WO1993009122A1 - Cns active tetrahydrobenzothienopyridines - Google Patents

Abstract

Tetrahydrobenzothienopyridines of formula (I), processes for their preparation and their use in the treatment and/or prophylaxis of CNS disorders (I).

Description

CNS ACTIVE TETRAHYDROBENZOTHIENOPYRIDINES

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.

WO 91/17165 (published 14 November 1991) describes a class of compounds of formula (A) or a pharmaceutically acceptable salt thereof:

wherein:

Ri is hydrogen, C\.Q alkyl, phenyl or phenyl C1.4 alkyl wherein the phenyl moiety is optionally substituted by one or more C .Q alkyl, C^. alkoxy, C^.g alkylthio, hydroxy, C2-.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;

R2 and R3 are independently selected from hydrogen, Cι_g alkyl, C^.Q alkyl, C3.7 cycloalkyl, C3.7 cycloalkyl-Cι.4 alkyl, C2-6 alkenyl, C^ alkanoyl, Cj.g alkylsulphonyl, di-(Cι_g alkyDamino Cj.g alkyl, 3-oxobutyl, 3-hydroxybutyl, phenyl, phenyl C1.4 alkyl, benzoyl, phenyl C2-7 alkanoyl or benzenesulphonyl any of which phenyl moieties are optionally substituted by one or two halogen, .Q alkyl, C^.g alkoxy, CF3, amino or carboxy, or R2 and R3 together are C2- polymethylene optionally interrupted by oxygen or NRg wherein Rg is hydrogen or C^.g alkyl optionally substituted by hydroxy;

R5 is hydrogen or Cj.g alkyl and RQ is hydrogen or R5 and R ^~ g together form a C_j. alkylidene group at the 8-position; and

-CO2 is a pharmaceutically acceptable ester group, which compounds are described as possessing CNS activity, in particular anxiolytic and/or antidepressant activity.

WO 91/17165 also describes a class of intermediates which comprises compounds of formula (VID or a salt ester or amide thereof:

wherein R4" is R wherein R4¹ is CO2R as defined in formula (A) or a group convertible to -CO2R4, Xis NR2'R3 » OH or chloro, R]_' is Ri as defined in formula (A) or a group convertible thereto, 2' and R3' are R2 and R3 as defined in formula (A) or N-protecting groups, J and K together represent a keto group or a group convertible thereto and R5 and Rg are as defined in formula (A), provided that when X is NR2 3, J and K together represent a keto group and R]_' is R^, R4" is other than CO2 4 including the methyl, ethyl, propyl, cyclopropylmethyl, prop-2-enyl, but-3- enyl, but-2-ynyl, but-3-ynyl and 2,2,2-trifluoroethyl esters of 4r-amino-7,7- e1^ylenedioxy-2-methyl-5,6,7,8-tetrahydrobenzoMthieno[2,3-b]pyridine-3- carboxyiic acid. These compounds are not disclosed as possessing any pharmacological activity at all.

It has now been discovered that certain compounds of formula (VII) possess CNS activity, in particular anxiolytic and/or antidepressant and/or anticonvulsant activity and/or activity useful in the treatment of sleep disorders.

Accordingly, the present invention provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof:

R. R,

wherein:

Rl is hydrogen, Cι_g alkyl, phenyl or phenyl C1.4 alkyl wherein the phenyl moiety is optionally substituted by one or more C^. alkyl, C^.g alkoxy, C^.g alkylthio, hydroxy, C2-7 alkanoyl, halo, trifluoromethyl, nitro, amino optionally substituted by one or two C^.g alkyl groups or by C2-7 alkanoyl, cyano, carbamoyl or carboxy groups;

R2 and R3 are independently selected from hydrogen, Cj.g alkyl, C3.7 cycloalkyl, C3.7 cycloalkyl-Cι.4 alkyl, C^.Q alkenyl, C1.7 alkanoyl, C_j.g alkylsulphonyl, di-(Cι_g alkyl)amino Ci.g alkyl, 3-oxobutyl,

3-hydroxybutyl, phenyl, phenyl C1.4 alkyl, benzoyl, phenyl C2.7 alkanoyl and benzenesulphonyl any of which phenyl moieties are optionally substituted by one or two halogen, Cj.g alkyl, Cj.g alkoxy, CF3, amino or carboxy, or R2 and R3 together are C2-g polymethylene optionally interrupted by oxygen or NRg wherein Rg is hydrogen or C^.g alkyl optionally substituted by hydroxy;

R5 is hydrogen or C^. alkyl and is hydrogen or R5 and Rg together form a Cj.g alkylidene group at the 8-position;

-CO2R4 is a pharmaceutically acceptable ester group;

J is X'Ri3 and K is Z'Ri4, X and Z' are independently oxygen or sulphur and R13 and R14 are independently C^.g alkyl or together are C2.4 polymetiiylene optionally substituted with one or more Cι_g alkyl groups or with a Cj.g alkylidene group; and a pharmaceutically acceptable carrier.

The invention further provides novel compounds of formula (I), in particular compounds of formula (I) in which J and K together are other than ethylenedioxy.

Alkyl moieties within the variables Rχ_s R2, R3, R5, Rg, R13 and R1 are preferably Cχ_ alkyl, such as methyl, ethyl and n- and iso-propyl.

Values for Rj include hydrogen, methyl, ethyl, n- and iso-propyl. phenyl and benzyl. Preferably, R^ 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, 11- and iso-propyl. n-, sec-, iso- and iert-butyl, n-, sec, iso- and ngo_-pentyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentyl-Cι.4 alkyl, cyclohexyl-Cχ.4 alkyl and cycloheptyl-Cι.4 alkyl, where values for Cχ.4 alkyl include methylene and ethylene, but-2-enyl, but-3-enyl, l-methylprop-2-enyl, formyl, acetyl, propionyl, methylsulphonyl, 3-dimethylaminobutyl, 3-oxobutyl, 3-hydroxybutyl, phenyl, benzyl, benzoyl, benzylcarbonyl and benzenesulphonyl, or R2 and R3 together form -(CH2)_r-X "-(CH.2)_S- wherein r and s are independently 1, 2 or 3 and X" is a bond, O or NRg, for example C4 or C5 polymetiiylene, -(CB-2)2-0-(CH2)2- or -(CH_2)2-NRg- CH2)2- where Rg is preferably methyl.

Preferably R2 is hydrogen and R3 is hydrogen or Cχ.g alkyl, for example methyl.

Most preferably 2 and R3 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 igρ_-propyl, a-» ISQr, J3___£- and ierfc-butyl and 2,2,2-trifluoroethyl esters, C2-g alkenyl esters such as vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-3-enyl, pent-4- 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, but-3-ynyl and pent-4-ynyl, C3_g cycloalkyl esters such as cyclohexyl and C3_ cycloalkyl-Cι.4 alkyl esters such as cyclopropylmethyl, cyclopropylethyl and cyclobutylmethyl. Preferably the pharmaceutically acceptable ester is the methyl, ethyl, n-propyl, iso-butyl_τ prop-2-ynyl, but-3-enyl, but-2-ynyl, but-3-ynyl or cyclopropylmethyl ester, most preferably the ethyl, cyclopropylmethyl, prop-2-ynyl, but-2-ynyl or but-3-ynyl ester i.e. R4 is methyl, ethyl, n-propyl, iso-butyl. prop-2-ynyl, but-3-enyl, but-2-ynyl or cyclopropylmethyl, most preferably ethyl, cyclopropylmethyl, prop-2-ynyl, but-2-ynyl or but-3-ynyl.

Suitable values of R5 include hydrogen, methyl, ethyl and n and iso propyl, preferably hydrogen. Alternatively, R5 and Rg together may represent an 8-(l-methylethylidene) group.

X and Z are preferably the same and Rχ3 and R14, when C .g alkyl, are preferably the same, most preferably methyl or ethyl.

When J and K are linked, Rχ3 and R14 polymethylene is optionally substituted by one or two Cχ.g alkyl groups or by Cχ.g alkylidene, more preferably Cχ_4 alkyl or Cχ.4 alkylidene, and most preferably is unsubstituted.

Examples of linked J and K include ethylenedioxy, ethylenedithio, propylenedioxy, 2,2-dimethyl propylenedioxy and 2-methylene propylenedioxy.

There is a preferred group of compounds within formula (I) of formula (II) or a pharmaceutically acceptable salt thereof:

wherein R3I is hydrogen or Cχ_g alkyl, Rχ_} CO2R4, R5 and Rg are as defined in formula (I) and J and K are X'Rχ3 and Z'Rχ4 in which X' and Z' are both oxygen and 3 and Rχ together represent an ethylene group.

Preferred values for Rx, R3I, CO2R4, R5 and Rg 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, methanesulphonic and oxalic acid.

