MXPA99010621A - 3-substituted pyrido [3',4':4,5]thieno [2,3-d]pyrimidine derivatives, and production and use of the same - Google Patents

Abstract

The invention relates to 3-substituted 3,4,5,6,7,8-hexahydro-pyrido [3',4':4,5]thieno [2,3-d]pyrimidine derivatives of formula (I) wherein R1 is a hydrogen atom, a C1-C4 alkyl group, an acetyl group, a phenyl alkyl C1-C¿4 ?radical, the aromatic being optionally substituted by halogen, C1-C4 alkyl, trifluoromethyl, hydroxy, C1-C4 alkoxy, amino, cyano or nitro groups, or a phenylalkanon radical in which the phenyl group can be substituted by halogen, R2 means a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which is optionally mono- or disubstituted by halogen atoms, C1-C4 alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C1-C4 alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups and said group can be optionally anellated with a benzene nucleus which can be optionally mono- or disubstituted by halogen atoms, C1-C4 alkyl, hydroxy, trifluoromethyl, C1-C4 alkoxy, amino, cyano or nitro groups and may contain one nitrogen atom, or with a 5 or 6-membered ring which may contain 1-2 oxygen atoms, A represents NH or an oxygen atom, Y is CH2, CH2-CH2, CH2-CH2-CH2 or CH2CH, Z represents a nitrogen atom, carbon atom or CH and the bond between Y and Z can also be a double bond, and n represents the number 2, 3 or 4. The invention also relates to the physiologically compatible salts of the inventive 3-substituted pyrido [3',4':4,5]thieno [2,3-d]pyrimidine derivatives. The inventive compounds show a high level of affinity for the serotonin receptors 5-HT1B, 5-HT1D and 5-HT1A. The affinity for said receptors is approximately equal, at least on the same scale. Some of the inventive compounds also have a good capacity for inhibiting serotonin reuptake, a property used in most antidepressants.

Description

DERIVATIVES OF PIRIDO [3 ', 4': 4,5] TIENO [2,3-d] PYRIMIDINA 3-SUBSTITUTE, ITS OBTAINING AND USE.

Description The invention relates to novel 3-substituted pyrido derivatives [3 ', 4': 4,5] thieno [2,3-d] pyrimidine, their preparation and use for the manufacture of pharmaceutical active substances.

The classic antidepressants and also the new selective serotonin-reuptake inhibitors (SSRIs) develop their antidepressant action-, among other factors, by the inhibition of the active readmission of the transmitter in the pre-synaptic terms of the nerves. Unfortunately, the antidepressant effect is presented here only after a treatment of at least three weeks, and also, approx. 30% of patients are resistant to ttherapy.

The blockade of the presynaptic serotonin autoreceptors increases, due to the suppression of the negative coupling, the libration of serotonin and with it the current concentration of the transmitter in the synaptic cavity. Tincrease in transmitter concentration is considered as the beginning of the antidepressant action. Tmechanism of action differs from that of the antidepressants known to date, which simultaneously activate the presynaptic and somatosensory autoreceptors and, consequently, produce only after the desensitization of these autoreceptors in a delayed manner the desired effect . With the direct blocking of autoreceptors teffect is avoided.

Current knowledge teaches that the pre-synaptic serotonin autoreceptor is a 5-HTβ subtype (Fink et al., Arch. Pharmacol 352 (1995), p.451). Its selective blockade by antagonists of 5-HTIB / D increases the libration of serotonin in the brain: G.. Price et al., Behavioral Brain Research 73 (1996), pp. 79-82; P.H. Hutson et al., Neuropharmacology Vol. 34, No. 4 (1995), pp. 383-392.

However, the selective 5-HT ?B antagonist, GR 127 935, surprisingly reduces, after systemic administration, the serotonin libration in the cortex. One possible explanation for tmay be the stimulation of somato-dendritic 5-HTIA receptors in the Raphe region, due to the serotonin released, which inhibits the firing rate of serotonergic neurons and thereby the spilling of serotonin (M. Skingle et al. al., Neuropharmacology Vol. 34 No. 4 (1995), pp. 377-382, pp. 393-402).

