NZ238055A - 4-amino-7-oxo-tetrahydrobenzothienopyridine-3-carboxylic acid derivatives, precursors and medicaments - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £38055 238 05 5 :\o * I \ s.) ° 11 ■ Co-lQU-c'.Sioi^ 'JLO; 0^VCS\ \ I m 2 6 AUG 1993 (31 ! "4 It »*. < ; t" \ '.

NEW ZEALAND PATENTS ACT, 1953 No.' Date.

COMPLETE SPECIFICATION NOVEL COMPOUNDS r i p ^ T}-, xk/We, BEECHAM GROUP p.I.e. a British Company of SB House, Great West Road, Brentford, Middlesex TW8 9BD, England hereby declare the invention for which X& / we pray that a patent may be granted to fwa/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- (followed by page la) 23 8 0 Q 32981 - 1°L •" NOVEL COMPOUNDS This invention relates to compounds having pharmacological activity, to a process for their preparation, to 5 compositions containing them and to their use in the treatment of mammals.

EP-A-0 327 223 (Beecham Group pic) discloses a class of tecranydrobenzothienopyridines which have anxiolytic and/or :c anti-depressant activity.

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

Accordingly, the present invention provides a compound of formula (I) or a pnarmaceutically acceptable salt thereof: R2 "j \ / wherein: is hydrogen, alkyl, phenyl or phenyl alkyl wherein the phenyl moiety is optionally substituted by one or more alkyl, C^_g alkoxy, C_g alkylthio, hydroxy, C2_7 alkanoyl, halo, trifluoromethyl, nitro, amino (J c/ o V ccticnally substituted by cne or two C^_g alkyl groups or by -2-7 alkanoyl, cvano, carbamoyl or carboxy groups; ?>2 and R3 are independently selected from hydrogen, C-^.g alkyl, Ct_-; cyclcalkyl, C-^-j cycloalkyl-C-| _4 alkyl, C2_g alkenyl, C* alkar.cyl, C-_- alkylsulphony 1, di-(C-_g alkyl) amino C-_g alkyl, 3-cxobutyl, 3-hydroxybuty 1, phenyl, phenyl C-, alkyl, benzoyl, phenyl C9_7 alkanoyl and benzenesulphc.nyl, any of which phenyl moieties are optionally :o substituted bv one or two halccen, C-*- alkyl, C-t- alkoxy, CF^1 amino or carbcxy, or R2 and R3 together are C2_g pclymethylene optionally interrupted by oxygen or NRg wherein Rr is hvdrccen or C- - alkvl octicnallv substituted 0 - - _ ~ c - - by hydroxy; R= is hydrogen or C-_g alkyl and Rg is hydrogen or R^ and Rg together form a C-_- alkylidene group at the 8-position; -CC'2^4 is a pharmaceutical!-/ acceptable ester group.

Alkyl moieties within the variables R-, to R5 are preferably C_2 alkyl, such as methyl, ethyl and n- and iso-propyl.

Values for R-_ include hydrogen, methyl, ethyl, n- and i q J'jNi'C iso-propyl, phenyl and benzyl. Preferably, R-^ is methyl.

It will be appreciated in selecting variables R9 and R3 that the nitrogen atom is not directly attached to unsaturated 30 aliphatic carbon.

Values for R2 and R3 include hydrogen, methyl, ethyl, n- ana iso-propyl, n-, sec-, iso- and tert-butyl, n-, sec, iso- and neo-pentyl, cyclopentyl, cyclohexyl, cycloheptyl, 35 cyclopenty 1-C]__4 alkyl, cyclohexyl-c^.^ alkyl and 23 8 0 B2S31 «. *3 — -w> cycloheptyl-CT alkyl, where values for alkyl include methylene and ethylene, but-2-enyl, but-3-enyl, 1-methylprop-2-eny1, formyl, acetyl, propionyl, methylsulphonyl, 3-dimethylaminobutyl, 3-oxobutyl, 3-hydroxybuty1, phenyl, benzyl, benzoyl, benzylcarbonyl and benzenesulphonyl, or anc^ R3 together form - (CH2) V--X-(CH2) s~ wherein r and s are independently 1, 2 or 3 and X is a bona, 0 or NRg, for example C4 or polymethylene, — (Cno) 2~"^~ (CH2) 2~ ~~ (CH2) (CH2) 2 — where R^- is preferably methyl. o 1 Preferably R2 is hydrogen and R3 is hydrogen or C-^.g alkyl, for example methyl.