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 Rg 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 Rg represent an alkylidene group may exist in E and Z forms, while substituents Rχ_} R2, R3, R4, R5, Rχ3 and Rχ4 may contain asymmetric carbon atoms. It should also be appreciated that compounds in which J is not the same as K possess a chiral centre at the carbon atom attached to J and K. The present invention extends to any single stereoisomers such as enantiomers or diastereomers, or mixtures thereof including racemates, of compounds of formula (I). A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof comprises the cyclisation of a compound of formula (III):

or i ine tautomer thereof, wherein ' is Rx 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), R7 is hydrogen or an N-protecting group, J' and ' represent J and K as defined in formula (I) or together represent a keto group or a group convertible thereto, Y is a group CN or COLχ, wherein Lx 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 COLχ 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 as defined in formula (I) or N-protecting groups, removing any R2', R3^* or R7 N-protecting group, converting any electron-withdrawing group R4' to CO2R4, converting Rx' when other than to Rχ_t converting J' and K' when a keto group to J and K, converting J' and K' when a group convertible to a keto group, to a keto group and thereafter to J and K, interconverting R2, R3, R4, R5, Rg, J and K, separating any stereoisomers such as enantiomers or diastereomers 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 or sodium ethoxide in a suitable solvent such as methanol or ethanol, at elevated temperature, or in the presence of a Lewis acid such as ZnCl2, SnCl4 or CuOCOCB-3 in a suitable solvent such as n-butyl acetate at elevated temperature.

Lewis acid catalysed cyclisation using copper (I) acetate is preferred especially when cyclising to give compounds of formula (I) directly i.e. where 4^T is CO2R4, except where X and Z' are oxygen and R4 is ethyl when sodium ethoxide in ethanol is generally preferred.

Preferably J' and K' represent J and K or together represent a group convertible to a keto group such as a protected hydroxy group. A protected hydroxy such as a silyl ether, for example trimethylsilyl ether, tetrahydropyranyl ether or Cχ.g alkyl or benzyl ester optionally substituted as described hereinafter for the protecting group Q when benzyl, may be de-protected conventionally to give a hydroxy group which may be oxidised conventionally for example using oxalyl cMoride/dimethylsulphoxide or pyridinium chlorochromate to give the ketone.

Conversion of a J'/K' keto group to J and K may be carried out conventionally by reacting the ketone with the appropriate alcohols or thiols χ3XΗ and Rχ4YH under acid conditions such as anhydrous hydrochloric acid, para-toluenesulphonic acid or 10-camphorsulphonic acid or in the presence of a Lewis acid such as FeCl3 or BF3 in an inert solvent such as toluene or the alcohol itself.

Interconversion of J and K may be carried out by converting J and to a keto group and then converting to other values of J and K or alternatively J and K may be directly interconverted, for example in a compound wherein J and K together represent an ethylenedioxy group may be converted to a compound wherein J and K together represent an ethylenedithio group by reaction with ethane dithiol in the presence of an acid catalyst such as BF3 in an inert solvent such as chloroform. The conversion of J and K to a keto group maybe carried out as follows:

When X and Z' are both oxygen, the group -X-Rχ3 and -Z'-Rχ4 may be conventionally converted to a keto group for example by treatment with aqueous hydrochloric, formic or trifluoroacetic acid. When one of X or Z' is an oxygen atom and the other is a sulphur atom, the group -X-Rχ3 and -Z'-Rχ4 may be conventionally converted to a keto group, for example by treatment with aqueous hydrochloric acid or quaternisation of the sulphur atom followed by hydrolysis, for example using an alkyl halide followed by water.

When X' and Z' are both sulphur the group -X'-Rχ3 and -Z'-Rχ4 may be conventionally converted to a keto group by reacting one of the sulphur atoms with:

a heavy metal cation such as silver; or

a quaternising agent such as an alkyl halide; or

an oxidising agent such as a peracetic acid;

and thereafter, hydrolysing off the protecting group to afford a keto group, for example using aqueous acetone or aqueous acetonitrile.

When J' and K' together represent a keto group, R5 and Rg hydrogen may be converted to an alkylidene group in the 8-position by an aldol type condensation with an appropriate aldehyde or ketone, such as acetone. The alkylidene group may then be hydrogenated to the corresponding 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, Cχ.g alkyl, C3.7 cycloalkyl Cχ.4 alkyl or C3.7 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, Cχ.g alkoxy, Cχ.g alkyl or nitro, cyano and -CON 9RX0 where R9 and Rχo are independently selected from hydrogen, Cχ.g alkyl, Cχ.g alkoxy and phenyl or phenyl

Cχ_4 alkyl optionally substituted as described above for optional substituents in the phenyl ring of a benzyl ester, or together form a C2- polymethylene chain optionally interrupted by oxygen or NItχχ wherein

RXX is hydrogen or Cχ_g alkyl, e.g. morpholino or piperazino.

A protecting group Q maybe 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 hydroxide or carbonate in an inert solvent such as diinethylformamide. Alternatively, Q may be converted directly to R4 by transesterification under basic conditions.

It should be appreciated that if R2 and/or R3 are hydrogen it may be necessary to conventionally protect the nitrogen atom to which R2 and R3 are attached.

An intermediate amide may be hydrolysed to the free acid which 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 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 Crθ3 and esterified as above.

^* COR_a α-methylene keto groups may be converted to CO2R4 via the acid by a haloform reaction and esterification.

R4 groups may be interconverted via the intermediate acid or directly by transesterification as described above.

Suitable examples of a leaving groups Lx and L2 when Y or M is COLχ or COL2 include hydroxy and, more preferably, alkoxy such as Cχ_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 HN 2'R3' under conventional conditions for nucleophilic aromatic displacements, at elevated ternperatures in an inert solvent such as toluene, methanol, ethanol, dimethylformamide or dioxan. Alternatively, the reaction may be carried out in neat HNR2^* 3' which functions as the solvent.

An R2¹ or R3' protecting group such as p-methoxybenzyl may be removed conventionally.

Conversion of R2 and R3 hydrogen to other 2 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 COLχ or COL2 in the compound of formula (III), by displacement of the leaving group with the compound HN 2^*R3' as discussed above.

An Rx' group such as hydroxy or chloro may be converted to alkyl or phenyl Cχ.4 alkyl or phenyl, by a palladium mediated anion coupling reaction (V.N. Kalinin, Synthesis, 1992, 413).

A further process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises the ketalisation of a compound (Ilia):

wherein Rχ_> R2, R3, CO2R4, R5 and Rg are as defined in formula (I), to convert the keto group to J and K as defined in formula (I), and thereafter optionally interconvertingR2, R3, R4, R5 and or Rg, optionally separating any stereoisomers such as diastereomers or enantiomers and/or forming a pharmaceutically acceptable salt of a compound of formula (I).

Separation of diastereomers or enantiomers may be carried out conventionally, for example using chiral HPLC.

Pharmaceutically acceptable salts maybe 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):

R,

with a compound of formula (V):

wherein Rχ\ R4^*, R5, R7, Rg, 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.

Suitable examples of the leaving group L include halogens, such as chloro and bromo, hydroxy, Cχ.g acyloxy such as acetoxy, Cχ.g alkoxy, such as methoxy or ethoxy, preferably methoxy or NR_aR]-, where R_a and R_]-, are independently hydrogen or Cχ.4 alkyl or together form a C2_ polymetiiylene chain optionally interrupted by oxygen or NR_C where R_c is hydrogen or Cχ.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, pyridine, dimethylformamide, mesitylene or dioxan, optionally in the presence of a catalyst such as para-toluene sulphonic acid or 10-camphorsulphonic acid, with water separation if appropriate.

For the preparation of compounds of formula (I) in which Rx is hydrogen, the compound of formula (V) may be used in which:

L and M together represent a bond or L is hydroxy and M is hydrogen, and Rx' is a Cχ.g alkoxycarbonyl group. The reaction with the compound of formula (IV) may then be followed by a decarboxylation step to give Rx hydrogen;

L is a leaving group and Rχ^τ is hydroxy. In the resulting compound, the Rχ^f 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 Rx hydrogen may be carried out before or, more preferably, after cyclisation of the compound of formula (III);

L is a leaving group, M and R4' are both Cχ.g alkoxycarbonyl, and x' is hydrogen. Compounds of formula (IV) are prepared analogously to the methods described in K. Gewald g£ a , Chem. Ber., 1960, 94, by reacting compounds of formula (VI):

wherein R5, Rg, J' and K^r are as defined in formula (HI), with NCCH2 and sulphur in the presence of a base such as diethylamine in an inert solvent such as methanol or ethanol. When R5 is not hydrogen, mixtures of isomers of formula (IV) may be formed and can be advantageously separated at this stage.

Where X' and Y in the compound of formula (I) are both sulphur, they are preferably present in the compound of formula (VI).

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, Rx^* is CH3 and R4 is CO2R4 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, 5J 2431. The compound of formula (V) in which Rχ^f 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 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, sleep disorders, depression or diseases treatable with anti¬ convulsant agents such as epilepsy, will vary in the usual way with the seriousness of the disorder and the disorder itself, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, for anxiety 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.

No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the invention.

