FI103667B - Process for Preparation of N-Substituted 3-Azabicyclo-3.2.0 µg Hepan Tere derivatives and of Physiologically Usable Acid-Formed Salts Therein - Google Patents

Description

103667

The invention relates to the preparation and use of new N-substituted azabicycloheptane derivatives and their salts with physiologically acceptable acids.

It is known that basic substituted butyrophenone derivatives or benzoic acid amide derivatives 10 act as neuroleptics or brain protecting agents (US 4,605,655, EP 410,114, DE 1 289 845, EP 400 661, DE 2 941 880, EP 190 472).

The observed affinities for sigma receptors then appear to be of great importance in addition to the dopamine and sero-15 tonin affinities.

In Helv. Chim. Acta. 59, 1186 (1976) discloses a stereoselective synthesis of benz [f] isoindole derivatives, Preparation of cis-anti-cis-3-benzyl-6,7-diphenyl-3-aza-bicyclo [3.2.0] heptane. However, no effects have been shown for the compound.

It is known from US-A-3 328 390 that certain azabicycloalkane derivatives show effects as sedatives.

: 25 It was now found that the N-substituted 3-azabicyc

lo [3. 2. 0] heptane derivatives of general formula I

R 1 - 6 ^ TT Nj (CH 2) n A j 5 R 2 '' where R 1 is phenyl optionally substituted by halogen or v alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, cyano or nitro groups; 10 is a thienyl group, 103667 2 R 2 is a hydrogen atom or a phenyl group, n is a number 1, 2, 3 or 4, A is a hydrogen atom or any of -α®> -Qf, -co - (O-10-nrs-co - or - ch = ch2 R3 represents a hydrogen atom, a hydroxy group or a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, R5 represents a hydrogen, fluorine, chlorine or bromine atom or a hydroxy, nitro, C1-4 alkyl or methoxy group and R6 is a hydrogen atom or a methyl group and their salts with physiologically usable acids have valuable pharmacological properties.

The substituents R 1, R 2, R 3, R 5 and R 6 and n in formula I preferably have the following meanings: R 1 is phenyl optionally substituted with: fluorine, chlorine, ethoxy, trifluoromethyl, nitro, hydroxy or amino, R 2 is hydrogen, n is 2 and 3, R3 is hydroxy, p-fluorophenyl, R5 is hydrogen, fluoro, chloro: R6 is hydrogen, methyl.

The following compounds are particularly preferred: 1- (4-Fluoro-phenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-one, 3 103667 1- (4-Fluoro-phenyl) -4- [exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-one, 1-phenyl-4 - [ exo-6-phenyl-3-azabicyclo [3.2.0] -heptan-3-yl] butan-1-one, = 5-phenyl-4- [exo-6-p-fluoro-phenyl-3-azabicyclo- [3.2.0] heptan-3-yl] butan-1-one, 1- (4-fluoro-phenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3 yl] butan-1-ol, 1- (4-fluoro-phenyl) -4- [exo-6-p-fluoro-phenyl-3-10-azabicyclo [3.2.0] heptan-3-yl] -butan-1- was, 1-phenyl-4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-ol, 1-phenyl-4- [exo-6-p-fluoro -phenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-ol, 15 1- (bis-4-fluorophenyl) -4- [exo-6-phenyl-3-azabicyclo [ 3.2.0] heptan-3-yl] butane, N- (3- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] propyl) -4-fluoro-benzamide, N- (2- [exo-6-phenyl-3-azabicyclo [3.2.0] heptane-3-20 yl] ethyl) -4-fluoro-benzamide, N- (2- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] ethyl) -N-methyl-4-fluorobenzamide N - (2- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] ethyl) -N-methylbenzamide, N- (3- [exo-6-p-fluoro) -phenyl-3-azabicyclo [3.2.0] heptan-3-yl] propyl) -4-fluoro-benzamide, N- (2- [exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] .0] heptan-3-yl] ethyl) benzamide and N- (2- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] -30 heptan-3-yl] ethyl) -N methyl-benzamide.

Compounds of formula I according to the invention may be prepared so that a compound of formula II.

Nu- (CH 2) n -A (II), 35 103667 4

wherein A and n are as defined above and Nu is a nucleofugic leaving group, preferably a halogen atom, especially bromine or chlorine, is reacted with a 3-azabicyclo [3.2.0] heptane derivative of formula III

j \ NH III

R 2 1 3 10 wherein R 1 is a hydrogen atom or optionally a halogen atom, a C 1 -C 6 alkyl, a trifluoromethyl, a hydroxy, a C 1 -C 4 alkoxy, an amino, a monomethylamino, a dimethylamino, a cyano or a nitro group; a disubstituted phenyl, pyridyl, thienyl, or pyrrolyl group, and R 2 is a hydrogen atom or a phenyl group optionally substituted by halogen, ethoxy, hydroxy or amino, and the compounds so obtained are optionally converted into their acid addition salts with physiologically acceptable acids.

The manufacturing process of the invention is characterized in what is set forth in claim 1.

