z forms, while

substituents R₁, R₂, R₃, R₄, and R₅ 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 R₁' is R₁ 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 R₈ 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 thereto, Y is a group CN or COL₁, wherein L₁ 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, optionally or as necessary, and in any appropriate order, converting R₇ when hydrogen to an N-protecting group, when Y or M is a group COL₁ or COL₂, converting the resulting hydroxy group to a leaving group and reacting the latter with a compound HNR₂'R₃' wherein R₂' and R₃' are R₂ and R₃ or N-protecting groups, removing any R₇ N-protecting group, converting any electron-withdrawing group R₄' to CO₂R₄, converting R₁' when other than R₁ to R₁, interconverting R₂, R₃, R₄, R₅ and R₈, 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 ZnCl₂, SnCl₄ or CuOCOCH₃ 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. Protected keto groups J and K are exemplified by compounds of formula (III) wherein J is XR₁₃ and K is ZR₁₄, X and Z are independently oxygen or sulphur and R₁₃ and R₁₄ are independently C_1-6 alkyl or together are C_2-4 polymethylene optionally substituted with one or more C_1-6 alkyl groups.

When X and Z are both oxygen, the group -X-R₁₃ and -Z-R₁₄ 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 -X-R₁₃ and -Z-R₁₄ 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-R₁₃ 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

(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.

R₅ and R₈ 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. The

alkylidene group may then be hydrogenated to the

corresponding R₅ 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 R₇ is hydrogen.

Suitable examples of groups R₄' include the groups

hereinbefore described for -CO₂R₄, COR_a where R_a is

hydrogen, C_1-6 alkyl, C_3-7 cycloalkyl C_1-4 alkyl or C_3-7 cycloalkyl, CH=NOH, CO₂H, 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, CF₃, C_1-6 alkoxy, C_1-6 alkyl or nitro, cyano and -CONR₉R₁₀ where R₉ and R₁₀ are independently selected from hydrogen, C_1-6 alkyl, C_1-6 alkoxy and phenyl or phenyl C_1-6 alkyl optionally substituted as described above for optional substituents in the phenyl ring of a benzyl ester, or together form a C_2-6 polymethylene chain optionally

interrupted by oxygen or NR₁₁ wherein R₁₁ is hydrogen or C_1-6 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 of 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 R₄OH 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 CrO₃ and esterified as above. R₄' COR_a groups may be converted to CO₂R₄ via the acid by a haloform reaction and esterification.

Suitable examples of a leaving groups L₁ and L₂ when Y or M is COL₁ or COL₂ 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 HNR₂'R₃' under conventional conditions for nucleophilic aromatic displacements, at elevated temperatures in an inert solvent such as toluene, methanol, ethanol, ine, dimethylformamide or dioxan.

Alternatively, the reaction may be carried out in neat

HNR₂'R₃' which functions as the solvent.

An R₂' or R₃' protecting group such as p-methoxybenzyl may be removed conventionally.

Conversion of R₂ and R₃ 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 COL₁ 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):

(IV) with a compound of formula (V) :

(V) wherein R₁', R₄', R₅, R₇, R₈, Y, J, 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_1-6 acyloxy such as acetoxy, C_1-6 alkoxy, such as methoxy or ethoxy, preferably methoxy or NR_aR_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. 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. For the preparation of compounds of formula (I) in which R₁ 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 R₁' is a C_1-6 alkoxycarbonyl group. The reaction with the compound of formula (IV) may then be followed by a decarboxylation step to give R₁ hydrogen;

(ii) L is a leaving group and R₁' is hydroxy. In the resulting compound, the R₁' 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 R₁ 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 C_1-6 alkoxycarbonyl, and R₁' 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) wherein R₅, R₈, J and K are as defined in formula (III), with NCCH₂Y and sulphur in the presence of a base such as diethylamine in an inerz solvent such as methanol or ethanol.

Compounds of formula (VI) are either known compounds or car. 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 R₁ is CH₃ 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 R₁' 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:

wherein R₄'' is R₄' as defined in formula (III) or a group convertible to CO₂R₄, X is NR₂/R₃', OH or chloro, R₁', R₂', R₃', J and K are as defined in formula (III) and R₄, R₅ and R₈ are as defined in formula (I), provided that when X is NR₂R₃, J and K together represent a keto group and R₁' is R₁, R₄'' is other than CO₂R₄. Novel compounds of formula (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 NR₂R₃, R₄'' is CO₂R₄ and R₁' is R₁, 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 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.

