SI9300628A - N-substituted azabicycloheptane derivatives, their preparation and use - Google Patents

Abstract

Compounds of formula I in which they are present are described the substituents mentioned in the description, as well as their substituents preparation. The new compounds are suitable for treatment diseases.

Description

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N-substituted azabicycloheptane derivatives, their preparation and use

The invention relates to novel N-substituted azabicycloheptane derivatives, their preparation and use for the preparation of medicaments.

Basically substituted butyrophenone derivatives are known to exhibit. benzoic acid amide derivatives effects as neuroleptics or. cerebroprotectives (US 4 605 655, EP 410 114, DE 12 89 845, EP 400 661, DE 29 41 880, EP 190 472).

In addition to affinity for dopamine and serotonin, the observed affinities for the σ-receptors appear to play a special role.

We have now found that the N-substituted derivatives of 3-azabicyclo [3.2.0] heptane of formula I

in which

R ¹ means optionally halogen atoms, C 1 -C 6 alkyl, trifluoromethyl, hydroxyl, C 1 -C 6 alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups, a mono- or disubstituted phenyl, pyridyl, thienyl or pyrrole group,

R ² is a hydrogen atom or optionally halogen, methoxy, hydroxy or amino substituted phenyl group, n is a number of 1, 2, 3 or 4,

A is a hydrogen atom or one of the residues

-nr ⁶ -co

or -CH = CK ₂ ,

R ³ represents a hydrogen atom, a hydroxy radical or optionally substituted by a fluorine, chlorine or bromine phenyl radical,

R ⁴ represents a hydrogen atom or

R ³ and R ⁴ together represent an oxygen atom,

R ⁵ represents a hydrogen, fluorine, chlorine or bromine atom or a hydroxy, nitro, C 1 -C 6 alkyl or methoxy group, and

R ⁶ represents a hydrogen atom or a methyl group, and their salts with physiologically acceptable acids have valuable pharmacological properties.

In Formula I, the substituents R ¹ to R ^7, as well as n, preferably have the following meanings:

R ¹ : phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, nitro, hydroxy or amino,

R ² : hydrogen, n: 2 and 3,

R ³ : hydroxy, p-fluorophenyl,

R ⁴ : hydrogen or together with R ³ oxygen,

R ⁵ : hydrogen, fluorine, chlorine,

R ⁶ : hydrogen, methyl.

-J

The following compounds are particularly preferred:

1- (4-fluorophenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] -heptan-3-yl] butan-1-one, 1- (4-fluorophenyl) -4- [exo -6-p-fluorophenyl-3-azabicyclo [3.2.0] -heptan-3-yl] butanone, 1-phenyl-4- [exo-6-phenyl-3-azabicyclo [3.2.0] -heptane- 3-yl] butan-1-one, 1-phenyl-4- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] -heptan-3-yl] butan-1-one, 1- (4 -fluorophenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] -heptan-3-yl] butan-1-ol, 1- (4-fluorophenyl) -4- [exo-6-p -fluorophenyl-3-azabicyclo [3.2.0] -heptan-3-yl] butan-1-ol, 1-phenyl-4- [exo-6-phenyl-3-azabicyclo [3.2.0] -heptan-3- yl] butan-1-ol, 1-phenyl-4- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] -heptan-3-yl] butan-1-ol, 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-fluorobenzamide,

N- (2- [Exo-6-phenyl-3-azabicyclo [3.2.0] -heptan-3-yl] ethyl) -4-fluorobenzamide,

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-methyl-benzamide,

N- (3- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] -heptan-3-yl] propyl) -4-fluorobenzamide,

N- (2- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] -heptan-3-yl] ethyl) -benzamide and

N- (2- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] -heptan-3-yl] ethyl) -N-methyl-benzamide.

The compounds of formula I according to the invention can be prepared by treating a compound of formula II

Nu- (CH ₂ ) _n -A (II), in which A and n have the meanings given and Nu represents a nucleophage leaving group, is reacted with a 3-azabicyclo [3.2.0] heptane derivative of formula III

NH

III in which

R ¹ means a hydrogen atom or optionally halogen atoms, C 1 -C 6 alkyl, trifluoromethyl, hydroxy, C 1 -C 6 alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups mono- or disubstituted phenyl, pyridyl, thienyl or pyrrole group and is

R ² is a hydrogen atom or optionally halogen, methoxy, hydroxy or amino substituted phenyl group, and the compounds thus obtained are optionally converted into their acid addition salts with physiologically acceptable acids.

