CA1056378A - Amino-substituted piperidino-derivatives - Google Patents

Abstract

Abstract of the disclosure The invention discloses novel compounds of the general formula:

and salts thereof, in which the amino(alkyl) moiety is present at position 2 or 3 and in which X stands for oxygen, sulphur, the group or the group -CR8R9-;
R1, R2, R3 and R4 represent hydrogen, hydroxy, halogen, alkyl (1-6 C), alkoxy (1-6 C), alkylthio (1-6 C) or trifluoromethyl;
R5 and R6 represent hydrogen, alkyl (1-6 C), aralkyl (7-10 C) or together in combination with the nitrogen atom a heterocyclic five- or six-membered ring;
R7 stands for hydrogen or alkyl (1-4 C);
R8 and R9 stand for hydrogen or methyl and n is the number 0, 1, 2 or 3, having valuable central nervous system (CNS) activities, especially antidepressant activity.
The invention further discloses novel intermediates of the general formula:

in which the keto group is present at position 2 or 3, as well as biologically active intermediates of the formula:

in which A stands for a moiety or a

Description

1C)5637B
The present invention relates to no~el biologically active amino-substituted piperidino-derivatives and to processes for the preparation thereof.
It was found that compounds of the general formula I:

R

2 n \ R6-~

as well as the pharmaceutically acceptable salts thereof, whereby the - (CH2)n-N < 5 ~moiety is present at position 2 or 3 and in which X stands for oxygen, sulphur~ the group~NR7 or the group -CR8R9-; R1, R2, R3 and R4 represent hydrogen, hydroxy, halogen~ alkyl (1-6 C)~ alkoxy (1-6 C)~
aIkylthio (1-6 C) or trifluoromethyl; R5 and R6 represant hydrogen~ alkyl (1-6 C)~ aralkyl (7-10 C) or together with the nitrogen atom represent a heterocyclic five- or six-membered ring in which one oxygen atom and one ` additional nitrogen atom may be present as a hetero atom; R7 stands for hydrogen or alkyl (1-4 C); R8 and R9 stand for hydrogen or methyl and n is the number 0~ 1~ 2 or 3~ possess valuable C.N.S. activities. The toxicity of these compounds is exceedingly low.
The compound~ accordine to tho invention may bc prepared in a manner used for analogous oompounds.
A very easy starting point for the synthesis of the compo~mds in ~uestion is a compound of the general ~ormula II:

.

~D~

Rl X~ R3 11 R2 <4 :~ ~4 in which the ketogroup is present at position 2 or pos~tion 3 and in which Rl, R2, R~, R4 and X have the meanings mentioned above. The compounds II are, as far as known, novel compounds.
rhe starting material II can be prepared in various manners. The most simple method to prepare the compound II is the condensation of vinylmethylketone ~CH3-3-CH=CH2) with a derivative o morphanthridine, dibenzooxazepine, dibenzothiaze-pine or dibenzodiazepine of the general formula III:

2 X ~ R43 111 in which Rl, R2, R3, R4 and X have the meanings mentioned above.
In this condensation reaction the 2-keto compound II is obtained in a fairly good yleld.
The 3-keto compound of formula II may be prepared from the corresponding 2-keto-compound ~I ln a conventional manner.
For example, the 2-keto compound is con~erted into the correspond-¦ ing 2-keto-3-hyd~oxy-;mino compound with isoamylnitrite and potassium in tert.butanol ~see reaction scheme 4 at page 5), after which the carbonyl group at position 2 is reduced by means of a Wolff-Kishner reduction and the 3-hydroxy-imino moiety in the compound thus obtained saponified under ., ~.

, 30 ,. ~.

~.

- : .- .. : . . ~ . .

1~56378 acidic conditions or with the aid of sodiumbisulfite in an alcohol/water mixture.

Starting from a compound with formula II the endproducts according to formula I can be prepared in various manners.
All these routes are known per se and are standard procedures commonly used for the preparation of similar compounds.
In principle, the amino(alkyl)compounds of the invention are prepared starting from the 2- or 3-keto compound II by two different approaches, namely the amino(alkyl)group can be introduced into the position ad~acent to the keto group~
or the keto-group itself can be converted into the amino (alkyl)group desired. In the first approach a 3-amino(alkyl) compound I is prepared from a 2-keto-compound II or a 2-lS amino(alkyl)compound I is prepared from a 3-keto-compound II; in the second approach a 2-amino(alkyl)compound I is prepared from a 2-keto compound II or a 3-amino(alkyl) compound I is prepared from a 3-keto compound II.

The endproducts according to formuia I may be manufac-tured, for example, by reducing the carbonyl group of a ¦ compound of the general formula: IV ~ or IV B.

l ~ X ~ R3 Rl ~ x ~ ~
25 ~ ~ ~ or ~R4 (Cl12)h (CH2)t, N IV A N IV B

~5 , .

. , -~56378 or a salt thereof, in which Rl, R2, R3, ~4, 5' 6' have the meanings afore-mentioned.
This reduction from /C=0 to /CH2 is performed in a way usual for similar reductlons, for example by means of a Wolff-Kishner, Huang-Minlon or Clemmensen reduction or by hydrogenolysis of di-alkylthio-acetals that are prepared from the relative keto-compound IV.
Besides the use of the compounds IV A and IV B as intermediates in the synthesis for the preparation of the compounds according to the general formula I, these com-pounds (IV A and IV B) can also be applied as biologically active substances. Like the compounds of formula I, they have C.N.S. in particular antidepressant activities. The compounds IV A and IV B can be administered bo~h orally and parenteral-ly~ preferably in a daily dose of 0.01-10 mg per kg body weight.
The compound IV required in the above-mentioned synthesis can be prepared from the starting product II in various ways.
By way of example a number of reaction schemes, given on the next page, illustrate the preparation of a compound IV
starting from a compound II in which the keto group is at position 2. For compounds II with the keto group at position

3 these reactions p~oceed ln an ldentLcal way.

':~

:'.
"' :

- 4 -., , .: , . . , . - .. . , . . : , .

-1. ~ HCOOC2H~ ~ tosylation~ Pd/H2 NH~R5 NaOCH3 ,CH IC~ > C 2 ~ CH~
OH OTOS OTOS l-R IV

2, ~ ____ ~ Br O ~ N ~ O IV

~ 5~ 6 HN I ~ ~ormaldehyde 3 ~ 2~ ~R~' ~Mannich reaction) ~ IV
~ / R5 N

`I 4 ~ iSO~ImY1n1trite ' potassium t.butoxidë N ~ Pd/C/H2 ~ IV
;, OH
3 2 1) NaNH2 ~~ -- t ~ IV
CH2 CH2 N~ , 1 2 6 CH2 ::
¦ ~ RS~\

base tKoc2H5) ~ ~3 2 ( ~Tos ~ tosyl) IN 0Neber rearrangement) NH o IV
OTos 2 ethylformate ~ / 5 sodiummethoxide ~ ~ ~ pd/H2 ~ ~ 2 ~ IV

OH N\/RR6~J N~ R5 ~ ~
.

.

1~56378 It will be clear that the steps mentioned in these reaction schemes for preparing starting product IV need not necessarily be carried out in this strict sequence to obtain the endproduct according to formula I.
Thus the Wolff-Kishner reduction (keto group reduction to -CH2), to which compound IV in reaction scheme 4 would have to be subjected to obtain the endproduct according to formula I~ can also be performed at an earlier stage, especially on the 2-keto-3-oxime compound (scheme 4). Eurther it is possible to have the reduction of the double bond (position 3) in re-action scheme 1 or 7 performed at an earlier or later stage of the synthesis to the endproduct I.
These and other obvious modifications in the reaction scheme are, without being claimed apart, considered to be fully analogous to the route claimed.
The conversion of a 2- or 3-keto compound II into a compound according to formula I having the amino(alkyl) group at the same position as the keto group of the starting material II may be carried out in various manners. All these methods are conventional methods~ already described for similar compounds.
For preparing compounds of formula I in which n = 0~ a compound of formula II~ as defined above~ is reacted with an amine of formula VI
HN < R

R6 _ ' wherein R5 and R6 are as defined above, in the presence of a reducing agent.
A method which can generally be used in preparing the compounds I
of the invention, consists of the condensation of a compound with the general ; formula V:

(CH2)n- y lOS6378 in which the -CcH2)n-y group is present at position 2 or 3, Rl, R2, R3, R4, n and X have the meanings specif~ed before and Y represents a suitable leaving group, such as halogen, or an etherified or esterified hydroxyl group, with ammonia or an amine according to the general formula VI:
/ R5~
HN J VI

or an acid addition salt thereof, in ~hich R5 and R6 have . .
the meanings defined previously.
Leaving groups are well defined groups, described in various chemical handbooks.
Suitable leaving groups for this condensation react-ion are for example a tosyloxy group, a mesyloxy group, a p-bromophenyl-sulphonyloxy group, a chlorine, bromine or iodine atom.
The compound V required for this contensation reaction may be prepared from the starting materia~ ~I described before by reducing the keto group to a hydroxyl group, for instance by catalytic hydrogenation or with metal hydrides such as LiAlH4, NaBH4 or diboran, ollowed by converting this hydroxyl group,into the desir~d leaving group in 8 conventional manner, for instance by tosylation, mesylation, reaction with SOC12, PC15, PBr3, etc.
Extension o the alkyl chainlength ~from n~0 to nal, 2 or ~) can be performed in the usual way, for instance br treating a compound V, in which naO, with a cyanide suc~ as potassium- or sodiumcyanide. The cyanogroup in the compound thus obtained can either be reduced to the corrosponding amihomethylgroup or be hydrolysed to the :1~56~71~

corresponding carboxyl group. The aminomethyl compound is then treated w;th nitrous acid at low temperature (Piria), whereas the carboxyl compound is reduced. Both reactions afford the hydroxy-methyl compound in fairly good yields.
Finally the hydroxym0thyl compound thus obtained is con-verted into a compound in which the hydroxyl group is replaced by a leaving group.
By repeating the aboYe-mentioned reaction steps, a further extension of the alkyl chain is obtained.
The compounds I in question can further be prepared by reduction of the cyanide or azide group of compounds with the general formula VII:

Vli in which R is present at position 2 or 3, representing one of the following moieties: -~CH2)n l-CN or -~CH2)n-N3, and in which Rl, R2, R3, R4, X ~nd n have the meanings indicated ` 20 beore.
The reduction is performed in the us~al way or this kind of compounds. The cyanide group is preferably reduced j by means of metalhydrides, especially lithium-aluminium-hydride, the azide group by a metalhydride such as LiAlH4 ¦ or NaBH4 or~by hydrogenation in the presence of a metal catalyst such as palladium, Raney nickel, etc.

; The starting materials with ormula VII required in this method can, for example, be prepared by treating a compound of ormula V with sodiumcyanide or sodiumazide, or by treating a compound II with ~ICN, eliminating the hydroxyl group and re- :

105637~3 ducing the double bond formed, possibly together with -CN or -N3 A simple and direct method in preparlng the compound I
~with n = 0) consists of the reactlon of the starting material II with the amine according to formula VI in the presence of a reducing agent, such as formic acid, metal hydrides such as LiAlH4, NaBH4, Na~CN)BH3, etc. or by means of hydrogen, lf required in the presence of a catalyst, such as palladium, platina, palladium on charcoal, nickel etc.
This reductive amination is well-Xnown ln organic chemistry and descrlbed ln any chemlcal handbook.
The compounds of the inventlon ~with n = 0) can further be prepared by reduction of a compound of the general formula VIII:
Rl R3 R2 ~ 4 N-OH
whereby the oxime group is present at position 2 or 3 and in which Rl, R2, R3, R4 and X have the meanings indicated before.
This reductlon ls performed ln the way as usual for reduction of an oxime, for instance with sodium or sodlum-amalgam in alcohol, by hydrogenation preferably in the presence of a metal catalyst, or with metalhydrides such as LiAlH4.
The compound VIII is prepared direct from the corresponding keto compound II by treatlng the latter with hydroxylamine in the usual way, or indirect from the Xeto compound II by reac-_ g _ .
.

.. , .. ~

ting it will isoamylnitrite/potassium-t.butoxide, followed by a Wolff-Kishner reduction of the keto group ~see reaction scheme 4 on page 5).
A very convenient method for the preparation of the compounds I with n ~ 1 is the reduction of an amide of the general formula IX:
1 ~ 4 , 10 ~CH2)n-1 I C;O- R-~ ~
' i ~ R6"' in which the amide-side chain is present at position 2 or 3 and Rl, R2, R3, R4, R5, R6, X and n have the meanings defined ~ previously.
;~ The r~sduction is carried out in a conventional manner :
for the reduction of amides, for example with metalhydrides, especially LiAlH4.
~1; The starting compounds IX for this reduction can be prepared by hydrolysls of the cyano-compound of the general formula VII, yielding the corresponding carboxyl compound, , t which compound i.s converted into the corresponding amide in the usual way, for example by halogenating the carboxyl I group affording the acid halide, followed by reacting the .~ acid halide with an amine of the formula VI. The primary amide of formula IX may, of course, be prepared directly 1 by partial hydrolysis o the cyano-compound VII.

;`.1 Finally the present compounds of the invention with,.,,.~
~:j general formula I may be prepared by a reduction of a com-,~

.~ pound with the general formula X:

. ~j R ~ ~ X

Cl /R5 ~ 2)n-1 N~R

in which the aminoalkylidene sidechain is present at position 2 or 3 and in which Rl, R2, R3, R4, R5, R6, X and n have the meanings mentloned previously.
This reduction is carrled out in the usual manner, for example, by hydrogenation in the presence of a catalyst such as palladium, palladium on charcoal, Raney nickel etc.
The starting oompounds X for this reduction can be preparet quite e~sily starting from the keto compount II by means of a Wittig reaction with the aid of the reagent:
Ph3P=CH-~CH2) l-B ;;
I in which n has the aforesaid meaning, Ph generally represents I an aryl, in particular a phenyl group ant B stants for an amino group ~-N~ 5 ~ ) or for a group which can be converted ~;
into an amino group, such as a carboxyl group, a carbonyl group, a hydroxy group or a cyanide group.
A very simple method for the preparation oP a compount X with n ~ 2 consists of the reaction of the keto compound ¦ II with acetonitril'~in the presence o, for instance, sodiumethoxide, followed by reduction of the cyano group in the compound thus obtained. If necessary the reduction o the cyano group and the reduction o the double bond can take place simul~aneously, c~. by catalytic hytrogen-a~ion ~Raney nickel~ or with diboran.
l ..
.. ~ - . .. ..
- 1 1 - . :

-~ \
1~5~37~
The starting material II contains an asymmetric carbon which means that besides the racemate II also the separate optical antipodes can be used as starting material.
By converting the starting product II into the amine according to the invention a second asymmetric centre is introduced. This asymmetric centre leads to compounds, in which the amino(alkyl)-substituent at position 2 or 3 of the molecule is in equatorial or axial position, or to a mixture of both types of compounds.
In general the above-mentioned methods in preparing the compounds I (n = O), starting from the starting material II, are resulting in compounds, in which the amino-substituent is substantially in the equatorial position. Only in the case that a leaving group is used in one of the aforesaid methods, generally an inversion occurs so that mainly the axial position is obtained.
A mixture of compounds I having the amino(alkyl) substituent in equatorial and axial position can, if desired, be separated very easily, for instance by column chromatography, or in many cases by mere crystallization as HCl salt or another acid addition salt.

The pharmaceutically acceptable salts of the compounds I according to the invention are acid addition salts and quaternary ammonium compounds.
The novel compounds according to the invention may be isolated from the reactlon mixture in the form of a pharmaceutically acceptable acid addition salt, dependent upon the conditions in which the reaction is carried out.
The acid addition salts may also be obtained by treating .

., , , , . . . ---~056378 the free base with a pharmaceutically acceptable organic or inorganic acid. Acids that can be used in this connection are: hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphoric acid, acetic acid, propionic acid, glycollic acid, ;
maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid or benzoic acid.
The quaternary ammonium compounds and in particular the lower ~1-4 C) alkyl quaternary ammonium compounds are ob-tained by reacting the compounds of the general formula I
with an alkyl halide, for example methyl iodide or methyl ;~bromide.
It is possible as a matter of course to introduce or to modify the substituents at one or both phenyl nucleii even after the condensation reaction described before. Thus a hydroxyl group can be converted into an alkoxy group, an amino group into a hydroxy- or halogen group, a methoxy group into a hydroxy group etc.
I The unsubstituted or monosubstituted amines of the ;I general formula I ~R5 and/or R6 ~ H) may be alkylsted in the usual way, for example by reaction with an alkyl-or aralkylhalide. More common for this purpose is, how ever, the acylation of the nitrog0n atom in question with, for exampl0, an acid chloride or anhydride followed by a retuction of the carbonyl group of the N-acyl derivative thus obtained. For the introductlon of methyl groups at the nitrogen atom the proceture aocording to Eschweiler-Clarke ~heating with a mixture o formaldehyde and formic ¦ acid~ or the reaction with formaldehyde and sodiumcyano-borohydride in a suitable solvent, such as acetonitril~ is 3~ preferred.

