3-substituted derivatives of 3,4,5,6,7,8-hexahydropyrazino[4', 3':4,5]-thieno[2,3-d]pyrimidine

 

(57) Abstract:

The invention relates to new 3-substituted derivatives 3,4,5,6,7,8-hexahydropyrazino[4', 3': 4,5] -thieno[2,3-d] pyrimidine of the General formula I and their physiologically acceptable salts with selective action of antagonists 5HT1Band 5HT1Aand has inhibiting effect of reuse of serotonin. The compounds may be used for the preparation of drugs, in particular for the treatment of depression and related diseases. In the compounds of the formula I R1denotes hydrogen, alkyl with 1-4 carbon atoms, acetyl or benzoyloxy group, phenylalkyl residue with 1-4 carbon atoms in the alkyl part, and aromatic fragment can be substituted with halogen, alkyl with 1-4 carbon atoms, trifluoromethyl, hydroxyl group, alkoxygroup with 1-4 carbon atoms, amino group, langroup or nitrogroup, nuptially residue with 1 to 3 carbon atoms in the alkyl part, the rest of phenylalanine with 2-3 carbon atoms in alanovoy part or phenylcarbamoyloxy residue with 2 carbon atoms in the alkyl part, and phenyl group may be substituted with halogen, R2represents resumes timetokill, hydroxyl groups, alkoxycarbonyl with 1-4 carbon atoms, amino groups, monomethylamine, dimethylamino-, cyano - or nitro groups phenyl, pyridyloxy, pyrimidinyl or personilnya group, which may be bellrowan with six-membered aromatic nucleus which may have one or two deputies from among halogen, alkyl with 1-4 carbon atoms, hydroxyl group, triptorelin group, alkoxygroup with 1-4 carbon atoms, amino group, langroup or nitro, and optionally may contain one nitrogen atom, or a 5 - or 6-membered ring which may contain 1-2 oxygen atom, or may be substituted phenylalaninol group or vinylalcohol with 1-2 carbon atoms in the alkyl part, and phenyl residue may be substituted with halogen, methyl group, triptorelin group or methoxy group, And means aminogroup or oxygen atom, means hydrogen or methyl, With means hydrogen, methyl or hydroxyl group, X denotes a nitrogen atom, Y represents CH2CH2-CH2CH2-CH2-CH2or CH2-SN, Z denotes a nitrogen atom, a carbon atom or CH, and the relationship between Y and Z can also be dual, n means h is tositsa to new nitrogen-containing heterocyclic compounds, possessing pharmacological activity, and more particularly to 3-substituted derivatives 3,4,5,6,7,8-hexahydropyrazino[4',3':4,5]-thieno[2,3-d]pyrimidine, which can be used as selective antagonists of 5-HT1Band 5-HT1A.

Classical antidepressants and also new selective inhibitors reuse of serotonin (5-hydroxytryptamine) manifest their antidepressant action, inter alia, by inhibiting the active re-use of neurotransmitter into the presynaptic nerve endings. Unfortunately, while the antidepressant effect occurs only after at least three weeks after treatment, in addition, approximately 30% of patients unresponsive to treatment.

Blockade of presynaptic autoreceptors serotonin increases by eliminating the negative coupling the release of serotonin and thereby the actual concentration of the neurotransmitter in the synaptic cleft. It is believed that this rise in the concentration of the mediator lies in the basis of antidepressant action principle. This mechanism of action differs from that previously known antidepressants, which simultaneously activate presynaptic and somatodendritic autoreceptor and so Toa blockade of autoreceptor bypasses the effect.

According to well-known information in the case of presynaptic serotonin autoreceptors we are talking about the subtype of 5-HT1B(Fink and others, Arch. Pharmacol. 352 (1995), page 451). Its selective blockade by antagonists of 5-HT1B/Dincreases the release of serotonin in the brain: G. W. Price, etc.. Behavioural Brain Research 73 (1996), pp. 79-82; R. N. Hutson and others, Neuropharmacology, T. 34, 4 (1995), pp. 383-392.

Selective antagonist of 5-HT1Bno patent Greece 127935 suddenly reduces, however, the release of serotonin in the cerebral cortex after systemic administration. An explanation could be the stimulating somatodendritic receptors 5-HT1Ain the weld area released serotonin, which inhibits the degree of excitability of serotonergic neurons and thus the distribution of serotonin (M Skingle and others, Neuropharmacology, T. 34, 4 (1995), pages 377-382, 393-402).

Strategy crawl autoinhibitory effects of serotonergic primary areas also aims blockade of presynaptic receptors 5-HT1B. This hypothesis is based on the observation that the effect of paroxetine on the release of serotonin in the dorsal nucleus of the seam in rat potentiaries antagonists of the receptor 5-HT1Baccording to the patent Greece 127935 (Davidson and Stamford, Newoscience Letts., 188 (1995), to enhance neuronal excitability, and receptors 5-HT1Bto start the terminal release of serotonin (Starkey and Skingle, Neuropharmacology, 33 (3-4) (1994), 393).

Antagonists of 5-HT1B/Done or antagonistic components associated with the receptor 5-HT1Awere therefore further increase the release of serotonin in the brain and could therefore be useful in the treatment of depression and related mental illnesses.

It was found that 3-substituted derivatives of 3,4,5,6,7,8-hexahydropyrazino[4',3':4,5]-thieno[2,3-d]pyrimidine of the formula I

It was found that 3-substituted derivatives of 3,4,5,6,7,8-hexahydropyrazino[4',3':4,5]-thieno[2,3-d]pyrimidine of the formula I

< / BR>
where R1denotes hydrogen, alkyl with 1-4 carbon atoms, acetyl or benzoyloxy group, phenylalkyl residue with 1-4 carbon atoms in the alkyl part, and aromatic fragment can be substituted with halogen, alkyl with 1-4 carbon atoms, trifluoromethyl, hydroxyl group, alkoxygroup with 1-4 carbon atoms, amino group, cyano or nitro-group, nuptially residue with 1 to 3 carbon atoms in the alkyl part, the rest of phenylalanine with 2-3 carbon atoms in alanovoy part, or phenylcarbamoyloxy residue with 2 carbon atoms in Alemanno or mono-, di - or tizamidine halogen atoms, alkyl with 1-4 carbon atoms, triptoreline, triptoreline, hydroxyl groups, alkoxycarbonyl with 1-4 carbon atoms, amino groups, monomethylamine, dimethylamino, cyano or nitro groups, phenyl, pyridyloxy, pyrimidinyl or personilnya group, which may be bellrowan with chastising aromatic nucleus which may have one or two deputies from among halogen, alkyl with 1-4 carbon atoms, hydroxyl group, triptorelin group, alkoxygroup with 1-4 carbon atoms, amino group, ceanography or nitro group and may contain one nitrogen atom, or 5 - or 6-membered cycle which may contain 1 or 2 oxygen atoms or may be substituted phenylalaninol group or vinylalcohol with 1-2 carbon atoms in the alkyl part, and phenyl residue may be substituted with halogen, methyl group, triptorelin group or methoxy group,

And means aminogroup or oxygen atom,

In the mean hydrogen or methyl,

With means hydrogen, methyl or hydroxyl group,

X denotes a nitrogen atom,

Y represents CH2CH2-CH2CH2-CH2-CH2the Noi,

and

n means the number 2, 3, or 4

and their salts with physiologically acceptable acids have valuable pharmacological properties.

