CA1049512A - Amino-substituted piperidino-derivatives - Google Patents

Abstract

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

in which the keto group is present at position 2 or 3 and in which X stands for oxygen, sulphur, the group

Description

~L0~9~2 The present invention relates to novel compounds which are useful as intermediates in the production of biologically active amino-substituted piperidino-derivatives and to processes for their preparation. lhis application is divided out of application Serial No. 199,229.
Our patent application Serial No. 199,229, filed May 18, 1974 des- -cribes and claims compounds of the general formula I:

Rl 3 R2 ~ 2~ 4 ¦ / 5 ~\
~CH2 ) n~N l :

as well as the pharmaceutically acceptable salts thereof, wherein the R5`

2)n N \ I moiety is present at position 2 or 3 and in whish X stands R6~
for oxygen, sulphur, the group ,NR7 or ~he group -CR8Rg-; Rl, R2, R3 and R4 represent hydrogen, hydroxy, halogen, alkyl ~1-6 C), alkoxy ~1-6 C), alkyl-thio (1-6 C) or trifluoromethyl; R5 and R6 represent hydrogen, alkyl ~1-6 C), aralkyl ~7-10 C) or R5 and R6 together with the nitrogen atom represent a saturated or unsaturated heterocyclic five- or six-membered ring, in which one oxygen atom or one additional nitrogen atom may be present as a further hetero atom; R7 stands for hydrogen or alkyl ~1-4 C); R8 and Rg 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.
A very easy starting point for the synthesis of the compounds which are the subject of our application Serial NoO 199,229 is a compound of the general formula II:

, .
,. . .

~ 3 (Il) in which the ketogroup is present at position 2 or position 3 and in which Rl, R2, R3, R4 and X have the meanings mentioned above.
According to this invention there is provided a process for pre-paring a compound of formula II
Rl 3 ~ ~ II

O
in which X represents oxygen, sulphur, the group `NR7 or the group -CR8Rg-, Rl, R2, R3 and R4 represent hydrogen, hydroxy, halogen, alkyl ~1-6 C), alkoxy ~1-6 C), alkylthio Cl 6 C) or trifluoromethyl, R7 represents hydrogen or alkyl C1~4 C), R8 and Rg represent hydrogen or methyl and the keto gTOUp is in the 2- or 3-position which comprises condensing a compound of formula III

in which Rl, R2, R3, R4 and X are as defined above with vinylmethylketone to obtain the desired 2-keto compound and if required, converting the 2-keto ~ -compound to the corresponding 3-keto compound.
The 3-keto compound of formula II may be prepared from the corres-ponding 2-keto-compound of formula II in a conventional manner. For example~
this may be done by converting a 2-keto compound of formula II which comprises converting a 2-keto compound of formula II into the corresponding 2-keto-3 1~495~Z
hydroxy-imino compound, reducing the carbonyl group at the 2-position and hydrolysing the 3-hydroxy-imino group to a carbonyl group. l~e 2-keto-3-hydroxy-imino compound may be obtained by reacting the 2-keto compound of formula II with isoamyl nitrite and potassium in tert.butanol (see reaction scheme 4 at page 5), afterwards the carbonyl group at position 2 may be reduced by means of a Wolff-Kishner reduction. The 3-hydroxy-imino moiety in the com-pound thus obtained is then saponified under acidic conditions or with the aid of sodium bisulfite in an alcohol/water mixture.
Starting from a compound of formula II compounds of 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 principley the amino(alkyl) compounds of the invention are pre-pared starting from the 2- or 3-keto compound of formula II by two different approaches, namely the amino(alkyl) group can be introduced into the position adjacent 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) com-pound of formula I is prepared from a 2~keto-compound of formula II or a 2-amino~alkyl) compound of formula I is prepared from a 3-keto-compound of formula II; in the second approach a 2-amino(alkyl) compound I is prepared from a 2-keto compound o formula II or a 3~amino(alkyl) compound of formula I is prepared from a 3-keto compound of formula II.
The endproducts according to formula I may be manufactured, for example, by reducing the carbonyl group of a compound of the general formula:
IV A or IV B:

CCH2)n t IV A N IV B

R5 R6 ~5 ,~6 , ~ ,, ~ 3 ~

: - . .:

~9S~
or a salt thereof/ in which Rl, R2, R3, R4, R5, R6, n and X have the meanings afore-mentioned.
This reduction from _C-O to `CH2 is performed in a way usual for similar reductions, for example by means of a ~olff-Kishner, Huang-Minlon or Clemmensen reduction or by hydrogenolysis of di-alkylthio-acetals that are prepared from the relative keto-compound of formula IV.
Besides the use of the compounds of formula IV A and IV B as inter-mediates in ~he synthesis for the preparation of the compounds according to the general formula I, these compounds (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 of formula IV A and IV B can be administered both orally and parenterally, preferably in a daily dose of 0.01 - 10 mg per kg body weight.
The compounds of formula IV required in the above-mentioned synthe-sis can be prepared from the compounds of formula II in various ways. By way o~' example a number of reaction sc'hemes, given on the next page, illustrate --the preparation o a compound of formula IV starting from a compound of for- ~' ,m,ula II in which the keto group is at position 2. For compounds of formula ~ ' II w~th the keto group at position 3 these reactions proceed in an identical ~ ;
~0 way. ~ ~

~:

, . , - . : . . -~04~3531~2 2 HCOOC2H5 3 2 tos lation 3 2 Pd/H 3 2 NH 5~ 3 2 IV
NaOCH3 ~ ~ ~ Y ) ~ ~ 2t - \ `R6' ~ ~
0 , CH 0 CH 0 ~ CH 0 OH OTos OTos N ,R5 0 Br 0 ~ ~ IV

HN 5 ` ~ formaldehyde

3. ~ R6~' ~3 2l IV
(Mannich reaction~ ~ CH2 `b ¦ /R5 ~ ,.

R6~ ~

4 3 2 isoamylnitrite ~ 3 2/ Pd/C/H 3 2/ IV
~ potassium t.butoxide ~ \ 2 ) ~

OH

5. ~ ) N 2 /R5~' ~ IV

2) Cl CH2 CH2 N \ , CIH2 R6' Cl H2 N \ ~ :

6. 3 2 1) 2N \3 2/ base (KOC2H5) ~ IV
0 2) TosCl > ~ ~Neber rearrangemen /
(Tos = toxyl) N NH2 OTos et lformate /R5~ 3 21 P H
hy ~ ~ 0 ~ ~H O CH2 IV
OH ' R - N / 5 ~

, \ R ~ \ R ' ~:
, '-"' ~ ' ' ' ' "' ~ ' ' ~, , .

951.2 It will be clear that the s~eps mentioned in these reaction schemes for preparing starting product I~ need not necessarily be carried out in this strict sequence to obtain the compound of formula I.
Thus the Wolff-Kishner reduction (keto group reduction to -CH2), to which compound of formula IV in reaction scheme 4 would have to be subjected to obtain the compound according to formula I, can also be performed at an earlier stage, especially on the 2-keto-3-oxime compound (scheme 4). Purther it is possible to have the reduction of the double bond (position 3) in reaction scheme 1 or 7 performed at an earlier or later stage of the synthesis of the compound of formula Io These and other obvious modifications in the reaction scheme are considered to be fully analogous to the routes described above.
The conversion o a 2- or 3-keto compound of formula II into a com-pound according to formula I ha~ing the amino(alkyl) group at the same posi-tion as the keto group of the compound of formula II may be carried out in :~
various manners. All these methods are conventional methods, already describ-ed for similar compounds. :
The method, which can generally be used in preparing the compounds -~
of formula I, consists of the condensation of a compound with the general formula V: :~
Rl , 3 ~: :
~ ~X~

: ( 2)n in which the -(CH2)n-Y group is present at position 2 or 3, Rl, R2, R3, R4, n and X have the meanings specified 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: ~

~; - 6 - :

.