Most preferably R2 and Ro are hydrogen.

Suitable examples of pharmaceutical esters of the compounds of formula (I) include C-j__g alkyl esters wherein the alkyl moiety is optionally substituted by up to three halo atoms 20 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, ^2-^ al^enY- esters such as vinyl, prop-l-enyl, prop-2-enyl, 1-methylviny1, but-l-enyl, but-3-enyl, 1-methylenepropyl and l-methylprop-2-enyl, (in 25 both their E and Z forms where stereoisomerism exists), C2_g alkynyl esters such as prop-2-ynyl, but-2-ynyl and but-3-ynyl, C3_g cycloalkyl esters and C3_g cycloalkyl-C1_4 alkyl esters such as cyclopropylmethyl. Preferably the pharmaceutically acceptable ester is the methyl, ethyl, 30 2, 2, 2-trifluoroethyl, propyl, prop-2-enyl, prop-2-ynyl, but-3-enyl, but-2-ynyl, but-3-ynyl or cyclopropylmethyl ester, i.e. R^ 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. 0 5 5 B2981 Suitable values of R^ include hydrogen, methyl, ethyl and n and iso propyl, preferably hydrogen. Alternatively, and Rg together may represent an 8-(1-methylethyliaene) group.

There is a preferred group of compounds within formula (I) of formula (II) or a pharmaceutically acceptable salt thereof: nhr: C02R4 :ii: wherein R^-1- is hydrogen or C-, _g alkyl and R-j_ and are as defined in formula (I). :o Preferred values for R- and R^* are as described for the corresponding variables in formula (I).

The compounds of the formula (I) can form acid addition 25 salts with acids, such as the conventional pharmaceutically acceptable acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulpnonic.

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. 23 8 0 32 5 S1 When referred co herein, it is understood that the term ''ccmcound of formula (I)'' also includes solvates thereof.

It should be appreciated that compounds of formula (I) in 5 which Rg is hydrogen and R^ is other than hydrogen have a chiral centre on the carbon atom adjacent to the R^ moiety. In addition, compounds in which R^ and Rg represent an alkylidene group may exist in E and Z forms, while substituents R-, , R?, R3, R4, and R5 may contain asymmetric 10 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 15 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 R-^' is R-^ as defined in 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 Rg are as defined as in 20 formula (I), R-j 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, <•>' o o . «_/ optionally or as necessary, and in any appropriate order, ::r.ver:ir.g P- when hydrogen to an M-protecting group, when Y or M is a group COLi or COL?, converting the resulting hydroxy group to a leaving group and reacting the latter with a compound HNR2'R3' wherein R2' and R31 are R2 and R3 as defined in formula (I) or M-protectir.g groups, removing any R7 N-protecting group, converting any electron-withdrawing group R*' to CC^R^, converting R-, ' when other than to , intercor.verting R9, R-, Rj, R= 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 The cyclisatior. of the enamine of formula (III) or imine tautomer thereof may be carried cut under conventional conditions, in the presence of a strong base such as an alkali metal alkoxide, for example sodium methcxide in a suitable solvent such as methanol, at elevated temperature, or in the presence of a Lewis acid such as ZnC^, SnCl^ or CuGCOCK-; in a suitable solvent such as n-butyl acetate at elevated temperature. lev/is acid catalysed cyciisation using copper (I) acetate or tin (IV) chloride is preferred especially when cvciising to give compounds of formula (I) directly i.e. where R^' is ^2^4 • ■ s 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 tetrahydropyranyI may be de-protected conventionally to give a hydroxy group which may be oxidised conventionally for example using oxalylchloride/ dimethylsulpnoxide or pyridinium chlorochromate to give the ketone. 2 3 8 0 32 931 Protected keto groups J and K are exemplified by compounds of formula (III) wherein J is XR-, - and K is ZR14, X and Z are independently oxygen or sulphur and R-^ and R-j 4 are independently alkyl or together are p°lymethylene optionally substituted with one or more C-,_g alkyl groups.

