N-substituted derivatives of 3-azabicyclo (3.2.0)heptane or their salts with physiologically compatible acids

 

(57) Abstract:

Describes compounds of formula I, where R1, R2, n, R3, A, X, Y, and Z have the values listed in paragraph 1 of the formula. The new compounds are suitable for controlling diseases, such as neuroleptic tools, anti-depressive drugs, sedatives, hypnotics and means to protect the Central nervous system or muscle relaxants. 1 C.p. f-crystals.

The invention relates to new N-substituted azabicycloalkanes.

It is known that substituted through the grounds, 5 - or 6-tier heterocyclic derivatives of nitrogen have neuroleptic activity (European patent application 196132, European application 70053, European application 110435).

Thus the observed high affinity with serotonin receptors, along with dopamine-affinity, plays, apparently, a special role.

It was found that N-substituted derivatives of 3-azabicyclo[3.2.0]heptane of formula I

< / BR>
where R1denotes phenyl, optionally, one or disubstituted by a halogen atom, a C1-C4-alkyl, trifluoromethyl, hydroxy, C1-C4-alkoxy, amino, monomethylamine, dimethylamino, cyano or nitro; thienyl, optionally substituted atoms ha is>/BR>n denotes the number 0, 1, 2, 3, or 4

R3denotes a hydrogen atom, a C1-C4-alkyl, or together with the adjacent carbon atom represents a group C=O; and the ring in the right part of the formula I may be saturated or may contain 1-3 double bonds, denoted by ---, when X represents a carbon atom, Y represents nitrogen, NH or C1-C4-alkyl-N -, and Z denotes CO-group or a C1-C4-alkoxy-C-group and the nitrogen atom in the first position may be hydrogen or C1-C4-alkyl,

A denotes a hydrogen atom, amino, C1-C4-alkylamino, C1-C4allylthiourea or together with the adjacent carbon atom represents a group C=O, or when X represents a carbon atom, nitrogen, CH, Y is a carbon atom or nitrogen, and the nitrogen atom in the first position may carry a hydrogen atom, a C1-C4alkyl or benzyl, And means associated with the Y group selected from-S-CH2-CH2-, -S-CH2-CH2-CH2, -S-CH= CH-, -CH2-CH2-CH2-CH2- and-CH=CH-CH-CH=CH-, and in the case of the latter group, it can be one-deputizing fluorine atom or chlorine, or mono - or disubstituted hydroxy or methoxy group, or their salts with physiologically compatible acids.

As ewenny optionally fluorine atom or chlorine, methoxy-, nitro-, trifluoromethyl-, hydroxy - or amino - group,

R2: hydrogen,

R3: methyl, and

n: 2.

Cyclic system in the right part of the formula 1 represents, in particular,

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Preferred are compounds in which

R1represents preferably phenyl substituted in para-position by a fluorine atom and chlorine, or m-position by fluorine atom or chlorine,

R2denotes hydrogen and

R3denotes methyl

and cyclic system in the right part of the molecule is made up of

7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-it,

7-methyl-2,3-dihydro-5H-thiazolo [3,2-a]pyrimidine-5-it,

8-methyl-2N,6N-pyrimido[2,1-b] [1,3]thiazin-6-it,

2,4-(1H,3H)-chineselanguage,

2-methyl-4H-pyrido[1,2-a]pyrimidine-4-it,

6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-or

2-methylamino-3,6-dimethyl-4(3H)pyrimidinone.

The following connections should be specified as particularly preferred:

6-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-7 - methyl-5H-thiazolo[3,2-a]pyrimidine-5-he,

6-- [Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl-7-methyl-5H-thiazolo [3,2-a]pyrimidine-5-he,

6-- [Exo-6-p-forfinal-sabillo[3.2.0] heptane-3-yl] -ethyl-8 - methyl-2N,6N-pyrimido[2,1-b][1,3]thiazin-6-he,

3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]-ethyl-2,4- (1H, 3H)-hintlinin,

3-- [Exo-6-p-triptoreline-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl-2,4-(1H,3H)-hintlinin,

3--[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2 - methyl-4H-pyrido-[1,2-a]pyrimidine-4-one,

3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]-pyrimidine-4-one,

5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-2-methylamino-3,6-dimethyl-4(3H)-pyrimidinone,

5-- [Exo-6-m-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl] ethyl-2 - methylamino-3,6-dimethyl-4(3H)-pyrimidinone.

The compounds of formula I according to the invention can be obtained by converting the compounds of formula II

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in which n, R3X, Y, Z and A have the above meanings and Nu represents oleophobol end group, using 3-azabicyclo[3.2.0]heptane-derived formula III

< / BR>
where R1and R2have the above values, and the transformation of the thus obtained compounds respectively in additive salt of physiologically compatible acids.

As nucleopore tsepliaeva group for Nu discusses preferably the atoms of halogen, in particular bromine or chlorine.

The transformation is carried out usually at a temperature of from 20 to 150oC, especially from 80 to 140oC and ends usually within 1-10 hours.

The compounds of formula I can precrystallization or by recrystallization from common organic solvents, preferably from a lower alcohol, as ethanol, or can be purified by using column chromatography.

The racemates can be separated in a simple way by classical splitting with optically active carboxylic acids, for example, derivatives of tartaric acid, in an inert solvent, for example, lower alcohols, for enantiomers.

Free 3-azabicyclo[3.2.0]heptanedione formula I can be translated in the usual way in additive salt of the pharmacologically compatible acid, preferably by mixing the solution with the equivalent of the appropriate acid. Pharmaceutically compatible acids are, for example, hydrochloric acid, phosphoric cikadiketha, tartaric acid or citric acid.

Compounds according to the invention have valuable pharmacological properties. They can be used as adjunct tools (in particular, atypical), anti-depressive drugs, sedatives, hypnotics, means for protecting the Central nervous system or muscle relaxants. In the same connection according to the invention can be combined several of these properties. Pharmacological efficacy is confirmed both in vivo and in vitro, with the substance is possible, in particular, due to the partly very high and selective affinity for subtypes of receptors, such as dopamine D1-, D2-, D3-, D4receptors; serotonin 1A-1D and 2 receptors; alpha 1 and 2 receptors; histamine 1-and muscarine receptors.

To obtain the characteristics of in vivo following methods were applied:

a) Impact on the alignment motor skills

In the new environment mice show heightened arousal, which is expressed in increased motor activity. This motor activity measured in cells with a light barrier for time from 0 to 30 minutes after placing animals (NMRI-mouse wives. individuals) in cells.