1 .

~OS6~78 With an alkyl group ~ith 1-6 carbon atoms is meant a branched or unbranched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, n.pentyl, isopentyl and hexyl. ~
The alkyl group ls the alkoxy and alkyl~hio moieties ;
has the same meaning.
An aralkyl group mentioned in the definition of R5 and R6 is preferably a phenylalkyl group, in which the alkyl group contains 1-4 carbon atoms, such as benzyl, phenyl-ethyl, phenylpropyl, phenylisopropyl, phenylbutyl and phenylisobutyl.
The heterocyclic 5- or 6-membered ring ~definition of R5 and R6~ may either be saturated or unsaturated, such a* a pyrrollno group, a pyrrolidino group, a plperidino group, an oxazolidino group, a morpholino group, a pi-perazino group, etc.
Amines according to the general formula VI, that may be used in the various condensation reactions to obtain the compounds of the invention, are, for example ammonia, 2~ methylamine, dlmethylamine, diethylamine, isopropylamine, dibutylamine, t.butylamine, benzylamine, phenylethylamine, phenylpropylamine, 2-phenyl-1-methyl-ethylamine, pyrroline, pyrrolidine, piperldine, oxazolldine, morpholine, piperazine, etc.
~ As: already po~nted out preYiously the compounds of the ¦ inYention I exert a Yaluable central nerVous system j actiVi`ty. This C.N.S. actiVity can be concluded from the results of various pharmacologlcal experlments, such as th~ reserpine antagonism test, reserpine reversal test, .~ ~
- 14 _ ~56;~7~
aggression isolated mice test, ambulation test, rotarod test, grip strength test, muricidal inhibition test, etc.
The surprising high activity of the compounds I in anta-gonizing hypothermia induced by reserpine (reserpine anta-gonism test) give strong indications that the present com-pounds can be used as antidepressants.
The compounds I may be administered both orally and parenterally, preferably in a daily dose of from 0.1 to 10 mg per kg bodyweight.

Mixed with suitable auxiliaries the present compounds can be compressed into solid dosage units such as pilIs, tablets or coated tablets, or they can be processed into capsules. With the aid of suitable liquids the compounds can be appliecl as injection preparations in the form of solutions, emulsions or suspensions.
Preferably compounds I are used in which X stands for a methylene moiety ~-CH2-) or a /N-alkyl moiety~ in particular, a /N-CH3 moiety. Especially the latter type of compounds (X = ~N-alkyl) excels in a very potent anti-depressant activity.
Furthermore the compounds I, in which n is 0 or 1 are to be preferred over the compounds I, having a longer side I chain (n = 2 or 3).
;ll 25 In the Examples the following nomenclature has been used:
9 ~/ 11 8 ~ C ~ l~ 1,2,3,4,10,14b-hexahydro-~ ~ , ~ ,J,3 pyridinoLl,2-a]-dibenzo[c,f]-30 ~ ' azepine , .

. , .

''' ~05637~
g ~ 'l 8 ~ ~ 12 X = O or S
1~3~4~14b-tetrahydro-2H-pyridino

5~ ~ 13 [1,2-d]-dibenzo[b,f](1,4)-oxaze-4 pine or -thiazepine 9 ' 8 ~ ~ 1,2,3,4,10,14b-hexahydro-pyridino ,3 [1,2-d]-dibenzo[b,f](1,4)-diazepine By way of example the preparation of various starting products are disclosed. The preparation of analogous starting products proceeds in exactly the same way.

STARTING PRODUCTS
1. PreParation 2-keto-compounds accordinq to qeneral formula II
A. 2-keto-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a3-dibenzo ~ [c,f]-azepine.
¦ To a solution of iOO g of morphanthridine in 2.5 litres of benzene are added 100 ml of methylvinylketon. The mixture is then refluxed. To the boiling solution are added dropwise 50 ml of a solution of 35% HCl in ethanol, ater which the solution is refluxed ~or another 15 hours. After cooling of the mixture the benzene layer is washed with 500 ml of water (3x) and ¦ then evaporated in vacuo. The residue is recrystallized ¦ from ethanol.
Obtained in this manner: 44 g with a melting point of 140-142C.
Rf in toluene: ethylacetate (9:1) = 0.80 on SiO2.

i .~ .

` l~S63~8 In the same way as described under A are prepared:
B. 2-keto-8-bromo-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f~-azepine; melting point 183-185C.
C. 2-keto-8-chloro-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a]-dibenzoLc,f]-azepine; melting point 144-147C.
D. 2-keto-11,12-dimethyl-1,2,3,4,10,14h-hexahydro-pyridino [1,2-aJ-dihenzoLc,f]-azepine (oil).
Rf in toluene-ethylacetate (9:1) = 0.85 on SiO2.
E. 2-keto-8-hydroxy-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine; (oil).
Rf in toluene = 0.60 on SiO2.
F. 2-keto-8-methoxy-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine (oil).
~f in toluene:ethylacetate (8:2) = 0.78 on SiO2.
G. 2-keto-7~chloro-1,3,4,14b-tetrahydro-2H-pyridinoLl,2-d]-dibenzo[b,f](l,4)-thiazepine (oil).
Rf in toluene:ethylacetate (8:2) = 0.75 on SiO2.
H. 2-keto-7-trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyridino L 1, 2-d]-dibenzo[b,f](1,4)-thiazepine (oil) Rf in toluene:ethylacetate (9:1) = 0.90 on SiO2.
I. 2-keto-13-methyl-1,3~4,14b-tetrahydro-2H-pyridino[1~2-d]-dibenzo[b,f](l,4)-thiazepine; melting point 104-107C.
K. 2-keto-7-methyl-1~3~4,14b-tetrahydro-2H-pyridino[1,2-d]-dibenzo[b,f](l,4~-oxazepine; melting point 105-107C.
L. 2-keto-11-methyl-1,3,4,14b-tetrahydro-2H-pyridino[1,2-d]-dibenzoLb,f](1,4)-oxazepine; melting point 164-166C.
M. 2-]ceto-7~11-dimethyl-1,3,4,14b-tetrahydro-2H-pyridino [1,2-d]-dibenzoLb,f](1,4)-oxazepine; (oil) Rf in toluene:ethylacetate (8:2) = 0.70.
N. 2-keto-10-methyl-1,2,3,4,10,14b-hexahydro-pyridinoLl,2-d]-l~S637~3 dibonzo[b,f~ ~,4)-diazepine, melting point 176-178C.
P. 2-keto-10-methyl-13-methoxy-1,2,3,4,10,14b-hexahydro-pyridino~l,2-dJ-dibenzo[b,f~1,4)-diazepine; melting point 127-128C.
Q. 2-keto-1,3,4,14b-tetrahydro-2H-pyr~dino~1,2-d~-dibenzo [b,f~ ~,4)-oxazepine; melting point 101-103C.
2. Preparation 3-keto-compounds according to formula II
A. 3-keto-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo ~c,f~-azepine.
2.6 g of 2-keto-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a~-dibenzo~c,~-azepine are added under nitrogen atmosphere to a solution of 3.9 g of potassium in tertiary butanol.
The mixture is stirred or 10 hours while every 2 hours 4 ml of isoamylnitrite are added ~the total ~uantity of iso~nylnitrite is 20 ml).
After that the mixture is filtered and the precipitate ~2-keto-3-oxime compound)`washed with t.butanol and ether.
The product is then added to 17 ml o diethyleneglycol ater which 5 ml o hydrazinehydrate and 2 g o KOH are 1 20 added and the mixture obtainet is heated at 160C or 4 hours.
The reaction mixture is poured into water wher~ater the precipitated oxim is iltered o.
Yield o the 3-oxim: 2.0 g. The oxime is re1uxed in a I mixture of 20 ml o water, 20 ml o ethanol and 4 g o I sodium bisulphite or 2.5 hours. The alcohol is then `I distilled o and the remaining solution is éxtracted into ether. The ether layer is evaporated to dryness.

:

-~\
~5~37~3 Yield of the 3-keto compound: 1.8 g (oil).
I~f in toluene:ethylacetate (9:1) = 0.70.
In the same way are prepared:
B. 3-keto-8-bromo-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo L c,f]-azepine Rf in toluene = 0.15 on SiO2.
C. 3-keto-7-trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyridino [1,2-d]-dibenzo[b,f](1,4)-thiazepine Rf in toluene:ethylacetate (9:1) = 0.90.
D. 3-keto-11-methyl-1,3,4,14b-tetrahydro-2H-pyridinoLl,2-d]-dibenzo~b,f](l,4)-oxazepine Rf in toluene:ethylacetate (8:2) = 0.75.
E. 3-keto-10-methyl-1,2,3,4,10,14b-hexahydro-pyridinoL1,2-d]-dibenzo-[b,f](1,4)-diazepine Rf in toluene:ethylacetate (9:1) = 0.90 Rf in hexane:acetone (9:1) = 0.20.