One strategy to avoid self-inhibiting effects in the regions of serotonergic origin is, therefore, the blockade of presynaptic 5-HT? B receptors. Thypothesis is supported by the observation that the influence of paroxetine on the serotonin libration in the Raphe Nucleus dorsalis of the rat is potentiated by the 5-HT? B receptor antagonist, GR 127 935, (Davidson and Stamford, Neuroscience Letts., 1M (1995), 41).

The second strategy includes the blocking of both types of autoreceptors, namely, the 5-HT? A receptors, in order to reinforce the firing of neurons, and the 5-HT? B receptors, in order to increase the serotonin libration (Starkey and Skingle, Neuropharmacology 33. (3-4) (1994), 393).

The 5-HTIB / D- antagonists, alone or coupled with an antagonist component of the 5-HT? Receptor & they should, therefore, increase the libration of serotonin in the brain, so that they could have advantages in the therapy of depressions and similar psychic illnesses.

It has now been found that the derivatives of 3, 4, 5, 6, 7,8-e-xahidro-pyrido [3 ', 4':, 5] thieno [2,3-d] pyrimidine 3-substituted of the formula I where R1 means a hydrogen atom, a C? -C4-alkyl group, an acetyl group, a phenyl-C1-C4 alkyl radical, the aromatic being optionally substituted by halogen, C1-C4-alkyl, trifluoromethyl, hydroxy, C1 groups -C4- alkoxy, amino-, cyano or nitro, or a phenylalcanone radical, the phenyl group being able to be substituted, R 2 means a phenyl, pyridyl, pyrimidinyl or pyridinyl group optionally mono- or di-substituted by halogen atoms, C 1 -C 4 -alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C 1 -C 4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro , which may be bonded with a benzene nucleus, which is optionally mono- or di-substituted by halogen atoms, C1-C4-alkyl, hydroxy, trifluoromethyl, C? -C4-alkoxy, amino, cyano- or nitro and contains, if necessary, a nitrogen atom, or with a ring of five or six members that can contain 1-2 oxygen atoms, A means NH or an oxygen atom, And it is CH2, CH2-CH2, CH2-CH2-CH2 or CH2-CH, Z means a nitrogen atom, a carbon atom or CH, the bond between Y and Z being also a double bond, and n represents the figure 2, 3 or and their salts with physiologically tolerated acids may have valuable pharmacological properties.

Composites are especially preferred, in which R1 means methyl, ethyl, benzyl R2 means o-methoxyphenyl, 1-naphthyl, 2-methoxy-1-naphthyl, 2 - . 2-methyl-1-naphthyl means an oxygen atom means CH2-CH2 means a nitrogen atom and n represents figures 2 and 3.

The compounds according to the invention of the formula I can be obtained by reacting a compound of the formula II wherein R i has the meanings indicated above, R 3 signifies a cyano group or an ester group of C 3 -3-alkylcarboxylic acid and R 4 signifies C 3 -alkyl, with a primary amine of formula III (CH2) n- -N Z R2 III, \ / H2N Y where R2 has the meanings indicated above, and by converting the compound thus obtained, optionally, into the acid addition salt of a physiologically tolerated acid.

The reaction is conveniently carried out in an inert organic solvent, especially a lower alcohol, for example methanol or ethanol, or a saturated cyclic ether, especially tetrahydrofuran or dioxane.

The reaction is generally carried out at temperatures of 20 h at 110 ° C, especially 60 up to 90 ° C, and is generally completed within 1 to 10 hours.