ED50: RBS, 50%.

b) Apomorphine-antagonism

Female NMRI mice get to 1.21 mg/kg of apomorphine subcutaneously. Apomorphine at this dose leads to increased motor activity, which is expressed, if animals are kept in cages of wire mesh, constant climbing. The lasagna is determined by a scoring system (every 2 minutes for 30 minutes):

0: four paws animal on the floor

1: two paws of an animal on a wire

2: four paws pet on a wire (scrambles).

By pre-processing antipsychotic means you can suppress this state of excitement.

ED50: dose that inhibits the activity of climbing the animal compared to control animals treated with placebo, 50%.

C) Methamphetamine-antagonism

Female NMRI-mice receiving 1 mg/kg methamphetamine oral and after 30 minutes, placed in a cell with a light barrier for the measurement of motor activity (2 animals/cage, 4 cells/dose). The subjects of the substances are administered orally 30 minutes prior to methamphetamine. Increased activity of methamphetamine is calculated for the period of time from 15 to 60 minutes after placing the animals in the cage and is defined as the difference between relevant is ebo, and set to 100%. ED100 is a dose of the test substance, which eliminates the activity.

g) L-5-str-antagonism

Female rats Sprague-Dawlay get L-5-HTP at a dose of 316 mg/kg intraperitoneally. After that, the animals receive an excitation syndrome with symptoms:

- pulling legs and

- shake,

which are determined by a scoring system (0 = no, 1 = moderate, 2 = pronounced) every 10 minutes within 20-60 minutes after administration of L-5-HTP. On average after the introduction of L-5-HTP is achieved score = 17. Subjects substances are introduced orally 60 minutes prior to L-5-HTP. ED50 is the dose sufficient to reduce the control points on average by 50%.

The methods are suitable for obtaining the characteristics of the substances as antipsychotic drugs; in particular, the suppression of locomotor stimulation induced by methamphetamine, is the assessment of antipsychotic action. Suppression syndrome caused by L-5-HTP, you can confirm the antagonistic action of serotonin, i.e. efficiency, which is typical for the so-called atypical antipsychotic funds.

In these tests, the new compounds show high efficiency.

In sommeeeeeoneee formula I or its pharmacologically compatible additive salt of the acid as the active substance together with conventional excipients and diluents, as well as the application of new compounds in disease control.

Compounds according to the invention can be administered in the usual way orally or parenterally, intravenously or intramuscularly.

The dosage depends on age, condition and weight of the patient and on the type of application. As a rule, the daily dose of active substance is from about 1 to 100 mg/kg BW after oral introduction and from 0.1 to 10 mg/kg body weight at parenteral administration.

New connections can be used in conventional galenical solid or liquid form, for example, in the form of tablets, pills in the shell, capsules, powders, granules, pills, suppositories, solutions, ointments, creams or sprays. The active substance can be manufactured with conventional galenovye AIDS, such as binders, fillers, preservatives, wetting agents, means for regulating fluidity, softeners, moisturizing agents, dispersing agents, emulsifiers, solvents, retarding agents, antioxidants and/or blowing means (cf. N. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978).

Thus obtained forms applied for the s biological testing of the compounds of formula I, demonstrating high activity of these compounds as antagonists of dopamine D4 receptors. The study of binding was carried out using transfection Cos7 cells expressing the cloned human D4 receptor. Lysed cells were resuspendable in incubation buffer (50 mM Tris-HCl, pH 7,4) containing 5 mM add, 1.5 mM CaCl, 50 mM KCl, 1200 nM NaCl and 5 mM MgCl2at concentrations of 105cells in the experience. Incubation was carried out at 25oC with 50 PM [125I] spiperone in the presence or in the absence of the tested compounds.

Nonspecific binding was determined with 10-6M haloperidol. After 60 min incubation of radioactively labeled cells and without labels was determined by rapid filtration through glass fiber filter GF/B (Whatman, England), using Satanovsky harvester cells (Skatron, Lier, Norwey). The filters were washed Tris-HCl - buffer, pH 7.0, containing 20 mM MgCl2and 7% of polyethylene glycol 6000. Bound radioactivity was determined using liquid scintillation counter Packard 2200 CA.

The value of Ki [nmol/1] using the analysis of nonlinear regression using the program LIGAND.

The following results were obtained:

The connection of PR 137 - 2.4GHz

141 - 1.3

148 - 1,7

152 - 6

Antagonistic properties towards the D4 dopamine receptor is very important, because the affinity for D4 dopamine receptors play a huge role in terms of antipsychotic activity. The influence of dopamine receptors in the origin and course of mental illness, particularly schizophrenia, when the number of these receptors exceeds six times compared with the normal level, quite clearly shown in the recent works in this area, therefore, the value obtained new compounds is extremely high.

Given that they are very low-toxic substances, the prospects for their use in the treatment of mental illness no doubt.

Substances of the formula II required as starting substances for the synthesis of new compounds, are known or can be synthesized according to methods of obtaining described in the literature, from a similar source materials.

Substances of the formula III can be obtained by the fact that the amine of the formula

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where R1and R2have the above meanings and R4denotes hydrogen, acetyl, benzyl or TRIFLUOROACETYL, is subjected to the accession of cycle 2 + 2 photo is well proceeds in an inert solvent, preferably acetone, at temperatures from 20 to 80oC. as a light source is particularly well suited mercury lamp high pressure. Under certain conditions it is advisable to carry out photocycloaddition in a quartz apparatus in a nitrogen atmosphere under certain conditions with the addition of about 1 mol of hydrochloric acid per mole of amine.

Photocycloaddition flows in most cases vysokovostrebovannye relative to the bicyclic compounds of the formula III with Exo-configuration relative to R1and R2:

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By splitting of the racemate, for example, using active derivatives of tartaric acid, it is possible to allocate both enantiomers in pure form.

Cleavage of accelgroup is carried out by known methods. By analogy is removed benzinga.

Amines of formula IV are known from the literature or can be obtained either by converting the aldehyde R1-CHO-vinyl chloride magnesium allyl alcohol V

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subsequent rearrangement using hydrogen chloride in allylchloride VI

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and finally, by substitution of the appropriate allylamino VII

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or cinnamic aldehyde VIII

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put the bar

The following examples serve to explain the invention.