The invention further provides a pharmaceutical composition for use in the treatment of CNS disorders, in particular anxiety, sleep disorders, depression or disorders treatable with anti-convulsant agents such as epilepsy, which composition comprises an effective, non-toxic amount of compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention further provides a method for the treatment and/or prophylaxis of CNS disorders, in particular anxiety, sleep disorders, depression or disorders treatable with anticonvulsant agents such as epilepsy in mammals, including humans, which comprises administering to the sufferer an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof for the use in the treatment and or prophylaxis of CNS disorders, in particular anxiety, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy.

The invention yet further provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment and/or prophylaxis of CNS disorders, in particular anxiety, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy.

The following descriptions illustrate the preparation of intermediates and the examples illustrate the preparation of compounds useful in the invention.

Description 1

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

The title compound was prepared from 1,4-cyclohexanedione mono- ethylene ketal using a procedure similar to that of K. Gewald et al.. Chem. Ber. 1966, 94 (49% yield), m.p. 190-193°C after recrystaUization from methanol.

NMR (CDCI3) δ: 1.95 (2H, t), 2.72 (4H, m), 4.02 (4H, s), 4.72 (2H, bs).

Found: C, 55.61; H, 5.22; N, 11.51%

CχχHχ2N₂θ2S requires C, 55.91; H, 5.12; N, 11.86%

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 Dl (13.16g; 55.7 mmol) and ethyl β- ethoxycrotonate (26g; 164 mmol) in mesitylene (400 ml) 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 (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).

The title compound D2 may also be prepared from the aminonitrile Dl and 3-oxobutyric acid, ethyl ester by a procedure similar to that of Description 5.

Description 3

N-3-(2-(3-Cyano-6,6-ethylenedioxy-4,5,^β,7-tetrahydrobenzo[b]- thienyl) amino) -2-butenoic acid, methyl ester (D3)

The title compound was prepared from aminonitrile Dl and 3-oxobutyric acid, methyl ester, in 55% yield by a procedure similar to that of Description 5, as a pale yellow solid.

Description 4

N-3-(2-(3-Cyano-6,6-ethylenedioxy-4,5_t6,7-tetralιydrobenzo[b]- thienyl) amino)-2-butenoic acid, cyclopropylmethyl ester (D4)

The title compound was prepared from the aminonitrile Dl and 3- oxobutyric acid, cyclopropylmethyl ester in 98% yield by a procedure similar to that of Description 5 as a yellow gum after chromatography on Eieselgel 60. This solidified on standing.

m/z = 374 (M+)

Description 5

N-3-(2-(3-Cyano-6,6-ethyienedioxy-4,5,6,7-tetrahydrobenzo[b]- thienyl) amino)-2-butenoic acid, but-2-ynyl ester (D5)

The aminonitrile Dl (8.0g, 34 mmol), 3-oxobutyric acid, but-2-ynyl ester (6.2g, 40 mmol), 10-camphorsulphonic acid (CSA) (0.8g) and toluene (300 ml) were heated at reflux under a Dean and Stark apparatus for lh. The reaction mixture was cooled and evaporated to dryness. The residue was chromatographed on Kieselgel 60 eluting with dichloromethane to afford the title compound as a yellow solid (8.9g, 70%).

NMR (CDCI3) δ: 1.86 (3H, t), 1.96 (2H, t), 2.10 (3H, s), 2.82 (2H, t), 2.86 (2H, s), 4.04 (4H, s), 4.73 (2H, q), 4.94 (1H, s), 10.88 (1H, s).

Description 6

N-3-(2-(3-Cyano-6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo[b]- thienyl) amino) -2-butenoic acid, cyclobutylmethyl ester (D6)

The title compound was prepared from the aminonitrile Dl and 3-oxo¬ butyric acid, cyclobutylmethyl ester by a procedure similar to that of Description 5.

NMR (CDCI3) δ: 1.70-2.15 (11H, bm), 2.65 (1H, m), 2.82 (2H, t), 2.86 (2H, s), 4.04 (4H, s), 4.13 (2H, t), 4.90 (1H, s), 10.98 (1H, s).

Description 7

N-3-(2-(3-Cyano-6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo[b]- thienyl) amino) -2-butenoic acid, cyclohexyl ester (D7)

The title compound was prepared in 70% yield from the aminonitrile Dl and 3-oxobutyric acid, cyclohexyl ester, by a procedure similar to that outlined in Description 5.

NMR (CDCI3) δ: 1.10-2.00 (12H, bm), 2.10 (3H,s), 2.84 (4H, m), 4.05 (4H, s), 4.86 (2H, m), 11.03 (1H, bs). Description 8

N-3-(2-(3-Cyano-6,6-ethylenedio_s_y-4,5,6,7-tetralιydrobenzo[b]- thienyI)amino)-2-butenoic acid, cyclopropylethyl ester (D8)

The title compound was prepared from aminonitrile Dl and 3-oxobutyric acid, cyclopropylethyl ester by a method similar to that of Description 5. A portion of the product was rechromatographed on silica with a gradient of 30-50% diethyl ether/pentane as eluant to remove 3-oxobutyric acid, cyclopropylethyl ester.

m/z = 388 (M+)

Description θ

2-Am_no-6,6-(2,2-dimethyl)propylenedio_sy-4,5,6,7-tetrahydro- benzo[b]thiophene-3-carbonitrile (D9)

The title compound (D9) was prepared from 1,4-cyclohexanedione mono (2,2-dimethyl)propylene ketal by a procedure similar to that of Description 1. RecrystaUization from methanol afforded the title compound as a yeUow solid (68%), m.p. 181-184°C.

NMR (CDCl₃)δ. 0.96 (3H, s), 1.03 (3H, s), 2.22 (2H, t), 2.60 (2H, t), 2.86 (2H, s), 3.55 (4H, m).

Found: C, 60.16; H, 6.35; N, 10.04% C 4H gN₂θ2S requires C, 60.41; H, 6.52; N, 10.06% Description 10

N-3-(2-(3-Cyano-6,6-(2,2-dimethyl)propylenedioxy-4,5,6,7- tetrahydrobenzo[b]thienyl)amino)-2-butenoic acid, but-2-ynyl ester (D10)

The title compound (DIO) was prepared from the aminonitrile D9 and 3- oxobutyric acid, but-2-ynyl ester in 53% yield by a procedure similar to that of Description 5.

NMR (CDCl₃)δ: 0.96 (3H, s), 1.04 (3H, s), 1.87 (3H, t), 2.10 (3H, s), 2.17 (2H, t), 2.70 (2H, t), 2.98 (2H, s), 3.56 (4H, m), 4.72 (2H, q), 4.92 (IH, s), 10.77 (IH, s).

Description 11

N-3-(2-(3-Cyano-6,6-(2,2-dimethyl)propylenedioxy-4,5,6,7- tetrahydrobenzo[b]tbienyl)amino)-2-butenoic acid, cyclo- propylmethyl ester (Dll)

The title compound (Dll) was prepared from the aminonitrile D9 and 3- oxobutyric acid, cyclopropylmethyl ester in 54% yield by a procedure similar to that of Description 5.

NMR (CDCl₃)δ: 0.28 (2H, m), 0.58 (2H, m), 0.97 (3H, s), 1.05 (3H, s), 1.15 (IH, m), 2.12 (3H, s), 2.16 (2H, t), 2.69 (2H, t), 2.97 (2H, s), 3.56 (4H, m), 3.98 (2H, t), 4.92 (IH, s), 10.97 (IH, s).

Description 12

4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-b]- pyridine-3-carboxylic acid, ethyl ester (D12).

The ester El (6.00g, 17 mmol) was stirred in trifluoroacetic acid/water (30ml 2ml) for 18h. The reaction mixture was added dropwise with ice- cooling to a solution of potassium carbonate (30g) in H2O (50ml). The aqueous mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulphate.

Evaporation to dryness afforded the title compound as a pale yellow solid

(4.80g, 92%).

NMR (CDCl₃)δ: 1.43 (3H, t), 2.73 (3H, s), 2.80 (2H, t), 3.43 (2H,t), 3.66 (2H, s), 4.42 (2H, q), 6.57 (2H, bs).

Description 13

4-Amino-2-nιethyl-7-oxo-5,6,7,8-tetrahydrobenzo[b]tbieno[2,3-b]- pyridine-3-carboxylic acid, cyclopropylmethyl ester (D13)

The title compound was prepared from the ketal E3 by a procedure similar to that of Description 12, as a pale yellow solid (93%).

NMR (CDCl₃)δ: 0.38 (2H, m), 0.67 (2H, ), 1.28 (IH, m), 2.77 (3H, s), 2.81 (2H, t), 3.44 (2H, t), 3.67 (2H, s), 4.18 (2H, d), 6.59 (2H, bs).