3. 2-hydroxY-1,2,3,4~_10,14b-hexahydro-p~ridinoL1~2-al-dibenzo ~clfl- zepine To a suspension of 10 g of Li/~lH4 in 800 ml of dry ether is added a solution of 30 g o~ 2-keto-1,2,3,4~1V,14b-hexahydro-pyridinoLl,2-aJ-dibenzo~c,f~-azepine in 1 liter of ether/T~I~ mixture (7:3). The suspension obtained is heated while stirring for 30 minutes.
After cooling the mixture 40 ml of water are added care-fully so as to decompose the excess of liAlH4, after which the solution is filtered off and the filtrate is evaporated and recrystallized. Obtained in this manner: 25 g; melting point 146-147C (equatorial).
Rf in toluene:ethylacetate (8:2) = 0.25.

4. 2-tosylox -1 2 3 4 10 14b-hexahydro-~ridino~ a ~ ibenzo ~ Y
[c~f ~azepine 4 g of the 2-hydroxy compound from 3 are dissolved in 50 ml of dry pyridine. This solution is cooled on ice and then 5 g of tosylchloride is added while stirring.
After left to stand the solution for 24 hours at room temperature it is poured into 400 ml of water. After that the aqueous solution is extracted into ether, the ether layer is washed with 2N hydrochlorid acid and then with water. After this the ether layer is dried and evaporated to dryness.
Obtained in this manner: 5 g; melting point 130-132C
(equat.).
Rf in hexane:acetone (95:5) = 0.45 on SiO2; in toluene:
0.31.

5. 2-cYano-1.2,3~4,10114b-hexah~dro-py_idinoLl,2-al-dibenzo [c,fl-azeeine 4.6 g of the compound obtained in 4 are dissolved in 50 ml of dimethylsulfoxide, after which 2 g of micropowdered NaCN are added. The mixture is heated while stirring at 90C for 2 hoursO ~fter cooling the mixture it is poured into 300 ml of water yielding a light yellow precipitate.
This precipitate is dried.
Obtained in this manner: 2.2 g; melting point 184-186C
(axial.).
Rf in hexane:acetone (95:5) = 0.60 on SiO2.

6. ~-azido-11?,3,4,10~4b-hexahydro-pyL ~ nzo ~c~f¦ ~ e - 20 _ 105~37B
To 4.5 g of the compound obtained in 4,dimethylformamide (25 ml) are added and after that 1.5 g of activated sodium-azide. The mixture is refluxed for 5 hours, after which this mixture is poured into water and extracted S into ether~ whereafter the ether layers are dried and evaporated to dryness.
The precipitate is immediately used for further conversions.
Rf in hexane:acetone (9:1) = 0.6S on SiO2 (axial position),

7. 2-c-yanomethylidene-l~2~3~4~lo~l4b-hexahydro-pyridino[l~2-a dibe ~ -azepine 1 g of 2-keto-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-di-benzo[c,f]-azepine is mixed with 1 ml of benzene, 0.5 ml of acetonitril and 0.5 g of molecular sieve (4 A) . 50 mg of sodlum-ethoxyde are added and the mixture is heated for 3 hours (90-100C). After cooling the mixture the molecular sieve is filtered off and the filtrate evaporated.
The precipitate is recrystallized from ethanol.
Obtained in this manner: 200 mg; melting point 215-217C.

8. 2-carboxY-l92~3?4~lo~]4b-hexahyd-ro-pyridino[l~2-al-dibenzo ~c~fl-azePi~ne (axial.) 1.1 g of the 2-cyano-compound obtained ln 5 and 55 ml concentrated HCl solution are heated in a sealed ampoùle for 4 hours. The precipltate formed is filtered off and dried. Yield: 8.6 g of the HCl salt of the title compound;
melting point 260-263C.
Dissolvlng thls salt ln 2 n NaOH and treating the alkaline solution wlth 0.1 n HCl to neutral yields a precipitate of the free base, wIlich is filtered off and dried. Yield:

~. ,.

--1~563~B
5.1 g; melting point 207-209C.
Rf in toluene:ethanol (8:2) = 0.55 on SiO2.

Example I
Pre aration 2-amino-1 2 3 4 10 14b-hexahydro-pyridino ~,2-al------ P - _Ll ! 1 2_ dibenzol c,fl-a7~nine 15 g of 2-keto-1,2,3,4,10,14b-hexahydro-pyridinoïl,2-a]-dibenzoLc,f]-azepine are dissolved in 500 ml of ethanol. To this solution are added 5 g of hydroxylamine.HCl and 10 ml of pyridine. The solution is then heated on a vapour-bath for one hour, after which the solution is evaporated to dryness in vacuo. The precipitate is added to ether and washed with a diluted acid. The etherlayer is washed with water once more and after that evaporated to dryness. Yield of the corresponding 2-oxim compound: 18 g (oil).
Rf in toluene:ethylacetate (8:2) = 0.45.
600 mg of this oximeis dissolved in 30 ml of isopropanol, after which 2 g of sodium are added to the solution. The mlxture is heated until all sodium has been dissolved.
After cooling the solution it is poured into 300 ml of water and extracted with ether. The ether layer is evaporated to dryness and the precipitate is recrystallized from ethanol.
Melting point: 5~-61C (position NH2 group: equatorial).
Me]ting point of the hydrochloride: 223-226C (equatorial).
l~f in methanol:acetone (9:1) = 0~15.

Example Il In the same way as described in example I are prepared by reduction of the corresponding 2- or 3-oxim compound:
2-amino-~-bromo-1,2,3,~,1(),1~b-hexahydro-pyridinoLl,2-a]-~L~56~7~
dibenzoLc,f]-azepine (oil); Rf in methanol:acetone (9:1) = 0.10.
2-amino-8-methoxy-1,2,3,4,10~14b-hexahydro-pyridinoLlt2-a]-dibenzo[c,f]-azepine;
Rf in methanol:acetone (85:15) = 0.15 on SiO2.
2-amino-13-methyl-1,3,4,14b-tetrahydro-2H-pyridino[1,2-d]-dibenzo[b,f](l,4)-thiazepine (oil);
Rf in methanol:acetone (9:1) = 0.12 on SiO2.
2-amino-7-trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyridino [1,2-d]-dibenzo[b,f](1,4)-thiazepine (oil);
Rf in chloro~orm:methanol (8:2) = 0.30.
2-amino-7-chloro-10-methyl-1,2,3,4,10,14b-hexahydro-pyridino Ll,2-d]-dibenzo[b,f](1,4)-diazepine (oil).

2-amino-1,3,4,14b-tetrahydro-2H-pyridinoLl,2-d]-dibenzo~b,f]
(1,4)-oxazepine;
Melting point HCl salt: 230-235 (dec.).
2-amino-10-methyl-13-methoxy-1,2,3,4,10,14b-hexahydro-pyridino [1~2-d]-dibenzo[b~f](1,4)-diazepine (oil);
Rf in methanol:acetone (8:2) = 0.20 on SiO2.
3-amino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f~-azepine;meltin~ point HCl salt: 220-225C (dec.).
3-amino-11-methyl-1,3~4,14b-tetrahydro-2H-pyridino[1,2-d]-di-benzo~b,f](l,4)-oxazepine (oil).
2-amino-7-hydroxy-10-methyl-l,Z,3,4,10,14b-hexahydro-pyridino [1,2-d]-dibenzo[b,f](1,4)-diazepine ~oil).

Example III
Preparation 2-methYlamin~2,3L4,10~14b-he~ dro-pyridino [1 ~ nzo Lc fl-azepine 1 y of 2-keto-1,2,3,4,]0,14b-hexahydro-pyridino[1,2-a]-:.

