CA1051877A - Amino-substituted tetracyclic compounds - Google Patents
Amino-substituted tetracyclic compoundsInfo
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- CA1051877A CA1051877A CA199,996A CA199996A CA1051877A CA 1051877 A CA1051877 A CA 1051877A CA 199996 A CA199996 A CA 199996A CA 1051877 A CA1051877 A CA 1051877A
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Abstract
Abstract of the Disclosure The invention discloses novel compounds of the general formula:
and salts thereof, 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), 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 stands for hydrogen or methyl, n is the number 0, 1 or 2 and the dotted line means an optional C-C bond, with valuable central nervous system (CNS) activities, especially antidepressant activity.
The invention further discloses novel intermediates of the general formula:
as well as biologically active intermediates of the formula:
and salts thereof, 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), 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 stands for hydrogen or methyl, n is the number 0, 1 or 2 and the dotted line means an optional C-C bond, with valuable central nervous system (CNS) activities, especially antidepressant activity.
The invention further discloses novel intermediates of the general formula:
as well as biologically active intermediates of the formula:
Description
The present invention relates to novel biologically active amino-substituted tetracyclic compounds and to processes for the preparation thereof.
The invention provides compounds of the general formula I:
I
~ R5`
(CH2) n~N \
as well as the pharmaceutically acceptable acid addition and quaternary ammonium salts thereof, in which X represents oxygen, sulphur, the group = NR7 or the group -CH2-, ring A is either unsubstituted or substituted in the 6- or 7-position by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the ll-and 12-positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, R5 and R6 are the same or different and represent hydrogen atoms or alkyl groups of 1 to 4 carbon atoms which are either unsubstituted or substituted by a phenyl group, or the group NR5R6 together represents a morpholino, piperidino or W rrolidino group, R7 represents hydrogen or methyl, n is zero, one or two, and the dotted line in the nucleus signifies an extra bond which is optional when n is zero, possess valuable C.N.S. activities. The toxicity of these compounds is exceedingly lowO
The compounds according to the invention may be prepared in a manner commonly used for analogous compounds. Thus, according to the invention, the compounds of fo Dula I and their salt, as defined above, are prepared by a process which comprises either:
105~877 a) condensing a compound of the general formula IV:
IV
~ 2)n in which n and X are as previously defined and Y is a leaving group~ with ammonia or an amine of the general formula V:
"~R5-~ V
R6~
or an acid addition salt thereof, wherein R5 and R6 are as previously defined;
or b) reducing a compound of the general formula VI:
~ ~ VI
in which R represents - (CH2)p -CN or -~CH2)pN3 wherein p represents zero or one and X is as previously defined; or c) for preparing compounds of general formula I in which n is zero and the dotted line in the nucleus signifies an extra bond, reacting a compound of the general formula V as defined above with a compound of the general formula II:
II
la-105~77 in which X is as previously defined in the presence of a reducing agent; or d) reducing a compound of the general formula IX:
IX
(CH2)n~N 5 ~
in which R5, R6, X and n are as previously defined, or e) for preparing compounds of general formula I, in which n is zero and the dotted line in the nucleus signifies an extra bond, reducing a compound of the general formula VII:
VII
~OH
in which X is as herein before defined, by reaction with a metal hydride or by catalytic hydrogenation; or f) for preparing compounds of general formula I, in which n is zero and the dotted line in the nucleus does not signify an extra bond reducing a compound of general formula VII as defined above by reaction with sodium or sodium amalgam; or g) for preparing compounds of general formula I in which n ~-1, reducing a compound of general formula VIII:
,~ ~ VIII
~C~12)p ,-R
R ~J
-lb-/
~OS~877 in which R5, R6, X and p are as previously defined; and wherein steps (a) to (g) may be followed by the additional step of alkylating or phenylalkylating a compound of formula I obtained in which one or both of R5 and R6 is hydrogen to obtain the corresponding compound of formula I in which one or both of R5 and R6 are alkyl or phenylalkyl groups; and wherein a base of formula I may be connected into a corresponding pharmaceutically acid addition or quaternary a~rcniu~ salt.
", ~'' ,/
,,, . , . . . , , . . . , , , . ~
-lc--~' J
The compounds II are, as far as known, novel compounds. They can be prepared in various manners. The most simple method to prepare the compound II is the condensation of vinylmethylketone (CH3-C-CH=CH2) with a compound of the general formula III:
~ III
in which A, B and X have the meanings mentioned above. This condensation re-action in preparing the starting material II is performed in a suitable sol-vent, preferably in the presence of a base, such as sodium hydroxide, potas-sium hydroxide, sodium ethoxide or sodium hydride. An intermediate product formed in this condensation reaction, namely a compound of formula III with a y-keto-butyl moiety at position 6, can, if desired, be isolated though it is not necessary to do so.
Starting from a compound with formula II the end products 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 si=ilar compounds. ~
r~
,, ~
~51877 In the compounds of general formula IV, Y represents a suit-able leaving group, Y is e.g. halogen or an etherified or esterified hydroxyl group. Leaving groups are well defined groups, described in various chemical handbooks. Thus suitable leaving groups for this condensation reaction are for example a tosyloxy group, a mesyloxy group, a p-bromophenyl-sulphonyloxy group, a chlorine, bromine or iodine atom.
The compound IV required for this condensation reaction may be prepared from the starting material II described before by reducing the keto group to a hydroxyl group, preferably with metal hydrides such as LiAlH4, diboran or in particular NaBH4, followed by converting this hydroxyl group into the desired leaving group in a conventional manner, for instance by tosylation,~
/' D
1~518~7 mesylation, reaction with SOCl , PC15, PBr3, etc.
Extension of the alkyl chain (from n=O to n=l or 2) can be performed in the usual way, for instance by treating a compound IV, in ¦ which n=O, with a cyanide such as potassium- or sodiumcyanide. The cyano-group in the compound thus obtained can then be hydrolysed to the corres-ponding carboxyl group. A further extension of the alkyl chain can be obtained by reducing the carboxyl compound to afford the hydroxy-methyl compound. The hydroxy-methyl compound thus obtained is converted into a compound in which the hydroxyl group is replaced by a leaving group, and repeating the above-mAntioned cyAnide r.action.
lOS1877 The reduction of compounds of formula VI is performed in the usual way for this kind of compounds. The cyanide group is preferably reduced 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 formula VI required in this method can, for example, be prepared by treating a compound of formula IY
with sodium cyanide or sodium azide.
Suitable reducing agents for use in the reaction of the starting material II with the amine according to formula V in the presence of a reducing agent, are metalhydrides, e.g. NaBH4, LiAlH4, NaCNBH3, etc.
but preferably formic acid (Leuckart reaction) or hydrogen in the presence of a suitable catalyst, such as palladium, palladium on charcoal, Raney nickel, etc.
This reductive amination is well-known in organic chemistry and described in any chemical handbook.~
/
/
': /
D
The reduction of a compound VII may be performed by hydro-genation preferably in the presence of a usual metallic hydrogenation catalyst, or with metalhydrides such as LiAlH4.
The compound VII is prepared direct from the corresponding keto co~pound II by treating the latter with hydroxylamine in the usual way, or indirect from the keto compound II by reacting it with isoamylnitrite/
potassium-t.butoxide yielding the 2-keto-3-oxime compound, followed by a Wolff-Kishner reduction of the keto group.
The reduction of a compound VIII is carried out in a conven-tional manner for the reduction of amides, for example with metalhydrides, especially LiAlH4.
The starting compounds YIII for this reduction can, forexample, be prepared by hydrolysis of the cyano-compound of the general formula VI, yielding the corresponding carboxyl compound, which compound is converted into the corresponding amide in the usual way, for example by _ - 7 ~ _ ____ __ _ _ _ halogenating the carboxyl group affording the acid halide, followed by re-acting the acid halide with an amine of the formula V. The primary amide of formula VIII may, of course, be prepared directly by partial hydrolysis of the cyano-compound VI.
Finally, the reduction of a compound IX is carried out in a conventional manner, for example with metalhydrides, such as LiAlH4, etc.
or by hydrogenation in the presence of a catalyst such as palladium, pal-ladium on charcoal, Raney nickel, etc.
The starting compounds IX may be prepared in ~arious manners.
For example, a compound IX with n-O (enamine) may be prepared by treating the ketone II with an amine of formula V, preferably in the presence of a Lewis acid, such as AlC13, SnC14, etc.
A compound IX with n=l may be prepared by treating the ketone II with HCN, eliminating the hydroxyl group formed to obtain a double bond and con~erting the cyano ~ ~
D~
~05~877 group in a conventional manner into an aminomethyl group. Another method consists of the rcaction of the ketone II with the reagent (CH3)2S(~ 0)=CH2, whereupon the compound thus obtained is treated with the amine V followed by eliminating the hydroxyl group formed to obtain a double bond.
A compound IX with n = 2 may be obtained by a Wittig reaction, a Wittig-Horner reaction, a Reformatski reaction or a reaction with acetonitrile carried out on the starting ketone II. Reagents necessary in these reactions are well-known and described in any chemical handbook, for example: Ph3P=CH-B' (Wittig), (EtO)2-P(-~ O)-cH2-coR~ in NaH and a suitable solvent (Wittig-Horner), BrZn-CH2-COR' (Reforma~ski) and CH3CN
in the presence of sodiumalkoxide, whereby Ph stands for an aryl group, in particular a phenyl group, B' represents a -CH2-N ~ 5 ~ moiety or a group R6~
that can easily be converted into this aminomethyl moiety, such as a carboxyl group, an esterified carboxyl group, an amide group, a cyano group or a hydroxyl group, and R' stands for an esterified hydroxyl group. An additional reaction may then be necessary to convert these moieties into a carboxyl group.
The Reformatski reaction requires an additional step to obtain the al(2) double bond by elminating the hydroxy group formed, whereas in all methods in which the amino-moiety is not present already in the reagent used, an additional reaction has to be carrird out in order to convert the moiety present (carboxyl, hydroxy, cyano, amide, etc.) into the desired amino-moiety.
Most reactions described preparing the starting material IX
involve-the reduction of a cyano group or- ,~
, ,, an amide group. It is, of course, possible to reduce these moieties simultaneously with the al(2) double bond present in the molecule.
In all afore-mentioned methods, in which a reduction has been carried out in the last step of the synthesis or in one of the previous steps, the conjugated double bond between the phenyl nuclei is not reduced under the usual reaction conditions.
By carrying out the reduction in question und~r strong reductive conditions, e.g. by increasing the reaction temperature and reaction time, by increasing the quantity of the reducing agent and/or by performing the reduction under high pressure, it is possible to isolate also the compounds I
with a saturated C-C bond instead of the C=C bond, in particular where a catalytic hydrogenation with PtO2 in acetic acid has been used for the reduction.
A more preferred synthesis for the preparation of these "saturated" compounds I consists of the reduction of the compound VII:
VII
N-OH
in which A, B and X have the aforesaid meanings, with sodium or sodlumamalgam in a suitable liquid, such as sodium in isopropanol, or by a hydrogenation in the presence of platinumoxide (Adams - ~
D
catalyst) under the usual conditions, especially in acetic acid. In this reduction the ~4a(13b) double bond as well as the oxime moiety are reduced simultaneously.
The best method for the preparation of the compounds I, in which the 4a~13b) bond is saturated, consists of a reduction of the ~4a(13b) double bond of the ketone II.