Description 14

4,4-Ethyleneditlιiocyclohexanone(D14)

A stirred mixture of ethanedithiol (3.0 ml, 35.8 mmol) and 1,4- cyclohexanedione mono-ethylene ketal (4.68g, 30 mmol) in dichloromethane (30 ml) was treated with ferric chloride on silica (14.4g). The resulting black suspension rapidly changed back to yellow and after a few minutes the reaction was stopped by addition of 10% sodium hydroxide. After filtration the layers were separated and the aqueous fiirther extracted with chloroform (x3). The combined organic layers were dried over anhydrous sodium sulphate and evaporated to dryness. After chromatography on silica with dichloromethane as eluant the title compound was obtained as a mixture with l,l-ethylenedioxy-4,4- ethylenedithiocyclohexane (2.348 g). This was stirred with trifluoroacetic acid (25 ml) at room temperature overnight. After evaporation to dryness the residue was treated with water and then saturated aqueous sodium bicarbonate until slightly basic. After extraction with chloroform (x3) the title compound was obtained as a pale yellow oil (2.35 g, 42%).

NMR (CDCI3) δ: 2.41 (4H, t), 2.57 (4H, t),3.4 (4H, s).

m/z = 188 (M+)

Alternative, instead of working up the reaction with 10% sodium hydroxide, the ferric chloride on silica can be simply filtered off and reused. The filtrate is evaporate to dryness and then purified as above.

Description 15

2-Amino-6,6-ethylenedithio-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carbonitrile (D15)

The title compound was prepared in 37% yield, after crystalUzation from methanol, from the ketone D 14 by a method similar to that of Description 1 and was used without further purification.

NMR (CDCI3) δ: 2.28 (2H, t), 2.77 (2H, t), 3.12 (2H, s), 3.37 (4H, s), 4.66 (2H, bs)

MS measured 268.0164, calculated for CχχHχ2N₂S3 268.0160

Description 16

N-3-(2-(3-Cyano-6,6-ethylenedithio-4,5,6,7-tetrahydrobenzo[bl- thienyl)amino)-2-butenoic acid, ethyl ester (D16)

The title compound was prepared from the aminonitrile D15 and 3- oxobutyric acid, ethyl ester by a method similar to that of Description 5 in a yield of 45% after chromatography on silica with dichloromethane as eluant.

m/z = 380 (M+)

Description 17

4-Am__no-2-πιethyl-7-o___:o-5,6,7,8-tetrahydrobenzoIblthieno[2,3-b]- pyridine-3-carboxylic acid, methyl ester (D17)

The ketal E2 was converted to the title compound with trifluoroacetic acid by a similar procedure to that of Description 12 and after recrystallisation fro chloroform/pentane was obtained as a pale yellow solid (78%), m.p. 202-207°C.

NMR (CDC1₃) δ: 2.70 (3H, s). 2.80 (2H, t), 3.45 (2H, t), 3.67 (2H, s), 3.93 (3H,s), 6.55 (2H,bs).

Found: C, 57.62; H, 4.81; N, 9.69% CX4HX4N2O3S requires C, 57.92; H, 4.86; N, 9.65%

Description 18

N-3-(2-(3-Cyano-6,6-ethylenedithio-4,5,6,7-tetrahydrobenzo[b]- thienyl)amino)-2-butenoic acid, cyclopropylmethyl ester (D18)

The title compound was prepared from the aminonitrile D15 and 3- oxobutyric acid, cyclopropylmethyl ester by a method similar to that of Description 5 in yield of 74% after chromatography on silica with dichloromethane as eluant. The resulting sticky yellow solid was triturated with pentane.

MS measured 406.0844, calculated for CX9H22N2O2S3 406.0841.

Example 1

4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydrobenzo[b]- thieno[2,3-b]pyridine-3-carboxylic acid, ethyl ester (El, R_j _= CH3, R = C₂H₅, J,K = -OCH₂CH₂0 )

Method A

A solution of enaminoester D2 (11.7g, 33.6 mmol) in toluene (400 ml) was treated with a 1M solution of sodium ethoxide in ethanol (40 ml) 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 on TLC alumina, eluting with a 0-2% methanol in dichloromethane gradient, afforded the title compound as a yellow gum (7g, 60%).

NMR (CDCI3) 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).

Method B

A mixture of aminonitrile Dl (25g; 106 mmol) and 3-oxobutyric acid, ethyl ester (16.5g; 127 mmol) in toluene (1.2L) was warmed with stirring to give solution and then CSA (2.5g) added. The mixture was heated at reflux under Dean and Stark conditions for 1.5h and then, after cooling, a 1M solution of sodium ethoxide in ethanol (125 ml; 1.2 equiv.) was added. Heating was continued for 2.25h collecting the first 120 ml of distillate. The resulting dark brown solution was allowed to cool and then poured into water (1L) and ethyl acetate (250 ml) and the layers separated. The aqueous layer was further extracted with ethyl acetate (500 ml) and the combined organic layers then washed with brine, dried over anhydrous sodium sulphate and evaporated to dryness. This crude product was purified by chromatography on Kieselgel 60 eluting with a 30-50% ethyl acetate in pentane gradient to give the title compound as a yellow solid

(21.29g, 58%) having spectroscopic properties identical to material prepared by Method A. A small sample was recrystalhsed from ethyl acetate petrol (bpt: 40-60°C), m.p. 122< C.

As an alternative to purification by chromatography the crude product can be triturated with ethyl acetate to give the title compound as a yellow solid (43.2%).

Found: C, 58.62; H, 5.76; N, 8.04% C1 H20N2O4S requires C, 58.60; H, 5.79; N, 8.04%

Example 2

4-Aπιino-7,7-etbylenedioxy-2-nιethyl-5,6,7,8-tetrahydrobenzo[bl- thieno[2,3-b]pyridine-3-carboxylic acid, methyl ester (E2, R_j = CH3, R₄ _= CH3, J,K = -OCH₂CH₂0-)

The enamine D3 was cyclized with copper (I) acetate by a procedure similar to that of Example 4 to give the title compound as pale yellow flakes (42%) after recrystaUization from ethyl acetate/pentane, m.p. 140- 141.5°C.

NMR (CDCI3) δ: 2.07 (2H, t), 2.69 (3H, s), 3.02 (2H, s), 3.23 (2H, t), 3.92 (3H, s), 4.07 (4H, s), 6.60 (2H, bs).

Found: C, 57.46; H, 5.46; N, 8.41%

CχgH gN2θ4S requires C, 57.47; H, 5.43; N, 8.38%

m z = 334 (M+) Example 3

4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydrobenzo[bl- tbieno[2,3-blpyridine-3-carboxylic acid, cyclopropylmethyl ester (E3, Ri = CH₃, R = CH₂-c-C₃H₅, J,K = -OCH₂CH₂0-)

The enamine D4 was cyclized by a procedure similar to that of Example 4 to give the title compound as a pale yellow gum (65%) which solidified on standing. Recrystallisation from ethyl acetate pentane gave a white crystalline solid, m.p. 115-116.5°C.

NMR (CDC1₃) δ: 0.38 (2H, m), 0.65 (2H, m), 1.27 (IH, m), 2.05 (2H, t), 2.74 (3H, s), 3.01 (2H, s), 3.22 (2H, t), 4.06 (4H, s), 4.15 (2H, d), 6.54 (2H, bs).

Found: C, 61.19; H, 5.83; N, 7.53% CX9H22N2O4S requires C, 60.94; H, 5.92; N, 7.48%

Example 4

4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydrobenzo[b]- thieno[2,3-blpyridine-3-carboxylic acid, but-2-ynyl ester (E4, R_j = CH3, R4 = CH₂C≡CCH₃, J,K = -OCH₂CH₂0 )

The enamine D5 (1.8g, 4.8 mmol) and copper (I) acetate (200 mg) in n- butyl acetate (40 ml) were heated under reflux for 0.5h. The reaction mixture was cooled and filtered through Kieselguhr. Ethyl acetate (100 ml) was added and the solution was washed with aqueous ammonium hydroxide then brine. The organic solution was dried (Na2SO4) and evaporated to dryness. The residue was chromatographed on Kieselgel 60 eluting with 30% ethyl acetate/pentane to give the title compound as a yellow solid (l.lg, 61%), m.p. 148-149<>C.

NMR (CDCI3) δ: 1.88 (3H, t), 2.05 (2H, t), 2.74 (3H, s), 3.02 (2H, s), 3.23 (2H, t), 4.06 (4H, s), 4.88 (2H, q), 6.60 (2H, bs). Found: C, 61.36; H, 5.38; N, 7.46% C19H20N2O4S requires C, 61.27; H, 5.41; N, 7.52%

Compounds E2, E3 and E4 may also be prepared from aminonitrile Dl using a procedure similar to that of Description 2 and Example 1, Method A.

Example 5

4-Anι__no-7,7-ethylenedio_^-2-nιethyl-5,6,7,8-tetrahydrobenzo[b]- thieno[2,3-b]pyridine-3-carboxylic acid, cyclobutylmethyl ester (E5, Ri = CH₃, R4 = CH2-C-C4H7, J,K = -OCH₂CH₂0-)

The title compound was prepared in 43% yield from enamine D6 by a procedure similar to that outlined in Example 4, m.p. 115-116°C.