., . ~, . :: . ' - -105637~ ~
dibenzo[c~ -azeplne is dissolved in 100 ml of ethanol, after which 10 ml of methylamine and 2Q0 mg of palladium ¢10%) on charcoal are added. Then hydrogen is passed through this mixture until no hydrogen is absorbed any longer.
The mixture is filtered and the filtrate is evaporated and recrystallized from ethanol.
Obtained in this manner; 0.9 g ~oil).
Rf in methanol:acetone ~9:1) a 0.15 on SiO2.
Melting point as fumarate: 185-187C ~equatorial position).
By taking instead of methylamine one of the following reagents, namely ethylamine, isopropylamine, morpholine or piperidine the following compounds are obtained:
2-ethylamino-1,2,3,4,10,14b-hexahydro-pyridino`~1,2-a~-dibenzo ~c,f~-azepine, 2-isopropylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzolc,fJ-azepine, 2-morpholinol,2~3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo { [c,f~-azepine, 2-piperidino-lJ2,3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo ~c,f~-azepine.
Exam~le IV
2-dimethylamino-1,2,3,4,10,14b-hexa_ydro-~yridinoC1,2-a~-I dibenzo[c,l-azepine 1 20 g o 2-keto-1,2,3,4,10,14b-hexahydro-pyridinoC1,2-a~-dibenzoCc,f~-azepine are suspended in 600 ml o ethanol. To this mixture are added 25 ml o dimethylamine and 2 g of palladium tl0~) on charcoal. The mixture is hydrogenated until no hydrogen is absorbed anymore. Ater this the catalyst `! is iltered o, the iltrate evaporated and the precipitate ., ' - 24 -: j :

recrystallized from ethanol.
Obtained in this manner: 16 g.
Melting point free base 88-89C Cequatorial), melting point HCl salt 266-269 C Cequatorial). Rf in methanol:acetone t9:1 = 0.20 on SiO2.
Treatment of the free base with methyliodide yields the iodomethylate; melting point 202-205C.
By having the keto compound first reacted ~ith dimethyl-amine at low temperature, e.g. at 0C, in the presence o a Lewis acid, such as TiC14, AlC13, etc. the enamine formed as intermediate-product can be isolated and reduced aterwards. -Example V -In the same manner as described in example IV the following compounds are prepared starting from the corresponding 2- or 3-keto compound:
2-dimethylamino-8-bromo-1,2,3,4,10,14b-hexahydro-pyridinoC1,2-a~- :
dibenzo[c,f~-azepine toil);
Rf in methanol:acetone C8:2) o 0.20 on SiO2 Cequatorial).
2-dimethylamino-13-methyl-1,3,4,14b-tetrahydro-2H-pyridino C1,2-d~-dibenzo[b,~tl,4)-thiazepine;

melting point 141-143C, melting point of the maleatc salt 192-195C Cequatorial).
2-dimethylamino-8-methoxy-1,2,3,4,10,14b-hexahydro-pyridino C1,2-a~-dibenzo~c,f~-azepine Coil);
Rf in methanol:acetone C8:2~ # 0.25 on Si02 C~quatorial).
2-dimethylamino-7-tri1uoromethyl-1,3,4,14b-tetrahydro-2H-pyridinoC1,2-d~-dibenzocb,~tl,4~-thiazepine Coil);
R~ in chloroorm:methanol ~8:2) - 0.45 on SiO2 Ceq.).

1056~7l3 2-dimethylamino-7-chloro-1,3,4,14b-tetrahydro-2H-pyridino[1,2-dJ-dibenzo~b,f~ ~,4)-thiazepine;
melting point free base 63-68C ~equatorial~.
2-dimethylamino-ll-methyl-1,3,4,14b-tetrahydro-2H-pyridino C1,2-d~-dibenzo[b,f~1,4)-oxazepine;
melting point free base 111-113C ~eq.);
melting point HCl salt 263-265C ~eq.).
2-dimethylamino-1,3,4,14b-tetrahydro-2H-pyridino[1,2-d~-dibenzo [b,f~ ~,4)-oxazepine;
melting point HCl salt 260-265 C ~equatorial).
2-dimethylamino-7,11-dimethyl-1,3,4,14b-tetrahydro-2H-pyridino [1,2-d~-dibenzo[b,f~(1,4)-oxazepine ~oil);
Rf in methanol: acetone ~9:1) = 0.20 on SiO2 ~eq~atorial).
2-dimethylamino-10-methyl-1,2,3,4,10,14b-hexahydro-pyridino [1,2-d~-dibenzo[b,f]~1,4)-diazepine;
melting point HCl salt 209-211C ~equatorial).
2-dimethylamino-10-methyl-13-methoxy-1,2,3,4,10,14b-hexahydro-pyridino[l,2-d~-dibenzo[b,f] ~,4)-diazepine;
melting point HCl salt: 194-197C ~equatorial).
2-dimethylamino-10-methyl-13-chloro-1,2,3,4910,14b-hexahydro-pyridino[l,2-d]-dibenzo~b,f]~1,4)-diazepine.
Example VI

3-dimethylamipo,-~2,~3,4,1,0,14b-hexahydro-dibenzo~c,~-pyridino [1,2-a~-azepine 3,5 g o 3-keto-1,2,3,4,10,14b-hexahydro-dibenzo[c,f~-pyridino ~1,2-a~-azepine are dissolved in 100 ml of ethanol. To this sol~tion are added 4 ml of dimethylamine and 0.4 g o palladium ` 10% on charcoal. The mixture is hydrogenated while stirring in-; tensively. A~ter the theoretical quantity o hydrogen has .

:~ .

:
- -, - - . . . ,. : : .

1~56378 been absorbed the catalyst is filtered off and the filtrate evaporated to dryness by means of a film evaporator. Obtained in this manner: 3.6 g of the 3-dimethylamino compound. Treating this compound with a solution of HCl in alcohol results into - 2.8 g of the HCl salt, melting point 242-248C ~equatorial) ~-position).
In the same manner are prepared:
3-dimethylamino-11-methyl-1,3,4,14b-tetrahydro-2H-pyridino ~1,2-d~-dibenzo~b,f~ ~,4)-oxazepine;
Rf in methanol:acetone ~8:2) = 0.20 ~e~uatorial).
3-dimethylamino-7-trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyridino[l,2-d~-dlbenzo[b,f~¢1,4)-thiazepine;
Rf in chloroform:methanol ~8:2) ~ 0.40 on SiO2 ~eq.).
3-dimethylamino-8-bromo-1,2,3,4,10,14b-hexahydro-dibenzo[c,f~-pyridino[l,2-a~-azeplne;
Rf in methanol:acetone ~8:2) = 0.20.
3-dimethylamino-10-methyl-1,2,3,4,10,14b-hexahydro-pyridino [1,2-d~-dlbenzo[b,~1,4~-diazepine ~oil);
Rf = 0.25 in methanol:acetone ~8:2) Cequatorial).
Example VII
2-aminomethyl-1,2,3,4,10,14b-hexahydro-pyridinoL1~2-a~-dibenzo ~c,f~-azepine~
To a suspenslon o 10 g LlAlH4 in 400 ml o dry ether a solution o 8 g o 2-cyano-1,2,3,4,10,14b-hexahydro-pyridino ~1,2-aJ-dibenzo~c,f~-azepine ~axial) in 300 ml of THF is added. Then the mixture is refluxed or 30 minutes, where-upon it is cooled by means of ice. Ater that 40 ml of water are added to the mixture careully so as to hydrolyse the excess of LiAlH4. The resulting precipitate is filtered off after which the filtrate is evaporated.
Obtained in this manner: 8.0 g ~oill.
Rf in methanol:acetone ~ 0.45 on SiO2.
Melting point maleate salt: 172-174C ~axial position~.
ample VIII
3-aminomethyl-11-methyl-1,3,4,14b-tetrahydro-2H-;~yridinoC1,2-d~-dibenzo Lb,f~¢1,4~-oxazepine 12 g of 3-keto-11-methyl-1,3,4,14b-tetrahydro-2H-pyridino ~1,2-d~-dibenzo[b,f~1,4)-oxazepine are hydrogenated with hydrogen and pallad;um on charcoal in ethanol. After all hydrogen has been absorbed the catalyst is filtered off, where-after the 3-hydroxy compound is obtained by evaporating the solvent. The product is dissolved in 100 ml of pyridine.
While cooling in ice water and stirring 8 g of mesylchloride are added to the solution. The mixture is let to stand at ambient temperature for 18 hours and is poured into water after that.
The aqueous solution is extracted into ether. The ether extracts are washed with 2N sulphuric acid and water and finally dried on dry sodium sulphate.
The dry ethereal solution is evaporated and the resi-due dissolved in 100 ml o dimethylsulphoxide.
6 g o sodiumcyanide ~dry) are added to the solution.
While stirring the solution is heated or 3 hours at 100C, I followed by pour;ng the reaction mixture into water. Extract-ing with benzene, washing the benzene-extract with water, drying on sodium sulphate and evaporating the solvent yields 8.~ g o the crude nitrile. The product is purified over silicagel by means of chromatography. Reduction of the .

