Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-14
2001-04-24
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S124000, C546S126000, C546S132000, C546S112000, C514S299000
Reexamination Certificate
active
06221879
ABSTRACT:
The present invention relates to compounds of general formula (I)
in which
U represents
A) either a 2,3-dihydro-1H-inden-2-yl group of general formula (A)
B) or a heterocyclic group of general formula (B)
in which
V represents a hydrogen or halogen atom, a (C
1
-C
3
)alkyl group or one or two (C
1
-C
3
)alkoxy groups,
W and X each represent, respectively, either two oxygen atoms, or an oxygen atom and a CH
2
group, or a CH
2
group and an oxygen atom, or an oxygen atom and a CO group,
n represents the number 0 or 1,
R represents either a propyl group when U represents a 2,3-dihydro-1H-inden-2-yl group of general formula (A), or a hydrogen atom or a (C
1
-C
3
)alkyl group when U represents a heterocyclic group of general formula (B),
Y represents one or more atoms or groups chosen from the following: hydrogen, halogen, (C
1
-C
3
)alkyl and (C
1
-C
3
)alkoxy,
Z represents two hydrogen atoms or an oxygen atom.
The compounds of the invention can exist in two forms of geometrical isomers, namely the &agr;, or endo, isomeric form in which the CH
2
group in the 3 position of the tropane ring-system (azabicyclooctane) is in an axial position, and the &bgr;, or exo, isomeric form in which the said CH
2
group is in an equatorial position, in the so-called “chair” conformation of the piperidine unit of the tropane ring-system.
The compounds of the invention can also exist in the form of bases or of addition salts with acids.
When U represents a 2,3-dihydro-1H-inden-2-yl group of general formula (A), the compounds of the invention correspond to the general formula (IA)
They can be prepared according to a process illustrated by Scheme 1A which follows.
Ethyl 8-(phenylmethyl)-8-azabicyclo[3.2.1]-octane-3-carboxylate of formula (IIA) is reacted with a dimethylaluminium amide, prepared beforehand from trimethylaluminium and a 2,3-dihydro-1H-indene-2-amine derivative of general formula (IIIA), in which V is as defined above, in an inert solvent, for example toluene, at a temperature of from 0 to 100° C.; a compound of general formula (IVA) is obtained, which is reduced by the action of a mixed alkali metal hydride such as lithium aluminium hydride, in an ether solvent, for example tetrahydrofuran, at a temperature of from 0 to 60° C., to give a compound of general formula (VA). This compound is subjected to an acylation using propanoyl chloride, in a chlorinated solvent, for example dichloromethane, in the presence of a base such as triethylamine, at a temperature of from 0 to 40° C., to give an amide of general formula (VIA), which is reduced by the action of a mixed alkali metal hydride such as lithium aluminium hydride, in an ether solvent, for example tetrahydrofuran, at a temperature of from 0 to 60° C., to give a compound of general formula (Ia) which corresponds to the general formula (IA) when Y represents a hydrogen atom and Z represents two hydrogen atoms. To prepare another compound of general formula (IA), debenzylation is then carried out, for example by catalytic hydrogenation, to give the amine of general formula (VIIA), and finally this amine is reacted either with an acid chloride of general formula (VIIIA) in which Y is as defined above, Z represents an oxygen atom and T represents a chlorine atom, in a chlorinated solvent, for example dichloromethane, in the presence of a base such as triethylamine, at a temperature of from 20 to 40° C., or with a halogenated derivative of general formula (VIIIA) in which Y is as defined above, Z represents two hydrogen atoms and T represents a halogen atom, in an aprotic solvent, for example N,N-dimethylformamide, in the presence of a base such as potassium carbonate, at a temperature of from 20 to 100° C.
The 2,3-dihydro-1H-indene-2-amine of general formula (IIIA) in which X represents hydrogen is commercially available; the substituted derivatives of 2,3-dihydro-1H-indene-2-amine of general formula (IIIA) can be prepared by methods analogous to those described in
Can. J. Chem.
(1974) 52 381-389.