When X and Z are both oxygen, the group -X-R-^ and -Z-R14 may be conventionally converted to a keto group for example by treatment with aqueous hydrochloric acid. — ~j When one of X or Z is an oxygen atom and the other is a sulphur atom, the group -X-R^ ana -Z-R-^ may be conventionally converted to a keto group, for example by treatment with aqueous hydrochloric acid or quaternisaticn 15 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-R^ and -Z-R^ 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 30 aqueous acetonitrile.

Preferably X and Z are oxygen.

R^ and Rg hydrogen may be converted to an alkylidene group 35 in the 8-position by an aldol condensation with an 23 8 0 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 R-j N-protecting groups include trimethylsilyl and 2-(trimethylsilyl)ethoxymethyl, which may be removed conventionally, for example using tetra-n-butylammonium fluoride.

Preferably R-j is hydrogen.

Suitable examples of groups R^' include the groups hereinbefore described for -CO-R^, C0R-, where R, is *1 d a. hydrogen, Ci_g alkyl, C3,7 cycloalkyl C-|__4 alkyl or cycloalkyl, CH=MOH, CO^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, CF3, C|_g alkoxy, alkyl or nitro, cyano and -CONRgR]_Q where Rg and R-, g are independently selected from hydrogen, C^_g alkyl, C-j__g alkoxy and phenyl or phenyl 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 25 interrupted by oxygen or wherein R^1 is hydrogen or C,_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 30 can then be esterified under conventional conditions by reaction with the appropriate alcohol R^OK, 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 35 leaving group such as chloro, bromo or iodo, in the presence 23 8 0 32981 of a suitable base such as potassium carbonate in an inert -r.such as dimethylformamide .

An intermediate amide may be hydrolysed to the free acid 5 v;hich can then be esterified as described above.

An R^' 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 -CvtR/i .

An R^' 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 CrO^ ana esterified as above.

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

Suitable examples of a leaving groups and L2 when Y or M is COLt or COL2 include hydroxy and, more preferably, alkoxy 25 such as 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 30 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 35 elevated temperatures in an inert solvent such as toluene, methanol, ethanol, pyridine, dimethylformamide or dioxan. 238055 B2981 Alternatively, the reaction may be carried out in neat HNR^/R^' which functions as the solvent.

An R2' or R3' protecting group such as p-methoxybenzyl may 5 be removed conventionally.

Conversion of R2 and R^ hydrogen to other ^2/^3 may be carried out in accordance with conventional procedures for the alkylation or acylation of a primary amine. Acylation 10 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^j'Ry 15 as discussed above.

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

Compounds or formula (III) may be prepared by the reaction of a compound of formula (IV): 7 R 8 (IV) with a compound of formula (V): 23 8 g 32381 m r 4 r l 1 (v) wherein R^_' , R^' , Rq, R-j, Rg, Y, J, and K are as defined as in formula (III), L is a leaving group ana 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 15 further aspect to the present invention.