NMR (CDCI3) δ: 1.75-2.23 (8H, bm), 2.68 (3H, s), 2.78 (IH, m), 3.02 (2H, s), 3.23 (2H, t), 4.05 (4H, s), 4.30 (2H, d), 6.61 (2H, bs).

Found: C, 61.66; H, 6.15; N, 7.02%

C20H24N2O4S requires C, 61.84; H, 6.23; N, 7.02%

Example 6

4-Amino-7,7-ethylenedio_qτ-2-methyl-5,6,7,8-tetrahydrobenzo[bl- t eno[2,3-b]pyridine-3-carboxylic acid, prop-2-ynyl ester (E6, Ri = CH3, R₄ = CH₂C≡CH, J,K = -OCH₂CH₂0 )

Ester El, (4.3g, 12 mmol) and potassium hydroxide (2.0g, 36 mmol) in methanol / H₂O (80 ml / 9 ml) were heated under reflux for 24h. The reaction mixture was cooled and evaporated to dryness. The residue was dissolved in dimethylformamide (100 ml). Propargyl bromide (1.7 ml, 80 wt% in toluene) was added and the mixture was stirred at room temperature for 2h. It was necessary to add a further portion of propargyl bromide (1.7 ml). After stirring for a further 2h, water (100 ml) was added. The aqueous solution was extracted with ethyl acetate. The combined organics were washed with brine, dried and evaporated. The residue was chromatographed on Kieselgel 60 eluting with 30% ethyl acetate/pentane to give the title compound as a yellow solid (3.6g, 81%). sample was crystallised from ethyl acetate, m.p. 128-129°C.

NMR (CDC1₃) δ: 2.06 (2H, t), 2.54 (IH, t), 2.74 (3H, s), 3.00 (2H, s),

3.22 (2H, t), 4.06 (4H, s), 4.94 (2H, d), 6.63 (2H, bs).

Found: C, 60.37; H, 5.08; N, 7.90% CχgHχgN₂θ4S requires C, 60.32; H, 5.06; N, 7.82%

Example 7

4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydrobenzo[b]- thieno[2,3-blpyridine-3-carboxylic acid, but-3-ynyl ester (E7, Rx = CH₃, R₄ = CH₂CH₂C≡CH, J,K = -OCH₂CH₂0-)

The title compound was prepared from the ester El in 88% yield by a procedure similar to that outlined in Example 6, m.p. 154-155°C.

NMR (CDCI3) δ: 2.07 (3H, m), 2.69 (2H, dt), 2.75 (3H, s), 3.02 (2H, s), 3.23 (2H, t), 4.07 (4H, s), 4.45 (2H, t), 6.63 (2H, bs).

Found: C, 61.34; H, 5.34; N, 7.59%

C19H20N2O4S requires C, 61.27; H, 5.41; N, 7.52%

Example 8

4-Amino-7,7-ethylenedioxy-2-niethyl-5,6,7,8-tetrahydrobenzo[b]- thieno[2,3-blpyridine-3-carboxylic acid, but-3-enyl ester (E8, R_X = CH3, R₄ = CH₂CH₂CH=CH₂, J,K = -OCH₂CH₂0 )

The title compound was prepared from the ester El in 83% yield by a procedure similar to that outlined in Example 6, m.p. 100-101°C. NMR (CDCI3) δ: 2.06 (2H, t), 2.55 (2H, m), 2.70 (3H, s), 3.00 (2H, s),

3.22 (2H, t), 4.06 (4H, s), 4.39 (2H, t), 5.10-5.26 (2H, bm), 5.77-5.97 (IH, bm), 6.57 (2H, bs).

Found: C, 60.79; H, 5.83; N, 7.31% C19H22N2O4S requires C, 60.94; H, 5.92; N, 7.48%

Example 9

4-Am-_no-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydrobenzo[b]- t eno[2,3-blpvridine-3-carboxylic acid, propyl ester (E9, Ri = CH₃, R₄ = CH₂CH₂CH₃, J,K = -OCH₂CH₂0-)

The title compound was prepared in 71% yield from the ester El by a procedure similar to that outlined in Example 6, m.p. decomposes above 85⁰C .

NMR (CDC1₃> δ: 1.05 (3H, t), 1.80 (2H, m), 2.07 (2H, t), 2.73 (3H, s), 3.00 (2H, s), 3.22 (2H, t), 4.06 (4H, s), 4.28 (2H, t), 6.62 (2H, bs).

Found: C, 59.48; H, 6.04; N, 7.70% CχgH₂2N₂θ4S requires C, 59.65; H, 6.12; N, 7.73%

Example 10

4-Amino-7,7-ethylenedioxy-2-m^ethyl-5,6,7,8-tetrahyd^robenzo[b]- thieno[2,3-b]pyridine-3-carboxyIic acid, (2-methyl)propyl ester (E10, Ri β CH3, R₄ = CH₂CH(CH₃)₂, J,K __- -OCH₂CH₂0-)

The title compound was prepared in 93% yield from the ester El by a procedure similar to that outlined in Example 6, m.p. 95-97°C.

NMR (CDCI3) δ: 1.04 (6H, d), 1.97-2.20 (3H, bm), 2.72 (3H, s), 3.03 (2H, s), 3.23 (2H, t), 4.05 (4H, s), 4.13 (2H, d), 6.64 (2H, bm). Found: C, 60.60; H, 6.38; N, 7.35%

C19H24N2O4S requires C, 60.62; H, 6.43; N, 7.44%

Example 11

4-Amino-7,7-ethylenedioxy-2-phenyl-5,6,7,8-tetrahydrobenzo[bl- thieno[2,3-b]pyridine-3-carboxylic acid, ethyl ester (Ell, Ri = C₆H₅, R₄ = C₂H₅, J,K = -OCH₂CH₂0 )

The title compound was prepared in 29% yield from the aminonitrile Dl and ethyl β-ethoxycinnamate by a procedure similar to that of Example 1, method B, m.p. 114-116°C.

NMR (dg-DMSO) δ:0.71 (3H, t), 1.89-2.03 (2H, bt), 2.93-3.03 (2H, bs), 3.13-3.27 (2H, bt), 3.92 (2H, q), 3.98 (4H, s), 6.46-6.59 (2H, bs), 7.40 (5H, s).

Found: C, 63.97; H, 5.43; N, 6.80% C22H22N2O4S requires C, 64.37; H, 5.40; N, 6.82%

Example 12

4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydrobenzo[bl- thieno[2,3-b]pyridine-3-carboxylic acid, pent-4-enyl ester (E12, Rx = CH3, R₄ = (CH₂)₃CH=CH₂, J,K = -OCH₂CH₂0-)

The ethyl ester, El (l.Og; 2.87 mmol), was heated in 4-penten-l-ol (4 ml) until dissolution was complete, then sodium hydride (80% dispersion in mineral oil, 6 mgs) was added. The reaction mixture was then heated under nitrogen in an oil bath at 150°C for 4 h, cooled, poured onto dilute brine and extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried (Na₂SO4) and evaporated to dryness. The residue was chromatographed on Kieselgel 60, eluting with a 0-50% ethyl acetate in pentane gradient. Recrystallisation from ethanol afforded white crystals (0.78g, 70%), m.p. 93-94<>C. NMR (CDCI3) δ: 1.90 (2H, m), 2.06 (2H, t), 2.23 (2H, m), 2.71 (3H, s), 3.01 (2H, s), 3.23 (2H, t), 4.06 (4H, s), 4.34 (2H, t), 5.06 (2H, m), 5.83 (IH, m), 6.60 (2H, bs).

Found: C, 61.46; H, 6.14; N, 7.13% C20H24N2O4S requires C, 61.84; H, 6.23; N, 7.21%

Example 13

4-Amino-7,7-ethyIenedioxy-2-m.ethyl-5,6,7,8-tetrahydrobenzo[b]- hieno[2,3-b]pyridine-3-carboxylic acid, cyclohexyl ester (E13, i __. CH3, R₄ = c-C₆Hn, J,K s -OCH₂CH₂0-)

The titie compound was prepared in 38% yield from the enamine D7 by a procedure similar to that outlined in Example 4.

NMR (CDCI3) δ: 1.20-2.10 (12H, bm), 2.71 (3H, s), 3.01 (2H, s), 3.22 (2H, t,), 4.05 (4H, s), 5.07 (IH, m), 6.58 (2H, bs).

Example 14

4-An__ino-2-ethyl-7,7'^thylenedioxy-5,6,7,8-tetrahydrobenzo[b]- t eno[2,3-b]pvridine-3-carboxylic acid, ethyl ester, oxalate (E14, Ri a C H5, R₄ = C₂H₅, J,K = -OCH₂CH₂0-)

The title compound was prepared in 20% yield from the aminonitrile Dl and 3-oxopentanoic acid, ethyl ester by a procedure similar to that outlined in Example 1, method B, m.p. 187-188°C.