A. Obtaining raw materials

AA) 1-(4-forfinal)-allyl alcohol

In a flask with a capacity of 4 liters with a stirrer in a nitrogen atmosphere poured 1550 ml (2.0 M) Of 1.29 M solution of vinylmania in tetrahydrofuran. Then, under stirring and under nitrogen atmosphere was added within 30 minutes at a temperature of 30-35oC solution of 222,0 g (1,764 M) 4-forventelige in tetrahydrofuran, and the reaction mixture was cooled with ice. The reaction mixture was stirred for another 2.5 hours in a nitrogen atmosphere at room temperature. Thereafter, under stirring and ice cooling was added 180 ml of water have been pumped out and the filtrate washed three times with 150 ml of tetrahydrofuran. The filtrates were combined, dried using sodium sulfate and concentrated. Got 265,7 g (99%) of product as a yellow-brown oil.

ab) 3-(4-forfinal)-allylchloride

273,6 g (1,798 M) 1-(4-forfinal)-allyl alcohol was dissolved with stirring in 2000 ml of methanol. Then for 3 hours was introduced 101.0 g (2,770 M) hydrogen chloride, and the temperature was raised to 37oC. and Then stirred for 1 hour. After washing with 600 ml of ice water and a mixture of 150 ml of a saturated solution of powerengine oil.

AC) N-allyl-N-[3-(4-forfinal)-allyl]-amine

To a solution of 795,0 g (13,92 M) allylamine in 360 ml of toluene was added at reflux for 25 minutes 231,8 g (1,359 M) 3-(4-forfinal)-allylchloride and stirred for 1 hour at a temperature of heating under reflux. Then drove 1000 ml in 10-cm distillation column (5 mm glass rings) with a bath temperature of up to 125oC. the distillation Residue was mixed with 1000 ml of water and with 38% hydrochloric acid, the pH was set to 0.7. The organic phase was separated and removed. the pH of the aqueous phase was established by 12.7 using 50% aqueous sodium hydroxide and was extracted with toluene and concentrated. The rest drove through the column at a pressure of from 0.7 to 1 mbar. With a bath temperature of 120-160oC got 191,8 g (74%) of light yellow oil.

ad) [Exo-6-(p-forfinal)-3-azabicyclo[3.2.0]heptane

of 19.4 g (102 mm) of N-allyl-N-[3-(4-forfinal)-allyl]-amine in 130 ml of acetone was mixed with 130 ml of 10% hydrochloric acid and 600 mg of michler ketone and in nitrogen atmosphere for 55 hours was irradiated with a mercury lamp high pressure power 150 watts in a quartz apparatus at room temperature. Then the reaction mixture was concentrated and the residue Rau was extracted twice more with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated. The product yield 19.3 g (99%), melting point 165-166oC (malaikat).

For the separation of the antipodes 15.0 g (78.5 mm) of the racemate was treated with a solution of 31.7 g (78.5 mm) (-)-di-O-toluoyl-L - tartaric acid in 300 ml of boiling ethanol. Crystals (13.8 g), dropped under cooling with stirring, was aspirated with additional washing with ethanol and recrystallized from 200 ml of ethanol with the addition of 200 ml of water. By liberating the Foundation received (+)-antipode of (5.5 g) with []D+97,0 (EtOH, C = 0,969).

From the above stock solution were led during the night of 14.2 g of salt, which was recrystallized from 400 ml of ethanol, filtering off the insoluble parts of boiling ethanol (concentration up to 300 ml). By liberating the Foundation received a 4.0 g -(-)-antipode c []D= -96,0o(EtOH, C = 0,940).

Configuration Exo-phenyl were traced using x-ray diffraction analysis.

ae) Exo-6-phenyl-3-azabicyclo[3.2.0]heptane

50.0 g (28,9 mm) N-cinnamyl-N-allylamine in 1600 ml of acetone was mixed with 300 ml of 10% hydrochloric acid and irradiated in a nitrogen atmosphere for 48 hours mercury lamp high pressure power is especilaly between methylene chloride and water. Using an aqueous solution of ammonia was podslushivaet and the aqueous phase was extracted twice more with methylene chloride. The combined organic phases were dried with sodium sulfate and concentrated.

Yield: 49,0 g (98%) of a viscous oil having a melting point of 177-178oC (malaikat).

af) [Exo-6,7-diphenyl-3-azabicyclo[3.2.0]heptane

To 12.0 g (35.4 mm) [Exo-6,7-diphenyl-3-benzyl-3-azabicyclo[3.0 - 2.0] heptane in a mixture of 300 ml of n-propanol and 1 ml of water was added 16.0 g (254 mm) of ammonium formate, and 2.0 g of palladium (10%) on coal and the reaction mixture is boiled for 4 hours under reflux (carbon dioxide). After cooling, was aspirated from the catalyst, washed with propanol and methylene chloride and the filtrate was concentrated. The residue was distributed between methylene chloride and water, with an aqueous solution of ammonia was podslushivaet and the aqueous phase was extracted twice more with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated. Got to 8.1 g (92%) of product, melting point 140 to 142oC (malaikat).

ag) N-allyl-N-3-(3,5-dichlorophenyl)-allylamine

To 12.0 g (59,7 mm) 3,5-dichloroamino aldehyde in 180 ml of methylene chloride was added to 4.5 ml (60 mm, 3.4 g) temperature. Then was filtered sodium sulphate, washed with methylene chloride and the filtrate was concentrated to dryness. Thus obtained yellow oil was dissolved in 200 ml of absolute methanol in a nitrogen atmosphere portions was added 2.5 g (66,0 mm) of sodium borohydride. Easily heated the reaction mixture was stirred again for 1 hour and then neutralized 10% hydrochloric acid (pH = 7). The solvent was removed in vacuo and the resulting residue was dissolved in methylene chloride. The organic phase is washed twice with water, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, methylene chloride + 5% methanol). The yield of 9.2 g (63%) of yellow oil.

ah) N-allyl-2,2,2-Cryptor-N-[3-(3-pyridyl)-allyl]-ndimethylacetamide

To a solution of 10.0 g (57.5 mm) of N-allyl-N-3-(3-pyridyl)-allylamine and 10.7 ml of triethylamine in 100 ml of tetrahydrofuran is slowly dropwise added to 16.1 g (76,6 mm) triftoratsetata at a temperature of 0oC. the Solution was stirred another 2 hours at room temperature. Then the reaction solution was poured into 250 ml of ice water and was extracted three times with portions of 150 ml simple tert. -butyl ether. The combined organic phases were dried over sulfate is(3-pyridyl)-3-azabicyclo [3.2.0]hept-3-yl] -alanon

