MXPA99002081A - 3-substituted pyrido[4',3':4,5]thieno[2,3-d]pyrimidine derivatives, their preparation and their use - Google Patents

Abstract

The invention concerns 3-substituted 3,4,5,6,7,8-hexahydro-pyrido[4,3':4,5]thieno-[2,3-d]pyrimidine derivatives of formula (I) in which:R1 designates a hydrogen atom, a C1-C4 alkyl group, an acetyl or benzoyl group, a phenylalkyl C1-C4 group - the aromatic optionally being substituted by halogen, C1-C4 alkyl, trifluoromethyl, hydroxy, C1-C4 alkoxy, amino, cyano or nitro groups - a naphthylalkyl C1-C3 group, a phenylalkanone C2-C3 group or a phenylcarbamoylalkyl C2 group, wherein the phenyl group can be substituted by halogen;R2 designates a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which can optionally be mono-, di- or tri-substituted by halogen atoms, C1-C4 alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C1-C4 alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups and can optionally be anellated with a benzene nucleus, which can optionally be mono- or di-substituted by halogen atoms, C1-C4 alkyl, hydroxy, trifluoromethyl, C1-C4 alkoxy, amino, cyano or nitro groups and can optionally contain 1 nitrogen atom, or with a 5- or 6-member ring which can contain between 1 and 2 oxygen atoms, or can be substituted by a phenyl-C1-C2 alkyl or alkoxy group, wherein the phenyl group can be substituted by halogen, a methyl, trifluoromethyl or methoxy group;A designates NH or an oxygen atom;B designates hydrogen or methyl;C designates hydrogen, methyl or hydroxy;X designates a nitrogen atom;Y is CH2, CH2-CH2, CH2-CH2-CH2 or CH2-CH;Z designates a nitrogen atom, a carbon atom or CH, wherein the bond between Y and Z can also be a double bond;and n is the number 2, 3 or 4, and their physiologically compatible salts. These compounds are suitable as medicaments for treating diseases in which the serotonin concentration is reduced and in which the activity of the presynaptic receptors 5-HT1B, 5-HT1A, 5HT1D is to be blocked within a therapeutic context without greatly influencing other receptors. Such diseases include, for example, depression.

Description

DERIVATIVES OF PIRIDOÍ 4 ', 3': 4.5) TIEN0 (2. -d \ PYRIMIDINA REPLACED IN 3. ITS PREPARATION AND USE The invention relates to novel derivatives of pyrids (4".3 '.4, 5) ieno (2 , 3-d) iridi idine substituted in 3, and the preparation and use thereof for the production of pharmaceutically active substances Classical antidepressants and novel selective serotonin reuptake inhibitors (SSRIs) present their antidepressant effect, inter alia, By inhibiting the active reabsorption of the transmitter at the terminals of the presynaptic nerve, unfortunately, in these cases, the antidepressant effect starts only after a treatment of at least 3 weeks and, in addition, approximately 30% of the patients resist The blocking of pre-synaptic serotonin receptors increases, through the abolition of negative coupling, the release of serotonin and consequently the concentration of transmitter present e in the synaptic cleft. This increase in transmitter concentration is considered as the beginning of the antidepressant effect. This mechanism of action differs from the mechanism of action of previously known antidepressants that activate both presynaptic sperm-cell autoimceptors and, consequently, cause a delayed onset of action only after the dessibilization of these autoreceptors. Direct blocking of autoreceptors avoids this effect. In accordance with current knowledge, the presynaptic serotonin autoreceptor is of the 5-HT1B subtype (Fink et al., Arch. Pharmacol 352 (1995), 451). Selective blockade of it by 5-HT1B / D antagonists increases the release of serotonin in the brain: 6.W. Price et al-, Behavioral Brain Reserch (investigation of cerebral behavior) 73 (1996), 79-82; P.H. Hutson et al., Neuropharmacology (neurofarmacolaqia) 34 (1995), 383-392.

However, the 5-HT 1B antagonist GR 127 935 surprisingly reduces the release of seratonin in the cortex after systemic administration. One explanation may be the stimulation of the 5-HT1A or atodendritic receptors in the raphe region by the serotinipa released, which inhibits the rate of discharge of serotonergic neurons and consequently the release of serotonin (M. Skingle et al., Neuropharmacology ( neurafarmacología) 34 (1995), 377-382 and 393-402). One strategy to avoid the effects of self-inhibition in the serotonergic areas of origin is the blockade of presynaptic 5-HT1B receptors. This theory is supported by the observation that the effect of parsxetine on the release of seronin in the rat dorsal raphe nucleus is enhanced by the 5-HT1B receptor antagonist, GR 127 935 (Davidson v Stamford, Neuroscience Letts., 188 (1995), 41). The second strategy includes the blocking of both types of autarecpetsres, that is, the 5HT1A receptors, in order to enhance the neuronal discharge, and the 5-HT1B receptors, in order to increase the release of terminal serotonin (Starkey and Skingle, Neuropharmacology 33 (3-4) (1994), 393). 5-HT1B / D antagonists alone or coupled with a 5-HT1A receptor antagonist component must therefore increase the increase of serotonin release in the brain and may therefore have advantages for the treatment of depression and psychological disorders related It has now been found that 3,4,5,6,7,8-hexahydropyrido derivatives (4 ', 3': 4,5) tiepo (2,3-d) pyrimidine substituted in 3 of the formula I where R 1 is hydrogen, (C 1 -C 4) alkyl, acetyl or benzoyl, a phenol radical (C 1 -C 4), the aromatic ring is unsubstituted or substituted by halogen, alkyl (Cl-C 4) , trifluramethyl, hydroxyl, (C 1 -C 4) alkoxy, amino, cyano or nitro groups, or is a naphthyl radical (C 1 -C 3) alkyl, a phenylalkanone radical (C 2 -C 3) or a phenylcarbamalalkyl radical C 2, it being possible for the phenyl to be substituted by halogen, R 2 is phenyl, pyridyl, pyrimidipyl or pyrazinyl, each of which is unsubstituted either mono-, di- or trisubstituted by halogen atoms, (C 1 -C 4) alkyl ), trofluoromethyl, trifluoromethoxy, hydroxyl, (C 1 -C 4) alkoxy, amine, mannomethyl, dimethylamino, cyano or nitro groups, each of which may be fused with a benzene nucleus which may be unsubstituted or monosubstituted or well disubstituted by halogen atoms, (C 1 -C 4) alkyl, idraxyl, trifluoromethyl, (C 1 -C 4) alkoxy, amino, cyano or nitro groups, and may contain a nitrogen atom or with a five or six membered ring which may contain 1-2 oxygen atoms or may be substituted by a phenyl (Cl-C2) -alkyl or -alkoxy group, it being possible for the phenyl to be substituted by halogen, a methyl, trifluoromethyl or methoxy group. A is NH or an oxygen atom, B is hydrogen or methyl, C is hydrogen, methyl or hydroxyl, X is a nitrogen atom, Y is CH2. CH2-CH2, CH2-CH2-CH2 or CH2-CH, Z is a nitrogen atom, carbon atom or CH, it being also possible that the bond between Y and Z is a double bond, and "n" is 2 , 3 or 4, and the salts thereof with physiologically tolerated acids, have valuable pharmacological properties. Especially preferred compounds are the compounds in which R 1 is methyl, ethyl, isopropyl, benzyl, substituted benzyl, phenethyl, substituted phenethyl, R 2 is o-methoxyphenol, 1-naphthyl, pyrimidip-2-yl, 2-methoxy-1 -naphthyl, 2-methyl-1-naphthyl. A is NH or an oxygen atom. ) (is a nitrogen atom, Y is CH2-CH2, CH2-CH, Z is a nitrogen atom, a carbon atom or CH, and "n" is 2 and 3. Compounds of formula I in accordance with The present invention can be prepared by the reaction of a compound of the formula II Where R 1 has the above-mentioned meaning, R 3 is cyano or an ester group of (C 1 -C 3) alkyl carboxylic acid. R4 is (C1-C3) alkyl and C is hydrogen, methyl or hydroxyl, with a primary amine of formula III B (CH), X Z R2 III, B2N \ / where R2 and B have the meanings mentioned above, and copying the resulting compound, if appropriate, into the addition salt with a physiologically tolerated acid. The reaction is conveniently carried out in an inert organic solvent, particularly in a lower alcohol, for example, methanol or ethanol, or a saturated cyclic ether, particularly tetrahydrofuran or dioxane, or without a solvent. Generally speaking, the reaction is carried out at a temperature of 20 to 190 ° C, particularly 60 to 90 ° C, and it generally ends within 1 to 10 hours or a compound of the formula II c where R1 has the above-mentioned meaning, R3 