. " ' ' .,; ' . ~ ., ' . : .: ' : '' , ~gs~
R
/ 5 ~
HN I VI
R6 ~
or an acid addition salt thereof9 in which R5 and R6 have the me~nings defined preYious ly .
Leaving groups are well defined groups, described in various chemical handbooks.
Suitable leaving groups for this condensation reaction are for ex-ample a tosyloxy group, a mesyloxy group, a p-bromophenyl-sulphonyloxy group, a chlorine, bromine or iodine atom.
The compound of formula V required for this condensation reaction may be prepared from the compound of formula II 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, followed by convert-ing this hydroxyl group into the desired leaving group in a conventional manner, for instance by tosylation, mesylation, reaction with SOC12, PC15, PBr3, etc.
Extension of the alkyl chainlength (from n=0 to n=l, 2 or 3) can be performed in the usual way, for instance by treating a compound of formula V, in ~hich n=0, with a cyanide such as potassium- or sodiumcyanideO The cyano-gxoup in the compound thus obtained can either be reduced to the corresponding aminomethyl group or be hydrolysed to the corresponding carboxyl group. The aminomethyl compound is then treated with ni~rous acid at low temperature ~Piria), whereas the carboxyl compound is reduced. Both reactions afford the hydroxy-methyl compound in fairly good yields. Finally the hydroxymethyl com- - -pound thus obtained is converted into a compound in which the hydroxyl group is replaced by a leaving groupO
By repeating the above-mentioned reaction steps, a further extension of the alkyl chain is obtained.
The compounds of formulaIcan further be prepared by reduction of the cyanide or a~ide group o~ compounds with the general formula VII:

- 7 -~" ' `' ` ' ` ` ' ` ' ' ` . .
.:., . ~!~,' . ` `, ' SlZ

, ~ / X ~ Vll ~4 R~

. R
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 and n -have the meanings indicated before~
The reduction is performed in the usual way for this kind of com- ~
pound.... The cyanide group is preferably reduced by means of metalhydrides, - -especially lithium-aluminiumhydride, 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, etcO :~
The s~arting materials with formula VII required in this method can, for example, be prepared by treating a compound of formula V with sodium~
cyanide or sodiumazide, or by treating a compound of formula II with HCN, .-eliminating the hydroxyl group and reducing the double bond formed, possibly together with -CN or -N
A simple and direct method in preparing the compound of formula I
(with n = 0) consists of the reaction of the compound of formula II with the amine according to formula VI in the presence of a reducing agent, such as for~mic acid, metal hydrides such as LiAlH4, NaBH4, Na~CN)BH3, etc. or by means of hydrogen, if required in ~he presence of a catalyst, such as palladium~
platina, palladium on charcoal, nickel etcO `~ :
This reductive amination is well-known in organic chemistry and described in any chemical handbookO
The compounds of formula I (with n = 0) can further be prepared by reduction of a compound of the general formula VIII: .
..
' ~ ~ .

~ ' ~ 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 reduction is performed in the way as usual for reduction of an oxime, for ins~ance with sodium or sodiumamalgam in alcohol, by hydrogenation preferably in the presence of a metal catalyst, or with metalhydrides such as -LiAlH4.
The compound of formula VIII is prepared direct from the correspon-ding keto compound of formula II by treating the latter with hydroxylamine in ~ :
the usual way, or indirectly from the keto compound of formula II by reacting it with 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 of formula I with n > 1 is the reduction of an amide of the general formula IX:

Rl 3 ~X\~

2 ~ R4 (CH2) C=~) \ / R

.1 6 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 reduction is carried out in a conventional manner for the reduction of amides, for example with metalhydrides, especially LiAlH4.

. .:

~L0~95~2 The starting compounds of formula IX for this reduction can be pre-pared by hydrolysis of the cyano-compound of the general formula VII, yielding the corresponding carboxyl compound, which compound is converted into the corresponding amide in the usual way, for example by halogenating the carboxyl group affording the acid halide, followed by reacting the acid halide with an amine of the formula VIo The primary amide of formula IX may, of course, be prepared directly by partial hydrolysis of the cyano-compound of formula VIIo Finally the compounds of formula I may be prepared by a reduction of a compound with the general formula X:

Rl 3 ~X~

R2 ~ 4 CH R

2)n-1 N~ -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 men~ioned previously.
This reduction is carried 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 compounds of formula X for this reduction can be pre~
pared quite easily s~arting from the keto compound of formula II by means of a Wittig reaction with the aid of the reagent:
Ph3P=CH- (CH2)n-1 in which n has the aforesaid meaning, Ph generally represents anR aryl, in particular a phenyl group and B stands for an amino group (-N \ ,') 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.

