This invention relates to novel tetracyclic compounds having mood-modifying, particularly anti-depressant and/or anxiolytic activity, to pharmaceutical compositions containing them, and to a process for their preparation.

UK Patent 1,404,642 describes compounds of the formula (A) :

in which R _a and R _D ^are hydrogen, hydroxy, halogen, alkyl or alkoxy with 1-6 carbon atoms, acyloxy with 1-8 carbon atoms, or a t ifluoromethyl group;

R: is hydrogen, an alkyl group with 1-6 carbon atoms, an aryl group or an aralkyl group with 7-9 carbon atoms; and

Q is a single bond, a -CH2-CH2- group, a -CH=CH- group or a -CHR- group where R is hydrogen or an alkyl group 1-6 carbon atoms.

A class of tetracyclic compounds has now been discovered to have useful mood-modifying, particularly anti-depressant activity and/or anxiolytic activity.

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

R. whs.c=in :

X is CH2, O, S or NR where R is Cι_4 alkyl;

]_ and R2 are independently selected from hydrogen, hydroxy, C3.--4 alkyl, Cι_4 alkoxy, halogen or CF3;

R3 is Cι_7 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-7 cycloalkyl, 04-7 cycloalkenyl or Cι_6 alkyl substituted ^b Y ^c 2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, hydroxy, thiol, Cι_6 alkoxy, Cι_6 alkylthio, carboxy, ^c l-6 alkoxycarbonyl, C2-7 alkanoyl, amino optionally substituted by one or two C1-4 alkyl or by C4.-6 polymethylene optionally containing an oxygen or nitrogen atom, aminocarbonyl optionally N-substituted by one or two C]__g alkyl groups, or benzoyl or phenyl either being optionally ring-substituted by one or two

C _4 alkyl, Cι_4 alkoxy, halogen or trifluoromethyl; and

one of R4, R5 and R5 is C]__5 alkyl and the other two a independently hydrogen or C _j L_g alkyl.

When X is MR, suitable examples of R include methyl, ethyl, n_- or iso-propyl, n_, sec- or tert-butyl.

Suitable examples of Ri and 2 include hydrogen, hydroxy, methyl, ethyl; methoxy and ethoxy; fluoro, chloro, bromo; and CF3. Often i and R2 will be hydrogen or 7-ha.lo, such as chloro bromo. Preferably Rl and R2 ^a ∑"e both hydrogen.

When R3 is C1--4 alkyl substituted by phenyl optionally substituted as hereinbefore defined, examples of such optional substituents include methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo or trifluoromethyl. Preferably, phenyl is unsubstituted.

When R3 is C__4 alkyl substituted by a ino optionally substituted as hereinbefore defined, examples of such optional substituents include methyl and ethyl and, together with the nitrogen atom, piperidino and morpholino.

Preferably, R3 is C1-4 alkyl, such as methyl and ethyl, most preferably methyl.

When R4, R5 or R6 are hydrogen or Ci-6 alkyl suitable values include hydrogen, methyl, ethyl, n- and iso-propyl, 11, sec- and tert-butyl. In such cases R4, R5 or R6 will often be hydrogen or methyl or ethyl. Preferably, at least one of R5 and R6 ^is hydrogen.

Suitable examples of salts of the compounds of formula (I) include acid addition salts with pharmaceutically acceptable inorganic and organic acids, such as hydrochloric, hydrobromic, sulphuric, maleic and succinic acids.

The compounds of formula (I) have asymmetric centres and are capable of existing in a number of stereoisomeric forms. The invention extends to each of these forms and to mixtures thereof.

There is a group of compounds within formula (I) wherein R3 is Ci-6 alkyl, C2-5 alkenyl, C2-5 alkynyl, 3-7 cycloalkyl, 05-7 cycloalkenyl or Cχ_4 alkyl substituted by 03-7 cycloalkyl or phenyl or Cχ-6 alkyl substituted by hydroxy, C__g alkoxy, carboxy, C2-7 alkanoyl, benzoyl or aminocarbonyl or amino optionally substituted by one or two C]__5 alkyl groups and the remaining variables are as defined in formula (I).

A group of compounds within formula (I) is of formula (II) :

wherein R^l is hydrogen or halogen, one of R5I and Rδ^- is Ci-6 alkyl and the other is hydrogen or Cι_6 alkyl; and X is as defined in formula (I).

Suitable values for R]_l> R5I and Rβ ¹ are as described under formula (I) for relevant R , R5 and RQ .

Preferably one of R5 ¹ and R6 ¹ is hydrogen and the other is Cι_5 alkyl. Preferably R± is hydrogen.

A sub-group of compounds within formula (II) is of formula (III):

wherein 52 is C]__g alkyl Λnd R]_^- is as defined in formula (II).

Suitable values for R5 ² are as described for re -van R5 under formula (I).

^» reF. r-bly _ ₅ 2 is methyl or ethyl, most preferably

:.,<ii hy.l.

_O PI

A further sub-group of compounds within formula ( II ) is of formula ( IV ) :

wherein ^χ l is oxygen or sulphur; and

Rl ¹ and R5 ² are as defined in formula (III).

Suitable and preferred values for R^ and R^ are as described for relevant R^ and R5 under formula (I).

Preferably R _$ 2 is methyl or ethyl, most preferably methyl.

There is another sub-group of compounds within formula (II) of formula (V):

wherein 2 s NR as defined in formula (I) and Rχl and 52 are as defined in formula (III).

Suitable and preferred values for Ri ¹ and R5 ² are as described for the corresponding variables under formula

(I).

There is another group of compounds within formula (I) of formula (VI) :

wherein 4 is C _g alkyl and Rj_l is as defined in formula (II) .

Suitable values for Rχl and R4 include those described under formula (I) for relevant R^ and R4.

Preferably 4I is methyl.

The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises the reaction of a compound of formula (VII):

with a compound of formula (VIII)

\

/ \

(VIII)

wherein R3' is R3 or a group convertible thereto,. Ri, ^R 2, ^R 5 and Rg are as defined in formula (I), one of Yi and Y2 is hydrogen and the other is R4 as defined or (when R4 in formula (I) is hydrogen), Y and Y2 together form an oxo or thiocarbonyl group; and Z]_ and Z2 are leaving groups, and thereafter reducing the resulting compound formed when Y and Y2 together form an oxo or thiocarbonyl group, and/or converting R3' to R3 and/or forming a pharmaceutically acceptable salt.

Z]_ and Z2 are suitably groups which are readily displaceable by a secondary amino nucleophile.

Favourable values for Zi and Z2 when 1/Y2 are hydrogen and R4, include halo or hydroxy. When Yi and Y2 are both hydrogen, reagents therefore include methylene chloride, methylene bromide and ethylene diol (aqueous or ethanolic formaldehyde).

Favourable values for Zi and Z2 when Yi and Y2 together are oxo or thiocarbonyl include halo, Cχ_ alkoxy, Cι_g alkylthio, amino optionally substituted by one or two Cχ_g alkyl or Cχ_g acyl groups.

Such reagents of formula (VIII) therefore include phosgene, thiophosgene, haloformic esters, such as ethyl chloroformate, carbonic acid esters, such as diethyl carbonate, urea derivatives, such as urea, thiourea or N, Nl-carbonyl-di-imidazole.

When R4 is hydrogen, the compound of of formula (VII) is preferably methylene diol.

The reaction may be carried out in a suitable solvent. Aprotic, polar solvents such as dimethyl- sulphoxide, sulfolane or acetonitrile are suitable.