is cyano or a (C1-C3) carboxylic alkyl ester group, R4 is (C1-C3) alkyl, and C is hydrogen, methyl or hydroxyl, reacts with a primary amine of formula IV B I < CH) n- OH IV, H2N where B has the above-mentioned meaning, in an inert solvent, preferably alcohols such as, for example, ethanol, at a temperature comprised between 60 and 120 ° C to provide the product V for cyclization (D = OH) subsequently converted into a halogenating agent such as, for example, thionyl chloride or hydrobromic acid, in an organic solvent such as, for example, a halohydrocarbon or without a solvent at a temperature within the temperature range from room temperature to 100"C in the corresponding halo derivative V (D = Cl, Br)." Finally, the halo derivative of the formula V (D = Cl, Br) reacts with an amine of the formula VI HX Z R2 vi. \ / Y where X, Y. Z and R2 have the meanings mentioned above, to provide the final product of formula I according to the invention. This reaction is best carried out in an inert organic solvent, preferably toluene or oxy fuel, in the presence of a base such as, for example, potassium carbonate or potassium hydroxide, at a temperature between 60 and 150 ° C. of the formula I according to the present invention can either be recrystallized by recrystallization from conventional organic solvents, preferably from a lower alcohol such as, for example, ethanol, or purified by means of column chromatography. of free substituted pyrido (4 ', 3': 4,5) thieno (2,3-d) pyrimidine of the formula I can (lagoon) in conventional manner in acid addition salts of a solution containing the amount stoichiometric of the appropriate acid Examples of pharmaceutically suitable acids are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, sulphamic acid, maleic acid, fumaric acid. oxalic acid, tartaric acid or citric acid. The invention thus also relates to a therapeutic composition having a content of a compound in formula I or a pharmacologically suitable acid addition salt of the same active substance in addition to conventional excipients and diluents, and to the use of the compounds novelties to control diseases. The compounds according to the present invention can be administered conventionally orally or parenterally, intravenously or intramuscularly. The dosage depends on the age, condition and weight of the patient and the administration period. In general terms, the active daily dose is approximately 1-100 mg / kg of body weight in the case of oral administration and 0.1-10 mg / kg of body weight in the house of parenteral administration. The novel compounds can be used in conventional solid or liquid dosage forms, for example in the form of uncoated or coated tablets (by films), capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These dosage forms are produced in a conventional manner. The active substances can be processed, for this purpose, with conventional pharmaceutical auxiliaries, such as, for example, tablet binders, conservative volume agents, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, lubricating agents. prolonged release, anti-oxidants and / or booster gases (see H. Sucker et al .: Pharmazeutische Technologie, Thieme-Verlag, Stuttgar, 1878). The administration forms obtained from this drug normally contain from 1 to 99% by weight of active substance The substances of the formulas II and III required with initial materials for synthesizing the novel compounds are known or can be synthesized by methods of administration. preparation described in the literature from appropriate initial materials (F. Sa? ter and P. Stanetty, onatsh.Chem. 106 (5) (1975), 1111-1116; K. Gewald et al., Chem. Ber. 99 (1966), 94-100). The compounds according to the present invention have a high affinity for the serotonin 5-HT1B, 5-HT1D and 5-HT1A receptors. The affinity is approximately the same, at least of the same order of magnitude, for each of these receptors. In addition, some of the compounds according to the present invention show good inhibition of serotonin reuptake, a principle implemented in most antidepressants. These compounds are suitable as drugs for the treatment of pathological conditions in which the concentration of serotanine is reduced and in which it is desired for the purposes of treatment to specifically block the activity of presynaptic 5-HT1B, 5-HT1A and 5-HT1D receptors. without having a great effect on atros receivers. An example of a pathological state of this type is depression. The compounds of the present invention may also be useful for the treatment of central nervous mood disorders such as, for example, seasonal affective disorders and dysthymia. These also include states of anxiety as, for example, generalized anxiety, panic attacks, sociaphobia, obsessive-compulsive neuroses as well as symptoms of pastraumatic stress, memory disorders including dementia, amnesia and related memory loss, with age. as well as psychogenic disorders of food intake such as, for example, anorexia nervosa and bulimia nervosa. The compounds according to the present invention can additionally be used for the treatment of endocrine disorders such as, for example, hyperprolactimenia and for the treatment of vasospasm (specifically of brain vessels), hypertension and gastrointestinal disorders associated with disorders of the secretories and of the Motivation Another area of use includes sexual disorders. The following examples serve to illustrate the invention: A preparation of the starting materials of the formula II, V and VI The 2-amino-3-carboethoxy (cyano) -4,5,6,7-tetrahydratiena (2,3-c) ) -pyridine can methyl, benzyl, actila or benzoyl in position 6 to either a 6 unsubstituted position, which are used as initial materials are presented in the literature (K. Sewald et al.). a) 2-Ethoxymethylene-amino-3-cyano-6-methyl- .5,6,7, -t-trahydrothieno (2, 3-c) iri ina. 46.0 g (238 nM (sic)) of 2-amine-3-cyano-6-methyl-4,5,6,6-tetrahydratiene (2,3-c) iridin were mixed in 250 ml of triethyl artoformate with 3.5 ml of acetic anhydride and refluxed under nitrogen for 4 hours. The mixture was then filtered under suction, and the filtrate was completely evaporated in a rotary evaporator at a temperature of 80 ° C: The residue was taken up in 300 ml of methyl t-butyl ether and heated up to the boiling point. After removal of the insoluble solids by suction filtration, 45.4 g (777.) of the product was crystallized under stirring in an ice bath. 1.7 g (3i) of product was obtained as the second fraction of the mother liquor. Melting point: 88-89 ° C. b) 2-Ethoxymethi leneamipo-3-carbaethoxy-6-methyl-4, 5,6,7-t t ahi ratiena (2,3-c) iridina. 40.0 q (167 nM (sic)) of 2-amino-3-carboethoxy-6-methyl-4,5,6,7-tetrahydratiene (2, 3-c) pyridine in 250 ml of triethyl orthoformate can be mixed 3.2 ml of acetic anhydride and refluxed under nitrogen for 3 hours. The mixture was then completely evaporated in a rotary evaporator at a temperature of 80 ° C. 48.0 g (977.) of crude product was isolated in the form of a dark oil sufficiently pure for the next reaction. c 2-Amino-3-carboethoxy-6- (4-chloro) benzyl 1-4,5,6,6-tetrahydrothien (2, 3-c) iridine (sic) 20.4 g (90.2 M (sic)) were mixed of 2-amine-3-carboethoxy-, 5,6,7-tetrahydratiena (2, 3-c) iridine in 250 ml of tetrahydrofuran with 25.6 g (204 mM (sic)) of 4-chlorobenzyl chloride and 12.4 g ( 90 M (sic)) of fine powdered potassium carbonate and refluxed for 3 hours. The mixture was completely evaporated in a rotary evaporator. The residue was divided between methyl t-butyl ether and water, and, after rendering it alkaline with a sodium hydroxide solution, the organic phase was washed with water and concentrated. The crude product was dissolved in 100 ml of hot ethanol and allowed to crystallize with stirring. 