14.0 g (51,8 mm) of N-allyl-2,2,2-Cryptor-M-[3-(3-pyridyl)- allyl]-ndimethylacetamide was dissolved in 140 ml of acetone, mixed with 30 ml of 10% aqueous hydrochloric acid and the nitrogen atmosphere was irradiated for 48 hours mercury lamp high pressure power of 150 W in the apparatus of glass "Durand" at room temperature. Then the reaction solution was concentrated, dissolved in 150 ml of water and with aqueous ammonia solution pH was brought to 8-9. The aqueous phase was twice extracted with simple tert.-butyl methyl ether, the combined organic phases were dried over sodium sulfate and concentrated. The residue was separated into fractions using column chromatography (silica gel, methylene chloride + 2% methanol). Obtained 6.2 g (42%) of the original N-allyl-2,2,2-Cryptor-N- [3-(3-pyridyl)-allyl] -ndimethylacetamide and 3.7 g (26%) of 2,2,2-Cryptor-1- [Exo-6-(3-pyridyl)-3-azabicyclo[3.2.0] hept-3-yl] -ethanone in the form of a dark oil.

ak) [Exo-6-(3-pyridyl)-3-azabicyclo[3.2.0]heptane

To a solution of 3.7 g (13,7 mm) 2,2,2-Cryptor-1-[Exo-6-(3-pyridyl)-3 - azabicyclo[3.2.0]hept-3-yl]-ethanone in 50 ml of ethanol was added 2.5 g of the pellets of potassium hydroxide. The reaction solution was stirred another 2 hours at room temperature and then was poured into 100 ml ice water. The aqueous phase was extracted three times simple tretched product 2.3 g (96%) of yellow oil, melting point 202-205 areoC (hydrochloride).

By analogy can be obtained from the following ingredients:

al) [Exo-6-(m-forfinal)-3-azabicyclo[3.2.0]heptane,

am) [Exo-6-(o-forfinal)-3-azabicyclo[3.2.0] heptane, melting point 118-120oC (malaikat),

an) [Exo-6-(p-chlorophenyl)-3-azabicyclo[3.2.0] heptane, melting point 152-154oC (malaikat),

ao) [Exo-6-(m-chlorophenyl)-3-azabicyclo[3.2.0] heptane, melting point 130-132oC (malaikat),

ap) [Exo-6-(p-methoxyphenyl)-3-azabicyclo[3.2.0]heptane,

aq) [Exo-6-(m-methoxyphenyl)-3-azabicyclo[3.2.0]heptane,

ar) [Exo-6-(p-nitrophenyl)-3-azabicyclo[3.2.0]heptane, melting point 158-160oC (malaikat),

as) [Exo-5-(m-nitrophenyl)-3-azabicyclo[3.2.0]heptane,

at) [Exo-6-(p-triptoreline)-3-azabicyclo[3.2.0]heptane, melting point 155-156oC (malaikat),

au) [Exo-6-(m-triptoreline)-3-azabicyclo[3.2.0]heptane,

av) [Exo-6-(3,4-dichlorophenyl)-3-azabicyclo[3.2.0]heptane,

aw) [Exo-6-(3,5-dichlorophenyl)-3-azabicyclo[3.2.0] heptane, melting point > 250oC (hydrochloride),

ax) scso-6-(3,4-acid)-3-azabicyclo[3.2.0]heptane,

ay) [Exo-6-(m-hydroxyphenyl)-3-azabicyclo[3.2.0]heptane,

az) [Exo-6-(p-hydroxyphenyl)-3-sabicic the CLO[3.2.0]heptane,

be) scso-6-(m-were)-3-azabicyclo[3.2.0]heptane,

bd) [Exo-6-(p-tert.-butylphenyl)-3-azabicyclo[3.2.0]heptane, melting point > 255oC (hydrochloride),

bc) [Exo-6-(m-AMINOPHENYL)-3-azabicyclo[3.2.0]heptane,

bf) [Exo-6-(p-AMINOPHENYL)-3-azabicyclo[3.2.0]heptane,

bg) [Exo-6-(p-cyanophenyl)-3-azabicyclo[3.2.0]heptane, melting point 168-178oC (malaikat),

bh) [Exo-6-Tien-2-yl-3-azabicyclo[3.2.0] heptane, melting point 180-182oC (hydrochloride),

bi) [Exo-6-Tien-3-yl-3-azabicyclo[3.2.0] heptane, melting point 143-145oC (hydrochloride),

bk) [Exo-6-(5-chlortan-2-yl)-3-azabicyclo[3.2.0] heptane, melting point 156-157oC (malaikat),

bl) [Exo-6-pyrrol-2-yl-3-azabicyclo[3.2.0]heptane,

bm) [Exo-6-pyrid-4-yl-3-azabicyclo[3.2.0]heptane,

bn) [Exo-6-pyrid-2-yl-3-azabicyclo[3.2.0]heptane.

C. the final product

Example 1

The dihydrochloride 6---[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-7-methyl-5H-thiazol[3.2-a]pyrimidine-5-it

< / BR>
2.5 g (13.1 mm) [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane in 40 ml of xylene was mixed with 3.6 g (26 mm) 6-(2-chloroethyl)-7-methyl - 5H-thiazole[3,2-a] pyrimidine-5-it, and from 5.6 g (40 mm) of finely powdered potassium carbonate and 0.5 g of potassium iodide and cipal on a rotary evaporator apparatus and distributed the residue between methylene chloride and water.

The aqueous phase was twice extracted with methylene chloride and then the organic phase was concentrated after drying with sodium sulfate. The crude product (7.7 g) was purified by column chromatography (silica gel, the solvent methylene chloride/methanol in the ratio of 96/4).

The free base (3.5 g) was dissolved in 150 ml of simple ether, was filtered insoluble flakes and the ether solution was mixed with excess ethereal hydrochloric acid. Then, in a nitrogen atmosphere was sucked out solids in the cold, hydrochloride was washed with a sufficient number of simple ether and the salt was dried on a suction filter in a nitrogen atmosphere. Allocated 3.5 g (60%) of product x 2 HCl, melting point 222-224oC. Maleinate melts at 133-135oC.

