AMINO-SUBSTITUTED TETRACYCLIC COMPOUNDS

COMPOSES TETRACYCLIQUES A FONCTION AMINE SUBSTITUEE

English Abstract

ABSTRACT OF THE DISCLOSURE

This invention relates to a process for the preparation of compounds
of the general formula:

Image II

in which
X represents oxygen, sulphur, the group Image or the
group -CR8R9-,

R1, R2, R3 and R4 represent hydrogen, hydroxy, halogen, alkyl (1-6 C) alkoxy (1-6 C), or trifluoromethyl.

R7 stands for hydrogen or alkyl (1-4 C), and

R8, R9 stand for hydrogen or methyl,
characterized in that a compound of the general formula:

Image III

is condensed with vinylmethylketone Image. The compounds so
produced are useful as intermediates in the synthesis of compounds having
useful pharmacological properties.

Claims

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

1. Process for the preparation of compounds of the general formula:

Image II

in which X represents 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), or trifluoromethyl, R7 stands for hydrogen or alkyl (1-4 C), and R8,
R9 stand for hydrogen or methyl, characterized in that a compound of the
general formula:

Image III
is condensed with vinylmethylketone Image.


2. Process according to claim 1 in which the reaction is carried out
in a solvent.


3. Process according to claim 1 in which the reaction is carried out
in the presence of a base.


4. Process according to claim 3 in which the base is sodium hydroxide,



5. Process according to claim 1 in which the reaction is carried out
in the presence of sodium methoxide and a solvent.




6. Compound of the formula

Image II

when prepared by the process according to claim 1 or by an obvious chemical
equivalent thereof.

7. A process for the preparation of 2-keto-1,2,3,4-tetrahydro-
tribenzo (b,d,f)-oxepine which comprises reacting 10-keto-10,11-dihydro-
dibenzo(b,f)-oxepine with methyl vinyl ketone.

8. 2-keto-1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine when prepared
by the process according to claim 7 or by an obvious chemical equivalent
thereof.

9. A process for the preparation of 2-keto-11-methyl-1,2,3,4-
tetrahydro-tribenzo-oxepine which comprises reacting 10-keto-7-methyl-
10,11-dihydro-dibenzo (b,f)-oxepine with methyl vinyl ketone.

10. 2-keto-11-methyl-1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine
whenever prepared by the process according to claim 9 or by an obvious
chemical equivalent thereof.

11. A process for the preparation of 2-keto-11,12-dimethyl-1,2,3,4-
tetrahydro-tribenzo (b,d,f)-oxepine which comprises reacting 10-keto-
7,8-dimethyl-10,11-dihydro-dibenzo (b,f) oxepine with methyl vinyl ketone.

12. 2-keto-11,12-dimethyl-1,2,3,4-tetrahydro-tribenzo (b,d.f)-
oxepine whenever prepared by the process according to claim 11 or by
an obvious chemical equivalent thereof.



13. A process for the preparation of 2-keto-12-chloro-1,2,3,4-
tetrahydro-tribenzo (b,d,f)-oxepine which comprises reacting 10-keto-
8-chloro-10,11-dihydro-dibenzo (b,f) oxepine with methyl vinyl ketone.

14 2-keto-12-chloro-1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine
whenever prepared by the process according to claim 13 or by an obvious
chemical equivalent thereof.

15. A process for the preparation of 2-keto-11-trifluoromethyl-
1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine which comprises reacting
10-keto-7-trifluoromethyl-10,11-dihydro-dibenzo (b,f) oxepine with methyl
vinyl ketone.

16. 2-keto-11-trifluoromethyl-1,2,3,4-tetrahydro-tribenzo (b,d,f)-
oxepine whenever prepared by the process according to claim 15 or by
an obvious chemical equivalent thereof.

17. A process for the preparation of 2-keto-6-chloro-1,2,3,4-tetrahy-
dro-tribenzo (b,d,f)-oxepine which comprises reacting 10-keto-2-chloro-
10,11-dihydro-dibenzo (b,f) oxepine with methyl vinyl ketone.

18. 2-keto-6-chloro-1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine
whenever prepared by the process according to claim 17 or by an obvious
chemical equivalent thereof.

19. A process for the preparation of 2-keto-6-methyl-1,2,3,4-tetrahy-
dro-tribenzo (b,d,f)-oxepine which comrpises reacting 10-keto-2-methyl-
10,11-dihydro-dibenzo (b,f) oxepine with methyl vinyl ketone.

20. 2-keto-6-methyl-1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine
whenever prepared by the process according to claim 19 or by an obvious
chemical equivalent thereof.


21. A process for the preparation of 2-keto-1,2,3,4-tetrahydro-
tribenzo (b,d,f)-thiepine which comprises reacting 10-keto-10,11-dihydro-




dibenzo (b,f)-thiepine with methy vinyl ketone.

22. 2-keto-1,2,3,4-tetrahydro-tribenzo (b,d,f)-thiepine whenever
prepared by the process according to claim 21 or by an obvious chemical
equivalent thereof.