20.5 g (657.) of product with a melting point of 134-135 β C were isolated. d) 2-Ethoxymethylene-3-methyl-3-carbaethoxy-6- (4-chloro) -benzyl-4,5,5,6-tetrahydrathenia (2, 3-c) pi.ridine (sic) 19.3 q (55.0 mM (sic)) were mixed ) of 2-amins-3-carboetsxy-6- (6-chlorobenzyl) -4,5,6,7-tetrahydratiene (2,3-c) pi.ridine in 125 ml of triethyl orthoformate with 2.0 ml of acetic anhydride and refluxed in nitrogen for 1 hour. The mixture was then completely evaporated in a rotary evaporator at a temperature of 80 ° C. 21.9 g (987.) of crude product was isolated in the form of a dark oil sufficiently pure for the next reaction. e) 2-Amine-3-carboethoxy-6- (3-penyl) prapi 1-4,5,6,7-tetrahydratiene (2,3-c) pyridine (sic) 10.0 g (44.2 M (sic)) were mixed ) of 2-amino-3-carboethoxy-4,5,6,6-tetrahydrothieno (2, 3-c) pyridine (sic) in 100 ml of toluene with 9.0 g (45 M (sic)) of 1- f nil-3-bromopropane, 400 mg of potassium iodide and 6.1 g (44.2 mM (sic)) of fine powdered potassium carbonate and refluxed for 6 hours. The residue, after concentration in a rotary evaporator, was collected in water, adjusted to pH = 10 and extracted 2 times with methylene chloride. The crude product, after drying and concentration of the organic phase was extracted by stirring in 50 ml of isopropanol. The pale solid was removed by filtration with suction and washed with isapropanal. 7.8 g (517.) of product with a melting point of 0.08-110 ° C were isolated. Other derivatives of 4,5,6,7-te >were prepared; trah? drot? ene (?, 3-c) pyridine substituted in position 6 as in c) and e), for example: 2-am? no-3-carbaeto-,? - 6-et? 1 -4, 5,6,7-tetrah? Drat? Ene- (, 3-c) p? R? Dma, melting point: 74-76 ° C. -am? no-3-carbaeto:? -6-? saprap l-4, 5,6,7-tetrah? drat? ene- (2,3-c) p? pd? na 2-am? no-3 -carboetox? -6-bep? 1-4, 5,6,7-tetrahydro-ene- (2,3-c) p? Pd? Na, melting point: 116-118 ° C. 2-am? No-3-carbseto :; ? -6- (4-met 11) ben ci 1-4, 5,6,7-tetrah? Drot? Ene- (2,3-c) pipdma (sic) 2-am? No-3-carboetax? - 6- (4-n? Tra) bencl 1-4,5,6,7-tetrah? Drat? Ena- (2,3-c) p? Pd? Na (sic), melting point: 170- 172 ° C 2 -amino-3-carboethoxy -6- (4-meta?) Benzyl 1-4,5,6,7-tetrah? Drot? Epo- (2,3-c) p? Pd? Na ( sic), melting point: 154- 156 ° C 2-am? no-3- arboethoxy? -6- (2-pen? l) et? l-4, 5,6,7-tetrah? drot? epa- (2,3-c) p? Pd? Na (sic), melting point: 80- 83? C 2-am? No-3-carboethoxt-6- (2- (4-methox? Phen? L) et? L ) -4, 5,6,7-tetrah? Drot? Ene- (2, -c) pyridine, melting point: 76-78"C 2-am non-3-carboetho -6- (2- (4-chlorophenyl) et? 1) -4,5,6,7-tetrah? Drot? Ene- (2, 3-c) p ridma, point Fusion: 102-105 ° C 2-am? No-3- arboeto? -6- (3- (4- laro) f em 1) propi 1) - 4, 5, 6,7-tetrah? Drot? Ene- (2, 3-c) p? pd? na (sic) 2-amylo-3-carboethoxy-6- (4-phenyl) buty 1-4, 5,6,7-tetrahydrothieno- (2, 3-c) pyridine (sic) 2-amino -3-carboethoxy-6- (3-benzoyl) propi 1-4, 5,6,7-tetrahydratiene- (2, 3-c) pyridine (if) 2-amino-3-carbaethoxy-6- (2-benzoylamino) ) ethyl-4, 5,6,7-tetrahydratiens- (2,3-c) pyridine (sic), melting point: 190-292 ° C 2-amino-3-carboethoxy-6- (3-benzolamino) propi 1-4, 5,6,7-tetrahydrotiena- (2, 3-c) iridine (sic) f) N- (3-carboethoxy-6-methyl-4,5,6,7-tetrahydrstiena- (2, 3-c) pyridine-2-and 1) ethyl ethanimidate. 3.0 g 912.5 M (sic)) of 2-amino-3-carboethoxy-4,5,6,7-tetrahydrothieno (2,3-c) pyridine were mixed in 25 ml of triethyl orthoacetate with 0.8 ml of acetic anhydride and it was refluxed under nitrogen for 2 hours. The mixture was then completely evaporated in a rotary evaporator at a temperature of 80 ° C. 3.6 g (937.) of crude product was isolated in the form of a dark oil sufficiently pure for the next reaction. g) 2-carboethoxyamine-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothiepo- (2, 3-c) pyridine 5.0 g (18.6 mM (sic)) of 2-carboethoxyamino-6 were mixed acetyl-4,6,6,7-tetrahydrothieno- (2, 3-c) pyridine in 50 ml of toluene with 3.0 g (28 mM (sic)) of chlorafor ethyl acetate and 2.6 g (18.6 M (sic)) of potassium cabanato in fine powder and refluxed for 2 hours. The reaction mixture was then taken up in ice / water, the toluene phase was separated, and the aqueous phase was extracted again from toluene. The combined organic phases were dried and then concentrated. 5.8 g (927.) of product was isolated in pharma from an oil that crystallized slowly. h) 3,4,5,6,7,8-hexahydra-3- (2-hydroxy) eti 1-7-methyl-irido- (4 ', 3': 4,5) thieno (2,3-d) ) pyridone-4-one (sic) 86.4 g (292 mM (sic)) of 2-ethoxymethylene-3-arboe were mixed with i-6-me i 1-4, 5, 6, 7-tetrahydrothienine (2.3 -c) iridine in 200 ml of ethanol with 17.6 ml (292 mM (sic)) of ethanole ina and refluxed for 2 hours. The mixture was then concentrated under reduced pressure, and the residue was taken up in 30 ml of ethyl acetate with stirring. The solid that was precipitated overnight was removed by suction filtration and washed with a small amount of ethyl acetate. After recrystallization from ethanal, 48.0 g (627.) of product having a melting point between 163 and 165 ° C were isolated. i) 3,4,5,6,7,8-hexahydro-3- (2-clear) ethyl-7-methylpyride (4 ', 3': 4,5) thien (2,3-d) pyrimidine-4 -one (sic) 42.0 g (158 mM (sic)) of 3,4,5,6,7,8-hexahydra-3- (2-hydroxy) -ethyl-7-methylpyrido (4 ', 3') were heated. : 4,5) thieno (2,3-d) pyrimidine-4-opa (sic) in 240 ml of refluxing 1,2-dichloroethane and then 12.7 ml (1.75 M (sic)) of sodium chloride were added dropwise. Thionyl in 20 ml of 1,2-dichloroethane after refluxing the mixture for 2 hours, said mixture was allowed to cool and was emptied in ice / water. After division between methylene chloride and water at pH = 10, the aqueous phase was extracted again with methylene chloride. The combined organic phases were dried and concentrated. The crude product (40 q) was recrystallized from 400 ml of isopropanol. 30.5 g (787.) of product having a melting point of 159-161 ° C were isolated. The following compounds were prepared as in h) and i): 3,4,5,6,7,8-hexahydro-3- (1-hydroxy) prop-2- and 1-7-methylpyrido (4 ', 3': 4, 5) thieno (2,3-d) pyrimidin-4-one (sic) 3,4,5,6,7,8-hexahydro-3- (l-chlora) prop-2-yl-7-methylpyrido (4 ', 3': 4, 5) ieno (2,3-d) irimidin-4-one (sic) 3,4,5,6,7,8-hexahydra-3- (2-hydroxy) propyl- 7-methylpyrida- (4 ', 3': 4,5) thieno (2,3-d) pyrimidin-4-one (sic) melting point 158-160 ° C 3,4,5,6,7,8 -hexahydro-3- (2-chloro) propyl-7-methylpyrida- (4 ', 3': 4, 5) thieno (2,3-d) irimidin-4-one (sic) k) N- (1-) Naphthyl) piperazine 83.2 g (966 M (sic)) of piperazine were added, 38.0 g (339 M (sic)) of potassium tert-butoxide and 50.0 g (241 M (sic)) of 1-bromo-naphthalene to a mixture of 5.4 g (24.2 mM (sic)) of palladium acetate and 14.7 g (48.3 M (sic)) of tri-o-tolyl-phosphide in 500 ml of xylene, and the mixture was refluxed with efficient stirring under a nitrogen atmosphere for 10 hours. The mixture was then diluted with methylene chloride, the insoluble residue was removed by filtration and the filtrate was concentrated. The crude product was purified by column chromatography (silica gel), mobile phase THF / methanol / amanic 85/13/2). 21.5 g (427.) of product with a melting point of 84-86 ° C were isolated. 1) N- (2-Methyl-l-naphthyl) piperazine. 13.0 g (82.7 mM (sic)) of l-amino-2-ethylnaphthalene in 100 ml of chlorobenzene were mixed with 14.7 g (82.7 M (sic)) of bis (2-chloroethyl) amine x HCl and subjected to low reflux nitrogen for 90 hours. The mixture was then concentrated and divided between methylene chloride and water at pH = 9, and the organic phase was dried and then concentrated. The crude product was purified by column chromatography (silica gel, mobile phase / THF / methanol / ammonia 85/13/2), 11.6 g (product 627.0 m) 4-i-Piperazinyl isoquinol ina (sic) were isolated. ) 4.50 g (21.7 mM (sic)) of 4-bromaisoquinoline, 4.56 g (25.0 mM (sic)) of t-butyl piperazine-N-carbaxylate, O.lg (0.11 mM (sic)) of tris (dibenzyl) were mixed. idenacetone) dipaladia, 0.11 g (0.18 mM (sic)) of 2.2 '-bis (dipenylphospino) -1, 1-binaphthyl and 2.92 g (30.4 M (sic) of sodium t-butoxide in 50 ml of toluene and The mixture was stirred at a temperature of 75 ° C. for 2 hours, the mixture was added to ice / sodium chloride and extracted with ethyl acetate, the organic phase was dried in sadium sulfate, and the solvent was removed in a rotary evaporator. It was crystallized and was removed by suction filtration and washed with pentane to obtain 5.5 g (817.) of the piperazine protected with Boc (melting point: 11 ° C.) 5.2 g (16.6 M (sic)) of this was absorbed. The mixture was dried in 17 ml of diclaromathane and, at a temperature of 0 ° C, 17 ml (5.22 mM (sic)) of trifluoacetic acid were added slowly. The mixture was stirred at 0 ° C for 4 hours, poured into ice-water and extracted with dichloromethane. The aqueous phase was filtered, made alkaline and extracted with dichloromethane. After drying in sodium sulfate, substantial removal of the solvent and after dilution with diethyl ether, the hydrochloride was precipitated with ethereal clarhydric