DE1443403A1 - Process for the preparation of therapeutically utilizable N-substituted 1-aminoindanes - Google Patents

Description

Process for the preparation of therapeutically utilizable H-substituted 1-aminoindanes.

It has been found that certain N-substituted 1-aminoindanes -as Inhibitors of monoamine oxidase in animals Body work and also an adrenolytic effectiveness own. These products are therefore valuable as agents against depression or as psychostimulants imd can also dee in the treatment of diseases cardiovascular system.

The present patent is a method for Production of therapeutically usable N-substituted 1-Aminoindanes of the general formula

> R ₁

wherein R ₁ and Rg, ^which can be the same or different, represent hydrogen atoms, alkyl radicals having 1 or 2 carbon atoms, halogen atoms, hydroxyl groups or lower alkoxy groups; R, for hydrogen or a lower alkyl group; Rj is a cyclopropyl group or a group of the formula -CH ₂ -C ^ CR ₅ ; Hc for hydrogen, a lower alkyl group, a phenyl group or a group

of the formula -CO-N ^ and Rg and R ™ which are the same

R ₇

or can be different for hydrogen atoms or lower alkyl groups,

as well as salts of these compounds with pharmaceutically acceptable acids, which is characterized in that

80980e / 080a

a) a 1-indanone of the general formula

II

wherein R ₁ and R _{2 have} the same meaning as before

to have,

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

HGO-NH-R,

III

where R * has the same meaning as before, implemented and the 1-indanformamide obtained an acidic or is subjected to alkaline hydrolysis} or

b) a 1-haloindane of the general formula

IV

wherein R ₁ and H _{2 have} the same meaning as before and X is a halogen,

in a manner known per se with an amine of the general formula

wherein R ₊ dit gltiche importance wi · has previously condensed or wirtj

BATH ORIGINAL

109896/0309

c) a 1-aminoindane of the general formula

VI

where R ₁ and R _{2 have} the meaning already mentioned and R _{& stands} for a lower alkyl group or for R.,

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

X - R _g VII

where R «is a lower alkyl group when R ₈ is R ^, Rq is R ^ when R _{8 is} a lower alkyl group, and X is the eliminable group of the alkylating agent, condensation is carried out with elimination of 1 mole of HX; or

d) a compound of the general formula

VIII

where R-,

-, R ₂ u * ¹ ** ^R 5 ^ ^{e have the} same meaning as before,

methylated in a manner known per se with a mixture of formaldehyde, formic acid and sodium formate will; or

e) 'a compound of the general formula

BATH

8 0 9 3 0 6/0809

-C ^ - CH

IX

^B 2

. wherein R ₁ , R ₂ and R, have the same meaning as before,
carboxylated, esterified and with an alumina of the formula

! Η '

the same meaning as before

where Rg and
have j
is implemented; and

f) the compounds obtained in this way are optionally converted in a manner known per se into salts of acceptable acids *

They expressions "lower alkyl group" and "lower alcohol" group "means saturated in the sense of the present invention Alkyl and alkoxy groups with .1 »4 C ** AtQßien im Alkyl seat.

Within the links of the general forests! I should prefers the compounds of the general

where Hj has the same meaning as in formula t and ¹ R «j _{o stands} for the cyclopropy group, the bropargyl group or a group of the formula

- BAD ORfGIfSiAL

809806/0803

stands,

as well as their salts with pharmaceutically acceptable acids will.

The compounds of the general formula X and their salts are particularly preferred if Ά ~ is hydrogen or methyl and RQ is propargyl or cyolopropyl, as is the case, for example, with H-methyl-N-propargy1-1-aminoindan, N-propargyl-1- arainoindan and N-cyclopropyl-1-aminoindan is the case.

The salts can be prepared by mixing the free bases of the general formula I with the selected acid be implemented in a manner known per se. For example, the hydrochloric acids can be prepared by reaction the bases with essential hydrochloric acid.