- 10 - ' -9S~a~

A very simple method for the preparation of a compound of formula X with n = 2 consists of the reaction of the keto compound of formula II with acetonitrile in the presence of, for instance, sodium ethoxide, followed by reduction of the cyano group in the compound thus obtainedO If necessary the reduction of the cyano group and the reduction of the double bond can take place simultaneously, cq. by catalytic hydrogenation (Raney nickel) or with di-boron.
The compounds of formula 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 compound of formula II into the amine of formula I
a second asymmetric centre is introducedO 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 of preparing the compounds of formula I ~n = 0), starting from the compounds of formula II result in com-pounds, in which the amino-substituent is substantially in the equatorial positionO Only in the case that a leaving group is used in one of the afore-said methods, generally an inversion occurs so that mainly the axial position is obtained.
A mixture o compounds o formula I having the amino(alkyl) sub-stituent in equatorial and axial position can, if desired, be separated very easily, for instance by column chromatography, or in many cases by mere cry-stallization as ~ICl salt or another acid addition salt.
The pharmaceutically acceptable salts of the compounds of formula I
are acid addition salts and quaternary ammonium compoundsv The novel compounds of formula I may be isolated from the reaction mixture in the form of a pharmaceutically acceptable acid addition salt, dependent upon the conditions in which the reaction is carried outO The acid l~9S~2 addition salts may also be obtained by treating the ree base with a pharma-ceutically acceptable organic or inorganic acld. 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 obtained by reacting the compounds of the general formula I with an alkyl halide, for example methyl iodide or methyl bromlde.
It is possible as a matter of course to in~roduce or to modify the substituents at one or both phenyl nuclei of the compounds of formula I even ater the condensation reactions 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.
The unsubstituted or monosubstituted amines of the general formula I
(R5 and/or R6 = H) may be alkylated in the usual way, for example by reaction uith an alkyl- or aralkylhalide~ More common for this purpose is, however, the acylation of the nitrogen atom in question with, for example, an acid chloride or anhydride followed by a reduction of the carbonyl group of the N~ac~l derivative thus obtained. For the introduction of methyl groups at the nitrogen atom the procedure according to Eschweiler-ClaTke ~heating with ~- ; ;
a mixture of formaldehyde and formic acid) or the reaction with formaldehyde ; -and sodiumcyanoborohydride in a suitable solvent, such as acetonitrile, is preferredO ' ~ith ~l al~rl group with 1-6 carbon atoms is meant a branched or unhranched alkrl group such as meth~l, ethyl, propyl, isopropyl, butyl, iso-but~l, tert.butrl, n.pent~l, isopentyl and hexyl.
The alkyl group in the alkoxy and alkylthio moieties has the same meaning.

~L95~2 An aralkyl group mentioned in the d0finition of R5 and R6 is pre- -ferably a p~en~lalk~l group, in which the alkyl group contains l-~ carbon atoms, such as benzyl, phen~lethyl, phenylpropyl, phenylisopropyl, phenyl-but~l and phen~lisobut~l.
The heterocyclic 5- or 6-membered ring (definition of R5 and R6) may either be saturated or unsaturated9 such as a pyrrolino group, a pyrrolidino group, a piperidino group, an oxazolidino group, a morpholino group, a pipera-zino 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 a~monia, methylamine, dimethylamine, diethylamine, isopropylamine, dibutylamine, t.but~lamine, benzylamine, phenylethylamine, phenylpropylamine, 2-phen~ meth~l-ethylamine, pyrroline, pyrrolidine, piperidine, oxazolidine, morpholine, piperazine, etc.
As already pointed out previously the compounds of formula I exert a valuable central nervous system activity. This C.N.S. activity can be concluded from the results o various pharmacological experiments, such as the reserpine antagonism test, reserpine reversal test, aggression isolated mice test, ambulation test~ rotarod test, grip strength test, muricidal inhibition test, etc.
The surprising high activity of the compounds of formula I in anta-gonizing hypothermia induced by reserpine ~reserpine antagonism test) give strong ind~cations that the present compounds can be used as antidepressants.
The compounds of formula I may be administered both orally and parenterall~, preferably in a daily dose of from O.l to lO mg per kg body-weight.
Mixed with suitable auxiliaries the compounds of formula I can be co~pressed into solid dosage units such as pills, tablets or coated tablets, Qr they can be processed into capsules. With the aid of suitable liquids the compounds can be applied as injection preparations in the form of solutions, , .