acid. 3.2 g (67") of the product with a melting point of 293-294 ° C. were obtained Other piperazine derivatives (see example) not shown in the literature (see also patent application DE 19636769.7) were prepared as in k), 1) and m) B Preparation of the final products Example 1 3,4,5,6,7, B-hexahydra-7-methyl-3- (2- (2- (2-m ta ifeni 1 ) -l-piperazinyl) ethyl) pyrido (4 ', 3': 4,5) thieno (2, 3-d) pyrimidin-4-imine x 3HC1 3.0 g (12.1 M (sic)) of 2-ethoxymethylene-amino were mixed 3-cyana-6-methyl-4, 5,6,7-tetrahydrothieno (2, 3) pyridine in 60 ml of ethanol with 3.3 g (12.1 M (sic)) of i- (2-aminoethyl) -4 - (3-meta ifeni 1) iperazine and refluxed for 3 hours The mixture was then evaporated on a rotary evaporator and the residue was taken up in 100 ml of ethyl acetate The trihydralaride was precipitated by addition of ethereal hydrochloric acid with stirring, and the product was removed by filtration with suction under a nitrogen atmosphere and washing with ethyl acetate. Drying at 50 ° C in a vacuum oven resulted in the isolation of 3.6 g (557.) of product that showed decomposition at a temperature of 282-284 ° C. Example 2 3,4,5,6,7,8-hexahydro-7-methyl 1-3- (2- (4-methoxyphenyl) -1-piperazinyl) ethyl) pyrido (4 ', 3': 4, 5) thieno (2,3-d) pyrimidin-4-one x 3 HCl 3.0 g (12.1 M (sic)) of 2-ethoxymethylene-amino-3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothien were mixed (2,3-c) pyridine in 50 ml of ethanol with 2.4 g (10.2 M (sic)) of l- (2-amyloethyl) -4- (2-methoxyf nor 1) piperazine and refluxed for 3 hours . The mixture was then evaporated in an evaporator qi mouse, and the crude product was purified by column chromatography (silica, mobile phase, methane / methanol chlorine 93/7). The free base was co-drilled as above in the hydrophobic tp (3.2 g, 487.) which decomposed at 288-290 ° C. Example 3 3,4,5,6,7,8-hexah? Dro-7- ( -c1oorobenz 1) -3- (2- (4- (2-methoxyphenyl) -p? eraz? n? l) et? l) p? pda (4 ', 3': 4,) ieno (2, -d) ) p? pm? d? n-4-ana Y 3 HC] 3.5 g (8.6 M (sic)) of 2-ethoxy? met? leneam? no-3-carbaeta? -6- (4-rloraben? l) -4, 5,6,7-tetrahydroxy ene (2, 3-c) pipdine in 60 ml of ethanol with 2.0 g (8.6 M (sic)) of 1- (2-am? noet? l) -4 - (2-metax? Phen? 1) iperazine and refluxed for 4 hours. The mixture was then evaporated on a rotary evaporator and the crude product was purified by column chromatography (silica gel, mobile phase methylene chloride / methanol 95/5). The free base was converted as above to the tphidrochloride (3.2 g 577.) which was uncovered at a temperature of 290-293 ° C. Use 4,4,5,6,7,8-Hexah? Dro-7-met? L-3- (3- (4-) 2-methox? Phenyl) -l-pipera inyl) prapi l) p ? pda (4 ', 3': 4,5) ti ene (2, 3-d) p? r? m? d? n-4-one x 3 HCl x 2 H20 3.5 g (11.8 M (sic) were mixed )) of 2-etax? met leneam? no-3-carbo-ethoxy? -6-met? l-4, 5,6,7-tetrah? drot? ene (2,3-c) pipdine in 40 ml of Ethane 3.0 g (11.8 mM (sic)) of l- (3-aminoprap.il) -4- (2-metsxifepi 1) piperazine and refluxed for 2 hours. The mixture was then evaporated on a rotary evaporator, and the crude product was purified by column chromatography (silica gel, mobile phase methylene chloride / methane 93/7). The free base was converted as above to the trihydrochloride (3.1 g, 447.) which decomposes at 122-124 ° C. Example 5 3,4,5,6,7,8-Hexahydro-7-methyl-3- (3- (4-pyridin-2-yl) -l-piperazinyl) propyl) pyrido (4 ', 3': 4.5 ) thieno (2, 3-d) pyrimidip-4-imine (sic) x 4 HCl x 2 H20 3.0 g (12.1 mM (sic)) of 2-ethoxymethylene-amino-3-cyano-6-methyl-, 5 were mixed, 6,7-tetrahydratyena (2,3-c) pyridine in 60 ml of ethanol with 2.65 g (12.1 mM (sic)) of i- (3-aminopropyl) -4- (2-pi.ridini 1) piperazine and refluxed for 6 hours. The mixture was then evaporated on a rotary evaporator, and the crude product was taken up in 100 ml of ethyl acetate. The solid that crystallized during the night was converted as above into the tetrahydrochloride. 2.7 g (387.) of product that decomposed at 261-264ßC were isolated. Example 6 3,4,5,6,7,8-Hexahydro-7-methyl-3- (3- (4- (2-thiamethyl-phenyl) -l-piperazinyl) propy1) pyrid (4 ', 3': 4 , 5) thieno (2, 3-d) pyrimidine -4-? Mna (sic) x 3 HC] 3.0 q (12.1 mM (sic)) of 2-ethoxy? Met? Leneam? No-3- were mixed. c? ana-6-met? l-4, 5, 6,7-tetrah? drot? ene (2,3-c) pipdine in 50 ml of ethanol with 3.2 q (12.1 mM (sic)) of l- ( -am? noprop? 1) -4- (2-t? smet? Ifil) piperazm (sic) and refluxed for 4 hours. The mixture was then evaporated in a rotary evaporator, and the residue was taken up in 100 ml of boiling ethyl acetate. After cooling, the more soluble particles were removed by filtration, the trihydrochloride was precipitated from the filtrate by the addition of ethereal hydrochloric acid with stirring, and the product was removed by filtration with suction under nitrogen and washing with ethyl acetate. The crude product (5.1 q) was subsequently recrystallized from methanol. 3.8 g (547.) of product with boiling point were isolated: 306-307'C. Example 7 3,4,5,6,7,8-Hexah dro-7-met? L-3- (2- (4-2-p? Pd? Ll-piperazipyl et? L) p? R? Do ( 4 ', 3': 4,5) thieno (2, -d) p? Pm? D? N-4-one (sic) x 3 HCl x 2 H20 2.2 g (7.8 mM (sic)) of 3 were mixed , 4, 5,6,7, 8-hexah? Dra-3- (2-chloro) et? L-7-met? Lp? Pda (4 ', 3':, 5) t? Ena (2,3 -d) p? r? d? n-4-one (sic) in 50 ml of exylene with 1.6 g (10.0 mM (sic)) of l- (2-p? pd? l) -p? perazma, 1.4 g (10.0 M (sic)) of fine powdered potassium carbonate and 400 mg of potassium iodide and refluxed for 24 hours, the mixture was then concentrated on a rotary evaporator, and the residue was partitioned between methylene and water at pH = 10. The aqueous phase was extracted once more with methylene chloride, and the combined organic phases were dried and then concentrated. The crude product was purified by column chromatography (silica gel, mobile phase acetone). 2.3 g (727.) of product were isolated and dissolved in 100 ml of ethyl acetate and converted with a solution of HCl / ethyl acetate in the hydrazide with a melting point of 233-235 ° C. Example 8 3,4,5,6,7,8-Hexahydro-7-methyl-3- (1- (4- (l-naphthyl) -l-piperazinyl) prop-2-l) pyrido (4 ', 3 ': 4, 5) ti ene (2,3-d) pyrimidin-4-one x 3 HCl x 2 H20 2.7 g (9.0 M (sic)) of 3.4, 5,6,7,8- were mixed hexahydro-3- (l-chloro) -2-propyl-7-methylpyrido (4 ', 3': 4,5) thieno (2,3-d) pyrimidin-4-ana (sic) in 50 ml of exylene with 2.1 g (10.0 mM (sic)) of 1- (1-naphthyl) -piperazine, 1.4 g (10.0 M (sic)) of fine powdered potassium carbonate and 250 mg of potassium iadide and refluxed for 70 hours. hours. The mixture was then concentrated in a rotary evaporadar, and the residue was partitioned between methylene chloride and water at pH = 10. The aqueous phase was extracted once more with methylene chloride, and the combined organic phases were then concentrated. The crude product was purified by column chromatography (silica gel, mobile phase acetone). 1.6 g (387.) of product were isolated and dissolved in ethyl acetate and converted with a solution of HCl / ethyl acetate in the hydrochloride with a melting point: 242-244 ° C. Example 9 3,4,5,6,7,8-Hexahydro-7-me 111-3- (2- (4- (2-meto ifen 11) -1-piperazinyl) prap? L) p? Pdo (4 ', 3 ': 4, 5) thieno (2, 3-d) p? Pm? D? N-4-one x 3 HCl 2.9 g (8.9 mM (sic)) of 3.4, 5,6,7 were mixed. , 8-hexah? Dra-3- (2-chloro) rop? L-7-met? Lp? R? Da (4 ', 3': 4, 5) t? Ene (2,3-p? Rm? d-n-4-one (sic) in 60 m] of e "ilene with 3.5 g (18.0 M (sic)) of l- (2-methox? phenyl) ~ p? peraz? na, 1.4 g (10.0 M) (sic)) of fine powdered potassium carbonate and 400 mg of potassium iodide and refluxed for 100 hours.The mixture was then concentrated on a rotary evaporator, and the residue was divided between methylene chloride and water at pH = 10. The aqueous phase was extracted once more with methylene chloride, and the combined organic phases were dried and then concentrated.The crude product was purified by chromatography on silica gel, mobile phase acetone. g (257.) of product and dissolved in 100 ml of ethyl acetate and converted with a solution of HCl / ethyl acetate in the? 7 hirirpclnrurp with a melting point: 190-192 * C (decomposition). Example 10 3,4,5,6,7, 8-Hexahi dro-2, 7-dime111 -3- (- (- (2-meto i fen 11) -1-piperazini 3) -et? L) p? pda (4 ', 3': 4, 5) t ene (2, 3-d) p? r? m? dm-4-on 1.9 96.2 mM (sic)) of N- (3-carbaetax? 