Alternatively, the reagent may act as the solvent such as methylene chloride. If urea is used as the reagent the reaction can be carried out in a melt.

If Zi and/or Z2 are halo, an agent capable of binding the hydrogen halide released in the condensation, is usually added. Suitable agents include pyridine and triethylamine.

It will be appreciated that, if R3' is a carbonyl containing group, the carbonyl group is preferably protected, for example as the ketal during the reaction between compounds (VII) and (VIII).

The subsequent reduction of the compound formed between a compound of formula (VI) and a compound of formula (VII) wherein Y1/ 2 ^{re o o or} n o is normally carried out using a conventional reducing agent, such as metal hydrides eg. sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride or diborane. Catalytic hydrogenation is also suitable. It will be appreciated that, if R3 ' is a group susceptible to reducing agents,

OMPI "

suitable protection or selection of reagents and reaction conditions must be selected.

Examples of an optional conversion of R3 in a compound of formula (I) into another R3 include the conversion of Cι_6 alkyl substituted by hydroxy into Ci-g alkyl substituted by thiol by, for example, first forming a ^' Ci-g halide, such as the chloride, .and then reacting the Cχ_g alkyl halide with potassium hydrogen sulphide, or into Cl-g alkyl subsituted by Cl-g alkoxy using, for example, sodium hydride and a Cχ_g alkyl halide; the conversion of Cχ-g alkyl substituted by thiol into Cι_g alkyl substituted by C]__g alkylthio using, for example, a base and a C]__g alkyl halide; the conversion of C__g alkyl substituted by C _] __g alkoxycarbonyl into Cχ_g alkyl substituted by carboxy by hydrolysis; the conversion of Cχ_g alkyl substituted by carboxy into Cχ_g alkyl substituted by aminocarbonyl optionally N-substituted by one or two C _] __g alkyl by,for example, first forming the carboxylic acid halide, such as the chloride, and then reacting the acid halide with ammonia optionally substituted by one or two Cχ_g alkyl; and the conversion of Cχ_5 alkyl substituted by aminocarbonyl optionally N-substituted by one or two Cχ_g alkyl into Cl-g alkyl substituted by amino optionally substituted by one or two Ci-g alkyl by reduction.

Compounds of the formula (VII) - y be prepared by reduction of a compound of formula (IX):

wherein Ri, R2, R3' , R5 and Rg are as hereinbefore defined.

The reduction may be carried out using either catalytic hydrogenation or by complex metal hydride reduction or using other conventional reducing agents such as diborane or sodium cyanoborohydride.

Conventional reaction conditions may be used. For example with sodium borohydride, the reaction temperature is suitably around 0°C, and a solvent such as ethanol is suitably used; and with lithium aluminium hydride low temperatures such as -80°C to 0°C are suitably used, in a solvent such as ether or THF.

Sodium cyanoborohydride reduction is suitably carried out at ambient temperatures using methanol or ethanol as solvent, suitably at pH 3-4. 'When catalytic hydrogenation is used, acetic acid (or other conventional solvent plus acid catalyst) using platinum as catalyst may be used; and the reaction effected ^{^} at slightly above atmospheric pressure at non-extreme temperatures such as 0°C to 40°C. The choice of reducing agent will of course be affected by the desired stereochemistry in the reaction product, since for example diborane and LiAlH4 are stereoselective in their mode of action. It will also be appreciated that the selection of reducing agent will depend upon the nature of R3. It may be necessary to protect any carbonyl or thiocarbonyl groups during the reduction step.

After the processes of the invention it will be appreciated that R]_ and R2 groups may be varied. For

O P

example a compound of formula (I) wherein R^ and R2 are hydrogen may be halogenated.

Compounds of the formula (IX) may be prepared from a compound of the formula (X), which is known or prepared analogously to known compounds:

wherein L is a group readily displaceable by a nucleophile, and other variables are as hereinbefore defined, by treatment with H R3'.

Suitable examples of L include halide, such as chloride or bromide or activated ester such as mesyl- or tosyloxy.

Intermediates of the formula (VII) and (IX) are novel and thus form an aspect of the present invention.

Compounds of the formula (I) have useful pharmacological activity, in that they have mood-modifying in particular anti-depressant and anxiolytic activity.

The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt

The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations.

Tablets and capsules for oral administration may - be in unit dose presentation form, and may contain conventional excipients such as binding agents, fillers, tabletting lubricants, distintegrants, 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 suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dosage forms are prepared utilising the compound of the formula (I) 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 filing into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a .local anaesthetic, preservatives and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.

The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant of wetting agent is included in the composition to facilitate uniform distribution of the compound.

Preferred unit dosage forms include tablets, capsules and their equivalents.

The compositions of this invention may be formulated by conventional methods of blending, filling and compressing.

Suitable carriers for use in this invention include diluents, binders, disintegrants, colouring agents, flavouring agents and preservatives. These agents may be utilized in conventional manner, for example in a manner similar to that already used for other mood-modifying agents such as anti-depressants and anxiolytics.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

Mood-modifying compositions will most suitably be presented as oral or parenteral unit dose compositions containing from 1 to 100 mg, more usually from 5 to 50 mg, for example 10 to 25 mg , such as 12.5, 15 and 20 g. Such compositions will normally be taken from 1 to 6 times daily, for example 2, 3 or 4 times daily, so that the total amount of active agent administered is usually within the range 5 to 400 mg .

Preferred unit dosage forms include tablets, capsules and their equivalents, such as granules or lozenges.

The invention also provides a method of treatment of CNS disorders in mammals including man which method comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof to the sufferer.

The invention also provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in treating CNS disorders in mammals.

The following Examples illustrate the invention; the following Descriptions intermediates thereto.

OMPI

Description 1

2-Chloro-N-[2- (phenylmeth 1)-phenyl] ropanamide (Dl)

2-Chloropropionyl chloride (41.91g, 0.33 mol) in sodium- dry toluene (70ml) was added over 3 hours, at such a rate that the reaction temperature did not exceed 9 , to an ice-cooled, stirred, solution of 2-benzyl-aniline (54.9g, 0.30 mol) in dry toluene (600 ml) containing pyridine

(25 ml) . After 1 hour at 18 , water (6 ml) was added and the mixture kept at 18 for a further 1 hour. The result¬ ant precipitate was removed by filtration, washed well with water and then dissolved in dichloromethane . The solution was washed with water, saturated brine, dried

(Na_S0.) and concentrated under reduced pressure to yield a solid residue. Recrystallisation from ethanol gave the title compound (63.6g, 78%) . m.p. 142-5 .

H vmax (nujol) : 3250 (N-H) and 1663 (N. CO) cm -1

NMR δ„ (CDC1-): 6.90-7.40 (8H, m, aromatic); H ά

4.30 (IK, q, 7Hz, CHCH ₃ ); 3.90 (2H, s, CH ₂ ); 1.60 (3H, d, 7Hz, CH ) .