For parenteral administration, 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. 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 weight of 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 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. Description 1

2-Amino-6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carbonitrile (D1)

The title compound was prepared from 1,4-cyclohexandione mono-ethvlene ketal using a procedure similar to that of Gewald et al., Chem. Ber. 1966, 94 (49% yield).

NMR (CDCI₃) 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)

A mixture of aminonitrile (D1) (13.16g; 55.7mmol) and ethy] 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. Trituraticn 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 (CDCI₃) 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 (1H, s).

Description 3

4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydrcbenzo[b]thieno[2 ,3-b]pyridine-3-carboxylic acid, ethyl ester (D3)

A solution of enaminoester D2 (11.7g, 33.6 mmol) in toluene (400ml) was treated with a 1M 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 half-saturated aqueous ammonium chloride. The mixture was filtered, the organic phase separated, dried (Na₂SO₄) and evaporation in vacuo gave a brown oil. Chromatography cn 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]

thieno[ 2 ,3-b2pyridine-3-carboxylic acid, ethyl ester

(E1, 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 vacuo 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

C₁₅H₁₆N₂O₃S requires C, 59.19; H, 5.30; N, 9.20

NMR (CDCl₃) 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 [b] thieno

[ 2 ,3-b]pyridine-3-carboxylic acid, cyclopropylmethyl ester (E2, R₄ = CH₂-c-C₃H₅)

The title compound was prepared from D1 and 3-oxo-butyric acid, cyclopropylmethyl ester via the intermediate

4-amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydro- benzo[b]thieno[2,3-b]pyridine-3-carboxylic 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

C₁₇H₁₈N₂O₃S requires C, 61.80; H, 5.49, N, 8.48% Example 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 = CH₃)

The title compound was prepared from D1 and methyl

acetoacetate via the intermediate 4-amino- 7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydro- 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]pyridine-3-carboxylic acid, propyl ester

(E4, R₄ = CH₂CH₂CH₃)

The title compound was prepared in 11% overall yield from Dl and 3-oxo-butyric acid, propyl ester via the intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydro- benzo[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) NMR (d₆ 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-blpyridine-3-carboxylic acid, prop-2-enyl ester (E5, R₄ = CH₂CH=CH₂)

The title compound was prepared in 8% overall yield from D1 and 3-oxo-butyric acid, prop-2-enyl 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, prop-2-enyl ester using a procedure similar to that described in Example 2. m.p. 148-150° (from ethyl acetate).

NMR (CDCl₃) 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 (1H, 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, R₄ = CH₂C≡CCH₃)

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).

NMR (CDCI₃) 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

[2,3-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 D1 via the

intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic 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⁺). Example 8

4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b]thieno

[2 ,3-blpyridine-3-carboxylic acid, but-3-enyl ester (E8, R₄ = (CH₂)₂ CH=CH₂)

The title compound was prepared from D1 and 3-oxo-butyric acid, but-3-enyl 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-3-enyl ester using copper (I) acetate following a procedure similar to that of Example 2. m.p. 130-2° (from ethyl acetate).

NMR (CDCl₃) 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 (1H, 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)₂C≡CH).

The title compound was prepared in 5% overall yield from D1 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]pyridine- 3-carboxylic acid, but-3-ynyl ester using a procedure similar to that of Example 2, but in which the cyclisation step was carried out in n-butyl acetate using SnCl₄. m.o. 167-8°C

NMR (CDCI₃) δ: 2.05 (1H, 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-1-ethylidene)-7-oxo-5,6,7,8- tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, but-3-enyl ester (E10)

The amine D1 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. m.p. 136-8°

NMR (CDCl₃) δ: 2.25 (3H, s), 2.27 (3H, s), 2.55 (2H, m),

2.74 (3H, s), 2.80 (2H, t, J = 8.5Hz), 3.40 (2H, t, J=8.5Hz), 4.42 (2H, t, J=8.5Hz), 5.10-5.25 (2H, broad m), 5.75-5.98 (1H, broad m), 6.70 (2H, broad s).