Preferably, halogen atoms, in particular bromine or chlorine, are considered as the nucleophage leaving group for Nu.

The metabolism is effected in the presence of an inert base, such as triethylamine or potassium carbonate, as an acid-binding agent, in an inert solvent, as a cyclic saturated ether, in particular tetrahydrofuran or dioxane, or in a benzene hydrocarbon, such as toluene or xylene.

The metabolism is generally carried out at temperatures from 20 to 150 ° C and is generally completed within 1 to 10 hours.

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

You can easily racemate with classical cleavage with optically active carboxylic acids, e.g. tartaric acid derivatives, in an inert solvent, e.g. in lower alcohols, separated into enantiomers.

The free derivatives of 3-azabicyclo [3.2.0] heptane of formula I can be conveniently converted into the acid addition salt of a pharmacologically acceptable acid, preferably by adding an equivalent of the corresponding acid to the solution. Pharmaceutically acceptable acids are e.g. 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 exhibit valuable pharmacological properties. They can be used as neuroleptics (especially atypical), antidepressants, sedatives, hypnotics, central nervous system protectors, or muscle relaxants. In the compound of the invention, several of these effects may occur in combination. Pharmacological evidence of the effect is done both in vivo and in vitro, whereby characterization of the substance is possible, in particular with a very high and selective affinity for receptor subtypes, e.g. dopamine D ^, D ₂ -, D ₃ -, D ₄ receptors; serotonin 1A-, ID- and 2-receptors; alpha 1- and 2-receptors; histamine 1 as well as muscarinic receptors.

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

a) Impact on orientational motility

Mice exhibit increased exploratory behavior in the new environment, which is manifested as a greater motor activity. This motor activity was measured in cages with light barriers between 0 and 30 min after placing the animals (NMRI female mice) in the cages. ED50: a dose that reduces motor activity by 50% compared with placebo-treated controls.

b) Antagonism against apomorphine

Female NMRI females obtained 1.21 mg / kg of apomorphine s.c. Apomorphine causes motor activation at this dose, which is indicated by the presence of animals in wire mesh cages as continuous climbing. Climbing is evaluated by scoring (every 2 min for 30 min):

0: The animal has 4 points on the ground

1: The animal has 2 points online

2: The animal has 4 points online (climb).

Pre-treatment with antipsychotics can inhibit climbing behavior.

ED50: A dose that suppresses the climbing activity of animals by 50% compared to placebo-treated controls.

c) Antagonism against L-5-HTP

The rat Sprague-Dawley rats of L-5-HTP age 316 mg / kg ip.The animals then develop arousal syndrome, which is evaluated by scoring (0 = not present, 1 = moderately expressed, 2 = clearly expressed) every 10 min for 20 to 60 min after administration of L-5-HTP symptoms for paw treading in - tremor.

On average, 17 points are obtained after administration of L-5-HTP. The test substances are administered p.o. 60 min before L-5-HTP. As ED50, we calculate a dose that reduces control points by an average of 50%.

The above methods are suitable for characterizing a substance as an antipsychotic. Inhibition of L-5-HTP syndrome may result in an antagonistic effect against serotonin, an effect that is characteristic of e.g. atypical neuroleptics.

The substances of the invention show good effect in these tests.

The invention also relates appropriately to a therapeutic agent characterized by the content of a compound of formula I or its pharmacologically tolerable acid addition salts as active ingredients in addition to conventional carriers and diluents, as well as to the use of new compounds in the treatment of diseases.

The compounds of the invention may 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 the route of administration.

As a rule, the daily dose of the active substance is between about 1 and 100 mg / kg body weight when given orally and between 0.1 and 10 mg / kg body weight when administered parenterally.

The novel compounds can be used in conventional galenic usable forms, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. We prepare them in the usual way. In doing so, the active ingredients can be processed with conventional galenic auxiliaries such as tablet binders, fillers, preservatives, disintegrators, fluid regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (compare H. Sucker et al: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The useful forms thus obtained contain the active ingredient normally in an amount of from 1 to 99% by weight.

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

Substances of formula III can be prepared by the amine of formula IV

R ¹

R ⁷

IV in which R ¹ and R ^{2 have} the above meanings and R ⁷ represents hydrogen, acetyl, benzyl or trifluoroacetyl, photochemically undergo 2 + 2 cycloaddition and then optionally cleave the acyl or benzyl group.