Or a compound of the formula II is reacted wherein Ri has the meanings indicated above, R3 signifies a cyano group or an ester group of C? -3-alkylcarboxylic acid and R4 signifies C1-3 -alkyl, with a primary aminoalcohol of the formula IV (CH2) n-OH H2N "IV in an inert solvent, preferably alcohols, eg ethanol, at temperatures between 60 ° and 120 ° C, giving the cylindrical product V (X = OH) which is then transformed with a halogenating agent, such as, for example, thionyl chloride or hydrobromic acid, in an organic solvent, such as, for example, a halogenated hydrocarbon or without a solvent, at temperatures between room temperature and 100 ° C. the corresponding halogen derivative V (X = G1, Br), Finally, the halogen derivative of the formula is reacted V (X = C1, Br) with an amine of the general formula VI HN Z R2 VI, Y wherein Y, Z and R2 have the meanings indicated above, in the final product according to the invention of the formula I. This reaction is advantageously carried out in an inert organic solvent, preferably toluene or xylene, in the presence of a base, such as, for example, potassium carbonate, at temperatures between 60 ° C and 150 ° C.

The compounds according to the invention of formula I can be purified, either by recrystallization from the usual organic solvents, preferably a lower alcohol, such as ethanol, or by column chromatography.

The free [3 ', 4': 4,5] thieno [2, 3-d] pyrimidine 3-unsaturated pyrido derivatives of the formula I can be converted in the usual manner to the acid addition salts with the stoichiometric amount of the acid The pharmaceutically tolerated acids are, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.

The invention therefore also relates to a therapeutic product, characterized in that it contains a compound of the formula I or its pharmacologically tolerated acid addition salt, together with customary carriers and diluents, as well as the use of the novel compounds for combating diseases.

The compounds according to the invention can be administered customarily in oral or parenteral, intravenous and intramuscular form.

The dose depends on the age, the state and weight of the patient, as well as on the form of apliasation. As a rule, the daily dose of active substance varies between approx. 1 and 100 mg / kg body weight in oral administration, and between 0.1 and 10 mg / kg body weight in parenteral administration.

The new compounds can be used in the usual solid or liquid galenic application forms, eg in the form of tablets, film tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are prepared in a customary manner. The active substances can be prepared with the usual galenic auxiliaries, such as tablet vehicles, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarders, antioxidants and / or blowing gases. (see H. Sucker et al: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The application forms thus obtained contain the active substance, usually in an amount of 1 to 99% by weight.

The active substances necessary for the synthesis of the new compounds of the formulas II to VI are known or can be synthesized, using the methods described in the literature from analogous starting materials (F. Sauter and P. Stanetty, Monatsh. Chem. (1975), 106 (5), 1111-1116, K. Ge ald et al, Chem. Ber. £ 9, 94-100 (1966), patent application DE 196 3676.7).

The compounds of the invention exhibit a high affinity for the serotonin 5-HT? B, 5-HTp > And 5-HT? The affinity with these receptors is equally high, at least in the same order. In addition, some of the compounds according to the invention have a good inhibition of serotonin Re-uptake, a principle that is carried out in most antidepressants.

These compounds are suitable as medicaments for the treatment of disease states, in which the concentration of serotonin is decreased, and where in therapy it is desired to specifically block the activity of the 5-HT? B, 5-HTIA receptors, 5-HT? D presynaptic, without significantly affecting other receptors. Such a morbid state is, for example, depression.

The compounds of the present invention are also suitable for the treatment of psychic conditions that are due to central nervous system conditions, such as temporary affective disorders and dysthymia. To these belong states of anguish, such as general anguish, panic attacks, socio-phobia, obsessive neuroses and post-traumatic stress symptoms, memory disorders, including dementia, amnesias and memory loss due to age, as well as disorders. appetite psychics, such as Anorexia nervosa and Bulimia nervosa.

The compounds according to the invention can also be used for the treatment of endocrine diseases, such as hyperprolactinemia, as well as for the treatment of vascular spasms (especially cerebral vessels), hypertonia and gastrointestinal disorders, which are accompanied by disorders of the motility and secretion. Another field of application are sexual disorders.

