DE2345423A1 - N-Substd.-4,4-dimethyl-isoquinolin-1,3-diones - as hypotensive agents also showing bradycardisant, antiarythmic and sedative effects - Google Patents

Abstract

Isoquinolines and their salts have the formula: (where R1 is H, Hal, MeO or MeS, R2 is H or MeO, n is 2 or 3, A is R3 = H or Me, R4 is pyridyl opt. substd. by Me or Ph opt. substd. by Cl, CF3, one or two, Me, Et or MeO, and R5 and R6 are H or MeO). (I) are useful as hypotensive agents but also showing bradycardisant, anti-arythmic and sedative effects.

Description

Case 5/611
Dr.Cr./Kp.

DR. KARL THOMAE GMBH., BIBERACH AN DER RISS

New substituted phenylethylamine derivatives, their acid addition salts, Medicinal products containing them and processes for their production

The invention relates to new substituted phenylethylamine derivatives of the general formula I,

OCH,

(D

in the

R _{1 is} a hydrogen or chlorine atom or a methoxy or methyl

mercapto group,

Rp is a hydrogen atom or a methoxy group, R, a hydrogen atom or a methyl group and Ri ₁ and R ₁ -, which can be the same or different, a hydrogen

atom or a methoxy group, and η represents the number 2 or 3 and their acid addition salts with valuable pharmacological properties.

509812/1072

ZJ «4 - · ^; 4 Z

The invention also relates to compounds of the ^ ormel I and their Medicaments containing acid addition salts and processes for their preparation.

The new compounds of the formula I can be prepared by the following processes produce:

a) Implementation of a homophthalic anhydride or imide of the general Formula II,

(II)

wherein

R. and R have the abovementioned meaning and A represents an oxygen atom or an optionally substituted imino group, or a dicarboxylic acid of the formula Ha,

C (CH ₃ ) ₂ -C00H

(Ha) COOH

and Rp are as defined at the outset, with an H-aminoalkyl-

in which R ₁ and phenethylamine of the formula III,

H ₂ N- (CH ₂ J _n -N-CH ₂ -CH ₂ - ^ /

ORIGINAL! NSFECTED 509812/1072

wherein R-ζί R

R (- and η have the meaning given above or its

Acid addition salt.

The reaction is preferably carried out in a solvent, for example glycol, or in the melt at temperatures of about 50-25O ⁰ C, especially when the compound of the formula III is used as an acid addition salt.

b) Implementation of an N-alkyl-isoquinoline-dione of the general formula IV,

N - (CH ₂ ) _n -

(IV)

in which R ^, Rp and η are defined as indicated above and Z is a nucleophilically easily exchangeable group, preferably a chlorine, bromine or iodine atom or an alkylsulfonyloxide or Arylsulfonyloxy group, e.g., toluenesulfonyloxy. With a phenethylamine of the formula V,

HN-CH ₂ - CH ₂
I.

4th
OCH,

(V)

wherein R. ,, R ₁ , and Rf- have the meaning given above,

50 9 812/1072

The reaction is optionally carried out in a solvent, e.g. in methanol, ether, tetrahydrofuran, methylformamide, dimethylformamide, Dimethyl sulfoxide or benzene and expediently depending on the reactivity of the radical Z at temperatures carried out between -50 and 25O ° C. The present is advantageous an acid binding agent such as an alcoholate, a metal hydroxide, oxide or carbonate.

c) implementation of a homophthalimide of the formula VI,

(VI)

in the

R ₁ and Rp have the meaning given above, or its metal salt, preferably the alkali metal salt, with a substituted phenethylamine of the formula VII,

Z - (CH ₂ J _n - N-CH ₂ - CH ₂ _ / 3 £ - OCH, (VII)

wherein

R ,, R ₁ J, R ₁ -, Z and η have the meaning given above.

The reaction is preferably carried out in the presence of an acid-binding agent, such as an alcoholate, a metal oxide, metal hydroxide, kaibonats expediently in a solvent, e.g. methanol, Isopropanol, dimethylformamide or dimethyl sulfoxide at temperatures between 0 ° and the boiling point of the used Solvent carried out.

509812/1072

The reaction can also be carried out in such a way that directly an alkali metal salt of the imide of the general formula VI is used will.