NMR(d -DMSO) δ:1.18 (3H, t), 1.30 (3H, t), 1.85-1.99 (2H, bt), 2.80 (2H, q), 2.87-2.97 (2H, bs), 3.07-3.19 (2H, bt), 3.97 (4H, s), 4.35 (2H, q), 6.40-6.53 (2H, bs). Found: C, 53.00; H, 5.27; N, 6.24% C20^H24N2θgS requires C, 53.09; H, 5.35; N, 6.19%

4-Amino-2-ethyl-7,7-ethylenedioxy-5,6,7,8-tetrahydrobenzo[b]- thieno[2,3-blpyridine-3-carboxyUc acid, ethyl ester, tartrate , hydrate (E14, R_x = C₂H₅, R = C₂H₅, J,K = -OCH₂CH₂0-)

Treatment of the free base with tartaric acid in ethanol gave the title compound as a hydrate, m.p. 144-146°C.

NMR (d -DMSO) δ: 1.17 (3H, t), 1.33 (3H, t), 1.93 (2H, t), 2.80 (2H, q), 2.93 (2H, s), 3.12 (2H, t), 3.21-3.43 (1.34H, 2H of tartaric acid intergrating as 0.67 equivalents of tartrate salt, bs), 3.96 (4H, s), 4.30 (1.34H of tartaric acid intergrating as 0.67 equivalents of tartrate salt, s), 4.33 (2H, q), 6.4t) (2H, s).

Water content: Found 4.33% by weight.

C,H,N indicated the presence of other non-organic contaminants.

Example 15

4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydrobenzo[b]- tbieno[2,3-b]pyridine-3-carboxylic acid, cyclopropylethyl ester (E15, Rx = CH₃, R₄ = CH₂CH₂-c-C₃H₅, ,K = -OCH₂CH₂0 )

The title compound was prepared in 68% yield from the enamine D8 by a method similar to that of Example 4 as a pale yellow gum which slowly solidified on standing, m.p. 94-96.5°C.

NMR(CDCl3) δ: 0.12 (2H, m), 0.50 (2H, m), 0.82 (IH, m), 1.68 (2H, m), 2.05 (2H, t), 2.70 (3H, s), 3.01 (2H, s), 3.22 (2H, t), 4.06 (4H, s), 4.39 (2H, t), 6.60 (2H, bs)

MS measured 388.1460, calculated for C20H24N2O4S 388.1456. Example 16

4-Amino-7,7-ethylenedioxy-2-nιethyl-5,6,7,8-tetrahydrobenzo[b]- thieno[2,3-b]pyridine-3-carboxylic acid, pent-4-ynyl ester (E16, Ri - CH₃, R₄ __. (CH₂)3C≡CH, J,K = -OCH₂CH₂0-)

The title compound was prepared from the ethyl ester El (l.Og) by a procedure similar to that given in Example 12 using 4-pentyn-l-ol. RecrystaUization (ethanol) afforded a white crystalline solid (0.58g, 52%). m.p. 84-86°C.

NMR (CDCl₃)δ: 1.95-2.10(5H, m), 2.34-2.44 (2H, m), 2.71 (3H, s) 3.01 (2H, s), 3.22 (2H, t), 4.05 (4H, s), 4.45 (2H, t) 6.61 (2H, bs).

Found: C, 61.90; H, 5.83; N, 7.49%

C20H22N2O4S requires C, 62.16; H, 5.74; N, 7.25%

Example 17

4-Amino-2-methyl-7,7-(2,2-d__methyl)propylenedioxy-5,6,7,8- tefa*ahydrobenzorøt eno[2,3-blpyridine-3-carboxylic acid, ethyl ester (E17, i = CH3, R₄ =_ C₂H₅, J,K = -OCH₂C(CH₃)₂CH₂0-)

The title compound E17 was prepared in 38% yield from aminonitrile D9 by a procedure similar to that of Example 1, Method B. RecrystaUization from ethyl acetate afforded a pale yeUow solid, m.p. 193-195°C.

NMR (CDCl₃)δ: 1.00 (3H, s), 1.04 (3H, s), 1.43 (3H, t), 2.23 (2H, t), 2.72 (3H, s), 3.12 (2H, t), 3.18 (2H, s), 3.60 (4H, s), 4.40 (2H, q), 6.58 (2H, bs).

Found: C, 61.40; H, 6.59; N, 7.05% C20H26N2O4S requires C, 61.52; H, 6.71; N, 7.17% Example 18

4-Amino-2-methyl-7,7-(2,2-dimethyl)propylenedioxy-5,6,7,8- tetrahydrobenzo[blthieno[2,3-blpyridine-3-carboxylic acid, but-3- ynyl ester (E18, R = CH₃, R₄ = (CH₂)₂C≡CH, J,K = -OCH₂C(CH₃)₂CH₂0-)

The title compound E18 was prepared from the ester E17 in 98% yield by a procedure similar to that outlined in Example 6, m.p. 152-154°C.

NMR (CDCl₃)δ: 0.98 (3H, s), 1.03 (3H, s), 2.06 (IH, t), 2.23 (2H, t), 2.68 (2H, dt), 2.74 (3H, s), 3.12 (2H, t), 3.17 (2H, s), 3.58 (4H, s), 4.45 (2H, t), 6.60 (2H, bs).

Found: C, 63.71; H, 6.36; N, 6.70%

C22H26N2O4S requires C, 63.75; H, 6.32; N, 6.76%

Example 19

4-Amino-2-methyl-7,7-(2,2-dimethyl)propylenedioxy-5,6,7,8- tetrahydrobenzo[b]thieno[2,3-blpyridine-3-carboxylic acid, but-2- ynyl ester (E19, R_x = CH3, R₄ = CH₂C=CCH₃, J,K = -OCH₂C(CH₃)₂CH₂0 )

The title compound E19 was prepared in 45% yield from enamine DIO by a procedure similar to that outlined in Example 4, m.p. 148-150°C.

NMR (CDCl3)δ: 1.00 (3H, s), 1.04 (3H, s), 1.88 (3H, t), 2.22 (2H, t), 2.73 (3H, s), 3.00 (2H, t), 3.17 (2H, s), 3.58 (4H, s), 4.88 (2H, t), 6.57 (2H, bs).

Found: C, 63.64; H, 6.32; N, 6.63% C22^H26^N2°4^S requires C, 63.75; H, 6.32; N, 6.76% Example 20

4-A_ιnino-2-ιnethyl-7,7-(2^-dimethyl)propylenedioxy-5,6,7,8- tetrahydrobenzo[b]ti-ieno[2,3-b]py- dine-3-carboxylic acid, cyclopropylmethyl ester (E20, Ri = CH₃, R₄ = CH2-C-C3H5, J,K = -OCH₂C(CH₃)₂CH₂0-)

The title compound E20 was prepared in 38% yield from enamine Dll by a procedure similar to that outlined in Example 4, m.p. 148-150°C.

NMR (CDCl3)δ: 0.37 (2H, m), 0.65 (2H, m), 0.98 (3H, s), 1.04 (3H, s), 1.28 (IH, m), 2.22 (2H, t), 2.73 (3H, t), 3.12 (2H, t), 3.17 (2H, s), 3.58 (4H, s), 4.15 (2H, d), 6.54 (2H, bs).

Found: C, 63.37; H, 6.67; N, 6.70 %

C₂2^H28^N2⁰4^S requires C, 63.44; H, 6.78; N, 6.73%

Example 21

4-Amino-7,7-diethoxy-2-methyl-5,6,7,8-tetrahydrobenzo[bl- thieno[2,3-b]pyrid__ne-3-carboxylic acid, ethyl ester (E21, i = CH3, R₄ = C₂H₅, J = K = C₂H₅0-)

The ketone D12 (2.00g, 7mmol) was added to a solution of acetyl chloride (1.5ml, 21mmol) in dry ethanol (70ml). The mixture was heated under reflux for 1.5h and was then aUowed to cool. The reaction mixture was then added to water (150ml) and after neutraHzation with saturated aqueous sodium bicarbonate the product was extracted into ethyl acetate. The combined organics were washed with brine and dried over sodium sulphate. The solvent was removed in υacuo. Chromatography on alumina eluting with dichloromethane afforded a white solid which was crystallized from ethyl acetate to give the title compound, E21 (1.40g, 52%), m.p. 152-154°C.

NMR (CDCl₃)δ: 1.08 (6H, t), 1.42 (3H, t), 2.14 (2H, t), 2.71 (3H, s), 3.07 (4H, m), 3.58 (4H, m), 4.40 (2H, q), 6.58 (2H, bs) Found: C, 59.97; H, 6.72; N, 7.21% ^C19^H26^N2°4^S requires C, 60.29; H, 6.92; 7.40%

Example 22

4-Amino-7,7-dimethoxy-2-methyl-5,6,7,8-tetrahydrobenzo[b]- thieno[2,3-blpyridine-3-carboxyUc acid, ethyl ester (E22, Rx = CH₃, R₄ = C₂H₅, J = K = CH3O-)

The title compound E22 was prepared from ketone D12 in 63% yield by a similar procedure to that outlined in Example 21, using methanol instead of ethanol, m.p. 165-167°C.

