WO1984002704A2

WO1984002704A2 - Tetracyclic compounds

Info

Publication number: WO1984002704A2
Application number: PCT/GB1983/000353
Authority: WO
Inventors: Anthony Christopher Connell
Original assignee: Beecham Group Plc
Priority date: 1982-12-30
Filing date: 1983-12-29
Publication date: 1984-07-19
Also published as: AU2416384A; JPS60500176A; WO1984002704A3; EP0130202A1

Abstract

Compounds of formula (I) or a pharmaceutically acceptable salt thereof wherein: X is CH2, O, S, or NR where R is C1-4 alkyl; R1 and R2 are independently selected from hydrogen, hydroxy, C1-4 alkyl, C1-4 alkoxy, halogen or CF3; R3 is C1-7 alkyl, C2-5 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl or C1-6 alkyl substituted by C2-7 alkenyl, C2-7alkynyl, C3-7 cycloalkyl, hydroxy, thiol, C1-6 alkoxy, C1-6 alkylthio, carboxy, C1-6 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 C1-6 alkyl groups, or benzoyl or phenyl either being optionally ring-substituted by one or two C1-4 alkyl, C1-4 alkoxy, halogen or trifluoromethyl; and one of R4, R5 and R6 is C1-6 alkyl and the other two are independently hydrogen or C1-6 alkyl, having anti-depressant and/or anxiolytic activity, a process for their preparation and their use.

Description


  
 



   TETRACYCLIC COMPOUNDS
 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):
EMI1.1     
  in which Ra and Rb are hydrogen, hydroxy, halogen, alkyl or alkoxy with 1-6 carbon atoms, acyloxy with 1-8 carbon atoms, or a trifluoromethyl group;
 Rc 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=CHgroup 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 anziolytic activity.



   Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically   acceptable    salt thereof:
EMI2.1     
 wherain:
 X is CH2, O, S or NR where R is C1-4 alkyl;
 R1 and R2 are independently selected from hydrogen, hydroxy,   C1-4    alkyl,   C14    alkoxy, halogen or
CF3;

  ;  
R3 is C1-7 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl or C1-6 alkyl substituted by C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, hydroxy, thiol, C1-6 alkoxy, C1-6 alkylthio, carboxy,   C16    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 C1-6 alkyl groups, or benzoyl or phenyl either being optionally   ring-substituted    by one or two
C1-4 alkyl, C1-4 aqlkoxy, halogen or trifluoromethyl; and
 one of R4, R5 and R6 is C1-6 alkyl and the other two are independently hydrogen or C1-6 alkyl.



     Then    X is   WR,    suitable examples of R include methyl,   methyl,    n- or   iso-propyl,    n, sec- or tert-butyl.



   Suitable examples of   R1    and R2 include hydrogen, hydroxy, methyl, ethyl; methoxy and ethoxy; fluoro, chloro, bromo; and CF3. Often   R1    and R2 will be hydrogen or 7-ha.lo, such as chloro bromo. -Preferably   R1    and R2 are both hydrogen.



  When R3 is C1-4   alkyl    substituted by   pherlyl    optionally substituted as hereinbefore defined,   examples    of such optional substituents include methyl,   ethyl,    methoxy, ethoxy, Fluoro, chloro, bromo or   t@ifluoromethyl.   



  Preferably, phenyl is unsubstituted.



     When    R3 is C1-4 alkyl substituted by amino optionally substituted as hereinbefore defined, examples of such optional substituents include methyl and ethyl and, together with the nitrogen atom, piperidino and   morphol ino.     



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



   When R4, R5 or R6 are hydrogen or C1-6 alkyl suitable values include hydrogen, methyl, ethyl, n- and iso-propyl, n, 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   aclds.   



   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   5    a group of compounds within formula (I) wherein R3 is C1-6 alkyl, C2-5 alkenyl,   C25    alkynyl,
C3-7 cycloalkyl, C5-7 cycloalkenyl or C1-4 alkyl substituted by   C37    cycloalkyl or phenyl or C1-6   alkyl    substituted by hydroxy,   C16      alkoxy,    carboxy, C2-7 alkanoyl, benzoyl or aminocarbonyl or am no optionally substituted by one or two C1-6   alkyl      groups    and the remaining variables are as defined in formula (I).



   A group of   compounds    within formula (I) is of formula   (II):   
EMI4.1     
  wherein R1Ú is hydrogen or halogen, one of R51 and R61 is C1-6 alkyl and the other is hydrogen or C1-6 alkyl; and X is as defined in formula (I).



   Suitable values for R1Ú, R51 and R61 are as described under formula (I) for relevant R1, R5 and   Rg.   



   Preferably one of R5Ú and R61 is hydrogen and the other is C1-6 alkyl. Preferably R1 is hydrogen.



   A sub-group of compounds within formula (II) is of formula (III) :
EMI5.1     
   wherein    R52 is C1-6   alkyl      nd    R1Ú is as defined in formula (II).



   Suitable   values    for R52 are as described for relevant R5 under formula (I).



   Preferably R5ê is methyl or ethyl, most preferably methyl.  



   A further sub-group of compounds within formula (II) is of formula (IV):
EMI6.1     
 wherein X1 is oxygen or sulphur; and
 Rll and R52 are as defined in formula (III).



   Suitable and preferred values for R11 and R52 are as described for relevant R1 and   R5    under formula (I).



   Preferably   R52    is methyl or ethyl, most preferably methyl.



   There is another sub-group of compounds within formula (II) of formula (V):
EMI6.2     
  wherein   X2    is NR as defined in formula (I) and R11 and
R52 are as defined in formula (III).



  Suitable and preferred values for Rll and R52 are as described for the corresponding variables under formula (I).



   There is another group of compounds within formula (I) of formula (VI):
EMI7.1     
 wherein R41 is   C16    alkyl and R11 is as defined in formula (II).



   Suitable values for R11 and R41 include those described under formula (I) for relevant R1 and R4.



   Preferably R41 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 redaction of a   compound    of   formula    (VII):
EMI7.2     
  with a compound of formula (VIII):
EMI8.1     
 wherein R3' is R3 or a group convertible thereto,   Ri,   
R2, R5 and R6 are as defined in formula (I), one of Y1 and Y2 is hydrogen and the other is R4 as defined or (when R4 In formula (I) is hydrogen), Y1 and Y2 together form an oxo or   thiocarbonyl    group; and Z1 and
Z2 are leaving groups, and thereafter reducing the resulting compound formed when Y1 and Y2 together form an oxo or   thiocarbonyl    group, and/or converting R3' to
R3 and/or forming a pharmaceutically acceptable salt.

