Alkylaminobenzothiazole and-benzoxazole derivatives

Details Alkylaminobenzothiazole and-benzoxazole derivatives Alkylaminobenzothiazole and-benzoxazole derivatives

2000-06-27

2001-05-01

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001850, C424S001890, C435S007200, C435S007210, C436S504000, C544S368000

Reexamination Certificate

active

06224849

ABSTRACT:

The present invention concerns alkylaminobenzothiazoles and -benzoxazoles; it further relates to processes for their preparation, compositions comprising them, as well as their use as a medicine. The compounds of the present invention exhibit specific dopamine D
4
receptor antagonism and may particularly be useful as antipsychotics, especially in the treatment and/or prevention of psychotic disorders such as schizophrenia. In addition, the present invention concerns compounds of formula (I) containing a radioactive isotope; a process of marking dopamine D
4
receptor sites; and a process for imaging an organ.
It is generally accepted knowledge that dopamine receptors are important for many biochemical functions in the animal body. For example, altered functions of these receptors not only participate in the genesis of psychosis, but also of anxiety, emesis, motoric functions, addiction, sleep, feeding, learning, memory, sexual behaviour, regulation of immunological responses and blood pressure. Since dopamine receptors control a great number of pharmacological events, some of which are thus far unknown, there is a possibility that compounds which exhibit a specific binding affinity for the D
4
receptor may exert a wide range of therapeutic effects in humans.
EP-A-0,335,586, published on Oct. 4, 1989, describes 2-[4-(diarylmethyl)-1-piperazinyl)alkylamino]benzothiazoles and -benzoxazoles having antihistaminic and antiallergic activity.
The alkylaminobenzothiazoles and -benzoxazoles of the present invention surprisingly show a high degree of dopamine D
4
receptor binding affinity. Moreover, the present compounds have a selective affinity for the dopamine D
4
receptor over other dopamine receptors in the human body. The subject compounds also show variable affinity for other receptors such as, for example, serotonin receptors, histamine receptors, adrenergic receptors, cholinergic receptors and the &sgr;-binding site.
The present invention concerns compounds having the formula
the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein
X is O or S;
n is 2, 3, 4 or 5;
R
1
is hydrogen, C
1-6
alkyl, C
1-6
alkyloxy or halo;
R
2
is hydrogen, C
1-6
alkyl, phenyl, phenylC
1-6
alkyl or phenylcarbonyl;
R
3
and R
4
each independently are selected from hydrogen, halo, nitro, C
1-6
alkyl, C
1-6
alkyloxy, haloC
1-6
alkyl, aminosulfonyl, mono- or di(C
1-4
alkyl)aminosulfonyl; or
R
3
and R
4
may also be taken together to form a bivalent radical of formula —CH═CH—CH═CH—.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C
1-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C
1-6
alkyl is meant to include C
1-4
alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; haloC
1-6
alkyl is defined as polyhalosubstituted C
1-6
alkyl, in particular C
1-6
alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. Said salts can be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, hydroxy-acetic, 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.
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-oxides of the present compounds are meant to comprise those compounds of formula (I) wherein one or more nitrogen atoms are oxidized to the so-called N-oxide.
The term “stereochemically isomeric forms” as used hereinbefore and hereinafter defines all the possible isomeric forms in which the compounds of formula (I) may occur. 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. Stereochemically isomeric forms of the compounds of formula (I) and mixtures of such forms are obviously intended to be encompassed by formula (I).
Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For instance, compounds of formula (I) wherein R
2
is hydrogen may exist in their corresponding tautomeric form.
An interesting group of compounds are those compounds of formula (I) wherein X is S and R
2
is hydrogen, C
1-6
alkyl, phenyl or phenylC
1-6
alkyl.
Another interesting group of compounds are those compounds of formula (I) wherein X is O and R
2
is hydrogen, C
1-6
alkyl or phenylC
1-6
alkyl.
Also interesting compounds are those compounds of formula (I) wherein R
3
and R
4
are selected from the goup consisting of hydrogen, nitro, halo, C
1-6
alkyl, C
1-6
alkyloxy and trifluoromethyl, or R
3
and R
4
are taken together to form a bivalent radical of formula —CH═CH—CH═CH—.
Particular compounds are those interesting compounds wherein n is 2, 3 or 4.
Preferred compounds are those compounds of formula (I) wherein X is S, R
2
is hydrogen, C
1-6
alkyl, phenyl or phenylC
1-6
alkyl, and n is 2.
Other preferred compounds are those compounds of formula (I) wherein R
2
and R
3
are hydrogen and R
4
is chloro.
Most preferred are the compounds N-[2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine; N-[2-(4-phenyl-1-piperazinyl)ethyl]-2-benzothiazolamine; N-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine; N-[2-[4-(4-bromophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine; the N-oxides, the stereoisomeric forms and the pharmaceutically acceptable acid addition salts thereof.
The compounds of the present invention can generally be prepared by N-alkylating an intermediate of formula (III) with an intermediate of formula (II) wherein W
1
represents an appropriate reactive leaving group such as, for example, a halogen.
Said N-alkylation may be performed by stirring and heating the reactants in a reaction-inert solvent such as ethanol, 2-ethoxyethanol, 1-butanol, methylisobutylketon or toluene, preferably in the presence of a suitable base such as sodiumcarbonate, and optionally in the presence of a catalyst such as, for example, potassium iodide.
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography.
Compounds of formula (I) wherein X is S, said compounds being represented by formula (I-a), may be prepared by reacting an intermediate of formula (III) with an intermediate of formula (IV) in a reaction-inert solvent such as, for example, tetra-hydrofuran, and subsequently cyclizing the thus formed intermediate of formula (V) in a reaction-inert solvent such as, for example, chloroform, and in the presence of a suitable reagent such as, for example, thionylchloride. Alternatively, compounds of formula (I-a) can be prepar

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