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

: The reaction is usually carried out at a temperature between 20 ° C and 150 ° C and is usually complete within 1 to 10 hours.

The compounds of the formula I according to the invention can be purified either by recrystallization from standard 103667 'organic solvents, preferably from a lower alcohol such as ethanol, or by column chromatography.

The racemates can be separated into their enantiomers in a simple manner by classical cleavage with 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 the acid addition salt of a pharmacologically usable acid, preferably by adding to the solution an equivalent of the corresponding acid. Pharmaceutically acceptable acids include, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.

The compounds of the invention have valuable pharmacological properties. They can be used as neuroleptics, ie drugs for the treatment of psychoses (especially atypical), antidepressant agents, sedatives, hypnotics, central nervous system preservatives or muscle relaxants. Many of these properties may be combined in a compound of the invention. Demonstration of pharmacological activity occurs both in vivo and in vitro, whereby the substances can be characterized in particular because they have, in part, very high and selective affinity for receptor subtypes, for example, dopamine Dx, D2, D3, D4 receptors; serotonin IA, ID and 2 receptors; ?: Alpha 1 and 2 receptors; histamine 1 and muscarinic receptors.

The following methods were used to characterize the new substances in vivo: 35 a) Effect on orientation mobility 6 103667

In new environments, mice exhibit increased research behavior, which is manifested as an increase in motor activity. This motor activity is measured in cages with a photoelectric boom 0-30 minutes after the animals (NMRI female mice) have been placed in the cages. ED50: Dose that reduces motor activity by 50% compared to placebo-treated controls.

b) Interaction of Apomorphine Female NMRI mice receive 1.21 mg / kg amomorphine injected subcutaneously. Amomorphine at this dose results in motor activation, which is manifested as permanent climbing if the animals are kept in steel wire straps. Climbing is rated on a reference scale (every 15 minutes for 30 minutes): 0: The animal has four feet on the ground 1: The animal has two feet on a steel wire 2: The animal has four feet on a steel wire (climbs).

20 Climbing can be prevented by prior administration of antipsychotic agents.

ED50: Dose that inhibits animal climbing activity by 50% compared to placebo treated controls.

; C) Counteraction of L-5-HTP

Female Sprague-Dawley rats receive L-5-HTP intraperitoneally at a dose of 316 mg / kg. The animals then develop an irritation syndrome of which the symptoms - for paw treading 30 - tremor: assessed on a scale of scale from 0 to 0, 1 to moderate, 2 to clear, every 10 minutes for 20 to 60 minutes L -5-HTP doses. Following administration of L-5-HTP, a mean of 35 is reached with a reference scale of 17. The test substances are administered orally 60 to 7103667 minutes prior to administration of L-5-HTP. The ED50 is the dose that lowers the control reference scale by an average of 50%.

The methods disclosed are suitable for characterizing agents as antipsychotic agents. In addition to the inhibition of L-5 HTP syndrome 5, a serotonin counter-effect, a characteristic of so-called atypical neuroleptics, can be demonstrated.

The compounds of the invention show good activity in these tests.

Accordingly, the invention also relates to a therapeutic agent, characterized in that it contains a compound of formula I or a pharmacologically usable acid addition salt thereof as an active ingredient in addition to conventional carriers and diluents, and to the use of new compounds in the treatment of diseases.

The compounds of the invention may be administered orally or parenterally, intravenously or intramuscularly, in conventional manner.

The dosage depends on the age, condition and weight of the patient as well as on the route of administration. Generally, the daily dose of the active ingredient will be about 1 to 100 mg / kg body weight for oral administration and 0.1 to 10 mg / kg body weight for parenteral administration.

The novel compounds may be used in conventional ga-25 lenic dosage forms as solid or liquid, for example, tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, lotions or sprays. These are prepared in a conventional manner. The active ingredients 30 can then be processed to release the active ingredients of conventional galenic excipients, such as tablet binders, fillers, preservatives, tablet disintegrants, solubilizers, wetting agents, wetting agents, dispersing agents, emulsifying agents, solubilizing agents. , antioxidants, i.e. antioxidants and / or propellants (cf. e.g. H. Sucker et al., Pharmaz-eutische Technologie, Thieme Verlag, Stuttgart, 1978). The dosage forms thus obtained contain 5 to 1 to 99% by weight of the active ingredient.

The compounds of formula II required as starting materials for the synthesis of new compounds are known.

The compounds of formula III may be prepared so that the amine of formula IV

10

, N-R7 IV

wherein R 1 and R 2 are as defined above and R 7 is hydrogen, acetyl, benzyl or trifluoroacetyl, is subjected to a photochemical 2 + 2 cycloaddition followed by optionally cleavage of the acyl or benzyl group.

The photoreaction is very successful in an inert solvent, preferably acetone, at a temperature between 20 and 80 ° C. The light source is particularly well suited for high-pressure mercury lamps. It is possible to carry out photo-cycloaddition in a quartz apparatus under a nitrogen atmosphere, optionally adding about 1 mole of hydrochloric acid per mole: 25 amines.