The photoreaction is well mediated in an inert solvent, preferably acetone, at temperatures from 20 to 80 ° C. A mercury high-pressure lamp is particularly suitable as a light source. In this case, it is advantageous to perform photocycloaddition in a quartz apparatus under a nitrogen atmosphere, optionally adding about 1 mole of hydrochloric acid per mole of amine.

In most cases photocycloading is highly diastereoselective to bicyclic compounds III with exo-configuration relative to R ¹ and R ² :

R ¹

R ²

With vaccination of racemates, e.g. with optically active tartaric acid derivatives, both enantiomers can be isolated pure.

The cleavage of the acyl residue (R ⁷ ) is efficiently effected by saponification by known methods. The same applies to the cleavage of a benzyl residue.

Amines of formula IV are known in the literature or can be prepared by reacting either the RLCHO aldehyde with vinyl magnesium chloride into allyl alcohol V

OH

Renate is transferred with hydrogen chloride to allyl chloride VI _C1

VI and finally metabolised with the corresponding allylamine VII

R ² NHR ⁷ VII or cinnamon aldehyde VIII

VIII is directly reductively aminated with allylamine VII.

The following examples are used to illustrate the invention:

A) Preparation of starting materials

Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptane

To 19.4 g (102 mM) of N-allyl-N- [3- (4-fluorophenyl) allyl] amine in 130 ml of acetone was added 130 ml of 10% hydrochloric acid and 600 mg of Michler ketone and irradiated under nitrogen 55 hs 150 watt mercury high pressure lamp in quartz apparatus at room temperature. The reaction mixture was then evaporated and the residue partitioned between methylene chloride and water. They were basified with aqueous ammonia and extracted twice with methylene chloride. The combined organic phases were dried with sodium sulfate and evaporated.

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

To separate the antipodes, a solution of 31.7 g (78.5 mM) (-) - di-O-toluoyl-L-tartaric acid in 300 ml of boiling ethanol was added to 15.0 g (78.5 mM) of the racemate. The crystals, which were removed by stirring under stirring (13.8 g), were sucked off and recrystallized from 200 ml of ethanol with 200 ml of ethanol, with the addition of 200 ml of water. Base release gave the (+) - antipode (5.5 g) with [a] _D = - 97.0 ° (EtOH, c = 0.969).

From the upper mother liquor, 14.2 g of salt was crystallized overnight, which was recrystallized from 400 ml of ethanol (filtration of the insoluble portion at boiling point) (evaporation to 300 ml). The release of the base gave 4.0 g (-) - antipode, [a] _D = - 96.0 ° (EtOH, c = 0.940).

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

2. Exo-6-phenyl-3-azabicyclo [3.2.0] heptane

To 50.0 g (28.9 mM) of N-cinnamyl-N-allylamine in 1600 ml of acetone was added 300 ml of 10% hydrochloric acid and irradiated under nitrogen for 48 h with a 150 watt mercury high pressure lamp in a quartz apparatus at room temperature. The reaction mixture was then evaporated and the residue partitioned between methylene chloride and water. They were basified with aqueous ammonia and extracted twice with methylene chloride. The combined organic phases were dried with sodium sulfate and evaporated. Yield: 49.0 g (98%) of viscous oil, m.p. 177-178 ° C (maleinate).

3. Exo-6,7-diphenyl-3-benzyl-3-azabicyclo [3.2.0] heptane

To 70.0 g (206 mM) of bis- [N-cinnamyl) -benzylamine in 2500 ml of acetone was added 0.8 g of Michler ketone and irradiated 25 h with a 150 watt mercury high-pressure lamp in a Duran® glass apparatus at room temperature. . The reaction mixture was then evaporated and the residue partitioned between methylene chloride and water. They were basified with aqueous ammonia solution and extracted twice with methylene chloride. The combined organic phases were dried with sodium sulfate and evaporated. Purification of the crude product (65.0 g) was carried out by column chromatography (silica gel, eluent toluene, ethanol 98/2). 58.0 g (83%) of the product are obtained, m.p. 230232 ° C (hydrochloride).

4. Exo-6,7-diphenyl-3-azabicyclo [3.2.0] heptane

To 12.0 g (35.4 mM) of exo-6,7-diphenyl-3-benzyl-3-azabicyclo [3.2.0] heptane in a mixture of 300 ml n-propanol and 16 ml water was added 16.0 g (254 mM) of ammonium formate and 2.0 g of palladium (10%) on charcoal and the reaction mixture was boiled for 4 h at reflux (developing carbon dioxide). After cooling, they were sucked off from the catalyst, washed with propanol and methylene chloride, and the filtrate was evaporated. The residue was partitioned between methylene chloride and water, basified with aqueous ammonia solution and extracted twice with methylene chloride. The combined organic phases were dried with sodium sulfate and evaporated.