Preferred, in particular, compounds in which

R1means methyl, ethyl, isopropyl, benzyl, benzyl substituted specified in paragraph 1 for phenylalkylamine residue groups phenethyl, phenethyl, substituted specified in paragraph 1 for phenylalkylamine residue groups

R2means o-methoxyphenyl, 1-naphthyl, pyrimidine-2-yl, 2-methoxy-1-naphthyl, 2-methyl-1-naphthyl,

And means aminogroup or oxygen atom,

X denotes a nitrogen atom,

Y represents CH2-CH2CH2-CH,

Z denotes a nitrogen atom, carbon or CH

and

n is the number 2 and 3.

Compounds according to the invention of formula I are obtained when the compound of formula II

< / BR>
in which R1has the above meaning, R3represents a cyano or ester group, which includes the balance alkalicarbonate acids with 1-3 carbon atoms in the alkyl, R4means alkyl with 1-3 carbon atoms and C is hydrogen, stands or hydroxyl, is subjected to reaction with a primary amine of the formula III

< / BR>
where R2and are above the ski acceptable acid.

The reaction should be carried out in an inert organic solvent, in particular in a lower alcohol, for example methanol or ethanol, or a cyclic saturated simple ether, in particular tetrahydrofuran or dioxane, or without solvent.

The reaction is carried out usually at a temperature of from 20 to 190oWith, in particular from 60 to 90oWith, and in General it ends in the range from 1 to 10 hours.

Or the compound of formula II

< / BR>
in which R1has the above meaning, R3represents a cyano or ester group, which includes the balance alkalicarbonate acids with 1-3 carbon atoms in the alkyl, R4means alkyl with 1-3 carbon atoms and C is hydrogen, stands or a hydroxyl group is introduced into the reaction with the primary amine of formula IV

< / BR>
where has the abovementioned meaning, in inert solvents, preferably in alcohols, such as ethanol, at temperatures between 60 and 120oWith to obtain a product of the cyclization V (D=IT)

< / BR>
then with the help of halogenation means, as, for example, thionyl chloride or Hydrobromic acid, in an organic solvent such as halogenated hydrocarbon, or without ng). Finally, halide derivative of the formula V (D=Cl, Br) is subjected to reaction with the amine of General formula VI

< / BR>
where X, Y, Z, and R2have the above values, and get the final product according to the invention of formula I. This reaction is the best place in an inert organic solvent, preferably toluene or xylene, in the presence of a base, such as potassium carbonate or potassium hydroxide, at temperatures between 60 and 150oC.

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

Free 3-substituted derivatives of pyrido[4',3':4,5]thieno[2,3-d]pyrimidine of the formula I can generally when adding the solution with the stoichiometric amount of the appropriate acid to form a salt. Pharmaceutically acceptable acids are, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonate, monoamide sulfuric acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.

The invention relates thus also to a therapeutic salt with acid as biologically active substances, together with conventional carriers or diluents, as well as the application of new compounds to combat disease.

Compounds according to the invention can be administered by conventional means orally or parenterally, intravenously or intramuscularly.

The dosage depends on age, condition or weight of the patient, and the method of application. As a rule, the daily dose of active substance is between about 1 and 100 mg/kg body weight for oral use and is between 0.1 and 10 mg/kg body weight at parenteral administration.

New connections can be used in the form of used solid or liquid galenic forms, such as tablets, pills in plastic wrap, capsules, powder, granules, pills, suppositories, solutions, ointments, creams or sprays. Get them in a common manner. Biologically active substances can be processed by conventional galenovye AIDS, such as binders in the preparation of tablets, fillers, preservatives, means to prevent the breakage of tablets, means regulating the fluidity, plasticizers, wetting, dispersing agents, emulsifiers, solvents, AIDS in slowing the release of the active substance, an antioxidant and/or army for applications usually contain a biologically active substance in an amount of from 1 to 99 wt.%.

Required as starting materials for the synthesis of new compounds substances of the formulae II and III are known or they are synthesized according to the literature methods from a similar source materials (F. Sauter and P. Stanetty, Monatsh. Chem. (1975), 106(5), 1111-1116; K. Gewald, etc., Chem. Ber. 99, 94-100(1966)).

Compounds according to the invention reveal a high affinity for serotonin receptors 5-HT1B, 5-HT1Dand 5-HT1A. The affinity for these receptors are approximately the same, at least the order of magnitude is the same. In addition, some of the compounds according to the invention are characterized by good inhibition reuse of serotonin, this principle is embodied by a majority of antidepressants.

These compounds are suitable as pharmaceuticals for the treatment of painful conditions in which the concentration of serotonin is reduced and in which, in the framework of targeted therapies for the activity of presynaptic receptors 5-HT1B, 5-HT1A, 5-HT1Dcould be blocked without providing a strong effect on other receptors. This painful condition is, for example, depression.

Compounds represented by the invention can be also useful for the treatment of the e disorders and dysthymia. This includes state of fear, as, for example, generalized fear, panic attacks, social phobia, neurosis obsessive-compulsive disorder and post-traumatic stress symptoms, memory impairment, including dementia, amnesia and age memory loss, and psychogenic disturbances of appetite, such as anorexia nervosa and bulimia nervosa.

Compounds according to the invention can also be useful for the treatment of endocrine diseases, such as hyperprolactinemia, as well as for treatment of spasms of the blood vessels (in particular, the vessels of the brain), hypertension and gastrointestinal disorders accompanied by disturbances of motility and secretion. Another area of application is sexual violation.

The following examples serve as an explanation to the invention.

And getting the starting compounds of formulas II, V, and VI

Used as starting compounds 2-amino-3-carbethoxy-(cyan)-4,5,6,7-tetrahydrothieno[2,3-C] pyridine with being in position 6 of methyl, benzyl, acetyl, bentilee groups or unsubstituted at position 6 is known in the literature (K. Gewald, and others).

a) 2-Ethoxymethyleneamino-3-cyan-6-methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine

Mixed 46,0 g (ned and boiled for 4 hours under reflux in nitrogen atmosphere. Then the mixture was filtered hot on a suction filter and the filtrate was completely evaporated in a rotary evaporator at 80oC. To the residue was added 300 ml of a simple methyl(tert-butyl)new ether and heated to boiling. After suction under vacuum insoluble solids product has led in the bath with ice with stirring, got to 45.4 g (77%) of product. From the mother liquor was given to 1.7 g (3%) of the product as the second fraction. So pl.: 88-89oC.

b) 2-Ethoxymethyleneamino-3-carbethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine

Mixed 40,0 g (167 mmol) of 2-amino-3-carbethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 250 ml of triethylorthoformate with 3.2 ml of acetic anhydride and boiled for 3 hours under reflux in nitrogen atmosphere. Then the mixture was evaporated at 80oWith dryness in a rotary evaporator. Allocated to 48.0 g (97%) of the crude product as a dark oil, the product is pure enough for further reactions.

