DE1443403C - N Cyclopropyl 1 aminoindan derivatives and process for their preparation - Google Patents

Description

a) a 1-indanone of the general formula

(H)

20th

in a manner known per se with a compound of the general formula

HCO-NH-R ₁ (III)

wherein R _{1 has} the meaning mentioned, reacted and the 1-indanformamide obtained is subjected to an acidic or alkaline hydrolysis or
b) a 1-haloindan of the general formula

X-R.

(VII)

It has been found according to the invention that certain N-substituted 1-aminoindanes as inhibitors for the Monoamine oxidase act in the animal body and also have an adrenolytic effect. These products are therefore valuable and can be used as agents against depression or as psychostimulants also be used in the treatment of diseases of the cardiovascular system.

The invention thus relates to new, N-substituted 1-aminoindanes of the general formula

(I)

in which R ₁ denotes a cyclopropyl _{radical and R 2} denotes a hydrogen atom or a methyl radical, as well as their salts with acids.

The inventive method for preparing these N-substituted 1-aminoindanes of the formula is characterized in that

a) a 1-indanone of the general formula

F = O

(IV)

wherein X stands for a halogen atom, in a manner known per se with an amine general formula

H ₂ NR ₁ (V)

wherein R _{1 has} the meaning mentioned, is condensed or
c) a 1-aminoindari of the general formula

(VI)

wherein R _{3 stands} for a methyl group or for R ₁ , in a manner known per se with a compound of the general formula

35

40

45 (Π)

in a manner known per se with a compound of the general formula

HCO-NH-R ₁ (III)

in which R _{1 has} the meaning mentioned, reacted and the 1-indanformamide obtained is subjected to acidic or alkaline hydrolysis or b) a 1-haloindane of the general formula

(IV)

wherein X stands for a halogen atom, in a manner known per se with an amine of the general formula

H ₂ NR ₁

(V)

55

wherein R _{4 is} a methyl group when R ₃ is R ₁ , or R _{4 is} R ₁ when R _{3 is} a methyl group, and X is the removable group of the alkylating agent, is condensed with cleavage of 1 mole of HX and

d) the compounds obtained in this way, if appropriate in a manner known per se, in salts of Acids are transferred.

wherein R _{1 has} the meaning mentioned, is condensed or
c) a 1-aminoindane of the general formula

(VI)

wherein R _{3 stands} for a methyl group or for R ₁ , in a manner known per se with a compound of the general formula

XR ₄ (VII)

wherein R _{4 is} a methyl group when R ₃ is R ₁ , or R _{4 is} R ₁ when R _{3 is} a methyl group, and X is the removable group of the alkylating agent, is condensed with cleavage of 1 mole of HX and

d) the compounds obtained in this way, if appropriate in a manner known per se, in salts of acids be transferred.

The salts can be prepared by using the free bases of the general formula I with the selected acid are implemented in a manner known per se. For example, the production the hydrochloride is done by reacting the bases with ethereal hydrochloric acid.

The 1-indanones used as starting materials of the formula II can by catalytic reduction of the corresponding cinnamic acids and cyclization the obtained hydrocinnamic acids with thionyl chloride and aluminum chloride according to "Organic Reactions", Vol. II, p. 114.

If the compounds of the formula I by condensation of a 1-haloindane of the general Formula IV prepared with an amine of the formula V with elimination of 1 mol of hydrogen halide it is advantageous to use the amine of the formula V-in excess or a proton acceptor, for example, adding an organic base such as pyridine. Appropriate means of introduction the methyl or cyclopropyl group are the corresponding methyl or cyclopropyl bromides, -iodides, -sulphates, -benzenesulphonates or -p-toluenesulphonates. The reactions are advantageously carried out in an inert solvent such as ether, benzene, toluene or dioxane.

The introduction of a second substituent (methyl or cyclopropyl radical) in the already monosubstituted Amino group can, for example, by reacting the amino compound with a haloalkyl compound respectively. This reaction is expediently carried out in an inert solvent, such as ether, benzene, Toluene or dioxane, and in the presence of a proton acceptor. As a proton acceptor can be advantageous here an excess of the amino compound or an additional inorganic base, such as an alkali metal hydroxide, an alkali metal amide or an alkali metal hydride can be used.

It has already been mentioned that the compounds of the general formula have good activity as Possess inhibitors of monoamino oxidase. According to the present invention, in animal Body's effects of the monoamine oxidase enzyme can be suppressed by sufficient, however non-toxic dose of a compound of the general formula I or a salt of such a compound is administered with a pharmaceutically acceptable acid.

