HRP931499A2 - N-substituted azabicycloheptane derivatives, their production and use - Google Patents

Description

Description

The invention deals with new N-substituted aza-bicycloheptane derivatives, their production and use for the production of medicinally active substances.

It is known that basic substituted five- or six-membered heterocyclic nitrogen derivatives act as non-uroleptics (EP 196 132, EP 70 055, EP 110 435).

It seems that in addition to dopamine affinity, the observed high affinity for serotonin receptors plays a significant role in this.

It has now been found that N-substituted 3-azabicyclo[3,2,0]heptane derivatives of formula I and their salts with physiologically tolerable acids possess valuable pharmacological properties;

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where

R1 means a hydrogen atom or, in a given case, a phenyl, pyridyl, thienyl or pyrrole group mono- or disubstituted with a halogen atom, C1-C4-alkyl, tri-fluoromethyl, hydroxyl, C1-C4-alkyl, amino, monomethylamino, dimethylamino, cyano or nitro group,

R2 is a hydrogen atom or, in a given case, a phenyl group substituted with a halogen atom, methoxyl, hydroxyl or amino group,

n means the number 0, 1, 2, 3 or 4,

R3 means a hydrogen atom, a hydroxyl, C1-C4-alkyl or C1-C4-alkyl group, or together with an adjacent carbon atom a C=O- or C=S-group, X and Y mean carbon atoms, CH-, CH2-, NH- or C1-C4-alkyl-N-groups or nitrogen atoms,

Z represents a direct bond, a CO-group, a CS-group or a CH- or CH2-group, in which one hydrogen atom can be replaced by a hydroxyl, amino or C1-C4-alkyl group or a halogen atom, and

A means a hydrogen atom, a hydroxyl, amino, mercapto, C1-C4-alkylamino, di-C1-C4-alkylamino, C1-C4-alkyl-thio or C1-C4-alkyl group or together with an adjacent carbon atom a C=O-group , or

A means a C3-C4-alkylene group joined to Y, wherein the alkylene group may contain one or two but not adjacent double bonds, and one CH- or CH2-group may be replaced by an NH- or N-CH3-group, and at whereby the ring may be substituted by a fluorine or chlorine atom or a methyl, methoxyl, nitro or amino group, or in the case of a benzene ring which may be mono-, di- or trisubstituted with a fluorine or chlorine atom or methyl, trifluoromethyl, nitro, hydroxyl, methoxyl, amino, monomethyl or dimethylamino group,

and where the ring in the right part of formula I on nitrogen atom no. 1 may bear a C1-C4-alkyl, allyl or benzyl group and contain 1 to 3 double but not contiguous double bonds.

As the substituents R1, R2, R3 and n, the following meanings are particularly indicated:

R1 phenyl group substituted in a given case with fluorine, chlorine, iodine, methoxyl, nitro, trifluoromethyl, hydroxyl or amino group,

R2 hydrogen,

R3 methyl and hydroxyl group,

n 2.

The ring system in the right part of formula I is special

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Compounds in which it is especially preferred

R1 phenyl group substituted primarily in the p-position with fluorine and chlorine or in the m-position with fluorine or chlorine,

R2 hydrogen and

R3 methyl and hydroxyl group, and the ring system in the right part of the molecule is derived from

7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one,

7-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one,

8-methyl-2H, 6H-pyrimido[2,1-b][1,3]thiazin-6-one,

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

2-methyl-4H-pyrido[l, 2-a]pyrimidin-4-one,

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

2-methylamino-3,6-dimethyl-4(3H)pyrimidinone. The compounds with particular advantages are:

6-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2-a]pyrimidine- 5-he

6-β-[exo-6-p-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-i]-ethyl-7-methyl-5H-thiazolo[3,2-a]pyrimidine- 5-he

6-β-[exo-6-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-2,3-dihydro-5H-thiazolo[3,2- a]pyrimidin-5-one,

7-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]ethyl-8-methyl-2H, 6H-pyrimido[2,1-b][ 1,3] thiazin-6-one,

3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione,

3-β-[exo-6-p-trifluoromethyl-phenyl-3-azabicyclo[3,2,0]-heptan-3-yl]-ethyl-2,4-(1H, 3H)-quinazolidione,

3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methyl-4H-pyrido-[1,2-a]pyrimidine -4-he,

3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-6,7,8,9-tetrahydro-2-methyl-4H- pyrido[1,2-a]-pyrimidin-4-one,

5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H)-pyrimidinone ,

5-β-[exo-6-m-chloro-phenyl-5-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methylamino-3,6-dimethyl-4-(3H)- pyrimidinone.

Compounds according to the invention of formula I can be produced, whereby the compound of formula II

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reacts with the 3-azabicyclo[3,2,0]heptane derivative of formula III

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and the thus obtained compound is in the given case converted into an acid addition salt of a physiologically tolerable acid. In formula II, n, R3, X, Y, Z and A have the aforementioned meaning, and Nu represents a nucleophilic starting group. In formula III, R1 and R2 have the previously stated meaning.

Halogen atoms, especially bromine and chlorine, come into consideration as nucleophilic starting groups for Nu.

The conversion conveniently takes place in the presence of some inert base, such as triethylamine or potassium carbonate, as an acid binder in an inert solvent, and in a cyclic saturated ether, especially tetrahydrofuran or dioxane, or in a benzene hydrocarbon, such as toluene or xylene.

The conversion usually takes place at temperatures from 20 to 150°C, especially from 80 to 140°C, and is generally completed within 1 to 10 hours.

Compounds suitable for the invention of formula I can be recrystallized from common organic solvents, primarily from a lower alcohol, such as ethanol, or purified by column chromatography.

Racemates can be separated into enantiomers in a simple way by classical separation using optically active carboxylic acids, e.g. tartaric acid derivatives, in an inert solvent, e.g. lower alcohols.

The free 3-azabicyclo[3,2,0]heptane derivatives of formula I can be converted in a conventional manner into acid addition salts of a pharmacologically tolerable acid, primarily by mixing the solution with an equivalent of the corresponding acid. Examples of pharmacologically tolerable acids are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.