6-met?] -4, 5,6,7-te rah? Drot? Ena (2,3-c) p? Pd? N-2-y 1) ethyl ethani-idate in 30 ml of ethanol 1.5 g ( 6.2 mM (sic)) of l- (2-aminoethyl) -4- (2-methoxyphen1) piperazm and was refluxed for 7 hours. The mixture was then concentrated in a rotary evaporator, and the residue was taken up in 20 ml of ethyl acetate. 2.1 q of the crude product were crystallized overnight and were filtered by suction filtration and (gaps) by column chromatography (silica gel, mobile phase rnetylene chloride / metapol 92/8). 0.8 g (297.) of product was isolated. EXAMPLE 11 3,4,5,6,7,8-Hexah? Dra-2? -hydro? -7-acet? L-3- (2 ~ (4- (2-meta-phen-1) -lp? perazm? l) -et? l) p? r? do (4 ', 3': 4,5) t? ene (2,3-d) p? pm? d? n-4-one (sic) Se heated 2.5 g (7.3 M (sic)) of 2-carbaetox? am? no-3-carboethoxy? -6-acet? l-4, 5,6,7-tetrah? drat? ene (2,3-c) pipdin with 1.7 g (7.3 M (sic)) of i- (2-aminophenyl) -4- (2-metaxyphenyl) piperazine at a temperature of 180 ° C for 2 one nitrogen atmosphere while stirring efficiently the fusion. After cooling, the crude product was purified by column chromatography (silica gel, mobile phase metal chloride / methanol 95/5). 0.7 g (207.) of product with a melting point of 135-137 β C was isolated. Example 12 3,4,5,6,7, 8-Hex h? Dro-7-a et? ] -3- (2- (4- (2-methox i phen 11) -1- piperazinyl) -et? L) p? Pdo (4 ', 3': 4,5) t? Ene (2,3- d) p? pm? d? n-4- ona 5.8 g (23.4 M (sic)) of 2-ethoxy? met? leneam? no- 3- arboeto? -6-aceti l ~ 4.5,6 were mixed. , 7-tetrahydrate (2,3-c) p? Pd? Na in 50 ml of ethanol with 5.5 g (23.4 mM (sic)) of l- (2-ammoethyl) -4- (2-methox? Phenyl) ) piperazine and refluxed for 2 hours. The mixture was then concentrated in a rotary evaporadar, and the residue was taken up in 30 ml of ethyl acetate, heated to boiling and allowed to cool with addition. The solid that crystallized was removed by suction filtration after the < "> Cooling in an ice bath and the product was washed with ethyl acetate 8.7 g (807.) of product can be isolated with a melting point of 170-72 ° C. Example 13 3.4.5.6 , 7, 8-Hexah? Ra-3- (2- (- (2-methox? Phen 11) -1 5 -p? Per? N? L) -et? L) p? Pda (4 ', 3' : 4,5) thieno (2, 3-d) p? Pm? D? N? 4 -pna SP di olienden 4.0 g (8.6 mM (sic)) of 3,4,5,6,7,8-hexah ? dra-7-acet? l-3 ~ (2- (4- (2-methox? phen l) -lp? peraz? m 1) -eti l) p? pdo (4 ', 3': 4, 5 ) t? ene (2,3-d) p? pm? d? n-4-one in 80 ml of hydrochloric acid at 107. and stirred at a bath temperature of 10? "C for 2 hours. The mixture was then poured into molten water, made alkaline with a concentrated sodium hydroxide solution and extracted twice with methylene chloride. The combined organic phases were dried and concentrated. 3.7 g of crude product were isolated and recrystallized from 50 ml of isopropanol. 2.4 g (667.) of product were obtained csn a melting point of 168-170 ° C. Example 14 3,4,5,6,7,8-Hexah? Dro-7- (2- (1-naphthi 1) eti 1) -3- (2- (4- (2-methoephenyl) -lp? Peraz? n? l) -et? l) p? pdo (4 ', 3': 4, 5) t? ena (2,3-d) p? pm? d? n-4-one x 3HC1 1.0 g was dissolved (2.3 mM (sic)) of 3,4,5,6,7,8-hexahydro-3- (2- (4-l "2-methoxypheni 1) -l-piperazinyl) -eti 1) p? pdo (4 ', 3': 4, 5) t? ene (2,3-d) p? pm? d? n-4-one in 35 ml of exile with 0.8 g (3.4 mM (sic)) of 2 brsmo-ll-naphthyl-ethane (sic) and can 0.3 g (2.4 mM (sic)) of fine powdered potassium carbonate and refluxed for 12 hours.The mixture was then concentrated in a rotary evaporator, and the residue was divided between • chlorine methylene and water at a pH = 10. The aqueous phase was extracted once more with methylene chloride. The organic phases were dried and then concentrated. 2.7 g of crude product were obtained in the form of a dark oil which (pond) by column chromatography (silica gel, mobile phase chloride rneti leno / acetone 7/3). After conversion into the hydrazide in ethyl acetate, 1.0 g (637.) of product with a melting point of 293-295 ° C (decomposition) was isolated. The following were prepared in a manner similar to Examples 1 to 14: 15. 3,4,5,6,7, 8-Hexahydro-7-methyl 1-3- (3- (4- (2-methoxypheni 1) - 1-pi erazinyl) propyl) pyrido (4 ', 3': 4,5) thieno (2, 3-d) pyrimidin-4-i ina, melting point: 112-114 ° C 16. 3.4.5 , 6,7,8-Hexahydro-7-benzyl 1-3- (3- (4- (2-methoxypheni-1) -1-piperazinyl) propyl) pyrido (4", 3 ': 4,5) thieno ( 2, 3-d) pyrimidip-4-imine x 2 HCl, melting point: 258-261 ° C (decomposition) 17. 3,4,5,6,7,8-Hexahydro-7-benzyl-3- (2- (4-f or 1-l-piperazinyl) -ethyl) pyrido (4 ', 3': 4,5) thieno (2,3-d) pyrimidin-4-imine, melting point: 168-170 ° C 18. 3,4,5,6,7,8-Hexahydro-7-benzyl-3- (3- (4- (2-methoxyphenyl) -1-piperazinyl) ropil) pyrids (4 ', 3': 4, 5) thieno (2,3-d) pyrimidin-4-one, melting point: 66-67 ° C 19. 3 4,5,6,7,8-Hexahydro-7-benzyl-3- (2- (4-phenyl-1-piperazinyl) ethyl) pyrido (4 ', 3': 4,5) thien (2, 3 -d) pyrirnidip-4 -one, melting point: 70-71"C 20. 3,4,5,6,7, 8-Hexahydro-7-methyl-3- (3- (4- (2-metaxyphenyl -l-piperazyl) ethyl) pyrido (4 ', 3': 4"5) tiepa (2,3-d) piri idin-4-i ina, mp 112-114 ° C 21. 3.4.5 , 6,7,8-Hexahydro-7-methyl-3- (3- (4- (3-methoxy penyl-l-pi erazinyl) propyl) pyrids (4 ', 3': 4,) thieno (2,3- d) pyrimidin-4-i ina x 3 HCl x 2 H20, melting point: 268-270 ° C (desco position) 22. 3,4,5,6,7,8-Hexahydro-7-methyl-3- (3- (4-l-naphthyl-1-piperazinyl) propyl) pyrido (4 ', 3': 4,5) thieno (2,3-d) pyrimidin-4-i ina (sic) x 3 HCl, point of fusion: 250- 253 ° C (decomposition) 23. 3,4,5,6,7,8-Hexahydro-7-me i 1-3- (3- (4- (2-nitropheni-1-piperazinyl) propyl) pyrido (4) ', 3': 4, 5) thieno (2,3-d) pyrimidin-4-imine x 3 HCl x 2 H20, melting point: 271-273 ° C (decomposition) 24. 3,4,5,6 , 7,8-Hexahydro-7-methyl-3- (3- (4- (2-methyl-l-piperazinyl) prapil) pyrido (4 ', 3': 4, 5) thieno (2,3-d) pyrimidip-4-imine (sic) x 3 HCl, melting point: 280-282 ° C (decomposition) 25. 3,4,5,6,7,8-Hexahydro-7-methyl-3- (3- ( 4- (2-aminophenyl-1-piperazinyl) prapil) irido (4 ', 3': 4, 5) thieno (2,3-d) pyrimidin-4-imine x HCl x. 4 H20, melting point: 113-115 ° C (decomposition) 26. 3,4,5,6,7,8-Hexah? Dro-7-met? ] -3- (- (4- (2-larophen? Ll-piperazinyl) prop? L) p? Pda (4 ', 3': 4.5) thieno (2, 3-d) p? Pm? D? N- 4-ymine x 3 HCl, melting point: 261-2e> 3 ° C (decomposition) 27. 3,4,5,6,7,8-Hexah? Dro-7-met? l-3- (2- (4-2-p? pm? d? n? llp? peraz? n? l) et? l) p? pdo (4 ', 3': 4,5) thieno (2, 3-d) p? Pm? Dm-4-one (sic), melting point: 146-148ßC 28. 3,4,5,6,7, 8-Hexah? Dro-7-met i 1 -3- (3- (4-benz? 1-1-p? Per? D? N? L) -prop? L) p? R? Da (4 ', 3': 4,5) thieno (2, 3-d) ) p? pm? d? n-4-? m? na x 3HC1, melting point: 295-297 ° C (decomposition) 29. 3,4,5,6,7, 8-Hexah? dra-7-met i] -3- (3- (4- (2-d? dro? in i 1-1-p? peraz? n? l) propal) p? pdo (4 ', 3': 4 , 5) tan (2, 3-d) p? Pm? D? N-4-ymin, melting point: 164-166 ° C 30. 3,4,5,6,7, 8-He:; ah? d ro-7-met? 1 -3- (4- (4- (-metox if eni 1) -1-pi erazmil) but l) p? r? do (4 ', 3': 4, 5) thieno (2, 3-d) p? Pm? D? P-4-imma x HCl x 3 H20, melting point: 272-274 ° C (decomposition) 31. 3,4,5,6,7, 8-Hexah? dro-7-met? 1-3- (3- (4- (2-etho i phen i 1) -1-piperalenyl) prop? 1) p? Pdo (4 ', 3': 4,5) t? Ene. { 2,3-d) p? R? M? D? N-4-i ma x 3 HCl x 3 H20, melting point: 284-286 ° C (decomposition) 32. 3,4,5,6,7 , 8-Hexah? D ra-7-met? 1-3- (- (4- (2-et? 1 f in 11) -1-piperazinyl) prop? L) p? Pdo (4 ', 3': 4,5) t? Ene (2, 3- d) p? pm? d? n-4-yna x 3 HCl, melting point: 303-305 ° C (decomposition) 33. 3,4,5,6,7,8-Hexah? Dro-7-met? L-3- (3- (4- (2-c? Anophen? L) -lp? Peraz? Nil) prap? L) p? pda (4 ', 3': 4,5) t? ena (2,3-d) p? pm? d? n-4- ana - 2 HCl x 2 H20, melting point: 136-138 ° C (decomposition) 34. 3,4,5,6,7, 8-Hexah? Dro-7-met11-3- (3- (4-Fen? 1-1-pipepdinil) propí)) p? R? Do (4 ', 3: 4, 5) t? Epo (2, 3-d) p? R? M? Dm-4-ymin x 3 HCl, melting point: 280-282 ° C (decomposition) . 3,4,5,6,7,8-Hexah? Dro-7-met? L-3- (3- (4-2-p? Raz? N? Ll-piper zipil) pro? L) p? Pds (4, 3 ': 4,5) t? Ene (2, 3-d) p? Pm? D? N-4-ymin (sic) x 4 HC] x H20, melting point: 284-286 ° C (decomposition) 36. 3,4,5,6,7,8-Hexah? dro-7 ~ met? l-3- (3- (4-2 ~ p? r? m? d? n? l? l -pipera inil) propí l) p pdo (4, 3 ': 4,5) t? ene (, 3-d) p? pm? d? n-4-í ina (sic), melting point: 161- 163 ° C 37. 3,4,5,6,7,8-Hexah? Dro-7-met? L-3- (3- (4- (2-c? Anophen? L) -l-piperazinyl) prop ? l) p? r? da (4 ', 3': 4, 5) t? ene (2,3-d) p? r? m? d? n-4-í ina, melting point: 148- 150 ° C (decomposition) 38. 3,4,5,6,7,8-Hexah? Dra-7-benc? 1-3- (2- (4- (2-methoxypheni1) -1-p? Peraz? N? L) et? L) p? Pdo (4 ', 3': 4, 5) thien (2, 3- d) p? pm? d? n-4-one x 3 HCl x H20, melting point: 288-290 ° C (decomposition) 39. 