 

   Z1 and Z2 are suitably groups which are readily displaceable by a secondary amino nucleophile.



   Favourable values for Z1 and Z2 when   ±1/Y2    are hydrogen and R4, include halo or hydroxy.   When    Y1 and   Y2 are    both hydrogen, reagents therefore include methylene chloride, methylene   brojnide    and   ethylene    diol (aqueous or ethanolic   formaldehyde).   



   Favourable values for Z1 and Z2 when Y1 and Y2 together are oxo or thiocarbonyl include halo,   C16    alkoxy, C1-6 alkylthio, amino optionally substituted by one or two C1-6 alkyl or C1-6 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 dimethylsulphoxide, sulfolane or acetonitrile are suitable.



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



   If Z1 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/Y2 are oxo or   thio is    normally carried out using a conventional reducing agent, such as metal hydrides eg. sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or diborane. Catalytic   hydrogenation    is   aso    suitable. It will be appreciated that, if R3' is a group susceptible to reducing agents,  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   C16    alkyl substituted by hydroxy into C1-6 alkyl substituted by thiol by, for example, first forming a
C1-6 halide, such as the chloride, and then reacting the C1-6 alkyl halide with potassium hydrogen sulphide, or into C1-6 alkyl subsituted by C1-6 alkoxy using, for example, sodium hydride and a C1-6 alkyl halide; the conversion of C1-6 alkyl substituted by thiol into C1-6 alkyl substituted by C1-6 alkylthio using, for example, a base and a C1-6 alkyl halide; the conversion of C1-6 alkyl substituted by C1-6 alkoxycarbonyl into C1-6 alkyl substituted by carboxy by hydrolysis;

   the conversion of C1-6 alkyl substituted by carboxy into   C16    alkyl substituted by aminocarbonyl optionally
N-substituted by one or two C1-6 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 C1-6   alkyl;    and the conversion of   C15    alkyl substituted by   a:nnocarbonyl    optionally N-substituted by one or two
C1-6 alkyl into C1-6 alkyl substituted by   amino      optonally    substituted by one or to C1-6 alkyl by reduction.



   Compounds of the   formula    (VII) may be   prepared    by reduction of a   compound    of formula (IX):
EMI10.1     
  wherein R1, R2, R3',   R5    and R6 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   OOC,    and a solvent such as ethanol is suitably used; and with lithium aluminium hydride low temperatures such as -800C to   OOC    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   inlay    be necessary to protect any carbonyl or   thlocarbonyl    groups during the reduction step.



   After the processes of the invention it will be appreciated that   21    and R2 groups may be varied. For  example a compound of formula (I) wherein R1 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:
EMI12.1     
 wherein L is a group readily displaceable by a   nucleophlle,    and other variables are as hereinbefore defined, by treatment with   HNR3'.   



   Suitable examples of L include halide, such as chloride or bromIde or activated ester such as mesylor   tosyloxy.   



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



   Compounds of the formula (I) have useful pharmacological activity, in that they have   ood-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 thereof and a pharmaceutically acceptable carrier.  



   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,   disintegrants,    and acceptable wetting agents. The tablets ;nay 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.   Advane.ageouslyt    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 my be utilized in conventional manner, for example in a manner similar to that already used for other   mood-nodifylng    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-modify-ng    compositions will   ost    suitably   b    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   r.tg,    such as 12.5, 15 and 20   ntg.    Such   compositions    will normally be taken from 1 to 6 times daily, for   Example    2, 3 or 4 tines 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   foll.oing    Descriptions intermediates thereto.  



  Description 1 2-Chloro-N-[2-(phenylmethyl)-phenyl]propanamide (D1) 2-Chloropropionyl chloride (41.91g, 0.33 mol) in sodiumdry 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 resultant precipitate was removed by filtration, washed well with water and then dissolved in   dichlorornethane    The solution was washed with water, saturated brine, dried
   (Na2S04)    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 -l   vmax    (nujol): 3250 (N-H) and 1663 (N.CO) cm
NMR   6H      (CDCl3):    6.90-7.40 (8H, m, aromatic);
 4.30   (1H,    q, 7Hz, CHCH3);
 3.90 (2H, s, CH2);
 1.60 (3H, d, 7Hz, CH3).  



  Description 2 6-(1-Chloroethyl)-11H-dibenzo[b,e]azepine (D2)
EMI17.1     

The anilide   D1    (40.95g, 0.15 mol) was added to polyphosphoric acid (409.5g) and the mixture was warmed to 1250 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 dichloromethane (3 x 1 litre) and the combined organic extracts were washed with brine and dried   (Na2S04).    Evaporation under reduced pressure gave crude   6-(l-chloroethyl)-llH-      dibenzotb,e)azepine    which on trituration with ether gave a product (34.7g, 91%) of sufficient purity for further reaction (see Description   3).   



      (nujol): 1618 (C=N) cm-1
 max      KMR      6H      (CDC13):    6.9-7.6 (8H, m, aromatic) ;
 5,2 (1H, q, 6.5Hz, CH) ;
 3.45 (2H, s, CH2);
 1.88 (3H, d,   6,5Hz,    CHCH3).  



  Description 3 6-[1-(Methylamino)ethyl]-11H-dibenzo[b,e]azepine (D3)
EMI18.1     

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 (2xlOOml), brine (lOOml) and dried   (Na2S04).    Evaporation in vacuo gave crude 6-[1-
 (methylamino)ethyl]-11H-dibenzo[b,e]azepine in 92% yield and this was used   immediately    without further purification as shown in Descriptions 4 and 5.



  NMR   dH    (CDCl3): 6.8-7.7   (813,    m, aromatic);
 3.9   (1,    q, 7Hz,   CffCH3);   
 4.5 (2H, s, CH2) ;
 2.5 (3H, s, NCH3) ;
 1.3   (313,    d, 7Hz, CH3).



  This was converted to the monomaleate salt, m.p. 1631710 (recrystallised from acetone).



  Found: C, 68.70; H, 6.06; , 7.56% ; C21H12N2O4.



  requires: C, 68.84; H, 6.05; N, 7.65%.  



  Description 4 5,6-Dihydro-6-[1-methylamino)ethyl]-11H-dibenzo[b,e] azepine
Diastereoisomer A (D4)
EMI19.1     

A solution of 6-(1-(methylamino)ethyl]-11H-dibenzo[b,e] azepine (10 mmol) in dry ether (20 ml) and dichloromethane (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.