8.1 g (92%) of the product are obtained, m.p. 140-142 ° C (maleinate).

5. Exo-6-phenyl-3-benzyl-3-azabicyclo [3.2.0] heptane

To 9.2 g (35.0 mM) of [N-cinnamyl) -N-allylbenzylamine in 1100 ml of acetone was added 100 mg of Michler ketone and irradiated under nitrogen with 5 h 150 watt mercury high-pressure lamp in a Duran® glass apparatus at room temperature. The reaction mixture was then evaporated. Purification of the crude product (9.4 g) was performed by column chromatography (silica gel, eluent methylene chloride / methanol 98/2). 3.3 g (36%) of the product are obtained, m.p. 126-128 ° C (maleinate).

6. 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 were dissolved in 140 ml of acetone, 30 ml of 10% was added aqueous hydrochloric acid and irradiated 48 hs 150 watt mercury high-pressure lamp in a Duran® glass apparatus at room temperature under nitrogen. The reaction solution was then evaporated, taken up in 150 ml of water and adjusted with aqueous ammonia to pH 8 to 9. The aqueous phase was extracted twice with tert.butyl methyl ether, the combined organic phases were dried over sodium sulfate and evaporated. The residual residue was fractionated by column chromatography (silica gel, methylene chloride + 2% methanol). 6.2 g (42%) of the unchanged N-allyl-2,2,2-trifluoro-N- [3- (3-pyridyl) -allyl] -acetamide were obtained and 3.7 g (26%) of 2.2 , 2-Trifluoro- [exo-6- (3-pyridyl) -3-azabicyclo [3.2.0] hept-3-yl] ethanone as a dark oil.

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

To a solution of 3.7 g (13.7 mM) of 2,2,2-trifluoro-1- [exo-6- (3-pyridyl-3-azabicyclo [3.2.0] hept-3-yl] ethanone in 50 ml ethanol was added 2.5 g of potassium hydroxide in pellets, the reaction solution was stirred for 2 h 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, mp 202 to 205 ° C (hydrochloride).

The following substances can be prepared analogously:

8. Exo-6- (m-fluorophenyl) -3-azabicyclo [3.2.0] 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),

11. Exo-6- (m-chlorophenyl) -3-azabicyclo [3.2.0] heptane, m.p. 130-132 ° C (maleinate),

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-nitro-phenyl) -3-azabicyclo [3.2.0] heptane, m.p. 158-160 ° C (maleinate)

15. Exo-6- (m-nitro-phenyl) -3-azabicyclo [3.2.0] heptane,

16. Exo-6- (p-trifluoromethyl-phenyl) -3-azabicyclo [3.2.0] heptane, m.p. 155-156 ° C (maleinate),

17. Exo-6- (m-trifluoromethyl-phenyl) -3-azabicyclo [3.2.0] heptane,

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

19. Exo-6- (3,5-dichlorophenyl) -3-azabicyclo [3.2.0] heptane, m.p. > 250 ° C (hydrochloride),

20. Exo-6- (3,4-dimethoxyphenyl) -3-azabicyclo [3.2.0] heptane,

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

22. Exo-6- (p-hydroxyphenyl) -3-azabicyclo [3.2.0] heptane,

23. Exo-6- (3,4-dihydroxyphenyl) -3-azabicyclo [3.2.0] heptane,

24. Exo-6- (p-methylphenyl) -3-azabicyclo [3.2.0] heptane,

25. Exo-6- (m-methylphenyl) -3-azabicyclo [3.2.0] heptane,

26. Exo-6- (p-t-butylphenyl) -3-azabicyclo [3.2.0] heptane, m.p. > 255 ° C (hydrochloride),

27. Exo-6- (m-aminophenyl) -3-azabicyclo- [3.2.0] heptane,

28. Exo-6- (p-aminophenyl) -3-azabicyclo- [3.2.0] heptane,

29. Exo-6- (p-cyanophenyl) -3-azabicyclo- [3.2.0] heptane, m.p. 168-170 ° C (maleinate),

30. Exo-6-thien-2-yl-3-azabicyclo [3.2.0] heptane, m.p. 180-182 ° C (hydrochloride),

31. Exo-6-thien-3-yl-3-azabicyclo- [3.2.0] heptane, m.p. 143-145 ° C (hydrochloride),

32. Exo-6- (5-chlorothien-2-yl) -3-azabicyclo- [3.2.0] heptane, m.p. 156-157 ° C (maleinate),

33. Exo-6-pyrrol-2-yl-3-azabicyclo- [3.2.0] heptane,

34. Exo-6-pyrid-4-yl-3-azabicyclo [3.2.0] heptane,

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

Preparation of finished products

Example 1 1- (4-Fluorophenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-one x HCl