23. A process for the preparation of 2-keto-1,2,3,4-tetrahydro-
9H-tribenzo (b,d,f)-cycloheptatriene which comprises reacting 10-
keto-10,11-dihydro-5H-dibenzo (a,d) cycloheptene with methyl vinyl
ketone.

24. 2-keto-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene
whenever prepared by the process according to claim 23 or by an obvious
chemical equivalent thereof.

25. A process for the preparation of 2-keto-12-hydroxy-1,2,3,4-
tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene which comprises reacting
10-keto-8-hydroxy-10,11-dihydro-5H-dibenzo (a,d) cycloheptatriene
with methyl vinyl ketone.

26. 2-keto-12-hydroxy-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-
cycloheptatriene whenever prepared by the process according to claim
25 or by an obvious chemical equivalent thereof.

27. A process for the preparation of 2-keto-12-methoxy-1,2,3,4-
tetrahydroxy-9H-tribenzo (b,d,f)-cycloheptatriene which comprises
reacting 10-keto-8-methoxy-10,11-dihydro-5H-dibenzo (a,d) cycloheptene
with methyl vinyl ketone.

28. 2-keto-12-methoxy-1,2,3,4-tetrahydroxy-9H-tribenzo (b,d,f)-
cycloheptatriene whenever prepared by the process of claim 27 or
by an obvious chemical equivalent thereof.


11


29. A process for the preparation of 2-keto-11-methyl-12-methoxy-
1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene which comprises
reacting 10-keto-7-methyl-8-methoxy-10,11-dihydro-5H-dibenzo (a,d) cyclo-
heptene with methyl vinyl ketone.


30. 2-keto-11-methyl-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-
cycloheptatriene whenever prepared by the process of claim 29 or by an
obvious chemical equivalent thereof.


31. A process for the preparation of 2-keto-12-methyl-1,2,3,4-tetra-
hydro-9H-tribenzo (b,d,f)-cycloheptatriene which comprises reacting 10-keto-
8-methyl-10,11-dihydro-5H-dibenzo (a,d) cycloheptene with methyl vinyl ketone.


32. 2-keto-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-cyclohep-
tatriene whenever prepared by the process of claim 31 or by an obvious
chemical equivalent thereof.


33. A process for the preparation of 2-keto-12-trifluoromethyl-1,2,3,4-
tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene which comprises reacting 10-
keto-8-trifluoromethyl-10,11-dihydro-5H-dibenzo (a,d) cycloheptene with
methyl vinyl ketone.


34. 2-keto-12-trifluoromethyl-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-
cycloheptatriene whenever prepared by the process of claim 33 or by an
obvious chemical equivalent thereof.



35. A process for the preparation of 2-keto-7-chloro-1,2,3,4-tetrahydro-
9H-tribenzo (b,d,f)-cycloheptatriene which comprises reacting 10-keto-3-chloro-
10,11-dihydro-5H-dibenzo (a,d) cycloheptene with methyl vinyl ketone.


36. 2-keto-7-chloro-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-
12


cycloheptatriene whenever prepared by the process of claim 35 or
by an obvious chemical equivalent thereof.

37. A process for the preparation of 2-keto-1,2,3,4-tetrahydro-
9H-tribenzo (b,d,f)-azepine which comprises reacting 10-keto-10,11-
dihydro-5H-dibenzo (b,f)azepine with methyl vinyl ketone.

38. 2-keto-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-azepine whenever
prepared by the process of claim 37 or by an obvious chemical equivalent
thereof.

39. A process for the preparation of 2-keto-9-methyl-1,2,3,4-
tetrahydro-9H-tribenzo (b,d,f)-azepine which comprises reacting 5-
methyl-10-keto-0,11-dihydro-5H-dibenzo (b,f) azepine with methyl
vinyl ketone.

40. 2-keto-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-
azepine whenever prepared by the process of claim 39 or by an obvious
chemical equivalent thereof.


41. A process for the preparation of 2-keto-7-methoxy-9-methyl-
1,2,3,4-tetrahydro-9H-tribenzo (b,d,f)-azepine which comprises reacting
3-methoxy-5-methyl-10-keto-10,11-dihydro-5H-dibenzo (b,f) azepine
with methyl vinyl keto.

42. 2-keto-7-methoxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo
(b,d,f)-azepine whenever prepared by the process of claim 41 or by
an obvious chemical equivalent thereof.

13

Description

3fJ . ~

This application is a divisional of our copending Canadian
Patent Application Serial No. 199,996 filed l~ay 15, 1974.
The present invention relates to certain components useful
in the preparation Ofnovelbiologically active aminosubsti~uted tetracyclic
compounds and to processes for the preparation thereof.
In our copending Canadian application number 199,996, filed
May 15, 1974 certain compounds are disclosed which possess valuable
C.N.S. activities, but at the same time exhibited exceedingly low toxicity.
These compounds are of the general formula I:



; n ~ ~ ' I



as well as the pharmaceutically acceptable salts thereof, in which
X stands for oxygen, sulphur, the group ~ NR7
or the group CR8Rg-;
Rl, R2, R3 and R4 represent hydrogen, hydroxy, halogen, alkyl
6 C), alkoxy (1-6 C), ~ ;lthio (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 Rg stand for hydrogen or methyl,
n is the number 0, 1 or 2 and
the dotted line means an optional C-C bond.