Description 2

6- (l-Chloroethyl)-llH-dibenzo[b _f e]azepine (D2)_

The anilide Dl (40.95g, 0.15 mol) was added to polyphos- phoric acid (409.5g) and the mixture was warmed to 125° over 1 hour and stirring continued at this temperature for a further 6 hours. The mixture was allowed to cool to room temperature, poured onto crushed ice and stirred for 1 hour. The product was extracted into dichloro- methane (3 1 litre) and the combined organic extracts were washed with brine and dried (Na 2_S04.). Evaporation ' under reduced pressure gave crude 6- (1-chloroethyl) -11K- dibenzo [b,e ] azepine which on trituration v.'ith ether gave a product (34.7g, 91%) of sufficient purity for further reaction (see Description 3) .

v iπ (nujol) : 1618 (C=N) cm -1 sx

NMR δ„ (CDC1 _-j) 6.9-7.6 (8H, m, aromatic); 5.2 (IK, σ, 6.5KZ, CH) ;

3.45 (2H, s, CH ₂ );

1.88 (3H, d, 6.5Kz, CH . CH )

OMPI

Description 3

6 - [ HMethylamino) eth l ] -llH-dibenzo [ b , e 3 azepine (D3^

A solution of the chloroethyl compound D2 (2.55g, 10 mmol) in methylamine (100 ml, 33% solution w/v in IMS) was kept at 18 for 7 days in the dark. The reaction mixture was concentrated under reduced pressure and the residue dissolved in dichloromethane, washed with 10% aqueous sodium carbonate solution (2x100ml) , brine (100ml) and dried (Na^SO.) . Evaporation in vacuo gave crude 6-[l- (methylamino)ethyl]-llK-dibenzorb,e3azepine in 92% yield and this was used immediately without further purification as shown in Descriptions 4 and 5.

N.MR & (CDC1_) : 6.8-7.7 (8H, m, aromatic);

3.9 (IK, q, 7Kz, CHCH ₃ ) ;

4.5 (2K, s, CH ₂ );

2.5 (3H, s, NCK ₃ );

1.3 (3K, d, 7Hz, CH ) .

This was converted to the mono aleate salt, .p. 163- 171 (recrystallised from acetone) .

Found: C, 68.70; H, 6.06; N, 7.56%; C.-H. N.O ..

21 12 2 4 requires: C, 68.84; H, 6.05; N, 7.65%.

Description 4

5 , 6-Dihydro-6- [ l- (methylamino) ethyl 3-llH-dibenzo [b , e 3 azepine Diastereoisorner A (D4)

A solution of 6-[l-(methylamino)ethyl3-llH-dibenzo[b,e3 azepine (10 mmol) in dry ether (20 ml) and dichloro- ethane (10 ml) was added to a stirred suspension of lithium aluminium hydride (190 mg, 5 mmol) in dry ether at -78 , under nitrogen. After 45 minutes, the temperature of the reaction mixture was raised to -20 over 1 hour. Net ether was then carefully added, followed by water and the resultant granular precipitate removed by filt¬ ration. The residue was washed with dichloromethane and the combined organic phases were washed with brine, dried (Na ₂ S0.) and evaporation in vacuo gave the product (1.99g, 77%). This was shown by t.l.c. and n. .r. to be a single isσmer - diastereoisorner A.

NMR δ _H (CDC1 ₃ ) : 6.2-7.4 (8H, m, aromatic)

4.5 (1H, d, 14Hz, H-ll)

4.3 (1H, d, 5Hz, H-6)

3.35 (IK, d, 14Hz, H-ll)

2.7-3.2 (1H, , CH-CH ₃ )

2.35 (3H, s, N-CH )

1.1 (3H, d, 6Kz, CH-CH ₃ )

Conversion to a onomaleate salt followed by recryst- allisation from acetone-ether gave the title compound . p . 151-55 .

Found: C, 68.46; H, 6.57; N, 7.60%. ^C 21 ^H 24 ^N 2°4 requires: C, 68.33; H, 6.70; N, 7.27%.

Description 5

5,6-Dihydro-6-ri- (methylamino)ethyl3-llH-dibenzό[b,e3 azepine

Diastereisomer B (D5)

Sodium cyanoborohydride (3.16g, 50 mmol) in methanol (30 ml) was added dropwise to a solution of 6- [ 1- ( ethyl- amino)ethyl3-llK-dibenzo.b,e3azepine (12.5g, 50 mmol) in methanol (150 ml) maintained at pH 3-4 by the addition of methanolic HCl as appropriate. The reaction was allowed to proceed until all the starting material had been consumed and then pH of the solution was lowered to 0. When effervesence had ceased, the solution was concen¬ trated under reduced pressure and the residue dissolved in dichloromethane (300 ml) . The solution was washed with saturated sodium carbonate solution (2 x 250 ml) , brine (250 ml) and dried (Na SO ) . Evaporation in_ vacuo gave a 45:55 mixture of the two diastereoisomers A and B. (R _f 0.17 and 0.04 on Si0 ₂ /Et0Ac respectively). Trituration of the crude product with ether-pentane gave diastereoisorner B as a solid (3.0g, 24%) .

NMR δ _u (CDCl,): 6.25-7.2 (8H, , aromatic); H -J

4.2 (1H, d, 9Hz, C-6 CH) ;

3.9 (2H, s, CH ₂ );

2.9-3.3 (1H, m, CH CH ₃ ) ;

2.4 OH, s, NCH ₃ );

0.9 (3H, d, 7Hz, CH ₃ )

Conversion into a monomaleate salt followed by recrystall- isation from acetone-ether gave 5,6-dihydro-6-[l(me hyl- amino) ethyl] -llH-dibenzo[b,e] azepine monomaleate diastereo¬ isorner B, m.p. 170-173 .

Found: C, 68.37; H, 6.54; N, 7.61%. ^C 2l ^H 24 ^N 2°4 requires: C, 68.46; H, 6.57; and N, 7.60%

The soluble fraction from the foregoing trituration was chromatographed on Kieselgel 60 (200g) in 10% 60: 80 petroleum ether-ether and gradually increasing the polarity of the eluant to 10% methanol-ether . Combination of appropriate fractions gave pure diastereoisorner B (3.12g, 25%) and pure diastereoisorner A (4.44g, 35%) . The latter was shown to be identical with the compound obtained in Description 4.

^" > ? 704 PCT/GB83/00353

Description 6 -" (1-Bromoethy 1) -TlH-dibenzo Tb , el ^' aze ^' p ^' ine ^' (D6 )

The title compound was prepared from 2-bromopropionyl chloride using a method similar to that in Descriptions 1 and 2. 83% yield, m.p. 92-94 (from ether/60: 80° petrol)

Description 7

6- (1-Bromopropyl) -llH-dibenzo[b,e 3 azepine (D7)

The title compound was prepared in 55% yield using a method similar to that in Descriptions 1 and 2.

Description 8

6- [l-(Ethylamino) ethyT]-llH-dibenzofb ,e ^" 3 azepine .(D8)

6- (l-Bromoethyl)-llK-dibenzo[b,elazepine D6 (1.37g; 4.5 mmol) in ethyla ine (50ml; 33% solution v/v in ethanol) was kept at 18 for 1 day in the dark. The solvent was removed, water and ether added and organic layer separated, dried (MgSO.) and evaporated in. vacuo. Column chrom- atography on Kieselgel 60 eluted with ether gave the title compound in 58% yield. This was converted to the mono¬ maleate salt, .p. 160-161 (from acetone) .

Found: C, 69.18; H, 6.29; N, 7.31% C. _H„ .N_0.

22 24 2 4 requires: C, 69.46; H, 6.36; N, 7.36%

Description 9

6- [ 1- (Phenylmethylamino) ethyl] -llH-dibenzo[b,e 3 azepine (D9)

The bromoethyl compound D6 (lg, 3.3mmol) was dissolved in DMF (20ml) and potassium carbonate (0.54g, 3.9mmol) added. Benzylamine (0.42g, 0.46ml, 3.9πmol) was then added and the mixture stirred at 18° for 2.5 hours. Water was then added and product extracted into ether. Organic

phase washed well with water, dried (MgSO ) and evap¬ orated in vacuo. Chromatography on Kieselgel 60 eluted with 50% ether in petrol, gave the title compound in 70% yield. This was converted to the monomaleate salt, .p. 141-143 (from acetone/ether).