In most cases, photocycloadduction occurs very diastereoselectively to obtain bicyclic compounds III having an exo configuration with respect to R 1 and R 2: R 11 9 103667

Both enantiomers can be isolated neat by racemate cleavage, for example with optically active tartaric acid derivatives.

Cleavage of the acyl group (R7) is carried out according to purpose-5 by saponification according to known methods. The same applies to the cleavage of the benzyl group.

The amines of formula IV are known in the literature or can be prepared by reacting either the R 1 -CHO of the aldehyde with vinylmagnesium chloride 10 to form the allyl alcohol V

OH

15 are then regrouped with hydrogen chloride in the

to the chloride VI

C1 VI

20 and finally allowed to react with the corresponding allylamine VII nhr7

VII

or Cinnamon Aldehyde VIII 25

R1 ^^ 5 ^ CH0 VIII

directly reducing amination with allylamine VII.

The following examples illustrate the invention: '' A) Preparation of starting materials: 1. Exo-6- (p-fluoro) -phenyl-3-azabicyclo [3.2.0] -heptane in 19.4 g (102 mmol) of N-allyl. -N- [3- (4-Fluorophen-35-yl) allyl] amine in 130 mL of acetone was added 130 mL of 1.

10 103667 10% Hydrochloric acid and 600 mg Michler's ketone and irradiated under nitrogen at room temperature for 55 hours with a 150 W mercury high pressure lamp in a quartz apparatus. The reaction mixture was then evaporated and the residue partitioned between methylene chloride and water. The aqueous ammonia solution was then made alkaline and the aqueous phase was extracted twice more with methylene chloride. The combined organic phases were dried over sodium sulfate and evaporated.

Yield: 19.3 g (99%), m.p. 165-166 ° C (maleate).

To separate the antipodes, a solution of 31.7 g (78.5 mmol) of (-) - di-O-toluoyl-L-tartaric acid in 300 ml of boiling ethanol was added to 15.0 g (78.5 mmol) of the racemate. After cooling and stirring, the crystals formed (15, 13.8 g) were suction filtered, further washed with ethanol and recrystallized from 200 ml of ethanol with 200 ml of water. Liberation of the base gave the (+) - antipode (5.5 g) with [α] D + 97.0 ° (EtOH, c = 0.969).

Overnight, 14.2 g of salt crystallized from the above mother liquor, which was recrystallized from 400 ml of ethanol (filtering off the insoluble component at reflux) (evaporation to 300 ml). Release of the base gave 4.0 g of (-) - antipod, [α] D = -96.0 ° (EtOH, c = 0.940).

Exo-phenyl configurations were confirmed by X-ray structural analysis.

2. Exo-6-phenyl-3-azabicyclo [3.2.0] heptane To 50.0 g (28.9 mmol) of N-cinnamyl-N-allylamine in 1600 ml of acetone was added 300 ml of 10 % bog-30 acid and irradiated under a nitrogen atmosphere at room temperature for 48 hours in a 150 watt high pressure mercury beaker in a quartz apparatus. The reaction mixture was then evaporated and the residue partitioned between methylene chloride and water. It was then made alkaline with aqueous ammonia 35 and the aqueous phase was extracted twice more with methylene chloride. The combined organic phases were dried over sodium sulfate and evaporated.

Yield: 49.0 g (98%) of a viscous oil, m.p. 177-178 ° C (maleate).

3. Exo-6,7-diphenyl-3-benzyl-3-azabicyclo [3.2.0] heptane To 70.0 g (206 mmol) of bis-N- (cinnamyl) -benzylamine in 2500 mL of acetone was added 0.8 g Michler coil pushed and irradiated under nitrogen atmosphere at room temperature for 25 hours with a 150 watt high pressure mercury lamp in a Duran glass apparatus. The reaction mixture was then evaporated and the residue partitioned between methylene chloride and water. The aqueous ammonia solution was then made alkaline and the aqueous phase was extracted twice more with methylene chloride. The combined organic phases were dried over sodium sulfate and evaporated. The crude product (65.0 g) was purified by column chromatography (silica gel, eluent: toluene, ethanol 20/2 98/2). 58.0 g (83%) of product are obtained, m.p .: 230-232 ° C (hydrochloride).

4. Exo-6,7-diphenyl-3-azabicyclo [3.2.0] heptane in 12.0 g (35.4 mmol) of exo-6,7-diphenyl-3-benzyl-3-azabicyclo [3.2.0 ] heptane in a mixture of 300 ml of n-propanol and 16 ml of water was added 16.0 g (254 mmol) of ammonium formate and 2.0 g of palladium (10%) on carbon and the reaction mixture was refluxed for 4 hours (evolution of carbon dioxide). After cooling, suction was filtered off from the catalyst, washed with propanol and methylene chloride, and the filtrate was evaporated. The residue was partitioned between methylene chloride and water, made alkaline with aqueous ammonia solution, and the aqueous phase was extracted twice more with methylene chloride. The combined organic phases were dried over sodium sulfate and evaporated. 8.1 g (92%) of product were obtained, m.p. 140-142 ° C (maleinate).