The following examples illustrate the invention: To obtain the starting materials a) 2-amino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydro-thieno [3,2-c] pyridine To 96.1 g (588 mM) of 1-ethyl-3-piperidone x HCl in 350 ml ethanol are added 62.9 ml (588 mM) of ethyl cyanoacetate and 18.8 g (588 mM) of sulfur polyol and then added in drops. and under nitrogen atmosphere 150 ml (1080 mM) of tri-ethylamine. After 0.5 h the preparation is heated for 6 h at reflux and stirring is continued overnight at room temperature. The reaction mixture was poured into 3 1 of ice water, adjusted to pH = 9 and extracted twice with methylene chloride. After drying and concentrating the organic phase, the crude product was purified by column chromatography (silica gel, chloride eluent). methylenic / methanol 93/7). 29.2 g (20%) of product are isolated as slightly fat solids. b) 2-ethoxymethylene-amino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydro-thieno [3,2-c] pyridine 3.8 g (14.9 mM) of 2-amino-3-carboethoxy-5-ethyl-4,5,7,7-tetrahydro-thieno [3,2-c] pyridine in 40 ml of orthoformate. triethyl are mixed with 0.5 ml of acetic anhydride and boiled for one hour at reflux. After having decanted the insoluble black deposit of the wall of the flask, the preparation is concentrated, then, at 80 ° C in the rotary evaporator. 3.5 g (94%) of crude product are isolated as dark oil, which is sufficiently pure for further reactions.

In analogy to a) and b) it is prepared from l-acetyl-3-pipe-ridone (P. Krogsgaard-Larsen, H. Hjeds: Acta Chem. Scand B 30, 884 (1976)) the 5-acetyl derivatives. c) 3- (2-Hydroxy-ethyl) -6-ethyl-3,4,5,6,7,8-hexahydro-pyrido [3 ', 4': 4,5] thieno [2,3-d] pyrimidin-4-one 17. 0 g (55 mM) of 2-ethoxymethylene-amino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydro-thieno [3,2-c] pyridine in 130 ml of ethanol is mixed with 5.0 ml (81 mM) of ethanolamine and boiled for 2 h at reflux. Then, the preparation is concentrated to approx. 50 ml volume and stir in the ice bath. The fine solids precipitated by suction are filtered and washed with cold acetic ester. 10.5 g (63%) of light brown product are isolated. d) 3 - (2-chloro-ethyl) -6-ethyl-3,, 5, 6, 7, 8-hexahydro-pyridine [3 ', 4': 4,5] thieno [2,3-d] pyrimidine -4 -one 10.5 g (37.6 mM) of 3- (2-hydroxy-ethyl) -6-ethyl- [3,4,5,6,7,8-hexahydro-pyrido [3 ', 4': 5] ] thieno [2,3-d] pyrimidin-4 -one in 100 ml of 1-dichloro-anus are heated to reflux (slow dissolution) and then 3.5 ml (48 mM) of thionyl chloride are added dropwise. in 20 ml of 1,2-dichloroethane. After boiling for one hour at reflux, the reaction mixture is allowed to cool and the solids are filtered off by suction, subsequently washing with 1,2-dichloroethane. The crude product is partitioned between methyl chloride and water at pH = 9. After drying and the concentration of the organic phase, 9.3 g (83%) of the product are isolated as dark steeping, which crystallizes slowly thoroughly and is sufficiently pure for further reactions, m.p. 94-96 ° C. e) N- (1 -naph il) -piperazine To a mixture from 5.4 g (24.2 mM) of palladium acetate and 14.7 g (48.3 mM) of tri-o-tolylphosphine in 500 ml of xylene is added 83.2 g (966 mM) of piperazine, 38.0 g (339 mM) of potassium tert-butylate and 50.0 g (241 mM) of l-bromonaphthalene and the reaction mixture is heated for 10 h, while stirring thoroughly and under a nitrogen atmosphere, at reflux. The preparation is then diluted with methylene chloride, the insoluble residues are filtered and the filtrate is concentrated. The crude product is purified by column chromatography (silica gel, eluent THF / methanol / ammonia 85/13/2). 21.5 g (42%) of product are isolated with m.p. 84-86 ° C. f) N- (2-methyl-1-naphthyl) -piperazine 13.0 g (82.7 mM) of l-amino-2-methyl-naphthalene in 100 ml of chlorobenzene are mixed with 14.7 g (82.7 mM) of bis- (2-chloroethyl) -amine x HCl and heated for 90 h under nitrogen at reflux. The mixture is then concentrated, partitioned between methylene chloride and water at pH = 9 and the organic phase is concentrated after drying. The crude product is purified by column chromatography (silica gel, eluent / THF / methanol / ammonia 85/13/2), 11.6 g (62%) of product are isolated. 4-piperazin-1-yl-isoquinoline 4.51 g (21.7 mM) of 4-bromoisoquinoline, 4.65 g, (25.0 mM) of piperazin-N-carboxylic acid t-butylester, 0.1 g (0.11 mM) of tris- (dibenzylidenaceton) -di-palladium are combined. 0.11 g (0.18 mM) of 2,2'-bis- (diphenylphos-fine) -1,1-biphenyl and 2.92 g (30.4 mM) of sodium t-butylate in 50 ml of toluene is stirred 2 h 75 ° C. The reaction mixture is poured onto ice / common salt, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is removed in the rotary evaporator. The product crystallizes, is filtered by suction and washed with pentane. 5.5 g (81%) of the Boc-protected piperazine are obtained (mp .: 111 ° C). 5.2 g (16.6 mM) of this substance are taken up in 17 ml of dichloromethane and absorbed slowly at 0 ° C with 17 ml of dichloromethane and at 0 ° C slowly with 17 ml (0.22 mM) of trifluoroacetic acid. It is stirred for 4 h at 0 ° C, poured into ice water and extracted with dichloromethane. The aqueous phase is filtered, adjusted to an alkaline value and extracted with dichloromethane. After drying over sodium sulfate and substantially removing the solvent, it is diluted with diethyl ether and the hydrochloride is precipitated with ethereal hydrochloric acid. 3.2 g (67%) of the product are obtained with m.p. 293-294 ° C.