A catalytic hydrogenation of the ketone II with platinumoxide in a suitable liquid, preferably acetic acid, yields the corresponding 4a(13b)-saturated alcohol X quantitatively:
~ X
OH
in which A, B and X have the meanings afore-defined. This alcohol X may be oxidized to the 4a(13b)-saturated ketone of the general formula XI:
~ XI
o in which A, B and X have the meanings afore-defined. This oxidation may be carried out in a conventional manner, for example with manganesedioxide or chromic acid-pyridine complex. A very useful oxidation is the biphasic one in which a benzenic solution of the alcohol X is shaken with a solution of CrO3 in acetic acid/water mixture. ~ C_ .. ... , _ . .. . . ..... ..
_10-All additional reactions described before starting from the "unsatuTated" ketone II or the corresponding alcohol, yielding the "unsaturated" compounds I can also be applied to the ketone XI or the corresponding alcohol X to obtain the 4a(13b)-saturated compounds I. In other words the ketone XI or the alcohol X can be converted into the 4a(13b~-saturated analogues of the compounds IV, VI, VII, VIII or IX followed by conversion of these compounds into the 4a(13b)-saturated compounds I in the manner described. The ketone XI can further be subjected to the reductive amination as described previously.
. ., lO ' A specific series of biologically active intermediates used in the present methods for the preparation of the compounds I are compounds of the general formula XII:
~ ~ XII
~>
(CH2)n-1 COOH
as well as salts and esters thereof, in which A, B, X and n have the aforesaid meaning. These intermediates exert potent anti-inflammatory activity. They can be administered orally, parenterally or locally in a daily dose of from 0.1 mg to 10 mg per kg/body weight.
These compounds XII can be prepared in various manners, indicated already in this specification. In this connection there is referred to the hydrolysis of a cyano group and to methods such as the hi Wl g ~n r an ~ o na ~ ... . , . . . . .. ... _ . ,. ... _ . ......... . . . .. ... . .. .
1051~77 reactions mentioned previously~ In the latter methods the double bond (~1,2) has to be reduced additionally by means of a catalytic hydrogenation.
Compounds XII with n = 0 can further be prepared by treating a compound of formula IV, in which Y stands for halogen, in particular lodine, with magnesium, after which the magnesium halide thus obtained ~Y - .~gHal) is converted into the corresponding carboxyl-compound by treating with CO2 ~
Esters of the compound XII are derived from alipha~-ic, cycloaliphatic, aromatic or araliphatic alcohols w1th 1-18 carbon atoms, which may be substituted by hydroxy or halogen groups, especially lower aliphatic alcohols with 1~6 carbon ato~s, or phenylaliphatic alcohols with 7-10 C-atoms, such as methanol, ethanol, isopropanol, butanol, hexanol, phen-ethylalcohol~ benzylalcohol, phenylpropylalcohol, p-chloro-benzylalcohol~ p-hydroxyphenethylalcohol~ etc.
The compounds according to the invention contain an asymmetric carbon at position 2 of the tetracyclic molecule.
Besides the racemate optical antipodes are thus possible which also belong to the compounds according to the invention.
These optical isomers are prepared from the corresponding racemate by a resolution in the usual way. By resolving a starting product or an intermediate product in the syn-thesis, the optical isomers can also be obtained in a direct way.
The pharmaceutically acceptable salts of the compounds I according to the invention are acid addition salts and quaternary ammonium compounds.
The novel compounds of the formula I may be isolated from the reaction mixture ln the form of a pharmaceutically accept-able acid additlon salt, dependent upon the conditions in S which the reaction is carried out. The acid addition salts may also be obtained by treating the free base with a pharmaceutically acceptable organic or ~norganic acid. Aclds 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 Iwith an alkyl halide, for example methyl iodide or methyl bromide.
It is possible as a matter of cours~ to introduce or to modify the substituents at one or both phenyl nucleii even after 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 andJor R6 ~ H) may be alkylated in the usual way, for example by reaction with an alkyl-or ar~lkylhalide. More common for this purpose is, how-ever, the acylation of the nitrogen atom in question with, for example, an acid chloride or anhydride followed by a ~51877 reduction of the carbonyl group of the N-acyl derivative thus obtained. For the introduction of methyl groups at the nitrogen atom the procedure accordinq to Eschweiler-Clarke (heating with a mixture of formaldehyd and formic acid) or the reaction with formaldehyde and sodlumcyano-borohydride in a suitable solvent~ such as acetonitril, is preferred.
With an alkyl group with 1-6 carbon atoms is meant a branched or un~ranched alkyl group such as methyl, ethyl, propyl, isopropyl~ butyl, isobutyl, tert.butyl, n.pentyl5 isopentyl and hexyl.
The alkyl group in the alkoxy and alkylthio 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 as a pyrrolino group, a pyrrolidino group, a piperidino group, an oxazolidino group, a morpholino group, a pi-perazino group, etc.
Amines according to the general formula V~ that may be used in the various condensation reactions to obtain the compounds of the invention, are, ~or example ammonia~
methylamine~ dimethylamine, diethylamine, isopropylamine, dibutylamine, t.butylamine, benzylamine, phenylethylamine, phenylpropylamine, 2-phenyl-1-methyl-ethy$amine, pyrroline, 1051~i7 pyrrolidine, piperidine, oxazolidine, morpholine, piperazine, etc.
As already pointed out previously the compounds of the invention I exert a valuable central nervous system activity.
This C.N.S. activity can be concluded from the results of various pharmacological experiments, such as the reserpine antagonism test, reserpine reversal test, aggression iso-lated 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 unlts such as pills, tablets or coated tablets, or they can be processed into capsules. With the aid of suitable liq~ids the compounds can be applied as in~ection preparations in the form of solutions, emulsions or suspensions.
Preferably compounds I and, in particular,compounds I A 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 antidepressant activity.
Furthermore the compounds I, in which n iS 0 or 1 are to be preferred over the compounds I, having a longer side chain (n ~ 2).
In the Examples the following nomenclature and numbering has been used:
\ / ,0 5 ~ ~ 1,2,3,4-tetrahydro-9H-tribenzo ~12 ( b,d,f)-cycloheptatriene 8 g lo 10 ~ ~ x ~ X = 0 or S
1,2,3,4-tetrahydro-tribenzo(b,d,f)-5 ~4 ~ ~3 oxepine or -thiepine W
q ,0 ~ ~ ~,2 1~2~3~4-tetrahydro-9H-tribenzo ~ ~ (b,d,f)-azepine By way of example the preparation of various starting products are disclosed. The preparation of analogous starting products proceeds in exactly the same way.
Preparation startinq materials 25 1. 2-keto-1~2~3~4-tetrahvdro-tribenzo(b~d~f)-oxePine To a solution of 42 g of the compound 10-keto-10,11-dihydro-dibenzo(b,f)-oxepine in 200 ml of dry ethanol a solution of sodiumethoxide (7 g of sodium ln 500 ml of ethanol) is added dropwise. After stirring the mixture for 30 minutes 16.2 ml of methylvinylketon in S0 ml of ethanol are added, where-~051877 upon the solut~on is refluxed for one hour. The solution i~ cooled then and poured into 2 N HC1. After extracting into ether, washing the ether layer with water (till neutral) and drying the etherial phase, the solvent is S evaporated.
The residue, a redcoloured oil, is chromatographed after that over an alumina column and used ~or further con-version immediately. Yield: 37% oil.
In the same manner are prepared:
The invention provides compounds of the general formula I:
I
~ R5`
(CH2) n~N \
as well as the pharmaceutically acceptable acid addition and quaternary ammonium salts thereof, in which X represents oxygen, sulphur, the group = NR7 or the group -CH2-, ring A is either unsubstituted or substituted in the 6- or 7-position by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the ll-and 12-positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, R5 and R6 are the same or different and represent hydrogen atoms or alkyl groups of 1 to 4 carbon atoms which are either unsubstituted or substituted by a phenyl group, or the group NR5R6 together represents a morpholino, piperidino or W rrolidino group, R7 represents hydrogen or methyl, n is zero, one or two, and the dotted line in the nucleus signifies an extra bond which is optional when n is zero, possess valuable C.N.S. activities. The toxicity of these compounds is exceedingly lowO
The compounds according to the invention may be prepared in a manner commonly used for analogous compounds. Thus, according to the invention, the compounds of fo Dula I and their salt, as defined above, are prepared by a process which comprises either:
105~877 a) condensing a compound of the general formula IV:
IV
~ 2)n in which n and X are as previously defined and Y is a leaving group~ with ammonia or an amine of the general formula V:
"~R5-~ V
R6~
or an acid addition salt thereof, wherein R5 and R6 are as previously defined;
or b) reducing a compound of the general formula VI:
~ ~ VI
in which R represents - (CH2)p -CN or -~CH2)pN3 wherein p represents zero or one and X is as previously defined; or c) for preparing compounds of general formula I in which n is zero and the dotted line in the nucleus signifies an extra bond, reacting a compound of the general formula V as defined above with a compound of the general formula II:
II
la-105~77 in which X is as previously defined in the presence of a reducing agent; or d) reducing a compound of the general formula IX:
IX
(CH2)n~N 5 ~
in which R5, R6, X and n are as previously defined, or e) for preparing compounds of general formula I, in which n is zero and the dotted line in the nucleus signifies an extra bond, reducing a compound of the general formula VII:
VII
~OH
in which X is as herein before defined, by reaction with a metal hydride or by catalytic hydrogenation; or f) for preparing compounds of general formula I, in which n is zero and the dotted line in the nucleus does not signify an extra bond reducing a compound of general formula VII as defined above by reaction with sodium or sodium amalgam; or g) for preparing compounds of general formula I in which n ~-1, reducing a compound of general formula VIII:
,~ ~ VIII
~C~12)p ,-R
R ~J
-lb-/
~OS~877 in which R5, R6, X and p are as previously defined; and wherein steps (a) to (g) may be followed by the additional step of alkylating or phenylalkylating a compound of formula I obtained in which one or both of R5 and R6 is hydrogen to obtain the corresponding compound of formula I in which one or both of R5 and R6 are alkyl or phenylalkyl groups; and wherein a base of formula I may be connected into a corresponding pharmaceutically acid addition or quaternary a~rcniu~ salt.
", ~'' ,/
,,, . , . . . , , . . . , , , . ~
-lc--~' J
The compounds II are, as far as known, novel compounds. They can be prepared in various manners. The most simple method to prepare the compound II is the condensation of vinylmethylketone (CH3-C-CH=CH2) with a compound of the general formula III:
~ III
in which A, B and X have the meanings mentioned above. This condensation re-action in preparing the starting material II is performed in a suitable sol-vent, preferably in the presence of a base, such as sodium hydroxide, potas-sium hydroxide, sodium ethoxide or sodium hydride. An intermediate product formed in this condensation reaction, namely a compound of formula III with a y-keto-butyl moiety at position 6, can, if desired, be isolated though it is not necessary to do so.
Starting from a compound with formula II the end products 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 si=ilar compounds. ~
r~
,, ~
~51877 In the compounds of general formula IV, Y represents a suit-able leaving group, Y is e.g. halogen or an etherified or esterified hydroxyl group. Leaving groups are well defined groups, described in various chemical handbooks. Thus suitable leaving groups for this condensation reaction are for example a tosyloxy group, a mesyloxy group, a p-bromophenyl-sulphonyloxy group, a chlorine, bromine or iodine atom.