5. Exo-6-phenyl-3-benzyl-3-azabicyclo [3.2.0] heptane δ in 9.2 g (35.0 mmol) of N-cinnamyl-N-allyl-benzylamine in 1100 mL acetone was added with 100 mg of Michler's ketone and irradiated under nitrogen at room temperature for 5 hours with a 150 W mercury high pressure lamp in a Duran glass apparatus. The reaction-10 mixture was then evaporated. The crude product (9.4 g) was purified by column chromatography (silica gel, eluent: methylene chloride / methanol 98/2). 3.3 g (36%) of product were obtained, m.p. 126-128 ° C (maleinate).

6. 2,2,2-Trifluoro-1- [exo-6- (3-pyridyl) -3-aza-bicyclo [3.2.0] hept-3-yl] -ethanone (not according to the invention) 14.0 g (51.8 mmol) of N-allyl-2,2,2-trifluoro-N- [3- (3-pyridyl) -allyl] -acetamide were dissolved in 140 ml; acetone, 30 ml of 10% hydrochloric acid was added and irradiated under nitrogen at room temperature for 48 hours in a 150 W mercury high pressure lamp in a Duran glass apparatus. The reaction solution was then evaporated, dissolved in 150 ml of water and adjusted to pH 8-9 with aqueous ammonia. The aqueous phase was extracted twice with tert-butyl methyl ether, the combined organic phases were dried over sodium sulfate and evaporated. The remaining residue was fractionated by column chromatography (silica gel, methylene chloride + 2% methanol). Obtained: 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.

* i 103667 13 7. exo-6- (3-pyridyl) -3-azabicyclo [3.2.0] heptane (not according to the invention)

To a solution of 3.7 g (13.7 mmol) of 2,2,2-trifluoro-1- [exo-6- (3-pyridyl) -3-azabicyclo [3.2.0] hept-3-5 yl] -ethanone In 50 ml of ethanol, 2.5 g of potassium hydroxide plates were added. The reaction solution was stirred for another 2 hours at room temperature and then poured into 100 ml of ice water. The aqueous phase was extracted three times with tert-butyl methyl ether, the combined organic phases were dried over sodium sulfate and evaporated.

Yield: 2.3 g (96%) of a yellow oil, m.p. 202-205 ° C (hydrochloride).

Similarly, the following materials may be prepared: 8. exo-6- (m-fluorophenyl) -3-azabicyclo [3.2.0] -15 heptane 9. exo-6- (o-fluorophenyl) -3-azabicyclo [3.2. .0] -heptane, m.p. 118-120 ° C (maleinate) 10. exo-6- (p-chlorophenyl) -3-azabicyclo [3.2.0] heptane, m.p. 152-154 ° C (maleinate) 20 11. Exo-6- (m-chlorophenyl) -3-azabicyclo [3.2.0] heptane, m.p. 130-132 ° C (maleate) 12. exo-6- (p-methoxy-phenyl) -3-azabicyclo [3.2.0] heptane 13. exo-6- (m-methoxy-phenyl) -3-azabicyclo [3.2.0] heptane 14. exo-6- (p-nitrophenyl) -3-azabicyclo [3.2.0] heptane, m.p. 158-160 ° C (maleinate) 15. exo-6- (m-nitrophenyl) -3-azabicyclo [3.2.0] heptane 16. exo-6- (p-trifluoromethylphenyl) -3- azabicyclo [3.2.0] heptane, m.p. 155-156 ° C (maleate) 17. exo-6- (m-trifluoromethyl-phenyl) -3-azab. cyclo [3.2.0] heptane 18. exo-6- (3,4-dichloro-phenyl) -3-azabicyclo-35 [3.2.0] heptane 14 103667 19. exo-6- (3,5-dichloro-phenyl) ) -3-azabicyclo [3.2.0] heptane, m.p.> 250 ° C (hydrochloride) 20. exo-6- (3,4-dimethoxyphenyl) -3-azabicyclo [3.2.0] heptane 5 21. exo-6- (m-hydroxy-phenyl) -3-azabicyclo [3.2.0] heptane 22. exo-6- (p-hydroxy-phenyl) -3-azabicyclo [3.2.0] heptane 23. exo-6- (3,4-dihydroxy-phenyl) -3-azabicyclo [3.2.0] heptane 24. exo-6- (p-methylphenyl) -3-azabicyclo [3.2.0] heptane 2 5. exo-6- (m-methyl-phenyl) -3-azabicyclo [3.2.0] heptane 26. exo-6- (pt-butyl-phenyl) -3-azabicyclo [3.2.0] heptane, m.p. :> 255 ° C (hydrochloride) 27. exo-6- (m-amino-phenyl) -3-azabicyclo [3.2.0] heptane 28. exo-6- (p-amino-phenyl) -3-azabicyclo [ 3.2.0] - 20 heptane 29. exo-6- (p-cyano-phenyl) -3-azabicyclo [3.2.0] heptane, m.p. 168-170 ° C (maleinate) 30. exo-6-thien-2-yl-3-azabicyclo [ 3.2.0] heptane, mp: 180-182 ° C (hydrochloride) 31- Exo-6-thien-3-yl-3-azabicyclo [3.2.0] heptane, mp: 143-145 ° C (m.p. hydrochloride) 32. Exo-6- (5-chloro-thien-2-yl) -3-azabicyclo [3.2.0] heptane, m.p. 156-157 ° C (maleinate) B) Preparation of the final products Example 1 I 1- (4-Fluoro-phenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-one x HCl to 8.65 g (50 mmol) exo-6-phenyl-3-azabicyclo [3.2.0] heptane In 130 ml xylol was added 10.2 ml 1 «(60 mmol) <o-chloro-4-fluoro-butyrophenone and 11.5 g 10-667 (80 mmol) of finely ground potassium carbonate and 0.5 g of potassium iodide and refluxed for 7 hours with good stirring.