In analogy to e), f) and g) other piperazine derivatives are prepared (see the examples), as long as they are not known the literature (see also German patent application DE 19636769.7).

B Obtaining the final products Example 1 3,4, 5, 6,7, 8-Hexahydro-6-ethyl-3- [2- (4- (2-methoxy-f-enyl) -piperazin-1-yl) -ethyl] -pyrido [3 ', 4 ': 4,5] thieno [2,3-d] pyrimidin-4 -ona x 3 HCl x 2H20 3.1 g (10.0 mM) of 2-ethoxymethylene-amino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydro-thieno [3,2-c] pyridine in 50 ml of ethanol are mixed with 2.3 g (10.0 mM) of l- (2-amino-ethyl) -4- (2-methoxy-phenyl) -piperazine and boiled for 1 h at reflux. The preparation is then concentrated on the rotary evaporator and the crude product is purified by column chromatography (silica gel, eluent methylene chloride / methanol 93/7). 2.9 g (48%) of product are isolated after conversion to the hydrochloride in acetic ester with m.p. 172 -174 ° C.

Example 2 3,4,5,6,7,8-hexahydro-6-ethyl-3- [2- (4- (2-methoxy-1-naphthyl) -pi-peracin-1-yl) -ethyl] -pyrido [3 ', 4': 4, 5] thieno [2,3-d] pyrimidin-4 -ona x 2 HCl X 2 H20 1. 1 g (4.5 mM) of 3- (2-chloro-ethyl) -6-ethyl-3, 4, 5, 6, 7, 8-hexahi-dro-pyrido [3 ', 4': 4, 5] thieno [2, 3-d] pyrimidin-4-one in 40 '"ml of xylene are mixed with 1.3 g (4.5 mM) of N- (2-methoxy-1-naphthyl) -piperazine, as well as with 0.65 g (4.5 mM) of finely powdered potassium carbonate and boiled, in total, for 70 h under nitrogen at reflux, then the preparation is concentrated in vacuo and the residue is distributed at pH = 10. between methylenic chloride and water After drying and concentration of the organic phase, the crude product is purified by column chromatography (silica gel, eluent Ace-ton), 11 g (50%) of product are isolated with mp 232-234 °. C (decomp.).