 

     Wet    ether was then carefully added, hollowed by water and the resultant granular precipitate removed by filtration. The residue was washed with dichloromethane and the combined organic phases were washed with brine, dried
   (Na2S04)    and evaporation in vacuo gave the product
 (1.99g, 77%). This was shown by t.l.c. and n.m.r. to be a single isomer - diastereoisomer A.



  NMR   #H    (CDCl3): 6.2-7.4 (8H, m, aromatic)
 4.5 (1H, d, 14Hz, H-11)
 4.3 (1H, d, 5Hz, H-6)
 3.35   (113,    d, 14Hz, H-ll)
 2.7-3.2 (1H, m, CH-CH3)
   9.35      (313,    s, N-CH3)
 1.1 (3H, d, 6Hz, CH-CH3)
Conversion to a monomaleate salt followed by recrystallisation from acetone-ether gave the title compound m.p. 151-55 .  



  Found: C, 68.46; H, 6.57; N,   7.60%.    C21H24N204 requires: C, 68.33; H, 6.70; N,   7.27%.   



  Description 5 5,6-Dihydro-6-[1-methylamino)ethyl]-11H-dibenzo[b,e] azepine
Diastereisomer B (D5)
EMI20.1     

Sodium cyanoborohydride (3.16g, 50 mmol) in methanol
 (30 ml) was added dropwise to a solution of   6-t1-(methyl-    amino)ethyl]-11H-dibenzo[b,e]azepine   (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.



     linen    effervesence had ceased, the solution was concentrated 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   (Na2SO4).    Evaporation in vacuo save a   t5:55    mixture of the two diastereoisomers A and
B. (Rf 0.17 and 0.04 on   SiO2/EtOAc    respectively).



  Trituration of the crude product with ether-pentane gave diastereoisomer 3 as a solid (3.0g,   24g).   



  NMR   #H    (CDCl3): 6.25-7.2 (8H, m, aromatic) ;
 4.2   (1H,    d, 9Hz, C-6 CH);
 3.9 (2H, s, CH2);
 2.9-3.3   (1H,    m, CH CH3);
 2.4 (3H, s, NCH3);
 0.9 (3H, d, 7Hz, CH3);  
Conversion into a monomaleate salt followed by recrystallisation from acetone-ether gave 5,6-dihydro-6-[l(methylamino)ethyl]-11H-dibenzo[b,e]azepine monomaleate diastereoisomer B, m.p.   170-173 .   



  Found: C, 68.37; H, 6.54; N, 7.61%. C21H24N2O4 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 diastereoisomer B (3.12g, 25%) and pure diastereoisomer A (4.44g,   35%).    The latter was shown to be identical with the compound obtained in
Description 4.  



  Description 6 6-(1-Bromoethyl)-11H-dibenzo[b,e]azepine (D6)
EMI22.1     

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/60:800 petrol).



  Description 7 6-(1-Bromopropyl)-11H-dibenzo[b,e]azepine (D7)
EMI22.2     

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



  Description 8 6-[1-(Ethylamino)ethyl]-11H-dibenzo[b,e]azepine (D8)
EMI23.1     
 6-(1-Bromoethyl)-11H-dibenzo[b,e]azepine D6 (1.37g; 4.5 mmol) in ethylamine (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   (NgSO4)    and evaporated in vacuo. Column chromatography on Kieselgel 60 eluted with ether gave the title compound in 58% yield. This was converted to   he    monomaleate salt, m.p. 160-161  (from acetone).



  Found: C,   69.18;    H,   6.29;    N,   7.31    C22H24N2O4 requires: C, 69.46; H, 6.36; N, 7.36%
Description 9 6-[1-(Phenylmethylamino)ethyl]-11H-dibenzo[b,e]azepine (D9)
EMI23.2     

The bromoethyl   compound    D6 (lg,   3.3rol)    was dissolved in   DAF    (20ml) and potassium carbonate (0.54g, 3.9mmol) added. Benzylamine (0.42g, 0.46ml, 3.9nmol) was then added and the mixture stirred at 180 for 2.5 hours. Water was then added and product extracted into ether. Organic  phase washed well with water, dried (MgSO4) and evaporated 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, m.p.



  141-143  (from acetone/ether).



  Found: C, 73.29; H, 5.92; N, 6.29% C27H26N204 requires: C, 73.29; H, 5.92; N, 6.33%
Description 10 5,6-Dihydro-6-[1-(ethylamino)ethyl]-11H-dibenzo[b,e]azepine
Diastereoisomer A (D10)
EMI24.1     

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.    165167 -    iastereoisomer    A.



  Found: C, 68.97; H,   6.82;    N,   7.338    C22H26N2O4 requires: C, 69.09; H,   6.85;    N,   7.32.     



  Description 11 5,6-Dihydro-6-[1-(phenylmethylamino)ethyl]-11H-dibenzo [b,e]azepine
Diastereoisomer A   (Dll)   
EMI25.1     

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



  Found: C, 73.09; H, 6.39; N,   6-27t    C27H28N204 requires: C, 72.95; H, 6.35; N, 6.30%
Description 12 5,6-Dihydro-6-[1-methylamino)propyl]-11H-dibenzo[b,e] azepine
Diastereoisomer A (D12)
EMI25.2     

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

 

  Description 13 5,6-Dihydro-6-[1-(ethylamino)ethyl]-11H-dibenzo[b,e]azepine   Diastereoisomer    B   '(D13)   
EMI26.1     

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:
Diastereoisomer A - identical to the compound obtained in Description 10.



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



  Found: C, 68.76; H, 6.92; N, 7.25%   C22 H26N204    requires: C, 69.09; H, 6.85; N, 7.32%
Description 14 5,6-Dihydro-6-[1-(phenylmethylamino)ethyl]-11H-dibenzo [b,e]azepine
Diastereoisomer B (D14)
EMI26.2     
  
Using a similar method to that in Description 5 a mixture of the two diastereoisomers was obtained from the imine D9. Column chromatography on Kieselgel 60 eluted with ether gave:
Diastereoisomer A (D11) 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%    C27H28N204 requires: C, 72.95; H, 6.35; N,   6.308   
Diastereoisomer 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% C27H28N204 requires: C, 72.95; H, 6.35; N, 6.30%  
Description 15 2-Chloro-N-[4-chloro-2-(phenylmethyl)phenyl]propanamide (D15)
EMI28.1     

 A solution of chlorine in acetic acid (0.57M,   177ml,    101
 mmol) was added to a stirred solution of the anilide   D1   
 (25g, 92 mmol) in acetic acid (1.5 litre) containing
 sodium acetate (8.25g, 101 mmol) and left at 200C 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 (MgSO4).