After cooling, the mixture was evaporated in a rotary evaporator and the residue was partitioned between methylene chloride and water.

The aqueous phase was extracted twice with methylene chloride and then the organic phase was evaporated after washing once with water and drying over sodium sulfate. The crude product (21 g) was purified by column chromatography (silica gel, eluent: methylene chloride / methanol 94/4). The free base was dissolved in 200 mL of ether, the insoluble flakes were filtered off and an excess of ether-15 hydrochloric acid in ether was added to the ether solution. The solids were then suction filtered in the cold and the hydrochloride was further washed with copious amounts of ether.

8.3 g (45%) of product, m.p. Mp 169-171 ° C.

Similarly, the following may be prepared:. 1-phenyl-4- [exo-6-phenyl-3-azabicyclo-

[3.2.0] heptan-3-yl] -butan-1-one, m.p. 134-136 ° C

(hydrochloride) 3. 1- (4-Fluoro-phenyl) -4- [exo-6,7-diphenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-one, m.p. 174-176 ° C (hydrochloride)

4. 1- (4-Fluoro-phenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butane, m.p. 131-133 ° C

(hydrochloride) 5. 5-1-phenyl-2- [exo-6-phenyl-3-azabicyclo. : [3.2.0] heptan-3-yl] -etan-1-one, oil 6. 1- (4-Fluoro-phenyl) -4- [exo-6-p-fluoro-phenyl, 3-azabicyclo [ 3.2.0] heptan-3-yl] -butane, m.p. : 135-137 ° C (hydrochloride) 103667 16 7. 1- (4-Fluoro-phenyl) -4- [exo-6-m-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] - butan-1-one, m.p .: 137-139 ° C (hydrochloride) 8. 1- (4-Fluoro-phenyl) -4- [exo-6-o-fluoro-phenyl-5β-azabicyclo [3.2.0 ] heptan-3-yl] -butan-1-one, m.p .: 180-182 ° C (hydrochloride) 9. 1- (4-Fluoro-phenyl) -4- [exo-6-p-chloro-phenyl] 3-Azabicyclo [3.2.0] heptan-3-yl] -butan-1-one 10. 1- (4-Fluoro-phenyl) -4- [exo-6-m-chloro-phenyl-3- azabicyclo [3.2.0] heptan-3-yl] -butan-1-one, m.p. : 137-139 ° C (hydrochloride) 11. 1- (4-Fluoro-phenyl) -4- [exo-6-methoxy-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1 -one 12. 1- (4-Fluoro-phenyl) -4- [exo-6-m, p-dichlorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-one 13th 1- (4-Fluoro-phenyl) -4- [exo-6-m, p-dimethoxyphenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-one.

Example 14 1- (4-Fluoro-phenyl) -4- [exo-6-p-fluoro-phenyl-3-20-azabicyclo [3.2.0] heptan-3-yl] -butan-1-one x HCl 4, To 5 g (23.5 mmol) of exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptane in 50 r of toluene was added 6.0 g (30 mmol) of (o-chloro-4- fluorobutyrophenone and 4.2 g (30 mmol) of finely ground potassium carbonate and 0.5 g of potassium iodide were refluxed for 7 hours with vigorous stirring, evaporated on a rotary evaporator and the residue partitioned between methylene chloride and water.

The aqueous phase was extracted twice with methylene chloride and then the organic phase was evaporated after washing once with water and drying over sodium sulfate. The crude product (9.4 g) was purified by column chromatography (silica gel, eluent: methylene chloride / methanol 96/4). The free base was dissolved in 150, 35 ml of ether, the insoluble flakes were filtered off in 1 liter and an excess of ethereal ether was added to the ether solution. After addition of 10 ml of acetone, the solids were suction filtered in the cold and the hydrochloride was further washed with plenty of ether. 4.9 g (53%) of product, m.p. 166 -5 168 ° C.