Found: C, 73.29; H, 5.92; N, 6.29% ^C ₂ 7 ^H 26 ^N 2°4 requires: C, 73.29; H, 5.92; N, 6.33%

Description 10

5,6-Dihydro-6-[ 1- (ethylamino)ethyl3-llH-dibenzofb,e]azepin

Diastereoisorner A (DIP)

The title compound was prepared in 60% yield from the imine D8 using a method similar to that in Description 4. This was converted to the monomaleate salt m.p. 165- 167 - diastereoisorner A.

Found: C, 68.97; H, 6.82; N, 7.33% C 2_ _n 2H 2_6,N 2_04. requires: C, 69.09; H, 6.85; N, 7.32%.

'

Description 11

5 ^' , 6-Dihydro-6-Tl-(ρhenylmethylamino) ethyl] -TlH-dlbenzo

[b , e ] azepine

Diastereoisorner A (Dll)

The title compound was obtained from D9, using a method similar to Description 4, in 77% yield after column chro - atography on silica gel eluted with ether. After recrys- tallisation from acetone/ether the monomaleate salt had m.p. 184-186 - dias ereoisorner A.

Found: C, 73.09; H, 6.39; N, 6.27% requires: C, 72.95; H, 6.35; N, 6.30%

Description 12

5 , 6 -Dihydro-6- [ 1- (me thy lamino) propy 13 -llK-dibe z [b , e ] azepine

Diastereoisorner A (D12)

(D12)

The title compound was obtained from the brornopropyl compound D7 in 35% yield using a method similar to that in Descriptions 3 and 4.

I c 04 PCT/GB83/00353

Description 13

5,6-Dihydro-6-[l- ^" (ethylamino)ethyl]-llH-dibenzo{b,e]azepine Diastereoisorner B (D13)

(D13)

Using a similar procedure to that in Description 5 a 1:2 mixture of the two diastereoisomers A and B was obained from the imine D8. Column chromatography on Kieselgel 60 eluted with ether gave:

Diastereoisorner A - identical to the compound obtained in Description 10.

Diastereoisorner B (D13) converted to monomaleate salt m.p. 171-173°.

Found: C, 68.76; H, 6.92; N, 7.25% C,„H N„ 0 _λ

' ' 22 26 2 4 requires: C, 69.09; H, 6.85; N, 7.32%

Description 14

5 ,6-Dihydro-6- [-1- (phenylmethylamino) ethyl 3 -HK-dibenzo

Tb,e 3azepine

Diastereoisorner B (D14)

- - IT--

Using a similar method to that in Description 5 a mixture of the two diastereoisomers was obtained from the imine D9. Column chroma ography on Kieselgel 60 eluted with ether gave:

Diastereoisorner A (Dll) obtained in 58% yield. A sample converted to the monomaleate salt, recrystallised from acetone/ether had m.p. 184-186 .

Found: C, 73.09; H, 6.39; N, 6.27% C„^H_ _Q N 0. requires: C, 72.95; H, 6.35; N, 6.30%

Diastereoisorner B (D14) obtained in 32% yield.

Conversion to the monomaleate salt, recrystallisation from acetone/ether had m.p. 151-154°.

Found: ^' C, 72.51; H, 6.34; N, 6.43% C._H_ _Q N_0.

2 I 2 o 2 4 requires: C, 72.95; H, 6.35; N, 6.30%

Description 15

2-Chloro-N-[ ^• 4-chloro-2- ^" (phenylmethyT)pheny1]propanamide (D15)

A solution of chlorine in acetic acid (0.57M, 177ml, 101 mmol) was added to a stirred solution of the anilide Dl

(25g, 92 mmol) in acetic acid (1.5 litre) containing sodium acetate (8.25g, 101 mmol) and left at 20°C for 21h. Acetic acid was then removed under reduced pressure, the residue taken up in ethyl acetate (500ml) , washed with aqueous sodium carbonate (10%, 3 x 200ml) brine,

(200ml) and dried (MgSO .) . Evaporation ir vacuo gave a crude reaction product which was purified by chroma- tography on silica gel, eluting with dichloro e th e in pentane, initially using 25% and gradually increasing to 50%. Combination of appropriate fractions gave- the title compound (20.3g; 72%) m.p. 150-151°.

NMR δ _H (CDC1 ₃ ) : 7.85 (1H, d, 10Hz, aromatic); 7.0-7.4

(8H, m, aromatic); 4.38 (1H, q, 7.5Hz, CHC1); 3.97 (2H, s, CH ₂ ); 1.65 (3H, d, 7.5Hz, CH ₃ ) .

Description 16

2-Chloro-6-[ -(methy amino) ethyl] -TlH-dibenzό [b , el azepine

The chlorocompound D15 was converted into the title compound in 59% yield using a method similar to that in Descriptions 2 and 3.

NMR δ „ (CDC1- : 7.0-7.4 (7H, m, aromatic) , 3.9 (1H, q, 7Kz, CHCH ₃ ), 3.4 (2H, s) , 2.3 (3H, s), 1.25 (3H, d, 7Hz, CHCH ) .

Description 17

2-Chloro-5 , 6-dihydro-6- [ 1- (methyla.mino) ethyl] -llK-dibenzo

[b,e ]azeoine

Diastereoisorner A (D17)

The title compound was prepared from D36 by a similar method to Description 4. The crude reaction product was chromatographed on silica, using 4% ethanol-ethylacetate Combination of the appropriate fractions follovved by trituration with methanol gave a light yellow solid in 50% yield.

OMPI

NMR δ„ (CDC1-) 6.95-7.4 (6H, m, aromatic), 6.74 (1H, a i d, 5Hz, aromatic), 4.6 (1H, d, 14Hz, H-ll) 4.4 (1H, d, 4.7Hz, H-6), 3.45 (1H, d, 14Hz H-ll), 2.9-3.25 (1H, , CHCH.-,), 2.55 (3H, s) , 1.27 (3H, d, 6Hz, CHCiy.

Description 18

2-Chioro-5 , 6-dihydro-6- [ 1- (methyl amino ) ethyl ] -llH-dibenzo [b,e]azepine Diastereoisorner B (D18)

Using a procedure similar to that of Description 5, treatirient of D16 gave a 40:60 mixture of the two dias- terioiso ers A and B (Rf's 0.3 and 0.1 respectively on Si0_ 5% methanol-ethyl acetate) . Trituration of the crude product with ether gave pure diastereoisorner B as a solid (38% yield) .

NMR ό r„i (CDC1 j_): 6.85-7.35 (7H, m, aromatic), 6.48 (1H, d, 8.7Hz) , 4.4 (1H, d) , 4.25 (1H, d, 15Hz) , 3.9 (1H, d, 15Kz) , 3.0-3.4 (1H, m) , 2.56 (3H, s, CH ₃ ), 1.1 (3H, d, 6Kz, CHCH ) .

Description 19

ll-(T-MethylamihθethyT) ibenzo[b-, f ] [ , 4] oxazepine' (D19)

11- (1-Methylaminoethyl) dibenzo[b,f ] [1, 4]oxazepine was obtained in a similar manner to that in Descriptions 1, 2 and 3. The crude free base was converted to a mono _¬ maleate salt m.p. 152-62 .

