3-substituted 3,4-dihydro-thieno[2,3-D]pyrimidine derivatives an

Details 3-substituted 3,4-dihydro-thieno[2,3-D]pyrimidine derivatives an 3-substituted 3,4-dihydro-thieno[2,3-D]pyrimidine derivatives an

1999-12-06

2000-12-12

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

51421706, 51425211, 51425216, 514258, 540575, 540600, 544278, C07D41706, C07D41714, A61K 31551, A61K 31559, A61P 2524

Patent

active

06159962&

DESCRIPTION:

BRIEF SUMMARY
This application is the National Stage Application of PCT/EP98/03230, which claims priority from German Application 19724980.9 filed Jun. 13, 1997, and is filed under 37 CFR 1.78.
The invention relates to novel 3,4-dihydrothieno[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 antidepressant 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 weeks, 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-dihydrothieno-[2,3-d]pyrimidine derivatives of the formula I ##STR2## where R.sup.1 and R.sup.2 are a hydrogen atom or a C.sub.1 -C.sub.4 -alkyl group, 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 may 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, CH.sub.2 --CH, between Y and Z also to be a double bond, pharmacological properties.
Particularly preferred compounds are those where 2-methyl-1-naphthyl
The novel compounds of the formula I can be prepared by reacting a compound of the for

REFERENCES:
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Monatshefte fur Chem. 106, 111-116 (1975) Sauter et al.
Neuropharmacology vol. 33, 3/4, 393-402, 1994 Starkey et al.
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2-Amino-Thiophene aus . . . Gewald et al., 94-100.
Subclassification of presynaptic . . . , Fink et al., Springer-Verlag 1995, 451-454
Neuropharmacology vol. 34, No. 4, 383-392, 1995 Hutson et al.
Neuropharmacology vol. 34, No. 4, 393-403 1995, Johansson et al.
Behavioural Brain Res. 73 (1996) 79-82, Price et al.
Neuropharmacology vol. 34, No. 4, 377-382, 1995, Skingle et al.

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