In analogy to examples 1 and 2, the following compounds are prepared: 3,4,5,6,7,8-hexahydro-6-ethyl-3- [2- (4- (2-methyl-1-naphthyl) -piperazin-1-yl) -ethyl] -pyrido [3 ' , 4 ': 4,5] thieno [2,3-d] -pyrimidin -one x 2 HCl x 3 H20, mp 238-240 ° C (decomp.) 3,4,5,6,7,8-hexahydro-6-ethyl-3- [2- (4- (1-naphthyl) -piperazin-1-yl) -ethyl] -pyrido [3 ', 4': 4, 5] ieno [2,3-d] pyrimidin-4 -one x 2HC1 x 3 H20, mp, 298-300 ° C (decomp.) 3,4,5,6,7,8-hexahydro- 6 - ethyl -3- [2- (4- (2-methyl-phenyl) -pyridin-1-yl) -ethyl] -pyrido [3 ',': 4,5] thieno [2,3-d] pyrimidine - 4 -one 6. 3, 4, 5, 6, 7, 8-hexahydro-6-ethyl-3- [2- (4- (2,3-dimethyl-phenyl) -piperazin-1-yl) -ethyl] -pyrido [3 ' , 4 ': 4,5] thieno [2, 3-d] pyrimidin-4 -one 3, 4, 5, 6, 7, 8-hexahydro-6-ethyl-3- [2- (4- (2-chloro-phenyl) -piperacin-1-yl) -ethyl] -pyrido [3 ' , 4 ': 4,5] thieno [2, 3-d] pyrimidin-4-one, mp 148 - 150 ° C 8. 3,4,5,6,7,8-hexahydro-6-ethyl-3- [2- (4-pyrimidin-2-yl-piperazin-1-yl) -ethyl] -pyrido [3 ', 4 ': 4,5] thieno [2, 3-d] pyrimidin-4 -one 9. 3, 4, 5, 6, 7, 8 -hexahydro-6-ethyl-3- [2- (4-pyridin-2-yl-pipera- "cin-l-yl) -ethyl] -pyrido [3 ', 4 ': 4,5] thieno [2,3-d] pyrimidin-4 -one . 3,4, 5, 6,7,8-hexahydro-6-ethyl-3- [2- (4-quinoline-2-yl-piperazin-1-yl) -ethyl] -pyrido [3 ', 4 ': 4,5] thieno [2, 3-d] pyrimidin-4 -one 11. 3,4,5,6,7,8-hexahydro-6-ethyl-3- [2- (4- (2-methoxy-phenyl) -piperidin-1-yl) -ethyl] -pyrido [3 ', 4 ': 4, 5] thieno [2,3-d] pyrimidin-4 -one 12. 3,4,5,6,7,8-hexahydro-6-ethyl-3- [2- (4- (2-methoxy-phenyl) -3,4-dehydropiperidin-1-yl) -ethyl] -pyrido [ 3 ', 4': 4, 5] thieno [2,3-d] pyrimidinone-13, 3,4,5,6,7,8-hexahydro-6-ethyl-3- [3- (4 - pyrimidin-2-yl-piperazin-1-yl) -propyl] -pyrido [3 ', 4': 4,5] thieno [2,3-d] - pyrimidin-4-one x 3 HCl x 4 H20, p.'f. 211-213 ° C (decomp.) 14. 3, 4, 5, 6, 7, 8-hexahydro-6-ethyl-3- [2- (4-tetralin-5-yl-piperazin-1-yl) -ethyl] -pyrido [3 ', 4 ': 4, 5] thieno [2, 3-d] pyrimidin-4-one, mp 287 ° C (hydrochloride) . 3,4, 5, 6,7,8-hexahydro-6-ethyl-3- [2- (4-indan-l-yl-pipera-cin-l-yl) -ethyl] -pyrido [3 ', 4 ': 4, 5] thieno [2, 3-d] pyrimidine-4 -one 16. 3,4,5,7,7,8-hexahydro-6-ethyl-3- [2- (4- (3-trifluoromethylphenyl) -piperazin-1-yl) -ethyl] -pyrido [3 ', 4' : 4,5] thieno- '[2,3-d] -pyrimidin-4-one 17. 3,4,5,6,7,8-hexahydro-6-ethyl-3- [2- (4- (2-cyanophenyl) -piperacin-1-yl) -ethyl] -pyrido [3 ', 4 ': 4,5] thieno- [2,3-d] -pyrimidin-4-one 18. 