a) 2-Amino-3-carbethoxy-6-(4-chloro)benzyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine

Mixed with 20.4 g (90,2 mmole) of 2-amino-3-carbethoxy-4,5,6,7-tetrahydrothieno[2,3-C]pyridine in 250 ml of tetrahydrofuran with 25.6 g (204 mmol) of 4-chlorobenzylchloride and 12.4 g (90 mmol) of melapor the second evaporator. The residue was distributed between simple methyl(tert-butyl)new ether and water, podslushivaet sodium hydroxide, the organic phase is washed with water and evaporated. The crude product was dissolved in 100 ml of hot ethyl alcohol and were led under stirring. Allocated to 20.5 g (65%) of the product so pl. 134-135oC.

g) 2-Ethoxymethyleneamino-3-carbethoxy-6-(4-chloro)benzyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine

Mixed 19.3 g (55,0 mmol) 2-amino-3-carbethoxy-6-(p-Chlorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-C]pyridine in 125 ml of triethylorthoformate with 2.0 ml of acetic anhydride and boiled for 1 hour under reflux in a nitrogen atmosphere. Then the mixture was evaporated to dryness at 80oWith in a rotary evaporator. Allocated to 21.9 g (98%) of the crude product as a dark oil, sufficiently pure for use in subsequent reactions.

d) 2-Amino-3-carbethoxy-6-(3-phenyl)propyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine

Mixed 10.0 g (a 44.2 mmole) of 2-amino-3-carbethoxy-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 100 ml of xylene with 9.0 g (45 mmol) of 1-phenyl-3-bromo-propane, 400 mg of potassium iodide and 6.1 g (a 44.2 mmole) melkopomolotogo potassium carbonate and boiled for 6 hours under reflux. After evaporation in a rotary evaporator, the residue was mixed is what phase the crude product was treated with 50 ml of isopropyl alcohol. Bright solid was filtered and then washed with isopropyl alcohol. Received of 7.8 g (51%) of the product so pl. 108-110oC.

Similarly, in) and d) received other substituted at 6-position derivatives of 4,5,6,7-tetrahydrothieno[2,3-C]pyridine, for example:

2-Amino-3-carbethoxy-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine, T. pl. 74-76oWITH

2-Amino-3-carbethoxy-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine

2-Amino-3-carbethoxy-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine, T. pl. 116-118oWITH

2-Amino-3-carbethoxy-6-(4-methyl)benzyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine

2-Amino-3-carbethoxy-6-(4-nitro)benzyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine, T. pl. 170-172oWITH

2-Amino-3-carbethoxy-6-(4-methoxy)benzyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine, T. pl. 154-156oWITH

2-Amino-3-carbethoxy-6-(2-phenyl)ethyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine, T. pl. 80-83oWITH

2-Amino-3-carbethoxy-6-(2-(4-methoxyphenyl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-C]pyridine, T. pl. 76-78oWITH

2-Amino-3-carbethoxy-6-(2-(4-chlorophenyl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-C]pyridine, T. pl. 102-105oWITH

2-Amino-3-carbethoxy-6-(3-(4-chlorophenyl)propyl)-4,5,6,7-tetrahydrothieno[2,3-C]pyridine

2-Amino-3-carbethoxy-6-(4-phenyl)butyl-4,5,6,7-tetrahydrothieno[2,3-C]PY-(2-benzoylamino)ethyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine, so pl. 190-192oWITH

2-Amino-3-carbethoxy-6-(3-benzoylamino)propyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine

e) Ethyl ester of N-(3-carbethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-2-yl)ethanimidothioic

Mixed 3.0 g (12.5 mmole) of 2-amino-3-carbethoxy-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 25 ml of triethylorthoformate with 0.8 ml of acetic anhydride and heated in nitrogen atmosphere under reflux for 2 hours. The mixture is then completely evaporated at 80oWith in a rotary evaporator. Allocated 3.6 g (93%) of product as a dark oil, sufficiently pure for further reactions.

W) 2-Carbamaxepine-3-carbethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine

Mixed 5.0 g (to 18.6 mmole) of 2-amino-3-carbethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 50 ml of toluene and 3.0 g (28 mmol) of the ethyl ether of Harborview acid and 2.6 g (to 18.6 mmole) melkopomolotogo potassium carbonate and boiled for 2 hours under reflux. Then to the reaction mixture were added ice water, the separated toluene phase and the aqueous phase was then extracted with toluene. The combined organic phase after drying was evaporated. Allocated 5.8 g (92%) of product as an oil, which slowly partially crystallisable to 86.4 g (292 mmole) 2-ethoxymethyleneamino-3-carbethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 200 ml of ethyl alcohol from 17.6 ml (292-mmol) of ethanolamine and boiled for 2 hours under reflux. Then the mixture was evaporated in vacuum and the residue was treated with stirring, 30 ml of ethyl acetate. Fallen during the night the precipitate solid was filtered under vacuum and then washed with a small amount of ethyl acetate. After recrystallization from ethanol was allocated to 48.0 g (62%) of the product so pl. 163-165oC.

and) 3,4,5,6,7,8-Hexahydro-3-(2-chloro)ethyl-7-methylpurine[4', 3': 4,5]thieno[2,3-d]pyrimidine-4-one

3,4,5,6,7,8-Hexahydro-3-(2-hydroxy)ethyl-7-methylpurine[4', 3': 4,5]thieno[2,3-d]-pyrimidine-4-one in the amount of 42.0 g (158 mmol) in 240 ml of 1,2-dichloroethane was heated to boiling and then to the reaction mixture was added dropwise to 12.7 ml (175 mmol) of thionyl chloride in 20 ml of 1,2-dichloroethane. After boiling for 2 hours under reflux the reaction mixture was allowed to cool and poured into water with ice. At pH 10 was distributed between methylene chloride and water and the aqueous phase was then extracted with methylene chloride. After drying the combined organic phase was evaporated. Technical product (40 g) was recrystallized from 400 ml of isopropyl alcohol. Allocated 30.5 g (68%) substances with so pl. 159-161oC.

Similarly, h) and I) received:

3,4,5,6,7,8-hexahydro-3-(1-hydroxy)prop-2-yl-7-methylpurine[4', 3':4,5] thieno-[2,3-d]pyrimi the hydro-3-(2-hydroxy)propyl-7-methylpurine[4', 3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 158-160oWITH

3,4,5,6,7,8-hexahydro-3-(2-chloro)propyl-7-methylpurine[4', 3': 4,5] thieno[2,3-d]pyrimidine-4-one.