The compounds suitable for the invention show valuable pharmacological properties. They can be used as neuroleptics (especially atypical), antidepressants, sedatives, hypnotics, CNS protectors or as muscle relaxants. In one compound suitable for the invention, several of the above may appear in combination. quality of action. Pharmacological proof of action is carried out both in vivo and in vitro, whereby the characterization of the substance is possible especially in part with very high and selective affinity towards receptor subtypes, e.g. D1-, D2-, D3-, D4-, dopamine receptors, 1A- , serotin 1D- and 2-receptors, alpha 1- and 2-receptors; 1- and muscarinic histamine receptors.

The following methods were used to prove new substances in vivo:

a) Influence on orientation mobility

In a new environment, mice show increased exploratory behavior, which is manifested by increased motor activity. This motor activity is measured in shaded cages during 0 - 30 minutes after placing the animal (NMRI-mice, females) in the cage.

ED50: dose that reduces motor activity by 50% compared to placebo-treated control animals.

b) Antagonism towards apomorphine

Female MMRI-mice received 1.21 mg/kg apomorphine s.c. At this dose, apomorphine leads to motor activity that manifests itself in constant climbing when the animal is kept in a wire mesh cage. Climbing is evaluated by the total score (every 2 minutes for 50 minutes):

0: the animal has four legs on the ground,

1: the animal has two legs on a wire,

2: the animal has four legs on the wire (climbing).

Pre-treatment with an antipsychotic relieves the animal's climbing behavior.

ED50: the dose that reduces the animal's climbing activity by 50% compared to placebo-treated control animals.

c) Antagonism towards methamphetamine

Female NMRI-mice received 1 mg/kg methamphetamine p.o. and after 30 minutes they are placed in shaded cages for measuring motor activity (2 animals per cage, 4 cages/dose). Test substances are administered orally 30 minutes before methamphetamine. The increase in activity due to methamphetamine is calculated during 15 to 60 minutes after placing the animals in the measuring cages and is the difference compared to the control animals that were given a placebo and is immediately set to 100%. ED100 is the dose of the test substance that completely neutralizes the increase in activity.

d) Antagonism of L-5-HTP

Female Sprague-Dawley rats received L-5-HTP at a dose of 316 mg/kg i.p. As a result, the animals develop an arousal syndrome with symptoms

- for paw treading i

- tremors

which is scored every 10 minutes for a period of 20 to 60 minutes after administration of L-5-HTP using a total score (0 = not present, 1 = measurable, 2 = (clearly expressed). On average, after administration of L-5- HTP achieves a total result of 17. The test substances are administered p.o. 60 minutes before L-5-HTP. The ED50 is calculated as the dose that, on average, reduces the total result by 50%.

The mentioned methods are suitable for proving substances as antipsychotics; especially stopping motor stimulation caused by methamphetamine is valid as a predicate for antipsychotic action. By stopping the syndrome, L-5-HTP can show serotonin antagonistic action, a quality of action that is characteristic of the so-called atypical neuroleptics.

In these tests, the new compounds show good activity.

Accordingly, the invention also relates to therapeutic agents characterized by the content of the compound of formula I or its addition salt with a physiologically tolerable acid as an active substance in addition to the usual carriers and diluents, as well as to the use of new compounds in disease control.

The compounds suitable for the invention can be administered in the usual way orally or parenterally, intravenously or intramuscularly.

The dosage depends on the age, condition and weight of the patient, as well as on the method of application. As a rule, the daily dose of the active substance is between 1 and 100 mg/kg of body weight if given orally, and between 0.1 and 10 mg/kg of body weight if given parenterally.

The new compounds can be applied in useful galenic application forms, solid or liquid, for example as tablets, film-coated tablets, capsules, powder, granules, dragees, suppositories, solutions, ointments, creams or sprays. They are done in the usual way. In doing so, the active substances can be processed with the usual galenic auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrators, flow control agents, softeners, crosslinkers, dispersing agents, emulsifiers, solvents, retarding agents, antioxidants and/or propellants, (compare H. Sucker et al: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The application forms thus obtained contain the active substance normally in an amount of 1 to 99% by weight.

Substances of formula II required as starting substances for the synthesis of new compounds are known or can be synthesized according to production procedures described in the literature from analogous starting materials.

Substances of formula III can be produced, whereby the amine of formula IV

[image]

undergoes photochemical 2+2 cycloaddition and finally cleaves off one acyl or benzyl group in the given case.

In formula IV, R 1 and R 2 have the previously stated meaning, and R 4 means hydrogen, acetyl, benzyl or trifluoroacetyl.

The photoreaction works well in an inert solvent, primarily acetone, at temperatures from 20 to 80ºC. A mercury high-pressure lamp is particularly good as a light source. Under the given circumstances, it is advisable to carry out the photocycloaddition in a quartz apparatus in a nitrogen atmosphere, possibly with the addition of approximately 1 mole of hydrochloric acid per mole of amine.

Photocycloaddition in most cases takes place with high diastereoselectivity to bicyclic compounds III with exo configuration with respect to R1 and R2:

[image]

Both enantiomers can be isolated by pure racemic separation, eg with optically active tartaric acid derivatives.

Separation of the acyl group succeeds according to known methods. The same applies to the removal of the benzylic group.

Amines of formula IV are known from the literature or can be prepared, whereby either the aldehyde R1-CHO reacts with vinylmagnesium chloride to form the allylic alcohol V, and

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then, using hydrogen chloride, it is converted into allyl chloride VI, and

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finally substituted with the corresponding allylamine VII, or

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cimetaldehyde VIII is directly subjected to reduction

[image]

amination with allylamine VII, in which R4 is a hydrogen atom. The following examples serve to explain the invention:

A) Production of starting substances

aa) 1-(4-Fluoro-phenyl)-allylalcohol

1550 ml (2.0 M) of a solution of 1.29 M vinylmagnesium chloride in tetrahydrofuran is placed in flask 4-1 under a nitrogen atmosphere. A solution of 222.0 g (1.764 M) of 4-fluorobenzaldehyde in tetrahydrofuran is then added under nitrogen atmosphere with stirring at a temperature of 30-35°C within 30 minutes, while the reaction mixture is cooled with ice. The reaction mixture is stirred for another 2.5 hours in a nitrogen atmosphere at room temperature. After that, with stirring and cooling with ice, 180 ml of water is added, suction is applied and the residue obtained by filtration is washed three times with 150 ml of tetrahydrofuran. The filtrates are collected, dried over sodium sulfate and concentrated. 265.7 6 (99%) of the product is obtained in the form of a yellow-brown oil.