The 1-indanones of the general formula II can be prepared by catalytically reducing the corresponding cinnamic acids and olying the hydrocinnamic acids obtained with thionyl chloride and aluminum chloride according to "Organic Reactions", Vol. II, p are prepared by condensation of a 1-haloindane of the general formula Hf with an amine of the general formula V with elimination of 1 mol of hydrogen halide, it is advisable to use the amine of the general formula V in excess or an organic base, such as pyridine, as protons . admit acceptor When R, in the general formula I is alkyl, the alkylation of the corresponding compound of formula I, in which R 'nor Viasserstoff can ssä & r ylbromiden for example, with low Al, iodides, sulfates, - Benzoleulfonaten or -p-toluenesulfonates. If in the compounds of the general formula I Rj for methyl and R, for the Group -OH ₂ CSfC-R ₅ , the alkylation can advantageously be carried out with a mixture of formaldehyde, formic acid and sodium formate.

BATH ORIGINAL

ROQPnc

The introduction of a second substituent in the already Inonoau-gtituierte amino group can for example by Reaction of the amino compound with a halo-alkyl compound take place. This conversion expediently takes place in an inert solvent such as ether, benzene, toluene or dioxane, and in the presence of a l'roton acceptor. as Frotonenacceptor 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 a Alkali metal hydride can be used. If a Gyclopropyl-Hest is to be introduced into the 1-position amino group, It should be noted that the reactivity of the Gyclopropy! -halogenide is not very good.

The compounds of the general formula I in which H. is a group of the formula -CH ₀ -C = C-CO-Lr °,

-VH ₇

are conveniently prepared by the corresponding N-propargyl-1-aminoindan prebond is carboxylated with a suitable compound, for example an alkali metal amide or a Grignard agent, then the obtained Acid with an alcohol, for example methanol, in the presence of an esterification catalyst, such as sulfuric acid, esterified and then the ester is reacted with an amine of the formula ΗΝ "** 6.

It has already been mentioned that the compounds of general formula I have good activity as inhibitors of the Possess monoamine oxidase · According to the present invention the effect of the monoamine oxidase enzyme can be suppressed in the animal body by sufficient, however non-toxic dose of a compound of the general Formula Ϊ or a salt of such a compound with a pharmaceutically acceptable acid will.

The compounds can be used for therapeutic purposes according to the invention according to known pharmaceuticals

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Methods are worked up to form preparations which contain a compound of the general formula I or a corresponding salt as ale 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, which is used in a mixture with the active ingredient, can also serve as a carrier. Examples are starch, lactose, mannitol, oorbit, Caloiumphosphat, talc _t Fognesiurastearat, stearic acid, ethyl, "cellulose, Theobroma ul, glycerol or VTasser, or a preservative such as p-Hydroxybenüoesäuremethylester or p-Hydroxybenzoesäurepropyleoter. The pharmaceutical preparation can be adjusted for oral, parenteral or rectal administration. It can, for example, be in the form of a sterile solution or suspension in. water or other fluids for parenteral administration or in the form of an oppositoriuras for regctale administration. In clinical practice, however, the compounds according to the invention should preferably be administered orally. The pharmaceutical preparations are therefore preferably adjusted to oral administration and, for example, brought into the form of solutions, suspensions, emulsions, elixirs, gyrups, powders or tablets.

Pharmaceutical uses are purely for clinical use Preparations are preferably brought into a form which has a dose unit for the administration method in question contains. For oral administration, the dose unit can, for example, be in the form of a tablet, pill, a compressed or packaged powder, a container made of dough or a hard or soft gelatin capsule «The capsule can be a liquid, semi-liquid or solid composition or the pure active ingredient hold on. For administration by way of the

SAO 809806/0809

Injection, the unit dose may be in the form of a container, e.g., an ampoule, containing an injectable solution or a fabric framework 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 not more than two or three units required for any therapeutic administration. For example, the dose unit can be 10 - 100, preferably contain 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:

1-chloroindane (24 ti) »propargylamine (12 g), sodium iodide (0.1 g) and ethanol (50 ml) are heated until the reaction subsides, which takes about 2 hours; the resulting mixture is heated under üüekfluß for 8 hours. Water (100 ml) is added to the cooled mixture. Then dilute sodium hydroxide solution is added until the mixture is strongly alkaline. The reaction mixture is extracted with ether and the ethereal layer is washed three times with 2.5 -NHCl (3 times 25 ml). Sin-solid body precipitates out of the acidic solution and is filtered off (P = 180 ⁰ O). The product obtained is probably IT-ir-di (i-indanyl) -propargylamine hydrochloride. The acidic filtrate is made basic with potassium carbonate solution and the oil formed is isolated by extraction with ether. The 01 is H-propargyl-1-aminoindan, which distills at 88-94 ° C / 0.5 mm. After the addition of ether and essential hydrochloric acid, a precipitate is obtained. This is the hydrochloride with ϊ ¹ = 183? -187 ° C according to. Recrystallize from isopropanol.

Found: C, 68.54 '/} 11.6.90 ^; H, 6.64 ^ j 01.17.10; calculated for

C H -JTOl .C »69.37s £; H, 6.79 ^; ff, 6.74f * j $ 1.17.07.

'■ "BAD ORIGINAL

809806/0809

Example 2 *

1-chloroindane (39 x 1 g), sodium iodide (0.5 c) and an ethanol sol Solution of methylamine (100 ml; 33 ',>) are mixed and left to stand for about 72 hours. The ethanol is evaporated off, water (100 ml) added and the oil which forms extracted with ether. The ether extract is diluted with Hydrochloric acid (25 ml) and the acidic layer with potassium carbonate solution made basic and the oil that forms isolated by extraction with Ither. Distillation of the dried Ether-TSxtraktes the H-Kethyl-1 -aminoindan, Sp. = * 74-76 ° C / 0.5 »am.

An ethereal solution of propargyl bromide (3.45 g in 20 ml ether) is slowly and with stirring to a solution I-Methy 1-1-amino indan (8.5 g) in ither (20 ml) / and the mixture is left to stand for 72 hours. The white precipitate is filtered off, washed with ether, the ethereal piltrate is dried and distilled. This gives the il-Hethyl-N-propargyl-1-aminoindan, bp = 110-118 ° C / 4.5 mm. After adding essential HGl, the hydrochloride is formed, j? "= 201-203 ° ö after TJmkrist _a llisation from isopropanol.

Found: 0.70.01 '/ .; H, 7.38 ^; ft, 6.12 ;;; 01,16.09) $, calculated for

0.70.41: ^; H, 7. 2ΨΜ N, 6.32? 5j Cl, 15.99'-. ° 13 ^H 16 ^NUL

Example 3 t

A mixture of 1-chloroindane (91 g; 1 equivalent) and liquid methylamine (110 ml; 4 equivalents) is heated ^{to 80 ° C. in an autoclave for 12 hours.} After cooling, water (50 μl) is added and the reaction mixture obtained is acidified by adding dilute hydrochloric acid (2 H). If an oil precipitates at this stage, it must be removed by extraction with ether. The clear aqueous solution is made strongly alkaline by adding 10N liatrium hydrox ^ 4 and the released oily base is isolated by extraction with ether. The distillation of the dried ether extract gives the N-Methy1-1-aminoindan, Sp. ■ 100-110 ° a / i5 bus, which is converted into N-methyl-N-propargyl-1-amino-

80 9806/0 80 9

indan Ilydrochlorid according to that described in Example 2 liethode is convicted.

Example 4:

; jin öe-iisch of 1-chlorindan (13.42 gj 0.088 ml) and övclopropylarain (10 g; 0.176 ml) is heated on the "Jasser bath for 4 1/2 hours. Two layers are formed; the lower layer solidifies after cooling. Jetroleumäther, _■:;.. p s 40-60 ⁰ C (100 mL) is added, the solid filtered off and the Cyelopropylamin-IJyärοchlorid ietrolather evaporated from Piltrat the resulting residue is dissolved (ml 30) in ether and washed with dilute hydrochloric acid ( 5 N) is extracted. In this 3tufe forms a white crystalline precipitate which is filtered off and recrystallized from isopropanol. Thus, the 1T-C3rclopropyl-aminoindan 1-is "condition 1 £ ig-190 ° C (4.8 g) 'hydrochloride salt, m.p. The separated acidic layer is made alkaline by adding 5 U-sodium hydroxide solution and the basic oil is extracted with ither. After adding ethereal hydrochloric acid to the dried essential extract, the H-Ojrclopropyl-1-arainoindan hydrochloride falls in ϊοπη. Von farolooeri crystals ? = 181-132 ° C after recrystallization from isopropanol from (2.8 g). (total yield 7.6 g.