  Evaporation in vacuo gave a
 crude reaction product which was purified by chroma-
 tography on silica   ael,    eluting with dichloromethane 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   dH    (CDC13): 7.85   (1H,    d, 10Hz, aromatic); 7.0-7.4
 (8H, m, aromatic); 4.38 (lH, q, 7.5Hz,
   CHC1);    3.97 (2H, s, CH2); 1.65   (3,    d,
 7.5Hz, CH3).  



  Description 16 2-Chloro-6-[1-(methylamino)ethyl]-11H-dibenzo[b,e]azepine (D16)
EMI29.1     

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



  NMR   6H      (CDC13):    7.0-7.4 (7H, m, aromatic), 3.9 (lH, q,
 7Hz, CHCH3), 3.4 (2H, s), 2.3 (3H, s),
 1.25 (3H, d, 7Hz, CHCH3).



  Description 17 2-Chloro-5,6-dihydro-6-[1-(methylamino)ethyl]-11H-dibenzo [b,e]azepine
Diastereoisomer A (D17)
EMI29.2     

The title compound was prepared from   D]6    by a similar method to Description 4. The crude   reaction    product   was    chromatographed on silica, using   At    methanol-ethylacetate.



  Combination of the appropriate fractions followed by trituration with methanol gave a light yellow solid in 50% yield.  



  NMR   dH    (CDCl3)   6.95-7 4    (6H, m, aromatic), 6.74   (1H,   
 d, 5Hz, aromatic), 4.6 (1H, d, 14Hz,   H-ll),   
 4.4 (1H, d, 4.7Hz, H-6), 3.45 (1H, d, 14Hz,
 H-11), 2.9-3.25 (1H, m, CHCH3), 2.55 (3H,
 s), 1.27 (3H, d, 6Hz, CHCH3).



  Description 18 2-Chloro-5,6-dihydro-6-[1-(methylamino)ethyl]-11H-dibenzo [b,e]azepine
Diastereoisomer B (D18)
EMI30.1     

Using a procedure similar to that of Description 5, treatment of D16 gave a 40:60 mixture of the two dias   terioisomers    A and B (Rf's 0.3 and 0.1 respectively on
Si02 5% methanol-ethyl acetate). Trituration of the crude product with ether gave pure   diastereoisomer    B as a solid (38% yield).



     NMR    6H (CDC13): 6.85-7.35 (7H,   m,    aromatic), 6.48 (1H,
 d, 8.7Hz), 4.4 (1H, d), 4.25 (1H, a,
 15Hz), 3.9 (lH, d, 15Hz), 3.0-3.4   (1H,   
 m), 2.56 (3H, s, NCH3), 1.1 (3H, d, 6Hz,
 CHCH3).  



  Description 19 11-(1-Methylaminoethyl)dibenzo[b,f][1,4]oxazepine (D19)
EMI31.1     
 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 monomaleate salt m.p. 152-62 .



  Purification was limited to thoroughly washing the crystals with acetone.



  NMR   #H    (d6-DMSO) : 7.2-7.9 (8H, m, aromatic) ;
 (monomaleate salt) 6.0 (2H, s);
   4.95    (1H, q, 9Hz);
 2.80 (3H, s);
 1.42 (3H, d, 9Hz);
Found: C, 64.67; H, 5.51; N,   7.57t.    C20H20N205 requires: C, 65.21; H, 5.47;   X,    7.60%.  
Description 20 10, 11-Dihydro-11-(1-methylaminoethyl)dibenzo[b,f] [1,4]oxazepine diastereoisomer A (D20)
EMI32.1     
 11-(1-methylaminoethyl)dibenzo[b,f][1,4]oxazepine (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   dH    (CDC13): 6.3-7.2 (8H,   m,    aromatic), 3.9 (lH, d,   9Hz),    3.5 (1H,   in) ,    2.32 (3H, s), 1.46 (3H, d, 6.5Hz).



  This was converted into a monomaleate salt and recrystallisation from methanol/ether gave 10, ll-dihydro-ll-(lmethylaminoethyl)dibenzo[b,f][1,4]oxazepine monomaleate   diastereoi.somer    A, m.p. 176-82 .



  Found: C, 64.51; H, 5.83; N, 7.63%. C20H22N205 requires: C, 64.85; H, 5.99; N, 7.63%.  



  Description 21 10,11-Dihydro-11-(1-methylaminoethyl)dibenzo[b,f][1,4]   oxazepihe    diastereoisomer B (D2'1)
EMI33.1     

According to the method given in Description 5, 11-(1methylaminoethyl)dibenzo[b,f][1,4]oxazepine was treated with sodium cyanoborohydride to give a 40:60 mixture of the two diastereoisomers A and B   tRf    0.15 and 0.07 on
SiO2/EtOAc/MeOH (95:5)] and these were isolated by chrom   atography    on silica   el,    eluting with ethyl acetate.

 

  The first to elute, diastereoisomer A, was shown to be identical with   the    compound obtained in Description 5.



  The second to elute was diastereoisomer B and this was obtained in 31% yield.



  NMR 6H (CDCl3): 6.15-7.3 (8E, m, aromatic), 3.75   (1H,   
 d, 9Hz),   3.25-3.6      (1H,    m), 2.3 (3H, s),
 0.85 (3H, d, 6Hz).



  This was converted to a   monomaleate    salt. Recrystallisation from methanol gave 10,11-dihydro-11-(1-methylaminoethyl)dibenzo[b,f][1,4]oxazepine monomaleate diastereo   isomer B, m.p. @@@@@@@@@   
Found: C, 65.16; H, 6.18; N, 7.63%. C20H22N2O5 requires: C, 64.85;   H,    5.99; N, 7.56%.  



     Description    22 2-Bromo-N-[2-(phenylthio)phenyl]propanamide (D22)
EMI34.1     

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



  NMR   H    (CDCl3) : 8.45   (1H,    m, aromatic), 7.05-7.8 (8H, m,
 aromatic), 4.40 (1H, q, 10Hz, CHBr), 1.78
 (3H, d, 10Hz, CHCH3).  



  Description 23    Th    11-[1-(Methylamino)ethyl]dibenzo[b,f][1,4]thiazepine (D23)
EMI35.1     

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   6H    (CDC13): 7.04-7.50 (8H, m, aromatic), 3.90 (1H, q,
 7Hz, CHCH3), 2.65 (3H, s, NCH3), 1.30 (3H,
 d, 7Hz, CHCH3).



