KR810000604B1 - Process for preparing aminoalkexyphenyl derivative - Google Patents

Abstract

New aminoalkoxyphenyl derivs. of formula I[A = lower alkoxy group or substituted benzene or pyridine ring; R1 = H, lower alkyl; R2 = C1-6 straight chain or side chain; R3 =H, OH; R4 = H, lower alkyl or alkoxy; R5 = H, lower alkyl; n = 0,1,2 and their acid added salts were prepd. by reacting of formula II[X = halogen, oxygen and formula III or formula IV and formula V. Title compds. are useful as antiarrhythmic, β- adrenergic recepto blocks and antianginous agents.

Description

Method for preparing aminoalkoxyphenyl derivative

The present invention relates to a novel aminoalkoxyphenyl derivative of general formula (I) and a physiologically competitive salt with inorganic or organic acids having valuable pharmaceutical activity, in particular antiangina, antiarrhythmic and β-receptor blocking effects. It is about.

Wherein A is a mono-, di- or trisubstituted phenyl group with a lower alkoxy group, an amino- and / or nitro group or a pyridyl group, R ₁ is a hydrogen atom or a lower alkyl group and R ₂ is a carbon source of 1 to 6 Linear or branched alkyl group having a group or a straight chain saturated alkylene group optionally substituted by hydroxy group with 1 to 4 carbon atoms. Wherein the alkylene group is an amino group, a group substituted terminally by a carboalkoxy group having 2 to 6 carbon atoms, a phenyl or phenoxy group and the phenyl or phenoxy group is mono-, di- by a lower alkyl and / or alkoxy group Or a tree substituted group.

R ₃ is a hydrogen atom or a hydroxy group, R ₄ is a hydrogen atom, a lower alkyl or an alkoxy group, R ₅ is a hydrogen atom or a lower alkyl group and n is 0, 1 or 2.

Accordingly, the subject of the present invention is a novel isoquinolin-1 (2H) -one, 1,6-, 2,6 substituted in the 3-position by an optionally substituted aminoalkoxyphenyl, aminoalkoxybenzyl or aminoalkoxyphenylethyl group -, 3,6- and 4,6-naphthyridin-5 (6H) -one and a process for preparing acid addition salts which are physiologically competitive with inorganic or organic acids.

“Lower alkyl group” as used in the definitions of A, R ₁ , R ₂ , R ₄ and R ₅ means an alkyl group having 1 to 3 carbon atoms, ie, methyl, ethyl, propyl or isopropyl group and A, R “Lower alkoxy group” as used in the definitions of ₂ and R ₄ represents an alkoxy group having 1 to 3 carbon atoms, ie methoxy, ethoxy, propoxy or isopropoxy group.

Subgenus A is phenyl, methoxyphenyl, dimethoxyphenyl or pyridyl group, R ₁ is hydrogen atom, methyl, ethyl, propyl or isopropyl group and R ₂ is phenyl, methoxyphenyl, dimethoxyphenyl, trimethoxy Phenyl, methylphenyl, amino carbmethoxy, carethoxy, carbpropoxy, carbobutoxy, carbopentoxy, carbisopropoxy, carbo tert-butoxy, carbo tertiary phenoxy, methylphenoxy or methoxyphenoxy Methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isoamyl, tertiary butyl or tertiary pentyl groups substituted by groups or are methylene, ethylene, hydroxy General structural formulas wherein ethylene, propylene, hydroxy propylene or butylene groups, R ₄ is a hydrogen atom, methoxy, ethoxy, propoxy or isopropoxy group and R ₅ is methyl, ethyl, propyl or isopropyl group ( I) is composed of a compound.

Preferred compounds of general formula (I) are those in which A is a phenyl, methoxyphenyl, dimethoxyphenyl or pyridyl group, R ₁ is a hydrogen atom, methyl or ethyl group and R ₂ is ethyl, isopropyl or tertiary butyl group or It is a straight chain saturated alkylene group having 2 or 3 carbon atoms optionally substituted by a oxy group. Wherein each group is terminally substituted with a phenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, amino, methylphenyl, isopropoxycarbonyl, tert-butoxycarbonyl, phenoxy, methylphenoxy or methoxyphenoxy group do.