found: C, 69.02. _a ; $ 11.7.76; ¥, 6.73; -; 01,17.2? - '»; calculated for

C H * HCl δ, 68.73 vi; H, 7.69 ^; H, 6.68 /; 01, 16.90; ".

Example 5:

tablets are made with the following composition:

II-Kethyl-IT-propargyl-1-aminoindan hydrochloride 10 mg

Lactose 144 mg

Corn oil starch (dried) 35 mg

Ethyl cellulose M.100 * 4 mg

Talc 6 mg

Magnesium stearate ■ 1 mg

* Ethyl cellulose M.100 is a commercially available ethoxylated

BATH

80980 6/0809

Cellulose with an ethoxyl content of 47.5: 49.0:. A 5; ' (calculated on weight) solution in 80 parts of toluene / 20 parts of ethanol has a viscosity of 80 to 105 el. at 25 ⁰ C.

The N-Ilethyl-N-propargy 1-1 -aminoindan hydrochloride, the lactose and part of the starch (20 mg / tablet) are passed through a mesh screen to Mr. 44 (BSd) pushed through and mixed together. The mixed powders are made into a paste with a 5% (calculated by weight) solution of ethyl cellulose in isopropyl alcohol and the dough is granulated through a Mr. 12 (B.Ö.U.) mesh sieve. The granulated i.:a3se is ^{dried at 40 0} G and through an ITr. 16 (BSS) hash sieve pressed. Finally, the talc, itagnef3ium stearate and the rest of the starch (after all these ingredients have been pressed through a No. 60 (B.; jy) I. ash sieve) are added to the granulated mass and the mixture is processed into tablets each weighing 200 mg.

Example 6:

Tablets with the filling composition are made «

Cyοlopropy1-1-aminoindan hydrochloride 50 mg

-otose 248 mg

Corn starch (dried) '70 mg

Ethyl cellulose N.100 8 mg

Talc 20 mg

Magnesium stearate 4 mg

The N-Cyclopropy1-1-aminoindan hydrochloride, the lactose and part of the starch (40 mg / tablet) are pressed through a No. 44 (B.L'.S.) Sieve and mixed together. The mixed rvlver are made into a paste with a $ 5 (calculated on the weight) solution of ethyl cellulose in isopropyl alcohol and the Hasse is through a Mr. (BoS) mesh sieve, granulated. The granulated mass is dried at 4O ⁰ C and passed through a 2Tr. 16 (BSS) liascheris sieve pressed through, then the talc _f

BATH ORIGINAL 809806/0809

Magnesium stearate and the hest of starch (after these ingredients by a Mr. 60 (B.S.S.) Mesh sieve pushed through were) added to the granulated mass and the mixture worked up on tablets each weighing 400 mg.

example It

Capsules are made with the following composition per capsule «

n-LIethyl-ST-propargy 1-1 -aminoindan hydrodiloride 5 mg Lactose 145 mg.

Jas E-Kethyl-lv ^T -propargyl-1 ~ aföinoinäan hydrochloride and the lactose are replaced by a Ur. 44 (BSS) Maschensiöb pressed and mixed well together. The mixed powders are filled into hard gelatin capsules of appropriate size so that each capsule contains 150 percent of the mixture.

Example B;

Capsules are made with the following composition per capsule:

H-Gyclopropy1-1-aminoindan hydrochloride 50 mg Lactose ■ 80 mg *

This recipe is made in the same way as in Example 7 described and processed in hard gelatin capsules filled so that each capsule 130 mg of the mixed powder contains:

Example 9t

Soup items are made with the following 2ussmmensetiiuag ί

ir-Möiiliyl-li «propariyl-1-aminoindane hydrochloride; 10 mg Iheobroiaa oil. .. 0

I * Methyl-ür-propargyl-1 -aminoindan HydiOöftLprid is replaced by an ITr. 60 (BSS) mesh sieve pressed and processed with the melted iDheobronia oil at 45 ⁰ C * .bcl that a smooth suspension is formed. The Gemisoh is stirred well and used for the production of suppositories.