3,4,5,6,7,8-Hexah? dro-7 -ment? l-3- (3- (4- (3,4-methylenedioxypheni 1) -l-pi eraziml) prop? l) p? pdo (4 ', 3': 4,5)? ena (2, 3-d) p? Pm? D? N-4-ymina x 3 HCl, melting point: 288-290 ° C (decomposition) 40. 3,4,5,6,7,8-Hexah? Dro-7 -met? 1-3- (- (4- (2-meti 1 f or 1) -1-piperazinyl) et? L) p? Pdo (4 ', 3': 4, 5) thieno (2,3-d) - p? pm? d? n-4 * 4 -one x 2 HC] x H20, melting point: 30 < VC 41. 3,4,5,6,7,8-Hexah? Dro-7-met? L-3- (2- (4- (2-clarofep? 1) -l-pipera iml) et? L) p (4 ', 3': 4.5 t? ena (2,3-d) -p? pm? d? n-4-one x 2 HCl; - H20, melting point: -30O ° C 42. 3,4,5,6,7,8-Hexah? Dra-7-met? L ~ 3- (2 ~ (4- (3,4 ~ dimethylphenyl) -lp? Peraz? P? L) et ? l) p? pdo (4 ', 3': 4,5) 11eno (2,3-d) -p? pm? d? n-4-one x 2 HCl, melting point: 307-310 ° C 43. 3,4,5,6,7,8 ~ Hexah? Drs-7-met? 1-3- (2- (4- (2,6-di-ethylphenyl) -lp? Peraz? N? 1) et ? l) p? pdo (4 ', 3': 4, 5) ieno (2, 3-d) -p? pm? d? n-4-sna x 2 HCl, melting point: 297-300 ° C 44. 3,4,5,6,7,8-Hexah? Dro-7-met? L-3- (2- (4- (2,3-di ethylphenyl) -lp? Pera? N? 1) et? L ) p? pdo (4 ', 3': 4, 5) thieno (2,3-d) -p? r? m? d? n-4-one, melting point: 163-167 ° C 45. 3 , 4,5,6,7,8-Hexah? Dro-7-met? 1-3- (2- (4- (2, 4-dimethyl phenyl) -lp? Peraz? N? 1) et? L) p? pdo (4 ', 3': 4,5) thieno (2, 3-d) -p? pm? d? n-4-one x 2HC1, melting point: 300-303 ° C 46. 3, 4,5,6,7, 8-Hexah? Dro-7-met? 1-3- (2- (4- (, 5-d? Chlorophen? L) -lp? Peraz? N? L) et? L )? pdo (4 ', 3': 4,5) t? ene (2,3-d) -p? pm? d? n-4-one, p Smell of fusion: 97-100 ° C 47. 3,4,5,6,7,8-Hexah? dro-7-met? l-3- (2- (4- (2,4-dimethoxyph nil) - l-pi erazinyl) et? l) p? pdo (4 ', 3': 4,5) t? ene (2,3-d) -p? pm? d? n-4-one x 2HC1, point fusion: 287-290 ° C 48. 3,4,5,6,7, 8-Hexah? dro-7-met? 1-3- (2- (4- (3-tpf luarometi lfepi 1) -l-piperazinyl) ethyl) pyrid (4 ', 3': 4, 5) t epo (2.3-d) -pi ri di n- 4-one x 2HC1. melting point: 309-312 ° C 49. 3.4.5, J7,8-Hexahydro-7-methyl-3- (2- (4-naphth-i-yl-l-piperazinyl) ethyl) pyrido ( 4 ', 3':, 5) thieno (2, 3-d) -pyrimidin-4-one (sic) 2HC1 and H20, melting point: 298-300 ° C (decomposition) 50. 3.4.5, 6,7,8-Hexahydro-7-methi 1-3- (3- (4- (3-hydroxy-phenyl-1-piperazinyl) propyl) -irido (4 ', 3': 4,5) thieno (2, 3-d) -pyrimidin-4-ylamine x 2HC1 x 2H20, melting point: 182-184 ° C (decay) 51. 3,4,5,6,7,8-Hexahydro-7-meti 1 -3- (2- (- (2-methoxy-5-chloraphenyl) -l-piperazine 1) ethyl) pyrido (4 ', 3': 4, 5) thieno (2,3-d) -pyrimidin-4- ona x 3HC1, melting point: 170-172 ° C (decomposition) 52. 3,4,5,6,7,8-Hexahydra-7-methyl-3- (2- (4- (2,5-dimethoxyphenyl) ) -l-piperazinyl) ethyl) pyrido (4 ', 3': 4, 5) thieno (2,3-d) -pyrimidin-4-one x 3HC1 x H20, melting point: 176-178 * C (decomposition) ) 53. 3,4,5,6,7,8-Hexahydro-7-methyl-3- (2- (4- (2-methoxy-5-phenyl-phenyl) -l-piperazinyl) ethyl) acid ( 4 ', 3': 4, 5) thieno (2, 3-d) -pyrimidin-4-ana x H20, melting point: 7 9-80 ° C 54. 3,4,5,6,7,8-Hexahydra-7-m ti 1-3- (2- (4- (2-methoxypheni-1) -3,4-dehydropiperi in-ly 1) ethyl) pyrid (4 ', 3': 4,5) thieno (2,3-d) -pyrimidin-4-one x 2HC1 x 2H20, melting point: 182-185 ° C (descampes ip? N) 55. 3,4,5,6,7, 8-Hes' ah? Dro-7-met? 1 -3- (2- (4- (2-h? Drox if in 11) -lp? Era? N? L et? L) p? Po (4 ', 3': 4,5) t? Ene ( 2, 3-d) -p? R.pud? N-4-one: * 2HC1 - H20, melting point: 281-283 ° C (decomposition) 56. 3,4,5,6,7, 8- Hexah dro-7-met? 1 -3- (- (4- (7-metn maf t-1-y3) -lp? Pera? N? L) et? 3) p? Po (4 ', 3': 4,5) t? Eps (2, 3-d) -p? R? M? Dm-4-one 2HC1 and H20, melting point: 272-274ßC (decomposition) 57. 3,4,5,6, 7,8-Hexah? Dra-7-met? L-3- (2- (4-naf tl-yl-p? Eraz? N? L) et? L) p? Pda (4 ', 3': 4 , 5) t? Ena (2, 3-d) -p? Pm? D? N-4-imma (sic) 3HC1, melting point: 288-289 ° C (decomposition) 58. 3,4,5,6,7, 8-Hexah? dra-7-met? 1 -3- (2- (4- (4, 5-ethylenedioxybenzyl 1) -l-pi pera inyl) et? 1) p? R? Da (4 ', 3: 4,5) t? Ena (2, 3-d) -p? Pm? D? N-4-ymin x 4HC1 x 2H20, melting point: 249-251 ° C (decomposition) 59. 3,4,5,6,7, 8-Hexah? -7-met? 1-3- 12- (4- (6-isopropyl-pyrimidin-4-y 1) -lp? Peraz? N? L) et? L) p? R? Ds (4 ', 3': 4,5) ti eno (2, -d) -p? pm? d? n-4-ymina x 3HC1"2H20, melting point: 250-253 * C (decomposition) 60. 3,4,5,6,7, 8-Hexah? dro-7-met? 1-3- (2- (4- (2-methox inaf t-1-l) -lp? Peraz? N? L) et? L) p? Pdo (4 ', 3': 4,5) ti eno (2, 3-d) - pi.rimidin-4-one x 2HC1 x 2H20, melting point: 241-243 ° C (decomposition) 61 .. 3,4,5,6,7,8-Hexahydra- 7-methyl-3- (2- (4- (2-methoxyphenyl) -piperidin-1-yl) ethyl) pyrido (4 ', 3': 4,) thieno (2,3-d) -pyrimidin-4- ona and 2HC1 x 2H20, melting point: 299-301 ° C (decomposition) 62. 3,4,5,6,7, 8-Hexahydro-7 ~ meti 1-3- (2- (4- (3, 4-di eto ifenil) -lpiperazipil) etil) pyrida <; 4 ', 3': 4,5) thieno (2,3-) -pyrimidin-4-one, melting point: 153-154 ° C 63. 3,4,5,6,7,8-Hexahydro- 7 ~ methyl-3- (3- (4-na tl-yl-1-pi and azinyl) propyl) pyrido (4 ', 3'; 4,5)? Ena (2,3-d) -pyrimidin-4 -ana (sic) x 3 HCl x 2H20, melting point: 206-208 ° C (decomposition) 64. 3,4,5,6,7,8-Hexahydro-7-methyl-3- (3- (4 -pyrimidin-2-yl-l-piperazinyl) prsp? 3) pyrido (4 ', 3': 4,5) iepo (2,3-d) -pyrimidin-4-opa (sic), melting point: 206 -208 ° C (decomposition) 65. 3,4,5,6,7,8-Hexahydro-7-methyl-3- (2- (4-quinolin-2-yl-i-piperazinyl) ethyl) pyrido (4 ', 3': 4, 5) ieno (2, 3-d) -pyrimidin-4-sna (sic), melting point: 143-145 ° C 66. 3,4,5,6,7,8-Hexahydro-7-methyl-3- ( 2- (4- (2-methanedi-l-yl) ethyl) pyrido (4 ', 3': 4,5) thien (2,3-d) -pi rimidin-4-one (sic) x 2HC1 x 2H20, melting point: 295-297 ° C (decomposition) 67. 3,4,5,6,7, 8-Hexahydro-7-methi 1-3- (2- (4- (2-methoxy-3 , 5-dichloraphenyl) -l-pi erazini l) ethyl) pyrido (4 ', 3': 4, 5) tiepa (2,3-d) -pyrimidin-4-one x 2HC1 x H20, melting point: 264 -267 ° C (des o osj pón) 68, ^, 4,5,6,7,8-Hexah? Dro-7-met? L-3- (2- (4- (2-c? Apofep? L ) -p? eraz? n-1-yl) et? l) p? pdo (4 ', 3': 4,5) t? na (2,3-d) -p? pm? d? p-4 -one, melting tip: 162-164 ° C 69. 3,4,5,6,7,8-Hexah? dra-7-met? l-3- (2- (4- (2-chlorophen? ) -l-pi pear ini l) et? l) p? pdo (4 ', 3': 4,5) t? ena (2,3-d) -p? pm? d? n-4-ana, melting point: 165-167 ° C 70. 3,4,5,6,7, 8-Hexah? dro-7-met? 1-3- (2- (4-p? pd? n-2-y 1-1-p? Era? N? L) et? L) p? Pdo (4 ', 3': 4,5) thieno (2, 3-d) -p? R? m? d? n-4-one (sic); 3HC1 x 2H20, melting point: 232-234 ° C (decomposition) 71. 3,4,5,6,7,8-Hexah? Dro-7-met? L-3- (2- (4-p? pd? n-4-yl-l-piperaz? nl) et? l) p? r? do (4 ', 3': 4,5) thieno (2, 3-d) -p? r? m? d n-4-one x 3HC1 x 2H20, melting point: 270-272 ° C (decomposition) 72. 3,4,5,6,7, 8-Hexah? dro-7-met11-3- (2- (4- (5-methox? P? Pm? D? N-4-y 1) -l-pipera im l) et? L) p? R? Do (4 ', 3': 4,5) thieno ( 2, 3-d) -p? R? M? D? N-4-opa x 3HC1 x 4H20, melting point: 266-268 ° C (decomposition) 73. 3,4,5,6,7,8 -Hexah? Dro-7-met? L-3- (2- (4-naft-2-yl-l-pipera mil) et? L) p? Pdo (4 ', 3': 4,5) thieno ( 2, 3-d) -p? Pm? D? P-4-ana (sic), melting point: 140-14i ° C (decomposition) 74. 3,4,5,6,7, 8-Hexah? dro-7-met? 1-3- (2- (-naft-2-1-1 -pipera iml) et? L) p? Pdo (4 ', 3': 4,5) t? Ene (2,3-d -p? r? m? d? n-4-pns (sir), melting point: 140-141 ° C (decomposition) 75. 3,4,5,6,7,8-Hexah? Dra-7-met? L-3- (2- (4-tetral? N-5-yl-l-piperazim l) et? L) p? R? Do (4 ', 3': 4, 5) t? Ene (2,3-d) -p? R? M? Dm-4-one (sic) x 3HC1 x 2H20. melting point: 285-287 ° C 'decomposition) 76. 3,4,5,6,7,8-Hexah? dra-7-met? l-3- (2- (4-? ndan-l-yl -i-piperazinyl) et? l) p? pda (4 ', 3': 4,5) ti ene (2, 3-d) -p? pm? d? n-4-one (sic) x 3HC1 x 2H20, melting point: 300-301 ° C (decomposition) 77. 3,4,5,6,7, 8-Hexah? dro-7-meti 1-3- (2- (4- (2-meto? -4-nitro-5-met? lfen? l) -lp? peraz? n? l) et? l) p? r? do (4 ', 3': 4, 5) thieno (2, 3-d) -p? pm? d? n-4-ana x 2HC1 x 2H20, melting point: 210-212 ° C (decomposition) 78 3,, 5,6,7,8-Hexah? Dro-7-met? L-3- (2- (4-4-? Soqu? Nol? N? L-1-piper inyl) et? L) p? pda (4 ', 3': 4,5) thieno (2,3-d) -p? prn? d? n-4-one (sic) x 3HC1 x 3H20, melting point: 290-292 ° C (decay) 79. 3,4,5,6,7,8-Hexah? Dro-7-met? L-3- (2- (4- (2-methox? -4-chloro-5-met ? lfen? l) -lp? peraz? n? l) et? l) p? pdo (4 ', 3': 4, 5) t? ene (2, 3-d) -p? pm? d? n -4-ona x 2HC1 x 2H20, melting point: 293-294 ° C (decomposition) 8. 3,4,5,6,7,8-Hexahydro-7-met11-3- (2- (4- (2, 4-di ethoxyphenyl) -lp? Peraz? N? L) et? L) p? Pdo (4 ', 3': 4,5) thieno (2, 3-d) -p? Pm? D? N-4-one x 3HC1 x 3H20, melting point: 290-291 ° C 4 (decomposition) 81. 