- 2~ _ nitrile with LiAlH4 in ether in the manner as indicated in example VII finally results i~ 6.2 g o axial 3-am~nomethyl compound as an oil.
Example IX
The following compounds are prepared from the corresponding cyano-compound by a reduction with LiAlH4 in the way as indicated in Example VII:
2-aminoethyl-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo ~c,f~-azepine ~oil);
Rf in methanol:acetone ¢9:1) = 0.45 ~axial), from the corre-sponding 2-cyanomethyl compound ~axial).
2-aminomethyl-13-methyl-1,3,4,14b-tetrahydro-2H-pyridino~1~2-d~-dibenzo[b,f~ ~,4)-thiazepine ~oil);
Rf in methanol:acetone ¢8:2) ~ 0.35, from the corresponding 2-cyano-compound ~axial).
3-aminomethyl-10-methyl-1,2,3,4,10,14b-hexahydro-pyridino [1,2-d~-dibenzo[b,~ ~,4)-diazepine, from the corresponding axial 3-cyano-compound.
Example X
2~ 2-aminoethyl-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a~-dibenzo [c,~-azepine Diborane gas, obtained rom 1.2 g o~ NaBH4 and 5.2 ml o BP~-etherate is let in into a solution of 200 mg o 2-cyano-methylidene-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo ~c,f~-azepine in 15 ml o THF ~under nitrogen atmosphere).
After that the mixture is refluxed for 1 hour. The excess of B2H5 present is then decomposed by adding ethanol, where-upon thD solution is evaporated.

:::

.:

~ - . . . . . . -- . . . . .

-~(~S637~
The re~idue is dis~ol~ed in 18 ml of a mixture of concentrated HCl and water ~ whereupon the solution is heated for some time. The acidic water layer is cooled down, made alkaline and then extracted with ether. Evaporating the solvent yields 0.85 g of thc title compound as an oil.
Exam~le XI
2-amino-1,2,3,4,10l14b-hexahydro-py-ridino~l~2-al-dibenzo[c~f~- -aze~ine 4 g of 2-azido-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a~- i dibenzo[c,f~-azepine ~axial) ls added to a suspension of 3 g of LiAlH4 in dry ether. The mixture obtained is heated or 1 hour, and after that cooled down. Then 12 ml o water are added to the mixture dropwise, whereby an inorganic precipitate is formed. The inorganic residue is removed by f;ltration after which the filtrate is evaporated to dryness.
Obtained in this manner: 3.5 g ~oil).
Rf in methanol:acetone ~9:1) ~ 0.28 ~axial position).
In the same way are prepared:
2-amino-8-bromo-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a~-dibenzo ~c,f~-azepine ~oil) from the corresponding 2-azido compound ~ax.).
3-amino-1,2,3,4,:LO,14b-hexahydro-pyr~d~no~1,2-a~-dlbenzo~cJf]-azepine rom the corresponding 3-azido compound ~ax.).
2-aminomethyl-1,2,3,4,l0,14b-hexahydro-pyridinoLl,2-a~-dibenzo ~c,~-azepine from the corresponding 2-azidomethyl compound ¢axial); melting point maleste: 170-174C Cax.).
2-aminomethyl-1,3,4,14b-tetrahydro-2H-pyridino[1,2-d~-dibenzo ~b,f~ ~,4~-cxazepineJ from the correspond;ng 2-az;domethyl compound ¢axial). i ;

ample XII
2-dimethylaminomethyl-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a~-4 g of the aminomethyl compound obtained in VII are dissolved in 100 ml of methyl-ormate. The solution is heated for 24 hours at 40C. Af~er that the solvent ~methylformate~ is distilled off in vacuo.
In this manner 4.5 g oily formylamino derivative is obtained.
Rf in methanol:acetone ~9:1) = 0.90.
4.5 g of this oil dissolved in 250 ml o tetrahydrofurane are added to a suspension of 5 g of lithiumaluminium hydride in 250 ml of dry ether. The suspension is re1uxed or 2 hours. Ater cooling do~n the suspehsion with ice, 20 ml of water are added drop~ise, after which the mixture obtained is iltered. The filtrate is evaporated to dryness.
Obtained in this manner: 4.3 g of axial 2-methylaminomethyl compound.
Rf in methanol:acetone ~g:2) ~ 0.45.
The above-mentioned product is treated with methylformate in the same way once again ~melting point N-ormyl-N-methyl-amino-methyl compound: 117-119C) and reduced ater that.
:~ .
Obtained ~n this manner: 3.4 g.
Melting point ~ax.): 2-dimethylaminomethyl-1,2,3,4,1Q,14b-hexahydro-pyridino[1,2-a~-dibenzoCc,~-azepine umarate:
174-176C.
R in methanol:acetone ~9:1) ~ 0.40 on SlO2.

I Example XIII
Separation o axial and equatorial 2-dimeth~lamino-1,2,3,4,10-14b-hexahydro-d;benzoCc,~-pyridino~1,2-a~-azep;ne ~ : .. , . . : - .. . : . . . - :

lOS6378 4.38 g o th~ mother liquor from example IV ~mixture of axial and equatorial compound) are dissolved in a mixture of methanol:acetone ~9:1). This solution is chromatographed in a column containing 4.5 kg of SiO2. The column is eluted with a mix~ure of methanol:acetone ~9:1).
Rf axial ~ 0.38 in methanol:acetone ~9:1).
Rf equatorial - 0.16 in methanol:acetone ~:1).
Melting point axial compound as fumarate: 190-192C.
Melting point equatorial compound as HCl salt: 266-269C.
Example XIV
2-dimethylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo [c,f~-azePine 4 g of 2-tosyloxy-1,2~3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo[c,f~-azepine teq.) are dissolved in 50 ml of dimethyl-sulphoxide. After that 15 ml of dimethylamine are added~to the solution. Th~s solution is now heated in a sealed ampoule on a vapour-bath for 2 hours. After cooling the solution, it is poured into 300 ml of water after which the mixture is extrac-ted with 3x200 ml of ether. The ether layers are washed and then dried, whereupon the solvent is evaporated and the residue i5 recrystallized. Yield: 1.3 g.
Melting point 84-87C ~axial form~; melting point ~umarate 192-193C.
Rf in methanol:acetone ~9:1) ~ 0.45 on SiO2.
Starting rom the corresponding equatorial 2- or 3-tosyloxy-compound the follow;ng substances with the 2- or 3-aminoalkyl group in ax;al pos;t;on are prepared in the way ind;cated previously:
2-di~ethylamino-8-bromo-1,2,3,4,10,14b-hexahydro-pyrid;no~1,2-a~-: - ~2 -- . .
, . - i . - . ~

lOS6378 dibenzo[c,f~-azepine ~oil);
Rf in methanol:acetone ~8:2) - 0.40, 2-morpholino-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a~-dibenzo [c,fJ-azepine ~oil);
Rf in m~thanol:acetone ~9:1) = 0.50.
2-pyrrolidino-1,3,4,14b-tetrahydro-2H-pyridino~1,2-d~-dibenzo ~b,f~ ~,4)-oxazepine ~oil);
Rf in methanol:acetone ~9:1) = 0.45.
2-amino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo[c,f~-azeplne;
Rf in methanol:acetone ~9:1) = 0.30 on SiO2.
2-methylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo [c,fJ-azepine, oil;-Rf in methanol:acetone ~9:1) = 0.35 on SiO2.
3-methylamino-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a~-dibenzo [c,f~-azepine ~oil);
Rf in methanol:acetone ~9:1) ~ 0.30 on SiO2.
3-dimethylamino-7-trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyridino[l,2-d~-dibenzo[b,f.~ ~,4)-thiazepine ~oil);
R in chloroform:methanol ~:2) = 0.45.
2-methylamino-10-methyl-7-methoxy-1,2,3,4,10,14b-hexahydre-pyrldinoll,2-d~-dibenzo Eb, f~ ~1,4)-diazepine.
Starting rom the corresponding equatorial 2- or 3-mesyloxy compounds the Pollowing substanccs are prepared in the way indicated previously ~see also example VIII from the preparation of mesyloxy compounds):
3-dimethylamino-11-methyl-1,3,4,14b-tetrahydro-2H-pyridino~1,2-d~-dibenzo[b,~ ~,4)-oxazepine ~axial).
2-amino-1,2,3,4,10,14b-hexahydro-pridino.~1,2-a~-dibenzo~c,~-1~56378 azepine ~axial);
Rf in methanol:acetone ~9:1) ~ 0.~0 on SiO2.
2-dimethylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-diben~o[c,f~-azepine ~axial);
Rf in methanol:acetone C9:1) ~ 0.45 on SiO2;
melting point 84-86C.
Starting rom the corresponding axial 2-tosyloxymethyl-compound the following compounds are obtained:
2-aminomethyl-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo [c,f~-azepine;
melting point maleate: 170-175C ~axial).
2-dimethylaminomethyl-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a~-dibenzo[c,f~-azepine;
melting point 172-175C as umarate ~axlal~.
Exam~le XV
. _ 2-dimethylamino-methyl-1,2,3,4,10,14b-hexahydro-pyradlno~1,2-a~-dibenzo~c,~-azepine 10 g o ~ax.) 2-dimethylaminocarbonyl-1,2,3,4,10,14b-hexa-hydro-pyridino[1,2-a~-dibenzo[c,~ -azepine, obtained rom the corresponding ~ax.~ 2-carboxy-1,2,~,4,1~,14b-hexahydro-pyridino ~ ~1,2-a~-dibenzo~c,f~-a~epine ~m.p. 207-209¢) are dissolved in 'I 100 ml tetrahydrouran ~THP~. This solution is slowly added to a stirred suspension o~ 15 g LiAlH4 in TH~. The mixture is refluxed or 2 hours ant then cooled down.
60 ml o water are now slowly added to the stirred mixture, whereupon the a~ueous mixture is iltered to remove the inorganic ~ solids. The iltrate is evaporated in vacuo yielding 9.8 g o the ¦ oily residue. The resldue i5 treated wlth fumaric acid in alcohol yielding the umaric acid salt o the title compound;
30- melting point 174-176C ~ax.).
,.. ..... .