R ₃ is a hydrogen atom or a hydroxy group, R ₄ is a hydrogen atom or a methoxy group, R ₅ is a methyl group and n is 0, 1 or 2.

The aromatic substituents of R ₂ here are in particular phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, phenoxy, 2-methylphenoxy , 4-methylphenoxy, 2-methoxyphenoxy or 4-methoxyphenoxy group.

However, particularly preferred compounds of formula (I) are those in which A is a phenyl, 2-methoxyphenyl or 2,3-dimethoxyphenyl group, R ₁ is a hydrogen atom, R ₂ is isopropyl or tert-butyl group and R ₃ is hydroxy A oxy group, R ₄ is a hydrogen atom or a methoxy group, R ₅ is a methyl group and n is 0, 1 or 2;

The novel compounds of general formula (I) above are prepared according to the following methods.

a) Reaction of propoxyphenyl derivative of formula (II) with amine of formula (III)

Wherein A, R ₃ , R ₄ , R ₅ and n and R ₁ and R ₂ are as defined above and X is a nucleophilic exchange group such as an oxygen atom together with a halogen atom or R ₃ .

The reaction is carried out in isopropanol, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide in a waste container at a temperature between 50 and 200 ° C., preferably between 80 and 160 ° C., in the presence of an acid binder such as an alkoxide or alkali carbonate. In a solvent such as However, it is advantageous if the amine of formula (III) used as a solvent is present in excess.

b) Reaction of the carboxylic acid of formula (IV) or a reaction derivative thereof with the amine of formula (V)

Wherein A, R ₁ to R ₄ and R ₅ are as defined above.

The reaction is carried out in the presence of a condensing agent, such as an alkoxide, at a temperature between 50 and 200 ° C., preferably between 80 and 140 ° C. in a waste container such as methanol, ethanol, isopropanol, dioxane or diethylformamide. It is effectively progressed within. However, the reaction is advantageously carried out when an excess of the amine of formula (V) is used as the solvent.

The novel compounds of formula (I) obtained according to the invention can be converted into salts which are physiologically competitive with inorganic and organic acids. Suitable acids are hydrochloric acid, phosphoric acid, hydrogenation, sulfuric acid, lactic acid, citric acid, tartaric acid, oxalic acid and maleic acid.

Compounds of formulas (II) to (V) are each prepared by known methods known from the literature. For example, the compound of formula (II) has a structure wherein the corresponding 0-halogen-carboxylic acid of formula (VI) is at a temperature between 60 and 100 ° C. in the presence of a catalyst of copper acetate and sodium alkoxide such as sodium ethoxide. It is prepared by reacting with ketone of. The carboxylic acid of formula (VIII) obtained is then treated with the amine of formula (V) to convert to the corresponding reduced ketone of formula (IX). The desired compound of formula (II) is to separate the group of R ₆ and then to the corresponding halogen epihydrin or the corresponding 1-bromo- in a solvent such as dimethylformamide or dimethylsulfoxide at room temperature in the presence of sodium ethoxide. Obtained by reaction with 3-chloropropane.

Wherein A, R ₄ , R ₅ and n are as defined above, Hal is a chlorine, cancel or iodine atom and R ₆ is methyl or benzyl group.

Starting compounds of formula (IV) are obtained by reacting the corresponding phenoxy derivatives of formula (X) with the corresponding 0-halogen-carboxylic acids of formula (VI) at a temperature of 60 to 100 ° C. in the presence of sodium ethoxide. .

In the above structural formula, A, R ₁ to R ₄ are as defined above and Hal is a chlorine, cancel or iodine atom.