The ethyl 8-(phenylmethyl)-8-azabicyclo[3.2.1]octane-3-carboxylate of formula (IIA) can be prepared by a method analogous to that described in
J. Med. Chem.
(1994) 37 2831.
When U represents a heterocyclic group of general formula (B), the compounds of the invention correspond to the general formula (IB)
They can be prepared according to processes illustrated by Schemes 1B to 3B which follow.
According to Schemes IBa, IBb and IBc, the compounds of general formula (IB), in which W and X each represent an oxygen atom and n represents the number 1, are prepared by reacting ethyl 8-(phenylmethyl)-8-azabicyclo[3.2.1]-octane-3-carboxylate of formula (IIA) with a dimethylaluminium amide, prepared beforehand from trimethylaluminium and a 2,3-dihydro-1,4-benzodioxane-2-methanamine derivative of general formula (IIB), in which V is as defined above, in an inert solvent such as toluene, at a temperature of from 0 to 100° C., to give a compound of general formula (IVB), which is reduced by the action of a mixed alkali metal hydride, for example lithium aluminium hydride, in an ether solvent such as tetrahydrofuran, at a temperature of from 0 to 60° C.
A compound of general formula (IBa) which corresponds to the general formula (IB) where R and Y each represent a hydrogen atom and Z represents two hydrogen atoms is obtained.
If a final compound is desired, in the general formula of which R represents a hydrogen atom or an alkyl group, the compound of general formula (IBa) is then treated by one of the processes illustrated by Schemes IBb or IBc.
Scheme IBb begins by protecting the secondary amine function of the compound of general formula (IBa) by the action of bis(1,1-dimethylethyl)dicarbonate; in a chlorinated solvent such as dichloromethane, to give a compound of general formula (VB), in which Boc represents a 1,1-dimethylethoxycarbonyl group. This compound is debenzylated by catalytic hydrogenation and the compound thus obtained, of general formula (VIB), is then reacted with an acid chloride of general formula (VIIB) in which Y is as defined above and Hal represents a chlorine atom, in a chlorinated solvent, for example dichloromethane, in the presence of a base such as triethylamine, at a temperature of from 20 to 40° C. A compound of general formula (VIIIB) is obtained, the secondary amine function of which is deprotected using trifluoroacetic acid to give a compound of general
formula (IBb).
Finally, and if so desired, this compound is reduced by the action of a mixed alkali metal hydride, for example lithium aluminium hydride, in an ether solvent such as tetrahydrofuran, to give a compound of general formula (IBa).
In Scheme IBc, a compound of general formula (IBa) is subjected to an acylation using an acetic-forming mixed anhydride or a C
2
-C
3
acid chloride, in a chlorinated solvent such as dichloromethane, at a temperature of from 0 to 40° C., to give a compound of general formula (IXB), in which R′ represents a hydrogen atom or a methyl or ethyl group, and this acylated compound is then reduced using a mixed alkali metal hydride, for example lithium aluminium hydride, in an ether solvent such as tetrahydrofuran, to give a compound of general formula (IBd), in which R″ represents a (C
1
-C
3
) alkyl group.
This compound is then treated as indicated with regard to the compound of general formula (VB), with the exception, of course, of the amine deprotect ion step.
In Scheme 2B, the compounds of general formula (IB), in which X represents an oxygen atom, W represents an oxygen atom or a CH
2
, group, R represents a hydrogen atom and n represents the number 1, are prepared by reacting a compound of general formula (XIB), in which V is as defined above and G represents a leaving group such as a halogen atom or a methanesulphonyloxy or 4 -methylbenzenesulphonyloxy group, with an 8-azabicyclo[3.2.1]octane-3-amine of general formula (XIIB), in which Y, Z and R are as defined above, in a solvent such as acetonitrile, in the presence of a base such as potassium carbonate.
In Scheme 3E, t
De Peretti Daniele
George Pascal
Machnik David
Marabout Benoit
Merly Jean-Pierre
Alexander Michael D.
Aulakh C. S.
Sanofi-Synthelabo
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