BAD ORs 809806/0809

cast suitable forms, each form taking about 1 g, each uuppositorium contains 10 mg of iMiethyl-N-propargyl-1-aminoindan Hydrochloride.

Example 10t

Na nuation be ■ juppositorien with the following Zusamme made:

Ef-Glycopropyl-1-aminoindane hydrochloride 50 mg Theobroma-rül 0.975. G.

The recipe is the same as in Example 9 described worked up. Each suppository contains 50 mg of the N-Cyclopropyl-i-arainoindan Hydrochloride.

Example 11t

A sterile powder is used for making an injectable solution de »w-! iethyΙ-ΪΤ-propargy 1-1 -aminoindane Hydrochloride manufactured as follows »

A (1) The N-methyl-N-propargy1-1 -aminoinotan hydrochloride is sterilized by contact with ethylene oxide. Amounts of 5 ng each are aseptically filled into the sterile final container, which is then aseptically closed . If this powder is to be used, it can be dissolved in 1 ml or more of a sterile normal saline solution suitable for in;) ection purposes.

A. (2) The N-methyl-üf-piropargyl-1-aminoindane hydrochloride is sterilized by contact with ethylene oxide. Quantities of 100 rag each are poured into the sterile aseptically 'The final container is filled, which is then aseptically sealed. When applied this sterile powder it can be in 1 ml or more of an egg-filled normal for injections Salaiö'eung to be dissolved

3 (1) The S-methyl-H-propargyl-1-aminoindane hydrochloride is dissolved in distilled water so that the resulting solution Contains 5 mg / ml, This solution will

BATH ORIGINAL

then filtered through a bacterially protected filter, aseptically transferred to the final sterile container and subjected to freeze-drying subjected to aseptic conditions. The sterile, freeze-dried powder can be divided into 1 ral or - more of a normal one suitable for injection purposes Saline solution to be dissolved.

Ti (2) x> AO-2f Metkyl-IT-propargyl-1-aminoindan hydrochloride is dissolved in distilled V'asser, ao that the Lorning obtained ΐης 100 / ml of. This solution is filtered through a bacterial-safe filter, aseptically transferred into the final sterile container and subjected to freeze-drying under aseptic conditions. The sterile freeze-dried powder can be dissolved in 1 1/2 or more normal saline solution for injections.

Example 12t

Injection solutions of the H-üyclopropyl-1-aminoindan Hydrochloride -are made as follows:

(1) Jas J-cyelopropyl-1-aminoindan hydrochloride is used in a normal solution suitable for injection purposes dissolved so that the solution contains 2 mg / ml. This solution is then protected against bacteria Filters filtered and aseptically transferred to final sterile containers.

(2) The IT-Gyclopropy 1-1 -aminoindan hydrochloride is in a normal saline solution suitable for injection purposes dissolved so that the solution contains 10 mg / ml · This solution is filtered through a bacterial filter filtered and aseptically in the final sterile Container transferred.

(3) The H-Cyclopropyl-1-aminoindan hydrochloride is in a normal saline solution suitable for insect purposes dissolved so that the solution contains 50 mg / ml.

BAD ORSQiNAL

80980R / ng

This solution is then protected against bacteria Filters filtered and aseptically placed in final sterile containers.

Example 13:

i-in Jyrup, which contains the N-Iviethyl-N-propar _L yl-1-aininoindan hydrochloride, is prepared as follows:

U-tiethyl-N-propargyl-1-aminoindan hydrochloride 1.0 G.

Glycerin 50.0 ml

Liquid invert zucfcer 500.0 ml

Ifethyl- £ -hydroxyt> enzoate 1.0 G.