Similarly, the following can be prepared: 15. 1-Phenyl-4- [exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-one, m.p. : 141-143 ° C (maleate) 10-16- (4-Fluoro-phenyl) -4- [exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl ] -butane, 17. 1- (4-fluoro-phenyl) -4- [exo-6-p-nitro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-one, m.p .: 68 -70 ° C (hydrochloride) 15 18. 1- (4-Fluoro-phenyl) -4- [exo-6-m-nitro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl ] -butan-1-one, m.p. : 184-187 ° C (tosylate) 19. 1- (4-Fluoro-phenyl) -4- [exo-6-p-trifluoromethyl-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-20 one, m.p .: 158-161 ° C (hydrochloride) 20. 1- (4-Fluoro-phenyl) -4- [exo-6-p-cyano-phenyl-3-azabicyclo [ 3.2.0] heptan-3-yl] -butan-1-one, m.p. : 158-160 ° C (fumarate) 21. 1- (4-Fluoro-phenyl) -4- [exo-6-thien-3-yl-3-25-azabicyclo [3.2.0] heptan-3-yl] - butan-1-one, m.p .: 148-150 ° C (hydrochloride) 22. 1- (4-Fluoro-phenyl) -3- [exo-6-p-fluoro-phenyl-3-azabicyclo [3.2. 0] heptan-3-yl] -propan-1-one, m.p. 151-154 ° C (hydrochloride).

30 Example 23. 1- (bis-4-fluoro-phenyl) -4- [exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butane x HCl, 5.0 g To exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptane (26.2 mmol) in 80 mL of xylol was added 8.8 g (28.4 mmol) of 1,1'- (4-Chlorobutylidene) bis-4'-fluorobenzene, and 7.0 g (50.6 mmol) of finely ground calcium carbonate and 0.3 g of potassium iodide and refluxed for 15 hours with good stirring. After cooling, it was evaporated in a rotary evaporator and the residue was partitioned between methylene chloride and water. The aqueous 5-phase was extracted twice with methylene chloride and then the organic phase was evaporated after washing once with water and drying over sodium sulfate. The crude product (110 g) was purified by column chromatography (silica gel, eluent: methylene chloride / methanol 96/4). The free base was dissolved in 350 mL of ether, the insoluble flakes were filtered off and an excess of ethereal hydrochloric acid was added to the ether solution. Evaporation gave 4.9 g (40%) of product, m.p. : 49-50 ° C.

Similarly, the following can be prepared: 24. 1- (bis-4-fluoro-phenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butane, m.p. : 54-55 ° C as the hydrochloride.

Example 25 1- (4-Fluoro-phenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-ol 4.6 g: To (13.6 mmol) 1- (4-fluoro-phenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-one in 60 mL of methanol was added portionwise. 0.6 g (16 mmol); 25 sodium borate. Stirring was continued for another 2 hours at room temperature and evaporated in a rotary evaporator. The flask residue was partitioned between methylene chloride and water at pH 10, the aqueous phase was extracted twice more with methylene chloride, the combined organic phases were washed with water and the organic phase evaporated after drying over sodium sulfate. The crude product (4.6 g) was purified by column chromatography (silica gel, eluent: methylene chloride / methanol 96/4). The free base was dissolved in 150 mL of ether, the insoluble flakes were filtered off, and an excess of ethereal hydrochloric acid was added to the ether solution. The solids were then suction filtered in the cold and the hydrochloride was further washed with plenty of ether. 3.1 g (61%) of product were isolated, m.p. 147-149 ° C.

In a similar manner, the following can be prepared: 1- (4-Fluoro-phenyl) -4- [exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan- l-ol, m.p. : 128-129 ° C (hydrochloride) 27. 1- (4-Fluoro-phenyl) -4- [exo-6,7-diphenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1 m.p .: 228-10231 ° C (hydrochloride) 28. 1-Phenyl-4- [exo-6-phenyl-3-azabicyclo-

[3.2.0] heptan-3-yl] -butan-1-ol, m.p. 128-129 ° C

(hydrochloride) 29. 1-Phenyl-4- [exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-ol 30. 1- ( 4-Fluoro-phenyl) -4- [exo-6-o-fluoro-phenyl -3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-ol, m.p. 167-168 ° C ( hydrochloride) 31. 1- (4-Fluoro-phenyl) -4- [exo-6-m-chloro-phenyl-20-yl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-ol m.p .: 143-145 ° C (hydrochloride) 32. 1- (4-Fluoro-phenyl) -4- [exo-6-p-trifluoromethyl-phenyl-3-azabicyclo [3.2.0] heptan-3 -yl] -butan-1-ol, m.p. 145-148 ° C (hydrochloride).

Example 33 1- (4-Fluoro-phenyl) -4- [exo-6-p-amino-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-one 6.6 g (17.2 mmol) 1- (4-Fluoro-phenyl) -4- [exo-6-p-nitro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-30 one was dissolved in 200 ml of glacial acetic acid, 1.7 g * 'palladium on carbon (10%) was added and hydrogenated for 4 hours at room temperature and pressure. After the catalyst was suction filtered, the mother liquor was evaporated, the residue partitioned between methylene chloride and water, made alkaline with concentrated ammonia solution and extracted twice with methylene chloride.

t «20 103667

After the organic phase was dried and evaporated, 5.0 g of crude product was obtained, which was purified by column chromatography (silica gel, eluent: methylene chloride / methanol 95/5). 2.2 g (36%) of 5 1- (4-fluoro-phenyl) -4- [exo-6-p-amino-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] were isolated. -butan-1-one (hydrochloride melting point: 136-139 ° C) and 1.4 g (23%) of 1- (4-fluorophenyl) -4- [exo-6-p-aminophenyl-3- azabicyclo [3.2.0] -heptan-3-yl] -butan-1-ol (hydrochloride melting point: 10 122-125 ° C).