Most of the compounds of the general formulas II-VII used as starting materials are known from the literature or are not known can be produced according to methods known from the literature.

The compounds of general formula I are bases and form addition salts with acids. Acids suitable for salt formation are, for example, mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid _t hydrofluoric acid, nitric acid, sulfuric acid, phosphoric acid or organic acids such as acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, Hydroxybenzoic acid, p-aminobenzoic acid, salicylic acid, acetylsalicylic acid, phthalic acid, terephthalic acid, ascorbic acid, methanesulfonic acid, ethanophosphonic acid.

The new compounds of the formula I and their acid addition salts are distinguished by a therapeutically useful effect. In particular, they have an antihypertensive, bradycardant, antiarrhythmic and inotropic effect and can therefore be used ^{for the} treatment of hypertension, tachycardia and corronary diseases. The compounds of the formula I according to the invention and their acid addition salts can also be used with other types of active ingredients, for example tranquilizers, muscle relaxants and diuretics. The compounds according to the invention are suitable for oral use in individual doses of about 20 to 300 mg, preferably between 20 and 200 mg.

The compounds according to the invention are used for pharmaceutical processing of the formula I and their acid addition salts with customary galenic auxiliaries, carriers, lubricants, disintegrants, suspension auxiliaries or substances to achieve a depot effect usual tablets, coated tablets, powders, emulsions, suspensions, solutions processed; the manufacture of pharmaceutical application forms takes place according to the usual galenic manufacturing methods.

509812/1072

The following examples illustrate the invention in a non-limiting manner Way:

A manufacturing examples example 1

> i2- (3 »^ - dimethoxyphenyl) -ethylamineL7-ethane hydrochloride

8.5 g of 2- (2-chloroethyl) -m-dimethyl-7-methoxy-l, 2,3, ⁱ »-tetrahydroisochinolin-dione (l, 3) and 13.6 g of 3» ¹ J-Dimethoxyphenyläthylamin ¹ I kept hours at l80 ° C bath temperature. Then water is added, the mixture is extracted with chloroform, and the chloroform phase is washed with water, dried and concentrated. The impurities are separated off by column chromatography (silica gel column, chloroform / methanol = 95: 5), the main fraction is isolated and the hydrochloride is precipitated with ethereal hydrochloric acid. Recrystallized from ethanol: mp 263-265 ⁰ C.

Example 2

1-ZJ, ² "-Dimethyl-1,3-dioxo- (2H, 4H) -isoquinolin-2-yi7-2- / 5- (3, ^ - di-. methoxy-phenyQ-ethylaminoJ-ethane hydrochloride

Prepared analogously to Example 1 with 2- (2-chloroethyl) -ii, iJ-dimethyll, 2,3,4-tetrahydroisoquinolin-dione- (1,3) and 3,1-dimethoxyphenylethylamine as starting materials.
Recrystallized from ethanol: melting point 1 * J8-151 ° C.

509812/1072

Example 3

l-jr, i | -Dimethyl-7-methoxy-l, 3-dioxo- (2H _t ilH) -ieoquinolin-2-yt7-2- / methyl - ^ - ^ j ^ -dimethoxy-phenylJ-ethyl ^ aminoJ- ethane-hydro- chloride

Manufacturer; analogously to Example 1 with N-'1ethyl-2- (3, ⁱ '-dimethoxyphenyl) · ethylamine and 2- (2-chloro Ithy I?) - ¹ J, ^ -dimethyW-methoxy-l, 2,3,4- tetrahydro-isoquinoline-dione- (i, 3) as starting materials. Melting point: 138-1 ¹ IO ⁰ C.

example

l- $, M-dimethyl-1,3-dioxo- (2H, HH) -isoquinoline-2- ^

(2- (3 , 4-dinethoxy-pheny1) -ethyI) -araino7-propane

Prepared analogously to Example 1 with 2- (3-ChIOrPrOPyI) ^-1 I, il-dimethyl- ¹ » ² » 3 » ^ -tetrahydroisoquinoline-dione- (1,3) and N-Methy1-2- (3,4 -dimethoxyphenyl) -thylamine as starting materials. Isolated as a free base: viscous oil.