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



  Found: C, 61.97; H, 5.06; N, 7.20 C20H20N204S requires: C, 62.48; H,   5.24;    N,   7.29.     



  Description 24 10,11-Dihydro-11-(1-methylamino)ethyl)dibenzo[b,f][1,4] thiazepine
Diastereoisomer A '(D24)
EMI36.1     

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



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



     N.ER      #H    (CDCl3): 6.50-7.60 (8H, m, aromatic), 6.60   (1H,    d,
 8Hz, H-6), 3.50-3.85   (1H,    m, CH-CH3), 2.45
 (3H, s, NHCH3), 1.30 (3H, d, 6Hz, CHCH3).



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



  Found: C, 62.21; H, 5.86; N, 7.25%, C20H22N2O4S requires: C, 62.15, H, 5.74, N, 7.25%.  



  uescription 25 10,11-Dihydro-11-(1-methylamino(ethyl)dibenzo[b,f]thiazepine
Diastereoisomer B (D25)
EMI37.1     

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   H    (CDC13): 6.40-7.60 (8H, m, aromatic), 6.55   (1H,    a,
 8Hz, H-6),   3.35-3.65    (1H,   m,    CHCH3), 2.40
 (3H, s, NHCH3), 1.07 (3H, d, 6Hz, CHCH3).



  Description 26 2-Chloro-N-[2-(N'-methyl-N'-phenyl)aminophenyl]propanamide (D26)
EMI37.2     

A solution of   N-methyl-N-phenyl-l,2-benzenediamine    (16.13g, 0.081 mol) in dry toluene (lOOml) containing pyridine
 (lOml) was   ir,mediately    cooled in an ice-bath and  2-chloropropionyl chloride   (11.38g,    0.090mol) added over 0.5h at such a rate that the reaction temperature did not exceed
After stirring.for ca 18h, solvent was evaporated under reduced pressure and the solid residue partitioned between dichloromethane and water.

  The organic phase was washed with 1N hydrochloric acid, water, saturated brine, and dried   (NgS04).    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 6H (CDCl3): 6.40-7.27 (9H, m, aromatic), 4.27   (1H,    q,
 7Hz, CHCH3), 3.13 (3H, s, NCH3), 1.60 (3H,
 d, 7Hz, CHCH3).



  Description 27 5-Methyl-11-(1-methylamino)ethyl)-5H-dibenzo[b,e][1,4-]   diazePine    (D27)
EMI38.1     

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



     NNR      6H    (CDCl3): 6.70-7.27 (8H, m, aromatic), 3.37   (1H,    q,
 6Hz, CHCH3), 3.10 (3H, s, NCH3), 2.47 (3H,
 s, NHCH3), 1.22 (3H, d, 6Hz, CHCH3).



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



  Example 1 1,2-Dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo[c,f]imidazo [1,5-a]azepine
Diastereoisomer A (E1)
EMI39.1     

Formaldehyde (1.9 ml of 37% solution in water,   15mmol)    was added to the amine D4 diastereoisomer 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   (2xlOml)    and the combined dichloromethane extracts washed with brine (25 ml) and dried
 (MgSO4). Evaporation in vacuo, followed by filtration through a silica gel column (20g), eluting with ether, gave the title compound (2.6g, 98%).



  NMR   #H    (CDCl3): 6.60-7.20 (8H, m, aromatic);
 4.65   (1K,    d 13Hz, H-9);
 4.35   (1H,    d 7Hz);
 4.20 (1H, d 3.5Hz);
 3.80   (1H,    d   3.5Hz);   
 3.45   (1H,    d 13Hz, H-9);
 2.85-3.35 (1H, m, H-l);
 2.52 (3H, s, NCH3);
 0.95 (3H, d 7Hz, CHCH3).  



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



  Found: C,   69.50;    H, 6.26; N, 7.14%. C22H24N204 requires: C, 69.46; H, 6.36; N, 7.36%.



  Example 2 1,2-Dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo[c,f]imidazo [1,5-a]azepine
Diastereoisomer B (E2)
EMI40.1     

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

 

      NMR #H (CDCl3): 6.1-7.3 (8H, m, aromatic);   
 5.22 (1H, d 9Hz);
 4.89   (1H,    d 14Hz, H-8);
 4.39   (1H,    d 4Hz);
 3.78 (lH, d   4Hz);   
 3.36    (1H, d 14Hz, H-9);   
 2.9-3.3 (1H, m, H-1);
 2.47 (3H, s, N-CH3);
 1.37 (3H, d 6Hz, CHCH3);
Conversion to a monomaleate salt,   followed    by recrystallisation from acetone gave 1,2-dimethyl-2,3,9,13b-tetra- hydro-dibenzo[c,f]imidazo[1,5-a]azepine monomaleate diastereoisomer B m.p. 169-73 .



  Found: C,   69.55;    H,   6.46;      X,    7.27%. C22H24N204 requires: C, 69.46; H, 6.36; N, 7.36%.  



  Example 3 2-Ethyl-1-methyl-2,3,9,13b-tetrahydro-1H-dibenzo[c,f]imidazo [1,5-a]azepine
Diastereoisomer   A    '(E3)
EMI41.1     

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



  Found: C, 70.74; H,   6.68;    N, 6.94 C23H26N204 requires: C, 70.03; H, 6.64 and N, 7.10% +
Found: . 278.1771 Calc. for   C19H22N2 278.1783   
Example 4 2-Ethyl-1-methyl-2,3,9,13b-tetrahydro-1H-dibenzo[c,f]imidazo [1,5-a]-azepine
Diastereoisomer B (E4)
EMI41.2     

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 C23H26N204.H20 requires: C, 66.99; H, 6.79 and N, 6.79%
Found:   M    278.1774 Calc. for C19H22N2 278.1783  
 Example 5
 1-Methyl-2-(phenylmethyl)-2,3,9.13b-tetrahydro-1H-dibenzo
 [c,f]imidazo[1,5-a]zaepine
Diastereoisomer A (E5)
EMI42.1     

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



  Found: C, 73.84; H, 6.27; N, 6.10 C28H28N204 requires: C, 73.66; H, 6.18 and N, 6.14% +
Found: 340.19A1   Cain.    for C24H24N2 340.1939.