By analogy, we can get:

1A. (+)-6 -- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-7-methyl-5H-thiazol[3.2-a] pyrimidine-5-he maleinate, melting point 158-160oC []D= +56,2o(EtOH),

1b. (-)-6- -- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] ethyl-7-methyl-5H-thiazol[3.2-a] pyrimidine-5-he maleinate, melting point 147-149oC []D= -52,8o(EtOH),

2. 6-- [Exo-6-phenyl-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-7-methyl - 5H-thiazole[3,2-a]Piri]-ethyl-7 - methyl-5H-thiazole[3,2-a]pyrimidine-5-he melting point 154-156oC,

4. 6-- [Exo-6,7-bis-(p-forfinal)-3-azabicyclo [3.2.0]heptane-3-yl]-ethyl-7-methyl-5H-thiazol[3.2-a]pyrimidine-5-he,

5. 6-- [Exo-6-m-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-7-methyl-5H-thiazole[3,2-a] pyrimidine-5-he, melting point 162-164oC (malaikat),

6. 6-- [Exo-6-m-methoxyphenyl-3-azabicyclo[3.2.0]- heptane-3-yl]-ethyl-7-methyl-5H-thiazole[3,2-a] pyrimidine-5-he, melting point 149 to 152oC (malaikat),

7. 6-- [Exo-6-m-hydroxyphenyl-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl-7-methyl-5H-thiazol[3.2-a] pyrimidine-5-he (also see example 49), the melting point of 76-78oC,

8. 6-- (2-[Exo-6-p-AMINOPHENYL-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-7-methyl-5H-thiazol[3.2-a]pyrimidine-5-he (also see example 50),

9. 6-- [Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl]- ethyl-7-methyl-5H-thiazole[3,2-a] pyrimidine-5-he, melting point 155-157oC (malaikat),oC

10. 6-- [Exo-6-p-methoxyphenyl-3-azabicyclo[3.2.0]heptane-3-yl] -ethyl-7-methyl-5H-thiazole[3,2-a] pyrimidine-5-he, melting point 168-170oC (malaikat),

11. 6-- [Exo-6-p-nitrophenyl-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-7-methyl-5H-thiazole[3,2-a]pyrimidine-5-he,

12. 6-- [Exo-6-m-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-7-methyl-5H-thiazole[3,2-a]pyrimidine-5-he,

13. 6-),

14. 6-- [Exo-6-p-triptoreline-3 - azabicyclo[3.2.0]heptane-3-yl]-ethyl-7-methyl-5H-thiazole[3,2 - a] pyrimidine-5-he, melting point 187-189oC (malaikat),

15. 6-- [Exo-6-(p-tert.-butylphenyl)-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-7-methyl-5H-thiazole[3,2-a] pyrimidine-5-he, decomposition temperature 207-209oC (malaikat),

16. 6-- [endo-6-(p-tert.-butylphenyl)-3-azabicyclo [3.2.0]heptane-3-yl] -ethyl-7-methyl-5H-thiazole[3,2-a] pyrimidine-5-he, melting point 131-133oC,

17. 6-- [Exo-6-(3,4-dichlorophenyl)-3-azabicyclo [3.2.0]heptane-3-yl]-ethyl-7-methyl-5H-thiazole[3,2-a]pyrimidine-5-he,

18. 6-- [Exo-6-(3,4-acid)-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-7-methyl-5H-thiazole[3,2-a] pyrimidine-5-he, decomposition temperature 210-212oC (dihydrochloride),

19. 6-- [Exo-6-p-cyanophenyl-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-7-methyl-5H-thiazole[3,2-a]pyrimidine-5-he, melting point 130-132oC,

20. 6-- [Exo-6-(3,4-dihydroxyphenyl)-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-7-methyl-5H-thiazole[3,2-a]pyrimidine-5-he (also see example 49),

21. 6-- [Exo-6-(o-forfinal)-3-azabicyclo [3.2.0]heptane-3-yl]-ethyl-7-methyl-5H-thiazole[3,2-a] pyrimidine-5-he, melting point 164-165oC (malaikat),

22. 6-- [scso-6-Tien-3-yl-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-7-methyl-5H-thiazole[3,2-a]pyrimidine-5-he,
Exo-6-pyrid-4-yl-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-7-methyl-5H-thiazole[3,2-a]pyrimidine-5-he,

25. 6-- [Exo-6-pyrid-3-yl-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl-7-methyl-5H-thiazole[3,2-a]pyrimidine-5-he,

26. 6-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3 - yl]-ethyl-7-methyl-2,3-dihydro-5H-thiazole[3,2-a] pyrimidine-5-he, melting point 253-255oC,

27. 6-- [Exo-6-m-chlorophenyl-3-azabicyclo[3.2.0]heptane-3-yl] -ethyl-7-methyl-2,3-dihydro-5H-thiazole[3,2-a]pyrimidine-5-he,

28. 6-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2,3,7-trimethyl-5H-thiazole[3,2-a]pyrimidine-5-he,

29. 6-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-5H-thiazole[3,2-a]pyrimidine-5-he, melting point 164-166oC (dihydrochloride2O)

30. 6-- [Exo-6-phenyl-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-5H-thiazole[3,2-a]pyrimidine-5-he.

Example 31

The dihydrochloride of 7---[Exo-6-p-forfinal-3 - azabicyclo[3.2.0]heptane-3-yl] -ethyl-8-methyl-3,4-dihydro-2H,6N - pyrimido[2.1-b][1.3]thiazin-6-it

< / BR>
2.5 g (13.1 mm) [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane in 40 ml of xylene was mixed with 3.3 g (13,6 mm) 7-chloroethyl-8 - methyl-2N,6N-pyrimido[2.1-b] [1,3] thiazin-6-it, and with 5.0 g (36 mm) of finely powdered potassium carbonate and 0.5 g of potassium iodide and boiled under reflux with careful stirring for 12 hours.

After cooling, concentrated on a rotary you Aravali with methylene chloride and, after drying with sodium sulfate the organic phase was concentrated. The crude product (5.6 g) was purified by column chromatography (silica gel, the solvent methylene chloride/methanol in the ratio of 93/7).

The free base was dissolved in 200 ml of simple ether, insoluble flakes were filtered and mixed solution of simple ether with excess ethereal hydrochloric acid. Then in the cold under nitrogen atmosphere was sucked out solids, washed hydrochloride sufficient number of ordinary ether, and dried salt on the suction filter in a nitrogen atmosphere. Allocated 3.2 g (52%) of product x 2 HCl, melting point from 120 to 121oC. similarly, we can get:

32. 7-- [Exo-6-phenyl-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl-8-methyl-3,4-dihydro-2H,6N-pyrimido[2.1-b][1.3]thiazin-6-he,

33. 7-- [Exo-6-m-chlorophenyl-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl-8-methyl-3,4-dihydro-2H,6N-pyrimido[2.1-b][1.3]thiazin-6-he,

34. 7-- [Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0]heptane-3 - yl]-ethyl-8-methyl-3,4-dihydro-2H,6N-pyrimido[2.1-b][1.3]thiazin-6-he,