9'~ 2 emulsions or suspensions.
Preferably compounds of formula I are used in which X stands for a methylene moiety (-CH2-) or a ~N-alkyl moiety, in particular, a ~N-CH3 moietyO
Especially the lat~er type of compounds (X = `N-alkyl) excels in a very potent antidepressant activity.
Furthermore the compounds of formula I, in which n is 0 or 1 are to be preferred over the compounds of formula I, having a longer side chain (n = 2 or 3).
In the Examples the following nomenclature has been used:
g 1,0 11

8 ~ ~ ~ 12 1,2,3,4,10,14b-hexahydro-~ 13 pyridino[l,2-a]-dibenzo[c,f]-7 6 /N 14a~ ~ ~ azepine ~4 1 \~/ :''

9 10 11 ~ / X \ ~ 12 X = O or S
8 ~ 1,3,4,14b-tetrahydro-2H-pyridino ~ [1,2-d]-dibenzo[b,f](1,4)-oxaze- --7 ~ ~ ~ 13 pine or -thiazepine ^
6 / 5 14b\ 14 ~4 1~
~ .,, ' :

8 ~ N ~ 12 1,2,3,4,10,14b-hexahydro-pyridino 7 ~ ,! , 13 [1,2-d]-dibenzo[b,f](1,4)-diaze-6 / 5 \ 14 1) ~ .
The preparation of various compounds of formula II is disclosed in the following ExamplesO The preparation of analogous compounds proceeds in exactly the same way.

, ' .. ,' ' ' ,~ ' ~ . ' ' ' ~Li[)~95~2 Example 1 Preparation 2-keto-comEounds according to genéral formula II
A. 2-keto-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine.
To a solution of 100 g of morphanthridine in 2.5 litres of benzene are added 100 ml of methylvinylketoneO The mixture is then refluxed. To the boiling solution are added dropwise 50 ml of a solution of 35% HCl in ethanol, after which the solution is refluxed for 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 140-142Co Rf in toluene:ethylacetate ~9:1) = 0080 on SiO2.
In the same way as descri~ed ~mder 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]-dibenzo [c,f]-azepine; melting point 144-147C.
D. 2-keto-11,12-dimethyl-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine ~oil)O
Rf in toluene:ethylacetate ~9:1) = 0085 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 SiO2o F. 2-keto-8-methoxy-1,2,3,4,10,14b-hexahydro~pyridino[1,2-a]-dibenzo [c,f]-azepine ~oil)O
Rf in toluene:ethylacetate ~8:2) = 0078 on SiO2.
G. 2-keto-7-chloro-1,3,4,14b-tetrahydro-2H-pyridino[1,2-d]-dibenzo b,f~1,4)-thiazepine ~oil).
Rf in toluene:ethylacetate ~8:2) = 0.75 on SiO2o H~ 2-keto-7-trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyridino[1,2-d]-dibenzo[b,f]~1,4)-thiazepine ~oil).

9S~L~
Rf in toluene:ethylacetate (9:1) = 0O90 on Si02.
I. 2-keto-13-methyl-1,3,4,14b-tetrahydro-2H-pyridino[1~2-d~-dibenzo [b,f](1,4)-thiazepine; melting point 104-107C.
K. 2-keto-7-methyl-1,3,4,14b-tetrahydro-2H-pyridino[1,2-d]-dibenzo[b,f]
(1,4)-oxazepine; melting point 105-107C.
L. 2-keto-11-methyl-1,3,4,14b-tetrahydro-2H-pyridino[1,2-d]-dibenzo[b,f]
(1,4)-oxazepine; melting point 164-166C.
M. 2-keto-7,11-dimethyl-1,3,4,14b-t0trahydro-2H-pyridino[1,2-d]-dibenzo -[b,f](1,4)-oxazepine; ~oil) Rf in toluene:ethylacetate (8:2) = OD70.
N. 2-keto-10-methyl-1,2,3,4,10,14b-hexahydro-pyridino[1,2-d]-dibenzo [b,f~(1,4)-diazepine; melting point 176-17~C.
P. 2-keto-10-methyl-13~methoxy-1,2,3,4,10,14b-hexahydropyridino[1,2-d]-dibenzo[b,f](l,4)-diazepine; melting point 127-128C.
Q. 2-keto-1,3,4,14b-tetrahydro-2H-pyridino[1,2-d]-dibenzo[b,f]~1,4)-oxazepine; melting point 101-103C.
Exa~æ e 2 Preparation 3-keto-co~pounds 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~1,273,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo Lc,f~-azepine are added under nitrogen atmosphere to a solution of 3.9 g of potassium in tertiary butanolO The mixture is stirred for 10 hours while e~ery 2 hours 4 ml of isoamylnitrite are added (the total quantity of iso-amylnitrite is 20 ml).
After that the mixture is filtered and the precipitate ~2-keto-3-oxime compound) washed with tObutanol and etherO The product is then added to 17 ml o~ diethyleneglycol after which 5 ml of hydrazinehydrate and 2 g of KOH are added and the mixture obtained is heated at 160C for 4 hoursO
The reaction mixture is poured into water whereafter the precipitated _ 16 -. .
j, , , : . .
-: , -.