The compound IV required for this condensation reaction may be prepared from the starting material II described before by reducing the keto group to a hydroxyl group, preferably with metal hydrides such as LiAlH4, diboran or in particular NaBH4, followed by converting this hydroxyl group into the desired leaving group in a conventional manner, for instance by tosylation,~
/' D
1~518~7 mesylation, reaction with SOCl , PC15, PBr3, etc.
Extension of the alkyl chain (from n=O to n=l or 2) can be performed in the usual way, for instance by treating a compound IV, in ¦ which n=O, with a cyanide such as potassium- or sodiumcyanide. The cyano-group in the compound thus obtained can then be hydrolysed to the corres-ponding carboxyl group. A further extension of the alkyl chain can be obtained by reducing the carboxyl compound to afford the hydroxy-methyl compound. The hydroxy-methyl compound thus obtained is converted into a compound in which the hydroxyl group is replaced by a leaving group, and repeating the above-mAntioned cyAnide r.action.
lOS1877 The reduction of compounds of formula VI is performed in the usual way for this kind of compounds. The cyanide group is preferably reduced 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 formula VI required in this method can, for example, be prepared by treating a compound of formula IY
with sodium cyanide or sodium azide.
Suitable reducing agents for use in the reaction of the starting material II with the amine according to formula V in the presence of a reducing agent, are metalhydrides, e.g. NaBH4, LiAlH4, NaCNBH3, etc.
but preferably formic acid (Leuckart reaction) or hydrogen in the presence of a suitable catalyst, such as palladium, palladium on charcoal, Raney nickel, etc.
This reductive amination is well-known in organic chemistry and described in any chemical handbook.~
/
/
': /
D
The reduction of a compound VII may be performed by hydro-genation preferably in the presence of a usual metallic hydrogenation catalyst, or with metalhydrides such as LiAlH4.
The compound VII is prepared direct from the corresponding keto co~pound II by treating the latter with hydroxylamine in the usual way, or indirect from the keto compound II by reacting it with isoamylnitrite/
potassium-t.butoxide yielding the 2-keto-3-oxime compound, followed by a Wolff-Kishner reduction of the keto group.
The reduction of a compound VIII is carried out in a conven-tional manner for the reduction of amides, for example with metalhydrides, especially LiAlH4.
The starting compounds YIII for this reduction can, forexample, be prepared by hydrolysis of the cyano-compound of the general formula VI, yielding the corresponding carboxyl compound, which compound is converted into the corresponding amide in the usual way, for example by _ - 7 ~ _ ____ __ _ _ _ halogenating the carboxyl group affording the acid halide, followed by re-acting the acid halide with an amine of the formula V. The primary amide of formula VIII may, of course, be prepared directly by partial hydrolysis of the cyano-compound VI.
Finally, the reduction of a compound IX is carried out in a conventional manner, for example with metalhydrides, such as LiAlH4, etc.
or by hydrogenation in the presence of a catalyst such as palladium, pal-ladium on charcoal, Raney nickel, etc.
The starting compounds IX may be prepared in ~arious manners.
For example, a compound IX with n-O (enamine) may be prepared by treating the ketone II with an amine of formula V, preferably in the presence of a Lewis acid, such as AlC13, SnC14, etc.
A compound IX with n=l may be prepared by treating the ketone II with HCN, eliminating the hydroxyl group formed to obtain a double bond and con~erting the cyano ~ ~
D~
~05~877 group in a conventional manner into an aminomethyl group. Another method consists of the rcaction of the ketone II with the reagent (CH3)2S(~ 0)=CH2, whereupon the compound thus obtained is treated with the amine V followed by eliminating the hydroxyl group formed to obtain a double bond.
A compound IX with n = 2 may be obtained by a Wittig reaction, a Wittig-Horner reaction, a Reformatski reaction or a reaction with acetonitrile carried out on the starting ketone II. Reagents necessary in these reactions are well-known and described in any chemical handbook, for example: Ph3P=CH-B' (Wittig), (EtO)2-P(-~ O)-cH2-coR~ in NaH and a suitable solvent (Wittig-Horner), BrZn-CH2-COR' (Reforma~ski) and CH3CN
in the presence of sodiumalkoxide, whereby Ph stands for an aryl group, in particular a phenyl group, B' represents a -CH2-N ~ 5 ~ moiety or a group R6~
that can easily be converted into this aminomethyl moiety, such as a carboxyl group, an esterified carboxyl group, an amide group, a cyano group or a hydroxyl group, and R' stands for an esterified hydroxyl group. An additional reaction may then be necessary to convert these moieties into a carboxyl group.
The Reformatski reaction requires an additional step to obtain the al(2) double bond by elminating the hydroxy group formed, whereas in all methods in which the amino-moiety is not present already in the reagent used, an additional reaction has to be carrird out in order to convert the moiety present (carboxyl, hydroxy, cyano, amide, etc.) into the desired amino-moiety.
Most reactions described preparing the starting material IX
involve-the reduction of a cyano group or- ,~
, ,, an amide group. It is, of course, possible to reduce these moieties simultaneously with the al(2) double bond present in the molecule.
In all afore-mentioned methods, in which a reduction has been carried out in the last step of the synthesis or in one of the previous steps, the conjugated double bond between the phenyl nuclei is not reduced under the usual reaction conditions.
By carrying out the reduction in question und~r strong reductive conditions, e.g. by increasing the reaction temperature and reaction time, by increasing the quantity of the reducing agent and/or by performing the reduction under high pressure, it is possible to isolate also the compounds I
with a saturated C-C bond instead of the C=C bond, in particular where a catalytic hydrogenation with PtO2 in acetic acid has been used for the reduction.
A more preferred synthesis for the preparation of these "saturated" compounds I consists of the reduction of the compound VII:
VII
N-OH
in which A, B and X have the aforesaid meanings, with sodium or sodlumamalgam in a suitable liquid, such as sodium in isopropanol, or by a hydrogenation in the presence of platinumoxide (Adams - ~
D
catalyst) under the usual conditions, especially in acetic acid. In this reduction the ~4a(13b) double bond as well as the oxime moiety are reduced simultaneously.
The best method for the preparation of the compounds I, in which the 4a~13b) bond is saturated, consists of a reduction of the ~4a(13b) double bond of the ketone II.
A catalytic hydrogenation of the ketone II with platinumoxide in a suitable liquid, preferably acetic acid, yields the corresponding 4a(13b)-saturated alcohol X quantitatively:
~ X
OH
in which A, B and X have the meanings afore-defined. This alcohol X may be oxidized to the 4a(13b)-saturated ketone of the general formula XI:
~ XI
o in which A, B and X have the meanings afore-defined. This oxidation may be carried out in a conventional manner, for example with manganesedioxide or chromic acid-pyridine complex. A very useful oxidation is the biphasic one in which a benzenic solution of the alcohol X is shaken with a solution of CrO3 in acetic acid/water mixture. ~ C_ .. ... , _ . .. . . ..... ..
_10-All additional reactions described before starting from the "unsatuTated" ketone II or the corresponding alcohol, yielding the "unsaturated" compounds I can also be applied to the ketone XI or the corresponding alcohol X to obtain the 4a(13b)-saturated compounds I. In other words the ketone XI or the alcohol X can be converted into the 4a(13b~-saturated analogues of the compounds IV, VI, VII, VIII or IX followed by conversion of these compounds into the 4a(13b)-saturated compounds I in the manner described. The ketone XI can further be subjected to the reductive amination as described previously.
. ., lO ' A specific series of biologically active intermediates used in the present methods for the preparation of the compounds I are compounds of the general formula XII:
~ ~ XII
~>
(CH2)n-1 COOH
as well as salts and esters thereof, in which A, B, X and n have the aforesaid meaning. These intermediates exert potent anti-inflammatory activity. They can be administered orally, parenterally or locally in a daily dose of from 0.1 mg to 10 mg per kg/body weight.
These compounds XII can be prepared in various manners, indicated already in this specification. In this connection there is referred to the hydrolysis of a cyano group and to methods such as the hi Wl g ~n r an ~ o na ~ ... . , . . . . .. ... _ . ,. ... _ . ......... . . . .. ... . .. .
1051~77 reactions mentioned previously~ In the latter methods the double bond (~1,2) has to be reduced additionally by means of a catalytic hydrogenation.
Compounds XII with n = 0 can further be prepared by treating a compound of formula IV, in which Y stands for halogen, in particular lodine, with magnesium, after which the magnesium halide thus obtained ~Y - .~gHal) is converted into the corresponding carboxyl-compound by treating with CO2 ~
Esters of the compound XII are derived from alipha~-ic, cycloaliphatic, aromatic or araliphatic alcohols w1th 1-18 carbon atoms, which may be substituted by hydroxy or halogen groups, especially lower aliphatic alcohols with 1~6 carbon ato~s, or phenylaliphatic alcohols with 7-10 C-atoms, such as methanol, ethanol, isopropanol, butanol, hexanol, phen-ethylalcohol~ benzylalcohol, phenylpropylalcohol, p-chloro-benzylalcohol~ p-hydroxyphenethylalcohol~ etc.
The compounds according to the invention contain an asymmetric carbon at position 2 of the tetracyclic molecule.
Besides the racemate optical antipodes are thus possible which also belong to the compounds according to the invention.
These optical isomers are prepared from the corresponding racemate by a resolution in the usual way. By resolving a starting product or an intermediate product in the syn-thesis, the optical isomers can also be obtained in a direct way.
The pharmaceutically acceptable salts of the compounds I according to the invention are acid addition salts and quaternary ammonium compounds.
The novel compounds of the formula I may be isolated from the reaction mixture ln the form of a pharmaceutically accept-able acid additlon salt, dependent upon the conditions in S which the reaction is carried out. The acid addition salts may also be obtained by treating the free base with a pharmaceutically acceptable organic or ~norganic acid. Aclds 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 Iwith an alkyl halide, for example methyl iodide or methyl bromide.
It is possible as a matter of cours~ to introduce or to modify the substituents at one or both phenyl nucleii even after 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 andJor R6 ~ H) may be alkylated in the usual way, for example by reaction with an alkyl-or ar~lkylhalide. More common for this purpose is, how-ever, the acylation of the nitrogen atom in question with, for example, an acid chloride or anhydride followed by a ~51877 reduction of the carbonyl group of the N-acyl derivative thus obtained. For the introduction of methyl groups at the nitrogen atom the procedure accordinq to Eschweiler-Clarke (heating with a mixture of formaldehyd and formic acid) or the reaction with formaldehyde and sodlumcyano-borohydride in a suitable solvent~ such as acetonitril, is preferred.
With an alkyl group with 1-6 carbon atoms is meant a branched or un~ranched alkyl group such as methyl, ethyl, propyl, isopropyl~ butyl, isobutyl, tert.butyl, n.pentyl5 isopentyl and hexyl.
The alkyl group in the alkoxy and alkylthio 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 as a pyrrolino group, a pyrrolidino group, a piperidino group, an oxazolidino group, a morpholino group, a pi-perazino group, etc.
Amines according to the general formula V~ that may be used in the various condensation reactions to obtain the compounds of the invention, are, ~or example ammonia~
methylamine~ dimethylamine, diethylamine, isopropylamine, dibutylamine, t.butylamine, benzylamine, phenylethylamine, phenylpropylamine, 2-phenyl-1-methyl-ethy$amine, pyrroline, 1051~i7 pyrrolidine, piperidine, oxazolidine, morpholine, piperazine, etc.
As already pointed out previously the compounds of the invention I exert a valuable central nervous system activity.