35. 7-- [Exo-6-p-methoxyphenyl-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl-8-methyl-3,4-dihydro-2H,6N-pyrimido[2.1-b][1.3]thiazin-6-he,

36. 7-- [Exo-6-m-hydroxyphenyl-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-8-methyl-3,4-dihydro-2H, 6N-pyrimido[2.1-b] [1.3] thiazin-6-he (also see example 49),

37. 3-- [Exo-6-p-forfinal-3-asabis henyl-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2,4-(1H, 3H)-hintlinin, melting point 160-162oC []D= +88,6o(CH2Cl2)

38b. (-)-3 -- [scso-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2,4-(1H, 3H)-hintlinin, melting point 161-162oC []D= -87,5o(CH2Cl2)

39. 3-- [3-azabicyclo[3.2.0]heptane-3-yl]-ethyl-2,4- (1H,3H)-hintlinin, melting point 158-160oC,

40. 3-- [Exo-6-phenyl-3-azabicyclo[3.2.0] heptane-3-yl]- ethyl-2,4-(1H, 3H)-hintlinin, melting point 144-146oC,

41. 3-- [Exo-6-m-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl-2,4-(1H,3H)-hintlinin, 284-286oC (hydrochloride),

42. 3-- [Exo-6-p-cyanophenyl-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl-2,4-(1H,3H)-hintlinin melting point 230-232oC,

43. 3-- [Exo-6-m-chlorophenyl-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl-2,4-(1H,3H)-hintlinin, melting point 183-185oC,

44. 3-- [Exo-6-p-hydroxyphenyl-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl-2,4-(1H, 3H)-hintlinin, melting point 220-223oC, (see also example 49),

45. 3-- [Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2,4-(1H,3H)-hintlinin, melting point 187-189oC,

46. 3-- [Exo-6-m-methoxyphenyl-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2,4-(1H,3H)-hintlinin, the temperature of the melt is temperature melting 209-211oC,

48. 3--[endo-6-p-nitrophenyl-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl-2, 4-(1H,3H)-hintlinin, melting point 212-214oC.

Example 49

3-- [Exo-6-m-hydroxyphenyl-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-2,4-(1H,3H)-hintlinin

< / BR>
To 4.6 g (11.8 mm) 3-- [Exo-6-m-methoxyphenyl-3-azabicyclo [3.2.0]heptane-3-yl] -ethyl-2,4-(1H,3H)-chineselanguage in 120 ml of methylene chloride was added dropwise to 28.5 ml (28.5 mm) tribromide boron (1 M solution in methylene chloride) at room temperature and the mixture was stirred over night. After cooling, was added 100 ml of 2N sodium hydroxide, separating the organic phase and the aqueous phase was extracted with methylene chloride. After drying and concentration was obtained 4.7 g of crude product, purified

using column chromatography (silica gel, the solvent methylene chloride/methanol in the ratio of 96/4). Yield 2.8 g (61%), melting point 149-151oC (hydrochloride).

Example 50

3-- [Exo-6-p-AMINOPHENYL-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-2,4-(1H, 3H)-hintlinin

16.3 g (40,1 mm) 3-- [Exo-6-p-nitrophenyl-3-azabicyclo [3.2.0]heptane-3-yl] -ethyl-2,4-(1H, 3H)-chineselanguage was dissolved in 300 ml of glacial acetic acid was mixed with 1.7 g of palladium on coal (10%) and was first made within 4 hours PR is the residue was dissolved in 400 ml of water, when mixing concentrated ammonia was podslushivaet was aspirated and fell in the sludge solids in the wash water. The crude product (15.3 g) was purified by column chromatography (silica gel, the solvent methylene chloride/methanol in a ratio of 95/5). Yield: 12.4 g (76%) with a melting point 196 - 198oC.

Example 51

3-- [Exo-6-p-iopener-3-azabicyclo[3.2.0] heptane-3-yl]- ethyl-2,4-(1H, 3H)-hintlinin

5.6 g (14,9 mm)3 - [Exo-6-p-AMINOPHENYL-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-2,4-(1H, 3H)-chineselanguage was dissolved in 100 ml policecontributing hydrochloric acid. At a temperature of 0-5oC was added dropwise a solution of 1.05 g (15,05 mm) of sodium nitrite in 6 ml of water and the mixture was stirred for another 20 min at the same temperature. Then was added a solution of 2.5 g (15.0 mm) of potassium iodide in 12 ml of water, the ice bath was removed and the mixture was slowly heated with thorough stirring to a temperature of 85-90oC. After 40 minutes left to cool, added to ice/water, using concentrated ammonia podslushivaet, was added 300 ml of methylene chloride and intensively stirred. After separation of the phases were extracted aqueous phase with methylene chloride, the combined organic phase was dried and concentrated. Raw prinosheniy 95/5). Yield: 3.2 g (57%), melting point 162-164oC.

52. 3-- [Exo-6-p-triptoreline-3-azabicyclo[3.2.0]- heptane-3-yl] -ethyl-2,4-(1H,3H)-hintlinin, melting point 190-192oC,

53. 3-- [Exo-6-(3,4-dichlorophenyl)-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl-2,4-(1H,3H)-hintlinin,

54. 3-- [Exo-6-(3,4-dihydroxyphenyl)-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-2,4-(1H,3H)-hintlinin (similar to example 49),

55. 3-- [Exo-6-(3,5-dichlorophenyl)-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2,4-(1H,3H)-hintlinin, melting point 189-192oC,

56. 3-- [Exo-6-o-forfinal-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl-2,4-(1H,3H)-hintlinin,

57. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3 - yl]-ethyl-8-methyl-2,4-(1H,3H)-hintlinin, melting point 170-173oC,

58. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-7-chloro-2,4-(1H,3H)-hintlinin, melting point 214-216oC,

59. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl] -ethyl-7-fluoro-2,4-(1H,3H)-hintlinin,

60. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]-ethyl - 5-chloro-2,4-(1H,3H)-hintlinin, 194oC (malaikat),

61. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl-6-fluoro-2,4-(1H,3H)-hintlinin, the melting point of 186-188oC,

62. 3-- [Exo-6C,

63 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl-8-methoxy-2,4-(1H,3H)-hintlinin,

64. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]-ethyl - 6-trifluoromethyl-2,4-(1H,3H)-hintlinin,

65. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]-ethyl - 7-nitro-2,4-(1H,3H)-hintlinin,

66. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl] -ethyl-6-nitro-2,4-(1H,3H)-hintlinin,

67. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl] -ethyl-7-amino-2,4-(1H,3H)-hintlinin,