- ~4 -lC~S6378 In the same manner the corresponding dimethylamino-methyl derivatives are prepared starting from:
2-carboxy-8-chloro-1,3,4,14b-tetrahydro-2H-pyridino-~1,2-d~-diben~o~b,f]~1,4)-oxazepine ~ax.), m.p. 211-214C.
2-carboxy-7-methyl-1,3,4,14b-tetrahydro-2H-pyridino[1,2-d~-dibenzo[b,f~l,4)-oxazepine ~ax.); m.p. 209-211C.
2-carboxy-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo [c,f~-azepine ~eq.); m.p. 193-195C.
Example XVI
2-aminomethyl-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-dibenzo Cc,f~-azepine 3 g of 2-cyano-1,2,3,4,10,14b-hexahydro-pyridinoLl,2-a~-dibenzo[c,f~-azepine ~ax.), is dissolved in 27 ml of concen trated H2SO4 and 0.3 ml of water. The solution is heated at a steambath for about 2 hours. The reaction mixture is then poured into 500 ml of water, whereupon the aqueous mixture I obtained is extracted into ether.
The ether layers are washed with water and dried. The axial-amide residue obtained tm.p. 200-202C) is converted 1 20 into the corresponding axial 2-amino-methyl derivative in j the manner as described in Example XV.
Melting point maleate: 172-174C.
~ ~ Example XVII
1 3-timethylamino-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a~
~ dibenzo~c,~-azepine .
10.5 g o 2-keto-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a~-dibenzo~c,~-azepîne are dissolved in 1 liter o THE. The solution is cooled down to 0C. Whilc stirring 30 g of phenyl-i, ll;~S6378 trimethylammoniumtribromide are added and after 2Q min. 250 ml of NaHCO3 solution Csaturated).
The mixture is extracted into ether, and the ether layer washed, dried and evaporated. The residue ~oil) is purified by means of chromatography. In this way 3 g uf crystalline 3-bromide is obtained; melting point 149-151C. This substance is dissolved in 90 ml of DMSQ ~dimethylsulphoxide) to which 10 ml of dimethylamine are added. After the mixture is left to stand for 2 days at room temperature, the excess of dimethyl-amine and the dimethylsulphoxide is removed by means of a rotary film evaporator. The residue is dissolved in water.
Extraction of this liquid into ether, washing the ether-extract with water, drying it on Na2SO4 and evaporation of the solvent results in 5.2 g of crude 3-dimethylamino-2-ketone, that is chromatographed over aluminiumoxide.
Obtained in this manner 4.3 g oil. A part of this oil crystallizes after some time: m.p. 118-122 C. The oil is dissolved in 25 ml glycol to which 5 g of solid KOH and 6 ml of hydrazinehydrate are added.
The mixture is heated at 150 for 12 hours and then poured into 200 ml of water. The 3-dimethylamino-derivative is isolated by extracting the mixture into an ether-benzene mixture ~1:1), washing the extract with wster, drying it on Na2SO4 and evaporating the solvent.
Obtained in this manner: 2.8 g ~oil)~ Melting point as picrate: -161-164C.
In the same way are prepared:
3-dimethylamino-11-methyl-1,3,4,14b-tetrahydro-2H-pyridino [1,2-d~-dibenzo~b,f~C1,4)-oxazepine;
Rf in methanol:acetone ~9:1) = 0.15.

3-dimethylamino-lO~methyl-1,2,3,4,10,14b-hexahydro-pyridino [1,2-d~-dibenzo[b,f~1,4)-diazepine;
Rf in methanol:acetone ~9:1) = 0.20.
3-morpholino-1,2,3,4,10,14b-hexahydro-pyridino~1,2-a~-dibenzo -[c,f]-azepine;
Rf in methanol:acetone ~8:2) = 0.40.
Example XVIII
In the same way as indicated in example XVII a 3-keto-2-amino-compound tmixture of 2 axial and 2 equatorial) is con-verted by means of a Wolff-Kishner reduction into the corre-sponding 2-amino-compound ~mixture of 2-axial and 2-equatorial) followed by a separation of both isomers with the aid of a silicagel column as described in example XIII.
In this manner are prepared:
2-dimethylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-di-benzo[c,f]-azepine ~2-equatorial);
melting point HCl salt: 268-270C.
2-dimethylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a~-di-benzo[c,fJ-azepine ~2-axial);
, 20 melting point: 87-88C.
2-dimethylamino-7-trifluoromethyl-1~3,4,14b-tetrahydro-2H-pyridino[l,2-d]-dibenzo~b,f~1,4)-thiazepine C2-equatorial), toil);
R ~ 0.45 in chloroform:methanol C8:2).
i 2-dimethylamino-11-methyl-1,3,4,14b-tetrahydro-2H-pyridino [1,2-d]-dibenzo[b,f]~1,4)-oxazepine ~2-equatorial);
melting point: 113-114C;
2-dimethylamino-10-methyl-1,2,3,4,10,14b-hexahydro-pyridino [1,2-d~-dibenzo~b,f~1,4)-diazepine ~2-equatorial);
melting point: 210-212C as HCl salt.

;,' `

1~56378 2-dimethylamino-10-methyl-7-methoxy-1,2,3,4,10,14b-hexahydro-pyridino[l,2-d~-dibenzo~b,f~C1,4)-diazepine.
Example XIX

2-dimethylaminomethyl-1,2,3,4,10,14b-hexahydro-pyrldinoC1,2-aJ- - -dibenzo~c,f~-azepine A mixture of 4 g of 3-keto-1,2,3,4,10,14b-hexahydro-pyridino [1,2-a3-dibenzo~c,f~-azepine, 60 ml of ethanolj 1.3 g of dimethyl-amine hydrochloride, 0.5 g of paraormaldehyde and 2 drops of concentrated hydrochloric acid is heated for 6 hours, after which the alcohol is distilled off. The residue is taken up in water and made strongly alkaline with 4N sodium hydroxide.
Extraction into ether, washing the extract with water and evaporation of the ether yields 3.7 g of the 2-dimethylamino-methyl-3-keton, that is subjected to a Wolff-Kishner reaction without a further purification. Yield: 2.9 g of the 2-dimethyl-aminomethyl compound. After purification over a sillcagel column the product is treated with an alcohollc fumarlc acld solution.
The fumarate obtained melts at 168-173C.
Example XX
3-diethylaminomethyl-1,3,4,14b-tetrahydro-2H-pyridino~1,2-d~-dibenzo~b,f~1,4)-thiazepine A mixture of 8.4 g o the 2-kcto-compound, 2.9 g of diethyl-amine hydrochloridc, 1 g o paraformaldehyde and a few drops of concentrated hydrochloric acid in 100 ml ethanol is refluxed ; for 5 hours. Then the reaction mixture is evaporated as much as possible, whereupon 200 ml o water are added to the residue.
; The aqueous mixture is made alkaline wlth 2N NaOH. Extracting into ether and washlng, drying and evaporating in the usual .~ . .

.,, : ' ' ,.