3,4,5,6,7,8-Hexahydro-6-ethyl-3- [2- (4-isoquinoline-1-yl-piperazin-1-yl) -ethyl] -pyrido [3 ', 4': 4 , 5] thieno [2, 3-d] pyrimidine-4 -one 19. "3,4,5,6,7,8-Hexahydro-6-ethyl-3- [2- (4-naphth-1-yl-hexahydro-l, 4-diazepin-1-yl) -ethyl] -pyrido [3 ', 4': 4, 5] - thieno [2,3-d] pyrimidin-4-one, mp 276-280 ° C (hydrochloride) . 3,4,5; 6,7,8-hexahydro-6-ethyl-3- [2- (4-naphth-l-yl-3,4-dehydropiperidin-1-yl) -ethyl] -pyrido [ 3 ', 4': 4, 5] thieno- [2, 3-d] pyrimidin-4 -one, MS: m + = 507.1 21. 3,4,5,6,7,8-hexahydro-6-ethyl-3- [2- (4-naphth-l-yl-piperidin-1-yl) -ethyl] -pyrido [3 ', 4': , 5] thieno [2, 3-d] - pyrimidin-4 -one 22. 3,4,5,6,7,8-hexahydro-6-ethyl-3 - [2- (4- (2-methoxy-naphth-1-yl-3,4-dehydropiperidin-1-yl) -ethyl] -pyrid [3 ', 4': 4,5] thieno- [2, 3-d] irimidi -4 -one 23. 3, 4, 5, 6, 7, 8-hexahydro-6-acetyl-3- [2- (4- (2-methoxy-phenyl) -piperazin-1-yl) -ethyl] -pyrido [3 ', 4 ': 4, 5] thieno- [2,3-d] - pyrimidin-4-one 24. 3,4,5,6,7,8-hexahydro-6-acetyl-3 - [2- (4- (2-methyl-1-α-aftyl) piperazin-1-yl) -ethyl] -pyrido [3 ', 4': 4, 5] thieno [2,3-d] - pyrimidin-4-one . 3, 4, 5, 6, 7, 8-hexahydro-6-acetyl-3 - [2- (4- (2-methoxy-1-naphthyl) -piperazin-1-yl) -ethyl] -pyrido [3 ' , 4 '; 4, 5] thieno- [2, 3-d] pyrimidin-4-one The acetyl group in position 6 can be separated in analogy to DE 19 636 769.7 with 10% hydrochloric acid, boiling under reflux, giving the corresponding secondary amines. The alkylations at N-6, giving the 6-alkyl derivatives can also be carried out in the manner described in DE 19 636 769.7. 3,4,5,6,7,8-hexahydro-3- [2- (4- (2-methoxy-phenyl) -pipera-sin-l-yl) -ethyl] -pyrido [3 ', 4': 4,5] thieno [2, 3-d] pyrimidine-4 -one 3, 4, 5, 6, 7, 8-hexahydro-6-benzyl-3- [2- (4- (2-methyl-phenyl) -pi-peracin-1-yl) -ethyl] -pyrido [3 ' , 4 ': 4,5] thieno [2, 3-d] pyrimidin-4 -one 3, 4, 5, 6, 7, 8-hexahydro-6- (4-chloro-phenyl-2-ethyl) -3- [2- (4- (1-naphthyl) -piperazin-1-yl) -ethyl ] -pyrant- [3 ', 4': 4, 5] -thieno [2, 3-d] pyrimidin-4 -one 3,4,5,6,7,8-hexahydro-6- (4-methoxy-benzyl) -3- [2- (4- (2-methyl-1-naphthyl) -piperazin-1-yl) -ethyl] -pyrant- [3 ', 4': 4, 5] thieno [2,3-d] pyrimidin-4 -one 3, 4, 5, 6, 7, 8-hexahydro-6-ethyl-3- [3- (4-phenylpiperi-din-l-yl) -propyl] -pyrido [3 ', 4': 4,5] thieno [2,3-d] pyrimidin-4 -one, mp 241 ° C (hydrochloride)