68. 3-- [Exo-6-p-forfinal-3-azabicyclo [3.2.0] heptane-3-yl]-ethyl-6-amino-2,4-(1H,3H)-hintlinin,

69. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-6-hydroxy-2,4-(1H,3H)-hintlinin, 225-227oC,

70. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-5-chloro-2,4-(1H,3H)-hintlinin, melting point 194-196oC (malaikat),

71. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl-6,7-dimethoxy-2,4-(1H,3H)-hintlinin, melting point 203-205oC,

72. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-6,8-dichloro-2,4-(1H,3H)-hintlinin,

73. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl-6,7,8-trimetoksi-2,4-(1H,3H)-hintlinin, 203-205oC,

74. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3 - yl]-ethyl-1-met the tan-3-yl]-ethyl - 1-ethyl-2,4-(1 H,3H)-hintlinin, the melting temperature of 92-95oC (hydrochloride),

76. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]-ethyl - 1-allyl-2,4-(1H,3H)-hintlinin,

77. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]-ethyl - 1-benzyl-2,4-(1H,3H)-hintlinin, the melting point of 133-135oC,

78. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]- propyl-2,4-(1H,3H)-hintlinin, melting point 75-77oC,

79. 3-- [Exo-6-p-forfinal-3-azabicyclo [3.2.0]heptane - 3-yl]-butyl-2,4-(1H,3H)-hintlinin, 157-159 (malaikat),

80. 3-- [Exo-6-(2-thienyl)-3-azabicyclo[3.2.0]heptane-3 - yl]-ethyl-2,4-(1H,3H)-hintlinin, melting point 171-173oC,

81. 3-- [Exo-6-(5-chloro-2-thienyl)-3 - azabicyclo[3.2.0]heptane-3-yl]-ethyl-2,4-(1H,3H)-hintlinin, decomposition temperature from 176oC,

82. 3-- [Exo-6-(3-thienyl)- 3-azabicyclo[3.2.0]heptane-3-yl]-ethyl-2,4-(1H,3H)-hintlinin, melting point 158-159oC,

83. 3-- [Exo-6-(2 - pyridyl)-3-azabicyclo[3.2.0]heptane-3-yl]-ethyl-2,4- (1H,3H)-hintlinin, decomposition temperature from 84oC,

84. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]-ethyl - 1H-thieno[3.2-d]pyrimidine-2,4-dione, melting point 230 - 232oC,

85. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-1H-thieno [2.3-d]pyrimidine-2,4-dione,

86. 3-- [Exo-6-p-the CLO[3.2.0] heptane-3-yl]-ethyl-1-methyl-1H,3H-pyrido[2.3-d]pyrimidine-2,4-dione,

88. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-2-methyl-3H-hinzelin-4-one, the decomposition temperature from 225oC (hydrochloride),

89. 3--[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl-2-methoxy-3H-hinzelin-4-one.

Example 90

The dihydrochloride 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-2-methyl-4H-pyrido[1.2-a]pyrimidine-4-it

< / BR>
3.0 g (15.7 mm) [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane in 60 ml of xylene was mixed with 3.8 g (17 mm) 3-(2-chloroethyl)-2 - methyl-4H-pyrido[1.2-a] pyrimidine-4-it, and from 4.2 g (30 mm) of finely powdered potassium carbonate and 0.5 g of potassium iodide and boiled under reflux with careful stirring for 11 hours. After cooling, concentrated on a rotary evaporator apparatus and the residue was divided between methylene chloride and water. The aqueous phase was twice extracted with methylene chloride and then the organic phase after drying with sodium sulfate concentrated. The crude product (7.8 g) was purified by column chromatography (silica gel, the solvent methylene chloride/methanol in the ratio 94/4). The free base (3.4 g) was dissolved in 200 ml of simple ether, was filtered insoluble flakes and mixed ether solution with excess ethereal the exact number of ordinary ether, and dried salt on the suction filter in a nitrogen atmosphere. Allocated 3.8 g (54%) product HCl, melting point > 250oC. similarly, we can get:

91. 3-- [Exo-6-phenyl-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl-2-methyl-4H-pyrido [1,2-a]pyrimidine-4-one,

92. 3-- [Exo-6-m-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one,

93. 3-- [Exo-6-m-methoxyphenyl-3-azabicyclo[3.2.0]heptane-3 - yl]-ethyl-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one,

94. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl-2,6-dimethyl-4H-pyrido [1,2-a] pyrimidine-4-one, melting point 59-61oC (dihydrochloride),

95. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl-2,7-dimethyl-4H-pyrido [1,2-a]pyrimidine-4-one, melting point 247-249oC (dihydrochloride),

96. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2,8-dimethyl-4H-pyrido [1,2-a] pyrimidine-4-one, melting point > 250oC (dihydrochloride),

97. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl-2,9-dimethyl-4H-pyrido [1,2-a]pyrimidine-4-one, the decomposition temperature > 208oC (dihydrochloride),

98. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2,6,8-trimethyl-4H-pyrido [1,2-a] pyrimidine-4-one, melting point > 260oC (dihydrochloride),

99. 3-- [Exo-6-m-chlorophenyl-3-azabicyclo[3.2.0] hepta. 3-- [Exo-6-o-forfinal-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl-2,7-dimethyl-4H-pyrido [1,2-a]pyrimidine-4-one, melting point 262 to 264oC (dihydrochloride),

101. 3-- [Exo-6-phenyl-3-azabicyclo[3.2.0] heptane-3-yl]- ethyl-2,8-dimethyl-4H-pyrido [1,2-a] pyrimidine-4-one, melting point > 250oC (dihydrochloride),

102. 3-- [Exo-6-m-chlorophenyl-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl-2,9-dimethyl-4H-pyrido [1,2-a] pyrimidine-4-one, melting point > 213oC (dihydrochloride),

103. 3-- [Exo-6-(5-chlortan-2-yl)-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2-methyl-4H-pyrido [1,2-a]pyrimidine-4-one,

104. 3-- [Exo-6-pyrid-4-yl-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one,

105. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidine-4 - one, melting point of 151-153oC (malaikat),

106. 3-- [Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a]pyrimidine-4-one,

107. 3-- [Exo-6-p-methoxyphenyl-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a]pyrimidine-4-one,

108. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-2-methyl-4H-pyrimido[1,2-a]pyrimidine-4-one,

109. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3 - yl]-ethyl-2-m is-1H,5H-imidazo[1,2-a]pyrimidine-5-he,

111. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl] -ethyl-2-methyl-7,8-dihydro-4H,6N-pyrrolo[1,2-a]pyrimidine-4-one,