To 8.65 g (50 mM) of exo-6-phenyl-3-azabicyclo [3.2.0] heptane in 130 ml of xylene was added 10.2 ml (60 mM) of o) -chloro-4-fluorobutyrophenone as well as 11. 5 g (80 mM) of finely powdered potassium carbonate, in addition to 0.5 potassium iodide, was boiled under reflux for 7 h with good stirring.

After cooling, they were evaporated on a rotary evaporator and the residue was partitioned between methylene chloride and water.

The aqueous phase was extracted twice more with methylene chloride and then the organic phase was washed once with water and dried with sodium sulfate. The crude product (21 g) was purified by column chromatography (silica gel, eluent methylene chloride / methanol 94/4). The free base was taken up in 200 ml of ether, the insoluble flakes were filtered off and excess ethoic hydrochloric acid was added to the ether solution. The solids were then aspirated in the cold and the hydrochloride was washed with plenty of ether. 8.3 g (45%) of product, m.p. 169171 ° C.

Analogically, we can prepare:

2. 1-Phenyl-4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-one, m.p .: 134 to 136 ° C (hydrochloride), 1- ( 4-fluorophenyl) -4- [exo-6,7-diphenyl-3-azabicyclo [3.2.0] heptan-3-yl] 13 butan-1-one, mp: 174 to 176 ° C (hydrochloride),

4. 1- (4-fluorophenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] butane, mp: 131 to 133 ° C (hydrochloride),

5. 1-phenyl) -2- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] ethan-1-one, oil,

6. 1- (4-fluorophenyl) -4- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] butane,

7. 1- (4-fluorophenyl) -4- [exo-6-m-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-one,

8. 1- (4-Fluorophenyl) -4- [exo-6-o-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-ylbutan-1-one, m.p. 180-182 ° C (hydrochloride),

9. 1- (4-fluorophenyl) -4- [exo-6-p-chlorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-one,

10. 1- (4-Fluorophenyl) -4- [exo-6-m-chlorophenyl-3-azabicyclo [3.2.0] heptan-3-ylbutan-1-one, m.p. 137-139 ° C (hydrochloride),

11. 1- (4-fluorophenyl) -4- [exo-6-p-methoxyphenyl-3-azabicyclo [3.2.0] heptan-3-ylbutan-1-one,

12. 1- (4-fluorophenyl) -4- [exo-6-m, p-dichlorophenyl-3-azabicyclo [3.2,0] heptan-3-yl] butan-1-one,

13. 1- (4-Fluorophenyl) -4- [exo-6-m, p-dimethoxyphenyl-3-azabicyclo [3.2.0] heptan3-yl] -butan-1-one.

Example 14 1- (4-Fluorophenyl) -4- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-one xHCl

To 4.5 g (23.5 mM) of exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptane in 50 ml of toluene was added 6.0 g (30 mM) of G) -chloro-4-fluorobutyrophenone as well as 4.2 g (30 mM) of finely powdered potassium carbonate in addition to 0.5 potassium iodide and boiled for 7 h under reflux with good stirring. After cooling, they were evaporated on a rotary evaporator and the residue was partitioned between methylene chloride and water.

The aqueous phase was extracted twice more with methylene chloride and then the organic phase was washed once with water and dried with 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 taken up in 150 ml of ether, the insoluble flakes were filtered off and ether hydrochloric acid was added to the ether solution. After addition of 10 ml of acetone, the solid was sucked off in the cold and the hydrochloride was washed with plenty of ether. 4.9 g (53%) of product, m.p. 166-168 ° C.

Analogically, we can prepare:

15. 1-Phenyl-4- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-one, mp: 141 to 143 ° C (maleinate),

16. 1- (4-Fluorophenyl-4- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan3-yl] butane,

17. 1- (4-fluorophenyl-4- [exo-6-p-nitrophenyl-3-azabicyclo [3.2.0] heptan-3-yl] butan-1-one, m.p. 68-70 ° C (hydrochloride).

