DE1793590C3 - N-Cyclopropyl-N-propargyl-1-aminoindan, its salts and medicinal products on this basis. Elimination from ': 1443403 - Google Patents

Description

The new N-substituted 1-aminoindane derivative is suitable as a drug for the treatment of diseases of the cardiovascular system.

N-Cyclopropyl-N-propargyl-1-aminoindan can be produced by methods known per se. For example, a compound of the formula

R ₃ O

in which R ₃ denotes an indane nucleus which is bonded to the oxygen atom in the 1-position, with an N-substituted formamide of the formula

HCONHR ₅

wherein R _{5 is} a cyclopropyl or propargyl group, reacted and the formamide obtained undergoes acidic or alkaline hydrolysis to form a compound of the formula

R ₃ -NH-R ₅

wherein R ₃ and R _{5 have} the meaning given above, are subjected. The secondary amine obtained is converted into the tertiary amine in the manner mentioned later.

The secondary amines can also be obtained by mixing a 1-haloindane, preferably 1-chloroindane R ₃ - X, with an amine of the formula

R ₅ -NH ₂

where .R _{5 is} a cyclopropyl or propargyl group, is condensed, preferably an excess of amine or an organic base, for example pyridine, being used as the proton acceptor.

The secondary amines, in which R _{5 is} a propargyl group, are then reacted with a cyclopropylating agent in order to obtain N-cyclopropyl-N-propargyl-1-aminoindan.

The compound of the invention can also be prepared in that the secondary amine N-Cyclopropyl-1-aminoindan propargylation is subjected. This method is generally used because of the poor reactivity of the above mentioned cyclopropylating agents are preferred.

The compound of the invention, which is prepared according to the reactions described above, can be isolated either as such or in the form of a pharmaceutically acceptable salt.

Suitable propargylating agents and cyclopropylating agents which can be used to carry out the reactions described above are, for example, propargyl and cyclopropyl halides, for example chlorides, bromides and iodides, and also sulfates, benzenesulfonates and p-toluenesulfonates. The reactions are advantageously in an inert solvent such as ether, benzene, toluene or dioxane and in the presence of a. Proton acceptor, for example in the presence of an excess of secondary amine of R ₃ - NH - R ₅ , or an inorganic base such as an alkali metal, an alkali metal amide or an alkali metal anhydride.

ίο The beneficial effectiveness of the invention Compound N- Cyclopropyl - N - propargyl -1 - aminoindan for lowering blood pressure compared with that known means Pargyline is shown by the comparison test described below.

»5 To carry out the comparative experiment, rats with a weight of about 350 g were tested partial occlusion of the left renal artery made hypertensive with a silver clamp, with a Method applied based on that of G ο I d-

ao sheet et. al. described based (J. Experimental Medicine, 1934, 59, 347). The systolic blood pressure was calmed in the caudal artery by, conscious animals using a Winston systolic blood pressure meter

»5 measured. Blood pressure readings were taken before starting treatment and 30 minutes after each daily administration of the drug. Both N-cyclopropyl-N-propargyl-1-aminoindan (AGN 2002) as well as Pargylin were carried out by

3 »Forced feeding administered in the form of aqueous solutions. Groups of six rats were used for each compound. The following were Results obtained:

Treatment

3 4th 5

Mean drop in blood pressure i s. C. (mm Hg)

AGN 2009 (16 mg / kg p. O.)

12.8 -t 7.2
29.3 -fc 15.7
25.5 ± 17.1
30.5 -t 13.6
28.5 + 12.5

Pargyline (16 mg / kg p. O.)

3.0 2.8

12.0 12.8

2.7 ± 10.5 11.0 + 8.6 10.8 + 6.9

In order to achieve an antihypertensive effect which is comparable to that of pargyline, a significantly smaller amount of the compound according to the invention must therefore be used. It has also been shown that N-cyclopropyl-N-prop ^ rgyl-1-aminoindan has an LD ₅₀ value of 500 mg / kg, while the LD ₅₀ value given in the literature for pargyline (perorally, in the mouse ) Is 680 mg / kg. So it results for the inventive

SS according to substance a much better ratio from antihypertensive efficacy to toxicity. Furthermore, the well-known remedy Pargyline acts as a Monoamine oxidase inhibitors. The inventive

. Compound also has an inhibitory effect on Mcmoaminoxidase, but to a much lesser extent as pargyline, which is another benefit for the therapeutic use of N-Cyclopropyl-N-jpropargyi-1-aminoindan because undesirable side effects can be avoided more easily.

For therapeutic use, the compounds according to the invention can per se known pharmaceutical methods are processed into preparations that contain a compound of the al Ige-

nieinen formula I or a corresponding salt as Contain 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, a pharmaceutical diluent or diluent can also be used as a carrier serve, which is used in a mixture 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 substance such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate. The pharmaceutical Preparation can be adjusted for oral, parental or rectal administration. For example, you can in the form of a sterile solution or suspension in water or other liquids for the. parenteral administration or the form of a suppository for rectal administration own. In clinical practice, however, the compounds according to the invention should preferably be taken orally administered. The pharmaceutical preparations are therefore preferred for oral administration set and for example in the form of solutions, suspensions, emulsions, elixirs, Syrups, powders or tablets brought.

For clinical use, the pharmaceutical Preparations preferably brought into a form that has a dose unit for the concerned Administration method contains. For oral administration, the dose unit can be, for example, in in the form of a tablet, pill, compressed or packaged powder, cachet, or hard or soft gelatin capsule. The capsule can be liquid, semi-liquid, or solid Substance composition or the pure active ingredient S included. For administration by injection, the dose unit can be in the form of a container, z. B. have an ampoule that can contain an injectable solution or a mixture of substances, from which such a solution can be made,

ίο The amount of active ingredient you want in each dose unit be such that one or more, suitably no more than two or three units for each therapeutic Administration are required, for example the dose unit 10 to 100, preferably 25 contain up to 60 mg of the active ingredient. The dose unit can be 2 to 4 times a day depending on the constitution of the Administered to patients.

example

"A mixture of N-CycIopropyl-1-ammoindane (8.65 g; 0.05 mol), propargyl bromide (3 g; 0.025 mol) and methyl cyanide (30 ml) was added for 12 hours heated to reflux. Methyl cyanide was evaporated under reduced pressure and the residue

»5 was warmed with anhydrous ether. The one left behind undissolved solid was filtered off and the filtrate was distilled, N-cyclopropyl-N-propargyl-l-aminoindan, Bp 93 to 100 ° C / 0.5 mm was obtained. The treatment of the amine with ether and ethereal hydrogen chloride and the crystallization the precipitated solid from methyl ethyl ketone gave N-cyclopropyl-N-propargyl-1-aminoindanhydrochloride, M.p. 130 to 133 ° C.

Claims (3)

Patent claims: 1. N-Cyclopropyl-N-propargyl-1-aminoindan and its salts. 2. Tertiary amine hydrochloride according to Claim 1. 3. Medicament consisting of a compound according to claim 1 or 2 as an active ingredient and pharmaceutical additives.