ab) 3-(4-fluoro>-phenyl)-allyl chloride

275.6 g (1.789 M) of 1-(4-fluoro-phenyl)-allyl alcohol are dissolved with stirring in 2000 ml of methanol. Then, 101.0 g (2.770 M) of hydrocarbons are introduced over 3 hours, during which the temperature rises up to 370C. After that, it is mixed for another 1 hour. After washing with 600 ml of ice-cold water and a mixture of 150 ml of saturated table salt, the organic phase is dried over sodium sulfate and concentrated. 294.6 g (98%) of brown oil is obtained.

ac) N-allyl-N-[3-(4-fluoro-phenyl)-allyl]-amine

251.8 g (1.559 M) of 3-(4-fluoro-phenyl)-allyl chloride was added within 25 minutes to a solution of 795.0 g (15.92 M) of allylamine in 360 ml of toluene under reflux and stirred for another hour at the condensation temperature. It is then distilled over a 10 cm distillation column (glass rings 5 mm) at a bath temperature of up to 125°C 1000 ml. The residue of the distillation is mixed with 1000 ml of water and adjusted to pH 0.7 using 38% hydrochloric acid. The organic phase is separated and discarded. The aqueous phase is basified with 50% sodium hydroxide solution to pH 12.7, extracted with toluene and concentrated. The residue is distilled through a column at 0.7 to 1 mbar. At a bath temperature of 120-160°C, 191.8 g (74%) of light yellow oil is obtained.

ad) exo-6-(p-fluoro-phenyl)-5-azabicyclo[3,2,0]heptane

19.4 g (102 mM) of N-allyl-N-[3-(4-fluoro-phenyl)-allyl]-amine in 150 ml of acetone was mixed with 150 ml of 10% hydrochloric acid and 600 mg of Michler's ketone and in irradiates in a nitrogen atmosphere for 55 hours with a 150-watt high-pressure mercury lamp. The reaction product is then concentrated and the residue is partitioned between methylene chloride and water. It is made alkaline with an aqueous ammonia solution and the aqueous phase is extracted two more times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated.

Yield 19.5 g (99%), melting point 165-166°0 (maleinate).

To separate the antipodes, 15.0 g (78.5 mM) of the racemate was mixed with a solution of 31.7 g (78.5 mM) (-)-di-O-toluene-L-tartaric acid in 300 ml of boiling ethanol. The crystals that fall on cooling with stirring (13.8 g) are filtered off with suction, washed with ethanol and recrystallized from 200 ml of ethanol with the addition of 200 ml of water. Liberation of the base gives the (+)-antipode (5.5) with /D = +97.0° (etOH, c=0.969).

From the above mother liquor, 14.2 g of salt crystallizes overnight, which is recrystallized from 400 ml of ethanol (insoluble particles are filtered off while heating to boiling point). (Before recrystallization, the ethanolic solution was reduced to 300 ml.) Liberation of the base gave 4.0 g of (-)-antipode with D = -96.0°. (ethOH, c = 0.940).

Exo-phenyl-configurations were proven by X-ray structure analysis.

ae) Exo-6-phenyl-5-azabicyclo[3,2,0]heptane

50.0 g (28.9 mM) of N-cinnamyl-N-allylamine in 1600 ml of acetone is mixed with 500 ml of 10% hydrochloric acid and illuminated in a nitrogen atmosphere for 48 hours with a mercury high-pressure lamp of 150 watts at room temperature. . The reaction product is then concentrated and the residue partitioned between methylene chloride and water. It is made alkaline with an aqueous ammonia solution and the aqueous phase is extracted two more times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated. Yield: 49.0 g (98%) of viscous oil; melting point 177 to 178C (maleinate).

af) Exo-6,7-diphenyl-3-azabicyclo[3,2,0]heptane

K 12.0 g (35.4 mM) of exo-6,7-diphenyl-3-benzyl-3-azabi-cyclo[3,2,0]heptane in a mixture of 300 ml of n-propanol and 16 ml of water is added 16.0 g (254 mM) of ammonium formate and 2.0 g of palladium (10%) on charcoal. The reaction mixture is refluxed for 4 hours (evolution of carbon dioxide). After cooling, the catalyst is sucked off, washed with propanol and methylene chloride and the filtrate is concentrated. The residue is partitioned between water and methylene chloride, basified with an aqueous ammonia solution and the aqueous phase is extracted two more times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated. 8.1 g (92%) of the pro-extract is obtained, melting point 140 to 142°C (maleinate).

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

To 12.0 g (59.7 mM) of 3,5-dichlorocymtaldehyde in 180 ml of methylene chloride was added 4.5 ml (60 mM, 3.4 g) of allylamine and 17.0 g of sodium sulfate. The reaction mixture is stirred for 24 hours at room temperature. After that, sodium sulfate is filtered off, washed with methylene chloride, and the filtrate is concentrated to dryness. The thus obtained yellow oil is dissolved in 200 ml of absolute methanol, and 2.5 6 (66.0 mM) sodium borohydride is added in portions under a nitrogen atmosphere. The reaction mixture, which is easily heated, is stirred for another hour and then neutralized with 10% hydrochloric acid (pH = 7). The solvent is removed in vacuo and the residue is taken up in methylene chloride. The organic phase is washed twice with water, dried over sodium sulfate and concentrated. The resulting residue is purified using column chromatography (silica gel, methylene chloride + 5% methanol). Yield: 9.2 g (65%) of yellow oil.

ah) N-allyl-2,2,2-trifluoro-N-[3-(3-pyridyl)-allyl]-acetamide In a solution of 10.0 g (57.5 mM) N-allyl-N-3- (3-pyridyl)-alamine and 10.7 ml of triethylamine in 100 ml of tetrahydrofuran at 0°C are slowly added 16.1 g (76.6 mM) of trifluoroacetic anhydride. It is mixed for another 2 hours at room temperature. After that, the reaction solution is poured into 250 ml of ice water and extracted three times with 150 ml of methyl tert.-butyl ether. The combined organic phases are dried over sodium sulfate and concentrated. Yield: 14.3 S (92%) of dark brown oil.

ai) 2,2,2-trifluoro-1-[exo-6-(3-pyridyl)-3-azabicyclo-[3,2,0]-hept-3-yl]-ethanone