3,4,5,6,7,8 ~ Hexah? dra-7-met? l-3- (2- (4-4-qu? nazalm? ll-pi peraz? n? l) et? 3 pi i do (4 ', 3': 4,5) thieno (2, 3-d) -p? pm? d? n-4-sna (sir) 3HC3 x 4H20, melting point: 258- 260 ° C (decomposition) 82, 3,4,5,6,7, S-Hexah? Dro-7-met? L-3- (2- (4- (3-tpf-luaromethyl-4-clarofen?)) -lp? pera? n? l) et? 1)? r? do (4 ', 3': 4, 5) t? ena (2,3-d) -p? pm? d? n-4-one x 2HC1 x 3H20, melting point: 311-312 ° C (decomposition) 83. 3,4,5,6,7,8-Hexah-dro-7- (4-chlorobenzyl) -3- (2- (4- (2-meto ifenil) ~ lp? Peraz? N? L) et? L) p? Pdo (4 ', 3: 4, 5) t? Ene (2, 3-d) -p? Pm? d-n-4-one x 3HC1 x H20, melting point: 290-292 ° C (decomposition) 84. 3,4,5,6,7, 8-Hexah? dra-7-eti 1-3- ( 2- (4- (-methyl-1-yl) -1-piperazinyl) et? L) p? R? Odo (4 ', 3': 4, 5) t? Ene (2, 3-d) -p? pm? d? n-4-one x 3HC1 H20, melting point: 295-297 ° C (decomposition) 85. 3,4,5,6,7, 8-Hexah? dro-7-isopropy 1 -3- (2- (4- (2-meto ifenil) -lp? Pera? N? L) et? L) p? Pda (4 ', 3': 4,5) t? Epo (2,3-d) - p? pm? d? n-4-sna x 3HC1 x H20, pun to fusion: 300-302 ° C (decomposition 86. 3, 4,5,6,7, 8-Hexah? Dro-7- (4-n itro) benz 1-3- (2- (4- (2-methox? Phen? L) -lp? Peraz? N? l) et? l) p? pdo (4 ', 3': 4, 5) thieno (2, 3-d) -p? pm? d? n-4-one (sic) x 3HC1 x H20, point melting: 214-217 ° C (decomposition) 87. 3,4,5,6,7, 8-Hexah? dro-7- (4-methoxy) benzyl 1 -3- (- (4- (2-meta in? l) -p? peraz? n? l) et? l) p? r? do (4 ', 3': 4,)? eno (2, 3-d) -p? r? m ? d? n-4-ana (sic) x 3HC1 x H20, melting point: 278- 2R1 ° C (decomposition) 88. 3,4,5,6,7,8-Hexah? dro-7- (2 -pen? l) et? l-3- (2- (4- (2-methox? phen? l) -lp? eraz? n? l) et? l) p? pdo (4 ', 3': 4 , 5) ti in o (2,3-d) -p? R? M? D? N ~ 4-one (sic) x 3HC1 and H20, melting point: 305-306 ° C (decomposition) 89. 3 , 4,5,6,7, 8-Hexah? Dra-7- (3-benza? 1) propí 1-3- (2- (4- (2-metax? Phen? L) -lp? Peraz? N ? l) et? l) p? pdo (4 ', 3': 4,5) t? ene (2,3-d) -p? pm? d? n-4-one (sic) x 3HC1 x H20 , melting point: 124-126 ° C (decomposition) 90, 3,4,5,6,7, e-Hexah? dro-7- (4-ammo) benz 1 -3- (2- (4- ( 2-meto? Fen? L) -lp? Peraz? N? L) et? L) p? Pdo (4 ', 3': 4, 5) thien (2, 3-d) -p? pm? d? n-4-ana (sic) x HCl x 3H20, melting point: 280-282 ° C (decomposition) 91. 3,4,5,6,7, 8-Hexah? 7- (3-f in 11) propí 1-3- (2- (4- (2-methox? Phen? L) -lp? Peraz? P? L) et? L) p? R? Do (4 ' , 3 ': 4, 5) thieno (2, 3-d) -p? Pm? D? N-4-one (sic) x 2HC1 x 3H20, melting point: 3 l-302 ° C (decomposition) 92 3,4,5,6,7, 8-Hexah? Dro-7- (3-f in 11) ropí 1-3- (2- (4-naf t-1-y 1) -lp? Pera? n? l) et? l) p? pds (4 ', 3': 4, 5) t? ene (2,3-d) -p? pm? d? n-4-one (sic) x 2HC1 x 2H20, melting point: 306-307 ° C (decomposition) 93. 3,4,5,6,7,8-Hexah? Dro-7- (2- (4-methox?) Phen? L) et? L -3- (2- (4-n ft-l-l) -lp? Peraz? N? L) et? L) p? Pdo (4 ', 3': 4, 5) thieno (2, 3-d) ) -p? pm? d? n-4-one (sic) x 2HC1 x 3H20, melting point: 306-308 ° C (decomposition) 94. 3,4,5,6,7,8-Hexah? dra ~ 7- (2- (4-c1aro) feni 1) eti 1-3- (2- (4-naft-l-l) -1-p? Perazm11) et? L) p? Pda (4 ', 3 ': 4,5) thieno (2,3-d) -p? Pm? D? N-4-ana (sac);; 2HC1 x 3H20, melting point: 3O0-303 ° C (decomposition) 95. 3,4,5,6,7, 8-Hexah? Dro-7- (2-pen? 1) eti 1-3- (2 - (-naft-1-yl) -lp? pera? n? l) et? l) p? pdo (4 ', 3': 4,5) t? ens (2,3-d) -p? pm ? d? n-4-one (sic) x 2HC1 x 3H20, melting point: 295-298 ° C 96. 96. 3,4,5,6,7,8-Hexah? dra-7- (2- h? drox?) pen? l) et? l-3- (2- (4-naft-l-yl) -lp? peraz? n? l) et? l) p? pdo (4 ', 3': 4,5) t? Ena (2, 3-d) -p? Pm? D? N-4-one (sic) x 2HC1 x 2H20, melting point: 254-256Â ° C 97. 3,4,5 , 6,7,8-Hexah? Dro-7- (2- (4-chloro) peni1) eti 1-3- (2- (4- (2-metax? Phenyl) -l-piperazinyl) ethyl)? Pds (4 ', 3': 4,5) thieno (2, 3-d) -p? Pm? D? N-4-ana (sic) x 3HC1 x 2H20, melting point: 304-306 ° C (decomposition) ) 98. 3,4,5,6,7,8-Hexah? Dra-7- (2-naft-l-y1) eti 1-3- (2- (4- (2-metaxyphenyl) -lp? Peraz ? n? l) et? l) p? r? do (4 ', 3': 4,5) t? ene (2,3-d) -p? pm? d? n-4-one (sic) x 2HC1 x 2H20, melting point: 293-295 ° C (decomposition) 99. 3,4,5,6,7,8-Hexah? dro-7- (2-benzo? lam? no) et? l- 3- (2- (4-naphth-l-yl) -lp? Pera? N? L et? L) p? Pds (4 ', 3': 4,5) t? Ens (2,3-d) -p? pm? d? n-4-one (sic) x 2HC1 and 2H20, melting point: 292-294"C (decomposition) 1. 3,4,5,6,7, 8-Hexah? Dro-7- (2-ben or? 3 ammo) eti 1-3- (2- (4- (2-methox? Phen? 1) -lp? eraz? n? l) et? l) p? r? da (4 ', 3': 4,5) t? ene (2, 3-d) -p? pm? d? p-4-one (sic) ) x 2HC1 x 3H20, melting point: 202-204 ° C (decomposition) 101. 3,4,5,6,7,8-Hexah? dra-7- (3-benza? lna) prop? l -3- (2- (4- (2-methox? Pheni 1) -l-pi erazinyl) et? L) p? Pdo (4 ', 3': 4,5) thieno t, 2, 3-d) -p? pm? d? n-4-ana (sic) x 3HC1 x 2H20, melting point: 182-183 ° C (desco pasicion ón) 102. 3,4,5,6,7, 8-H xh ? -7- (3-benza? 3 amine) prop11 -3- (2- (- (naphth-l-yl) -lp? pera? n? l) et? l) p? pdo (4 ', 3 ': 4,5) t? Ene (2,3-d) -p? Pm? D? N-4-one (sic) x 3HC1 x H20, melting point: 128-130 ° C (decomposition) 103. 3,4,5,6,7, 8-Hexah? Dro-7- (-feni 1) bu i 1-3- (2- (4- (2-metax? Phen? L) -lp? Peraz? N l) et? l) p? pdo (4 ', 3': 4, 5) thieno (2,3-d) -p? r? m? dm-4-ana (sic) x 3HC1 x H20, dot melting: 311-312 ° C (decomposition) 104. 3,4,5,6,7, 8-Hexah? dro-7- (4-pheny1) buty 1-3- (2- (4-paft- 1-y 1) -lp? Pera in? L) et? L) p? Pdo (4 ', 3': 4,5) t? Ene (2, 3-d) -p? Pm? D? P-4-one (sic) x 3HC1 x H20, melting point: 312-314 ° C (decomposition) 1 5. 3,4,5,6,7,8 -He "ah? Dro-7- (4 ~ meto: 'i'? Benc? L-3- (2- (4-naf t-1- / 1) -lp? Peraz? N? l) et? l) p? pdo (4 ', 3': 4,5) t? ene (2, 3-d) -p pm? d? n-4-one (sic) x 3HC1; H20, melting point: 275-277 ° C (decomposition) 106. 3,4,5,6,7, B-Hexah? Drs-7- (4-methoxy) pheny1) eti 1-3- (2 - (4-2-metax? Phen? L) -lp? Eraz? N? L) et? L?? P? Pdo (4 ', 3': 4,5) t? Ene (2,3-d) -p? pm? d? n-4-one (sic) x 3HC1 x 3H20, melting point: 297-298'C (decomposition) 107. 3,4,5,6,7,8-Hexah? dro- 7- (2-fen? L) et? l-3- (3- (4-naft-1-l) -lp? peraz? n? lprap? l) p? pdo (4 ', 3': 4, 5) t? ene (2.3 ~ d) ) -p? r? m? d? n-4-ana (sic), melting point: 153-155 ° C 108. 3,4,5,6,7,8-Hexah? dro-7- (2 -fen? 1) et? 3 -3- (2- (4-p? Pm? D? N-2-y 1) -l-piperalenyl) e? L) p? Pdo (4 ', 3': 4,5) thieno (2 , 3-d) -p? Pm? D? N-4-one (sic) x 2HC1 x 3H20, melting point: 304-305 ° C (decomposition) 109. 3,4,5,6,7, 8 -Hexah? Dro-7- (-feni 1) eti 1-3- (3- (4-p? Pm? D? N-2-y 1) -l-piperazyl) prop? L) p? Pda (4 ', 3': 4, 5) thieno (2.3-d) -p? Pm? D? N-4-one (sic) x 3HC1 x 2H20, melting point: 302-303"C (decomposition) 110. 3 , 4,5,6,7, 8-Hexah? Dro-7- (3-benzoi lamino) ropí 1-3- (2- (4-pi pm? D? N-2-y 1) -l-pipera mil) et? l) p? pdo (4 ', 3': 4,5) thieno (2,3-d) -p? r? m? d? n-4-ana (sic) x 3HC1 x 3H20, melting point: 125-172 ° C (decontamination) 111. 3,4,5,6,7,8-Hexah? dro-7- (4-pen? l) bu ti l-3- (2 - (4-pipmi dm-2-y 1) -1 -pipera inyl) et?]) P? Pdp (4 ', 3': 4,5) t? Ene (2,3-d) -p? Pm ? d? n-4-one (sic) x 3HC1 x 3H20, melting point: 317-319 ° C (decay) 112. 3,4,5,6,7,8-Hexah? dro-7- (2- (4-m tax?) Phen? L)? L-3- (2- (4-p? Pm? D? N-2-y 3) -l-piperazyl) et? L) p? Pdo (4 ', 3': 4, 5) thieno (2, 3-d) -p? R? M? Dm-4-opa (sic), point Fusion: 165-167 ° C (decomposition) 113. 3,4,5,6,7,8-Hexah? Dro-7-acet? L-3- (3- (4- (2-meta? Phen? L) -1-p? Pera m? L) prop 3) p? Pdo (4 ', 3': 4,5) t? Ene (2,3-d) -pi r? M? D? N-4-? M? Na x 2HC1, melting point: 265-268 ° C 114. 3,4,5,6,7, 8-Hexahi dro-7-aceti 1-3- (3- (4- (2-meto ifeni 1) -1-piperazyl) propyl) p ? pdo (4 ', 3': 4,5) t? ene (2,3-d) -p? pm? d? n-4-ana x 2HC1 x 2H20, melting point: 264-267 ° C 115. 3,4,5,6,7,8-Hexah? Dro-3- (2- (4- (2-methox? Pheni1) -1-p? Peraz? N? L) et? L) p? R? do (4 ', 3': 4,5) t? ene (2, 3-d) -p? pm? d? n-4-one, melting point: 168-170 ° C 116. 3.4, 5,6,7,8-Hexah? Dro-7-acet? L-3- (2- (4- (2-metax? Phen? L) -1-p? Peraz? N? L) et? L) p? pdo (4 ', 3': 4,5) thieno (2, 3-d) -p? r? m? d? n-4-ana, melting point: 170-172 ° C 1? 7. 3,4,5,6,7, 8-Hexah? Dro-7-benzo? 1-3- (2- (- (2-ethoxyphenyl) -lp? Peraz? N? L) et? L) p? R? Do (4 ', 3': 4,5) ieno (2,3-d) ) -p? pm? dm-4-one x 2HC1 x 2H20, melting point: 185-187 ° C (descompasi in) 118. 3,4,5,6,7, 8 ~ Hexah? dra-7-ben zsi 1-3- (2- (-naf tl-1) - 1-piperaziml) et? l) p? pda (4 ', 3': 4, 5) t? ene (2, 3-d) -p ? pm? d? n-4-one (sic), melting point: 185-187 ° C 119, 3,4,5,6,7,8-Hexah? dra-7-benzo? l-3- ( 2- (4-p? Pd? M-2-yl) - 1-p? Peraz? P? L) et? 1) p? Pda (4 ', 3: 4, 5) t? Ene (2, 3-d) -p? R? Rn? D? N-4-one (sic), melting point: 130-132 ° C (decomposition) 120. 3,4,5,6,7, 8-Hexah? dro-2, 7-d? met? 1 -3- (2- (4- (2-meto? Phen? L) -lp? Peraz? N? L) et? L) p? R? Da (4 ', 3': 4, 5) thieno ( 2, 3-d) -p? R? M? D? N-4-op, melting point: 176-178 ° C 121. 