SK812001A3 - N-SUBSTITUTED AZABICYCLOHEPTANE DERIVATIVES, PRODUCTION AND USEì (54) THEREOF - Google Patents

Abstract

The invention relates to compounds of formula (1), wherein R<1>, R<2> and R<3> have the meaning cited in the description. The novel substances are suitable for use in disease control.

Description

N -substituted azabicycloheptane derivatives, their preparation and use

Technical field

The invention relates to novel N-substituted azabicycloheptane derivatives, their preparation and use in the control of diseases.

BACKGROUND OF THE INVENTION

Exo-6-phenyl-3-azabicyclo [3.2.0] heptane derivatives exhibit interesting properties as potential neuroleptics (WO 94/00458, WO 95/15312). Particularly important in this regard are the high affinities observed for D ₄ and 5-HT ₂ receptors.

The most interesting compound of the above class of compounds with D4 / 5-HT2A affinity and good D ₂ selectivity is (+) - (1S, 5R, 6S) -exo-3- [2- [6- (4-fluorophenyl) - 3azabicyclo [3.2.0] heptan-3-yl] ethyl] -1H, 3H-quinazoline-2,4-dione (= substance A), which is potentially a neuroleptic. However, there is an upper limit on the dosage of Compound A due to prolongations that occur in the QT interval in the ECG.

We have now found substances that exhibit better properties.

SUMMARY OF THE INVENTION

The invention relates to N-substituted 3-azabicyclo [3.2.0] heptane derivatives of formula I

in which

^R1 is fluoro or chloro,

R ² represents C 1 -C ₃ -alkyl or cyclopropyl, and

R ³ represents hydrogen, fluorine or chlorine, and their salts with physiologically acceptable acids.

-2 ·············································· · ·· · ·· ···

Preferred compounds are those in which

^R1 is chloro, preferably in p-position,

R ² represents methyl or cyclopropyl, and

R ³ is hydrogen.

The following compounds are particularly preferred:

(+) - (1 S, 5 R _I, 6S) exo-1- [2- [6- (4-chlorophenyl) -3-azabicyclo [3.2.0] heptane-3-yl] ethyl] -3-methyl-2H-1 , 3-dihydro-benzoimidazol-2-one, (+) - (1 S, 5 R _I, 6S) exo-1- [2- [6- (4-chlorophenyl) -3-azabicyclo [3.2.0] heptane-3 yl] ethyl] -3-ethyl-2H-1,3-dihydrobenzimidazol-2-one, and (+) - (1S, 5R, 6S) -exo-1- [2- [6- (4-fluorophenyl) -3] azabicyclo [3.2.0] heptane-3-yl] ethyl] -3-cyclopropyl-2H-1,3-dihydro-benzoimidazol-2-one.

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

R ³ wherein R ² and R ³ have the above meanings and Nu represents a nucleophagic leaving group, with the 3-azabicyclo [3.2.0] heptane derivative of formula III as the (+) - (1S, 5R, exo-6S) enantiomer

(III), wherein R ¹ is as defined above, and optionally converting a compound obtained in this manner into an acid addition salt with a physiologically acceptable acid.

3 · ················································· 4 4 ····· ·· · ·· ·

Suitable and preferred nucleofusion leaving groups for Nu are halogen atoms, especially bromine or chlorine.

The reaction is conveniently carried out in the presence of an inert base such as triethylamine or potassium carbonate as the acid acceptor, in an inert solvent such as a cyclic saturated ether, especially tetrahydrofuran or dioxane, or a benzenoid hydrocarbon such as toluene or xylene.

The reaction is generally carried out at temperatures of from 20 to 150 ° C, in particular at temperatures of from 80 to 140 ° C, and is generally completed in the range of from 1 to 10 hours.

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

The free 3-azabicyclo [3.2.0] heptane derivatives of formula I can be converted in conventional manner into acid addition salts with a pharmaceutically acceptable acid, preferably by treating a solution with one equivalent of the appropriate acid. Examples of pharmaceutically acceptable acids are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, sulfamic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.

The compounds of the present invention have valuable pharmacological properties. They can be used as neuroleptics (especially atypically), antidepressants, sedatives, hypnotics, CNS preservatives or agents for the treatment of cocaine dependence. Certain types of the above effects may occur in a compound of the present invention in combination.