As already mentioned earlier, novel structural (I) compounds and physiologically competitive acid addition salts exhibit valuable pharmaceutical activity, in particular antiangina, antiarrhythmic and β-receptor-blocking effects.

The following compounds were tested for biological activity.

A = 2-Methyl-3- [4- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -7-methoxy-isoquinolin-1- (2H) -one, B = 2 -Methyl-3- [2- (2-hydroxy-3-isopropylamino-propoxy) -phenyl] -7-methoxy-isoquinolin-1- (2H) -one-oxalate, C = 2- Methyl-3- [2- (2-hydroxy-3-isopropylamino-propoxy) -4-methoxy-phenyl] -7-methoxy-isoquinolin-1 (2H) -one-oxalate, D = 2-Methyl-3- [2- (2-hydroxy-3-tert-butylamino-propoxy) -4-methoxy-phenyl] -7-methoxy-isoquinolin-1 (2H) -one Oxalenite, E = 2-methyl-3- [4- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -6,7-dimethoxy-isoquinoline-1 (2H) -One, F = 2-methyl-3- [3-methoxy-4- (2-hydroxy-3-isopropylamino-propoxy) -phenyl] -6,7-dimethoxy-isoquinoline-1 ( 2H) -one, G = 2-methyl-3- [3-methoxy-4- (2-hydroxy-3-isopropylamino-propoxy) -phenyl] -7-methoxy-isoquinoline-1 ( 2H) -one, H = 2-methyl-3- [4- (2-hydroxy-3-iso Propylamino-propoxy) -phenethyl] -7-methoxy-isoquinolin-1 (2H) -one.

1) Effects on blood circulation

Tests for blood circulation are performed by intravenously injecting Chlorrose-Urethane-Nembutal-Anasedesia (54 + 270 + 10 mg / kg) into dogs weighing 19-30 kg.

Open the rib cage in the fourth left intercostal cavity and supply air to the Harvard breathing apparatus. Arterial blood pressure is measured from the carotid artery with a statam-pressure exchanger and heart rate is determined electronically from the result of the R-deviation on the electrocardiogram. The maximum velocity of increasing pressure (dp / dt max) in the upper left is measured by the Konigsberg-pressure-apparatus and the Grass-diffevential gauge.

All parameters are indicated by direct documentation. Animals are injected intravenously with 10 mg / kg of polyethylene sulfonate dissolved in 20% polydiol for anticoagulant action. Four to six dogs are injected intravenously with the material to be tested. The following table shows the numerical values obtained.

2) Effect of guinea pigs on contractile force and heart rate of isolated atrium

Atrial isolated from spontaneously beating guinea pigs was stored at 37 ° C. in a Krebs-Hencelite solution in which carbogen (95% O ₂ + 5% CO ₂ ) was dissolved and again at this concentration of the material to be tested. The tension (isotropic contractile force) and the beat rate transmitted are measured.

3) determination of acute toxicity

The acute toxicity of the waters to be tested is determined after oral and intravenous injections into new rats (observation period: 14 days).

LD ₅₀ is determined from the percentage of animals that died after the various doses were administered during the observation period.

The novel structural formula (I) compounds obtained according to the invention are suitable for the treatment of coronary and hypotension.

For pharmaceutical administration, the novel compounds of formula (I) can be combined with other effective substances in the form of conventional herbal preparations such as tablets, sugars, powders, suspensions, solvents, or suppositories.

Single doses for adults range from 50 to 250 mg.

The following examples illustrate the invention. The chemical structure of the new compound is determined by IR-, UV-, MNR-spectra and elemental analysis.

Example 1

[2-Methyl-3- [4- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

a) 2-methyl-3- [4- (2,3-epoxypropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one

1.35 g (10 m mol) in 2.8 g (10 mmol) 2-methyl-3- (4-hydroxy-phenyl) -7-methoxy-isoquinolin-1 (2H) -one solution dissolved in 20 ml of dimethyl sulfoxide + 20%) potassium tert-butoxide is added with stirring and after a while the potassium salt is precipitated. 2.8 ml of epibromo hydrin is added. After stirring at room temperature until the reaction is complete, the mixture is poured into ice water and the crystalline precipitate is suction filtered, washed and dried.