NMR (CDCl3)δ: 1.43 (3H, t), 2.14 (2H, t), 2.71 (3H, s), 3.06 (4H, m), 3.30 (6H, s), 4.40 (2H, q), 6.57 (2H, bs).

Found: C, 58.18; H, 6.20; N, 7.94% CX7H22N2O4S requires C, 58.27; H, 6.33; N, 7.99%

Example 23

4-Amino-7,7-diethoxy-2-methyl-5,6,7,8-tetrahydrobenzo[b]- thieno[2,3-blpyridine-3-carboxylic acid, cyclopropylmethyl ester (E23, Ri = CH3, R₄ = CH₂-c-C₃H₅, J = K = C₂H₅O )

The title compound E23 was prepared from ketone D13 in 58% yield by a similar procedure to that outlined in Example 21, m.p. 175-178°C.

NMR (CDCl₃)δ: 0.38 (2H, m), 0.66 (2H, m), 1.18 (6H, t), 1.28 (IH, m), 2.14 (2H, m), 2.73 (3H, s), 3.07 (4H, m), 3.60 (4H, m), 4.16 (2H, d), 6.55 (2H, bs).

Found: C, 62.23; H, 6.77; N, 6.78% ^C21^H28^N2°4^S requires C, 62.35; H, 6.98; N, 6.92% Example 24

4-Amino-7,7-dinιethoxy-2-methyl-5,6,7,8-tetrahydrobenzoIb]- t-__ieno[2,3-b]pyridine-3-carboxylic acid, cyclopropylmethyl ester (E24, R_X = CH₃, R₄ = CH₂-c-C₃H₅, J - K = CH3O-)

The title compound E24 was prepared from ketone D13 in 73% yield by a similar procedure to that outlined in Example 22, m.p. 153-155°C.

NMR (CDCI3) δ: 0.46 (2H, m), 0.64 (2H, m), 1.27 (IH, m), 2.13 (2H, m), 2.72 (3H, s), 3.06 (4H, m), 3.28 (6H, s), 4.16 (2H, d), 6.56 (2H, bs).

Found: C, 60,57; H, 6.37; N, 7.48% CX9H24N2O4S requires C, 60.62; H, 6.43; N, 7.44%

Example 25

4-Am__no-2-πιethyl-7,7-propyleneQio___y-5,6,7,8-tetrahydrobenzo[b]- .tMeno[2,3-blpyridine-3-carboxyIic acid, ethyl ester (E25, R =. CH3, R₄ _= C₂H₅, J,K = -0(CH₂)₃0-)

The ketone D12 (2.00g, 6.6 mmol), 1,3-propanediol (4.00g, 53 mmol), para tolune-sulphonic acid (PTSA) (0.40g) and toluene (130 ml) were heated at reflux under a Dean and Stark apparatus for 16 h. The reaction mixture was cooled and diluted with EtOAc (100 ml). The resulting solution was washed with aqueous sodium bicarbonate and brine. Drying over sodium sulphate and evaporation afforded an off-white solid which was crystallised from ethyl acetate to give the title compound as a fawn solid (1.80 g, 75%), m.p. 128-130°C.

NMR (CDCI3) δ: 1.43 (3H, t), 1.81 (2H, m), 2.23 (2H, t), 2.70 (3H, s), 3.10 (2H, t), 3.18 (2H, s), 3.97 (4H, t), 4.40 (2H, q), 6.57 (2H, bm).

Found: C, 59.51; H, 6.06; N, 7.76%

^C18^H22^N2°4^S requires C, 59.65; H, 6.12; N, 7.73% Example 26

4-Aπι__no-2-methyl-7,7-propylenedioxy-5,6,7,8-tetrahydrobenzo[b]- thieno[2,3-blpyridine-3-carboxy_ic acid, (2-methyl)propyl ester (E26, Rx = CH₃, R₄ = CH₂CH(CH₃)₂, J,K = -0(CH₂)₃0 )

The title compound was prepared in 62% yield from the ester E25 by a procedure similar to that outlined in Example 6, m.p. 126-128°C

NMR (CDC1₃) δ: 1.03 (6H, d), 1.80 (2H, m), 2.08 (IH, m), 2.22 (2H, t),

2.72 (3H, s), 3.11 (2H, t), 3.18 (2H, s), 3.98 (4H, m), 4.12 (2H, d), 6.60 (2H, bs)

Found: C, 61.48; H, 6.56; N, 7.30% C20H-26N2O4S requires C, 61.52; H, 6.71; N 7.17%

Example 27

4-Amino-2-methyl-7,7-(2-methylene)propylenedioxy-5,6,7,8- tetrahydrobenzo[blthieno[2,3-blpyridine-3-carboxyUc acid, ethyl ester (E27, R = CH₃, R = C₂H₅, J,K = -OCH₂C(=CH₂)CH₂O-)

The title compound was prepared in 63% yield from the ketone D 12 by a procedure similar to that outlined in Example 25, m.p. 153-155°C

NMR (CDCI3) δ: 1.43 (3H, t), 2.22 (2H, t), 2.69 (3H, s), 3.17 (4H, m), 4.38 (6H, m), 4.92 (2H, s), 6.57 (2H, bs).

Found: C, 60.95; H, 5.89; N; 7.59%

C19H22N2O4S requires C60.94; H, 5.92; N, 7.48% Example 28 and 29

4-Aπι_uιo-7,7-ethyIeneclitlιio-2-methyl-5,6,7,8-tetrahydrobenzo[bl- thieno[2,3-bIpyridine-3-carboxylic acid, n-butyl ester (E28, R = CH3, R₄ = n-C₄Hg, J,K = -SCH₂CH₂S-)

and

4-Am__no-7,7-ethyIenedithio-2-methyl-5,6,7,8-tetrahydrobenzo[bl- ihieno[2,3-blpyridine-3-carboxyIic acid, ethyl ester (E29, R = CH₃, R = C₂H₅, J,K = -SCH₂CH₂S-)

The enamine D16 (0.818g, 2.15mmol) in n-butyl acetate (20ml) was heated at reflux under nitrogen with tin (IV) chloride (0.41 ml) for 10 minutes and aUowed to cool. The resulting dark orange solution was poured into 10% sodium hydroxide solution and the organic phase diluted with ethyl acetate. After separating the layers, the aqueous was further extracted with ethyl acetate (x2). The combined organic layers were washed with water and then brine before drying over anhydrous sodium sulphate and evaporation to dryness. This crude product was chromatographed on silica with 20% ethyl acetate/pentane as eluant. In this system the n-butyl ester E28 is the higher Rf component and was obtained as a pale yeUow crystaUine solid, m.p. 139-142°C.

NMR (CDCI3) δ: 0.98 (3H, t), 1.48 (2H, m), 1.75 (2H, m), 2.39 (2H, t), 2.69 (3H, s), 3.23 (2H, t), 3.49 (6H, overlapping s and m), 4.32 (2H, t), 6.59 (2H, bs).

MS measured 408.1000, calculated for CX9H24N2O2S3 408.0998.

The ethyl ester E29 was obtained in subsequent fractions as a white solid, m.p. 171-174⁰C.

NMR (CDCI3) & 1.42 (3H, t), 2.38 (2H, t), 2.69 (3H, s), 3.23 (2H, t), 3.49 (6H, overlapping s and m), 4.39 (2H, q), 6.57 (2H, bs).

MS measured 380.0663, calculated for CX7H20N2O2S3 380.0685. Example 30

4-An____no-7,7-ethylenedithio-2-πιethyl-5,6,7,8-tetrahydrobenzo- [b]thieno[2,3-blpyridine-3-carboxylic acid, cyclopropylmethyl ester (E30, R_X = CH₃, R₄ = CH₂-c-C₃H₅, J,K = -SCH₂CH₂S-)

The enamine D18 was cyclized with copper (I) acetate in n-butylacetate by a method similar to that of Example 4. The crude product E30 was purified by chromatography on silica gel with a gradient of 20-50% ethyl acetate/pentane giving an off white solid (61%), m.p. 183.5-185°C.

NMR (CDC1₃) δ: 0.37 (2H, m), 0.64 (2H, m), 1.25 (IH, m), 2.39 (2H, t), 2.73 (3H, s), 3.23 (2H, t), 3.38 (6H, overlapping s and m), 4.15 (2H, d), 6.54 (2H, bs).

MS measured 406.0876, calculated for CX9H22N2O2S3 406.0843

Example 31

4-Amino-2-methyl-7,7-propylenedioxy-5,6,7,8-tetrahydrobenzo- lt__deno[2,3-blpyridine-3-carboxylic acid, cyclopropylmethyl ester (E31, Rx = CH3, R4 = CH₂-c-C₃H₅ , J,K = -0(CH₂)₃0 )

The title compound was prepared in 63% yield from the ketone D 13 by a procedure similar to that outlined in Example 25, m.p. 148-152°C.

