DE1793590A1 - New tertiary amines - Google Patents

Description

The present invention "relates to new tertiary amines, namely N-substituted ones 1-aminoindane derivatives.

It has been found in accordance with the present invention that certain N-substituted 1-Aminoindanes as inhibitors for monoamine oxidase in the tie work on the body and also have an adrenaline effect. These products can therefore be used as agents in the treatment of diseases of the cardiovascular system

The present invention relates to new compounds tertiary:

Amines of the following general formula

- H _n

where R .. for the cyclopropyl radical, H "for the propargylate and B, stand for an indane nucleus attached to the nitrogen atom of the formula Z. is bonded in the 1-position and optionally its benzene ring can be substituted by one or more identical or various lower alkoxy groups,

as well as pharmaceutically acceptable salts thereof.

The term "lower alkoxy group" or ^M ~ radical "means in the context of the present invention alkoxy groups with 1-4 carbon atoms.

Within the Terbindungen of the general formula I. are preferred be those bonds in which the beazole ring of the! ^ group is unsubstituted or by one or more lower identical alkoxy groups is substituted. Examples of such preferred endings are

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N-Cyolopropyl-N-propargyl-I-aminoindan, and H-cyclopropyl-lf-propargyl-5,6-dimethoxy-1-aminoindan and their hydrochlorides

The compounds of the formula I can be prepared by processes known per se getting produced. For example, they can be prepared in that a compound of the formula

E ₃ -O II.

where R, has the same meaning as in formula I and the oxygen atom is in the 1-position)

with an N-substituted formamide of the formula

HCONHR-. III.

wherein R ₁ . the same meaning as R ₁ or

Has,

unset and the formamide obtained is acidic or alkaline Hydrolysis to produce a compound of the formula

R ₃ -NH-R ₅ IV.

wherein R, and R ₁ . have the same meaning as above,

is subjected. The compounds of the formula IV. Are naturally secondary amines.

In an alternative Veise the secondary amines of the formula IV. Dadurcl

be obtained that a compound of the formula

R-X V.

wherein R, has the same meaning as in formula I. and X is a Halogen atom, preferably chlorine in the 1-position,

with an amine of the formula

R ₅ -

VI.

wherein R _{5 has} the same meaning as R ₁ or Rg,

is condensed, preferably using an excess of ▲ min or an organic base, for example Pyridia, as proton acceptor.

The secondary amines of the formula IV, in which E ₅ denotes the propargyl group, are then reacted with buckets of cyelopropylating agents to produce a tertiary amine of the formula I, where R ₁ denotes the cyclopropylgram R ₂ denotes the propargyl group.

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These tertiary amines can also be prepared by _{subjecting a secondary amine of the formula I?., In which R 5 is} the cyolopropyl group, to propargylation. This method is generally preferred because of the poor reactivity of the above-mentioned cyclopropylating agents.

The tertiary amines according to the present invention, which are prepared according to the reactions described above, can be either old such or as pharmaceutically acceptable salts are isolated.

Suitable propargylating agents and cyclopropylating agents which z * r Carrying out the reactions described above can be used, for example, propargyl and cyclopropyl halides, for example Chlorides, bromides and iodides, as well as sulfates, benzenesulfonate and p-toluenesulfonates. The reactions are advantageously in a inert solvents such as ether, benzene, toluene or dioxane and in the presence of a proton acceptor, for example in the presence of an excess secondary amine of the formula IV. or an inorganic base such as an alkali metal, an alkali metal amide or an alkali metal anhydride carried out