Suitable examples of the leaving group L include halogens, such as chloro and brorno, hydroxy, acyloxy such as acetoxy, Cq_^ alkoxy, such as methcxy or ethoxy, preferably 2 0 methoxy or NR^k where Ra and R^ are independently hydrogen or alkyl or together form a C2_g polymethylene chain optionally interrupted by oxygen or NRC where Rc is hydrogen or alkyl optionally substituted by hydroxy. When L is hydroxy, it will be appreciated that the compound of formula 25 (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 30 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 1O-camphorsulphonic acid, with water separation if appropriate. 238 055 32 9 8 1 For the preparation of compounds of formula (I) in which is hydrogen, che compound of formula (V) may be used in which: (i) L and M togecher represent a bond or L is hydroxy and M is hydrogen, and R^' is a C]__g alkoxycarbonyl group. The reaction with the compound of formula (IV) may then be followed by a decarboxylation step to give R^ 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-^ hydrogen may be carried out before or, more preferably, after cvclisation of the compound of formula (III) ; (iii) L is a leaving group, M and R^' are both C-j__g alkoxycarbonyl, and R-, ' is hydrogen.

Compounds of formula (IV) are prepared analogously to the 25 methods described in K. Gewald et a_l, Chem. Ber. 94 (1966) by reacting compounds of formula (VI): R O (VI) 23 8 0 32 S 8 1 wherein Rq, Rg, J and K are as defined in formula (III), with NCCH9Y 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 10 prepared analogously to known compounds. For example, compounds of formula (V) wherein M is hydrogen, L is OH and R-] is CHt may be prepared by reacting diketene with the appropriate alcohol RdOK using a method similar to that of R.J. Clemens and J.A. Hyatt, J. Org. Chem., 1985 .50 2431. 15 The compound of formula (V) in which R-^' is phenyl, M is hydrogen, L is ethoxy and R4' is ethoxycarbonyl is described by V.L. Leighton, Amer. Chem. Journal (1898), 2_0, 133.

A class of intermediates comprises compounds of formula 20 (VII) or a salt ester or amide thereof: (VII) wherein R^'' is R^' as defined in formula (III) or a group convertible to CO2R4, X is NR2'R3', OH or chloro, R]_', R?', R3', J and K are as defined in formula (III) and R^, R^ ana Rg are as defined in formula (I), provided that when X is NR2R3, J and K together represent a keto group and R^' is 35 R-^, R4'' is other than CO2R4 • Novel compounds of formula »•* I. s.

(VI I) also form pare of the invention.

Examples of ' ' when other than CC^R^ include CC^H.

In a further aspect, the invention also provides a process :cr 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 NR2R7, -4'' is CC2R4 snd R-, ' is R-j , and J ana 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 ir.fusable solutions or suspensions. Orally administrable cc.t.ccsicicns aiT6 aer.erallv .

Tablets and capsules for oral administration may be in unit cose form, ar.d may contain conventional excipients, such as binding agents, fillers, tablettinc lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal • ,)t U ^ 3 11 l.\, '■ ("'■ <-"J pharmaceutical practice. *v ?•> Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or 23 8 0 B2981 elixirs, or may be in the form of a dry product for recor.stitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, 5 non-aqueous vehicles (which may include edible oils), preservatives,' and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are :o 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 15 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 20 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 25 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. 3 0 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 CMS 35 disorders, such as anxiety or depression will vary in the usual way with the seriousness of the disorders, the weight V-/ »■> ' of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, mere 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 10 0 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 CMS disorders, in particular anxiety or depression which composition comprises an effective, ncn-toxic amount of compound cf formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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 CMS 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 CMS disorders, in particular anxiety or depression.

The following examples illustrate the preparation of compounds of the invention. 238 05 5 B2981 description 1 2-Amine- 6 , 6-ethyleneaioxy-4, 5, 6, 7-tetrahvdrobenzo[bl thiophene-3-carbonitrile (D1) (Dl) The title compound was prepared from 1,4-cyclohexandione mono-ethylene ketal using a procedure similar to that of k, 15 Gewald et al., Chem. Ber. 1966, 94 (49% yield) .

NMR (CDCI3) 5: 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-ethyleneaioxy-4,5,6,7-tetrahydrobenzo fblthienyl)amino)-2-butenoic acid, ethyl ester (D2) O ^ V II \/° N H 0 I! c ch.