3,4,5,6,7, S-Hexah? Dro-7- acet? l-2-h? drox? -3- (2- (4- (2-metax? phen? l) -lp? peraz? n? l) et? 3) p? pdo (4 ', 3' : 4,5) t? Ene (2,3-d) -p? Pm? D? N-4-apa, melting point: 135-137 ° C 12. 3,4,5,6,7, 8-Hexah? Dro-7-acet? 1-3- (1- (4- (2-methox? F eni 1) -1-p? Peraz? N? L) prop-2-y 1) p? Pdo (4 ', 3': 4.5 ) thieno (2,3-d) -p? pm? d n-4-one, melting point: 184-186 ° C 123. 3,4,5,6,7,8-Hexah? dra- (l - (4-naph tly 1-1-piperazinyl) prop-2-y 1) pddo (4 ', 3': 4,5) t? Ene (2,3-d) -p? Pm? D? n-4-one (sic) x 2HC1 x 4H20, melting point: 242-244 ° C (decomposition) 124. 3,4,5,6,7, 8-Hexah? d ro-7-me ti 1 - 3- (2- (4- (2-me to if in 11) -lp? Peraz? N? L) prop? L) pipdo (4 ', 3': 4,5) t? Ene (2, 3- d) -p? pm? d? n-4-one x 3HC1 x 3H20, melting point: 190-192 ° C (decomposition) C Measurement of receptor binding Preparation of cell membranes carrying receptors Linkage studies with receptors were carried out with preparations of membranes obtained from cell cultures of line 293 of human embryonic kidney cells in each of which a specific serotonin receptor subtype (h5HTlA, h5JTlB) was cloned and permanently expressed. or hSHTID). Cells were cultured in a RPMT 1640 medium (Life Technologies) which also contained 107. of fetal calf serum (FCS), 2 mmol / i (sic) L-glutamine and 400 mg / l of genetesin G 418. The cells were embedded in a stack of trays under an atmosphere of air / 57. C02 in an incubator at a temperature of 37 ° C until obtaining a continuous monalayer of cells. The cells were then detached from the culture vessels employing a regulator of the following composition: (amounts per liter) trypsin 10 mg; EDTA 4 mg; ETTA 200 mg; fc'Cl 200 mg; I-? 2P04 200 mg; Na2HP04 1.15 G; NaCl 8.0 g; pH 7.4. The cell suspension was formed into pellets (lagoon), resuspended in a Dulbeccs phosphate buffered saline (PBS) solution and the cell density was adjusted to approximately 100,000,000 cells / ml. After a new formation in pellets, the PBS was replaced by the same volume of lysis buffer at ice temperature (5 mmsl / 1 tris; glycerol 107, pH 7.4) and was incubated at 4 ° C for 30 minutes. The cells used (= membrane) were stored in aliquots in liquid nitrogen until their use in studies of receptor binding. An aliquot of each preparation was used to determine the protein content. The compounds according to the present invention show a high affinity (.; (S? C) less than or equal to 30 nM) for the types of human 5-HT1A, 5-HT1B and 5-HT1D receptors expressed in cloned cell lines . Receptor binding assay Receptor binding studies were carried out in 1 ml macropod tubes containing the following components: - 50 μl of the test substance in various concentrations for competition measurements or 50 μl of assay buffer or biep 50μl of non-labeled serotanipa (1 μmol / 1 final) to determine the total non-specific binding control. - 200 μl of membrane suspension of the appropriate receptor subtype with a pratein content of 200 μg / tube - 250 μl of a solution of radioligand (3H) 5-carbaxamidotriptamipa (5-CT) for h5HT! B and hSHTID receptors or ( 3H) 8-hydroxypiplopilaminotetral ina (8-0H-DPAT) for hSHTIA receptors. The final concentrations of the radioligands were adjusted to 3 nmol / 1 and 0.3 nmol / 1 respectively.

The test regulator (H 7.4) has the following composition (per liters): tris 6.057 g; CaC12x2H20 = 5.88 g; ascorbic acid 1 g; Pargiline 1.96 mg. The assay mixture was incubated at 25 ° C for 30 minutes and then filtered through glass fiber filters (Whatman GF / B) using a cell-cased apparatus (St'-atron) and the filters were washed with water. to 9 ml of cold regulator. The filters were mixed in scintillation flasks with, in each case, 5 ml of Ultima GadxR liquid scintillation agent (Packard) and stirred for 1 hour, and then the radioactivity was determined in a beta counter (Wallac). The measured data were analyzed by iterative non-linear regression analysis using the statistical analysis system (SAS), which is similar to the LIGAND program described by Munson and Rodbard (Anal.Biachem: 107, 220 (1980)). The competition constants (Ki) are indicated in n ol / 1.

Claims (6)

1. CLAIMS 1. A derivative of 3,4, 5,6,7,8-hexahydropyrido (4 ', 3': 4,5) thieno (2,3-d) pi.rimidine substituted in 3 of the formula I where R 1 is hydrogen, (C 1 -C 4) alkyl, acetyl or benzoyl, a phenylalkyl radical (C 1 -C 4), the aromatic ring unsubstituted or substituted by halogen, alkyl (Cl-C 4), trifluoromethyl, hydroxyl, alkoxy (C 1 -) C4), amino, cyano or nitro groups, is either a naphthalyl (C1-C3) radical, or a phenylalkanone radical (C2-C3). or a phenylcarbamoylalkyl radical C2, it being possible for the phenyl to be substituted by halogen, R2 is phenyl, pyridyl, pyrimidinyl or pyrazinyl, each of which is unsubstituted either mono-, di- or trisubstituted by halogen atoms, alkyl ( C1-C4), trifluoromethyl, trifluoromethoxy, hydroxy, (C1-C4) alkoxy, amylo, monomethylamino, dimethylamino, cyano or nitro groups, and each of which may be fused with a benzene nucleus which may be unsubstituted or well anosubstituted or disubstituted by halogen atoms, r = > l
2. (C 1 -C 4) alkyl, hydroxyl, trifluoromethyl, alkoxy (CI-C 4, amiphos, cyano or nitro groups, and may have a nitrogen atom with either a 5- or 6-membered ring which may contain 1-2 pyrites. Oxygen, or it may be substituted by a fepyl group (C1-C2) alkyl or -alkoxy, it being possible for the phenyl to be substituted by halogen, a methyl group, trifluoromethyl or methoxy,
3. A is NH or an oxygen atom. B is hydrogenated to ethyl, C is hydrogen, methyl to hydroxyl, X is a nitrogen atom, Y is CH2, CH2-CH2, CH2-CH2-CH2 or CH2-CH, Z is a nitrogen atom, carbon atom or CH, and it is also possible that the bond between Y and Z is a linkable link, and n is 2, 3 or 4, and the phially tolerated salts thereof. 2. A compound according to claim 1, wherein R1 is methyl, ethyl, isapropyla, benzyl, substituted benzyl, phenethyl, substituted phenethyl, R2 is o-methoxyphepyl, l-naphthyl, pyrimidin-2-y, 2-methoxy -l-naphthyl, 2-methyl-l-naphthyl, A is NH or an oxygen atom, X is a nitrogen atom, Y is CH2-CH2, CH2-CH. Z is a nitrogen atom, carbon atom or CH, and n is 2 and 3. 3. The use of a compound according to claims 1-2 to produce drugs.
4. 4. The use according to claim 3, for the treatment of depression and related disorders.
5. 5. The use of a compound according to claims 1-2, as a selective antagonist of 5-HT1B and 5-HT1Z.
6. 6. The use according to claim 5, wherein the selective antagonism of serotonin is complemented by the inhibition of seratonipase reuptake. SUMMARY PE THE INVENTION. Derivatives of 3, 4, 5, 6, 7, '8-hexahydropyrido (4', 3 ': 4, 5) thieno (2,3-d) pirim.id.ina substituted in 3 of the formula I where R1 is hydrogen, (C1-C14) alkyl, acetyl c-bepzails, or a phenylalkyl (C1-C4) radical, the aromatic ring is ipsubstituted or substituted by halogen, alkyl (Cl-C4), trifluoroethyl, hydroxyl, (C 1 -C 4) alkoxy, amino, cyano or nitro groups is either a naphthalyl radical (Cl-C3), a radical of fepilalcanone (C2-C3), or a phenylcarba radical or C2 alkyl, it being possible for the phenyl is substituted by halogen, R 2 is phenyl, pyridyl, pyrimidinyl or pyrazinyl, each of which is unsubstituted or is monosubstituted, disubstituted or trisubstituted by halogen atoms, (C 1 -C 4) alkyl, trifluoromethyl. trifluoromethoxy, hydraxyl, (C 1 -C 4) alkoxy, amino, monomethylamino, dimethylamino, ciapo or nitro groups, and each of which may be fused with a benzene nucleus which may be more substituted to either monosubstituted or substituted by atoms of halogen, (C1-C4) alkylaryl, hydraxyl, tri-luoto et i3 o, (C1-C4) alkoxy, amino, cyano or nitro groups, and may contain a nitrogen atom, or may contain a ring of 5 or 6 members that can contain 1-2 oxygen atomsit may well be substituted by a phenyl (C1-C2) alkyl or alkoxy group, it being possible that the phenyl is substituted by halogen, a methyl group, trifluoromethyl or meta i, A is NH or an oxygen atom, B is hydrogen or methyl, C is hydrogen, methyl or hydraxyl, X is a nitrogen atom, Y is CH2, CH2-CH2, CH2-CH2-CH2 to a well CH2-CH, Z is a nitrogen, nitrogen carbon to good CH, it being also possible that the bond between Y and Z is a double bond, and n ee 2, 3 or 4, and the physiologically tolerated salts thereof.