Example 34 N- (3- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -propyl) -4-fluoro-benzamide in 3.5 g (20 mmol) of exo-6 -phenyl-3-azabicyclo-15.10 [3.2.0] heptane in 40 mL of toluene was added N- (3-chloropropyl) -4-fluorobenzamide, and 4.8 g (35 mmol) of finely divided potassium carbonate and of potassium iodide and boiled under reflux for 9 hours. After cooling, it was evaporated on a rotary evaporator and the residue was partitioned between methylene chloride and water. The aqueous phase was extracted twice with methylene chloride and then the organic phase was evaporated after drying over sodium sulfate. The crude product (8.4 g) was purified by column chromatography (silica gel, eluent: methylene chloride / methanol 96/4). The purified free base was dissolved in a mixture of 100 ml of ether and 10 ml of acetone, and a solution of 1.6 g of maleic acid in acetone was added dropwise with ice-cooling and stirring slowly. The resulting salt 30 was suction filtered under a nitrogen atmosphere, further washed with ether and dried under a nitrogen atmosphere. 4.9 g (70%) of the hygroscopic product was isolated as the maleate salt, m.p. 122-124 ° C.

*

Similarly, one can prepare: * 103667 21 35. N- (3- [exo-6-phenyl-3-azabicyclo [3.2.0] hept-n-3-yl] -propyl) -benzamide, m.p. 72 ° C (hydrochloride) 36. N- (2- [Exo-6-phenyl-3-azabicyclo [3.2.0] hepta-5n-3-yl] ethyl) -4-fluoro-benzamide

37. N- (2- [Exo-6-phenyl-3-azabicyclo [3.2.0] hept-n-3-yl] ethyl) -benzamide, m.p. 89-90 ° C

38. N- (2- [Exo-6-phenyl-3-azabicyclo [3.2.0] hept-n-3-yl] ethyl) -N-methyl-4-fluorobenzamide, m.p. Mp: 10 126-128 ° C (hydrochloride) 39. N- (2- [Exo-6-phenyl-3-azabicyclo [3.2.0] hept-n-3-yl] ethyl) -N-methylbenzamide, mp. : 121-122 ° C (hydrochloride) 40. N- (2- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] ethyl) -N-methyl-4- isopropylbenzamide, m.p. 184-185 ° C (hydrochloride) 41. N- (3- [exo-6-phenyl-3-azabicyclo [3.2.0] hept-n-3-yl] propyl) -4-chloro 42. N- (2- [Exo-6-p-trifluoromethyl-phenyl-3-aza-bicyclo [3.2.0] heptan-3-yl] -ethyl) -4-chloro-benzamide,

mp: 112-114 ° C

43. N- (3- [Exo-6-phenyl-3-azabicyclo [3.2.0] hept-n-3-yl] -propyl) -3-methoxy-benzamide 44. N- (3- [Exo-6-phenyl) -3-azabicyclo [3.2.0] hepta-25-n-3-yl] propyl) -3-nitrobenzamide 45. N- (3- [exo-6-p-fluorophenyl-3-azabicyclo- [3.2.0] heptan-3-yl] -propyl) -4-fluoro-benzamide, m.p .: 160-162 ° C (hydrochloride) 46. N- (3- [exo-6-p-fluoro-phenyl) 3-Azabicyclo [3.2.0] heptan-3-yl] -propyl) -benzamide, m.p. 177 DEG -178 DEG C. (hydrochloride) 47. N- (2- [exo-6-p-fluoro-phenyl-3-azabicyclo]

[3.2.0] heptan-3-yl] ethyl) -4-fluoro-benzamide, m.p. Mp: 111-113 ° C

103667 22 48. N- (2- [Exo-6-p-fluoro-phenyl-3-azabicyclo-

[3.2.0] heptan-3-yl] -ethyl) -benzamide, m.p. 94-95 ° C

49. N- (2- [Exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -N-methyl-4-fluoro-benzamide; m.p .: 170-171 ° C (hydrochloride) * 50. N- (2- [exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -N -methyl-benzamide, m.p. : 167-169 ° C (hydrochloride) 51. N- (2- [Exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -N-methyl -4-isopropylbenzamide, m.p. 189-190 ° C (hydrochloride) 52. N- (3- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl) ] -propyl) -4-chloro-benzamide, 53. N- (3- [exo-6-p-fluoro-phenyl-3-azabicyclo [15.0] heptan-3-yl] -propyl) -3 -methoxy-benzamide, m.p .: 130-132 ° C (hydrochloride) 54. N- (3- [exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] - propyl) -3-nitrobenzamide, m.p. :

121-123 ° C

20th 55. N- (2- [Exo-6-m-chloro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -4-chloro-benzamide, m.p.