Example 5

l- ^ i, ¹ l-dimethyl-7-methoxy-l, 3-dioxo- (2H, ¹ <H) -isoquinoline-2-yr7-3- £ hethy1- (2- (3 »^ - dimethoxy-pheny1 ) -äthy1) -aminp7-propane

Prepared analogously to Example H with 2- (3-chloropropyl) ^-1 l, ¹ l-dimethyl-7-methoxy-l, 2,3, ¹ l-tetrahydro-isoquinoline-dione (l, 3) and N-methy 1-2- (3, ¹ <-dimethoxyphenyl) ethylamine as starting materials. Isolated as a free base: viscous oil.

509812/1072

23A5A23

Example 6

^ "(3« ^ »5" trimethoxyphenyl) ethylamine Q7 propane hydrochloride

Prepared analogously to Example 1, 2- (3, ⁱ *, 5-'Trimethoxy-ühenyl) -ätyhlamin and 2- (3-chloropropyl) - * !, 4-dimethyl-7-methoxy-l, 2 _J 3, i < tetrahydro-isoquinoline-dione- (1,3) as starting materials. Recrystallized from isopropanol: melting point 157-159 ° C.

Example 7

Ci- (^ -methoxy-pheny 1) -ethy Iamino7-propane-hydrochloride

Prepared analogously to Example 1 from 2- (3-chloropropyl) -4, ^ - dimethyl-7-methoxy-l, 2,3, 'i-tetrahydro-isoquinoline-dxon- (1,3) and 2- ( ¹ I- Methoxypheny1) ethylamine.
Recrystallized from isopropanol: melting point 175-176 C,

Example 8

dimethoxyphenyl) ethylamine Q7 propane hydrochloride

Prepared analogously to Example 1 from 2- (3-chloropropyl) - * l, iJ-dimethyll, 2,3, i | -tetrahydroisoquinoline-dione- (1,3) and 2- (3, ^ - dimethoxypheny1) -ethylamine .
Recrystallized from isopropanol: melting point 162-165 ° C.

509812/1072

Example 9

^ J- (3 »^ - dimethoxy-phenyl) -äthylamine7-propane hydrochloride

a) 2- Q.- (3,4-Dimethoxypheny 1) -äthylaminoj-l-cyano-ethane

5 ^, 5 g 2- (3, ¹ * dimethoxy-phenyl) ethylamine are dissolved in 100 ml methanol at 50 ⁰ C, 16.2 g of acrylonitrile, dissolved in 50 ml of methanol was added dropwise for 1 hour at 50 ⁰ C. stirred. After concentration, the crude product obtained in this way is processed further.

b) 1-Q.- (3,4-Dimethoxypheny 1) -äthy laminö7-3-aminopropane

The crude product obtained according to 9a (70.3 g) is taken up in 1.3 l of methanolic ammonia and ^{hydrogenated at 80 °} C. and 50 atmospheres in an autoclave with Raney nickel catalysis.

mm

c) 1-A, H-Dimethyl-7-methoxy-1,3-dioxo- (2H, 4H) -isoquinoline-2- 3- ^ 2- (3 » ^/ t-dimethoxyphenyl) -ethylamineQ7-propane hydrochloride

13 * 2 gi "^ - dimethyl-7-methoxy-l, 2,3, ⁱ '-tetrahydro-isochromandion- (l, 3) and 14.3 g of l - ^ - (3, ^i» dimethoxy-phenyl ) -äthylaminQ7-3-amino-propane are boiled in 250 ml of toluene for 5 hours on a water separator. After cooling, the hydrochloride is precipitated with ethereal hydrochloric acid, and the greasy product is recrystallized from ethanol.
Melting point: 191-193 ⁰ C.