OC2H5 (D2) 23 8 0 5 5 32 981 A mixture of aminonitrile (Dl) (13.15g; 55.7mmol) and ethyl [3-ethoxycrotonate (26g; 164mmol) in mesitylene (400ml) was heated at reflux for I.5h then evaporated to dryness. The 5 residue was chromatographed on Kieselgel 60 eluting with a 0-2% methanol in aichloromethane 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 (CDCI3) 8: 1.30 (3 H, 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-Anuno-7,7-ethylenedioxv-2-methvl-5,6,7,8-tetrahvcro-benzo fb]thienof 2,3—b1pyridine-3-carboxvlic acid, ethyl 20 ester (D3) - oc2h5 cu.

(D 3) A solution of enaminoester D2 (11.7g, 33.6 mmol) in toluene 30 (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 238055 82981 half-saturated aqueous ammonium chloride. The mixture was filtered, the organic phase separated, dried (Na2SO^) and evaporation in vacuo gave a brown oil. Chromatography on TLC alumina, eluting with a 0-2% methanol in dichloromethane 5 gradient, afforded the title compound as a yellow gum (7g, 60%) .

NMR (CDC13) 5: 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) , 10 6. 60 (2H, bs) .

Example 1 4-Amino-2-methy1-7-0X0-5, 6,7,8-tetrahydrobenzorta 1 thienof2,3—b1oyridine-3-carboxvlic acid, ethyl ester (El, R^ = C3 H ^ X.

A solution of ketal D3 (4.62g, l3.3mmol) 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 30 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 (Na2S04) and concentrated in.

I 3 8 0 5 5 32 981 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 C15Hi6N2°3S requires c' 59.19; H, 5.30; N, 9.20 NMR (CDCI3) 5: 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) .

Ex article 2 4-Amino-2-methyl-7-oxo-5 , 6, 7 , 8-tet ra'nvdrober.zo f b] thie.no [2,3-blpyridine-3-carboxylic acid, cyclopropylmethyl ester (E2, R ^ = CH2-C-C3H::) The title compound was prepared from D1 and 3-oxo-butyric 20 acid, cyclopropylmethyl ester via the intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5,6,7, 8-tetrahydrobenzo [b]tnieno[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 ci 7H18N2°3S retires C, 61.80; H, 5.49, N, 8.48% 238055 B2981 4-Amino-2-methyl-7-oxo-5, 6, 7, 8-tet ra'nvdrobenzo rb 1 thieno f 2, 3-bl pyridine-3-carboy.vlic acid, methyl ester (E3, E4 = CH3l The title compound was prepared from D1 and methyl acetoacetate via the intermediate 4-amino-7 , 7-ethylenedioxy-2-methy 1-5 ,6,7, 8 -tetra'nydro-lO benzo[b]thieno[2,3-b]pyriaine-3-carboxylic acid, methyl ester using a procedure similar tc that of Example 2. m.p. 202-6° (from ethyl acetate) Found: C, 57.95; H, 4.86; N, 9.65 (-"14H14N2<^,3^ requires C, 57.92; H, 4.86; N, 9.65%.