This C.N.S. activity can be concluded from the results of various pharmacological experiments, such as the reserpine antagonism test, reserpine reversal test, aggression iso-lated 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 unlts such as pills, tablets or coated tablets, or they can be processed into capsules. With the aid of suitable liq~ids the compounds can be applied as in~ection preparations in the form of solutions, emulsions or suspensions.
Preferably compounds I and, in particular,compounds I A 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 antidepressant activity.
Furthermore the compounds I, in which n iS 0 or 1 are to be preferred over the compounds I, having a longer side chain (n ~ 2).
In the Examples the following nomenclature and numbering has been used:
\ / ,0 5 ~ ~ 1,2,3,4-tetrahydro-9H-tribenzo ~12 ( b,d,f)-cycloheptatriene 8 g lo 10 ~ ~ x ~ X = 0 or S
1,2,3,4-tetrahydro-tribenzo(b,d,f)-5 ~4 ~ ~3 oxepine or -thiepine W
q ,0 ~ ~ ~,2 1~2~3~4-tetrahydro-9H-tribenzo ~ ~ (b,d,f)-azepine By way of example the preparation of various starting products are disclosed. The preparation of analogous starting products proceeds in exactly the same way.
Preparation startinq materials 25 1. 2-keto-1~2~3~4-tetrahvdro-tribenzo(b~d~f)-oxePine To a solution of 42 g of the compound 10-keto-10,11-dihydro-dibenzo(b,f)-oxepine in 200 ml of dry ethanol a solution of sodiumethoxide (7 g of sodium ln 500 ml of ethanol) is added dropwise. After stirring the mixture for 30 minutes 16.2 ml of methylvinylketon in S0 ml of ethanol are added, where-~051877 upon the solut~on is refluxed for one hour. The solution i~ cooled then and poured into 2 N HC1. After extracting into ether, washing the ether layer with water (till neutral) and drying the etherial phase, the solvent is S evaporated.
The residue, a redcoloured oil, is chromatographed after that over an alumina column and used ~or further con-version immediately. Yield: 37% oil.
In the same manner are prepared:
2-keto~ methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
meltin~ point 146-147C.
2-keto-11,12-dimethyl-i,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; (oil).
2-keto-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point 107-108C.
2-keto-11-trifluoromethyl-1~2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; (oil).
2-keto-6-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point 128-129C.
2-keto-6-methyl-1,2,3,4-tetrahydro-tribenzo(bgd,f)-oxepine;
(oil).
2-keto-1,2~3~4-tetrahydro-tribenzo(b,d,f)-thiepine; (oil).
2-keto-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclohepta-triene; melting paint 132-133C.
2-keto-12-hydroxy-1,2,3,4-tetrahydro-9H-tribenzotb,d,f)-cycloheptatriene; (oil).
2-keto-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene; (oil).
2-keto-11-methyl-12-methoxy-1,2~3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene; (oil).
- 10~1~377 2-keto-12-methyl-1~2,3,4-tetrahydro-9H-tribenzo(b~d,f)-cycloheptatriene; melting point 158-163C.
2-keto-12-trifluoromethyl-1,2~3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene; (oil).
2-keto-7-chloro-1~2,3,4-tetrahydro-9H-tribenzo(b,d~f)-cycloheptatriene; (oil).
2-keto-1,2~3,4-tetrahydro-9H-tribenzo~b,d,f)-azepine; ~oil).
2-keto-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d~f)-azepine; loil).
2-keto-7-methoxy-9-methyl-1,2,3,4-tetrahydro-gH-triben2O
(b,d,f)-azepine; (oil).
¦ 2. ;2-hvdroxY-1,2~3,4-tetrahYdro-tribenzo(b,d,f)-oxepine ~ J 6.2 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added to a suspension of 3.7 g of lithiumaluminiumhy-dride in 300 ml of dry ether. After refluxing for 2 hours 14.8 ml of water are added carefully. The suspension ob-tained is filtered off and after that the filtrate is dried and evaporated to dryness.
meltin~ point 146-147C.
2-keto-11,12-dimethyl-i,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; (oil).
2-keto-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point 107-108C.
2-keto-11-trifluoromethyl-1~2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; (oil).
2-keto-6-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point 128-129C.
2-keto-6-methyl-1,2,3,4-tetrahydro-tribenzo(bgd,f)-oxepine;
(oil).
2-keto-1,2~3~4-tetrahydro-tribenzo(b,d,f)-thiepine; (oil).
2-keto-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclohepta-triene; melting paint 132-133C.
2-keto-12-hydroxy-1,2,3,4-tetrahydro-9H-tribenzotb,d,f)-cycloheptatriene; (oil).
2-keto-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene; (oil).
2-keto-11-methyl-12-methoxy-1,2~3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene; (oil).
- 10~1~377 2-keto-12-methyl-1~2,3,4-tetrahydro-9H-tribenzo(b~d,f)-cycloheptatriene; melting point 158-163C.
2-keto-12-trifluoromethyl-1,2~3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene; (oil).
2-keto-7-chloro-1~2,3,4-tetrahydro-9H-tribenzo(b,d~f)-cycloheptatriene; (oil).
2-keto-1,2~3,4-tetrahydro-9H-tribenzo~b,d,f)-azepine; ~oil).
2-keto-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d~f)-azepine; loil).
2-keto-7-methoxy-9-methyl-1,2,3,4-tetrahydro-gH-triben2O
(b,d,f)-azepine; (oil).
¦ 2. ;2-hvdroxY-1,2~3,4-tetrahYdro-tribenzo(b,d,f)-oxepine ~ J 6.2 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added to a suspension of 3.7 g of lithiumaluminiumhy-dride in 300 ml of dry ether. After refluxing for 2 hours 14.8 ml of water are added carefully. The suspension ob-tained is filtered off and after that the filtrate is dried and evaporated to dryness.
3. 2-hvdroxv-1~2~3,~4a,13b-hexahydro-tribenzo(b,d.f)-oxepine 1.0 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine is added to a suspension of 10 mg PtO2 (Adams catalyst) in 50 ml glacial acetic acid. The mixture is put in a hydro-genation apparatus under hydrogen atmosphere and shakenfor 3 hours. After that time the theoretical quantity of hydrogen has been absorbed. The mixture is then filtered to remove the catalyst, whereupon the filtrate is evapo-rated in vacuo, yielding a light yellow oil.
10518'-~'7
10518'-~'7
4. 2-mesyloxy-1,2,3,4-tetrah~dro-tribenzo(b,d,f)-oxepine 6.2 g of 2-hydroxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added to a mixture of 16.8 ml of pyridine and methane sulphonylchloride, after which the mixture is stirred for 2 hours at 0C and then another 2 hours at room temperature. After that ~he mixture is poured out into water and then extracted with ether. The ether layers are dried and evaporated to dryness.
5. 2-azido-1 ? 2,3.4-tetrahydro-tribenzo(b,d,f)-oxepine The mesylate obta~ned in 3 in brought into a mixture of 25 ml of dimethylformamide and 4.2 ml of water, to which 1.52 g of activated sodium azide is added. The mixture is refluxed for S hours. After cooling the mixture is poured out into water and extracted with ether. After that the ether layers are washed, dried and evaporated to dryness.
! 6. 2-cvano-1.2.3~4-tetrahYdro-trlbenzo(b.d,f)-oxePine 2~ ~ 2.62 g of the 2-hydroxy compound obtained in 2 is-dis-solved in 50 ml of benzene whereupon 5 g of phosphorus triiodide is added. The mixture is refluxed for 2 hours.
After cooling this mixture ice-water is cautiously added.
The organic layer is separated, washed with water and dried. The solvent (benzene) is then evaporated yielding 3.6 g of the oily 2-iodo-compound. This residue is imme-diately dissolved in 300 ml dimethylformamide, after which 4 g sodiumcyanlde is added. The mixture obtalned is heated at 90C for one hour stirring all the time. The reaction-mixture is then poured into 600 ml water and extracted with ether. The crude nitrile is obtained after evaporat~on of the ether and immediately used for further reactions.
7. 2-cyanomethylidene-1,2,3~4-tetrahydro-tribenzo(b~d,f)-oxepine 1 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine is mixed with 1 ml of benzene, 15 ml of acetonitril and 0.5 g of molecular sieve (4 ~). 50 m~ of sodium-ethoxide are added and the mixture is heated for 3 hours (90-100C).
After cooling the mixture the molRcular sieve is filtered off and the filtrate evaporated.
Example I
2-amino-1.2,3,4-tetrahYdro-trlbenzo(b,d,f)-oxepine 3.7 g of 2-azido-1,2,3,4-tetrahydro-tribenzo~b,d,f~-oxepine are added to a suspension of 3 g of lithiumaluminiumhydride in 100 ml of dry ether. The mixture is refluxed for one hour.
After the mixture has been cooled down, 12 ml of water are added carefully after which the mixture is stirred for some time~ The suspension is filtered and after that the filtrate ls dried and evaporated to dryness. The residue is converted with maleic acid into the maleate. Melting point of the maleate: 198-202C. Yield 85X.
Example II
In the way indicated in example I are prepared:
2-amino-9-methyl-1~2~3~4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
2-amino-7-chloro-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
2-amino-1,2,3,4-tetrahydro-9H-tribenzo(b~d,f)-cycloheptatrien~;
melting point as maleate: ]85-188C~
1~51~77 2-amino-12-methoxy-1~2~3,4-tetrahydro-9X-tribenzo(b~d,f)-cycloheptatr~ene; melting point as maleate: 165C (dec.).
2-amino-12-methyl-1,2~3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene; melting point as maleate: 196-201C.
2-amino-7-chloro-1~2~3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclo-heptatriene, (oil).
2-amino-11-trifluoromethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine, (oil).
2-amino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point as maleate: 190-192C.
2-amino-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point as maleate: 194-196C.
2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point as maleate: 178-180C.
2-amino-12-trifluoromethyl-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene, (oil).
2-amino-12-hydroxy-1~2,3,4-tetrahydro-9H-tribenzo(b~d,f)-cycloheptatriene, (oil).
,.
Example III
2-dimethylamino-1,2~3.4-tetrahYdro-9H-tribenzo(b~d,f)-cyclo-heptatriene In a 500 ml Parr apparatus a mixture of 20 g 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-cycloheptatriene in 300 ml of absolute ethanol and a solution of 6 g of dlmethyl-amine in 20 ml of ethanol to which 3.9 g of palladium 10%
on charcoal are added, is hydrogenated by means of hydrogen under a pressure of 3 kg/cm2.
The mixture is then filtered and the filtrate washed, dried and evaporated to dryness. The residue is an oily ~051877 substance. The oil ls crystallized by means of maleic acid.
Melting point after recrystallization from ether-ethanol 145-150C and 169-171C (double melting point).
Treatment of the free base with methyliodide resulted in the iodo methylate~
Example IV
2-dimethYlamino-6-chloro-ll2~3~4-tetrahydro-triben2o(b.d~f) oxePine To a mixture of 10 ml of dimethylamine and 3.1 ml of 98%
formic acid at -10C a solution of ll.S g of 2-keto-6-chloro-1~2~3,4-tetrahydro-tribenzo(b,d,f)-oxepine in 30 ml of dime-thylformamide are added dropwise. The mixture is refluxed for 10 hours. After cooling, the mixture is poured into water and extracted into ether. The ether layer is then washed with 300 ml of 2 N HCl. The acidic water layer is made alkaline with 2 N NaOH, after which the alkaline aqueous solution is extracted with ether once more. The ether layers are collected, dried and then evaporated. The oil obtained crystallizes as maleate:
melting point 171C.