  Example 6 1-Methyl-2-(phenylmethyl)-2,3,9.13b,tetrahydro-1H-dibenzo [c,f]imidazo[1,5-a]zaepine
Diastereoisomer B (E6)
EMI42.2     

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 C24H24N2 340.1939  
Example 7 1-Ethyl-2-methyl-2,3,9,13b-tetrahydro-1H-dibenzo[c,f] imidazo[1,5-a]azepine   Di as tereoisomer    A (E7)
EMI43.1     

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 C23H26N204 requires: C, 70.03; H, 6.64 and N, 7.10%
Found:   N+    278.1780 Calc. for ClgH22N2 278.1783.  



  Example 8 7-Bromo-1,2-dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo[c,f] imidazo[1,5-a]azepine (E8)
EMI44.1     

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 (MgSO4).



  Evaporation in vacuo, followed by chromatography on silica gel, eluting with ether gave the title compound   (860mg,    63%) as a light brown gum.



  NMR   dH    (CDCl3): 6.9-7.35 (6H, m, aromatic),   6.68      (1H,    d,
 9Hz), 4.63 (1H, d, 1SHz), 4.55 (lH, d,
 7.5Hz),   4.25' (lH,    d, 4Hz), 3.83   (1H,    d,
 4Hz), 3.5   (1H,    d, 15Hz), 3.1-3.22   (1H,    m),
 2.6 (3H, s,   N-CH3),    0.98 (3H, d, 7Hz,
 CHCH3).



  Found:   M    342.0721 Calc. for   C18HlgN2Br    342.0732.



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



  Example 9 2,3-Dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo[c,f]imidazo [1,5-a]azepine
Diastereoisomer   A (E9)   
EMI45.1     

Freshly distilled acetalodehyde (402mg, 510 l, 9.1mmol) was added to a stirred solution of 5,6-dihydro-N-methyl11B-dibenz[b,e]azepine-6-methanamine (2g, 8.3mmol) in dichloromethane (30ml) at 0  containing p-toluenesulphonic acid (lOOmg). After 2hr at 00 and 30 min at 200, water
 (20ml) and 10% aqueous sodium carbonate (lOml) were added and the aqueous layer extracted with dichloromethane (20 ml). The combined organic layers were washed with brine
 (30ml), dried (MgSO4) and evaporation in vacuo gave a yellow gum. Trituration in ether gave a solid (436mg; 20%) which was shown by NMR to contain 95% diastereoisomer A plus 5% diastereoisomer B.



  For Diastereoisomer A (E9):
NMR   #H    (CDCl3): 6.85-7.3 (6H, m, aromatic), 6.3-6.7
 (2H, m, aromatic), 5.52   (1H,    m), 4.6
 (lH, d, 14Hz), 4.2   (1H,    q, 5Hz, CHCH3),
 3.5   (1H,    m), 3.35   (1H,    d, 14Hz), 2.95
   (1H,    m), 2.57 (3H, s, NCH3), 1.4 (3H, d,
 5Hz, CHCH3).



  Found: M+ 264.1633 Calc. for C18H20N2 264.1626
For Diastereoisomer B:
NMR   #H    (CDCl3): 2.53 (3H, s, NCH3), 1.25 (3H, d, CHCH3).  



  Example 10 7-Chloro-1,2-dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo [c,f]imidazo[1,5-a]azepine
Diastereoisomer A (E10)
EMI46.1     

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



  NMR   #H    (CDCl3)
The title compound was converted into a monomaleate salt.



  Found: C, 63.58; H, 5.59; N, 6.44; C1, 8.62. C22H23N204C1
Requires: C, 63.69; H, 5.59; N, 6.75 and C1, 8.55%.  



  Example 11 7-Chloro-1,2-dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo [c,f]imidazo[1,5-a]azepine
Diastereoisomer B (E11)
EMI47.1     

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

 

  NMR   #H    (CDCl3) :
The' title compound was converted into a monomaleate salt.



   Found: C, 63.38; H, 5.56; N, 6.44; C1, 8.54. C22H23N204C1
Requires: C,   63.69;    H,   5.59;    N, 6.75 and C1, 8.55%.



  Found: M+ 298.1242 Calc. for C18H19N2Cl 298.1236.  



  Example 12 1,2-Dimethyl-1,2,3,13b-tetrahydro-dibenzo[b,f]imidazo [1,5-d][1,4]oxazepine monohydrogen maleate
Diastereoisomer A (E12)
EMI48.1     

The title compound was prepared from the amine D20 using a method similar to that of Example 1, m.p. 147149  (from acetone-ether).



  Found: C, 66.00; H, 5.93; N, 7.34 C21H22N205 requires: C, 65.96; H, 5.80; N,   7.32%.     



  Example 13 1,2-Dimethyl-1,2,3,13b-tetrahydro-dibenzo[b,f]imidazo[1,5-d] [1,4]oxazepine monohydrogen maleate
Diastereoisomer B (E13)
EMI49.1     

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 C21H22N205 requires: C, 65.96; H, 5.80; N, 7.32%.  



  Example 14 1,2-Dimethyl-1,2,3,-3b-tetrahydrodibenzo[b,f]imidazo [1,5-d][1,4]thiazepine
Diastereoisomer A (E14)
EMI50.1     

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



  NMR   #H    (CDCl3) : 6.20-7.70 (8H, m, aromatic), 6.52 (1H, d,
 5.9Hz), 4.27 (1H, d, 4Hz,   H-3),    3.63   (iH,   
 d, 4Hz, H-3), 2.80-3.1   (1H,    m, H-l), 2.45
 (3H, s, NHCH3), 1.37 (3H, d, 7Hz, CHCH3).



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



  Found: C, 63.36; H, 5.58; N, 7.04% C21H22N2S04 requires: C, 63.30; H, 5.57; N, 7.03%.  



  Example 15 1,2-Dimethyl-1,2,3,13b-tetrahydrodibenzo[b,f]imidazo [1,5-d][1,4]thiazepine
Diastereoisomer B (E15)
EMI51.1     

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



     NNR      H    (CDCl3) : 6.15-7.70 (8H, m, aromatic), 6.15 (1H, d,
 8.6Hz), 4.32   (1H,    d, 4Hz, H-3), 3.87
 (1H, d, 4Hz, H-3), 2.90-3.30 (1H, m,
 CHCH3), 2.47 (3H, s, NCH3), 1.26 (3H, d,
 6Hz, CHCH3).



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



  Found: C, 63.30; H, 5.62; N, 7.05% C21H22N2SO4 requires: C, 63.20; H, 5.57; N, 7.03%.  