K) N-(1-Naphthyl)piperazine

To a mixture of 5.4 g (or 24.2 mmole) of palladium acetate and 14.7 g (48.3 mmole) of tri-o-tolylphosphino in 500 ml of xylene was added to 83.2 g (966 mmol) piperazine, 38.0 g (339 mmol) of potassium tert-butylate and 50.0 g (241 mmol) of 1-bromonaphthalene and the reaction mixture is boiled under reflux for 10 hours with good stirring and under nitrogen atmosphere. The mixture is then diluted with methylene chloride, was filtered insoluble residues and the filtrate was evaporated. Technical product was purified by chromatography on a column (silica gel, the solvent is tetrahydrofuran/methanol/ammonia 85/13/2). Got a 21.5 g (42%) of the product so pl. 84-86oC.

l) N-(2-methyl-1-naphthyl)piperazine

Mixed 13,0 g (82,7 mmole) of 1-amino-2-methylnaphthalene in 100 ml of chlorobenzene from 14.7 g (82,7 mmole) of bis(2-chloroethyl)amine Hcl and boiled under reflux for 90 hours in a nitrogen atmosphere. Then the mixture was evaporated, the residue was distributed between methylene chloride and water at pH 9 and after drying the organic phase was evaporated. Technical product was purified by chromatography on a column (silica gel, the solvent tetr is stirred 4,51 g (21,7 mmole) of 4-bromoisoquinoline, the 4.65 g (25.0 mmol) of tert-butyl methyl ether piperazine-N-carboxylic acid, 0.1 g (of 0.11 mmole) of Tris-(dibenzylideneacetone)-diplodia, 0.11 g (0,18 mmole) of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and of 2.92 g (30,4 mmole) of tert-butyl sodium in 50 ml of toluene and stirred for 2 hours at 75oC. the Reaction mixture was poured into a mixture of ice and sodium chloride, was extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was removed in a rotary evaporator. Vegascasinoonline the product was filtered under vacuum and washed with pentane. Received 5.5 g (81%) piperazine with tert-butoxycarbonyl protecting group (so pl. 111oC). To 5.2 g (of 16.6 mmole) this substance was added 17 ml of dichloromethane and, at 0oWith slowly treated with 17 ml of dichloromethane and, at 0oWith slowly mixed with 17 ml (0.22 mmole) triperoxonane acid. Was stirred for 4 hours at 0oC, was poured into ice water and was extracted with dichloromethane. The aqueous phase was filtered, podslushivaet and was extracted with dichloromethane. After drying over sodium sulfate and subsequent removal of the solvent was diluted with ethyl ether and precipitated hydrochloride with a solution of hydrogen chloride in ether. Received 3.2 g (67%) of the product so pl. 293-294oC.

B. obtain the final product

Example 1

3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l

Mixed 3.0 g (12,1 mmole) 2-ethoxymethyleneamino-3-cyan-6-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 60 ml of ethyl alcohol from 3.3 g (12,1 mmole) 1-(2-amino-ethyl)-4-(2-methoxyphenyl)piperazine and boiled for 3 hours under reflux. Then the mixture was evaporated in a rotary evaporator and to the residue was added 100 ml of ethyl acetate. Besieged with stirring by adding ethereal solution of hydrogen chloride trihydrochloride, the product was filtered under nitrogen and then washed with ethyl acetate. After drying at 50oWith in a vacuum drying Cabinet allocated 3.6 g (55%) of the product so different. 282-284oC.

Example 2

3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l

Mixed 3.0 g (12,1 mmole) 2-ethoxymethyleneamino-3-carbethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 50 ml of ethanol with 2.4 g (10.2 mmole) of 1-(2-amino-ethyl)-4-(2-methoxyphenyl)piperazine and boiled under reflux for 3 hours. Then the mixture was evaporated in a rotary ispaad/methanol 97/3). The free base was converted into trihydrochloride, as described above, was obtained 3.2 g (48%) of the product so different. 288-290oC.

Example 3

3,4,5,6,7,8-Hexahydro-7-(4-Chlorobenzyl)-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)-ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l

Mixed 3.5 g (8.6 mmole) 2-ethoxymethyleneamino-3-carbethoxy-6-(4-chlorbenzyl)-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 60 ml of ethanol with 2.0 g (8.6 mmole) of 1-(2-amino-ethyl)-4-(2-methoxyphenyl)piperazine and boiled under reflux for 4 hours. Then the mixture was evaporated in a rotary evaporator and the technical product was purified by chromatography on a column (silica gel, the solvent is methylene chloride/methanol 95/5). The free base was converted into trihydrochloride, as described above, was obtained 3.2 g (57%) of the product so different. 290-293oC.

Example 4

3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-methoxyphenyl)piperazine-1-yl)propyl]-pyrido[4,'3':4,5]thieno[2,3-d]pyrimidine-4-3l22O

Mixed 3.5 g (11.8 mmole) of 2-ethoxymethyleneamino-3-carbethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 40 ml of ethyl alcohol with 3.0 g (11.8 mmole) of 1-(3-aminopropyl)-4-(2-methoxyphenyl)piperazine and boiled under reflux for 2 hours. Then the mixture was evaporated in a rotary evaporate the methanol 93/7). The free base was converted into trihydrochloride, as described above, was obtained 3.1 g (44%) of the product so different. 122-124oC.

Example 5

3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-pyridin-2-yl-piperazine-1-yl)propyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-4l2O

Mixed 3.0 g (12,1 mmole) 2-ethoxymethyleneamino-3-cyan-6-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 60 ml of ethanol with 2.65 g (12,1 mmole) of 1-(3-aminopropyl)-4-pyridin-2-yl-piperazine and boiled under reflux for 6 hours. Then the mixture was evaporated in a rotary evaporator and the crude product was extracted with 100 ml of ethyl acetate. Zakristallizuetsya overnight, the solid was converted into trihydrochloride, as described above. Allocated 2.7 g (38%) of the product so different. 261-264oC.

Example 6

3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-dimethylphenyl)piperazine-1-yl)propyl]-pyrido[4',3':4,5]thieno[2,3-d]-pyrimidine-4-3l

Mixed 3.0 g (12,1 mmole) 2-ethoxymethyleneamino-3-cyan-6-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 50 ml of ethanol and 3.2 g (12,1 mmole) of 1-(3-aminopropyl)-4-(2-dimethylphenyl)piperazine and boiled for 4 hours under reflux. Then the mixture was evaporated in a rotary evaporator and the residue was treated with 100 ml of ethyl acetate by heating to Ki and the ethereal solution of hydrogen chloride besieged trihydrochloride, the product was filtered under nitrogen and then washed with ethyl acetate. Technical product (5.1 g) and then recrystallized from methanol. Allocated 3.8 g (54%) of the product so pl. 306-307oC.

Example 7

3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyridin-2-yl-piperazine-1-yl)ethyl] pyrido-[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l22ABOUT

Mixed with 2.2 g (7,8 mmole) 3,4,5,6,7,8-hexahydro-3-(2-chloro)ethyl-7-methyl-pyrido[4', 3': 4,5]thieno[2,3-d]pyrimidine-4-it in 50 ml of xylene with 1.6 g (10.0-mmol) 1-(2-pyridyl)piperazine, 1,4 g (10.0-mmol) melkopomolotogo potassium carbonate, and 400 mg of potassium iodide and boiled under reflux for 24 hours. Then the mixture was evaporated in a rotary evaporator and the residue was distributed between methylene chloride and water at pH 10. The aqueous phase is once again was extracted with methylene chloride and, after drying the combined organic phase was evaporated. Technical product was purified by chromatography on a column (silica gel, the solvent is acetone). Was $ 2.3 g (72%) of product which was dissolved in 100 ml of ethyl acetate and converted into the hydrochloride with a solution of hydrogen chloride in ethyl acetate, so pl. hydrochloride 233-235oC.