Purification ^' was limited to thoroughly washing the crystals with acetone.

NMR ^< 5 H _TT : 7.2-7.9 (8H, m, aromatic);

(monomaleate salt) 6.0 (2H, s);

4.95 (1H, q, 9Hz) ;

2.80 (3H, s);

1.42 (3K, d, 9Hz);

Found: C, 64.67; H, 5.51; N, 7.57%. ^C 2o ^H 20 ^N 2°5 requires: C, 65.21; H, 5.47; N, 7.60%.

Description 2Q

10 ^" , ^• 11-Dihydro-ll- ( l-methylaminoethyl) dibenzo [b , f] [ 1 , 4] oxazepine diastereoisorner A (D20 )

11- (1-methyla inoethyl)dibenzo[b,f] [1,43oxazepine (5g, 20 mmol) in ethanol (200 ml) containing platinum oxide (200 mg) was hydrogenated at atmospheric pressure until uptake of hydrogen ceased. Catalyst was removed by filtration through Celite and the solution concentrated under reduced pressure to give a product which was shown by t.l.c. and n.m.r. to be a single isomer-diastereoisomer A.

NMR δ„ (CDC1_) : 6.3-7.2 (8H, m, aromatic) , 3.9 (1H, d, 9Hz) , 3.5 (1H, ) , 2.32 (3H, s) , 1.46 (3H, d, 6.5Hz).

This was converted into a monomaleate salt and recrystal¬ lisation from methanol/ether gave 10, 11-dihydro-ll- (1- methylaminoe hyl)dibenzo[b,f] [1,4 oxazepine monomaleate diastereoisorner A, m.p. 176-82 .

Found: C, 64.51; H, 5.83; N, 7.63%. ^C ₂ 0 ^H 22 ^N 2°5 requires: C, 64.85; H, 5.99; N, 7.63%.

Description 21

1 ⁰ , ir- ^D ihy ro-11- ⁽ -meth ^y Taminoe thyl) dibenzot _b -, f ] [ ₁ 41 - oxazepine diastereoisorner B (D21)

^A ccor ^d in ^g to the method given in Description ₅ , ₁ 1- _(l - m ^e t ^h y ^la m ⁱ n ^oe t ^h yl ^)d i ^b enzo[b,f] [1 , 4 ]oxazepine was treate _d with so ^d ium cyanoborohydride to give a 40 _:60 mixture of the two ^d iastereoisomers A and B [R _f 0.1 _{5 and 0} . _{07 o} n ^S i ⁰ ₂ / ^E t ^0A c/ ^M e ⁰ H ⁽ 95:5)] and these were isolated _b y _c hro - ato ^g raphy on silica gel, eluting with et _h y _{l ace} tat _e . ^T he first to elute, diastereoisorner A, was shown to be ^iden t ^ica l ^w ith the compound obtained in De _s cri _p tion ₅ . ^T he secon ^d to elute was diastereoisorner _B an _d this was obtained in 31% yield.

^N MR δ _H ⁽ CDC1 ₃ ⁾ : 6.15-7.3 (8H, m, aromati _c ), ₃ . _{75 (1H} , ^d , 9Hz ⁾ , 3.25-3.6 (1H, m) , 2.3 (3 _H , s ₎ , 0.85 (3H, d, 6Hz).

^Th is w ^a s ^c onverte ^d to a monomaleate salt. Recrystallis _¬ at ⁱ on from met ^ha nol gave 10, 11-dihydro-ll- ( ₁ - _rne thyl _a mino- ethyl ⁾ dibenzo ^[ b,f ^{] [} 1, ] xazepine monomaleate _d iast _e r _e o _¬ isorner B, m.p. 169-73°.

Found: C, 65.16; H, 6.18; N, 7.6 ₃ %. _{C H N 0} requires: C, 64.85; H, 5.99; N, ₇ . _56% .

Description 22

2-Broao-N-[ 2- ( phenylth o) henyl-] ropahamide- ^• (D22 )

(D22)

The title compound was prepared from 2-phenylthio- benzenamine and 2-broιrιopropionyl bromide in 65% yield using a method similar to that of Description 1.

NMR δ _R (CDC1 ₃ ): 8.45 (IH, m, aromatic), 7.05-7.8 ( 8H , m, aromatic), 4.40 (IH, q, lOHz, CHBr) , 1.78 (3H, d, 10Hz, CHCK ₃ ) .

Description 23

11-[1-(Methylamino)ethyl]dibenzo[b,f] [1, ]thiazepine (D23)

(D23)

The title compound was prepared in 27% yield from 2-bromo- N-[2-(phenylthio)phenyl]propanamide D22 using a method similar to that in Descriptions 2 and 3.

NMR _H (CDC1 ₃ ) : 7.04-7.50 (8H, m, aromatic), 3.90 (IK, q,

7Hz, CHCH ₃ ) , 2.65 (3H, s, NCH.J , 1.30 (3H, d, 7Hz, CHCH ₃ ) .

A portion of the title compound was converted into a mono¬ maleate salt, m.p. 179.5-184.5 (dec.) (from acetone).

Found: C, 61.97; H, 5.06; N, 7.20 C ₂₀ H ₂₀ N ₂ 0.S requires: C, 62.48; H, 5.24; N, 7.29%.

-^TJS-E

De s crip i on 24 lOyn-Dlhydro-Tl- . l- (mfethyTamino) eth ] dibenzo ^' lb , f ] [ 1 , 4 ] thiazepine Diastereoisorner A (D24 )

(D24)

The title compound was prepred from the imine D23 in 79% yield using a procedure similar to the one outlined in Description 4.

Purification was carried out on silica gel using ether and increasing the polarity of the eluent to 1% methanol ether.

NMR δ^ (CDC1.,): 6.50-7.60 (8H, m, aromatic), 6.60 (IH, d,

8Hz, H-6) , 3.50-3.85 (IH, m, CH-CH ₃ ) , 2.45 (3H, s, NHCH ₃ ), 1.30 (3K, d, 6Hz, CHCH_ ₃ ) .

A portion of the title compound was converted to a mono¬ maleate salt, m.p. 165-168 (from acetone) .

Found: C, 62.21; H, 5.86; N, 7.25%, ^c ₂ o ^H 22 ^N 2°4 ^S requires: C, 62.16, H, 5.74, N, 7.25%.

- -yr--

uescrip ion 25

10 , ll-Dihydro-lT-[ 1- (methylamino) eth l] dibenzoTb', f ] thiaze¬ pine Diastereoisorner B ^' (D2'5)

(D25)

The imine D23 was reduced using sodium cyanoborohydride according to the procedure outlined in Description 5 to give a 64:36 mixture of the two diastereoisomers A and B. Chromatography on silica gel using 5% methanol-ethyl acetate as eluent separated the diastereoisomers to give the title compound.

NMR δH„ (CDC1,-i) 6.40-7.60 (8H, , aromatic), 6.55 (IH, d, 8Kz, H-6), 3.35-3.65 (IH, m, CHCH.,), 2.40 (3H, s, NHCH ₃ ), 1.07 ( 3H , d, 6Hz, CHCH ^' ₃ ) .

Description 26

2-Chloro-N- [2- (N' -methyl-N '-phenyl) aminophenyljpropanamide

(D26)

A solution of N-methyl-N-phenyl-1,2-benzenediamine (16.13g, 0.081 mol) in dry toluene (100ml) containing pyridine (10ml) was immediately cooled in an ice-bath and

2-chloropropionyl chloride (11.38g, O.090mol) added over 0.5h at such a rate that the reaction temperature did not exceed 5 .