Yield: 2.86 g (85% of theory)

Melting Point: 153 ~ 155 ℃

C ₁₉ H ₂₀ NO ₄ (337.37)

Calculated Value: C 71.70, H 5.68, N 4.15

Found: 71.14 5.65 4.10

b) 2-methyl-3- [4- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one

2.55 g (7.5 m mole) of epoxide obtained according to example 1a) is heated to 120 ° C. with 25 ml of tertiary butylamine in a closed vessel. After 2 hours the excess amine used is removed under vacuum and the granular residue obtained is recrystallized from acetone.

Yield: 2.1 g (70% of theory) Melting point: 130 to 131 ° C

C ₂₄ H ₃₀ N ₂ O ₄ (410.51)

Calculated Value: C 70.22, H 7.32, N 6.82

Found: 69.90 7.29 6.75

Example 2

[2-Methyl-3- [4- (2-hydroxy-3- (3,4-dimethoxyphenyl-N-ethyl-amino) -propoxy-phenyl] -7-methoxy-isoquinoline-1 ( 2H) -on]

1.4 g (5 m mol) of 2-methyl-3- [4- (2,3-epoxypropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one obtained according to example 1a) The resulting composition was reacted with 1.5 g of 3,4-dimethoxyphenyl-N-ethyl-ethylamine at 140 ° C. and the resulting composition was filtered through a silica gel column (particle size: 0.2 to 0.5 mm, eluent: chloroform: methanol = 19: 1). do. The product obtained is evaporated and then dissolved in acetone and precipitated using etheric oxalic acid as oxalate.

Yield: 76.5 g of theoretical value (obtained with oxalate)

Melting Point: 152-155 ° C (From Methanol)

C ₃₄ H ₄₀ N ₂ O ₁₀ (636.30)

Calculated Value: C 64.14, H 6.33, N 4.40

Found: 63.86 6.46 4.36

Example 3

[2-Methyl-3- [4- (3- (3,4-dimethoxyphenyl-N-methyl-ethylamino) -propoxy-phenyl] -7-methoxy-isoquinolin-1 (2H) -one ]

a) 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one

Potassium tert-butoxide in 2.8 g (10 mmol) 2-methyl-3- (4-hydroxy-phenyl) -7-methoxy-isoquinolin-1 (2H) -one solution dissolved in 20 ml of dimethyl sulfoxide 1.35 g (10 m mol + 20%) of the seed is added and after a while the potassium salt is precipitated. 2.8 ml of 1-bromo-3-chloropropane is added to the mixture and stirring is continued at room temperature. After the reaction is completed, the reaction solution is poured into iced water and extracted with ethyl acetate. The organic extract is dried over sodium sulfate and evaporated in vacuo. The colorless oil obtained is coagulated and recrystallized from acetone / ether.

Yield: 3.2 g (89.6% of theory)

Melting Point: 102-104 ℃

C ₂₀ H ₂₀ ClNO ₃ (357.83)

Calculated Value: C 67.13, H 5.63, N 3.91, Cl 9.90

Found: 66.97 5.61 3.96 9.65

b) 2-methyl-3- [4- (3-3,4-dimethoxyphenyl-N-methyl-ethylamino) -propoxy) phenyl] -7-methoxy-isoquinolin-1 (2H) -one

The crude product obtained after reacting 1.8 g (5 mmol) of propyl chloride obtained according to Example 3a) with 1.8 g of 3,4-dimethoxyphenyl-N-methyl-ethylamine at 140 ° C. was subjected to silica gel column ( Particle size: 0.2 to 0.5 mm, eluent: chloroform: methanol = 19: 1) filtered. The product obtained is evaporated and then dissolved in acetone and precipitated with etheric hydrochloric acid.