Example 8

3,4,5,6,7,8-Hexahydro-7-methyl-3-[1-(4-(1-naphthyl)piperazine-1-yl)p is PR)prop-2-yl-7-methyl-pyrido[4', 3': 4,5] thieno[2,3-d]pyrimidine-4-it in 50 ml of xylene with 2.1 g (10.0-mmol) 1-(1-naphthyl)piperazine, 1,4 g (10.0-mmol) melkopomolotogo potassium carbonate, and 250 mg of potassium iodide and boiled under reflux for 70 hours. Then the mixture was evaporated in a rotary evaporator and the residue was distributed between methylene chloride and water at pH 10. The aqueous phase was extracted again with methylene chloride and, after drying the combined organic phase was evaporated. Technical product was purified by chromatography on a column (silica gel, the solvent is acetone). Allocated 1.6 g (38%) of product which was dissolved in ethyl acetate and was converted with a solution of hydrogen chloride in ethyl acetate hydrochloride with so pl. 242-244oC.

Example 9

3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)propyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l

Mixed 2.9 g (8.9 mmole) 3,4,5,6,7,8-hexahydro-3-(2-chloro)propyl-7-methyl-pyrido[4', 3': 4,5]thieno[2,3-d]pyrimidine-4-she's in 60 ml of xylene with 3.5 g (18.0-mmol) 1-(2-methoxyphenyl)piperazine, 1,4 g (10.0-mmol) melkopomolotogo potassium carbonate, and 400 mg of potassium iodide and boiled under reflux for 100 hours. Then the mixture was evaporated in a rotary evaporator and the residue re after drying the combined organic phase was evaporated. Technical product was purified by chromatography on a column (silica gel, the solvent is acetone). Allocated 1.0 g (25%) of product which was dissolved in 100 ml of ethyl acetate and a solution of hydrogen chloride in ethyl acetate was converted into hydrochloride with so pl. 190-192oC (decomp.).

Example 10

3,4,5,6,7,8-Hexahydro-2,7-dimethyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one

Mixed of 1.9 g (6.2 mmole) of ethyl ester of N-(3-carbethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-2-yl)ethanimidothioic in 30 ml of ethanol with 1.5 g (6.2 mmole) of 1-(2-amino-ethyl)-4-(2-methoxyphenyl)piperazine and boiled under reflux for 7 hours. Then the mixture was evaporated in a rotary evaporator and the residue was treated with 20 ml of ethyl acetate. Per night fell in the form of crystals 2.1 g of a technical product, which was filtered and subjected to purification using chromatography on a column (silica gel, the solvent is methylene chloride/methanol 92/8). Allocated 0.8 g (29%) of product.

Example 11

3,4,5,6,7,8-Hexahydro-2-hydroxy-7-acetyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one

Heated 2.5 g (7.3 mmole) 2-carbamaxepine-3-carbethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine-Swanee melt. After cooling, the technical product was purified by chromatography on a column (silica gel, the solvent is methylene chloride/methanol 95/5). Allocated 0.7 g (20%) of the product so pl. 135-137oC.

Example 12

3,4,5,6,7,8-Hexahydro-7-acetyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3]pyrimidine-4-one

Mixed 5.8 g (23.4 mmole) 2-ethoxymethyleneamino-3-carbethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-C] pyridine in 50 ml of ethanol with 5.5 g (23.4 mmole) 1-(2-amino-ethyl)-4-(2-methoxyphenyl)piperazine and boiled under reflux for 2 hours. Then the mixture was evaporated in a rotary evaporator and to the residue was added 30 ml of ethyl acetate, was heated to boiling and cooled with stirring. Vegascasinoonline solid after cooling in a bath of ice was filtered and then washed with ethyl acetate. Allocated 8.7 g (80%) of the product so pl. 170-172oC.

Example 13

3,4,5,6,7,8-Hexahydro-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one

Was dissolved 4.0 g (8.6 mmole) 3,4,5,6,7,8-hexahydro-7-acetyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl] pyrido[4', 3': 4: 5]thieno[2,3-d]pyrimidine-4-it is in 80 ml of 10% hydrochloric acid and stirred for 2 hours at a temperature in the bath 100oC. Then the mixture in the om. The combined organic phase was dried and evaporated. Allocated 3.7 g of the crude product, which was recrystallized from 50 ml of isopropyl alcohol. Received 2.4 g (66%) of the product so pl. 168-170oC.

Example 14

3,4,5,6,7,8-Hexahydro-7-(2-(1-naphthyl)ethyl)-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l

Was mixed with 1.0 g (2.3 mmole) 3,4,5,6,7,8-hexahydro-3-[2-(4-(2-methoxyphenyl)-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-it in 35 ml of xylene with 0.8 g (3.4 mmole) of 2-bromo-1-naphthas-1-yl-ethane, and with 0.3 g (2.4 mmole) melkopomolotogo potassium carbonate and boiled under reflux for 12 hours. Then the mixture was evaporated in a rotary evaporator and the residue was distributed at pH 10 between methylene chloride and water. The aqueous phase then was extracted with methylene chloride. The combined organic phase after drying was evaporated. Received 2.7 g of a technical product as a dark oil, which was purified by chromatography on a column (silica gel, the solvent is methylene chloride/acetone 7/3). After conversion into the hydrochloride in ethyl acetate was isolated by 1.0 g (63%) of the product so pl. 293-295oC (decomp.).

Analogously to examples 1-14 received: (examples 15-124)

15. 3,4,5,6,7,8-Hexahydro-7-M16. 3,4,5,6,7,8-Hexahydro-7-benzyl-3-[3-(4-(2-methoxyphenyl)piperazine-1-yl)-propyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-2l, so pl. 258-261oC (decomp.)

17. 3,4,5,6,7,8-Hexahydro-7-benzyl-3-[2-(4-phenylpiperazin-1-yl)ethyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-Imin, so pl. 168-170oWITH

18. 3,4,5,6,7,8-Hexahydro-7-benzyl-3-[3-(4-(2-methoxyphenyl)piperazine-1-yl)propyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 66-67oWITH

19. 3,4,5,6,7,8-Hexahydro-7-benzyl-3-[2-(4-phenylpiperazin-1-yl)ethyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 70-71oC

20. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(pyrimidine-2-yl-piperazine-1-yl)ethyl] -pyrido[4', 3': 4,5] thieno[2,3-d]pyrimidine-4-Imin tricentric, so pl. 112-114oC (decomp.)

21. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(3-methoxyphenyl)piperazine-1-yl)-propyl] pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l22O, so pl. 268-270oC (decomp.)

22. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-naphthas-1-yl-piperazine-1-yl)propyl] -pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-3l, so pl. 250-253oC (decomp.)

23. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-nitrophenyl)piperazine-1-yl)propyl] pyrido[4', 3': 4,5] thieno[2,3-d]pyrimidine-4-3HCl2H2O, so pl. 271-273oC (decomp.)

24. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-were)piperazine-1-yl)propyl] -pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-Imin is 3': 4,5] thieno[2,3-d] pyrimidine-4-HCl4H2O, so pl. 113-115oC(decomp.)

26. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-chlorophenyl)piperazine-1-yl)propyl] -pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-3l, so pl. 261-263oC (decomp.)

27. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyrimidin-2-yl-piperazine-1-yl)ethyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 146-148oWITH

28. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-benzylpiperidine-1-yl)propyl] pyrido-[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l, so pl. 295-297oC (decomp.)

29. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-hydroxyphenyl)piperazine-1-yl)-propyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-Imin, so pl. 164-166oWITH

30. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-(2-methoxyphenyl)piperazine-1-yl)-butyl] pyrido[4', 3': 4,5]thieno[2,3-d]pyrimidine-4-HCl32O, so pl. 272-274oC (decomp.)

31. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-ethoxyphenyl)piperazine-1-yl)-propyl] pyrido[4', 3': 4,5]thieno[2,3-d]pyrimidine-4-3l32O, so pl. 284-286oC (decomp.)

32. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-ethylphenyl)piperazine-1-yl)propyl] -pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-3l, so pl. 303-305oC (decomp.)

33. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-tianfeng)piperazine-1-yl)propyl] -pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-2l2O, so pl. 136-138oC (decomp.)

34. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-phenylpiperidine the Tyl-3-[3-(4-pyrazin-2-yl-piperazine-1-yl)propyl] -pyrido[4', 3': 4,5]thieno[2,3-d]pyrimido n-4-4l2O, so pl. 284-286oC (decomp.)

36. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(pyrimidine-2-yl-piperazine-1-yl)-propyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-Imin, so pl. 161-163oWITH

37. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-tianfeng)piperazine-1-yl)propyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-Imin, so pl. 148-150oWITH

38. 3,4,5,6,7,8-Hexahydro-7-benzyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)-ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-3lH2O, so pl. 288-290oC (decomp.)

39. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(3,4-methylenedioxyphenyl)piperazine-1-yl)propyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-3HCl, so pl. 288-290oC (decomp.)

40. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-were)piperazine-1-yl)ethyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-2HCl2O, so pl.>300oWITH

41. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-chlorophenyl)piperazine-1-yl)ethyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-2HCl2Oh, so pl.>300oWITH

42. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3,4-dimetilfenil)piperazine-1-yl)-ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-2HCl, so pl. 307-310oWITH

43. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2,6-dimetilfenil)piperazine-1-yl)-ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-2HCl, so pl. 297-300oWITH

44. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2,3-�Idro-7-methyl-3-[2-(4-(2,4-dimetilfenil)piperazine-1-yl)-ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-2HCl, so pl. 300-303oWITH

46. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3,5-dichlorophenyl)piperazine-1-yl)ethyl]-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 97-100oWITH

47. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2,4-acid)piperazine-1-yl)-ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-2l, so pl. 287-290oWITH

48. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-triptoreline)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-2l, so pl. 309 to 312oWITH

49. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-naphthas-1-yl-piperazine-1-yl)ethyl] pyrido-[4', 3':4,5]thieno[2,3-d]pyrimidine-4-2lH2O, so pl. 298-300oC (decomp.)

50. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(3-hydroxyphenyl)piperazine-1-yl)-propyl] pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-2l2H2Oh, so pl. 182-184oC (decomp.)

51. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxy-5-chlorophenyl)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l, so pl. 170-172oC (decomp.)

52. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2,5-acid)piperazine-1-yl)-ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-3lH2O, so pl. 176-178oC (decomp.)

53. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxy-5-phenyl-phenyl)piperazine-1-yl)ethyl] pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-UN2Oh, so pl. 79-80oWITH

54. 3,4,5,6,7,8-Hexage.sq. 182-185o(decomp.)

55. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-hydroxyphenyl)piperazine-1-yl)ethyl] pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-2l2O, so pl. 281-283oC (decomp.)

56. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(7-metaxilat-1-yl)piperazine-1-yl)-ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-2l2Oh, so pl. 272-274oC (decomp.)

57. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-naphthas-1-yl-piperazine-1-yl)ethyl]pyrido-[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l, so pl. 288-289oC (decomp.)

58. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(4,5-methylenedioxybenzyl)piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-4l2H2O, so pl. 249-251oC (decomp.)

59. 3,4,5,6,7,8-hexahydro-7-methyl-3-[2-(4-(6-isopropylpyrimidine-4-yl)-piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-3HCl22O, so pl. 250-253oC (decomp.)

60. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-metaxilat-1-yl)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-2l22O, so pl. 241 to 243oC (decomp.)

61. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxyphenyl)piperidine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-2l22Oh, so pl. 299-301o(decomp.)

62. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3,4-acid)-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 153-154oWITH

2O, so pl. 206-208oC (decomp.)

64. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(pyrimidine-2-yl-piperazine-1-yl)propyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 161-163oWITH

65. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(quinoline-2-yl-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 143-145oWITH

66. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-metalnet-1-yl)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-2l2H2O, so pl. 295-297oC (decomp.)

67. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxy-3,5-dichlorophenyl)-piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-2l2O, so square 264-267oC (decomp.)

68. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-tianfeng)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 162-164oWITH

69. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-chlorophenyl)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 165-167oWITH

70. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyridin-2-yl-piperazine-1-yl)-ethyl] pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3HCl22O, so pl. 232-234oC (decomp.)

71. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl] pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l22O, so pl. 270-272oC (decomp.)

72. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(5-methoxypyridine-4-yl)-piperazine-1-yl)ethyl] the feast of the CFT-2-yl-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 140-141oWITH

74. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyrazin-2-yl-piperazine-1-yl)ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-3HCl3H2O, so pl. 170-172oC(decomp.)

75. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-tetralin-5-yl-piperazine-1-yl)ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-3HCl2H2O, so pl. 285-287oC (decomp.)

76. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-indan-1-yl-piperazine-1-yl)-ethyl] pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3HCl22O, so pl. 300-301oC (decomp.)

77. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxy-4-nitro-5-methyl-phenyl)piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-2HCl22O, so pl. 210-212oC (decomp.)

78. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-isoquinoline-4-yl-piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-3l3H2O, so pl. 290-292oC (decomp.)

79. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxy-4-chloro-5-methyl-phenyl)piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-2l22Oh, so pl. 293-294oC (decomp.)

80. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2,4-acid)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l32O, so pl. 290-291oC (decomp.)

81. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-hinzelin-4-yl-piperazine-1-yl)-ethyl] pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l42O, so pl. 258-260the network[2,3-d]pyrimidine-4-2l3H2O, so pl. 311-312oC (decomp.)

83. 3,4,5,6,7,8-Hexahydro-7-(4-chloro)benzyl-3-[2-(4-(2-methoxyphenyl)-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l2O, so pl. 290-292oC (decomp.)

84. 3,4,5,6,7,8-Hexahydro-7-ethyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl] pyrido[4', 3': 4,5]thieno[2,3-d]pyrimidine-4-3HClH2O, so pl. 295-297oC (decomp.)