96-98 ° C

56. N- (2- [Exo-6-o-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -4-chloro-benzamide, m.p. :

Mp 25-91 ° C

57. N- (2- [Exo-6-p-fluoro-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -2-hydroxy-benzamide, m.p.

93-95 ° C

(See also Example 58) 30 Example 58. N- (2- [Exo-6-m-hydroxy-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -4-chlorobenzamide to 4.2 g (11 mmol) N- (2- [Exo-6-m-methoxy-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -4-chloro-benz-35 amide in 70 ml of methylene chloride was added dropwise to 13 ml. (13 103667 23 mmol) boron tribromide (1M solution in methylene chloride) at room temperature and the mixture was stirred overnight. After cooling, 100 ml of a 2N ammonium hydroxide solution were added, the organic phase was separated and the aqueous phase was further extracted with methylene chloride. After drying and evaporation, 4.5 g of crude product were obtained, which was purified by column chromatography (silica gel, eluent: methylene chloride / methanol 95/5). 2.8 g (69%) of product, m.p. 65-68 ° C.

EXAMPLE 59 Exo-3-n-Butyl-6-phenyl-3-azabicyclo [3.2.0] heptane m &lt; + &gt; O] heptane In 50 ml of tetrahydrofuran was added 4.2 ml (30 mmol) of triethylamine and 5.4 g (40 mmol) of n-butyl bromide and refluxed for 9 hours with vigorous stirring.

After cooling, it was evaporated in a rotary evaporator and the residue was partitioned between methylene chloride and water.

The aqueous phase was extracted twice with methylene chloride and then the organic phase was evaporated after drying over sodium sulfate. The crude product (4.2 g) was purified by column chromatography (silica gel, 25 mL, eluent: methylene chloride / methanol 96/4). The purified free base (3.1 g) was dissolved in 200 ml of ether and added dropwise with ice-cooling and stirring slowly with a stoichiometric amount of maleic acid in acetone. The salt formed was suction filtered under nitrogen, further washed with ether and dried under nitrogen.

4.4 g (64%) of the maleate salt was isolated, m.p. was 125-126 ° C.

60. Exo-3-methyl-6-phenyl-3-azabicyclo [3.2.0] -35 heptane, m.p. 129-131 ° C (maleate) 103667 24 61. exo-3-methyl -6-p-Fluoro-phenyl-3-azabicyclo [3.2.0] heptane, m.p. 129-131 ° C (maleate) 62. Exo-3-n-propyl-6-p-fluoro-phenyl- 3-Azabicyclo [3.2.0] heptane, 53. Exo-3-raethyl-6,7-diphenyl-3-azabicyclo [3.2.0] heptane, m.p. 197-188 ° C (hydrochloride) 64. Exo-3-n-propyl-6-m-hydroxy-phenyl-3-aza-bicyclo [3.2.0] heptane (see also Example 59), m.p. 148-150 ° C (hydrochloride). exo-3-allyl-6-m-methoxy-phenyl-3-azabicyclo [3.2.0] heptane, m.p. 118-120 ° C (hydrochloride) 66. exo-3- (3,4-dimethoxy) -phenethyl-6-phenyl-3-azabicyclo [3.2.0] heptane, m.p. 207-209 ° C (hydrochloride) 15 67. exo-3- (3,4-dimethoxy) -phenethyl-6-p-fluorophore -

nyyl-3-azabicyclo [3.2.0] heptane, m.p. M.p. 192-193 ° C

(hydrochloride) 68 exo-3- (3,4-dihydroxy) phenethyl-3-azabicyclo [3.2.0] heptane (analogous to Example 59) m.p.

Mp 202-205 ° C

69. exo-3-phenethyl-6-p-fluoro-phenyl-3-azabile; cyclo [3.2.0] heptane, mp 128-129 ° C (maleate).

β

Claims (5)

A process for the preparation of novel, therapeutically useful N-substituted 3-azabicyclo [3.2.0] heptane derivatives of formula I (I) 2 N 2 N 3 (CH 2) nA where R 1 is optionally halogen or CT -, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, cyano or nitro groups substituted phenyl group or thienyl group, R2 is a hydrogen atom or a phenyl group, n is a tai 1, 2, 3 or 4, A is a hydrogen atom or any of the groups 20 'CHR> ~ (~] f -NR 4 -CO-or -CH = CH 2 R 3 is a hydrogen atom, a hydroxy group or an optionally substituted phenyl group with a fluorine, chlorine or bromine atom, R 5 is a hydrogen, fluorine, chlorine or bromine atom or: a hydroxy, nitro, C wherein a compound of formula II Nu (CH 2) nA (II) m where reacting with a 3-azabicyclo [3.2.0] heptane derivative of the formula III R1ns6 / 10 10 (NH) R acids to acid addition salts thereof. ] «T 9 m _i: 1 Π