Halogen substituted tetracyclic tetrahydrofuran derivatives

Details Halogen substituted tetracyclic tetrahydrofuran derivatives Halogen substituted tetracyclic tetrahydrofuran derivatives

2000-04-06

2003-01-28

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S254110, C514S321000, C514S414000, C544S109000, C544S375000, C546S196000, C546S197000, C548S454000, C548S525000, C548S526000

Reexamination Certificate

active

06511976

ABSTRACT:

This invention concerns halogen substituted tetracyclic tetrahydrofuran derivatives having antipsychotic, cardiovascular and gastrokinetic activity and their preparations; it further relates to compositions comprising them, as well as their use as a medicine.
WO 97/38991, published on Oct. 23, 1997, discloses tetracyclic tetrahydrofuran derivatives. WO 96/14320 and WO 96/14321 both disclose isoxazolidine containing tetracyclic derivatives, all having antipsychotic, cardiovascular and gastrokinetic activity.
An article by Monkovic et al. (J. Med. Chem. (1973), 16(4), p. 403-407) describes the synthesis of (±)-3,3
a,
8,12
b
-tetrahydro-N-methyl-2H-dibenzo[3,4:6,7]-cyclohepta-[1,2-b]furan-2-methanamine oxalic acid. Said compound was synthesized as potential antidepressant; however, it was found that this particular tetrahydrofurfurylamine derivative was inactive as antidepressant at a dose of 300 mg/kg.
The present compounds differ structurally from the art-known compounds by their specific substitution pattern on the dibenzoazepine ring and the presence of a tetrahydrofuran ring instead of an isoxazolidine ring, and are further distinguished by valuable pharmacological and physicochemical properties.
This invention concerns compounds of formula (I)
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
n is zero, 1, 2, 3, 4, 5 or 6;
X is CH
2
or O;
R
1
and R
2
each independently are hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, halomethyl-carbonyl or C
1-6
alkyl substituted with hydroxy, C
1-6
alkyloxy, carboxyl, C
1-6
alkyl-carbonyloxy, C
1-6
alkyloxycarbonyl or aryl; or R
1
and R
2
taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or a radical of formula:
 wherein:
R
9
, R
10
, R
11
and R
12
each independently are hydrogen, halo, halomethyl or C
1-6
alkyl;
m is zero, 1, 2, or 3;
R
13
, R
14
, R
15
and R
16
each independently are hydrogen, C
1-6
alkyl, aryl or arylcarbonyl; or
R
15
and R
16
taken together may form a bivalent radical C
4-5
alkanediyl;
R
17
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, halomethylcarbonyl, C
1-6
alkyloxycarbonyl, aryl, di(aryl)methyl or C
1-6
alkyl substituted with hydroxy, C
1-6
alkyloxy, carboxyl, C
1-6
alkylcarbonyloxy, C
1-6
alkyloxycarbonyl or aryl;
R
3
and R
4
are both halogen; or
R
3
is halogen and R
4
is hydrogen; or
R
3
is hydrogen and R
4
is halogen; and
aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, C
1-6
alkyl and halomethyl.
In the foregoing definitions C
1-6
alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl; C
4-5
alkanediyl defines bivalent straight and branch chained saturated hydrocarbon radicals having from 4 to 5 carbon atoms such as, for example, 1,4-butanediyl, 1,5-pentanediyl; halo is generic to fluoro, chloro, bromo and iodo. The term halomethyl is meant to include mono-, di-, and trihalomethyl. Examples of halomethyl are fluoromethyl, difluoromethyl and particularly trifluoromethyl.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic base and acid addition salt forms which the compounds of formula (I) are able to form. The acid addition salt form of a compound of formula (I) that occurs in its free form as a base can be obtained by treating the free base form of the compound of formula (I) with an appropriate acid such as an inorganic acid, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Particular acid addition salts include hydrochloric acid and [R-(R*,R*)]-2,3-dihydroxy-butanedioic acid (other names are for instance tartaric acid, d-tartaric acid and L-tartaric acid).
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic base, i.e. metal or amine, addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein the nitrogen bearing the R
1
and R
2
substituents is N-oxidized.
The term “stereochemically isomeric forms” as used hereinbefore and hereinafter defines all the possible stereoisomeric forms in which the compounds of formula (I) may exist, thus, also including enantiomers, enantiomeric mixtures and diastereomeric mixtures. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, and in particular the racemic mixture, of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. The same applies to the intermediates as described herein, used to prepare endproducts of formula (I). Stereochemically isomeric forms of the compounds of formula (I) and mixtures of such forms are intended to be encompassed by formula (I).
Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term ‘stereoisomerically pure compounds or intermediates’ concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms ‘enantiomerically pure’ and ‘diastereomerically pure’ or equivalent terms should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.
The numbering of the tetracyclic ring-system present in the compounds of formula (I), as defined by Chemical Abstracts nomenclature is shown in formula (I′).
The compounds of formula (I) have at least three asymmetric centers, namely carbon atom 2, carbon atom 3a and carbon atom 12b. Carbon atoms 3a and 12b are part of an annelated ring system. In this case, where more than 2 asymmetric carbon atoms are present on a ring system, the substituent highest in priority (according to the Cahn-Ingold-Prelog sequence rules) on the reference carbon atom, which is defined as the asymmetric carbon atom having the lowest ring number, is arbitrarily always in the “&agr;” position of the mean plane determined by the ring system. The position of the highest priority substituent on the other a

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