14.0 g (51.8 mM) of N-allyl-2,2,2-trifluoro-N-[3-(3-pyridyl)-allyl]-acetamide was dissolved in 140 ml of acetone, mixed with 30 ml of 10% aqueous hydrochloric acid and in a nitrogen atmosphere, at room temperature, illuminate for 48 hours with a mercury high-pressure lamp of 150 watts in a Duran glass apparatus. After that, the reaction solution is compressed, mixed with 150 ml of water and adjusted to pH 8-9 with an aqueous ammonia solution. The aqueous phase is extracted twice with tert-butyl methyl ether, the combined organic phases are dried over sodium sulfate and concentrated. The resulting residue is fractionated by column chromatography (silica gel, methylene chloride + 2% methanol). 6.2 g (42%) of unchanged N-allyl-2,2,2-trifluoro-N-[3-(3-pyridyl)-allyl]-acetamide and 3.7 g (26%) of 2,2 ,2-trifluoro-1-[exo-6-(3-pyridyl)-3-azabicyclo[3,2,0]hept-3-yl]ethanone as a dark oil.

ak) exo-6-(3-pyridyl)-3-azabicyclo[3,2,0]heptane

K A solution of 5.7 g (15.7 mM) of 2,2,2-trifluoro-1-[exo-6-(3-pyridyl)-3-azabicyclo[3,2,0]hept-3-yl] of ethanone in 50 ml of ethanol, 2.5 g of potassium hydroxide granules are added. The reaction solution is stirred for another 2 hours at room temperature and then poured into 100 ml of ice water. The aqueous phase is extracted three times with tert-butyl methyl ether, the combined organic phases are dried over sodium sulfate and concentrated. Yield 2.5 g (96%) of yellow oil, melting point 202-205°0 (hydrochloride).

Analogously, the following substances can be produced:

al) exo-6-(m-fluoro-phenyl)-3-azabicyclo[3,2,0]heptane,

am) exo-6-(o-fluoro-phenyl)-3-azabicyclo[3,2,0]heptane,

melting point 118-120°0 (maleinate),

an) exo-6-(p-chloro-phenyl)-3-azabicyclo[3,2,0]heptane,

melting point 152-154C (maleinate),

ao) exo-6-(m-chloro-phenyl)-3-azabicyclo[3,2,0]heptane,

melting point 130-132°C (maleinate),

ap) exo-6-(p-methoxy-phenyl)-3-azabicyclo[3,2,0]heptane,

aq) exo-6-(m-methoxy-phenyl)-3-azabicyclo/3,2,0/heptane,

ar) exo-6-(p-nitro-phenyl)-3-azabicyclo[3,2,0]heptane,

melting point 158-160°C (maleinate),

as) exo-6-(m-nitro-phenyl)-3-azabicyclo[3,2,0]heptane,

at) exo-6-(p-trifluoromethyl-phenyl)-3-azabicyclo[3,2,0]-heptane,

melting point 155-156°C (maleinate),

au) exo-6-(m-trifluoromethyl-phenyl)-3-azabicyclo[3,2,0]-heptane,

av) exo-6-(3,4,-dichloro-phenyl)-3-azabicyclo[3,2,0]heptane,

aw) exo-6-(3,5-dichloro-phenyl)-3-azabicyclo[3,2,0]heptane,

melting point >250°C (hydrochloride),

ax) exo-6-(3,4,-dimethoxy-phenyl)-3-azabicyclo[3,2,0]-heptane,

ay) exo-6-(m-hydroxy-phenyl)-3-azabicyclo[3,2,0]heptane,

az) exo-6-(p-hydroxy-phenyl)-3-azabicyclo[3,2,0]heptane,

ba) exo-6-(3,4-dihydroxy-phenyl)-3-azabicyclo[3,2,0]-heptane,

bb) exo-6-(p-methyl-phenyl)-3-azabicyclo[3,2,0]heptane,

bc) exo-6-(m-methyl-phenyl)-3-azabicyclo[3,2,0]heptane,

bd) exo-6-(p-t-butyl-phenyl)-3-azabicyclo[3,2,0]heptane,

melting point >255°C (hydrochloride),

be) exo-6-(m-amino-phenyl)-3-azabicyclo[3,2,0]heptane,

bf) exo-6-(p-amino-phenyl)-3-azabicyclo[3,2,0]heptane,

bg) exo-6-(p-cyano-phenyl)-3-azabicyclo[3,2,0]Heptane,

melting point 168-178°C (maleinate),

bh) exo-6-thien-2-yl-3-azabicyclo[3,2,0]heptane,

melting point 180-182°C (hydrochloride),

bi) exo-6-thien-3-yl-3-azabicyclo[3,2,0]heptane,

melting point 143-145°C (hydrochloride),

bk) exo-6-(5-chloro-thien-2-yl)-3-azabicyclo[3,2,0]heptane,

melting point 156-157°C (maleinate),

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.

B) Production of final products

Example 1

6-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2-a]pyrimidine- 5-one dihydrochloride

2.5 g (13.1 mM) of exo-6-p-fluoro-phenyl-3-azabicyclo-[3,2,0]heptane in 40 ml of xylene was mixed with 3.6 g (26 mM) of 6-( 2-chloro-ethyl)-7-methyl-5H-thiazolo[3,2,0]pyrimidin-5-one and with 5.6 g (40 mM) of finely divided powdered

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calcium carbonate and 0.5 g of potassium iodide, and, with good mixing, cook for 11 hours with reflux.

After cooling, it is concentrated on a rotary evaporator and the residue is divided between methylene chloride and water.

The aqueous phase is extracted two more times with methylene chloride, and then the organic phase is concentrated after drying with sodium sulfate. The crude product (7.7 g) was purified by column chromatography (silica gel, eluant methylene chloride/methanol 96/4).

The free base (3.5 g) is taken up in 150 ml of ether, the insoluble flakes are filtered off and the ether solution is mixed with excess ethereal hydrochloric acid. The solid particles are then sucked off in a cold nitrogen atmosphere, the hydrochloride is washed abundantly with ether, and the salt is dried on a filter funnel in a nitrogen atmosphere. 3.5 g (60%) of product x 2HCl, melting point 222 to 224°C, is isolated. Maleinate melts at 133 to 135°C.