Propyl e-hydroxybenzoate 0.4 G.

lropylene glycol 10.0 ml

distilled water made up to 1.0 1

The i? - !, iQthyl «H-propargyl-1-a3iinoindan hydrochloride -r / is dissolved in 500 iv.1 distilled water? the liquid invert sugar is added to this solution. The methyl and propyl esters of p-oxybenzoic acid are dissolved in the propylene glycol with heating; the solution obtained is diluted with the glycerin. This solution becomes the prefabricated solution of N-methyl-H-propargyl-i-aminoi & dan

iroohlorid added and distilled water added, aο that results in a volume of 1 1,

The syrup made contains 5 mg of active ingredient per 5 ml oyrup.

Example 14 »

A syrup j aer IT-Cyclopropy 1-1-aminoindan Hy4roc \ hloa? Id contains * is made as follows:

HfCyolopropyl-1-aminoindan Hydrochloride 10.0 G. Glyoerin 50 * 0 ml

Liquid invert sugar 500 * 0 al. Methyl- £ -hydroa: y Alsoat 1.0 G.

Propyl e-hydroxybenzoate 10 ml

Distilled water made up to 1.0 1

This syrup is prepared in the same way as this

BATH ORIGINAL

game 13 is described, produced. Each 5 ml of the finished: jyrups contain 50 mg of active substance.

In Examples 5 to 14, the specified ■ irlietoff by other compounds within the scope of the invention, which have the necessary pharmacological activity, replaces v / earth. For example, this is N-proparßvl-1-aminoindan a soldier active ingredient. Other pharmaceutically acceptable salts can be used in place of the hydrochloride will.

BATH

Patent award 7

809806/0809

Claims (1)

wherein S ₁ B ₂ 1 Hiid the gleioh or Yereohieden "β in can, for Waeeeretof t atoms, Alkylreete having 1 or 2 carbon atoms, halogen atoms, hydroxy groups or alkoxy groups · low? R ^ for water or a lower alkyl group; R ^ for a uyoloprop; fl ~ 0 group or a group of the formula <* G £ L * 09CHEU S «* for Waeeeretoff, a lower alkyl group,« in a phenyl group or a group ["· '4jWf fOrtWir-CO-H and Rg and R ₇ , the same ^ or Yereehieden eein can »for We.ee only off atoms or lower alkyl groups, aowie τρη Sateen dieeer connections with pharmaaeutieoh Nominal acids, because they were not known, that . a) a 1-pidanone of the general formula, II BATH ORIGINAL 809806/0809 where B. and lip ^ ^{e have the} same meaning as past *, In a manner known per se with a connection of the general formula HGO-NII-R, III wherein R, has the same meaning as before, reacted and the 1-indanformamide obtained is an acidic or is subjected to alkaline hydrolysis; or b) a 1-haloindane of the general formula IV where R- and R _{2 have} the same meaning as before and X stands for a halogen, in a manner known per se with an amine of the general Pqrmel H ₂ NS ₄ V where R, has the same meaning as before, is condensed; or o) a 1-aminoindan of the general Pornel VI wherein R ₁ and R _{2 have} the meaning already mentioned and Rg is a low one. Alkyl group or R ^, in a manner known per se with a connection of the general BAD ORiGJNAL 809806/0809 my formula X-R, VII where Rg stands for a lower alkyl group when R _Q is R.let, Rq stands for R ^ when R _{y stands} for a lower alkyl group, and X denotes the removable group of the alkylating agent, condensation is carried out with cleavage of 1 mol of HX; or d) a compound of the general formula CH ₂ -G = CR ₅ VIII wherein R ₁ , R ₂ and Rc have the same meaning as before, in a known manner with a mixture of formaldehyde, Formic acid and iiatrium formate is methylated; or e) a connection of the general porv IX and R ~ the same meaning as before wherein R ₁ ,: have,
carboxylated, esterified and with an Arain of the formula -NH ^ ³ * ⁶ where Rg and R ~ have the same meaning as before,
is implemented; and BATH 809806/0809 f) the connections made in this way, if applicable known to be in salts of pharmaceutically acceptable ones Acids are transferred. BAD ORIGINAL ■ 80S8 0 6/0809