After stirring .for c 18h, solvent was evaporated under reduced pressure and the solid residue partitioned between dichloromethane and water. The organic phase was washed with IN hydrochloric acid, water, saturated brine, and dried (MgSO .) . Removal of solvent in_ vacuo afforded a crude product which was purified on silica gel using 5% ether - 60-80 petroleum ether as eluent to give the title compound (7.86g, 30%).

NMR δ„ (CDC1-.) : 6.40-7.27 (9H, , aromatic) , 4.27 (IH, q, H ~>

7Hz, CHCH ₃ ) , 3.13 (3H, s, NCH , 1.60 (3H, d, 7Hz, CHCH ₃ ).

Description 27

5-Methyl-ll-[ (1-methylamino) ethyl] -5H-dibenzo Tb,e ] [1, 4-3 diazepine (D27)

The title compound was prepared from D26 in 64% yield using a procedure similar to the one outlined in Descriptions 2 and 3.

NMR δr„i (CDC1J-.): 6.70-7.27 (8H, , aromatic), 3.37 (IH, q,

6Kz, CHCH ₃ ) , 3.10 (3H, s, NCH ₃ ) , 2.47 (3H, s, NHCH ₃ ), 1.22 (3H, d, 6Hz, CHCH ₃ ).

A portion of the title compound was converted into the monomaleate salt, m.p. 145-155 (dec.) (from acetone).

Example 1

1,2-Dime hy1-2,3,9,13b-tetrahydro-lH-dibeh'Zo[p,f]imidazo

[1,5-a]azepine

Diastereoisorner A (El)

Formaldehyde (1.9 ml of 37% solution in water, 15mmol) was added to the amine D4 diastereoisorner ^' A (2.5g, 10 mmol) in ethanol { 40 ml) with ice-cooling. After lh, ethanol was removed under reduced pressure and the residue partitioned between dichloromethane (50 ml) and water (30 ml). The aqueous layer was extracted with dichloromethane (2x10ml) and the combined dichloro- ethane extracts washed with brine (25 ml) and dried (MgSO .) . Evaporation _in vacuo, followed by filtration through a silica gel column (20g) , eluting with ether, gave the title compound (2.6g, 98%).

NMR δ H (CDC1_): 6.60-7.20 (8H, , aromatic);

4.65 (IE, d 13Hz, H-9); 4.35 (IK, d 7Hz) ; 4.20 (IH, d 3.5Hz) ; 3.80 (IH, d 3.5Hz) ; 3.45 (IH, d 13Hz, H-9) ;

2.85-3.35 (IK, m, H-l) ; 2.52 (3H, s, NCH ₃ );

0.95 (3H, d 7Hz, CHCH_ ₃ )

This was converted to a monomaleate salt, m.p. 182-4° (recrystallisation from acetone) .

Found: C, 69.50; H, 6.26; N, 7.14%. ^C ₂ 2 ^H 24 ^N 2°4 requires: C, 69.46; H, 6.36; N, 7.36%.

Example 2

1,2-Dimethyl-2,3,9,13b-tetrahydro-lH-dibenzo[c,f3imidazo

[l,5-a3azepine

Diastereoisorner B (E2)

This was prepared as outlined for Example 1 from the amine D5 diastereoisorner B in 98% yield.

NMR δ (CDC1 ₃ ) : 6.1-7.3 (8H, m, aromatic);

5.22 (IH, d 9Hz);

4.89 (IH, d 14Hz, K-8) ;

4.39 (IH, d 4Hz) ;

3.78 (IH, d 4Hz) ;

3.36 (IK, d 14Hz, H-9); 2.9-3.3 (IH, , H-l);

2.47 (3H, s, N-CK ) ;

1.37 (3H, d 6Hz, CHCH ) ;

Conversion to a monomaleate salt, followed by recrystal¬ lisation from acetone gave 1, 2 -dime thy 1-2 , 3 , 9 , 13b-tetra- hydro-dibenzo [c , f 3 imidazo [ 1, 5-a ] azepine monomaleate diastereoisorner B m.p. 169-73 .

Found: C, 69.55; H, 6.46; N, 7.27%. C^H^N^ requires: C, 69.46; H, 6.36; N, 7.36%.

\ϊiE

Example 3

2-E thy l-l-me'thyl-2-, 3 , S, 13b-t trahydro-lH-dibenzo [ c , f ] imidazo

[1,5 -a ] a z ep i e

Diastereoisomer A (E3)

The title compound was prepared from the amine D10 using a method similar to that in Example 1 and converted into a monohydrogen maleate, m.p. 173-175 (from acetone-ether)

Found: C, 70.74; H, 6.68; N, 6.94 C 2_3,H- 2 _c 6N 2-04. requires: C, 70.03; H, 6.64 and N, 7.10%

Found: M ⁺ 278.1771 Calc. for ₁₉ H ₂₂ N ₂ 278.1783

Example 4

2-Ethyl-l-methyl-2 , 3,9 , 13b-tetrahydro-lK-dibenzo _. [c, f 3 imidazo

[l,5-a3azepine

The title compound was prepared from the amine D13 using a method similar to that in Example 1 and converted into a monohydrogen maleate, m.p. 108-110 .

Found: C, 66.93; H, 6.46; N, 6.71 ^C ₂ 3 ^H 26 ^N 2°4 * ^H 2° requires: C, 66.99; H, 6.79 and N, 6.79%

Found: M 278.1774 Calc. for C ₁₉ H ₂₂ N ₂ 278.1783

Example 5 l-Methyl-2--(phenylmethyl) -2, 3 , 9 ,13b-tetrahydro-lH-dibenzo

[ c , f ] imidazo [ 1 ^' , 5 -a ] azepine

Diastereoisorner A (E5)

The title compound was prepared from the amine Dll using a method similar to that in Example 1 and converted into a monohydrogen maleate, m.p. 167-170 (from methanol- ether) .

Found: C, 73.84; H, 6.27; N, 6.10 ^C 28 ^H 28 ^N 2°4 requires: C, 73.66; H, 6.18 and N, 6.14%

Found: M 340.1941 Calc. for C 2 340.1939

Example 6 i-Methyl-2- ( pheny Ime thy 1) -2,3,9, 13b, tetrahydro-lK-άibenzo

[c, f ] imidazo [1,5-a] azepine

Diastereoisorner B (E6)

The title compound was prepared from the amine D14 using a method similar to that in Example 1 and converted into a monohydrogen maleate, m.p. 99-101° (from acetone-ether).

Found: M 340.1941 Calc. for ^C 24 ^H 24 ^N 2 340.1939

Example 7 l-EthyT-2-miethy T-2 ^" , 3 ^' , 9 ^" , 13b-tetrahyaro-lH-dibenzo [ c ,f ] imidazo [ , 5 -a] azepine

Diastereoisorner A (E7)

The title compound was prepared from the amine D12 using a method similar to that in Example 1 and converted into a monohydrogen maleate, m.p. 188-190 (from methanol-ether)

Found: C, 70.02; H, 6.72; N, 7.03 ^C 3 ^H 26 ^N 2°4 requires: C, 70.03; H, 6.64 and N, .7.10%

Found: M ⁺ 278.1780 Calc. for ^gH^^ 278.1783.