Analogously, the following compounds can be produced:

la. (+)-6-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2- a]pyrimidin-5-one, maleinate, melting point 158-160°C, //D +56.2° (etOH),

1b. (-)-6-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2- a]pyrimidin-5-one, maleinate, melting point 147-149°C, //D = -52.8°(etOH),

2. 6-β-[exo-6-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]ethyl-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one , melting point 167-168°C, (maleinate),

3. 6-β-[exo-6,7-diphenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2-a]pyrimidine- 5-one, melting point 154-156°C,

4. 6-β-[exo-6,7-bis-(p-fluoro-phenyl)-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[ 3,2-a]pyrimidin5-one,

5. 6-β-[exo-6-m-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2-a] pyrimidin-5-one, melting point 162-164° (maleinate),

6. 6-β-[exo-6-m-methoxy-phenyl-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-7-methyl-5H-thiazolo[3,2-a]pyrimidine -5-one, melting point 149-152° (maleinate),

7. 6-β-[exo-6-m-hydroxy-phenyl-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-7-methyl-5H-thiazolo[3,2-a]pyrimidine -5-one (see also example 49), melting point 76-78°C,

8. 6-β-(2-[exo-6-p-amino-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2 -a]pyrimidin-5-one, (see also example 50),

9. 6-β-[exo-6-p-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2-a] pyrimidin-5-one, melting point 155-157°C (maleinate),

10. 6-β-[exo-6-p-methoxy-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2-a] pyrimidin-5-one, melting point 168-170°0 (maleinate),

11. 6-β-[exo-6-p-nitro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-7-methyl-5H-thiazolo[3,2-a]pyrimidine -5-he,

12. 6-β-[exo-6-m-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-7-methyl-5H-thiazolo[3,2-a]pyrimidine -5-he,

13. 6-β-[exo-6-p-hydroxy-phenyl-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-7-methyl-5H--thiazolo[3,2-a] pyrimidin-5-one, (see also example 49),

14. 6-β-[exo-6-p-trifluoromethyl-phenyl-3-azabicyclo[3,2,0]-heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2-a ]pyrimidin-5-one, melting point 187-189°C (maleinate),

15. 6-β-[exo-6-(p-t-butyl-phenyl)-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2- a]pyrimidin-5-one, decomposition temperature 207-209°C (maleic acid),

16. 6-β-[endo-6-(p-t-butyl-phenyl)-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2- a]pyrimidin-5-one, melting point 131-133°C,

17. 6-β-[exo-6-(3,4-dichloro-phenyl)-3-azabicyclo[3,2,0]heptan-3-yl-ethyl]-7-methyl-5H-thiazolo[3, 2-a]pyrimidin-5-one,

18. 6-β-[exo-6-(3,4-dimethyl-phenyl)-3-azabicyclo[3,2,0]-heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3 ,2-a]pyrimidin-5-one, decomposition temperature 210-212°C (dihydrochloride),

19. 6-β-[exo-6-p-cyano-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2-a] pyrimidin-5-one, melting point 130-132°C,

20. 6-β-[exo-6-(3,4-dihydroxy-phenyl)-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3, 2-a]pyrimidin-5-one (see also example 49),

21. 6-β-[exo-6-(o-fluoro-phenyl)-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2- a]pyrimidin-5-one, melting point 164-165°0 (maleinate),

22. 6-β-[exo-6-thien-3-yl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2-a] pyrimidine-5-one,

23. 6-β-[exo-6-(5-chloro-thien-2-yl)-3-azabicyclo[3,2,0]-heptan-3-yl]-ethyl-7-methyl-5H-thiazolo [3,2-a]pyrimidin-5-one,

24. 6-β-[exo-6-pyrrol-2-yl-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-7-methyl-5H-thiazolo[3,2-a]pyrimidine -5-he,

25. 6-β-[exo-6-pyrid-4-yl-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-7-methyl-5H-thiazolo[3,2-a]pyrimidine -5-he,

26. 6-β-[exo-6-pyrid-3-yl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-5H-thiazolo[3,2-a] pyrimidine-5-one,

27. 6-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-7-methyl-2,3-dihydro-5H-thiazolo[3 ,2-a]pyrimidin-5-one, melting point 253-255°C,

28. 6-β-[exo-6-m-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-2,3-dihydro-5H-thiazolo[ 3,2-a]pyrimidin-5-one,

29. 6-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,3,7-trimethyl-5H-thiazolo[3, 2-a]pyrimidin-5-one,

30. 6-β-[exo-6-p-fluoro-phenyl-3-azabicyclo/3,2,0/heptane. 3-yl-ethyl-5H-thiazolo[3,2-a]pyrimidin-5-one, melting point 164-166°C, (dihydrochloride x H2O),

31. 6-β-[exo-6-phenyl-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-5H-thiazolo[3,2-a]pyrimidin-5-one.

Example 32

7-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-8-methyl-2H,6H-pyrimido[2,1-b] [1,3]Thiazin-6-one dihydrochloride

[image]

2.5 g (13.1 mM) of exo-6-p-fluoro-phenyl-3-azabicyclo-[3,2,0]heptane in 40 ml xylene was mixed with 3.3 g (13.6 mM) 7 -chloro-ethyl-8-methyl-2H,6H-pyrimido[2,1-b][1,3]-thiazin-6-one and with 5.0 g (36 mM) of finely powdered potassium carbonate and 0, 5 g of potassium iodide and, with good mixing, cook for 12 hours under reflux.

After cooling, concentrate on a rotary evaporator and partition the residue between methylene chloride and water.

The aqueous phase is then extracted twice with methylene chloride, after which the organic phase is dried using sodium sulfate and concentrated. The crude product (5.6 g) was purified by column chromatography (silica gel, eluant methylene chloride/methanol 95/7).

The free base is taken up in 200 ml of ether, the insoluble flakes are filtered off and the ether solution is mixed with excess ethereal hydrochloric acid. After that, the solid particles are suctioned off under a nitrogen atmosphere in the cold, washed with hydrochloride enriched with ether and dried on a filter funnel under a nitrogen atmosphere. 3.2 g (52%) of product x 2 HCl, melting point 120 to 121°C, is isolated.