~(~5~78 way, yields 6.8 g of the 3-diethylaminomethyl-2-keton.
This crude keton is dissolved in a mixture of 40 ml of diethyleneglycol and lO ml of dimethylsulphoxide. After adding lO ml of hydrazine hydrate and 4 g of ~OH the mixture is stirred for 0.5 hour and then heated at 120 for another hour. Finally the temperature is raised to 160 during 1 hour. After 3 hours' heating at 160 the greater part of the hydrazine hydrate is evaporated in vacuo and the residue poured into water. Extraction into ether and washing, drying and evaporation of the ether extract results in 5.2 g of the 3-diethylaminomethyl compound as a viscous oil. This oil is dissolved in a mixture of methanol:acetone (9:1) and chromato-graphed over SiO2. After elution with the same solvent the axial compound is obtained as an oil. Rf - 0.35 on SiO2~ fol-! 15 lowed by the equatorial compound: Rf = 0.18 on SiO2.
.

Claims (29)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for preparing a compound of the general formula I

I

or a pharmaceutically acceptable salt thereof, in which the moiety is present in the 2- or 3-position and in which X represents oxygen, sulphur, the group or the group -CR8R9-, R1, R2, R3 and R4 represent hydrogen, hydroxy, halogen, alkyl (1-6C) alkoxy (1-6C), alkylthio (1-6C) or trifluoromethyl, R5 and R6 represent hydrogen, alkyl (1-6C), aralkyl (7-10C) or R5 and R6 together with the nitrogen atom represent a saturated or unsatu-rated 5- or 6-membered heterocyclic ring, in which one oxygen atom or one additional nitrogen atom may be present as a further hetero atom, R7 represents hydrogen or alkyl (1-4C) R8 and R9 represents hydrogen or methyl, and n is the number 0, 1, 2 or 3, characterized in that a) a compound of the general formula IVA

IVA

or IVB

IVB

or a salt thereof, is reduced, or b) a compound of the general formula V

V

in which the -(CH2)n-Y group is in the 2- or 3-position and Y is a leaving group, is reacted with an amine of the general formula VI

VI

or a salt thereof, or c) a compound of the general formula VII

in which R is present at the 2- or 3-position and is -(CH2)n-1-CN or -(CH2)n-N3 is reduced, or d) a compound of the general formula X

X

in which the aminoalkylidene side chain is present at the 2- or 3-position is reduced, or e) for preparing compounds of the general formula I, in which n=0, a compound of the general formula II

II

in which the keto group is present in the 2- or 3-position is reacted with an amine of formula VI defined above in the presence of a reducing agent, or f) for preparing compound of general formula I, in which n=0, a compound of the general formula VIII

VIII

in which the oxime group is in the 2- or 3-position is reduced, or g) for preparing a compound of general formula I in which n is 1, 2 or 3, a compound of general formula IX

IX

in which the amide side chain is present in the 2- or 3-position is reduced and if required, the product is converted into a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof.

2. A process according to claim 1 in which the product is separated into its separate stereo-isomers.

3. A process according to claim 1 in which R5 or R6 are hydrogen which comprises alkylating or aralkylating the product of any one of process variants 1(a) to 1(g) to obtain the corresponding compound in which R5 or R6 are alkyl or aralkyl.

4. A process according to claim 3 in which the product is separated into its separate stereoisomers.

5. A process according to claim 1 for preparing a compound of formula I, in which the amino moiety or amino alkyl moiety is present in the 2-position of the molecule, by the process variant 1(a) using the compound of formula IVB or by one of process variants 1(b) to 1(g).

6. A compound of formula I as defined in claim 1 and its pharmaceutically acceptable salts when made by a process according to claim 1 or an obvious chemical equivalent thereof.

7. A compound of formula I as defined in claim 1 with the amino or amino alkyl moeity in the 2-position whenever prepared by a process according to claim 5 or an obvious chemical equivalent thereof.

8. A process according to claim 1 for preparing a compound of formula I, in which n=0.

9. A compound of formula I as defined in claim 1 in which n=0, whenever prepared by a process according to claim 8 or an obvious chemi-cal equivalent thereof.

10. A process according to claim 5 wherein X is CR8, R9, R1, R2, R3, R4, R8 and R9 are each hydrogen, n is O and R5 and R6 are both methyl.

11. A process according to claim 1(e) for preparing the com-pound 2-dimethylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine and its hydrochloride salt and iodomethylate salt which comprises re-acting 2-keto-1,2,3,4,10,14b-hexahydro-pyridino[1,2,-a]-dibenzo[c,f]-azepine with dimethylamine in the presence of a reducing agent and, if required, con-verting the product to the hydrochloride salt or iodomethylate salt.

12. A process according to claim 11 wherein the reducing agent is hydrogen gas in the presence of a palladium catalyst.

13. A process according to claim 11 wherein the 2-equatorial isomer is separated from the product.

14. The compound 2-dimethylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine, its hydrochloride salt and its iodomethy-late salt whenever prepared by a process according to claim 11 or 12 or an obvious chemical equivalent thereof.

15. The equatorial stereo-isomer of 2-dimethylamino-1,2,3,4,10, 14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine, its hydrochloride salt and its iodomethylate salt whenever prepared by a process according to claim 13 or an obvious chemical equivalent thereof.

16. A process according to claim 1(b) for preparing 2-dimethyl-amino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine having the 2-dimethylamino group in the axial position and its fumarate salt which com-prises reacting 2-tosyloxy-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo [c,f]-azepine having the 2-tosyloxy group in the equatorial position with di-methylamine and, if the fumarate salt is required, reacting the product with fumaric acid.

17. The compound 2-dimethylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine having the 2-dimethylamino group in the axial position and its fumarate salt when prepared by a process according to claim 16 or by an obvious chemical equivalent.

18. A process according to claim 1(a) for preparing 2-dimethyl-amino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine and its hydrochloride salt which comprises reducing 2-dimethylamino-3-keto-1,2,3,4,10, 14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine by a Wolff-Kishner reduction and, if the hydrochloride salt is required, reacting the product with hydrogen chloride.

19. A process according to claim 18 wherein the product of the Wolff-Kishner reduction is separated into the axial and equatorial isomers.

20. The compound 2-dimethylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine and its hydrochloride salt when prepared by a process according to claim 18 or by an obvious chemical equivalent.

21. The equatorial isomer of 2-dimethylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine and its hydrochloride salt when prepared by a process according to claim 19 or by an obvious chemical equiva-lent.

22. A process according to claim 5 wherein X is NR7, R1, R2, R3 and R4 are hydrogen, R5, R6 and R7 are methyl and n is O.

23. A process according to claim 1(e) for preparing 2-dimethyl-amino-10-methyl 1,2,3,4,10,14b-hexahydro-pyridino-[1,2-d]-dibenzo[b,f](1,4) diazepine and its hydrochloride salt which comprises reacting 2-keto-10-methyl-1,2,3,4,10,14b-hexahydro-pyridino[1,2-d]-dibenzo[b,f](1,4) diazepine with dimethylamine in the presence of a reducing agent and, if required, convert-ing the product to the hydrochloride salt.

24. A process according to claim 23 wherein the reducing agent is hydrogen in the presence of a palladium catalyst.

25. A process according to claim 1(a) for preparing 2-dimethyl-amino-10-methyl 1,2,3,4,10,14b-hexahydro-pyridino[1,2-d]-dibenzo[b,f](1,4) diazepine and its hydrochloride salt which comprises reducing 2-dimethylamino-3-keto-10-methyl 1,2,3,4,10,14b-hexahydro-pyridino[1,2-d]-dibenzo[b,f](1,4) diazepine by a Wolff-Kishner reduction and, if the hydrochloride salt is re-quired, reacting the product with hydrogen chloride.

26. A process according to claim 25 wherein the product of the Wolff-Kishner reduction is separated into the axial and equatorial isomers.

27. The compound 2-dimethylamino-10-methyl 1,2,3,4,10,14b-hexahydro-pyridino[1,2-d]-dibenzo[b,f](1,4) diazepine and its hydrochloride salt when prepared by a process according to claim 23, 24 or 25 or by an ob-vious chemical equivalent.

28. The equatorial stereoisomer of 2-dimethylamino-10-m0thyl 1,2,3,4,10,14b-hexahydro-pyridino[1,2-d]-dibenzo[b,f](1,4) diazepine and its hydrochloride salt when prepared by a process according to claim 26 or an ob-vious chemical equivalent.

29. A process according to claim 1 wherein R5 and R6 together with the nitrogen atom represent a heterocyclic 5- or 6-membered ring selected from the group consisting of pyrrolino, pyrrolidino, piperidine, oxazolidino, morpholino and piperazine.