^{^} ζϋ ^liE

Example 8

7-Bromo-l , 2-dimethyl-2 , , 9 , 13b-tetrahydro-lH-dibenzo [ c , f ] imidazo[1 ^" ,5-a]azepine (E8)

Pyridine hydrobromide perbromide (1.54g, 48mmol) was added to an ice-cooled, stirred solution of Example 1 (1.06g; 4 mmol) in chloroform (40ml). After lhr, 5% aqueous sodium carbonate (20ml) was added and the aqueous layer extracted with dichloromethane (2 x 10ml) „ The combined organic layers were washed with brine (20ml) and dried (MgSO ) . ^• Evaporation irι_ vacuo, followed by chromatography on silica gel, eluting with ether gave the title compound (860mg, 63%) as a light brown gum.

NMR δ _R (CDC1 ) : 6.9-7.35 (6H, m, aromatic), 6.68 (IH, d,

9Hz) , 4.63 (IH, d, 15Hz) , 4.55 (IH, d, 7.5Hz), 4.25 ^' (IH, d, 4Hz) , 3.83 (IH, d, 4Hz) , 3.5 (IH, d, 15Hz) , 3.1-3.22 (IH, m) , 2.6 (3H, s, N-CH ) , 0.98 (3H, d, 7Hz, CHCK ₃ ) .

Found: M ⁺ 342.0721 Calc. for C gH^ ^r 342.0732.

This was converted to a monomaleate salt, m.p. 160-4 (from methanol/ether) .

= T5~ -

Example 9

2 , 3-Dimethy 1-2, 3 , 9- 3b-tefrahydro-lH-dibenzo [ c , f 1 imidazo

[1,5 -a ] a zepine

Diastereoisorner A (E9)

Freshly distilled acetaldehyde (402mg, 510μl, 9.1mmol) was added to a stirred solution of 5 , 6-dihydro-N-methyl- llK-dibenz [b ,e] azepine-6-methanamine (2g, 8.3mmol) in dichlorome thane (30ml) at 0 containing p_-toluenesulphonic acid (lOO g) . After 2hr at O and 30 min at 20 , water

(20ml) and 10% aqueous sodium carbonate (10ml) were added and the aqueous layer extracted with dichlorome thane (20 ml) . The combined organic layers were washed with brine

(30ml) , dried (MgSO.) and evaporation in_ vacuo gave a yellow gum. Trituration in ether gave a solid (436mg; 20%) which was shown by NMR to contain 95% diastereo¬ isorner A plus 5% diastereoisorner B.

For Diastereoisorner A (E9):

KMR δ„ (CDC1-) : 6.85-7.-3 (6H, m, aromatic), 6.3-6.7

(2H, , aromatic), 5.52 (IH, m) , 4.6 (IH, d, 14Kz) , 4.2 (IH, q, 5Hz, CHCH ) , 3.5 (IH, ) , 3.35 (IH, d, 14Hz) , 2.95 (IH, ) , 2.57 (3H, s, NCH ₃ ), 1.4 (3H, d, 5 Hz, CHCH,) .

Found: M ⁺ 264.1633 Calc. for C ₁₈ ^H ₂₀ ^N ₂ 264.1626

For Diastereoisorner B:

NMR _R (CDC1 ₃ ) : 2.53 (3H, s, NCH ₃ ), 1.25 (3H, d, CHCH ₃ ) .

^"~ 46 ^"" - ^'

Example IP

7-Chloro-1,2-dimethyl-2,3,9, 3b-tetrah dro-lH-dibenzo

[c,f]imidazo[1,5-a]azepine Diastereoisomer A (E10)

The title compound was obtained from Diastereoisomer A D17 in a similar manner to Example 1 in 90% yield.

N.MR _β (CDC1 ₃ ) :

The title compound was converted into a monomaleate salt.

Found: C, 63.58; H, 5.59; N, 6.44; Cl, 8.62. C^H^N^Cl Requires: C, G3.69; K, 5.59; N, 6.75 and Cl, 8.55%.

Example 11

7-Chloro-1,2-dimethy1-2 ^' ,3,9 , 3b-te rahydro-lH-dibenzo [c,f]imldazo[1 ^' ,5-a]azep ^' ine Diastereoisomer B (Ell)

The title compound was obtained from Diastereoiso er B D18 in a similar manner to Example 1 in 84% yield.

^■ The ^" title compound was converted into a monomaleate salt.

Found: C, 63.38; H, 5.56; N, 6.44; Cl, 8.54. ^C ₂ 2 ^H 23 ^N 2°4 ^C1 Reσuires: C, 63.69; H, 5.59; N, 6.75 and Cl, 8.55%.

Found: M ⁺ 298.1242 Calc. for C^H^ ^l 298.1236.

Example 12

1 , 2 -Dime thy 1-1,2,3 ^" , 13b -te trahy dro-diben zo I b ^" , f ] imi dazo [l,5-d][T, ] oxazepine ^" monohydrogen- maleate Diastereoisomer ^" A ^" (E12)

The title compound was prepared from the amine D20 using a method similar to that of Example 1, m.p. 147- 149 (from acetone-ether) .

Found: C, 66. OO; H, 5.93; N, 7.34 C

21 ^H 22 ^N 2°5 requires: C, 65.96; H, 5.80; N, 7.32 ^!

Example 13 , 2-Dimethyl-l , 2 , 3 ^" , 13b-te trahy dro-dibenzoib , f Timidazό [ 1 , 5 -d ]

[1, '4 ^' ] oxazepine monohydrogen" maleate

Diastereoisomer B (E1 ^' 3) ^'

The title compound was prepared from the amine D21 using a method similar to that of Example 1, m.p. 148-149 (from acetone) .

Found: C, 65.82; H, 5.84; N, 7.28 C _2l H _{22 2} 0 requires: C, 65.96; H, 5.80; N, 7.32%.

" Example ^" 14 T, 2-Dimethyl-l, 2, ,-3b-tetrahydrodibenzo[b,f ] imidazo [T,5-d ^' ][T, 4] thiazepine Diastereoisomer A (E14)

The title compound was prepared from D24 in 79% yield using a procedure similar to the one outlined in Example 1.

NMR „ (CDCl-.): 6.20-7.70 (8H, m, aromatic) , 6.52 (IH, d, ri .3

5.9Hz), 4.27 (IH, -d, 4Hz, H-3), 3.63 (IH, d, 4Hz, H-3) , 2.80-3.1 (IH, , H-l), 2.45 (3H, s, NHCH ₃ ) , 1.37 (3H, d, 7Hz, CHCH ) .

This was converted to a monomaleate salt, m.p. 160-165° (from acetone) .

Found: C, 63.36; H, 5.58; N, 7.04% ^c ₂ ι ^H 22 ^N 2 ^S °4 requires: C, 63.30; H, 5.57; N, 7.03%.

Example' 15

1, 2-Dimethyl-l , 2 ^" , 3 ^" , ^• 13b ^" -tetrahyaro ^" dibenzo ^" [b ^" , f ] imidazo

[ l , 5-d] [ , 4 ] thiazepine

Diastereoiso er B (E15 )

The title compound was prepared from D25 in 62% yield using a method similar to that of Example 1.

NMR δ (CDC1 ₃ )

H 6.15-7.70 (SH, m, aromatic), 6.15 (IH, d, 8.6Hz) , 4.32 (IH, d, 4Hz, H-3), 3.87 (IH, d, 4Kz, H-3), 2.90-3.30 ^" (IH, m, CHCH ₃ ), 2.47 (3H, s, NCH _j ) , 1.26 (3H, d, 6Hz, CHCH ) .

This was converted to a monomaleate salt, m.p. 149-154 (from acetone) .