Example V
2-dimethvlamino-12-methoxv-1,2,3l4-tetrah~dro-9H-tribenzo (b~d~f)-cYcloheptatriene 500 mg of 2-keto-12-methoxy-1,2,3,4-tetrahydro-9H-tri-benzo(b,d,f)-cycloheptatriene in 2.7 ml of methanol is treated with 150 mg of sodiumborohydride and 0.14 ml of /~et~y~ e methanolic IICl solution (5 N). After mixing for 10 hours at an elevated temperature, the reaction mixture is filtered and the filtrate extracted with ether. The ether - ~)51877 layer is washed, dried and evaporated. The oil obtained is then chromatographed over an alumina column. Melting point as HCl salt: 210C. Yield 30%.
Example VI
In the way indicated in example III are prepared:
2-dimethylamino-7-methoxy-9-methyl-1,2 9 3 ~ 4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
2-amino-1,2,3 f 4-tetrahydro-9H-tribenzo(b,d,f)-cyclohepta-triene; melting point as maleate: 183-185C.
2-methylamino-1,2,3,4-tetrahydro-9H-tribPnzo(b,d,f)-cyclo-heptatriene; melting point as maleate: 162-165C.
2-dimethylamino-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene; melting point HCl salt: 210C
(dec.).
2-dimethylamino-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; melting point maleate: 195-196C.
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point HCl salt: 250-255 C (dec.).
2-morpholino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine, (oil).
2-dimethylamino-9-methyl-1,2~3~4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil); maleate salt 212-218C.
2-methylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo~b,d,f)-azepine, (oil).
2-piperidino-9-methyl-1,2~3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
2-benzylamino-9-methyl-1,2~3,4-tetrahydro-9H-tribenzo(b~d~f)-azepine, (oil).
2-benzylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclohep-tatriene, (oll).
1~51877 2-phenethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclo-heptatriene, (oil). -~
~ I ~ 0l ne ~
2-amino-1,2,3~4-tetrahydro-tribenzo(b,d,f)l ~ ,~(oil);
melting point maleate: 178C~
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)_thiazepine7 (oil); melting point HCl salt: 250 C (dec.).
2-dimethylamino-7-hydroxy-9-methyl-1,2,3,4-tetrahydro-9H-tri-benzo(b,d,f)-azepine, (oil).
2-dimethylamino-9,12-dimethyl-1,2,3,4-tetrahydro-9H-tribenzo (b~d,f)-azepine, (oil).
2-dimethylamino-9-methyl-11-trifluoromethyl-1,2~3~4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
Example VII
In the way indicated in example IV are prepared:
2-dimethylamino-1~2~3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclo-heptatriene; melting point maleate: 145-150C and 169-2-dimethylamino-12-methoxy-1~2~3~4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene; m.p. HCl salt: 210C.
2-dimethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene; m.p. maleate: 198-201C.
2-dimethylamino-7-chloro-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene, (oil).
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 103-108C.
2-dimethylamino-11-methyl-1,2,3 7 4-tetrahydro-tribenzo(b,d,f)-oxepine; melting point maleate: 140-142C.
2-dimethylamino-11,12-dimethyl-1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine~ (oil).
2-dimethylamino-12-chloro-1~2~3~4-tetrahydro-tribenzo(b 7 d, L ) -_ oxepine; melting point maleate: 195-196C.
2-dimethylamino-6-methyl-1,2,3,4-tetrahydro-tribenzo(b,d 9 f)-oxepine; melting point maleate: 182-183C.
2-dimethylamino-11-methyl-12-methoxy-1,2~3~4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene, (oil).
2-morpholino-1,2,3,4-tetrahydro-9~-tribenzo(b,d,f)-cyclo-heptatriene, (oil).
2-piperidino-3-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d~f)-thiepine;
melting point HCl salt: 250-255C.
2-dimethylamino-9-methyl-1~2~3,4-tetrahydro-9H-tribenzo (b,d,f)-azepine; melting point maleate: 210-220C (dec.).
2-dimethylamino-11-trifluoromethyl-1,2,3,4-tetrahydro-triben-zo(b,d~f)-oxepine, (oil).
2-dimethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
Example VIII
In the way indicated in example V, the following compounds are prepared:
2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 198-200C.
2-methylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine, (oil).
2-morpholino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine, (oil).
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 105-110C.
10511~77 2-dimethylamino-1,2~3,4-tetrahydro-9H-tribenzo(b,d~f)-cyclo-heptatriene; melting point maleate: 145-150C (and 168-170C) 2-dimethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cyclohept~triene; melting point maleate: 198-200C.
2-dimethylamino-12-hydroxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d~f)-cycloheptatriene, (oil).
2-dimethylamino-11-methyl-1,2,3,4-tet ahydro-tribenzo(b,d,f)-oxepine; melting point maleate: 138-142C.
2-amino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 190-193C.
2-pyrrolidino-1,2,3,4-tetrahydro-9H~tribenzo(b~d~f)-cyclohep-tatriene, (oil).
2-diethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene; melting point maleate: 187-192C.
2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point maleate: 178-180C.
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point HCl salt: 250C (dec.).
2-dimethylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine; melting polnt maleate: 210-228C (dec.).
2-dimethylamino-12-trifluoromethyl-1,2~3,4-tetrahydro-9H-tri-benzo(b,d,f)-cycloheptatriene, (oil).
Example IX
2-dimethvlamino-1~2~3~4-tetrahydro-tribenzo(b~d~f)-oxePine 1.7 g of 2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine is dissol~ed in 47.2 ml of formic acid and 47.2 ml of a 40% solution of formaldehyde in water. The mixture is heated at 100C for 5 hours after which the mixture is 105~877 cooled. The solution is then poured into water and made alkaline with diluted sodiumhydroxide. After that the mixture is extracted with ether and the ether layers obtained dried and evaporated. The oil obtained crystal-lizes with maleic acid as maleate: melting point 103-108C.
Obtained in this manner: 53%.
Example X
2~dimethylamino-12-methoxv-1,2,3,4-tetrahydro-9H-tribenzo (b,d.f)-cyclohePtatriene To a solution of 1 g of 2-amino-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo-cycloheptatriene in 15 ml of ace-tonitril, 2.7 ml of a 40% formaldehyde solution in water and 660 mg of cyanoborohydride are added. The reaction is exothermic. After stirring for one hour 0.8 ml of acetic acid is added after which the mixture is stirred for an-other 2 hours. The solution is made alkaline after that and then extracted with ether. The ether layer is dried and e~aporated. Melting point HCl salt: 210C.
~~~ Example XI
~ 2-dimethylaminoethyl-1,2,3.4-tetrahydro-9H-trib _ zo(b,d.f)-I' cydloheptatriene ~_ J 22.50 g of triethylphosphonoacetate (prepared by means of the Michaelis-Arbuzow reaction) is added dropwise at 20C to a slurry of 50% sodium hydride (4.9 g) in 200 ml of dry 1,2-dimethoxy-ethane. After addition the reaction mixture is stirred for 1 hour at room temperature until gas evolution ceased. Then 26 g of 2-keto-1,2,3,4-tetra-hydro-9H-trlbenzo(b,d,f)-cycloheptatriene is added slowly at such a rate that the temperature is maintained below 40C. After an additional quarter of an hour the mixture is poured into a large excess of water and the aqueous solution extracted with ether. The ether layer after belng dried over sodiumsulphate and evaporated gives 26.0 g of 2-ethoxycarbonylmethyl-3~4-dihydro-9H-tribenzo(b,d~f)-cycloheptatriene.
Catalytic hydrogenation of lS g of t~is product in methanol and palladium/charcoal-catalyst gives the 1,2,3,4-tetrahydro-compound. After evaporation of the methanol to a volume of 70 ml, the mixture is treated ~ith 30 g of dimethyl-amine in an ampoule at 100C for 14 hours to give the 2-di-methylamino-carbonylmethyl-compound, 13.5 g. This product is reduced with 15 g lithiumaluminiumhydride in ether (8 hours at boiling temperature) in the usual manner yielding 13.0 g of the title compound. The oily residue is converted to the maleate, melting point 131-133C.
The same product is obtained by carrying out the hydro-genation with palladium on charcoal in the last step of the synthesis instead of performing this hydrogenation previous to the amide formation and subsequent reduction ~f the amide moiety with LiAlH4.
In the same manner are prepared:
2-dimethylaminoethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-azepine and 2-aminoethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
Example XII
2-aminomethvl-1 2,3,4-tetrahvdro-9H-tribenzo(b.d.f)-cvclo-heptatriene 1.4 g of the 2-cyano-compound, prepared in a similar 1~15~877 manner as described (see '7starting materials" 6) is dissolved in 50 ml tetrahydrofuran after which 1.5 g LiAlH4 is added.
The mixture is boiled for 4 hours~ After cooling 12 ml of water is added slowly while stirring. Filtration and evap-oration of the solvent yields 2.4 g of the 2-aminomethyl-compound as an oil. Melting point maleate salt: 125-13?C.
In the same manner are prepared:
2-aminomethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
2-aminomethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azep~ne.
2-aminomethyl-7-methoxy-10-chloro-1,2,3~4-tetrahydro-9H-tri-benzo(b,d,f)-cycloheptatriene.
~ ~' Example XIII
1~ 2-d~methylaminomethyl-1.2,3,4-tetrahydro-tribenzo(b,d~f)-oxe~ine / 1.5 g of 2-cyano-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine ("starting material 6") is suspended in 80 ml diethyleneglycol and 65 ml of an aqueous KOH solution (40%). The mixture is refluxed for 5 hours. After cooling the mixture to ambient temperature, it is poured into 450 ml water. The aqueous mixture is extracted with ether to remove non-acidic material. The water-phase is acidified to about pH 3, whereupon the mixture is extracted with ether. The ether extracts are washed, dried and then evaporated, yielding 0.80 g of the crude 2-carboxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine. This carboxyl-compound is converted into the dimethylamide in the usual manner and then reduced with LiA1~4, yielding 0.5 g of the tltle product as an oil.
In the same manner are prepared:
2-dimethylaminomethyl-9-methyl-1,2,3,4-tetrahydro-9H-tri-benzo(b,d,f)-azepine, (oil).
2-dimethylaminomethyl-1,2,3,4,-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene, (oil).
2-aminomethyl-1,2~3,4-tetrahydro-9H-tribenzo(b,d~f)-cycloheptatriene, (oil).
2-benzylaminomethyl-9-methyl-1~2~3~4-tetrahydro-9H-tri-benzo(b,d,f)-azepine, (oil).
Example XIV
2-aminoethyl-112,3,4-tetrahydro-9H-tribenzo(b d~f ? -cyclo-hePtatriene Diborane gas, oDtained from 1.2 g of NaBH4 and 5.2 ml of BF3-etherate is let in into a solution of 200 mg of 2-cyanomethylidene-1~2~3~4-tetrahydro-9H-tribenzo(b~d~f)-cycloheptatriene (obtained in a similar manner as described in "Starting materials" 7) in 15 ml THF under nitrogen at-mosphere.
After that the mixture is refluxed for 1 hour. The excess of B2H5 present is then decomposed by adding ethanol, whereupon the solution is evaporated.
The residue is dissolved in 18 ml of a mixture of con-centrated HCl and water (1:1) whereupon the solution is heated for some time. The acidic water layer is c~oled dcwn, made alkaline and then extracted into ether.