Pharmacological 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 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). 2. [³⁵S]-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 1000g 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 (50μl) 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^-6M GABA. Non-specific binding is measured in the presence of 10 M picrotoxin.

Varying concentrations of test drugs (10^-7, 10^-6, 10^-5 and

10^-4M final concentration) are added in a volume of 50μl. The total assay volume is 500μl. Incubation is stopped by rapid filtration using a Skatron cell harvester and

radioactivity measured by liquid scintillation spectrometry.

IC₅₀'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% Compound E2 also showed a significant increase in responding in the 'conflict' session at a dose of 20mg/kg p.o.

2. [³⁵S]-TBPS binding procedure

Compound IC₅₀ Example 1 13μM, 17μm (2 determinations)

Compounds of Examples 2, 6, 7 and 10 showed an IC₅₀ of less than 20μM.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

R₁ 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 alkanoyl, 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;

benzenesulphonyl any of which phenyl moieties are optionally substituted by one or two halogen, C_1-6 alkyl, C_1-6 alkoxy, CF₃, amino or carboxy, or R₂ and R₃ together are C_2-6 polymethylene optionally interrupted by oxygen or NR₆ wherein R₆ is hydrogen or C_1-6 alkyl optionally substituted by hydroxy; R₅ is hydrogen or C_1-6 alkyl and R₈ is hydrogen or R₅ and R₈ together form a C_1-6 alkylidene group at the 8-position; and

-CO₂R₄ is a pharmaceutically acceptable ester group.

2. A compound according to claim 1 wherein R₄ is C_1-6 alkyl optionally substituted by up to three halo atoms, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl or C_3-6

cycloalkyl-C_1-4 alkyl.

3. A compound according to claim 1 or 2 wherein R₁ is hydrogen, C_1-3 alkyl, phenyl or benzyl.

4. A compound according to any preceding claim wherein R₂ and R₃ are independently hydrogen or C_1-6 alkyl.

5. A compound according to any preceding claim wherein R₈ is hydrogen.

6. A compound according to claim 5 wherein R₅ and R₈ 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.

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.

11. 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-trifluoro- ethyl 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-1-ethylidene)-7-oxo- 5,6,7,8-tetrahydrobenzo[b]thieno[2,3-b]pyridine-3- carboxylic 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): or imine tautomer thereof, wherein R₁' is R₁ 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 R₈ 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 thereto, Y is a group CN or COL₁, wherein L₁ 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, optionally or as necessary, and in any appropriate order, converting R₇ when hydrogen to an N-protecting group, when Y or M is a group COL₁ or COL₂, converting the resulting hydroxy group to a leaving group and reacting the latter with a compound HNR₂'R₃' wherein R₂' and R₃' are R₂ and R₃ or N-protecting groups, removing any R₇ N-protecting group, converting any electron-withdrawing group R₄' to CO₂R₄, converting R₁' when other than R₁ to R₁, interconverting R₂, R₃, R₄, R₅ and R₈, 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:

wherein R₄'' is R₄' as defined in claim 19 or a group convertible to CO₂R₄, X is NR₂'R₃', OH or chloro, R₁', R₂ ', R₃', J and K are as defined in claim 19 and R₄ , R₅ and R₈ are as defined in claim 1, provided that 'when X is NR₂R₃, J and K together represent a keto group and R₁' is R₁, R₄'' is other than CO₂R₄.

21. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, ethyl ester.

22. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, cyclopropylmethyl ester.

23. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, methyl ester.

24. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, propyl ester.

25. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, prop-2-enyl ester.

26. 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.

27. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- tetrahydrobenzo.b]thieno[2,3-b]pyridine-3-carboxylic acid, 2,2,2-trifluoroethyl ester.

28. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, but3-enyl ester .

29. 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, but-3-ynyl ester.

30. A salt of a compound according to any one of claims 21 to 29.

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 NR₂R₃, R₄''is CO₂R₄ and R₁' is R₁ 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).

32. A pharmaceutical composition which comprises a

compound according to claim 1 and a pharmaceutically

acceptable carrier.

33. A compound according to claim 1 for use an an active therapeutic substance.

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

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