In particular, the substances are characterized by a very high and selective affinity for the dopamine D ₄ and serotonin 2A receptors.

Prolongations of the QT interval measured using the guinea pig model papillary muscle are negligible. This means that new substances are well tolerated, even at high doses.

-4 · ········································································ ··························

The invention also relates to a therapeutic composition comprising a compound of formula I or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, in addition to conventional carriers and diluents, and to the use of the novel compounds for controlling diseases.

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

The dose depends on the age, condition and weight of the patient and the route of administration. The daily dose of the active ingredient is usually between about 1 and 100 mg / kg body weight for oral administration and between 0.1 and 10 mg / kg body weight for parenteral administration.

The novel compounds can be used in conventional solid or liquid pharmaceutical forms, for example, as uncoated or (film-coated) tablets, capsules, powders, granules, lace, solutions, ointments, creams or sprays. These are prepared in a conventional manner. For this purpose, the active ingredients may be formulated with the usual pharmaceutical auxiliaries such as tablet binders, swelling agents, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersing agents, emulsifying agents, solvents, delaying agents, antioxidants and antioxidants. and / or propellants (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this manner usually contain the active ingredient in an amount of from 1 to 99% by weight.

Compounds of formulas II and III which are required as starting materials for the synthesis of compounds of the invention are known (WO 94/00458; Heterocycles 40 (1), 319-330 (1995); J. Heterocyclic Chem. 18, 85-89 (1981) ) or may be synthesized from analogous starting materials using methods of preparation described in the literature.

The following examples serve to illustrate the invention:

DETAILED DESCRIPTION OF THE INVENTION

Preparation of starting materials

-5 ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

a) 1- (α-Phenylvinyl) -2H-1,3-dihydrobenzimidazol-2-one

A mixture of 21.6 g (200 mmol) of o-phenylenediamine and 37 ml (214 mmol) of ethyl benzoylacetic ester in 75 ml of 4-tert-butyltoluene with the addition of a spatula tip of p-toluenesulfonic acid was refluxed with a water trap at a bath temperature of 200 ° C. under nitrogen for one hour and the liberated water was separated. After cooling, 80 ml of acetonitrile was added to the reaction mixture, and after stirring in an ice bath, the solid was filtered off with suction and *

washed with cold acetonitrile. 39.5 g (84%) of the product was isolated. mp 167-169 ° C.

1- (α-Phenylvinyl) -6-chloro-2H-1,3-dihydrobenzimidazol-2-one can be prepared in an analogous manner (starting material: 4-chloro-1,2-diamino-benzene).

b) 1- (α-Phenylvinyl) -3-methyl-2H-1,3-dihydrobenzimidazol-2-one ml of 10% sodium hydroxide solution, 0.2 g of benzyltriethylammonium chloride and 1.76 ml (18.5 mmol) dimethyl sulfate was added to 3.5 g (14.8 mmol) of 1- (α-phenylvinyl) -2H-1,3-dihydrobenzimidazol-2-one in 70 ml of toluene and the mixture was stirred at 60 ° C for two hours. The toluene phase was then concentrated and 3.65 g (99%) of the product was isolated as an oil with a purity sufficient for use in the next reaction.

The following compounds were prepared in an analogous manner: 1- (α-phenylvinyl) -3-ethyl-2H-1,3-dihydrobenzimidazol-2-one (alkylating agent: diethyl sulfate) and 1- (α-phenylvinyl) -3-n -propyl-2H-1,3-dihydrobenzimidazol-2-one (alkylating agent 1-bromopropane), 1- (α-phenylvinyl) -3-methyl-6-chloro-2H-1,3-dihydrobenzimidazole-2 -όη (starting material: 1- (α-phenylvinyl) -6-chloro-2H-1,3-dihydrobenzimidazol-2-one) and 1- (2-chloroethyl) -3-methyl-5-chloro-2H-1 3-dihydrobenzimidazol-2-one (starting material: 1- (2-chloroethyl) -5-chloro-2H-1,3-dihydrobenzimidazol-2-one).

c) 1-Methyl-2H-1,3-dihydrobenzimidazol-2-one

3.65 g (14.6 mmol) of 1- (α-phenylvinyl) -3-methyl-2H-1,3-dihydrobenzimidazol-2-one were dissolved in 30 ml of ethanol and after addition of 60 ml of 10% hydrochloric acid and 10 ml of ethanol. ml of concentrated hydrochloric acid are added

-6 was stirred at 80 ° C for two hours. The mixture was then concentrated and ice was added to the remaining aqueous solution. The precipitated solids were stirred under cooling in an ice bath, suction filtered and washed with water. 1.7 g (79%) of product were isolated.