Evaporating the solvent yields 85 mg of the title compound as an oil.
In the same manner are prepared:
2-aminomethyl-1~2,3,4,tetrahydro-tribenzo(b,d,f)-oxepine.
2-aminomethyl-1,2,3,4-tetrahydro-9H_tribenzo~b,d,f)-azepine.
- lOS1877 Example XV
2-amino-1,2,3,4 4a,13b-hexahydro-9H tribenzo(b,d,f?-c~clo-heptatriene 10 g of 2-keto-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene is suspended in 400 ml of ethanol andsubsequently 20 g hydroxylamine ~Cl and 40 ml pyridine are added. After refluxing the mixture for 30 minutes, the mixture is concentrated to a thin oil in ~acuo, from which the oxime crystallized slowly. The precipitate is sucked off and washed with water. The dried oxime is sus-pended in isopropanol. O~er a period of 3 hours 20 g sodium are added while stirring. The reaction mixture is concen-trated to l/4 of its volume by evaporation (Rotavap) and then diluted with water and extracted with ether. The ether extract was dried over anhydrous potassium carbonate and finally evaporated to dryness. The oil obtained is converted into its maleate, meltlng point 212-213C.
Yield 7.3 g.
In the same way are prepared:
2-amino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine and 2-amino-9_methyl-1,2,3,4,4a,l3b-hexahydro-9H-tribenzo (b,d,f)-azepine.
By using palladium on charcoal (10%) the ox~me is hydrogenated into the 4a,13b-unsaturated compound:
2-amino-1~2~3~4-tetrahydro-9H-tribenzo(b,d,f)-cyclohepta-triene, (oil); meltin~ point maleate: 181-186C.
Example XVI
2-dimethylamino-1,2?3,4?4a,13b-hexa~ dro-gH-tribenzo(b,d,f)-cycloheptatriene 4 g of the primary amine prepared accordln~ to example XV is methylated with a formaldehyde/formic acid mixture (l:i) during S hours at 100C , (Clarke-Eschweiler procedure).
Obtained is 4.2 g of the dimethylamino product which is converted to its hydrochloride, melting point 256-263C.
s Example XVII
2-dimethylamino-1,2~3,4,4a,13b-hexahydro-9H-tribenzo(b,d f)-cyc lohePtatriene In the same manner as described in Example IV the compound 2-keto-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cyclohepta-triene, obtained by oxydation of the corresponding alcohol with chromic acid ln benzene, acetic acid, water at room temperature, is reacted with dimethylamine and formic acid in dimethylforma-mide at reflux temperature. Melting point HCl salt 260-263C.
The same product is obtained by converting 2-hydroxy-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene, obtained by hydrogenating the corresponding 2-keto-1,2,3,4-tetrahydro-compound with PtO2 in glacial acetic acid, into 2-mesyloxy-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene in the same manner as described in "starting materials" 3 and 4 and treating this mesyloxy compound with dimethylamine.
In the same manners are prepared:
2-dimethylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine.
2-dimethylamino-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tri-benzo(b,d,f)-azepine.
30 2-dimethylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-~ ie~ai~ c .
105~877 2-dimethylamino-12-methyl-1,2,3,4,4a,13b-hexahydro-9H-tri-benzo~b,d,f)-cycloheptatriene.
2-methylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine.
2-dimethylamino-7-methoxy-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-azepineO
2-morpholino-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-azepineO
Example XVIII
2-aminomethyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo~b,d,f)-cycloheptatriene 2-hydroxy-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cyclo-heptatriene is converted into the corresponding 2-mesyloxy compound in the same manner as described in "starting materials" 4 and then treated with sodiumcyanide, to obtain the 2-cyano-compound. This compound is immediately reduced with LiAlH4 in ether as described previously, yielding the 2-amino-methyl-compound as an oilO
Conversion of this oil with maleic acid yields the maleate; melting point:
128 - 132C.
In the same manner is prepared:
2-aminomethyl-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo (b,d,f)-azepineO
! 6. 2-cvano-1.2.3~4-tetrahYdro-trlbenzo(b.d,f)-oxePine 2~ ~ 2.62 g of the 2-hydroxy compound obtained in 2 is-dis-solved in 50 ml of benzene whereupon 5 g of phosphorus triiodide is added. The mixture is refluxed for 2 hours.
After cooling this mixture ice-water is cautiously added.
The organic layer is separated, washed with water and dried. The solvent (benzene) is then evaporated yielding 3.6 g of the oily 2-iodo-compound. This residue is imme-diately dissolved in 300 ml dimethylformamide, after which 4 g sodiumcyanlde is added. The mixture obtalned is heated at 90C for one hour stirring all the time. The reaction-mixture is then poured into 600 ml water and extracted with ether. The crude nitrile is obtained after evaporat~on of the ether and immediately used for further reactions.
7. 2-cyanomethylidene-1,2,3~4-tetrahydro-tribenzo(b~d,f)-oxepine 1 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine is mixed with 1 ml of benzene, 15 ml of acetonitril and 0.5 g of molecular sieve (4 ~). 50 m~ of sodium-ethoxide are added and the mixture is heated for 3 hours (90-100C).
After cooling the mixture the molRcular sieve is filtered off and the filtrate evaporated.
Example I
2-amino-1.2,3,4-tetrahYdro-trlbenzo(b,d,f)-oxepine 3.7 g of 2-azido-1,2,3,4-tetrahydro-tribenzo~b,d,f~-oxepine are added to a suspension of 3 g of lithiumaluminiumhydride in 100 ml of dry ether. The mixture is refluxed for one hour.
After the mixture has been cooled down, 12 ml of water are added carefully after which the mixture is stirred for some time~ The suspension is filtered and after that the filtrate ls dried and evaporated to dryness. The residue is converted with maleic acid into the maleate. Melting point of the maleate: 198-202C. Yield 85X.
Example II
In the way indicated in example I are prepared:
2-amino-9-methyl-1~2~3~4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
2-amino-7-chloro-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
2-amino-1,2,3,4-tetrahydro-9H-tribenzo(b~d,f)-cycloheptatrien~;
melting point as maleate: ]85-188C~
1~51~77 2-amino-12-methoxy-1~2~3,4-tetrahydro-9X-tribenzo(b~d,f)-cycloheptatr~ene; melting point as maleate: 165C (dec.).
2-amino-12-methyl-1,2~3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene; melting point as maleate: 196-201C.
2-amino-7-chloro-1~2~3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclo-heptatriene, (oil).
2-amino-11-trifluoromethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine, (oil).
2-amino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point as maleate: 190-192C.
2-amino-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point as maleate: 194-196C.
2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point as maleate: 178-180C.
2-amino-12-trifluoromethyl-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene, (oil).
2-amino-12-hydroxy-1~2,3,4-tetrahydro-9H-tribenzo(b~d,f)-cycloheptatriene, (oil).
,.
Example III
2-dimethylamino-1,2~3.4-tetrahYdro-9H-tribenzo(b~d,f)-cyclo-heptatriene In a 500 ml Parr apparatus a mixture of 20 g 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-cycloheptatriene in 300 ml of absolute ethanol and a solution of 6 g of dlmethyl-amine in 20 ml of ethanol to which 3.9 g of palladium 10%
on charcoal are added, is hydrogenated by means of hydrogen under a pressure of 3 kg/cm2.
The mixture is then filtered and the filtrate washed, dried and evaporated to dryness. The residue is an oily ~051877 substance. The oil ls crystallized by means of maleic acid.
Melting point after recrystallization from ether-ethanol 145-150C and 169-171C (double melting point).
Treatment of the free base with methyliodide resulted in the iodo methylate~
Example IV
2-dimethYlamino-6-chloro-ll2~3~4-tetrahydro-triben2o(b.d~f) oxePine To a mixture of 10 ml of dimethylamine and 3.1 ml of 98%
formic acid at -10C a solution of ll.S g of 2-keto-6-chloro-1~2~3,4-tetrahydro-tribenzo(b,d,f)-oxepine in 30 ml of dime-thylformamide are added dropwise. The mixture is refluxed for 10 hours. After cooling, the mixture is poured into water and extracted into ether. The ether layer is then washed with 300 ml of 2 N HCl. The acidic water layer is made alkaline with 2 N NaOH, after which the alkaline aqueous solution is extracted with ether once more. The ether layers are collected, dried and then evaporated. The oil obtained crystallizes as maleate:
melting point 171C.
Example V
2-dimethvlamino-12-methoxv-1,2,3l4-tetrah~dro-9H-tribenzo (b~d~f)-cYcloheptatriene 500 mg of 2-keto-12-methoxy-1,2,3,4-tetrahydro-9H-tri-benzo(b,d,f)-cycloheptatriene in 2.7 ml of methanol is treated with 150 mg of sodiumborohydride and 0.14 ml of /~et~y~ e methanolic IICl solution (5 N). After mixing for 10 hours at an elevated temperature, the reaction mixture is filtered and the filtrate extracted with ether. The ether - ~)51877 layer is washed, dried and evaporated. The oil obtained is then chromatographed over an alumina column. Melting point as HCl salt: 210C. Yield 30%.
Example VI
In the way indicated in example III are prepared:
2-dimethylamino-7-methoxy-9-methyl-1,2 9 3 ~ 4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
2-amino-1,2,3 f 4-tetrahydro-9H-tribenzo(b,d,f)-cyclohepta-triene; melting point as maleate: 183-185C.
2-methylamino-1,2,3,4-tetrahydro-9H-tribPnzo(b,d,f)-cyclo-heptatriene; melting point as maleate: 162-165C.
2-dimethylamino-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene; melting point HCl salt: 210C
(dec.).
2-dimethylamino-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; melting point maleate: 195-196C.
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point HCl salt: 250-255 C (dec.).
2-morpholino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine, (oil).
2-dimethylamino-9-methyl-1,2~3~4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil); maleate salt 212-218C.
2-methylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo~b,d,f)-azepine, (oil).
2-piperidino-9-methyl-1,2~3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
2-benzylamino-9-methyl-1,2~3,4-tetrahydro-9H-tribenzo(b~d~f)-azepine, (oil).
2-benzylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclohep-tatriene, (oll).
1~51877 2-phenethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclo-heptatriene, (oil). -~
~ I ~ 0l ne ~
2-amino-1,2,3~4-tetrahydro-tribenzo(b,d,f)l ~ ,~(oil);
melting point maleate: 178C~
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)_thiazepine7 (oil); melting point HCl salt: 250 C (dec.).
2-dimethylamino-7-hydroxy-9-methyl-1,2,3,4-tetrahydro-9H-tri-benzo(b,d,f)-azepine, (oil).
2-dimethylamino-9,12-dimethyl-1,2,3,4-tetrahydro-9H-tribenzo (b~d,f)-azepine, (oil).
2-dimethylamino-9-methyl-11-trifluoromethyl-1,2~3~4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
Example VII
In the way indicated in example IV are prepared:
2-dimethylamino-1~2~3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclo-heptatriene; melting point maleate: 145-150C and 169-2-dimethylamino-12-methoxy-1~2~3~4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene; m.p. HCl salt: 210C.
2-dimethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene; m.p. maleate: 198-201C.
2-dimethylamino-7-chloro-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene, (oil).
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 103-108C.
2-dimethylamino-11-methyl-1,2,3 7 4-tetrahydro-tribenzo(b,d,f)-oxepine; melting point maleate: 140-142C.
