Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-12-08
2000-12-12
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514212, 514267, 544250, 540600, A61K 31495, A61K 31505
Patent
active
061599816
DESCRIPTION:
BRIEF SUMMARY
The invention relates to novel 3-substituted pyrido[3',4':4,5]thieno[2,3-d]pyrimidine derivatives, their preparation and use for producing active ingredients for drugs.
Classical antidepressants, and the newer selective serotonin reuptake inhibitors (SSRIs) develop their antidepressent effect inter alia by inhibiting active reuptake of the transmitter into the presynaptic nerve endings. Unfortunately, the antidepressant effect thereof does not have its onset until treatment has lasted at least 3 months, and, moreover, about 30% of patients are therapy-resistant.
Blockade of presynaptic serotonin autoreceptors increases, by abolishing negative coupling, the serotonin release and thus the current transmitter concentration in the synaptic cleft. This increase in the transmitter concentration is regarded as the principle of the antidepressant effect. This mechanism of action differs from previously known antidepressants which activate both the presynaptic and somatodendritic autoreceptors and therefore result in a delayed onset of action, only after desensitization of these autoreceptors. Direct autoreceptor blockade bypasses this effect.
According to current knowledge, the presynaptic serotonin autoreceptor is of the 5-HT.sub.1B subtype (Fink et al., Arch. Pharmacol. 352 (1995), 451). Selective blockade thereof by 5-HT.sub.1B/D antagonists increases serotonin release in the brain: G. W. Price et al., Behavioural Brain Research 73 (1996), 79-82; P. H. Hutson et al., Neuropharmacology Vol. 34, No. 4 (1995), 383-392.
However, surprisingly, the selective 5-HT.sub.1B antagonist GR 127 935 reduces serotonin release in the cortex after systemic administration. One explanation might be stimulation of somatodendritic 5-HT.sub.1A receptors in the raphe region by the released serotonin, which inhibits the firing rate of serotonergic neurons and thus serotonin release (M. Skingle et al., Neuropharmacology Vol. 34 No. 4 (1995), 377-382, 393-402).
One strategy for bypassing the autoinhibitory effects in serotonergic areas of origin thus aims at blockade of presynaptic 5-HT.sub.1B receptors. This hypothesis is supported by the observation that the effect of paroxetine on serotonin release in the dorsal raphe nucleus of the rat is potentiated by the 5-HT.sub.1B receptor antagonist GR 127 935 (Davidson and Stamford, Neuroscience Letts., 188 (1995),41).
The second strategy includes blockade of both types of autoreceptors, namely the 5-HT.sub.1A receptors, in order to intensify neuronal firing, and the 5-HT.sub.1B receptors, in order to increase terminal serotonin release (Starkey and Skingle, Neuropharmacology 33 (3-4) (1994),393).
5-HT.sub.1B/D antagonists, alone or coupled to a 5-HT.sub.1A receptor antagonistic component, should therefore cause a greater increase in serotonin release in the brain and might therefore be associated with advantages in the therapy of depressions and related psychological disorders.
It has now been found that 3-substituted 3,4,5,6,7,8 hexahydropyrido[3',4':4,5]thieno[2,3-d]pyrimidine derivatives of ##STR2## where R.sup.1 is a hydrogen atom, a C.sub.1 -C.sub.4 -alkyl group, an acetyl group, a phenylalkyl C.sub.1 -C.sub.4 radical, the aromatic system being unsubstituted or substituted by halogen, C.sub.1 -C.sub.4 -alkyl, trifluoromethyl, hydroxyl, C.sub.1 -C.sub.4 -alkoxy, amino, cyano or nitro groups, or is a phenylalkanone radical, it being possible for the phenyl group to be substituted by halogen, unsubstituted or mono- or disubstituted by halogen atoms, C.sub.1 -C.sub.4 -alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl, C.sub.1 -C.sub.4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups and which may be fused to a benzene nucleus which can be unsubstituted or mono- or disubstituted by halogen atoms, C.sub.1 -C.sub.4 -alkyl, hydroxyl, trifluoromethyl, C.sub.1 -C.sub.4 -alkoxy, amino, cyano or nitro groups and may contain 1 nitrogen atom, or to a 5- or 6-membered ring which may contain 1-2 oxygen atoms,
A is NH or an oxygen atom, CH.sub.2 --CH, linkage between Y and Z to be
REFERENCES:
patent: 4835157 (1989-05-01), Press et al.
Bach Alfred
Dullweber Uta
Emling Franz
Garcia-Ladona Francisco-Javier
Starck Dorothea
BASF - Aktiengesellschaft
Owens Amelia
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