Example 4 4-Amino-2-methy1-7-0X0-5,6,7,8-tetrahvdrobenzofb1thieno r2,3 — b1pyridine-3-carboxvlic acid, Propyl ester (E4, R, = CH2CH2CH3) The title compound was prepared in 11% overall yield from 25 D1 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) 238 05 5 NMR (dg DMSO) 5: 0.95 (3H, t, J=7Hz), 1.75 (2H, sx, J=7Hz), 2.55 (3H, s), 2.70 (2H, c, J=oHz), 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-methvl-7-oxo-5,6,7,8-tetrahvdrobenzo[b1 thieno [2,3—b1pyridine-3-carboxylic acid, proo-2-envl 10 ester (E5, = CHoCH^CHo) The title compound was prepared in 3% overall yield from D1 and 3-oxo-butyric acid, prop-2-enyl ester via the intermediate 4-amino-7,7-ethyleneaioxy-2-methyl-5,6,7,8-15 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 (CDC13) 8: 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-tetrahvdrobenzo fb1thieno [2,3-b]pyridine-3-carboxylic acid, but-2-ynyl ester (E6, R ^ = CKoCsCCHo) The title compound was prepared in 5% overall yield from D1 and 3-oxo-butyric acid, 2-but-2-ynyl ester via the 238055 * * 9 32 981 ir.termediate 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 (CDC13) 5:1.90 (3H, t, J=3Hz) , 2.74 (3H, sj , 2.80 (2H, t, J=8Hz), 3.45 (2H, m) , 3.70 (2H, s) , 4.90 10 (2H, q, J=3Hz), 6.55 (2K, broad s).

Example 7 4-Amino-2-methvl-7-oxo-5 , 6, 7 , 5-tetrahvdrccenzo rb 1 thieno 15 r2,3-b1 pyridine-3-carbcxy1ic acid, 2, 2 , 2-trifluoroethyl ester (E7, R* = CHoCF-i The title compound was prepared in 1% overall yield from 2,2,2-trifluoroethyl aceccacecate and D1 via the 20 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. 2 5 m.p. 140-6° NMR (CDCI3) 5: 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=8Kz), 6.70 (2H, broad s) . m/z = 358 (M+). 2 3 8 0 5 5 B2981 Sxample 8 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahvdrobenzo fblthieno 5 i2,3-blpyridine-3-carboxylic acid, but-3-enyl ester (58, R, = (CH2)Q CH=CH2) The title compound was prepared frcm D1 and 3-oxo-butyric acid, but-3-enyl ester via the intermediate 4-amino-10 7,7-ethylenedioxy-2-methyl-5,6, 7,3-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) 5: 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 20 (1H, br, m) , 6.60 (2H, br, s).

Example 9 4-Amino-2-methyl-7-oxo-5, 6,7, 8-tetrahydrobenzo [b 1 thieno 25 12,3—b1pyridine-3-carboxy1ic acid, but-3-ynyl ester (E9, R/; = (CH2) qC=CH) .

The title compound was prepared in 5% overall yield from D1 and 3-oxo-butyric acid, but-3-yny1 ester via the 30 intermediate 4-amino-7,7-ethylenedioxy-2-methyi-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 cyciisation 23 8 0 32981 step was carried out in n-butyl acetate using SnCl^. m.p. 167-8°C NMR (CDC13) 5: 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-nethvl-8- (1-methyl-l-ethylider.e) -7-oxo-5, 6,7,8-tetrahydrobenzo[blthieno[2,3—b1oyridine-3-carboxvlic acid, but-3-enyl ester (E10) NH2 (E10) The amine D1 and 3-oxobutyric acid, but-3-enyl ester were converted into the cyclised product using copper(I) acetate 25 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 30 title compound which was recrystallised from ethyl acetate as yellow crystals. 238055 32 931 n.D. 136-8° NMR (CDC13) 5: 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] 238055 32981 Pharmacologi cal Data 1. Geller-Seifter Procedure Potential anxiolytic properties have beer, evaluated using the Geller-Seifter procedure based on that originally described by Geller and Seifter, (1960) Psychcpharmacologia, 1, 482-492. This procedure has been shown to be selective for drugs with anxiolytic properties (Cook and Sepinwall, 10 (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 3C sec schedule (7130) 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 foots'nock. 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 25 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 30 to normalise the data for statistical analysis using parametric methods (ANOVA). 2 3 8 0 2. i~^S1~T3?S binding to rat cerebral corce:-: merr.branes in vitro Peeled rat cerebral cortices are homogenised in 20 volumes of Q.32M sucrose and centrifuged at lOOCg 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 10 at 50, OOOg (4~'C, 20 mins) . This washing step is repeated three times and the pellet finally resuspendea in 20 volumes of buffer and stored at -70°C prior to use.