Yield: 1.45 g (52.5% of theory) obtained by hydrochloride

Melting Point: 155-160 ° C. (from Acetone)

C ₃₁ H ₃₇ ClN ₂ O ₅ (553.09)

Calculated Value: C 67.32, H 6.74, N 5.07, Cl 6.41

Found: 67.00 6.84 4.98 6.31

Example 4

[2-Methyl-3- [4- (2-hydroxy-3-isopropyl amino-propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Example 2-methyl-3- [4-2,3-epoxypropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and isopropylamine raising the reaction temperature to 50 ° C Produce similar to 1.

Yield: 63% of theory

Melting Point: 140 to 142 ° C

C ₂₃ H ₂₈ N ₂ O ₄ (396.48)

Calculated Value: C 69.68, H 7.12, N 7.06

Found: 69.38 7.14 7.10

Example 5

[2-Methyl-3- [4- (2-hydroxy-3- (3,4-dimethoxy phenylethyl amino) -propoxy) -phenyl] -7-methoxy-isoquinoline-1 (2H)- On]

Example from 2-methyl-3- [4- (2,3-epoxypropoxy) -7-phenoxy-methoxy-isoquinolin-1 (2H) -one and 3,4-dimethoxy-phenylethylamine Produced according to a method similar to 2.

Yield: 71% of theory (produced by oxalate)

Melting Point: 208 to 210 ° C (from acetone)

C ₃₂ H ₃₆ N ₂ O ₁₀ (608.64)

Calculated Value: C 63.14, H 5.96, N 4.59

Found: 62.68 5.90 4.49

Example 6

[2-Methyl-3- [2- (2-hydroxy-3-isopropylamino-propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Prepared according to the method similar to Example 1 from 2-methyl-3- [2- (2,3-epoxypropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and isopropylamine do.

Yield: 82.8% of theory (obtained with oxalate)

Melting Point: 216-218 ° C. (From Methanol)

C ₂₅ H ₃₀ N ₂ O ₈ (486.50)

Calculated Value: C 61.72, H 6.22, N 5.76

Found: 61.70 6.33 6.18

Example 7

[2-Methyl-3- [2- (2-hydroxy-3-isopropyl amino-propoxy) -4-methoxy-phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Reaction temperature is raised to 200 ° C. to 2-methyl-3- [2- (2,3-epoxypropoxy) -4-methoxy-phenyl] -7-methoxy-isoquinolin-1 (2H) -one and iso Prepared according to a method similar to Example 1 from propylamine.

Yield: 88% of theory (obtained with oxalate)

Melting Point: 165-168 ° C. (From Methanol)

C ₂₆ H ₃₂ N ₂ O ₉ (516.55)

Calculated Value: C 60.45, H 6.24, N 5.42

Found: 61.28 6.16 5.38

Example 8

[2-Methyl-3- [2- (2-hydroxy-3-tert-butylamino-propoxy) -4-methoxy-phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Example 1 from 2-methyl-3- [2- (2,3-epoxypropoxy) -4-methoxy-phenyl] -7-methoxy-isoquinolin-1 (2H) -one and tertiary butylamine It is prepared according to a similar method.

Yield: 90% of theory (obtained with oxalate)

Melting point: 115 to 120 ° C. (from acetone / ether)

C ₂₇ H ₃₄ N ₂ O ₉ (530.55)

Calculated Value: C 61.12, H 6.46, N 5.28

Found: 60.91 6.32 5.19

Example 9

[2-Methyl-3- [4- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -6,7-dimethoxy-isoquinolin-1 (2H) -one]

Similar method as Example 1 from 2-methyl-3- [4- (2,3-epoxypropoxy) -phenyl] -6,7-dimethoxy-isoquinolin-1 (2H) -one and tertiary butylamine Manufactured according to.