85. 3,4,5,6,7,8-Hexahydro-7-isopropyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l2O, so pl. 300-302oC (decomp.)

86. 3,4,5,6,7,8-Hexahydro-7-(4-nitro)benzyl-3-[2-(4-(2-methoxyphenyl)-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l2Oh, so pl. 214-217oC(decomp.)

87. 3,4,5,6,7,8-Hexahydro-7-(4-methoxy)benzyl-3-[2-(4-(2-methoxyphenyl)-piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-3lH2O, so pl. 278-281oC (decomp.)

88. 3,4,5,6,7,8-Hexahydro-7-(2-phenyl)ethyl-3-[2-(4-(2-methoxyphenyl)-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l2O, so pl. 305 - 306oC (decomp.)

89. 3,4,5,6,7,8-Hexahydro-7-(3-benzoyl)propyl-3-[2-(4-(2-methoxyphenyl)-piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-3l2O, so pl. 124-126oC (decomp.)

90. 3,4,5,6,7,8-Hexahydro-7-(4-amino)benzyl-3-[2-(4-(2-methoxyphenyl)-piperazine-1-yl)ethyl]pyrido[4',3':4-(2-methoxyphenyl)-piperazine-1-yl)ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-2l32Oh, so pl. 301-302oC (decomp.)

92. 3,4,5,6,7,8-Hexahydro-7-(3-phenyl)propyl-3-[2-(4-naphthas-1-yl-piperazine-1-yl)ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-2l2H2O, so pl. 306-307oC (decomp.)

93. 3,4,5,6,7,8-Hexahydro-7-(2-(4-methoxyphenyl)ethyl)-3-[2-(4-the naphthas-1-yl-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-2l32O, so pl. 306-308oC (decomp.)

94. 3,4,5,6,7,8-Hexahydro-7-(2-(4-chlorophenyl)ethyl)-3-[2-(4-the naphthas-1-yl-piperazine-1-yl)ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-2l32O, so pl. 300-303oC (decomp.)

95. 3,4,5,6,7,8-Hexahydro-7-(2-phenyl)ethyl-3-[2-(4-naphthas-1-yl-piperazine-1-yl)ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-2l32Oh, so pl. 295-298oWITH

96. 3,4,5,6,7,8-Hexahydro-7-(2-(4-hydroxyphenyl)ethyl)-3-[2-(4-the naphthas-1-yl-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-2l22O, so pl. 254-256oWITH

97. 3,4,5,6,7,8-Hexahydro-7-(2-(4-chlorophenyl)ethyl)-3-[2-(4-(2-methoxy-phenyl)piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-3HCl22O, so pl. 304-306oC (decomp.)

98. 3,4,5,6,7,8-Hexahydro-7-(2-naphthas-1-yl)ethyl-3-[2-(4-(2-methoxyphenyl)-piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-2HCl22O, so pl. 293-295oC (decomp.)

99. 3,4,5,6,7,8-Hexahydro-7-(2-benzoylamino)ethyl-3-[2-(4-naphthas-1-yl-papagika-7-(2-benzoylamino)ethyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-2HCl3H2O, so pl. 202-204oC (decomp.)

101. 3,4,5,6,7,8-Hexahydro-7-(3-benzoylamino)propyl-3-[2-(4-(2-methoxy-phenyl)piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-3l22O, so pl. 182-183oC(decomp.)

102. 3,4,5,6,7,8-Hexahydro-7-(3-benzoylamino)propyl-3-[2-(4-naphthas-1-yl-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3HCl2O, so pl. 128-130oC (decomp.)

103. 3,4,5,6,7,8-Hexahydro-7-(4-phenyl)butyl-3-[2-(4-(2-methoxyphenyl)-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3l2Oh, so pl. 311-312oC (decomp.)

104. 3,4,5,6,7,8-Hexahydro-7-(4-phenyl)butyl-3-[2-(4-naphthas-1-yl-piperazine-1-yl)ethyl] pyrido[4', 3': 4,5]thieno[2,3-d]pyrimidine-4-3l2O, so pl. 312-314oC (decomp.)

105. 3,4,5,6,7,8-Hexahydro-7-(4-methoxy)benzyl-3-[2-(4-naphthas-1-yl-piperazine-1-yl)ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-3HClH2O, so pl. 275-277oC (decomp.)

106. 3,4,5,6,7,8-Hexahydro-7-(2-(4-methoxyphenyl)ethyl)-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl] pyrido[4', 3': 4,5]thieno[2,3-d]pyrimidine-4-3HCl3H2O, so pl. 297-298oC (decomp.)

107. 3,4,5,6,7,8-Hexahydro-7-(2-phenyl)ethyl-3-[3-(4-naphthas-1-yl-piperazine-1-yl)propyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 153-154oWITH

108. 3,4,5,6,7,8-Hexahydro-7-(2-phenyl)ethyl-3-[2-(4-(pyrimidine-2-yl-piperaz the ro-7-(2-phenyl)ethyl-3-[3-(4-(pyrimidine-2-yl-piperazine-1-yl)propyl] pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-3HCl2 H2O, so pl. 302-303oC (decomp.)

110. 3,4,5,6,7,8-Hexahydro-7-(3-benzoylamino)propyl-3-[2-(4-(pyrimidine-2-yl-piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-3HCl32Oh, so pl. 125-127oC(decomp.)

111. 3,4,5,6,7,8-Hexahydro-7-(4-phenyl)butyl-3-[2-(4-(pyrimidine-2-yl-piperazine-1-yl)ethyl] pyrido[4', 3':4.5]thieno[2,3-d]pyrimidine-4-3HCl32O, so pl. 317-319oC (decomp.)

112. 3,4,5,6,7,8-Hexahydro-7-(2-(4-methoxyphenyl)ethyl)-3-[2-(4-pyrimidine-2-yl-piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 165-167oWITH

113. 3,4,5,6,7,8-Hexahydro-7-acetyl-3-[3-(4-(2-methoxyphenyl)piperazine-1-yl)propyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-2HCl, so pl. 265-268oWITH

114. 3,4,5,6,7,8-Hexahydro-7-acetyl-3-[3-(4-(2-methoxyphenyl)piperazine-1-yl)propyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-2HCl22O, so square 264-267oWITH

115. 3,4,5,6,7,8-Hexahydro-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl] -pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 168-170oWITH

116. 3,4,5,6,7,8-Hexahydro-7-acetyl-3-[2-(4 -(2-methoxyphenyl)piperazine-1-yl)ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 170-172oWITH

117. 3,4,5,6,7,8-Hexahydro-7-benzoyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-2HCl22O, so pl. 185-187oC(decomp.)

118. 3,4,5,6,7,8-Hexahydro-7-b-Hexahydro-7-benzoyl-3-[2-(4-(pyrimidine-2-yl-piperazine-1-yl)ethyl] pyrido[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-one, so pl. 130-132oC(decomp.)

