Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-23
2001-08-28
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S313000, C544S363000, C544S405000, C546S163000
Reexamination Certificate
active
06281216
ABSTRACT:
The present invention relates to a group of novel 2-aminoquinoline derivatives, to a method for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.
It has surprisingly been found that the compounds and salts thereof of the formula (I)
wherein
(R
1
)
n
represents 1 or 2 substituents, which can be the same or different, from the group C
1-3
-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, and mono or dialkyl (C
1-2
)amino, or two groups R
1
at adjacent carbon atoms together with the benzene ring may form the benzdioxane group or benzofuran group,
X represents nitrogen or carbon, and the dotted line may represent a double bond,
(R
2
)
p
represents 0, 1 or 2 substituents, which can be the same or different, from the group methyl and ethyl, or (R
2
)
p
is a methylene bridge or ethylene bridge,
R
3
is hydrogen or methyl, and
(R)
m
represents 0, 1 or 2 substituents, which can be the same or different and can be located at all available positions of the quinolyl group, from the group C
1-3
-alkyl or akoxy, halogen, trifluoromethyl, nitro, amino, and mono- or dialkyl (C
1-2
)-amino,
on the understanding that R
1
cannot represent o-OCH
3
when X is nitrogen, (R
2
)
p
and R
3
are hydrogen, and m is 0 and n is 1,
are potent and selective agonists of the dopamine D4-receptor.
Compounds having formula (I) wherein R, R
1
and X have the above meaning, m is 0 or 1, n is 1, and (R
2
)
p
and R
3
represent hydrogen, and salts thereof are preferred.
Especially preferred are compounds having formula (I) wherein R, R
1
, X, m, n, (R
2
)
p
and R
3
have the meanings given in claim
2
and salts thereof.
Of particular interest is the compound 1-(2-[2-quinolyl]amino)-ethyl-4-(4-methoxyphenyl) piperazine, and salts thereof.
Due to the potent and selective D4-agonistic activity the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, neurological disorders such as Parkinson's disease and ischaemia and other CNS-diseases involving dopaminergic neurotransmission.
The affinity of the compounds of the invention for dopamine D4 receptors was determined using CHO-K1 cells which are stably transfected to express the human recombinant dopamine receptor, D4.2 subtype (Van Tol et al, Nature 350, 610, 1991) and using [3H]-Spiperone as the ligand. After incubation of a freshly prepared cellmembrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiberfilters (Research Biochemicals International protocol, Catalog No. D-177). Radioactivity on the filter was measured by liquid scintillation counting. Results are expressed as IC50 values and transformed into inhibitory constants (Ki).
The dopamine D4 agonistic activity of compounds of the invention was determined by functional studies using CHO-K1 cells stably expressing the human dopamine D4.4 receptor (Van Tol, et al, Nature, 358, 149, 1992). These cells were fitted with a construct encoding a truncated form of alkaline phosphatase, causing it to get secreted by the cells. Expression of this secretable alkaline phosphatase (SeAP) is under direct control of cellular cyclic AMP (Berger et al, Gene, 66, 1, 1988). SeAP measurements were done with p-nitrophenylphosphate (pNPP) as the substrate using colorimetric readout at 450 nm. Dopamine D4 agonist activity was determined by incubation of cells with prostaglandin PGE1 (1 uM), with or without addition of compounds of the invention, and subsequent quantification of the concentration-dependant attenuation of dopamine D4 receptor mediated SeAP formation, yielding estimates of intrinsic activity and potency (pEC50 values). Quinpirole and dopamine were used as reference dopamine agonists.
Absence of dopamine D4 antagonistic activity was confirmed using the same assay, but co-incubating cells with prostaglandin PGE1 (1 uM) and the standard agonist quinpirole (1 uM), with or without addition of compounds of the invention. In this way, the antagonistic effect of compounds of the invention against agonist dependant attenuation of dopamine D4 receptor mediated stimulation of adenylate cyclase and subsequent SeAP formation was determined.
Dopamine D4 agonist properties and the absence of D4 antagonist properties of selected compounds of the invention were further confirmed using radioactive measurements of cAMP formation according to Salomon et al. (Anal Biochem, 58, 541, 1974) as modified by Weiss et al. (J Neurochem 45, 869, 1985).
The selectivity of the compounds of the invention with regard to the dopamine D2 receptor, was determined by measuring the affinity for dopamine D2 receptors using rat brain homogenates and [3H]-Spiperone as the ligand (Leysen et al, Biochem Pharmacol 27, 307, 1978). After incubation of a freshly prepared cellmembrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiberfilters. Radioactivity on the filter was measured by liquid scintillation counting. Results are expressed as IC50 values and transformed into inhibitory constants (Ki).
The dopamine D2 (ant)agonistic activity of compounds of the invention was determined by functional studies based on radioactive measurements of cAMP formation according to Salomon et al. (Anal Biochem, 58,541, 1974) as modified by Weiss et al. (J Neurochem 45, 869, 1985), using CHO cells, stably expressing human dopamine D2L receptors (Grandy et al, Proc Natl Acad Sci USA, 86, 9762, 1989).
Suitable acids with which the compounds can form pharmaceutically acceptable acid addition salts are for example hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methane sulphonic acid and naphthalene sulphonic acid.
The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances and/or liquid or solid carrier materials.
The compounds of the invention having formula (I) can be obtained according to methods known for the synthesis of structurally related compounds.
A suitable method for the preparation of the compounds having formula (I) is the following:
Step 1
Reaction of a compound having formula (II):
with chloroacetonitrile in a polar solvent such as acetonitrile in the presence of a base such as triethylamine.
Step 2
The obtained N-cyanomethyl derivative of the compound of formula (II) can be hydrogenated with a reducing agent such as lithium aluminium hydride in an aprotic solvent such as tetrahydrofuran to give the corresponding 2-aminoethyl derivative having formula (III):
Step 3:
The compound having formula (III) is then reacted with a suitable 2-chloroquinoline derivative of the formula (IV):
in the presence of a base such as potassium carbonate in a polar aprotic solvent such as dimethylsulfoxide at 20-140° C., to give the desired compound having formula (I).
The preparation of the compounds of the present invention is illustrated with the following examples.
REFERENCES:
patent: 5093333 (1992-03-01), Saab
patent: 0 512 755 A2 (1992-11-01), None
patent: 0 745 598 A1 (1996-12-01), None
den Hartog Jacobus A. J.
Kruse Cornelis G.
Ronken Eric
Tulp Martinus T. M.
Van Steen Bartholomeus J.
D'Souza Andrea M.
Duphar International Research B.V.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Lambkin Deborah C.
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