The present invention is directed to in~ermediates useful
in the synthesis of the compounds of formula I. Such intermediates




- 1 _


are compounds of the general formula II:




in which Rl, R2, R3, R4 and X have the meanings mentioned above. The
compounds II are, as far as known, novel compounds.
The intermediate of formula II can be prepared in ~arious
manners. The most simple method to prepare the compound 11 is the
condensation of vinylmethylketone (CH3-~-CH=CH2) with a compound of
the general formula III:
R R3
I\ ~ III

R2 4

in which Rl, R2, R3, R4 and X have the meanings mentioned above. This
condensation reaction in preparing the starting material II is performed
in a suitable solvent, preferably in the presence of a base, such as
sodium hydroxide, potassium hydroxide, sodium ethoxide or sodium hydride.
An intermediate product formed in this condensa~ion reaction, namely
a compound of formula III with a r-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 endproducts
according to formula I can be prepared in various manners. All these
routes are known per se and are standard procedures commonly used for
the preparation of similar compounds. These methods are described
in our copending Canadian Patent application 199,996. Thus the compounds
of formula I are prepared by a process which comprises either:
a) condensing a compound of the general formula IV:

~0'~43(~



IV




(C1~2)nY


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:


______-- 6
HN ~ 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:




in which R represents - (CH2)p -CH 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 o the general for~ula II:


~ II

~0~743~

in which X is as previously defined in the presence of a reducing agent;
or
d) reducing a compound of the general formula IX:




~ R5~
2 n ~ R6 J


n 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




NOH



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 ~ , reducing a compound of general formula VIII:


0 ~ t


VIII


(CH2) p
C=O
N R5 ~ ;
6-'


in which R , R6, X and p are as previously defined; and wherein steps
~a) to (g) may be foliowed 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 correspor.ding
pharmaceutically acid addition or quaternary ammonium salt.
The compounds according to this invention contain an asymmetric
carbon at position 2 of the tetracyclic molecule. By resolving these
compounds or a starting product in their synthesis, the optical isomers
can also be obtained in a direct way.
In the Examples the following nomenclature and numbering has
been used:

\ / ~O
1, 2, 3, 4-tetrahydro-9H-tribenzo
5 ~ (b,d,f3-cycloheptatriene

g !~`

^~'~\~ X = O or S
!3
1, 2, 3, 4-tetrahydro-~ribenzo~b,d,f)-
oxepine or -thiepine.

g g '
1, 2, 3, 4-tetrahydro-9H-tribenzo
h ~3~ (b,d,f)-azepine


By way of example the preparation of various compounds of
formula II disclosed. The preparation of analogous compounds proceeds
in exactly the same way.
Example
2-keto-1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine
To a solution of 42 g of the compound 10-keto-10,11-dihydrodibenzo (b,f)-
oxepine in 200 ml of dry ethanol a solution of sodium ethoxide (7 g
of sodium in 500 ml of ethanol) is added dropwise. After stirring the
mixture for 30 minutes 16.2 ml of vinylmethylketone in 50 ml of ethanol
are added, whereupon the solution is refluxed for one hour. The solution
is cooled then and poured into 2 N HCl. After extracting into ether,
washing the ether layer with water ~till neutral) and drying the etherial
phase, the solvent is evaporated.
The residue, a red coloured oil, is chromatographed after that over
an alumina column and used for further conversion immediately. Yield:
37% oil. In the same manner are prepared:
2-keto-11-methyl-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine; melting
point 146-147C.
2-keto-11,1~-dimethyl-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f}oxepine; (oil).

10743~-keto-12-chloro-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine; n.elting
point 107-108C.
-keto-11-trifluoromethyl-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine;
(oil).
-keto-6-chloro-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine; melting
point 128-129C.
-keto-6-methyl-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine; ~oil).
-keto-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-thiepine; (oil).
-keto-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene; melting
point 132-133C.
-keto-12-hydroxy-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene;
(oil).
-keto-12-methoxy-1, 2, 3, 4-tetrahydroxy-9H-tribenzo (b,d,f)-cyclohepta-
triene; (oil).
-keto-11-methyl-12-~ethoxy-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-
cycloheptatriene; (oil).
-keto-12-nlethyl-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene;
melting point 158-163C.
-keto-12-trifluoromethyl-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-
cycloheptatriene; (oil).
-keto-7-chloro-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene;
~oil).
-keto-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-azepine; (oil).
-keto-9-methyl-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-azepine; (oil).
-keto-7-methoxy-9-methyl-1, 2, 3~ 4-tetrahydro-9H-tribenzo (b,d,f)-
azepine; (oil).