· · 99 9 99 99 9 • 9 9 9 9 9 9 9 • 9 9 9 9 9 9 9 · • · 9 9 9999 9 9 9 • · • 9 9 9 9 9 ·· · 99 99 9 99

· · ·

The following compounds were prepared in an analogous manner: 1- (2-chloroethyl) -

5-chloro-2H-1,3-dihydrobenzimidazol-2-one (starting material: 1- (2'-chloroethyl) -3- (α-phenylvinyl) -5-chloro-2H-1,3-dihydrobenzimidazole-2- and 1-methyl-5-chloro-2H-1,3-dihydrobenzimidazol-2-one (starting material: 1 • (α-phenylvinyl) -3-methyl-6-chloro-2H-1,3-dihydrobenzimidazole 2-one).

d) 1- (2-Chloroethyl) -3-methyl-2H-1,3-dihydrobenzimidazol-2-one

1.7 g (11.5 mmol) of 1-methyl-2H-1,3-dihydrobenzimidazol-2-one in 40 ml of acetonitrile was mixed with 1.6 g (11.5 mmol) of finely powdered potassium carbonate and 2.9 g. ml (35 mmol) of 1-bromo-2-chloroethane and refluxed for 14 hours. After cooling, the solids were filtered off with suction, washed with acetonitrile, and the filtrate was concentrated. 2.3 g (95%) of product are isolated in the form of an oil which slowly crystallizes, m.p. 87-89 ° C.

The following compounds were prepared in an analogous manner: 1- (2-chloroethyl) -

3- (α-phenylvinyl) -5-chloro-2H-1,3-dihydrobenzimidazol-2-one (starting material: 1- (α-phenylvinyl) -6-chloro-2H-1,3-dihydrobenzimidazol-2-one ) and 1- (2-chloroethyl) -3-methyl-6-chloro-2H-1,3-dihydrobenzimidazol-2-one (starting material: 1-methyl-5-chloro-2H-1,3-dihydrobenzimidazole-2) -one).

e) (+) - (1S, 5R, 6S) -exo-6- (4-Chloro-phenyl) -3-azabicyclo [3.2.0] heptane (+) The enantiomer was isolated as described in Heterocycles 40 (1). , 326 (1995).

f) 1- (α-Phenylvinyl) -3-cyclopropyl-2H-1,3-dihydrobenzimidazol-2-one

1.35 g (45 mmol) of sodium hydride (80 percent) was added portionwise to

10.0 g (42.4 mmol) of 1- (α-phenylvinyl) -2H-1,3-dihydrobenzimidazol-2-one in 80 ml of dimethylformamide under vigorous stirring, and the reaction mixture was then stirred for 2 hours. Subsequently, 8.0 mL (100 mmol) of cyclopropyl bromide was added and the reaction mixture was transferred to a 0.3 L autoclave

r _ • ·· ·· · · • · · • · · · · · • · • · • · • • • · ···· • a · • · • · • · · · · • • ··· ·· · · • · · · · ·

with stirring, which was then heated at 200 ° C for 10 hours. After cooling and concentration on a rotary evaporator, the residue was partitioned between methylene chloride and water, acidified with 10% hydrochloric acid. The aqueous phase was extracted once more with methylene chloride. After drying and concentration of the organic phase, 12.4 g of crude product were isolated and this was purified by column chromatography (silica gel, mobile phase methylene chloride). Yield 3.6 g (31%) of adequate purity.