The compounds according to the invention can be used for therapeutic purposes according to known pharmaceutical methods to form preparations processed, which is a compound of the general formula I. or contain a corresponding salt as an active ingredient and a pharmaceutical carrier for the active ingredient. The pharmaceutical carrier can, for example be an orally insertable container for the active ingredient, for example a hard or soft gelatin capsule, all carrier material can also be serve as a pharmaceutical diluent or diluent that is used in admixture with the active ingredient. Examples of this are strength « Lactose, mannitol, sorbitol, calcium phosphate, talc, magnesium stearate, Stearic acid, ethyl cellulose, theobroma oil, glycerin or water, or a protective agent such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate. The pharmaceutical preparation can be adjusted for oral, parenteral or rectal administration. For example, you can in the form of a sterile solution or suspension in water

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BATH ORIGINAL

or other liquids for parenteral administration or the In the form of a suppository for rectal administration · In dec In clinical practice, however, the compounds according to the invention should preferably be administered orally. The pharmaceuticals are preferred Preparations are therefore adjusted for oral administration and, for example, in the form of solutions, suspensions, emulsions, elixirs, Syrups, powders or tablets brought.

Pharmaceutical preparations are used for clinical use preferably brought into a form which contains a dose unit for the administration method in question. For oral administration kaxfn the unit dose, for example, in the form of a tablet, pill, compressed or packaged powder, kaohet or hard egg or soft gelatin capsule. The capsule can be a liquid, semi-liquid or solid composition or also the. pure Contain active ingredient. For administration by injection, the dose unit can be in the form of a container, e.g. an ampoule, which can contain an injectable solution or a mixture of substances, from which such a solution can be made. The amount of the active ingredient in each dose unit should be such that one or more, expediently no more than two or three units are required for each therapeutic administration, for example the dose unit can contain 10-100, preferably 25-60 mg of the active ingredient. the Unit dose can be administered 2 to 4 times a day depending on the patient's condition.

Example 1"

A mixture of K-cyclopropyl-i-aainoindan (β.65 Si 0.05 aol), propargylbroaid (3 g | 0.025 aol) and methyl cyanide (30 al) was refluxed for 12 hours. Methyl anide was evaporated under reduced pressure and the residue was heated with anhydrous ether. The remaining, undissolved solid was filtered off and the filtrate was distilled, whereby F-Oyeloprepyl-li-propargyl-i-aainoindan, bp 98-100 ° O / O.5 aa was obtained. The treatment of the amine with ether and ethereal hydrogen chloride and the crystallization of the. Solid precipitated from methyl ethyl ketone gave M-Cyclopropyl-M-prepargyl-1-aainoindanhydroohlorid, 1. 130-133 ° C.

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Example 2:

K-Cyclopropyl-5 »δ-dimethoxy-i-aminoindane, (17 * 9 Si 0.08 mol), propargyl chloride (2.85 gj 0.04 mol) and methanol were stirred together, refluxed for 6 hours and then at room temperature overnight ditched. The methanol was distilled off, dry ether was added to the residue, and the undissolved solid that remained was filtered off. Pie distillation of the filtrate gave I-cyolopropyl-N-propargyl-Sj ^ -dimethoxy-i-aiainoin.daii, boiling point 130-134 ° C / 0.8 wa · Treatment of the base with ethereal hydrogen chloride and crystallization of the solid from isopropanol resulted H-Cyclopropyl-1-propargyl-5 »o-dimethoxy-i-aittinoindane hydrochloride F. 147 C *

Claims (4)

Claims 8 Tertiary amines of the formula R ₁ - ¹ I. where E _{1 stands} for the cyclopropyl radical, fi_ for the propargyl group and E ,, stands for an indane nucleus which is bonded to the nitrogen atom in formula I. in the 1-position and whose benzene ring can optionally be substituted by one or more identical or various lower alkoxy groups and pharmaceutically acceptable salts thereof. 2.) The compound H-Cyclopropyl-I-propargyl-i-aminoindan and their pharmaceutically acceptable salts. 3.) The compound I-Cyclopropyl-H-propargyl-iJje-dimethoxy-i-aminoindaxi and their pharmaceutically acceptable salts 4.) The hydrochlorides of the compounds according to claims 1-3 109886/1783