509812/107 2

Example 10

3-ZJ- (3.ty-dimethoxyphenyl) -ethylamineQ7-pronane hydrochloride

Prepared analogously to Example 9 with 1, T-nimethyl-6,7-dir.ethoxy-l, 2, 3, _J 4-tetrahydro-isochroman-dione (l, 3) and l- £ 2- (3, ^ -Mmethoxynhenyl ) · Äthylamino7-3-aminopropane as starting materials. Recrystallized from ethyl acetate: melting point 08-110 ° C

Example 11

1- £ ^, ¹ <-Dimethyl-6,7-dimethoxy-1 _J 3-dioxo- (2H, i) H) -isoquinolin-2-yl7 · 3- / methyl- (2- (3 »4-dimethoxy phenyl) ethyl) -aminoj-propane-hydro- chloride

Prepared analogously to Example 9 from ^ü , ^ - Dimethyl-öjT-dinethoxy-l, 2, 3, ^ - tetrahydro-isochroman-dione- (l, 3) and l- ^ J! - methoxyphenyl) ethylamine67-3-amino- propane. Melting point: 167-168 ° C.

Example 12

l- / T |, lJ-Dimethyl-7-methylmercapto-1,3-dioxo- (2H, iiH) -isoquinolin-2-yl7-3- / 2 * - (3, ¹ <-diinethoxyphenyl) -ethylamineq7 -pronan hydrochloride

Prepared analogously to Example 9 with U, l <-nimethyl-7-rcethylmercar> tol ^^ ji-tetrahydro-isochroman-dione-d ^) and l - / ^ - (3, ^ll -T) imethoxyphenyl) ethylamine <57 -3-amino-propane as starting materials. Recrystallized from ethanol: melting point 133-135 ° ^.

509812/1072 BAD original

Example 13

l - $, iJ-Dimethyl-7-chloro-l, 3-dioxo- (2H, 4H) - 18oquinolin-2-yl7-3- / 2 · (5 _! ^ ~ dinethoxyphenyl) -? tthylamine7propane hydrochloride

Prepared analogously to Example 9 with ίι, Ιΐ-dimethy 1-7-tetrahydro-isochroman-dione- (1,3) and 1- £ 2- (3, Ί-dimethoxy-phenyI) · ethylaminoT ^ -amino-propane as starting materials. Recrystallized from ethanol: mp 222-226 ⁰ C.

B formulation examples example

Tablets of 100 mg l- £?, 4-nimethyl-7-methoxy-1,3-dioxo- (2H, llH) -isoquinolin-2-yl7-3- £ 2- (3, ^ - dimethoxyphenyl) - ethylamino7 ~ propane hydrochloride

Composition:

VJi rks über s tan ζ milk sugar polyvinylpyrrolidone Carboxymethyl cellulose magnesium stearate

Manufacturing process;

The active ingredient and the milk sugar are evenly moistened with an aqueous solution of polyvinylpyrrolidone and granulated. After drying, the granules are mixed with the remaining active ingredients and the mixture is compressed into tablets in the usual way.

509812/1072

100.0 mg 50.0 mg 5.0 mg 19.0 mg 1.0 175.0 mg

Example 15

Coated tablets of 50 mg of dimethyl-7-methoxy-l _> 3-dioxo- (2H, i »H) -isoquinolin-2-yl7" 3- £ 2- (3, ⁱ * _> 5 -Trimethoxyphenyl) -äthylamino7-propane hydrochloride

1 dragee contains: 50.0 mg Active ingredient 20.0 mg Dried corn starch 2.0 mg soluble starch 7.0 mg Carboxymethyl cellulose 1.0 mg Magnesium stearate

80.0 mg Manufacturing process:

The mixture is processed into tablet cores as described in Example 1U, which are then coated with sugar and gum arabic.

Example 16

Suppositories of 150 mg l- / 5, ⁱ l-dimethyl-7-methoxy-1,3-dioxo- (2H, ¹ m) -isoquinolin-2-yl7-3- £ 5- (i | -methoxy-phenyl) -äthylamino-propane hydrochloride

Composition:

Active ingredient 150.0 mg

Suppository mass 1,550 »O mg

1,700.0 mg

Production method;

The active ingredient is evenly distributed into the melted suppository mass stirred in and suspended and the liquid mixture poured into cooled suppository molds.