The tissue suspension (5 0(11) is incubated (2 5'^C, 120 mins) 15 with [^S]-T5?S (2nM) in Tris citrate buffer (pH 7.1) containing 0.2M NaCl and 5 x 10-oM GA3A. Non-specific binding is measured in the presence of 10~^M picrotoxin. Varying concentrations cf test drugs (10~7, 10~°, 10""^ and 4 *M final concentration) are added in a volume of 50(11. 20 The total assay volume is 500(11. Incubation is stopped by rapid filtration using a Skatron cell harvester and radioactivity measured by liquid scintillation spectrometry. ICcq'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 p.o. + 52% • 238055 $ 32981 Compound E2 also showed a significant: increase in responding in the 'conflict' session at a dose of 2Omg/kg p.o.

O C f S1-TBPS binding procedure Compound ^^50 Example 1 13|iM, 17|im (2 determinations) Compounds of Examples 2, o, 7 and IC showed an IC^q of less than 2 0|!M. 2 . ^ «_•' L/ VJ

Claims (13)

1. WHAT WE CLAIM IS:

   -30-

   = r q n

   A compound of formula (I) or a pharmaceutically table salt thereof:

   wne:

   iin:

   ?>i is hydrogen, C~_g alkyl, phenyl or phenyl C-|_4 alkyl wherein the phenyl moiety is optionally substituted by one or more C-,_g alkyl, C-[__g alkoxy, C^_g alkylthio, hydroxy, '^2-1 £i-<snoyl, halo, trifluoromethvl, nitro, amino optionally substituted by one or two C-|_g alkyl groups or by C2_7 alkar.oyl, cyano, carbamoyl or carboxy groups;

   ?,7 and Rt are independently selected from hvdrocen, C-/. ^ ' 1 — o alkyl, C-2-1 cycloalkyl, C3_7 cycloalkyl-C^.j alkyl, C2_g alkenyl, C1-7 alkanoyl, C]._g alkylsulphonyl, di- (C-j__g alkyl) amino C^_ g alkyl, 3-o:-:obutyi, 3-hydroxybutyl, phenyl, phenyl alkyl, benzoyl, phenyl C2_- alkanoyl and benzenesulphonyl,any of which phenyl moieties are optionally substituted by one or two halogen, C^.g alkyl, C7_g alkoxy, CF^, amino or carboxy, or R2 and R, together are C2_g polymethylene optionally interrupted by oxygen or NRg wherein Rg is hydrogen or C^_g alkyl optionally substituted by hydroxy;

   23 8 0

   B2S31/A

   -31-

   is hydrogen or C]__g alkyl and Rg is hydrogen or R^ and Rg together form a C-,_g alkylidene group at the 8-position; and

   -CC^Rj is a pharmaceutically acceptable ester group.
2. 2. A compound according to claim 1 wherein is C^_g alkyl optionally substituted by up to three halo atoms, ^2-6 alkenyl, C2_g alkynyl, C3_g cycloalkyl or cycloalkyl-C-, alkyl.

   10
3. 3. A compound according to claim 1 or 2 wherein R| is hydrogen, C _ 3 alkyl, phenyl or benzyl.
4. 4. A compound according to any preceding claim wherein R2 15 and R3 are independently hydrogen cr alkyl.
5. 5. A compound according to any preceding claim wherein Rg is hydrogen.
6. 20 6. A compound according to claim 5 wherein R5 and Rg are both hydrogen.
7. 7. 4-Amino-2-metnyl-7-oxo-5,6,7,8-tetrahydrobenzo[b]

   thieno [2 , 3-b] pyridine-3-carbo>:ylic acid, ethyl ester.