2-dimethylamino-11,12-dimethyl-1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine~ (oil).
2-dimethylamino-12-chloro-1~2~3~4-tetrahydro-tribenzo(b 7 d, L ) -_ oxepine; melting point maleate: 195-196C.
2-dimethylamino-6-methyl-1,2,3,4-tetrahydro-tribenzo(b,d 9 f)-oxepine; melting point maleate: 182-183C.
2-dimethylamino-11-methyl-12-methoxy-1,2~3~4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene, (oil).
2-morpholino-1,2,3,4-tetrahydro-9~-tribenzo(b,d,f)-cyclo-heptatriene, (oil).
2-piperidino-3-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d~f)-thiepine;
melting point HCl salt: 250-255C.
2-dimethylamino-9-methyl-1~2~3,4-tetrahydro-9H-tribenzo (b,d,f)-azepine; melting point maleate: 210-220C (dec.).
2-dimethylamino-11-trifluoromethyl-1,2,3,4-tetrahydro-triben-zo(b,d~f)-oxepine, (oil).
2-dimethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).
Example VIII
In the way indicated in example V, the following compounds are prepared:
2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 198-200C.
2-methylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine, (oil).
2-morpholino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine, (oil).
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 105-110C.
10511~77 2-dimethylamino-1,2~3,4-tetrahydro-9H-tribenzo(b,d~f)-cyclo-heptatriene; melting point maleate: 145-150C (and 168-170C) 2-dimethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cyclohept~triene; melting point maleate: 198-200C.
2-dimethylamino-12-hydroxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d~f)-cycloheptatriene, (oil).
2-dimethylamino-11-methyl-1,2,3,4-tet ahydro-tribenzo(b,d,f)-oxepine; melting point maleate: 138-142C.
2-amino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 190-193C.
2-pyrrolidino-1,2,3,4-tetrahydro-9H~tribenzo(b~d~f)-cyclohep-tatriene, (oil).
2-diethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene; melting point maleate: 187-192C.
2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point maleate: 178-180C.
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point HCl salt: 250C (dec.).
2-dimethylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine; melting polnt maleate: 210-228C (dec.).
2-dimethylamino-12-trifluoromethyl-1,2~3,4-tetrahydro-9H-tri-benzo(b,d,f)-cycloheptatriene, (oil).
Example IX
2-dimethvlamino-1~2~3~4-tetrahydro-tribenzo(b~d~f)-oxePine 1.7 g of 2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine is dissol~ed in 47.2 ml of formic acid and 47.2 ml of a 40% solution of formaldehyde in water. The mixture is heated at 100C for 5 hours after which the mixture is 105~877 cooled. The solution is then poured into water and made alkaline with diluted sodiumhydroxide. After that the mixture is extracted with ether and the ether layers obtained dried and evaporated. The oil obtained crystal-lizes with maleic acid as maleate: melting point 103-108C.
Obtained in this manner: 53%.
Example X
2~dimethylamino-12-methoxv-1,2,3,4-tetrahydro-9H-tribenzo (b,d.f)-cyclohePtatriene To a solution of 1 g of 2-amino-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo-cycloheptatriene in 15 ml of ace-tonitril, 2.7 ml of a 40% formaldehyde solution in water and 660 mg of cyanoborohydride are added. The reaction is exothermic. After stirring for one hour 0.8 ml of acetic acid is added after which the mixture is stirred for an-other 2 hours. The solution is made alkaline after that and then extracted with ether. The ether layer is dried and e~aporated. Melting point HCl salt: 210C.
~~~ Example XI
~ 2-dimethylaminoethyl-1,2,3.4-tetrahydro-9H-trib _ zo(b,d.f)-I' cydloheptatriene ~_ J 22.50 g of triethylphosphonoacetate (prepared by means of the Michaelis-Arbuzow reaction) is added dropwise at 20C to a slurry of 50% sodium hydride (4.9 g) in 200 ml of dry 1,2-dimethoxy-ethane. After addition the reaction mixture is stirred for 1 hour at room temperature until gas evolution ceased. Then 26 g of 2-keto-1,2,3,4-tetra-hydro-9H-trlbenzo(b,d,f)-cycloheptatriene is added slowly at such a rate that the temperature is maintained below 40C. After an additional quarter of an hour the mixture is poured into a large excess of water and the aqueous solution extracted with ether. The ether layer after belng dried over sodiumsulphate and evaporated gives 26.0 g of 2-ethoxycarbonylmethyl-3~4-dihydro-9H-tribenzo(b,d~f)-cycloheptatriene.
Catalytic hydrogenation of lS g of t~is product in methanol and palladium/charcoal-catalyst gives the 1,2,3,4-tetrahydro-compound. After evaporation of the methanol to a volume of 70 ml, the mixture is treated ~ith 30 g of dimethyl-amine in an ampoule at 100C for 14 hours to give the 2-di-methylamino-carbonylmethyl-compound, 13.5 g. This product is reduced with 15 g lithiumaluminiumhydride in ether (8 hours at boiling temperature) in the usual manner yielding 13.0 g of the title compound. The oily residue is converted to the maleate, melting point 131-133C.
The same product is obtained by carrying out the hydro-genation with palladium on charcoal in the last step of the synthesis instead of performing this hydrogenation previous to the amide formation and subsequent reduction ~f the amide moiety with LiAlH4.
In the same manner are prepared:
2-dimethylaminoethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-azepine and 2-aminoethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
Example XII
2-aminomethvl-1 2,3,4-tetrahvdro-9H-tribenzo(b.d.f)-cvclo-heptatriene 1.4 g of the 2-cyano-compound, prepared in a similar 1~15~877 manner as described (see '7starting materials" 6) is dissolved in 50 ml tetrahydrofuran after which 1.5 g LiAlH4 is added.
The mixture is boiled for 4 hours~ After cooling 12 ml of water is added slowly while stirring. Filtration and evap-oration of the solvent yields 2.4 g of the 2-aminomethyl-compound as an oil. Melting point maleate salt: 125-13?C.
In the same manner are prepared:
2-aminomethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
2-aminomethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azep~ne.
2-aminomethyl-7-methoxy-10-chloro-1,2,3~4-tetrahydro-9H-tri-benzo(b,d,f)-cycloheptatriene.
~ ~' Example XIII
1~ 2-d~methylaminomethyl-1.2,3,4-tetrahydro-tribenzo(b,d~f)-oxe~ine / 1.5 g of 2-cyano-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine ("starting material 6") is suspended in 80 ml diethyleneglycol and 65 ml of an aqueous KOH solution (40%). The mixture is refluxed for 5 hours. After cooling the mixture to ambient temperature, it is poured into 450 ml water. The aqueous mixture is extracted with ether to remove non-acidic material. The water-phase is acidified to about pH 3, whereupon the mixture is extracted with ether. The ether extracts are washed, dried and then evaporated, yielding 0.80 g of the crude 2-carboxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine. This carboxyl-compound is converted into the dimethylamide in the usual manner and then reduced with LiA1~4, yielding 0.5 g of the tltle product as an oil.
In the same manner are prepared:
2-dimethylaminomethyl-9-methyl-1,2,3,4-tetrahydro-9H-tri-benzo(b,d,f)-azepine, (oil).
2-dimethylaminomethyl-1,2,3,4,-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene, (oil).
2-aminomethyl-1,2~3,4-tetrahydro-9H-tribenzo(b,d~f)-cycloheptatriene, (oil).
2-benzylaminomethyl-9-methyl-1~2~3~4-tetrahydro-9H-tri-benzo(b,d,f)-azepine, (oil).
Example XIV
2-aminoethyl-112,3,4-tetrahydro-9H-tribenzo(b d~f ? -cyclo-hePtatriene Diborane gas, oDtained from 1.2 g of NaBH4 and 5.2 ml of BF3-etherate is let in into a solution of 200 mg of 2-cyanomethylidene-1~2~3~4-tetrahydro-9H-tribenzo(b~d~f)-cycloheptatriene (obtained in a similar manner as described in "Starting materials" 7) in 15 ml THF under nitrogen at-mosphere.
After that the mixture is refluxed for 1 hour. The excess of B2H5 present is then decomposed by adding ethanol, whereupon the solution is evaporated.
The residue is dissolved in 18 ml of a mixture of con-centrated HCl and water (1:1) whereupon the solution is heated for some time. The acidic water layer is c~oled dcwn, made alkaline and then extracted into ether.
Evaporating the solvent yields 85 mg of the title compound as an oil.
In the same manner are prepared:
2-aminomethyl-1~2,3,4,tetrahydro-tribenzo(b,d,f)-oxepine.
2-aminomethyl-1,2,3,4-tetrahydro-9H_tribenzo~b,d,f)-azepine.
- lOS1877 Example XV
2-amino-1,2,3,4 4a,13b-hexahydro-9H tribenzo(b,d,f?-c~clo-heptatriene 10 g of 2-keto-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene is suspended in 400 ml of ethanol andsubsequently 20 g hydroxylamine ~Cl and 40 ml pyridine are added. After refluxing the mixture for 30 minutes, the mixture is concentrated to a thin oil in ~acuo, from which the oxime crystallized slowly. The precipitate is sucked off and washed with water. The dried oxime is sus-pended in isopropanol. O~er a period of 3 hours 20 g sodium are added while stirring. The reaction mixture is concen-trated to l/4 of its volume by evaporation (Rotavap) and then diluted with water and extracted with ether. The ether extract was dried over anhydrous potassium carbonate and finally evaporated to dryness. The oil obtained is converted into its maleate, meltlng point 212-213C.
Yield 7.3 g.
In the same way are prepared:
2-amino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine and 2-amino-9_methyl-1,2,3,4,4a,l3b-hexahydro-9H-tribenzo (b,d,f)-azepine.
By using palladium on charcoal (10%) the ox~me is hydrogenated into the 4a,13b-unsaturated compound:
2-amino-1~2~3~4-tetrahydro-9H-tribenzo(b,d,f)-cyclohepta-triene, (oil); meltin~ point maleate: 181-186C.
Example XVI
2-dimethylamino-1,2?3,4?4a,13b-hexa~ dro-gH-tribenzo(b,d,f)-cycloheptatriene 4 g of the primary amine prepared accordln~ to example XV is methylated with a formaldehyde/formic acid mixture (l:i) during S hours at 100C , (Clarke-Eschweiler procedure).
Obtained is 4.2 g of the dimethylamino product which is converted to its hydrochloride, melting point 256-263C.
s Example XVII
2-dimethylamino-1,2~3,4,4a,13b-hexahydro-9H-tribenzo(b,d f)-cyc lohePtatriene In the same manner as described in Example IV the compound 2-keto-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cyclohepta-triene, obtained by oxydation of the corresponding alcohol with chromic acid ln benzene, acetic acid, water at room temperature, is reacted with dimethylamine and formic acid in dimethylforma-mide at reflux temperature. Melting point HCl salt 260-263C.
The same product is obtained by converting 2-hydroxy-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene, obtained by hydrogenating the corresponding 2-keto-1,2,3,4-tetrahydro-compound with PtO2 in glacial acetic acid, into 2-mesyloxy-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene in the same manner as described in "starting materials" 3 and 4 and treating this mesyloxy compound with dimethylamine.
In the same manners are prepared:
2-dimethylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine.
2-dimethylamino-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tri-benzo(b,d,f)-azepine.
30 2-dimethylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-~ ie~ai~ c .