Analogously, they can be produced:

33. 7-β-[exo-6-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-8-methyl-2H, 6H-pyrimido[2,1-b][1 ,3]thiazin-6-one,

34. 7-β-[exo-6-m-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-8-methyl-2H,6H-pyrimido[2,1- b][1,3]thiazin-6-one,

35. 7-β-[exo-6-p-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-8-methyl-2H,6H-pyrimido[2,1-b ][1,3]thiazin-6-one,

36. 7-β-[exo-6-p-methoxy-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-8-methyl-2H,6H-pyrimido[2,1- b][1,3]thiazin-6-one,

37. 7-β-[exo-6-yne-hydroxy-phenyl-3-azabicyclo[3,2,0]-heptan-3-yl]-ethyl-8-methyl-2H,6H-pyrimido[2,1 -b][1,3]-thiazin-6-one, (see also example 49),

38. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 158 -160°C,

38a. (+)-3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 160-162°C, D= +88.6° (CH2Cl2),

38b. (-)-3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 161-162°C, D= -87.5° (CH2Cl2),

39. 3-β-[3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 158-160°0,

40. 3-β-[exo-6-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 144-146°C ,

41. 3-β-[exo-6-m-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione,

42. 3-β-[exo-6-p-cyano-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 230 -232°C,

43. 3-β-[exo-6-m-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]ethyl-2,4-(1H,3H)-quinazolindione, melting point 183- 185°0,

44. 3-β-[exo-6-p-hydroxy-phenyl-3-azabicyclo[3,2,0]-heptan-3-yl]-ethyl-2,4-(1H, 3H)-quinazolindione, melting point 220-223°C, (see also example 49),

45. 3-β-[exo-6-p-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 187 -189°C,

46. 3-β-[exo-6-m-methoxy-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 113 -115°C,

47. 3-β-[exo-6-p-nitro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 209 -211°C,

48. 3-β-[endo-6-p-nitro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 212 -214°C,

Example 49

3-β-[exo-6-m-hydroxy-phenyl-3-azabicyclo[3,2,0]heptain-3-yl]-ethyl-2,4-(1H,3H)-quinazolinedione

[image]

K 4.6 g (11.8 mM) 3-β-[exo-6-m-methoxy-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-( 1H,3H)-quinazolinedione in 120 ml of methylene chloride is added dropwise to 28.5 ml (28.5 mM) of boron tribromide (1 L solution in methylene chloride) at room temperature and the mixture is stirred overnight. After cooling, 100 ml of 2 N sodium hydroxide solution are added, the organic phase is separated and then the aqueous phase is extracted with methylene chloride. After drying and compression, 4.7 g of crude product is obtained, which is purified by column chromatography (silica gel, eluant methylene chloride/methanol 96/4). Yield: 2.8 g (61%), melting point 149-151°C (hydrochloride).

Example 50

3-β-[exo-6-p-amino-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolinedione

16.3 g (40.1 mM) 3-β-[exo-6-p-nitro--phenyl-3-azabicyclo-[3,2,0]heptan-3-yl]-ethyl-2,4- (1H, 3H)-quinazolinedione is dissolved in 300 ml of acetic acid, mixed with 1.7 g of palladium on charcoal (10%) and hydrated for 4 hours at room temperature and normal pressure. After suctioning off the catalyst, the mother solution is compressed, the residue is taken up in 400 ml of water, made alkaline by mixing with concentrated ammonia, and the precipitated solid particles are suctioned off while rinsing with water. The crude product (15.3 g) was purified by column chromatography (silica gel, eluant methylene chloride/methanol 95/5). Yield: 12.4 g (76%), melting point 196-198°C.

Example 51

3-β-[exo-6-p-iodo-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolinedione

5.6 g (14.9 mM) 3-β-[exo-6-p-amino-phenyl-3-azabicyclo-[3,2,0]heptan-3-yl]-ethyl-2,4-( 1H, 3H)-quinazolinedione is dissolved in 100 ml of semi-concentrated hydrochloric acid. At 0-50C, a solution of 1.05 g (15.0 mH) of sodium nitrite in 6 ml of water is added dropwise, and at the same temperature, the reaction mixture is left to stir for another 20 minutes. After that, a solution of 2.5 g (15.0 mM) of potassium iodide in 12 ml of water is added, the ice bath is removed and the mixture is heated to 85-90°C with gentle stirring. After 40 minutes, let it cool, add the ice/water mixture, make it alkaline with concentrated ammonia, add another 300 ml of methylene chloride and stir vigorously. After separating the phases, the aqueous phase is extracted with methylene chloride, the combined organic phases are dried and concentrated. The crude product (6.0 g) was purified by column chromatography (silica gel, eluant methylene chloride/methanol 95/5). Yield 3.2 g (57%), melting point 162-164°C.

52. 3-β-[exo-6-p-trifluoromethyl-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 190 -192°C,

53. 3-β-[exo-6-(3,4-dichloro-phenyl)-3-azabicyclo[3,2,0]-heptan-3-yl-ethyl-2,4-(1H,3H)- quinazolinedione,

54. 3-β-[exo-6-(3,4-dihydroxy-phenyl)-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-2,4-(1H,3H)-quinazolinedione , (similar to example 49),

55. 3-β-[exo-6-(3,5-dichloro-phenyl)-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-2,4-(1H,3H)-quinazolinedione , melting point 189-192°C,

56. 3-β-[exo-6-o-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione,

57. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]hep-tan-3-yl]-ethyl-8-methyl-2,4-(1H, 3H )-quinazolindione, melting point 170-173°C,

58. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]hep-tan-3-yl]-ethyl-7-chloro-2,4-( 1H, 3H )-quinazolindione, melting point 214-216°C,

59. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-fluoro-2,4-(1H, 3H)- quinazolinedione,

60. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-5-chloro-2,4-(1H, 3H)- quinazolindione, soluble

61. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]hep-tan-3-yl]-ethyl-6-fluoro-2,4-( 1H ,3H )-quinazolindione, melting point 186-188°C,

62. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-6-methyl-2,4-(1H,3H)- quinazolindione, melting point 166-168°C,

65. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-8-methoxy-2,4-(1H,3H)- quinazolinedione,

64. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-6-trifluoromethyl-2,4-(1H,3H)- quinazolinedione,

65. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-nitro-2,4-(1H,3H)- quinazolinedione,

66. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]hep-tan-3-yl]-ethyl-6-nitro-(1H, 3H)-quinazolindione,

67. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-amino-2,4-(1H,3H)- quinazolinedione,

68. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-6-amino-2,4-(1H,3H)- quinazolinedione,

69. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-6-hydroxy-2,4-(1H,3H)- quinazolinedione,

70. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-5-chloro-2,4-(1H,3H)- quinazolindione, melting point 194-196°C (maleinate),

71. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-6,7-dimethoxy-2,4-(1H,3H )-quinazolindione, melting point 203-205°C,

72. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-6,8-dichloro-2,4-(1H,3H )-quinazolinedione,

73. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-6,7-,8-trimethoxy-2,4-( 1H,3H)-quinazolinedione,

74. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1-methyl-2,4-(1H,3H)- quinazolinedione, melting point 89-90°C,

75. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1-ethyl-2,4-(1H,3H)- quinazolinedione, melting point 92-95°C (hydrochloride),

76. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1-allyl-2,4-(1H, 3H)- quinazolinedione,

77. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1-benzyl-2,4-(1H,3H)- quinazolindione, melting point 133-135°0,

78. 3-γ-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-propyl-2,4-(1H,3H)-quinazolindione, melting point 75 -77°0,

79. 3-δ-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-butyl-2,4-(1H,3H)-quinazolinedione,

80. 3-β-[exo-6-(2-thienyl)-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 171 -173°C,

81. 3-β-[exo-6-(5-chloro-2-thienyl)-3-azabicyclo[3,2,0]-heptan-3-yl]-ethyl-2,4-(1H,3H) -quinazolindione, decomposition temperature above 176°C,

82. 3-β-[exo-6-(3-thienyl)-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, melting point 158 -159°C,

83. 3-β-[exo-6-(3-pyridyl)-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,4-(1H,3H)-quinazolindione, decomposition temperature above 84°C,

84. 3-β-[exo-6-p-fluoro-phenyl-3-azatbicyclo[3,2,0]heptan-3-yl]-ethyl-1H-thieno[3,2-d]pyrimidine-2, 4-dione, melting point 230-232°C,

85. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1H-thieno[2,3-d]pyrimidine-2, 4-dione,

86. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1H-thieno[3,4-d]/pyrimidine-2 ,4-dione,

87. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1-methyl-1H, 3H-pyrido[2,3- d]pyrimidine-2,4-dione,

88. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methyl-3H-quinazolin-4-one, decomposition temperature above 225°C (hydrochloride),

89. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methoxy-3H-quinazolin-4-one.

Example 90

3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methyl-4H-pyrido[1,2-a]pyrimidine- 4-one dihydro

-chloride

[image]

3.0 g (15.7 mM) of exo-6-p-fluoro-phenyl-3-azabicyclo-[3,2,0]heptane in 60 ml of xylene was mixed with 3.8 g (17 mM) of 3-( 2-chloro-ethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and with 4.2 g (30 mM) fine powdered calcium carbonate and 0.5 g of potassium iodide. The reaction mixture is boiled for 11 hours while stirring with reflux. After cooling, it is concentrated on a rotary evaporator and the residue is partitioned between methylene chloride and water. The aqueous phase is then extracted twice with methylene chloride, and then the organic phase is concentrated after drying with sodium sulfate. The crude product (7.8 g) is purified by column chromatography (silica gel, eluant methylene chloride/methanol 94/4) . The free base (3.4 g) was taken up in 200 ml of ether, the insoluble flakes were filtered off, and the ether solution was mixed with excess ethereal hydrochloric acid. The solid particles are then suctioned off under nitrogen in the cold, the hydrochloride is washed abundantly with ether, and the salt is dried on a filter funnel under nitrogen.

3.8 g (54% product x 2 HCl) is isolated, melting point >250°C. Analogously, the following can be produced:

91. 3-β-[exo-6-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methyl-4H-pyrido[1,2-a.]pyrimidine-4 -he.,

92. 3-β-[exo-6-m-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-one,

93. 3-β-[exo-6-m-methoxy-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-one,

94. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,6-dimethyl-4H-pyrido[1,2- a]pyrimidon-4-one, melting point 59-61°C (dihydrochloride),

95. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one, melting point 247-249°C (dihydrochloride),

96. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-2,8-dimethyl-4H-pyrido[1,2-a ]pyrimidin-4-one, melting point >250°C (dihydrochloride),

97. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,9-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one, decomposition temperature >208°C (dihydrochloride),

98. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,6,8-trimethyl-4H-pyrido[1, 2-a]pyrimidin-4-one, melting point >260°C (dihydrochloride),

99. 3-β-[exo-6-m-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2, 7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one, melting point >250°C (dihydrochloride),

100. 3-β-[exo-6-o-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one, melting point 262-264-°C (dihydrochloride),

101. 3-β-[exo-6-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,8-dimethyl-4H-pyrido[1,2-a]pyrimidine- 4-one, melting point >250°C (dihydrochloride),

102. 3-β-[exo-6-m-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,9-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one, decomposition temperature >213°C (dihydrochloride),

103. 3-β-[exo-6-(5-chloro-thien-2-yl)-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one,

104. 3-β-[exo-6-pyrid-4-yl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-one,

105. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-6,7,8,9-tetrahydro-2-methyl- 4H-pyrido[1,2-a]pyrimidin-4-one, melting point 151-153°C, (male-inat),

106. 3-β-[exo-6-p-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-6,7,8,9-tetrahydro-2-methyl- 4H-pyrido-[1,2-a]pyrimidin-4-one,

107. 3-β-[exo-6-p-methoxy-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-6,7,8,9-tetrahydro-2-methyl- 4H-pyrido[1,2-a]pyrimidin-4-one,

108. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methyl-4H-pyrimido[1,2-a] pyrimidio-4-one,

109. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methyl-7-chloro-4H-pyrimido[1, 2-a]-pyrimidin-4-one,

110. 6-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-7-methyl-1H, 5H-imidazo[1,2- a]pyrimidin-5-one,

111. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methyl-7,8-dihydro-4H,6H- pyrrolo-[1,2-a]pyrimidin-4-one,

112. 2-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-methyl-benzimidazole, melting point 166-168°C,

113. 1-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-benzimidazole, melting point 94-96°C, (hydrochloride),

114. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2,3-dihydro-benzimidazol-2-one,

115. 2-[exo-6-m-methoxy-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-methyl-benzimidazole,

116. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]hep-tan-3-yl-ethyl-indole, melting point 193-195°C (hydrochloride),

117. 3-β-(2-[exo-6-m-chloro-phenyl-3-azabicyclo[3,2,0]-heptan-3-yl]-ethyl-indole,