For therapeutic use, the compounds according to the invention can per se known pharmaceutical methods are processed into preparations containing a compound of the general formula I or a corresponding salt as an active ingredient and a pharmaceutical carrier for contain the active ingredient. The pharmaceutical carrier may, for example, be an "orally insertable" container for the active ingredient, for example a hard or soft gelatin capsule, as a carrier can also be a Pharmaceutical diluents or co-solvents used in admixture with the active ingredient will.

The pharmaceutical preparation can be adjusted for oral, parenteral or rectal administration being. In clinical practice, however, the compounds according to the invention are preferably to be administered orally will.

For clinical use, the pharmaceutical preparations are preferably in a form brought, which contains a dose unit for the administration method in question. For example, can the dosage unit contain 10 to 100, preferably 25 to 60 mg of the active ingredient. The dose unit can be 2 to To be administered 4 times a day depending on the patient's condition.

example 1

A mixture of 1-chloroindane (13.42 g, 0.088 ml) and cyclopropylamine (10 g, 0.176 ml) is added to the

Water bath 4 heated for ¹ J _{2 hours.} Two layers are formed here; the lower layer solidifies after cooling. Petroleum ether, bp. 40 to 60 ⁰ C (100 mL) is added, the solid cyclopropylamine hydrochloride was filtered off and the petroleum ether evaporated from the filtrate.

The resulting residue is dissolved in ether (30 ml) and extracted with dilute hydrochloric acid (5 N). At this stage a white crystalline precipitate forms, which is filtered off and recrystallized from isopropanol. Thereby is obtained F. 189-190 ⁰ C (4.8 g), the N-Cyclopropyl-l-aminoindan hydrochloride. The separated acidic layer is made alkaline by adding 5N sodium hydroxide solution and the basic oil is extracted with ether. After the addition of ethereal hydrochloric acid to the dried ethereal extract, the N-cyclopropyl-1-aminoindane hydrochloride precipitates out in the form of colorless crystals, mp 181 ° to 182 ° C., after recrystallization from isopropanol (2.8 g). Total yield 7.6 g.

C ₁₂ H ₁₅ NHCl:
Found .
calculated .

C 69.02, H 7.76, N 6.73, Cl 17.2%; C 68.73, H 7.69, N 6.68, Cl 16.90%.

Example 2

A mixture of 1-indanone (43 g, 0.3 mol), N-cyclopropylformamide (100 g, 1.2 mol), formic acid (17.3 ml of an 80% aqueous solution, 0.3 mol), powdered glass ( 1 g) and anhydrous magnesium chloride (4.4 g, 0.046 mol) were ^{heated to 120 to 130 °} C. for 1 hour. The water formed in the reaction was allowed to distill off. The temperature was increased to 170 ^° C. for 1 hour and finally to 200 ^° C. for _{2 hours.} Concentrated hydrochloric acid (50 ml) was added to the cooled mixture, and the solution was heated I ¹ J ₂ hours at reflux. After dilution with cold water (250 ml) the solution was made alkaline by the addition of 5N sodium hydroxide and extracted with ether. The distillation of the dried ether extract gave 1 - (n - formyl - N - cyclopropylamino) indane.

A mixture of! - (N-Formyl-N-cyclopropylamino) -indane (25 g), potassium hydroxide (10.5 g), water (4 ml) and ethanol (100 ml) was added for 5 hours Heated to reflux. After dilution with cold water (300 ml) the mixture was extracted with ether, and the ether extracts were washed with 2N hydrochloric acid. The acidic washing liquors were with 5N sodium hydroxide made alkaline, extracted with ether, and the ether extracts dried and distilled, wherein N-Cyclopropyl-1-aminoindan, B.p. 182 to 184 ° C / 20 mm. the

The addition of ethereal hydrogen chloride gave the hydrochloride a temperature of 181 to 184 ° C.

Comparison search. ■ ·

To the beneficial: effects of an inventive To show the connection to a recognized effective inhibitor for monoamine oxidase, a comparative experiment was carried out with trans-2-phenylcyclopropylamine (tranylcypromine). The experiment was carried out using the in vitro method of Weißbach et al, J. Biol. Chem. 235, 1160 (1960) accomplished. The following results were achieved:

connection ! .0,3.XlO "⁶;
ο, ίχίο- ⁶ LD ₅₀ Tranylcypromine
According to the invention 32 mg / kg
200 mg / kg

Claims (2)

Patent claims: 1. N-substituted 1-aminoindanes of the general formula (I) in which R ₁ denotes a cyclopropyl _{radical and R 2} denotes a hydrogen atom or a methyl radical, as well as their salts with acids. 2. A method for preparing N-substituted 1-aminoindanes according to claim 1, characterized marked that