50981 2/1072

Claims (1)

23A5A23 Claims 1. New substituted phenylethylamine derivatives of the general formula I, OCH, in the R _{1 is} a hydrogen or chlorine atom, a wetnoxy or methyl mercapto group, Rp is a hydrogen atom or a methoxy group, R, a hydrogen or a methyl group, Rj and Rc, which may be the same or different, represent a hydrogen atom or a methoxy group and η denotes the number 2 or 3, as well as their acid addition salts. 2. 1- ^, 4-Dimethyl-7-methoxy-1,3-dioxo- (2H, ilH) -isoquinolin-2-yi7 · 3 - ^ - (3, ² I-dimethoxyphenyl) -ethylamino-7-propane and its acid addition salts. 3. lM, 4-dimethyl-7-methoxy-l, 3-dioxo- (2H, ^ H) -isoquinoline-2-yl7-3- / 2- (3, ^I l, 5-trimethoxy-phenyl) -äthylaming7 propane and its acid addition salts. 509812/1072 234b '* 23 1. 1-A, ^ - Dimethyl-7-methoxy-1,3-dioxo- (2H, üH) -isoquinolin-2-y17-3- / 2- (4-methoxyphenyl) -ethylamino-7-propane and its acid addition salts. 5.la, ⁱ l-dimethyl-6,7-dimethoxy-l, 3-dioxo- (2H, ^ H) -isoquinolin-2-yr7-3- / methyl- (2- (3, ⁱ t-dimethoxy- phenyl) ethyl) aninoJ-oronane and its acid addition salts. 6. Pharmaceutical preparations, characterized in that they as active ingredient a compound of the formula I or an acid addition salt of which contained in the usual auxiliaries and carriers. 7. A process for the production of pharmaceutical preparations according to claim 6, characterized in that a compound of Formula I or its acid addition salt with customary galenicals Auxiliaries, carriers, lubricants, disintegrants, suspending agents or substances to achieve a depot effect on tablets, Dragees, powders, emulsions, formulated solutions. 8. Process for the preparation of compounds of the general formula I or their acid addition salts according to Ansoruch 1, characterized in that one a) a homophthalic anhydride or imide of the general formula II, (II) in the R ₁ and R_ have the meanings given above and 509812/1072 ORIGINAL INSPECTED A denotes an oxygen atom or an optionally substituted imino group, or a dicarboxylic acid of the formula Ha, COOH (Ha) in which R and Rp are defined as indicated above, with an N-amino-alkyl-phenethylamine of the general formula III, H ₂ N- (CH ₂ J _n -N-CH ₂ -CH ₂ OCH, (III) in which R, R ^, R_ and η have the meanings given above, or whose acid addition salt converts; b) an N-alkyl-isoquinoline-dione of the general formula IV, N- (CH ₂ ) _B -Z (IV) in which R ₁ , R ₂ and η are defined as given above and Z is a nucleophilically easily exchangeable group, preferably a 50981 2/1072 Chlorine, bromine or iodine atom, or an arylsulfonyloxy or Alkylsulfonyloxygruppe means with a PhenäthyZamin der Formula V, HN-CH ₂ - OCH (V) in the R-, R ₁ J and R ₁ . have the meanings given above, converts; or c) a homophthalimide of the general formula VI, H, C (VI) wherein R. and Rp are as defined at the outset or its metal salt, preferably its alkali salt, with a substituted phenyl ethylamine of the general formula VII, Z - (CH ₂ ) _n - N-CH ₂ - CH ₂ _ </ '^ - OCH ₃ (VIl) in the R ,, Rj., R, -, η and Z are as defined above, reacted and optionally the compound obtained is converted into an acid addition salt. 509812/1072 23A5A23 9. The method according to claim 8, characterized in that the reaction is carried out in the presence of an organic solvent at temperatures between 0 ⁰ C and the boiling point of the solvent used. 10. The method according to claim 8b, characterized in that the reaction is preferably carried out in a solvent at temperatures between -50 and 250 ⁰ C in the presence of an acid-binding agent. 11. The method according to claim 8c, characterized in that the reaction .in the presence of an acid-binding agent in an organic solvent at temperatures between 0 C and the boiling point of the solvent used . 12. Methods for Bekämp ttn £ * g άφ hypertension, dß.r ^ i ^ aclVykardie and Coronarerkramcungen nfittels Verbiifaungen the formula I and their acid addition salts, characterized in that they are for oral / pplic ^ tflon in a dose of 20 apply up to 30Qr mg. 509812/1072