105~877 2-dimethylamino-12-methyl-1,2,3,4,4a,13b-hexahydro-9H-tri-benzo~b,d,f)-cycloheptatriene.
2-methylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine.
2-dimethylamino-7-methoxy-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-azepineO
2-morpholino-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-azepineO
Example XVIII
2-aminomethyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo~b,d,f)-cycloheptatriene 2-hydroxy-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cyclo-heptatriene is converted into the corresponding 2-mesyloxy compound in the same manner as described in "starting materials" 4 and then treated with sodiumcyanide, to obtain the 2-cyano-compound. This compound is immediately reduced with LiAlH4 in ether as described previously, yielding the 2-amino-methyl-compound as an oilO
Conversion of this oil with maleic acid yields the maleate; melting point:
128 - 132C.
In the same manner is prepared:
2-aminomethyl-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo (b,d,f)-azepineO
Claims (30)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of general formula I:
I
or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof, wherein X represents oxygen, sulphur, the group ?NR7 or the group -CH2-, ring A is either unsubstituted or substituted in the 6- or 7-position by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the 11- and 12-positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, R5 and R6 are the same or different and represent hydrogen atoms or alkyl groups of 1 to 4 carbon atoms which are either unsubstituted or substituted by a phenyl group, or the group NR5R6 together represents a morpholino, piperidino or pyrroli-dino group, R7 represents hydrogen or methyl, n is zero, one or two, and the dotted line in the nucleus signifies an extra bond which is optional when n is zero, which comprises either:
a) condensing a compound of the general formula IV:
IV
in which n and X are as previously defined and Y is a leaving group, with ammonia or an amine of the general formula V:
V
or an acid addition salt thereof, wherein R5 and R6 are as previously defined;
or b) reducing a compound of the general formula VI:
VI
in which R represents - (CH2)p -CN or - (CH2)pN3 wherein p represents zero or one and X is as previously defined; or c) for preparing compounds of general formula I in which n is zero and the dotted line in the nucleus signifies an extra bond, reacting a compound of the general formula V as defined above with a compound of the general formula II:
II
in which X is as previously defined in the presence of a reducing agent; or d) reducing a compound of the general formula IX:
IX
in which R5, R6, X and n are as previously defined, or e) for preparing compounds of general formula I, in which n is zero and the dotted line in the nucleus signifies an extra bond, reducing a com-pound of the general formula VII:
VII
in which X is as herein before defined, by reaction with a metal hydride or by catalytic hydrogenation; or f) for preparing compounds of general formula I, in which n is zero and the dotted line in the nucleus does not signify an extra bond reducing a compound of general formula VII as defined above by reaction with sodium or sodium amalgam; or g) for preparing compounds of general formula I in which n?1, reducing a compound of general formula VIII:
VIII
in which R5, R6, X and p are as previously defined; and wherein steps (a) to (g) may be followed by the additional step of alkylating or phenylalkylating a compound of formula I obtained in which one or both of R5 and R6 is hydrogen to obtain the corresponding compound of formula I in which one or both of R5 and R6 are alkyl or phenylalkyl groups; and wherein a base of formula I may be connected into a corresponding pharmaceutically acid addition or quaternary ammonium salt.
I
or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof, wherein X represents oxygen, sulphur, the group ?NR7 or the group -CH2-, ring A is either unsubstituted or substituted in the 6- or 7-position by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the 11- and 12-positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, R5 and R6 are the same or different and represent hydrogen atoms or alkyl groups of 1 to 4 carbon atoms which are either unsubstituted or substituted by a phenyl group, or the group NR5R6 together represents a morpholino, piperidino or pyrroli-dino group, R7 represents hydrogen or methyl, n is zero, one or two, and the dotted line in the nucleus signifies an extra bond which is optional when n is zero, which comprises either:
a) condensing a compound of the general formula IV:
IV
in which n and X are as previously defined and Y is a leaving group, with ammonia or an amine of the general formula V:
V
or an acid addition salt thereof, wherein R5 and R6 are as previously defined;
or b) reducing a compound of the general formula VI:
VI
in which R represents - (CH2)p -CN or - (CH2)pN3 wherein p represents zero or one and X is as previously defined; or c) for preparing compounds of general formula I in which n is zero and the dotted line in the nucleus signifies an extra bond, reacting a compound of the general formula V as defined above with a compound of the general formula II:
II
in which X is as previously defined in the presence of a reducing agent; or d) reducing a compound of the general formula IX:
IX
in which R5, R6, X and n are as previously defined, or e) for preparing compounds of general formula I, in which n is zero and the dotted line in the nucleus signifies an extra bond, reducing a com-pound of the general formula VII:
VII
in which X is as herein before defined, by reaction with a metal hydride or by catalytic hydrogenation; or f) for preparing compounds of general formula I, in which n is zero and the dotted line in the nucleus does not signify an extra bond reducing a compound of general formula VII as defined above by reaction with sodium or sodium amalgam; or g) for preparing compounds of general formula I in which n?1, reducing a compound of general formula VIII:
VIII
in which R5, R6, X and p are as previously defined; and wherein steps (a) to (g) may be followed by the additional step of alkylating or phenylalkylating a compound of formula I obtained in which one or both of R5 and R6 is hydrogen to obtain the corresponding compound of formula I in which one or both of R5 and R6 are alkyl or phenylalkyl groups; and wherein a base of formula I may be connected into a corresponding pharmaceutically acid addition or quaternary ammonium salt.
2. A process according to claim 1 in which R5 and R6 are the same or different and represent hydrogen alkyl of 1 to 4 carbon atoms or phenylalkyl of 7 to 10 carbon atoms.
3. A process according to claim 1 in which the dotted line in the nucleus represents an additional bond.
4. A process according to claim 1, 2 or 3 in which n is zero or one.
5. A process according to claim 1 in which X stands for the -NCH3 group.
6. A process according to claim 1 in which X stands for a methylene (-CH2-) group.
7. A process according to claim 1 in which X stands for oxygen or sulphur.
8. A process according to claim 1 in which ring A is either unsubstituted or substituted in the 6- or 7-position by a chlorine atom or a hydroxy, methyl, or methoxy, ring B is either unsubstituted or substituted in either or both of the 11- and 12-positions by chlorine, methoxy, methyl, hydroxy or tri-fluoromethyl groups, R5 and R6 are the same or different and represent hydrogen atoms or methyl, ethyl, benzyl or phenethyl groups or the group -NR5R6- forms a morpholino, piperidino or pyrrolidino group, X is oxygen, sulphur, -CH2- , -NH- or -N.CH3- and n is zero, one or two.
9. A process according to claim 1 in which R5 is hydrogen, methyl, ethyl, benzyl or phenethyl, R6 is hydrogen, methyl or ethyl or the group -NR5R6-represents a morpholino, piperidino or pyrrolidino group, X is oxygen, sulphur, -CH2-, -NH- or -N.CH3- and n is zero, one or two.
10. A process according to claim 1 in which the rings A and B are unsubstituted, R5 and R6 are methyl groups, X is -CH2-, n is zero and the dotted line in the nucleus represents an extra bond.
11. A process according to claim 1 in which 2-dimethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene and its maleate and methiodide are prepared by reducing a mixture of 2-keto-1,2,3,4-tetrahydro(b,d,f)-cyclo-heptatriene and dimethylamine; and when the maleate or methiodide is required, reacting the base so obtained with maleic acid or methyl iodide.
12. A process according to claim 11 in which the reduction is effected by catalytic hydrogenation or by reaction with formic acid or sodium boro-hydride.
13. A process according to claim 1 in which ring A is unsubstituted, ring B has a methyl group in the 12-position, R5 and R6 are methyl groups, X is -CH2-, n is zero and the dotted line in the nucleus represents an extra bond.
14. A process according to claim 1 in which 2-dimethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene and its maleate are prepared by reducing a mixture of 2-keto-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene and dimethylamine, and when the maleate is required reacting the base so obtained with maleic acid.
15. A process according to claim 14 in which the reduction is effected by reaction with formic acid or sodium borohydride.
16. A process according to claim 1 in which rings A and B are unsub-stituted, R5 and R6 are methyl groups, X is -CH2-, n is zero and there is no double bond present in the 4a-13b position.
17. A process according to claim 1 in which 2-dimethylamino-1,2,3,4,4a, 13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene and its hydrochloride are prepared by reacting the oxime of 2-keto-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene with sodium, methylating the 2-amino-1,2,3,4,4a,13b-hexa-hydro-9H-tribenzo(b,d,f)-cycloheptatriene so obtained, and when the hydro-chlororide is required reacting the base so obtained with hydrogen chloride.
18. A process according to claim 1 in which ring A has a methyl group in the 6-position, ring B is unsubstituted, R5 and R6 are methyl groups, R2, R3 and R4 are hydrogen atoms, X is an oxygen atom, n is zero and the dotted line in the nucleus represents an extra bond.
19. A process according to claim 1 in which 2-dimethylamino-6-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)oxepine and its maleate are prepared by reducing a mixture of 2-keto-6-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f) oxepine and dimethylamine and when the maleate is required reacting the base so obtained with maleic acid.
20. A process according to claim 19 in which the reduction is effected by reaction with formic acid.
21. A process according to claim 1 in which rings A and B are unsub-stituted, R5 and R6 are methyl groups, X is the -N.CH3- group, n is zero and the dotted line in the nucleus represents an extra bond.
22. A process according to claim 1 in which 2-dimethylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)azepine and its maleate are prepared by reducing a mixture of 2-keto-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f) azepine and dimethylamine.
23. A process according to claim 22 in which the reduction is effected by catalytic hydrogenation or by reaction with formic acid or sodium boro-hydride.
24. A compound of the general formula I as defined in claim 1 or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof whenever prepared by the process of claim 1 or by an obvious chemical equi-valent thereof.
25. A compound of the general formula I given in claim 1 or a pharma-ceutically acceptable acid addition or quaternary ammonium salt thereof in which rings A and B, R5, R6, X and n are as defined in claim 8 whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.
26. 2-Dimethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatri-ene and its maleate and methiodide whenever prepared by the process of claim 11 or 12 or by an obvious chemical equivalent thereof.
27. 2-Dimethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene and its maleate whenever prepared by the process of claim 14 or 15 or by an obvious chemical equivalent thereof.
28. 2-Dimethylamino-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cyclo-heptatriene and its hydrochloride whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.
29. 2-Dimethylamino-6-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)oxepine and its maleate whenever prepared by the process of claim 19 or 20 or by an obvious chemical equivalent thereof.
30. 2-Dimethylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)azepine and its maleate whenever prepared by the process of claim 22 or 23 or by an obvious chemical equivalent thereof.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA199,996A CA1051877A (en) | 1974-05-15 | 1974-05-15 | Amino-substituted tetracyclic compounds |
| CA000318927A CA1148539A (en) | 1974-05-15 | 1979-01-02 | Amino-substituted tetracyclic compounds |
| CA318,926A CA1074305A (en) | 1974-05-15 | 1979-01-02 | Amino-substituted tetracyclic compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA199,996A CA1051877A (en) | 1974-05-15 | 1974-05-15 | Amino-substituted tetracyclic compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1051877A true CA1051877A (en) | 1979-04-03 |
Family
ID=4100074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA199,996A Expired CA1051877A (en) | 1974-05-15 | 1974-05-15 | Amino-substituted tetracyclic compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1051877A (en) |
-
1974
- 1974-05-15 CA CA199,996A patent/CA1051877A/en not_active Expired
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