   25
8. 8. 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b] thieno[2,3-b]pyridine-3-carboxylic acid, cyclopropylmethyl ester.
9. 30 9. 4-Amino-2-rethyl-7-oxo-5,6,7,8-tetrahydrobenzo[b] thieno[2,3-b]pyridine-3-carboxylic acid, methyl ester.
10. 10. 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b] thieno[2,3-b]pyridine-3-carboxylic acid, propyl ester.

    35

    238055

    32981/A

    -32-
11. 11. 4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b] t hieno [2 , 3-b] pyridine-3-carbox.ylic acid, prop-2-enyl o C ^ ,
12. 5 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. 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-

    io ethyl ester.

    14. 4-Amino-2-metnyl-7-oxo-5,6,7,3-tetranydrobenzo[b] thieno[2,3-b]pyriaine-3-carboxylic acid, but-3-enyl ester,

    15 15. 4-Araino-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-oxo-5,6,7,8-tetrahydrobenzo[hjthieno[2,3-b]pyridine-3-

    20 carboxylic acid, but-3-enyl ester.

    17. A pharmaceutically acceptable salt of a compound according to any one of claims 7 to 16.

    25 13. 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 30 compound of formula (III) :

    -33-

    (>J O V/'

    :ni)

    or imine iautc"er thereof, wherein R-' is R-, as defined in claim 1 cr a group convertible thereto, ' is -CO9R4 as defined in claim 1 or an electron-withdrawing group convertible to -CO9R4, Rz and Rg are as defined as in claim 1, ?-7 is hydrogen or an N-crotecting group, J and K together represent a keto group or a group convertible thereto, Y is a group CN cr CCL^, wherein is a leaving group and M is hydrogen, cr Y is hydrogen ana 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 R-, when hydrogen to an N-protectinc group, when Y" or M is a group COL^ cr COL2, converting the resulting hydroxy group to a leaving group and reacting the latter with a compound

    KNR21R3' wherein R21 and R3' are R2 and r3 as defined in claim 1 or N-protecting groups, removing any R- N-protecting group, converting any electron-withdrawing group R^' to CO2R4, converting R-, ' when other than R-, to R^, intercor.verting R2 / R-?, R^, R5 and Rg, converting J and K to a keto group,

    separating any stereoisomers 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:

    <#

    23 8 05 5

    32 981/A

    -34-

    (VII)

    10 wherein '' is R^' as defined in claim 19 or a group convertible to CC^R^, X is ^2^3', OH or chloro, R]_', R2'/ r3', J and K are as defined in claim 19 and R^, R^ and Rg are as defined in claim 1, provided that when X is NR9R3, J and K together represent a keto group and R^' is R-j_, R^' ' is 15 other than CO2R4•

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

    20

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

    25 23. 4-Amino-7, 7-ethyleneaioxy-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-5/6,7,8-30 tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, propyl ester.

    2 5. 4-Amino-7, 7-ethylenedioxy-2-methyl-5, 6,7, 8-tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, 35 prop-2-enyl ester.

    -35-

    2 6 . 4-Amino-7, 7-ethyleneciio;<y-2-methy 1-5, 5,7,8-

    tet rahydrobenzo [b] thieno [ 2 , 3-b] pyridine-3-carboxylie acid,

    but-2-ynyl ester.

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

    2 3 . 4-Amino-7,7-ethylenedioxy-2-methy1-5, 5,7,8-

    tet rahydrobenzo[b}thieno[2,3-b]pyridine-3-carboxylic acid,

    but3-e.nyl ester.

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

    3G. 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 ir. claim 1 which process comprises deprotecting a compound of formula (VII) as defined in claim 20 in which X is NR2R3, R^''is CO2R4 and R-' is R- and J and K together represent a group convertible to a keto group and thereafter optionally separating any stereoisomers 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.

    Ks ... L*

    -36-

    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 process for the preparation of a compound as defined in claim 1, substantially as hereinbefore described in any one of Examples 1 to 10.

    LJA1E

    i

    ' '/■

    {