Yield: 65% of theory

Melting Point: 165-166 ° C. (from Acetone / Ether)

C ₂₅ H ₃₂ N ₂ O ₅ (440.53)

Calculated Value: C 68.15, H 7.32, N 6.36

Found: 67.70 7.23 6.41

Example 10

[2-Methyl-3- [4- (2-hydroxy-3-isopropylamino-propoxy) -phenyl] -6,7-dimethoxy-isoquinolin-1 (2H) -one]

In a method similar to Example 1 from 2-methyl-3- [4- (2,3-epoxypropoxy) -phenyl] -6,7-dimethoxy-isoquinolin-1 (2H) -one and isopropylamine Are manufactured accordingly.

Yield: 81% of theory

Melting Point: 206-207 ° C (from Acetone / Ethyr)

C ₂₄ H ₃₀ N ₂ O ₅ (426.50)

Calculated Value: C 67.58, H 7.09, N 6.57

Found: 67.36 7.02 6.63

Example 11

[2-Methyl-3- [3-methoxy-4- (2-hydroxy-3-isopropylaminopropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Example 1 from 2-methyl-3- [3-methoxy-4- (2,3-epoxypropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and isopropylamine Prepared according to a similar method.

Yield: 77% of theory

Melting Point: 144-146 ° C (From Acetone)

C ₂₄ H ₃₀ N ₂ O ₅ (426.507)

Calculated Value: C 67.58, H 7.09, N 6.57

Found: 67.35 7.15 6.76

Example 12

2-Methyl-3- [3-methoxy-4- (2-hydroxy-3- (2-methoxyphenylethyl-amino) -propoxy) -phenyl] -7-methoxy-isoquinoline-1 ( 2H) -on

From 2-methyl-3- [3-methoxy-4- (2,3-epoxypropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 2-methoxyphenylethylamine It is prepared according to a method similar to that of Example 2.

Yield: 56% of theory (obtained with oxalate)

Melting Point: 197 to 199 ° C (From Methanol)

C ₃₂ H ₃₆ N ₂ O ₁₀ (680.65)

Calculated Value: C 63.18, H 6.04, N 4.60

Found: 63.40 6.11 4.56

Example 13

[2-Methyl-3- [4- (2-hydroxy-3-isopropylamino-propoxy) -phenethyl] -7-methoxy-isoquinolin-1 (2H) -one]

From 2-methyl-3- [4- (2,3-epoxypropoxy) -phenethyl] -7-methoxy-isoquinolin-1 (2H) -one and isopropylamine according to a similar method as in Example 1 Are manufactured.

Yield: 77% of theory

Melting Point: 137-139 DEG C (from Acetone / Ether)

Calculated Value: C 70.75, H 7.59, N 6.60

Found: 70.40 7.48 6.61

Example 14

[2-Methyl-3- [3-methoxy-4- (2-hydroxy-3-isopropylaminopropoxy) -phenethyl] -7-methoxy-isoquinolin-1 (2H) -one]

Example 1 from 2-methyl-3- [3-methoxy-4- (2,3-epoxypropoxy) -phenethyl] -7-methoxy-isoquinolin-1 (2H) -one and isopropylamine It is prepared according to a similar method.

Yield: 80% of theory

Melting Point: 162-164 DEG C (from Acetone / Ether)

C ₂₆ H ₂₄ N ₂ O ₅ (454.56)

Calculated Value: C 68.70, H 7.54, N 6.16

Found: 68.60 7.54 6.03

Example 15

[2-Methyl-3- [3-methoxy-4- (3- (2-0-methoxy-phenyl-ethylamino) -2-hydroxy) -propoxy) -phenylethyl] -7-methoxy Isoquinolin-1 (2H) -one]

2-Methyl-3- [3-methoxy-4- (2,3-epoxypropoxy) -phenethyl] -7-methoxy-isoquinolin-1 (2H) -one and 2-methoxyphenyl-ethyl Prepared according to a method analogous to Example 2 from amines.