18. 1- (4-Fluorophenyl-4- [exo-6-m-nitrophenyl-3-azabicyclo [3.2.0] heptan3-yl] butan-1-one

19. 1- (4-fluorophenyl-4- [exo-6-p-trifluoromethylphenyl-3-azabicyclo [3.2.0] heptan3-yl] butan-1-one, mp 158-161 ° C (hydrochloride).

20. 1- (4-Fluorophenyl-4- [exo-6-p-cyanophenyl-3-azabicyclo [3.2.0] heptan3-yl] butan-1-one,

21. 1- (4-Fluorophenyl-4- [exo-6-thien-3-yl-3-azabicyclo [3.2.0] heptan-3-ylbutan-1-one,

22. 1- (4-Fluorophenyl-4- [exo-6-pyrid-3-yl-3-azabicyclo [3.2.0] heptane15)

3-yl] butan-1-one,

23. 1- (4-Fluorophenyl-3- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] propan-1-one, mp 151-154 ° C (hydrochloride).

Example 24 1- (bis-4-fluorophenyl) -4- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butane xHCl

To 5.0 g (26.2 mM) of exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptane in 80 ml of xylene was added 8.8 g (28.4 mM) of l, r- (4 -chlorobutylidene) bis-4'-fluorobenzene as well as 7.0 g (50.6 mM) of finely powdered potassium carbonate in addition to 0.3 potassium iodide and boiled under reflux for 15 h under good stirring. After cooling, they were evaporated on a rotary evaporator and the residue was partitioned between methylene chloride and water. The aqueous phase was extracted twice more with methylene chloride and then the organic phase was washed once with water and dried with sodium sulfate. The crude product (110 g) was purified by column chromatography (silica gel, eluent methylene chloride / methanol 96/4). The free base was taken up in 350 ml of ether, the insoluble flakes were filtered off and excess ether hydrochloric acid was added to the ether solution. Evaporation gave 4.9 g (40%) of product, m.p. 49-50 ° C.

Analogically, we can prepare:

25. 1- (bis-4-fluorophenyl) -4- [exo-6-3-azabicyclo [3.2.0] heptane-3-yl-butane, m.p. 54-55 ° C (as hydrochloride)

Example 26 1- (4-Fluorophenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butan-1-ol

K 4.6 g (13.6 mM) 1- (4-fluorophenyl) -4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3yl] -butan-1-one in 60 ml of methanol 0.6 g (16 mM) of sodium borate were added by rations. It was stirred for 2 h at room temperature and evaporated on a rotary evaporator. The residue in the flask at pH = 10 was partitioned between methylene chloride and water, the aqueous phase was extracted twice with methylene chloride, the combined organic phases were washed with water and the organic phase was evaporated after drying with 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 taken up in 150 ml of ether, the insoluble flakes were filtered off and excess ether hydrochloric acid was added to the ether solution. The solid was then sucked off in cold and the hydrochloride was washed with plenty of ether. 3.1 g (61%) of product, m.p. 147-149 ° C.

27. 1- (4-Fluorophenyl) -4- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3yl] -butan-1-ol, m.p. 128-129 ° C (hydrochloride),

28. 1- (4-Fluorophenyl) -4- [exo-6,7-diphenyl-3-azabicyclo [3.2.0] heptan-3yl] -butan-1-ol, m.p. 228-231 ° C (hydrochloride),

29. 1-Phenyl-4- [exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl-butan-1-ol, m.p. 128-129 ° C (hydrochloride),

30. 1-Phenyl-4- [exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3yl] -butan-1-ol,

31. 1- (4-Fluorophenyl-4- [exo-6-o-fluorophenyl-3-azabicyclo [3.2.0] heptan-3yl] -butan-1-ol, mp 167-168 ° C (hydrochloride).

32. 1- (4-Fluorophenyl-4- [exo-6-m-chlorophenyl-3-azabicyclo [3.2.0] heptan-3yl] -butan-1-ol, mp 143-145 ° C (hydrochloride).

33. 1- (4-Fluorophenyl-4- [exo-6-p-trifluoromethylphenyl-3-azabicyclo [3.2.0] heptan-3yl] -butan-1-ol, mp 145-148 ° C (hydrochloride).