Preparation of end products

Example 1

(+) - (1S, 5R, 6S) -exo-1- [2- [6- (4-Chloro-phenyl) -3-azabicyclo [3.2.0] heptan-3-yl] -ethyl] -3-methyl- 2H-1,3-dihydro-benzoimidazol-2-one x 2H ₂

2.5 g (12.1 mmol) of (+) - (1S, 5R, 6S) -exo-6- (4-chlorophenyl) -3-azabicyclo [3.2.0] heptane in 60 ml of xylene were mixed with 2, 55 g (12.1 mmol) of 1- (2-chloroethyl) -3-methyl-2H-1,3-dihydrobenzimidazol-2-one and 1.7 g (12.1 mmol) of finely powdered potassium carbonate were refluxed for 20 min. hours. The reaction mixture was then concentrated in a rotary evaporator and the residue was partitioned between water and methyl tert-butyl ether at pH 10. The aqueous phase was extracted once more with methyl tert-butyl ether and then the combined organic phases were concentrated. The crude product was purified by column chromatography (silica gel, methylene chloride / methanol 97/3). 3.3 g (71%) of the product were isolated as an oil which was dissolved in 200 ml of ether and converted with tartaric acid dissolved in ethanol (1.4 g, 9.3 mmol) to tartrate (m.p. 107-109). C). [α] _D = +

55.4 ° (EtOH)

Elemental Analysis C ₂₂ H ₂₄ N 3 OCl · C ₄ H ₆ O ₆ x 2H ₂ O

Calculated C 54.97 H 6.03 N 7.39 0 25.34 Cl 6.24

Found C 54.9 H 5.8 N 7.1 0 25.5 Cl6.2

The following compounds were prepared in an analogous manner:

-8 ·· ····· · t ··· e e · · · · ··············

(+) - (1S, 5R, 6S) -exo-1- [2- [6- (4-Chloro-phenyl) -3-azabicyclo [3.2.0] heptan-3-yl] -ethyl] -3- ethyl-2H-1,3-dihydrobenzimidazol-2-one x HCl, m.p. 174-176 ° C, [α] D = + 67.7 ° (EtOH)

3. (+) - (1S, 5R, 6S) -Exo-1- [2- [6- (4-Chloro-phenyl) -3-azabicyclo [3.2.0] heptan-3-yl] -ethyl] -3- n-propyl-2H-1,3-dihydrobenzimidazol-2-one x HCl, mp 178-180 ° C, [α] _D = + 66.4 ° (EtOH)

4. (+) - (1S, 5R, 6S) -Exo-1- [2- [6- (4-Chloro-phenyl) -3-azabicyclo [3.2.0] heptan-3-yl] -ethyl] -3- methyl 5-chloro-2H-1,3-dihydrobenzimidazol-2-one x HCl, mp 101-103 ° C, [α] D = + 92.3 ° (EtOH)

5. (+) - (1S, 5R, 6S) -Exo-1- [2- [6- (4-Chloro-phenyl) -3-azabicyclo [3.2.0] heptan-3-yl] -ethyl] -3- methyl 6-chloro-2H-1,3-dihydrobenzimidazol-2-one x HCl, mp 230-232 ° C, [.alpha.] _D = + 77.2 ° (EtOH)

6. (+) - (1S, 5R, 6S) -Exo-1- [2- [6- (4-Chloro-phenyl) -3-azabicyclo [3.2.0] heptan-3-yl-ethyl] -3-cyclopropyl- 2H-1,3-dihydrobenzimidazol-2-one x HCl, mp 109-111 ° C, [α] _D = + 73.5 ⁰ (EtOH)

7. (+) - (1S, 5R, 6S) -exo-1- [2- [6- (4-Fluorophenyl) -3-azabicyclo [3.2.0] heptan-3-yl] ethyl] -3- cyclopropyl-2H-1,3-dihydrobenzimidazol-2-one x HCl, mp 121-123 ° C, [α] _D = + 64.5 ° (EtOH)

Claims (2)

PATENT CLAIMS An N-substituted 3-azabicyclo [3.2.0] heptane derivative of the general formula I o in which ^R1 is fluoro or chloro, R ² represents C 1 -C ₃ -alkyl or cyclopropyl, and R ³ represents hydrogen, fluorine or chlorine, and their salts with physiologically acceptable acids. A compound of formula I according to claim 1 for use in the control of diseases.