112. 2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3 - yl]-methyl-benzimidazole, melting point 166-168oC,

113. 1-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-benzimidazole, melting point of 94-96oC (hydrochloride),

114. 1-- [Exo-6-p-forfinal-3-azabicyclo [3.2.0]heptane-3-yl]-ethyl-2,3-dihydro-benzimidazole-2-it, 122-124oC,

115. 2-[Exo-6-m-methoxyphenyl-3-azabicyclo[3.2.0] heptane-3 - yl]-methyl-benzimidazole,

116. 3-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl-indole, melting point 193-195oC (hydrochloride),

117. 3-- [Exo-6-m-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl]-ethylindole,

118. 3-- [Exo-6-phenyl-3-azabicyclo[3.2.0]heptane-3-yl] -ethylindole, melting point 104-105oC (hydrochloride),

119. 3-- [Exo-6-m-methoxyphenyl-3-azabicyclo[3.2.0]heptane - 3-yl]-ethylindole,

120. 2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]- methyl-3,4-dihydroquinazolin-4-one, melting point of 152 to 154oC,

121. 2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl] -methyl-3,4-dihydroquinazolin-4-tion,

122. 2-[Exo-6-phenyl-3-azabicyclo[3.2.0] heptane-3-yl]- methyl-3,4-dihydroquinazolin-4-one, Templin-4-one,

124. 2-[Exo-6-o-methoxyphenyl-3-azabicyclo[3.2.0] heptane-3 - yl]-methyl-3,4-dihydroquinazolin-4-one,

125. 2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl] -methyl-4-hydroxy-6-methylpyrimidin, melting point 174-175oC,

126. 6-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl] -methyl-2-methyl-4-hydroxypyrimidine, melting point 147-149oC (dihydrochloride),

127. 6-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]- methyluracil, melting point 201-203oC,

128. 6-[Exo-6-phenyl-3-azabicyclo[3.2.0]heptane-3-yl]- methyluracil, melting point 183-184oC,

129. 6-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - 1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrimidine, melting point 108-110oC (hydrochloride),

130. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl-1,2,3,4-tetrahydro-6-methyl-2,4-dioxopyrimidine, melting point 197-199oC,

131. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-d and oxo pyrimidine, melting point of 186-188oC,

132. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl-1,2,3,4-tetrahydro-3,6-dimethyl-2,4-dioxopyrimidine,

133. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl-1,2,3,4-tetrahydro-3,6-dimethyl-2,44-dioxopyrimidine, melting point 90-93oC (hydrochloride),

135. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2-thiomethyl-6-methyl-4(3H)-pyrimidinone,

136. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-2-mercapto-6-methyl-4(3H)-pyrimidinone,

137. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3 - yl]-ethyl-2-thiomethyl-3,6-dimethyl-4(3H)-pyrimidinone, melting point 132-135oC (dihydrochloride),

138. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl-1,2,3,4-tetrahydro-6-amino-1-methyl-2,4-dioxopyrimidine,

139. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl] -ethyl-2-amino-6-methyl-4(3H)-pyrimidinone,

140. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2-amino-3,6-dimethyl-4(3H)-pyrimidinone, melting point 78-80oC,

141. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H)-pyrimidinone, melting point 163-165oC (dihydrochloride),

142. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl-2-dimethylamino-4(3H)-pyrimidinone,

143. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3 - yl]-ethyl-2-methylamino-3-ethyl-6-methyl-4(3H)-pyrimidinone, 134-137oC (hydrochloride),

144. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2-amino-3-ethyl-6-methyl-4 (3H)-pyrimidyl]-ethyl-2-ethylamino-3,6-dimethyl-4(3H)-pyrimidinone, 190-191oC (dihydrochloride),

146. 5-- [Exo-6-p-fluoro-phenyl-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2-n-propylamino-3,6-dimethyl-4(3H)-pyrimidinone, 158-160oC (dihydrochloride),

147. 5-- [Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H)-pyrimidinone, decomposition temperature from 144oC (dihydrochloride x 2 H2O)

148. 5-- [Exo-6-m-chlorophenyl-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H)-pyrimidinone, melting point 147-149oC (dihydrochloride),

149. 5-- [Exo-6-o-forfinal-3-azabicyclo[3.2.0] heptane-3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H)- pyrimidinone, melting point 173-175oC (dihydrochloride),

150. 5-- [Exo-6-p-triptoreline-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl-2-methylamino-3,6-dimethyl-4(3H)-pyrimidinone,

151. 5-- [Exo-6-p-cyanophenyl-3-azabicyclo[3.2.0]heptane-3 - yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H)-pyrimidinone,

152. 5-- [Exo-6-m-forfinal-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H)-pyrimidinone,

153. 5-- [Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]-ethyl - 2-methylamino-4-methoxy-6-methyl-pyrimidine, 70-72oC (toilet)and

1. N-substituted derivatives of 3-azabicyclo[3.2.0]heptane of formula I

< / BR>
where R1denotes phenyl, when necessary WITH4-alkoxy, amino, monomethylamine, dimethylamino, cyano or nitro; thienyl, optionally substituted by halogen atoms, or pyridyl;

R2denotes a hydrogen atom or phenyl, possibly substituted by a halogen atom;

n denotes the number 0, 1, 2, 3 or 4;

R3denotes a hydrogen atom, a C1- C4-alkyl or together with the adjacent carbon atom represents a group C = 0;

ring in the right part of the formula I may be saturated or may contain 1 to 3 double bonds, denoted by ---,

when X represents a carbon atom, Y represents nitrogen, NH or C1- C4-Alkid-N -, and Z denotes CO-group, or WITH1- C4-alkoxy-S-group and the nitrogen atom in the first position may be hydrogen or C1- C4alkyl, a denotes a hydrogen atom, amino, C1- C4-alkylamino,1- C4allylthiourea or together with the adjacent carbon atom represents a group C=0, or when X represents a carbon atom, nitrogen, CH, Y is a carbon atom or nitrogen, and the nitrogen atom in the first position may carry a hydrogen atom, a C1- C4alkyl or benzyl, And means associated with the Y group selected from-S-CH2-CH2-, -S-CH2-CH2-CH2, -S-CH= CH-, -CH2-CH2if chlorine or mono - or disubstituted hydroxy or methoxy group, or their salts with physiologically compatible acids.

2. N-substituted derivatives of 3-azabicyclo[3.2.0]heptane of formula I under item 1, with neirolepticeski activity.

Priority points and features:

19.06.92 - PP.1 and 2;

21.12.92 - PP.1 and 2 kinds of radicals.

 

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