Example 34 1- (4-Fluorophenyl) -4- [exo-6-p-aminophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -butanone

6.6 g (17.2 mM) 1- (4-fluorophenyl) -4- [exo-6-p-nitrophenyl-3-azabicyclo [3.2.0] heptan3-yl] -butan-1-one was dissolved in 200 ml of glacial acetic acid, 1.7 g of palladium on charcoal (10%) were added and hydrated at room temperature and normal pressure for 4 h. After the catalyst was sucked off, the mother liquor was evaporated, the residue partitioned between methylene chloride and water, basified by mixing with a concentrated ammonia solution and extracted twice with methylene chloride. After drying and evaporating the organic phase, 5.0 g of the crude product was obtained, which was purified by column chromatography (silica gel, eluent methylene chloride / methanol 95/5). 2.2 g (36%) of 1- (4-fluorophenyl) -4- [exo-6-p-aminophenyl-3-azabicyclo- [3.2.0] -heptan-3-yl] butan-1-one was isolated (m.p. 136-139 ° C) and 1.4 g (23%) of 1- (4-fluorophenyl) -4- [exo-6-p-aminophenyl-3-azabicyclo- [3.2.0] -heptane- 3-yl] -butan1-ol (m.p. 122-125 ° C).

Example 35

N- (3- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3'yl] -propyl) -4-fluorobenzamide

To 3.5 g (20 mM) of exo-6-phenyl-3-azabicyclo [3.2.0] heptane in 40 ml of toluene was added N- (3-chloropropyl) -4-fluorobenzamide as well as 4.8 g (35 mM) ) of finely powdered potassium carbonate in addition to 0.5 potassium iodide and boiled for 9 h under reflux while stirring well. After cooling, they were evaporated on a rotary evaporator and the residue was partitioned between methylene chloride and water. The aqueous phase was extracted twice more with methylene chloride and then the organic phase was evaporated after drying with 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 the solution was slowly added dropwise with ice-cooling and stirring.

1.6 g of maleic acid in acetone. The recovered salt was filtered off under nitrogen, washed with ether and then dried under nitrogen. 4.9 g (70%) of the hygroscopic product were isolated as the maleate salt, m.p. 122-124 ° C.

In an analogous way, we can prepare:

36. N- (3- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -propyl) -benzamide, m.p. 70 to 72 ° C (hydrochloride),

37. N- (2- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -4-fluorobenzamide,

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

39. N- (2- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -N-methyl4-fluorobenzamide, m.p. 126 to 128 ° C (hydrochloride),

40. N- (2- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -N-methylbenzamide, m.p. 121 dol22 (hydrochloride),

41. N- (2- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -N-methyl4-isopropylbenzamide, m.p. 184 to 185 ° C (hydrochloride),

42. N- (3- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -propyl) 4-chlorobenzamide,

43. N- (2- [Exo-6-p-trifluoromethylphenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) 4-chlorobenzamide, m.p. 112-114 ° C,

44. N- (3- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -propyl) -3-methoxybenzamide,

45. N- (3- [Exo-6-phenyl-3-azabicyclo [3.2.0] heptan-3-yl] -propyl) -3-nitrobenzamide,

46. N- (3- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -propyl) -4-fluoro benzamide, m.p. 160 to 162 ° C,

47. N- (3- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -propyl) benzamide, m.p. 177 to 178 ° C (hydrochloride),

48. N- (2- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -4-fluorobenzamide, m.p. 111 to 113 ° C,

49. N- (2- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) benzamide, m.p. 94 to 95 ° C,

50. N- (2- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) N-methyl-4-fluorobenzamide, m.p. 170 to 171 ° C (hydrochloride),

51. N- (2- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) N-methyl-benzamide,

52. N- (2- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) N-methyl-4-isopropylbenzamide, m.p. 189 to 190 ° C (hydrochloride),

53. N- (3- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -propyl) 4-chlorobenzamide,

54. N- (3- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -propyl) 3-methoxybenzamide,

55. N- (3- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -propyl) 3- nitrobenzamide,

56. N- (2- [Exo-6-m-chlorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) 4-chlorobenzamide, m.p. 96-98 ° C,

57. N- (2- [Exo-6-o-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) 4-chlorobenzamide, m.p. 91-93 ° C,

58. N- (2- [Exo-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) 2-hydroxy-benzamide, m.p. 93-95 ° C (see also example 59).