  Example 16 1,2,3,13b-Tetrahydro-1,2,9-trimethyl-5H-dibenzo[b,f] imidazo[1,5-d][1,4]diazepine
Diastereoisomer A (E16)
EMI52.1     

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   #H    (CDCl3): 6.33-7.10 (8H, m, aromatic), 4.80 (1H, d,
 7Hz, H-14), 4.17   (1H,    d,   5Hz,    H-3), 3.70
 (1H, d, 5Hz, H-3), 3.22 (3H, s, ArN-CH3),
 2.77-3.22   (1H,    m, CHCH3), 2.63 (3H, s,
   NCH3),    1.06 (3H, d,   7Hz,    CHCH3).



  This was converted to a monomaleate salt.



     Example    17 1,2,3,13b-Tetrahydro-1,2,9-trimethyl-5H-dibenzo[b,f] imidazo[1,5-d][1,4]diazepine
Diastereoisomer B (E17)
EMI52.2     

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



   NMR   #H (CDCl3) :    6.10-7.90 (8H, m, aromatic), 5.45   (1H,    d,
 9.2Hz, H-14), 4.30 (1H, d, 4Hz, H-3),
 3.83 (1H, d, 4Hz, H-3), 3.25   (313,    s, Ar
 2.85-3.30 (1H, m, CHCH3), 2.45
 (3H, s, NCH3), 1.30 (3H, d, 7Hz, CHCH3).



  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   5T    antagonists. As such they   wpuld    be expected to possess antidepressant, (Ogren, S 0,   Fuxe,   
K, Agnati, L F, Gustafsson J A, Jonsson, G, and Holm
A C, 1979, J Neural Trans, 46, 85-103) and/or anxiolytic
 (Stein, L, Kline, D, and Bellugi, J D, 1975, in Advances in Biochemical Psychopharmacology, ed Costa, E, and   Greengard,    P, Vol 14, 29-44, Raven Press, NY) activity.



  Method
Mice   (6'    CD-1 Charles River) are pretreated with the compounds (10 animals/group) under   inxtestication    and lh later are injected with 10   mg/ks    i.p. 5-methoxy-N,Ndimethyltryptamine (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/roup. Results are expressed as the percentage inhibition compared to the group treated with   5-methoxy-i',N-dimethyl    tryptamine alone. The dose of compound inhibiting the symptoms by 50% is determined graphically.



  The results are shown in Table 1.  



  Table 1
Inhibition of 5-MDMT induced symptoms in the mouse
   ED;    mg/kg p.o.



   or % inhibition
 Compound at dose 1,2-Dimethyl-2,3,9,13b-tetrahydro-1H- 4.3 dibenzo[c,f]imidazo[1,5-a]azepine diastereoisomer A (Compound El) 1,2-Dimethyl-2,3,9,13b-tetrahydro-1H- 10 dibenzo[c,f]imidazo[1,5-a]azepine diastereoisomer B (Compound E2) 2-Ethyl-1-methyl-2,3,9,13b-tetrahydro- 1.6 1H-dibenzo[c,f]imidazo[1,5-a]azepine diastereoisomer A (Compound E3)   2-Ethyl-l-methyl-2,3,9,13b-tetrahydro-lH-    41% at 10 dibenzo[c,f]imidazo[1,5-a]azepine, diastereoisomer B (Compound E4) 1-Methyl-2-(phenylmethyl)-2,3,9,13b-tetra-   6%    at 10 hydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine diastereoisomer A (Compound E5)   l-Ethyl-2-methyl-2,3,9,13b-tetrahydro-lH-    61% at 10 dibenzo[c,f]imidazo[1,5-a]azepine, diastereoisomer A (Compound E7)  
Blockade of presynaptic   &alpha;

  ;2-adrenoceptors    on noradrenergic neurons effects an increase in intrasynaptic noradrenaline, and thus in the central nervous system could be expected to have an antidepressant effect.



   [ H]-clonidine binds to   &alpha;2-adrenoceptor    sites and inhibi ion of this binding correlates with the blockade of- a2adrenoceptors. In vitro inhibition by some of the present compounds of the binding of [ H]-clonidine to isolated ratbrain synaptic membrane fragment was therefore determined to prcvide an indication of antidepressant activity. This was carried out using standard biochemical binding study techniques, by the method of Maggi et al., Eur. J. Pharm.

 

  1980, 61, 91. The parameter determined was the concentration of [ H]-clonidine binding. K. values have been determined, using the Cheng-Prusoff equation, from IC50 values. The results are shown in Table 2 below.



   Table 2
 Compound KinM 1,2-Dimethyl-2,3,9,13b-tetrahydro-1H- 23   diben:::(c,f]imidazo(l,5-a)azepine,    diastereoisomer A (Compound El) 1,2-Dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo 126
   [c,f]Fidazo[l,S-a]azepine,    diastereoisomer B (Compound E2) 1-Ethyl-2-methyl-2,3,9,13b-tetrahydro-1H- 67 dibenzo[c,f]imidazo[1,5-a]azepine, diastereoisomer A (Compound E7)  
Pharmacological Data   Sho'ck'    Induced   Suppression of    Drinking in   the    Rat
The shock induced suppression of drinking (SSD) test
 (adapted from Vogel et al., 1971) is considered a reliable and specific method for showing up potential anxiolytics.



  20h Water-deprived rats   (# Hacking    and Churchill, CFHB), familiarised 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 min session Drugs were administered, intraperitoneally, 30 min before   test.   



  The number of shocks taken during a given test period are recorded and results   pressed    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    ranner.

 

  J.R. Vogel et al., (1971) Psychopharmacologia (Berl.) 21 7.



  The results are shown in Table 3.



     Taxi city   
No toxic effects were   obser'ec    in these tests.  



  Table 3
EMI58.1     


 <SEP> Dose <SEP> % <SEP> change <SEP> from <SEP> control
<tb>  <SEP> Compound <SEP> mg/kg <SEP> i.p. <SEP> no. <SEP> of <SEP> shocks <SEP> taken
<tb> 1,2-Dimethyl-2, <SEP> 10 <SEP> + <SEP> 103
<tb>  <SEP> 3,9,13b-tetrahydro
<tb>  <SEP> -1H-dibenzo[c,f]
<tb>  <SEP> imidazo[1,5-a]
<tb>  <SEP> azepine <SEP> mono
<tb>  <SEP> maleate <SEP> (Example <SEP> 1)
<tb>

Claims

Claims 1. A compound of formula (I) or a phamaceutically acceptable salt thereof; EMI59.1 wherein: X is CH2, O, S or NR where R is C1-4 alkyl; R1 and R2 are independently selected from hydrogen, hydroxy, C1-4 alkyl, C1-4 alkoxy, halogen or CF3i R3 is C1-7 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl or C1-6 alkyl substituted by C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, hydroxy, thiol, C1-6 alkoxy, C1-6 alkylthio, carboxy, C1-6 alkoxycarbonyl, C2-7 alkanoyl, amino optionally substituted by one or two C1-4 alkyl or by C4-6 polyrnethylene optionally containing an oxygen or nitrogen atom, aminocarbonyl optionally N-substituted by one.

or two C1-6 alkyl groups, or benzoyl or phenyl either being optionally ring-substituted by one or two C1-4 alkyl, C1-4 alkoxy, halogen or trifluoromethyl; and one of R4, R5 and R6 is C1-6 alkyl and the other two are independently hydrogen or C1-6 alkyl.