Found: C, 63.30; H, 5.62; N, 7.05% ^c ₂ ι ^H 22 ^N 2 ^S °4 requires: C, 63.20; H, 5.57; N, 7.03%.

Example 16

1', 2", 3 ^" , 13b-Tetrahydro-T, 2 , 9-trimethyl-5H-dibenzo [b , f ] imidazo ^" . X, 5 -d ] [ 1 ^" , 4 ] diazepine

Diastereoisomer A (E 16 )

The title compound was prepared from the imine from Description D27 using a combination of the procedures outlined in Description 5 and Example 1.

NMR δ H (CDC1 ₃ ) 6.33-7.10 (8H, m, aromatic), 4.80 (IH, d, 7Hz, H-14), 4.17 (IH, d, 5Hz, H-3), 3.70 (IH, d, 5Hz, H-3), 3.22 (3H, s, ArN-CH , 2.77-3.22 (IH, m, CHCH ₃ ) , 2.63 (3H, s, NCH_ ₃ ) , 1.06 (3K, d, 7Hz, CHCH ) .

This was converted to a monomaleate salt.

Example 17

1,2,3,13b-Tetrahydro-l,2,9-trimethyl-5H-άibenzo[b,f] imidazo[l,5-d] [1, 4]diazepine

Diastereoiso er B (E17)

The title compound was prepared from the imine Descrip¬ tion D27 using a combination of ϊ e procedures outlined

in Description 5 and Example 1.

NMR (CDC1 ₃ ): 6.10-7.90 (8H, , aromatic), 5.45 (IH, d,

9.2Hz, H-14), 4.30 (IH, d, ^" 4Hz, H-3), ^' 3.83 (IH, d, 4Hz, H-3), 3.25 (3H, s, Ar N-CH ₃ ) _# 2.85-3.30 (IH, m, CHCH...) , 2.45 (3H, S, NCH ₃ ), 1.30 (3H, d, 7Hz, CHCH ₃ ) .

This was converted to a monomaleate salt.

Pharmacological Data

) Compounds of the invention inhibit the behavioural symptoms induced by 5-methoxy-N,N-dimethyl tryptamine (5-MDMT) , a central 5-hydroxytryptamine agonist, and are central 5KT antagonists. As such they would be expected to possess antidepresεant, (Ogren, S O, Fuxe, K, Agnati, F, Gustafsson J A, Jonεson, G, and Holm A C, 1979, J Neural Trans, 4_6_, 85-103) and/or anxiolytic (Stein, L, Kline, D, and Bellugi, J D, 1975, in Advances in Biochemical Ps chophar acology, ed Costa, E, and Greengard, P, Vol 1_4, 29-44, Raven Press, NY) activity.

Method

Mice (C> CD-I Charles River ) are pretreated with the compounds ( 10 animals/group) under invest gation and lh later are injected v. _' i th 10 mg/kg i . p . 5-methoxy-N ,N- n ime thy 1 tryptamine (Sigma ) . The symptoms of fore-paw tapping movements , head jerks and splayed limbs are scored : 1 , present; 0 , absent , giving a maximum score of 3/mouse or 30/group . Results are expressed as the percentage inhibition compared to the group treated with 5-methoxy-N ,N-dimethyl tryptamine alone . The dose of compound inhibiting the symptoms by 50% i s determined graphically .

The results are shown in Table 1.

Table 1

Inhibition' of' 5-MDMT ^' induced" symptoms' in" the' mouse

ED ₅₀ g/ g p.o. or % inhibition

Compound at dose

1 , 2-Dime hy 1-2, 3,9, 13b-te trahy dro-lH- 4.3 dibena?[c, f 3 imidazo [ 1,5 -a 3 zepine diastereo¬ isomer A (Compound El)

1, 2-Dime thyl-2, 3,9 , 13b-te trahy dro-lH- 10 dibenzo[c, f 3 imidazo [1,5 -a 3 azepine diastereo¬ isomer B (Compound E2)

2-Ethyl-l-me hyl-2 ,3,9, 13b-tetrahydro- 1.6 lH-diben_p[c, f 3 imidazo [ 1,5-a] azepine dias ereo¬ isomer A (Compound E3)

2-Ethyl-l-methy 1-2 ,3,9, 13b-tetrahydro-lK- 41% at 10 dibenz?[ c , f 3 imidazo [1 , 5-a ] azepine , diastereo¬ isomer B (Compound E4)

1-Me thyl-2- (pheny Ime thyl) -2,3,9, 13b-tetra- 46% at 10 iιydro-lH-dibenz?[ c, f 3 imidazo [ 1, 5-a 3 azepine diastereoisomer A (Compound E5) l-Ethyl-2-me thyl-2 ,3,9, 13b-tetrahydro-lH- 61% at 10 dibenza[c, f] imidazo [1,5-a ] azepine, diastereo¬ iso er A (Compound E7)

^{" " " "} - ^~ iϊ ^~ - ^~

Blockade of presynaptic α ₂ -adrenoceptors ^on noradrenergic neurons effects an increase in intrasynaptic noradrenaline, and thus in the central nervous system could be expected to have an a tidep essant effect.

₃ ^" ) [ H]-clonidine binds to ₂ -adrenoceptor sites and inhibit¬ ion of this binding correlates with the blockade of' α_- adrenoceptors . In vitro inhibition by some of the present

3 compounds of the binding of [ H]-clonidine to isolated rat brain synaptic membrane fragment was therefore determined ) to provide an indication of antidepressant activity. This was carried out using standard biochemical binding study techniques, by the method of Maggi e_t al_. , Eur. J. Pharm. 1980, 6_1, 91. The parameter determined was the concen¬ tration of [ H]-clonidine binding. K. values have been determined, using the Cheng-Prusof f equation, from IC ^' 5 _t 0 values. The results are shown in Table 2 below.

Table 2

Co ^' mooun d K . nM

1

1 , 2 -Dime thy 1-2 ,3,9,13b- e trahy dro-lH- 23 dibensfc, f] imidazo [1,5 -a] azepine, diastereo¬ isomer A (Compound El)

1, 2-Dime thy 1-2, 3, 9 , 13b-te trahy dro-lK-dibenzo 126

[c, f ] imidazo [1,5-a] azepine, dias ereo¬ iso er B (Compound E2) l-Ethyl-2-methy 1-2 ,3,9, 13b-tetrah ro-lK- 67 dibenzo[c,f ] imidazo [1,5-a ] azepine, diastereo¬ iso er A (Compound Ξ7)

Pharmacological Data

Shock" Induced Suppression" of Drinking' In- the T.at

The shock induced suppression of drinking (SSD) test (adapted from Vogel e_t al., 1971) is considered a reliable and specific method for showing up potential anxiolytics.

20h .water-deprived rats (c^Hacking and Churchill, CFHB) , fajniliarised to the test apparatus the day before test, are allowed to drink for 30 sec and then receive 0.5m. sec. footshock, maximum 0.5mA, for every 5 sec of drinking time accumulated in a 3 in session. Drugs were administered, intraperitoneally, 30 min before test.-

The number of shocks taken during a given test period are recoroec and results expressed as percentage change from control. Anxiolytic drugs such as benzodiazepines release the behaviour of rats suppressed in this way, such that the number of shocks taken increases in a dose dependent manner.

J.R. Vogel et _al-, (1971) Psychopharmacologia (Ber ^' l.) 21., 1-7.

^• The results are shown in Table 3.

Toxicity

No toxi c effects were observed in these tests .

UfU&£ OMP

704

- 58 -

Table 3

- U &