Example 59

N- (2- [Exo-6-m-hydroxyphenyl-3-azabicyclo [3.2.0] heptan-3-yl] -ethyl) -4-chlorobenzamide

To 4.2 g (11 mM) of N- (2- [exo-6-m-methoxyphenyl-3-azabicyclo [3.2.0] heptan-3-yl] ethyl) -4-chlorobenzamide in 70 ml of methylene chloride was obtained at 13 ml (13 mM) of boron tribromide (1 M solution in methylene chloride) were added dropwise at room temperature and the mixture was stirred overnight. After cooling, 100 ml of 2 n 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 the 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 60

Exo-3-n-butyl-6-phenyl-3-azabicyclo [3.2.0] heptane maleinate

To 3.5 g (20 mM) of exo-6-phenyl-3-azabicyclo [3.2.0] heptane in 50 ml of tetrahydrofuran was added 4.2 ml (30 mM) of triethylamine as well as 5.4 g (40 mM) of n -butyl bromide and cooked under reflux for 9 h under good stirring.

After cooling, they were evaporated on a rotary evaporator and the residue was partitioned between methylene chloride and water.

The aqueous phase was extracted twice more with methylene chloride and then the organic phase was evaporated after drying with sodium sulfate. The crude product (4.2 g) was purified by column chromatography (silica gel, eluent methylene chloride / methanol 96/4). The purified free base (3.1 g) was dissolved in 200 ml of ether and the stoichiometric amount of maleic acid in acetone was slowly added under cooling with ice and stirring. The recovered salt was filtered off under nitrogen, washed with ether and dried under nitrogen. 4.4 g (64%) of maleate salt, m.p. 125 to 126 ° C.

In an analogous way, we can prepare:

61. Exo-3-methyl-6-phenyl-3-azabicyclo [3.2.0] heptane, m.p. 129-131 ° C (maleinate),

62. Exo-3-methyl-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptane,

63. Exo-3-n-propyl-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptane,

64. Exo-3-methyl-6,7-diphenyl-3-azabicyclo [3.2.0] heptane, m.p. 197 to 198 ° C (hydrochloride),

65. Exo-3-n-propyl-6-m-hydroxyphenyl-3'azabicyclo [3.2.0] heptane, (see also example 59), m.p. 148 to 150 ° C (hydrochloride),

66. Exo-3-allyl-6-m-methoxyphenyl-3-azabicyclo [3.2.0] heptane, m.p. 118 to 120 ° C (hydrochloride),

67. Exo-3- (3,4-dimethoxy) -phenethyl-6-phenyl-3-azabicyclo [3.2.0] heptane, m.p. 207 to 209 ° C (hydrochloride),

68. Exo-3- (3,4-dimethoxy) -phenethyl-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptane, m.p. 192 to 193 ° C (hydrochloride),

69. Exo-3- (3,4-dihydroxy) -phenethyl-3-azabicyclo [3.2.0] heptane, (analogous to example 59), m.p. 202 to 205 ° C,

70. Exo-3-phenethyl-6-p-fluorophenyl-3-azabicyclo [3.2.0] heptane, m.p. 128 to 129 (maleinate).

For

BASF Aktiengesellschaft:

Claims (1)

1. N-substituted 3-azabicyclo [3.2.0] -heptane derivatives of formula I R ¹ R ² in which R ¹ means optionally halogen atoms, C 1 -C 6 alkyl, trifluoromethyl, hydroxyl, C 1 -C 4 alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups mono- or disubstituted phenyl, pyridyl, thienyl or pyrrole group, R ² is a hydrogen atom or optionally a halogen, methoxy, hydroxy or amino substituted phenyl group, n is a number of 1,2, 3 or 4, A is a hydrogen atom or one of the residues R ³ represents a hydrogen atom, a hydroxy radical or optionally substituted by a fluorine, chlorine or bromine phenyl radical, R ⁴ represents a hydrogen atom or R ³ and R ⁴ together represent an oxygen atom, R ⁵ represents a hydrogen, fluorine, chlorine or bromine atom or a hydroxy, nitro, C 1 -C 4 -alkyl or methoxy group, and R ⁶ represents a hydrogen atom or a methyl group, and their salts with physiologically acceptable acids. -232. The use of the compounds of formula I according to claim 1 for the preparation of medicaments having a neuroleptic, antidepressant, sedative, hypnotic, protective effect on the central nervous system and a muscle relaxant effect. For BASF Aktiengesellschaft: 23472-III-94-MD N-substituted azabicycloheptane derivatives, their preparation and use