2. A compound according to claim 1 wherein R3 is C1-6 alkyl, C25 alkenyl, C25 alkynyl, C1-6 cycloalkyl, C1-6 cycloalkenyl or C1-4 alkyl substituted by C3-7 cycloalkyl or phenyl or C1-6 alkyl substituted by hydroxy, C1-6 alkoxy, carboxy, C2-7 alkanoyl, benzoyl or aminocarbonyl or amino optionally substituted by one or two C1-6 alkyl groups and the remaining variables are as defined in claim 1.

3. A compound according to claim 1 or 2 of formula (11): EMI60.1 wherein R11 is hydrogen or halogen, one of R51 and R61 is C16 alkyl land the other is hydrogen or C1-6 alkyl; and X is as defined in claim 1.

4. A compound according to claim 3 of formula (III): EMI61.1 wherein R52 is C16 alkyl and Rll is as defined in claim 3.

5. A compound according to claim 3 of formula (IV) : EMI61.2 wherein X1 is oxygen or sulphur; and Rll and R52 are as defined in claim 4.

6. A compound according to claim 3 of formula (V): EMI62.1 wherein X2 is NR as defined in claim 1 and R11 and R52 are as defined in claim 4.

7. A compound according to any one of claims 4 to 6 wherein R52 is methyl.

8. A compound according to claim 1 of formula EMI62.2 wherein R41 is C1-6 alkyl and R1Ú is as defined in claim 3.

9. 2-Ethyl-l-methyl-2,3,9,13b-tetrahydro-lH- dibenzo[c,f]imidazo[1,5-a]azepine, l-Methyl-2-(phenylmethyl)-2,3,9,13b-tetrahydro-lH- dibenzo[c,f] imidazo[l,5-a]azepine, 1-Ethyl-2-methyl-2,3,9,13b-tetrahydr-1Hdibenzo[c,f]imidazo[1,5-a]azepine, 7-Bromo-1,2-dimethyl-2,3,9,13b-tetrahydro-1H dibenzo[c,f] imidazo[l,5-a]azepine, 2,3-Dimethyl-2,3,9-13b-tetrahydro-1H-dibenzo[c,f] imidazo[l,5-a} azepine, 7-Chloro-1,2-dimethyl-2,3,9,13b-tetrahydro-1Hdibenzo[c,f]imidazo[1,5-a]azepine, 1,2-Dimethyl-1,2,3,13b-tetrahydro-dibenzo[b,f]imidazo [1,5-d][1,4]oxazepine, l,2-Dimethyl-l,2,3,-3b-tetrahydrodibenzo[b,f] imida'zo ,1,5-d] [1,4]thiazepine or 1,2,3,13b-Tetrahydro-1,2,9-trimethyl-5H-dibenzo [b,f]imidazo[1,5-b][1,4]diazepine,

or a pharmaceutically acceptable salt thereof.

10. 1,2-Dimethyl-2,3,9,13b-tetrahydro-1H[c,f] imidazo[1,5-a]azepine, or a pharmaceutically acceptable salt thereof.

11. A process for the preparation of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof which process comprises the reaction of a compound of formula (VII): EMI64.1 with a compound of formula (VIII): EMI64.2 wherein R3' is R3 or a group convertible thereto, Rl, R2, R5 and R6 are as defined in formula (I), one of yl and Y2 is hydrogen and the other is R4 as defined or (when R4 in formula (I) is hydrogen), Y1 and Y2 together form an oxo or thiocarbonyl group; and Z1 and Z2 are leaving groups, and thereafter reducing the resulting compound formed when Y1 and Y2 together form an oxo or thiocarbonyl group, and/or convrting R3' to R3 and/or forming a pharmaceutically acceptable salt.

12. A compound of formula (VII) as defined in claim 11 wherein R3' is R3 as defined in claim 1 or a compound of formula (IX): EMI65.1 wherein the variable groups are as defined in claim 1.

12. A compound according to claim 12 wherein R1 (or R1Ú), R2, R3, R5 (or R51 or R52), R6 and X are as defined in any one of clairns 1 to 9.

13. 6-[1-(Methylamino)ethyl]-11H-dibenzo[b,e]azepine, 5,6-Dihydro-6-[1-(methylamino)ethyl]-11H-dibenzo[b,e] azepine, 6-[1-(Ethylamino)ethyl]-11H-dibenzo[b,e,]azepine, 6- [l-(Phenyl:ethylanino)ethyl] -ilH-dibenzo [b,e] azepine, 5,6-Dihydro-6-[1-(ethylamino)ethyl]-11H-dibenzo[b,e] azeplne, 5,6-Dihydro-6-(phenylmethylamino)wthyl]-11H-dibenzo [b,e]azepine, 2-Chloro-6-[1-methylamino)ethyl]-11H-dibenzo[b,e] azepine, 2-Chloro-5,6-dihydro-6-[1-methylamino)ethyl]-11Hdibenzo[b,e]azepine, 11-(1-Methylaminoethyl)dibenzo[b,f][1,4]oxapine, 10,11-Dihydro-11-(1-methylaminoethyl)dibenzo[b,f] [1,4) oxazepine, 11-[1-(Methylamino)ethyl]dibenzo[b,f][1,4]thiazepine, 10,11Dihydro-11-[1-(methylamino)ethyl]dibenzo[b,f] [1,4]thiazepine or 5-Methyl-11-[(1-methylamino)ethyl]-5H-dibenzo[b,e] [1,4-]diazepine.

14. A pharmaceutical composition comprising a compound according to any of claims 1 to 10 and a pharmaceutically acceptable carrier.

. A method of treatment of CNS disorders in mammals including man which method comprises administering as effective amount a compound of formula (I), or a pharmaceutically accepable salt thereof to the sufferer.