Yield: 74% of theory

Melting Point: 117-118 DEG C (from Acetone)

C ₃₂ H ₃₈ N ₂ O ₆ (546.67)

Calculated Value: C 70.30, H 7.01, N 5.13

Found: 70.20 7.03 5.04

Example 16

[2-Methyl-3- [4- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Prepared analogously to Example 1 from 2-methyl-3- [4- (2,3-epoxypropoxy) -phenyl] -isoquinolin-1 (2H) -one and tertiary butylamine.

Yield: 84% of theory

Melting point: 130 to 132 ° C. (from acetone / ether)

C ₂₃ H ₂₈ N ₂ O ₃ (380.48)

Calculated Value: C 72.61, H 7.42, N 7.36

Found: 72.80 7.48 7.22

Example 17

[2-Methyl-3- [4- (3-methoxyphenyl-N-methyl-ethylamino) -propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Example 3 from 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 4-methoxyphenyl-N-phenylethylamine Accordingly prepared accordingly.

Yield: 75% of theory (obtained by hydrochloride)

Melting Point: 229-23 ° C. (from Acetone / Ether)

C ₃₀ H ₃₅ ClN ₂ O ₄ (523.07)

Calculated Value: C 68.88, H 6.75, N 5.36 Cl 6.78

Found: 68.60 6.70 5.36 6.82

Example 18

[2-Methyl-3- [4- (3- (3,4,5-trimethoxyphenyl-N-methyl-ethylamino) -propoxy) -phenyl] -7-methoxy-isoquinoline-1 ( 2H) -on]

2-Methyl-3- [4- (3-chloropropoxy) -phenoxy] -7-methoxy-isoquinolin-1 (2H) -one and 3,4,5-trimethoxyphenyl-N- Similarly prepared according to Example 3 from methyl-ethylamine.

Yield: 53% of theory (obtained with oxalate)

Melting Point: 224-225 ° C. (From Methanol)

C ₃₄ H4 ₄₀ N ₂ O ₁₀ (636.68)

Calculated Value: C 64.13, H 6.33, N 4.40

Found: 63.71 6.19 4.55

Example 19

[2-Methyl-3- [4- (3- (2-hydroxy-3-0-cresyl-propylamino-propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one ]

From 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 2-hydroxy-3-0-cresyl-propylamine Similarly prepared according to Example 3.

Yield: 70% of theory (obtained with oxalate)

Melting Point: 178-182 ° C (From Methanol)

C ₃₂ H ₃₆ N ₂ O ₉ (592.65)

Calculated Value: C 64.85, H 6.12, N 4.73

Found: 64.50 6.21 4.66

Example 20

[2-Methyl-3- [4- (3- (2-hydroxy-3-P-cresyl-propylamino) -propoxy-phenyl] -7-methoxy-isoquinolin-1 (2H) -one ]

From 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 2-hydroxy-3-P-cresyl-propylamine Similarly prepared according to Example 3.

Yield: 64% of theory (obtained with oxalate)

Melting Point: 195-197 ° C. (From Methanol)

C ₃₂ H ₃₆ N ₂ O ₉ (592.65)

Calculated Value: C 64.85, H 6.12, N 4.73

Found: 64.70 6.13 4.83

Example 21

[2-Methyl-3- [4- (3- (2-hydroxy-3-0-methoxyphenoxy-propylamino) -propoxy-phenyl] -7-methoxy-isoquinoline-1 (2H) -On]

2-Methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 2-hydroxy-3-0-methoxy-phenoxy- Similarly prepared according to Example 3 from propylamine.

Yield: 77% of theory (obtained with oxalate)

Melting Point: 156-158 DEG C (from Methanol)

C ₃₂ H ₃₆ N ₂ O ₁₀ (608.65)

Calculated Value: C 63.14, H 5.96, N 4.60

Found: 62.78 5.74 4.59

Example 22

[2-Methyl-3- [4- (3- (2-hydroxy-3-P-methoxyphenoxy-propylamino) -propoxy) -phenyl] -7-methoxy-isoquinoline-1 (2H )-On]

2-Methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 2-hydroxy-3-P-methoxy-phenoxy- Similarly prepared according to Example 3 from propylamine.