NMR (CDCI3) δ: 0.36 (2H, m), 0.66 (2H, m), 1.27 (IH, m), 1.80 (2H, m), 2.23 (2H, t), 2.72 (3H, s), 3.11 (4H, s), 3.98 (4H, t), 4.16 (2H, d), 6.55 (2H, bs)

Found: C, 61.86; H, 6.20; N, 7.45% C20H24N2O4S requires C, 61.84; H, 6.23; N, 7.21%. Example 32

4-Amino-2-methyl-7,7-(2-methylene)propylenedioxy-5,6,7,8- tetrahydrobenzo| ]tMeno[2,3-blpyridine-3-carboxy__ic acid, cyclopropylmethyl ester (E32, R •= CH3, R4 = CH₂-c-C3H5, J,K = -OCH₂C(=CH₂)CH₂0 )

The title compound was prepared in 59% yield from the ketone D 13 by a procedure similar to that outlined in Example 25, m.p. 145-146°C.

NMR (CDCI3) δ: 0.37 (2H, m), 0.66 (2H, m), 1.27 (IH, m), 2.22 (2H, t), 2.74 (3H, s), 3.14 (2H, t), 3.18 (2H, s), 4.16 (2H, d), 4.42 (4H, s), 4.92 (2H, s), 6.54 (2H, bs).

Found: C, 62.83; H, 6.01; N, 7.06%

C₂iH 4N₂O4S requires C, 62.98; H, 6.04; N, 6.99%

Example 33

4-Amino-7,7-dim.ethoxy-2-πιethyl-5,6,7,8-tetrahydrobenzo- rb]thieno[2,3-b]pyridine-3-carboxylic acid, methyl ester (E33, Ri = CH3, R₄ = CH3, J = K = -OCH3)

The title compound was prepared in 70% yield from ketone D 17 according to the procedure outlined in Example 22. m.p. 148-150°C.

NMR (CDCI3) δ: 2.14 (2H, t), 2.67 (3H, s), 3.04 (2H, s), 3.08 (2H, t), 3.30 (6H, s), 3.93 (3H, s), 6.58 (2H, bs).

Found: C, 57.08; H, 5.92; N, 8.36% CχgH2θN2θ₄S requires C, 57.13; H, 5.99; N, 8.33%. Example 34

4-Amino-7,7-diethoxy-2-methyl-5,6,7,8-tetrahydrobenzo- [blthieno[2,3-blpyridine-3-carboxylic acid, methyl ester (E34, Rx = CH₃, R₄ = CH₃, J = K •= -OC₂H₅)

The title compound was prepared in 64% yield from ketone D17 according to the procedure outlined in Example 21, m.p. 141-142°C.

NMR (CDC1₃) δ: 1.18 (6H, t), 2.13 (2H, t), 2.68 (3H, s), 3.05 (4H, m), 3.57 (4H, m), 3.90 (3H, s), 6.56 (2H, bs)

Found: C, 59.15; H, 6.38; N, 7.85% C18H24N2O4S requires C, 59.32; H, 6.64; N, 7.69%

Example 35

4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8 tetrahydrobenzo[bl thieno[2,3-blpyridine-3-carboxylic acid, 2,2,2-trifluoroethyl ester (E35, Rx = CH₃, R₄ = CH₂CF₃, J,K = -OCH₂CH₂0 )

The title compound was prepared from aminonitrile Dl and 3-oxobutyric acid, 2,2,2-trifluoroethyl ester by a procedure similar to that of Description 5 and Example 4.

NMR (DgDMSO) δ: 1.95 (2H, t, J=7 Hz), 2.65 (3H, s), 2.95 (2H, s), 3.15 (2H, t, J=7 Hz), 3.95 (4H, s), 5.00 (2H, q, J= 11 Hz), 6.80 (2H, s)

Example 36

4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8 tetrahydrobenzo[b] thieno[2,3-blpyridine-3-carboxyUc acid, prop-2-enyl ester (E36, R = CH3, R₄ = CH₂CH=CH₂, J,K = -OCH₂CH₂0 )

The title compound was prepared from aminonitrile Dl and 3-oxobutyric acid, prop-2-enyI ester by a procedure similar to that of Description 5, and

Example 4.

NMR (CDCI3) δ: 2.07 ( 2H, t), 2.72 (3H, s), 3.02 (2H, s), 3.22 (2H, t), 4.05 (4H, s), 4.84 (2H, m), 5.32 (IH, m), 5.43 (IH, m), 5.97-6.16 (IH, bm), 6.63 (2H, bs).

Compounds E35 and E35 may alternatively be prepared by a procedure similar to that of Description 2 and Example 1, method A.

Pharmacological Data

1. Geller-Seif ter 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

SepinwaU, (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 typicaUy 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 intraperitoneaUy 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).

Testing Results (Geller-Seifter)

Compounds of Examples 2, 3, 18, 21 and 24 showed a significant increase in responding in the 'conflict' session at 20 mg/kg, Examples 6, 10, 14, 15 and 25 at 10 mg kg and Example 4 at 5 mg/kg. Compounds of Examples 1, 5, 11, 16, 17, 19, 20, 22, and 23 showed no significant increase in responding in the 'conflict' session at 20 mg/kg and Examples 7-9 and 12 showed no significant increase at 10 mg/kg, but these compounds were not tested at higher doses.

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 lOOOg for 20 minutes (4°C). The supernatant is removed and recentrifuged at 50,000g (4°C, 20 mins). The P₂ peUet 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

[35g]-TBPS (2nM) in Tris citrate buffer (pH 7.1) containing 0.2M NaCl and 1 x 10'^M GAB A. Non-specific binding is measured in the presence of 10"⁴M 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 ceU 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 [³⁵S] - TBPS binding

Compounds of Examples 1-20, 22-29, 31 and 32 showed an IC50 of <25μM and Example 33 >30μM. Solubility problems prevented the determination of reliable IC50 values for some compounds.

Claims

Claims

1. A pharmaceutical composition which comprises a compound of formula (I) or a pharmaceuticaUy acceptable salt thereof:

wherein the variables Rχ_t R2, R3, R4, R5, Rg, J and K are as defined in the description, and a pharmaceutically acceptable carrier.

2. A compound of formula (I) as defined in Claim 1 or a pharmaceutically acceptable salt thereof excluding the methyl, ethyl, propyl, cyclopropylmethyl, prop-2-enyl, but-3-enyl, but-2-ynyl, but-3-ynyl and 2,2,2-trifluoroethyl esters of 4-amino-7,7-ethylenedioxy-2-methyl- 5,6,7,8-tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid.

3. A compound according to claim 2 wherein J and K are other than ethylenedioxy.

4. A compound according to claim 3 wherein X' and Z' are the same and Rχ3 and Rχ4, when Cχ.g alkyl, are the same or, when together represent C2-.4 polymetiiylene, are substituted by one or two Cχ.g alkyl group or by Cχ.g alkylidene.

5. A compound according to any of claims 2 to 4 wherein R4 is Cχ.g alkyl optionaUy substituted by up to three halo atoms, C2-g alkenyl, C2- alkynyl, C3_ cycloalkyl or C3_ cycloalkyl-Cχ.4 alkyl.

6. A compound according to any of claims 2 to 5 wherein Rx is hydrogen, Cχ.3 alkyl, phenyl or benzyl.

7. A compound according to any of claims 2 to 6 wherein R2 and R3 are independently hydrogen or Cχ.g alkyl.

8. A compound according to any preceding claim wherein R5 and Rg are both hydrogen.

9. A compound selected from E5, E6 and E10 to E34 as defined in the description, or a pharmaceuticaUy acceptable salt thereof.

10. A compound according to claim 2 as hereinbefore described in any one of Examples 5, 6 and 10 to 34.

11. A process for the preparation of a compound according to claim 2, which process comprises the cyclisation of a compound of formula (HI):

or imine tautomer thereof, wherein Rχ'_» R4', R5, R7, Rg, Y, M, J' and K' are as defined in the description; 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 CO χ or COL2, converting the resulting hydroxy group to a leaving group and reacting the latter with a compound HNR ^*R3' wherein R₂' and R3' are R2 and R3 as defined in formula (I) or N-protecting groups, removing any R₂\ R3^* or R7 N-protecting group, converting any electron-withdrawing group R4^* to CO2R4, converting Rx' when other than Rx to Rχ» converting J' and K' when a keto group to J and K, converting J' and K^f when a group convertible to a keto group, to a keto group and thereafter to J and K, interconverting R , R3, R4, R5, Rg, J and K, separating any stereoisomers such as enantiomers or diastereomers and/or forming a pharmaceuticaUy acceptable salt of a compound of formula (I).

12. A compound of formula (I) as defined in claim 1 or a pharmaceuticaUy acceptable salt thereof for use as a therapeutic substance.

13. A compound of formula (I) as denned in claim 1 or a pharmaceutical acceptable salt thereof for use in the treatment and/or prophylaxis of CNS disorders.

14. Use of a compound of formula (I) as defined in claim 1 or a pharmaceutical acceptable salt thereof in the preparation of a medicament for the treatment and/or prophylaxis of CNS disorders.

15. 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 of formula (I) as defined in claim 1 or a pharmaceutical acceptable salt thereof.