~1~49S~

oxime is filtered off.
Yield of the 3-oxime: 2.0 gO The oxime is refluxed in a mixture of 20 ml of water, 20 ml of ethanol and 4 g of sodium bisulphite for 2.5 hours.
The alcohol is then distilled off and the remaining solution is exLracted into etherO The ether layer is evaporated to dryness.
Yield of the 3-keto compound: 1.8 g ~oil)O
Rf 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 [c,f~-azepine Rf in toluene R 0.15 on SiO2o CO 3-keto-7-trifluoromethyl-l/3,4,14b-tetrahydro-2H-pyridino[1,2-d]-dibenzo~b,f~Cl,4)-thiazepine Rf in toluene:ethylacetate (9:1) = 0.90.
D. 3-keto-11-methyl-1,3,4,14b-tetrahydro-2H-pyridino[1,2-d]-dibenzo ~b,f~(1,4) oxazepine.
Rf in toluene:ethylacetate ~8:2) = 0.75.
E. 3-keto-10-methyl~1,2,3,4,10,14b-hexahydro-pyridino[1,2-d]-dibenzo-~b,f]~1,4)-diazepine.
Rf in toluene:eth~lacetate ~9:1) = 0.90 Rf in hexane:acetone (9:1) = 0.20.

Claims (14)

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

1. A process for preparing a compound of formula II

II

in which X represents 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, R7 represents hydrogen or alkyl (1-4 C), R8 and R9 represent hydrogen or methyl and the keto group is in the 2- or 3-position which comprises condensing a compound of formula III

in which R1, R2, R3, R4 and X are as defined above with vinylmethylketone to obtain the 2-keto compound and, if the corresponding 3-keto compound is re-quired, converting the 2-keto compound to the corresponding 3-keto compound.

2. A process according to claim 1 for preparing a 3-keto compound of formula II which comprises converting a 2-keto compound of formula II into the corresponding 2-keto-3-hydroxy-imino compound, reducing the carbonyl group at the 2-position and hydrolysing the 3-hydroxy-imino group to a carbonyl group.

3. A process according to claim 2 wherein the 2-keto-3-hydroxy-imino compound is obtained by reacting the 2-keto compound of formula II with iso-amylnitrite and potassium in tert.butanol.

4. A process according to claim 2 or 3 wherein the carbonyl group at the 2-position is reduced by means of the Wolff-Kishner reduction.

5. A process according to claim 2 or 3 wherein the hydrolysis of the 3-hydroxy-imino group is carried out under acidic conditions or with the aid of sodium bisulphite in an alcohol/water mixture.

6. A compound of formula II as defined in claim 1 when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

7. A process according to claim 1 wherein X is -CR8R9- and both R8 and R9 are hydrogen.

8. A process according to claim 1 wherein R1, R2, R3 and R4 are hydro-gen, X is -CR8R9- wherein R8 and R9 are both hydrogen and the keto-group is in the 2-position.

9. A process according to claim 1 for preparing 2-keto-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]dibenzo[c,f]-azepine which comprises refluxing morphanthridine with vinylmethylketone in the presence of HCl.

10. 2-keto-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine when prepared by a process according to claim 9 or an obvious chemical equivalent thereof.

11. A process according to claim 1 wherein X is and R7 is methyl.

12. A process according to claim 1 wherein R1, R2, R3 and R4 are hydro-gen, X is wherein R7 is methyl and the keto group is in the 2-position.

13. A process according to claim 1 for preparing 2-keto-10-methyl-1,2, 3,4,10,14b-hexahydro-pyridine[1,2-a]-dibenzo[b,f](1,4)-diazepine which com-prises refluxing dibenzodiazepine with vinylmethylketone in the presence of HCl.

14. 2-keto-10-methyl-1,2,3,4,10,14b-hexahydro-pyridine[1,2-a]-dibenzo [b,f](1,4)diazepine when prepared by a process according to claim 13 or an obvious chemical equivalent thereof.