Claims (3)

1. Claims Derivatives of 3, 4, 5, 6,7, 8-hexahydro-pyrido [3 ', 4': 4,5] thieno [2,3-d] pyrimidine 3-substituted of the formula I where R 1 is a hydrogen atom, a C 4 -C-alkyl group, an acetyl group, a phenyl-C 1 -C 4 radical, the aromatic being optionally substituted by halogen, Ci-Cj-alkyl, trifluoromethyl, hydroxy groups , C? -C4 -alkoxy, amino-, cyano or nitro, or a phenylalkane radical, the phenyl group being able to be substituted, R 2 means a phenyl, pyridyl, pyrimidinyl or pyridinyl group optionally mono- or di-substituted by halogen atoms, C 1 -C 4 -alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C i -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro , which may be bonded with a benzene nucleus, which is optionally mono- or di-substituted by halogen atoms, C1-C-alkyl, hydroxy, trifluoromethyl, C? -C4-alkoxy, amino, cyano- or nitro and optionally contains nitrogen atom, or with a ring of five or six members. which may contain 1-2 oxygen atoms, A means NH or an oxygen atom, And it is CH2, CH2-CH2, CH2-CH2-CH2 or CH2-CH, Z means a nitrogen atom, a carbon atom or CH, the bond between Y and Z being also a double bond, and n represents the number 2,3 or 4, as well as its salts with physiologically tolerated acids. Compounds according to claim 1, characterized in that Ri means methyl, ethyl, benzyl R2 means o-methoxyphenyl, 1-naphthyl, 2-methoxy-1-naphthyl, 2-methyl-l-naphyl means an oxygen atom And it means CH2-CH2 Z means a nitrogen atom and n represent figures 2 and 3. Use of compounds according to claim 1-2 for the production of medicines. Use according to claim 3 for the treatment of depressants and similar diseases. Use of compounds according to claim 1-2 as selective 5H IB and 5-fa? A antagonists. Use according to claim 5, wherein the selective antagonism of serotonin is accompanied by an inhibition of serotonin-Reuptake. SUMMARY OF THE INVENTION. Derivatives of 3, 4, 5, 6, 7, 8 -hexahydro-pyrido [3 ', 4': 4,5] thieno [2,3-d] pyrimidine 3-substituted of the formula I where Ri means a hydrogen atom, a C1-C-alkyl group, an acetyl group, a phenyl-C1-C4 alkyl radical, the aromatic being optionally substituted by halogen, C? -C4-alkyl, trifluoromethyl, hydroxy, C groups? ? -C4-alkoxy, amino-, cyano or nitro, or a phenylalcanone radical, the phenyl group being able to be substituted, R 2 is a phenyl, pyridyl, pyriraidinyl or pyrazinyl group optionally mono- or di-substituted by halogen atoms, C [alpha] -Calkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C [beta] -4-alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro, which may be bonded with a benzene nucleus, which is optionally mono- or di-substituted by halogen atoms, C? -C4-alkyl, hydroxy, trifluoromethyl, C3.-C4 -alkoxy, amino, cyano- or nitro and contains, optionally , a nitrogen atom, or with a five or six member ring that can contain 1-2 oxygen atoms. means NH or an oxygen atom, is CH2, CH2-CH2, CH2-CH2-CH2 or CH2-CH, Z means a nitrogen atom, a carbon atom or CH, the bond between Y and Z being also a double bond, and n represents the number 2,3 or 4, as well as its salts with physiologically tolerated acids.