118. 3-β-[exo-6-phenyl-3-azabicyclo[3,2,0]heptan-3-yl-ethyl-indole, melting point 104-105°0 (hydrochloride),

119. 3-β-[exo-6-m-methoxy-phenyl-3-azabicyclo[3,2,0]-heptan-3-yl-ethyl-indole,

120. 2-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-methyl-3,4-dihydro-quinazolin-4-one, melting point 152 to 154 °C,

121. 2-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl-methyl-3,4-dihydro-quinazolin-4-thione,

122. 2-[exo-6-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-methyl-3,4-dihydro-quinazolin-4-one, melting point 147-149°C,

123. 2-[exo-6-m-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-methyl-3,4-dihydro-quinazolin-4-one,

124. 2-[exo-6-o-methoxy-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-methyl-3,4-dihydro-quinazolin-4-one,

125. 2-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-methyl-4-hydroxy-6-methyl-pyrimidine, melting point 174-175°C ,

126. 6-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-methyl-2-methyl-4-hydroxy-pyrimidine, melting point 147-149°C (dihydrochloride),

127. 6-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-methyl-uracil, melting point 201-203°C,

128. 6-[exo-6-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-methyl-uracil, melting point 183-184°C,

129. 6-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-1,2,3,4-tetrahydro-1,3-dimethyl-2, 4-dioxopyrimidine, melting point 108-110°C (hydrochloride),

130. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1,2,3,4-tetrahydro-6-methyl- 2,4-dioxo-pyrimidine, melting point 197-199°0,

131. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1,2,3,4-tetrahydro-1, 6- dimethyl-2,4-dioxo-pyrimidine, melting point 186-188°C,

132. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1,2,3,4-tetrahydro-3,6- dimethyl-2,4-dioxo-pyrimidine,

133. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1,2,3,4-tetrahydro-3,6- dimethyl-2,4-dithio-pyrimidine,

134. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1,2,3,4-tetrahydro-1, 3, 6-trimethyl-2,4-dioxo-pyrimidine, melting point 90-93°C (hydrochloride),

135. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-thiomethyl-6-methyl-4-(3H)- pyrimidinone,

136. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-mercapto-6-methyl-4(3H)-pyrimidinone ,

137. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-thiomethyl-3,6-dimethyl-4(3H) -pyrimidine, melting point 132-135°C, (dihydrochloride),

138. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-1,2,3,4-tetrahydro-6-amino- 1-methyl-2,4-dioxo-pyrimidine,

139. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-amino-6-methyl-4(3H)-pyrimidinone ,

140. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-amino-3,6-dimethyl-4(3H) -pyrimidinone, melting point 78-80°C,

141. 5-β-[exo-6-p-fluoro-phenyl-3--azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H )-pyrimidinone, melting point 163-165°C (dihydrochloride),

142. 3-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-dimethylamino-4(3H)-pyrimidinone,

143. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methylamino-3-ethyl-6-methyl-4( 3H)-pyrimidinone,

144. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-amino-3-ethyl-6-methyl-4( 3H)-pyrimidinone,

145. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-ethylamino-3,6-dimethyl-4(3H) -pyrimidinone,

146. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-n-propylamino-3,6-dimethyl-4( 3H)-pyrimidinone,

147. 5-β-[exo-6-p-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H) -pyrimidinone, decomposition temperature above 144°C, (dihydrochloride x 2 H20),

148. 5-β-[exo-6-m-chloro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H) -pyrimidinone, melting point 147-149°C (dihydrochloride),

149. 5-β-[exo-6-o-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H) -pyrimidinone, melting point 173-175°C (dihydrochloride),

150. 5-β-[exo-6-p-trifluoromethyl-phenyl-3-azabicyclo-[3,2,0]heptan-3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H )-pyrimidinone,

151. 5-β-[exo-6-p-cyano-phenyl-3-azabicyclo[3,2,0]-heptan-3-yl]-ethyl-2-methylamino-3,6-dimethyl-4( 3H)-pyrimidinone,

152. 5-β-[exo-6-m-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methylamino-3,6-dimethyl-4(3H) -pyrimidinone,

153. 5-β-[exo-6-p-fluoro-phenyl-3-azabicyclo[3,2,0]heptan-3-yl]-ethyl-2-methylamino-4-methoxy-6-methyl-pyrimidine.

Claims (2)

1. N-substituted derivatives of 3-azaibicyclo[3,2,0]heptane of formula I and their salts with physiologically tolerable acids: [image] indicated by the fact that in formula I R1 means a phenyl, pyridyl, thienyl or pyrroyl group mono- or disubstituted with a halogen atom, a C1-C4-alkyl, trifluoromethyl, hydroxyl, C1-C4-alkyl, amino, monomethylamino, dimethylamino, cyano or nitro group, R2 is a hydrogen atom or, in a given case, a phenyl group unsubstituted or substituted with a halogen atom, methoxyl, hydroxyl or amino group, n means the number 0, 1, 2, 3 or 4, R3 means a hydrogen atom, a hydroxyl, a C1-C4-alkyl or a C1-C4-alkoxy group, or together with an adjacent carbon atom a C=O- or C=S-group, X and Y mean carbon, CH, CH2, NH or C1-C4-alkyl-N- or nitrogen, Z represents a direct bond, CO-, SC- or CH or CH2, in which one hydrogen atom can be replaced by a hydroxyl, amino or C1-C4-alkyl or halogen and A means a hydrogen atom, hydroxyl amino, mercapto, C1-C4-alkylamino, di-C1-C4-alkylamino, C1-C4-alkylthio or C1-C4 alkoxy or together with the adjacent carbon atom a C=O group, or A means C3-C4 alkylene fused to Y, wherein alkylene may contain one or two but not adjacent double bonds, and one CH- or CH2- group may be replaced by NC NH- or N-CH3 and wherein the ring may be substituted by a fluorine or chlorine atom or a methyl, methoxy, nitro or amino group, or in the case of a benzene ring which may be mono-, di- or trisubstituted with a fluorine or chlorine atom or methyl, trifluoromethyl, nitro, hydroxyl, methoxy, amino, monomethyl or dimethylamino group, and where the ring in the right part of formula I on nitrogen atom no. 1 may carry a C1-C4-alkyl, allyl or benzyl group and contain 1 to 3 double but not adjacent double bonds. 2. Compounds of formula I in accordance with claim 1, characterized by the fact that they are used in disease control.