120. 3,4,5,6,7,8-Hexahydro-2,7-dimethyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl] pyrido[4', 3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 176-178oWITH

121. 3,4,5,6,7,8-Hexahydro-7-acetyl-2-hydroxy-3-[2-(4-(2-methoxy-phenyl)piperazine-1-yl)ethyl] pyrido[4', 3':4,5)thieno[2,3-d]pyrimidine-4-one, so pl. 135-137oWITH

122. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[1-(4-(2-methoxyphenyl)piperazine-1-yl)prop-2-yl]pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-4-one, so pl. 184-186oWITH

123. 3,4,5,6,7,8-Hexahydro-[1-(4-naphthas-1-yl-piperazine-1-yl)prop-2-yl] pyrido-[4', 3': 4,5] thieno[2,3-d] pyrimidine-4-2l42O, so pl. 242-244oC (decomp.)

124. 3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxyphenyl)piperazine-1-yl)propyl] pyrido[4', 3': 4,5] thieno[2,3-d]pyrimidine-4-3HCl3H2O, so pl. 190-192oC(decomp.)

In the Measurement of the receptor binding

Receiving bearing receptors of cell membranes

Studies on binding to receptors was performed with membrane preparations, which were isolated from cell lines of human embryo kidney 293 (SOME 293), in which in each case the cloned specific subtype of serotonin receptor (h5HT1A, h5HT1B or h5HT1D) and constantly expressed.

Cultivation of the cells was carried out in medium RPMI 1640 (life Technoezine G 418. Cells were incubated in the closet for incubation in an atmosphere of air/5% carbon dioxide at 37oTo achieve a continuous single-layer cellular layer (monolayer) in cuvettes laid so-called "stack". Then the cells of vessels for culturing dissolved by applying a buffer of the following composition: (l) trypsin 10 mg, ethylenediaminetetraacetic acid 4 mg, ethylenebis(oxyethylenenitrilo)-tetraoxane acid 200 mg, potassium chloride 200 mg monopotassium phosphate potassium 200 mg, secondary acid phosphate potassium 1,15 g, sodium chloride 8.0 g, pH 7.4. Cell suspension was besieged in phosphate buffered saline solution Dulbecco (SFR), resuspendable and have established a cell density of about 108cells/ml After the second deposition SFR was replaced by the same volume of ice buffer for lysis (Tris /trihydroxystilbene/5 mmol/ l, 10% glycerol, pH 7.4) and incubated for 30 minutes at 4oC. Lysed cells (="membrane") is divided into an integer number of samples and kept in liquid nitrogen until use in studies on receptor binding. Used one aliquot of the preparation for the determination of protein content.

Compounds according to the invention upon discovering erogeny in cloned cell lines.

The analysis of binding with receptors

Studies of binding to receptors was performed in tubes Macrocell capacity of 1 ml, which contained the following components:

50 ál of the analyte at different concentrations to measure competition or 50 μl of buffer for analysis, or 50 µl of its serotonin (1 µmol/l final volume) to determine full or nonspecific binding

to 200 μl of membrane suspension of the corresponding subtype of the receptor protein of 200 μg/tube

to 250 μl of a solution of radioactive ligand ([3N]-5-carboxamidotryptamine) for h5HT1B and h51D receptors or [3H]-8-hydroxydiphenylamine for h5HT1A receptors. Final concentration of radioactive ligand brought up to 3 nmole/l or 0.3 nmole/L.

Buffer for analysis (pH 7.4) had the following composition (per liter): Tris 6,057 g, dihydrate calcium chloride 5,88 g, ascorbic acid 1 g, pargyline 1,96 mg.

Analyzed the mixture incubated for 30 minutes at 25oC and then filtered through a filter made of glass fiber (Whatman GF/B) using collecting cell unit (firm Skadron) and the filter was washed 5 to 9 ml of cold buffer. Filters were United in scintillation the measured radioactivity in the counter-particles (firm Wallac). These measurements were estimated using iterative nonlinear regression analysis using the Statistical analysis system", which is similar to that described by Munson and Rodbard (Anal. Biochem.: 107, 220 (1980)) "Ligand". The competitive binding constants (Ki) resulted in nolah/L.

The results of the above experiences are summarized in the table.

The proposed compounds belong to the category of low-toxic substances.

1. 3-substituted derivatives of 3,4,5,6,7,8-hexahydropyrazino[4',3':4,5]thieno-[2,3-d]-pyrimidine of the formula I

< / BR>
where R1denotes hydrogen, alkyl with 1-4 carbon atoms, acetyl or benzoyloxy group, phenylalkyl residue with 1-4 carbon atoms in the alkyl part, and aromatic fragment can be substituted with halogen, alkyl with 1-4 carbon atoms, trifluoromethyl, hydroxyl group, alkoxygroup with 1-4 carbon atoms, amino group, langroup or nitrogroup, nuptially residue with 1 to 3 carbon atoms in the alkyl part, the rest of phenylalanine with 2-3 carbon atoms in alanovoy part or phenylcarbamoyloxy residue with 2 carbon atoms in the alkyl part, and phenyl group may be substituted with halogen;

R2represents n and, triptoreline, hydroxyl groups, alkoxycarbonyl with 1-4 carbon atoms, amino groups, monomethylamine, dimethylamino-, cyano - or nitro groups phenyl, pyridyloxy, pyrimidinyl or personilnya group, which may be bellrowan with six-membered aromatic nucleus which may have one or two deputies from among halogen, alkyl with 1-4 carbon atoms, hydroxyl group, triptorelin group, alkoxygroup with 1-4 carbon atoms, amino group, langroup or nitro, and optionally may contain one nitrogen atom, or a 5 - or 6-membered ring which may contain 1-2 oxygen atom, or may be substituted phenylalaninol group or vinylalcohol with 1-2 carbon atoms in the alkyl part, and phenyl residue may be substituted with halogen, methyl group, triptorelin group or methoxy group;

And means aminogroup or an oxygen atom;

In the mean hydrogen or methyl;

With means hydrogen, methyl or hydroxyl group;

X is a nitrogen atom;

Y represents CH2CH2-CH2CH2-CH2-CH2or CH2-SN;

Z denotes a nitrogen atom, a carbon atom or CH, n is acceptable salt.

2. Connection on p. 1, wherein R1means methyl, ethyl, isopropyl, benzyl, benzyl substituted specified in paragraph 1 for phenylalkylamine residue groups, phenethyl, phenethyl, substituted specified in paragraph 1 for phenylalkylamine residue groups, R2means o-methoxyphenyl, 1-naphthyl, pyrimidine-2-yl, 2-methoxy-1-naphthyl, 2-methyl-1-naphthyl, And means aminogroup or oxygen atom, X denotes a nitrogen atom, Y represents CH2-CH2CH2-SN, Z denotes a nitrogen atom, a carbon atom or CH and n is the number 2 and 3.

3. The compounds of formula (I) PP.1 and 2 for the preparation of drugs.

4. The compounds of formula (I) under item 3 for the preparation of drugs for the treatment of depression and related diseases.

5. The compounds of formula (I) PP.1 and 2 having the effect of selective antagonists of 5-HT1Band 5-HT1A.

6. The compounds of formula (I) under item 4, with action, inhibiting reuse of serotonin.

 

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< / BR>
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< / BR>
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