Yield: 77% of theory (obtained with oxalate)

Melting Point: 172-175 ° C (From Methanol)

C ₃₂ H ₃₆ N ₂ O ₁₀ (608.65)

Calculated Value: C 61.72, H 6.22, N 5.76

Found: 61.70 6.33 6.18

Example 23

[2-Methyl-3- [4- (3- (2-methoxyphenyl-ethylamino) -propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

According to Example 3 from 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 2-methoxyphenyl-ethyl-amine Similarly made.

Yield: 67% of theory (obtained with oxalate)

Melting Point: 216 218 ° C (From Methanol)

C ₃₁ H ₃₄ N ₂ O ₈ (562.60)

Calculated Value: C 66.18, H 6.09, N 4.98

Found: 66.10 6.18 4.85

Example 24

[2-Methyl-3- [4- (3- (3-aminopropylamiamino) -propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Similarly according to Example 3 from 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 1,3-diaminopropane Are manufactured.

Yield: 50.8% of theory (obtained with dioxalate)

Melting Point: 220-225 ° C (From Methanol)

C ₂₇ H ₃₃ N ₃ O ₁₁ (575.56)

Calculated Value: C 58.50, H 5.95, N 6.45

Found: 58.333 5.87 6.30

Example 25

[2-Methyl-3- [4- (3- (2-hydroxy-3-phenoxy-propylamino) -propoxy-phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Example from 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 2-hydroxy-3-phenoxy-propylamine Similarly prepared according to 3.

Yield: 73% of theory (obtained with oxalate)

Melting Point: 170-175 ° C. (From Methanol)

C ₃₁ H ₃₄ N ₂ O ₉ (578.60)

Calculated Value: C 64.35, H 5.92, N 4.84

Found: 63.70 5.96 4.89

Example 26

[2-Methyl-3- [4- (3- (2-hydroxy-2-phenyl-ethylamino) -propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Example from 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 2-hydroxy-2-phenyl-ethyl-amine Similarly prepared according to 3.

Yield: 74% of theory (obtained with oxalate)

Melting Point: 215 220 ℃ (From Methanol)

C ₃₀ H ₃₂ N ₂ O ₈ (458.55)

Calculated Value: C 65.68, H 5.88, N 5.11

Found: 65.83 5.88 5.26

Example 27

[2-Methyl-3- [4- (3- (2-amino-ethylamino) -propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Similar to Example 3 from 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 1,2-diamino-ethane Is manufactured.

Yield: 73% of theory (obtained with dioxalate)

Melting Point: 235-240 ° C. (From Methanol)

C ₂₆ H ₃₁ N ₃ O ₁₁ (561.56)

Calculated Value: C 5.651, H 5.56, N 7.46

Found: 55.87 5.64 7.38

Example 28

[2-Methyl-3- [4- (3- (3-m-toluidine-propylamino-propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Similarly according to Example 3 from 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and 3-m-toluidinepropylamine Are manufactured.

Yield: 50% of theory (obtained from hydrogen chloride)

Melting Point: 204-205 DEG C (from Acetone)

C ₃₀ H ₃₆ N ₃ O ₃ (522.16)

Calculated Value: C 69.00, H 6.95, N 8.05 Cl 6.79

Found: 68.90 7.12 8.03 6.80

Example 29

[2-Methyl-3- [4- (3- (2-ispropyloxycarbonylethylamino) -propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Similarly prepared according to Example 3 from 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and β-aminopropionate do.

Yield: 53% of theory (obtained with oxalate)

Melting Point: 174 175 ° C (from Acetone)

C ₂₈ H ₃₄ N ₂ O ₉ (542.58)

Calculated Value: C 61.08, H 6.32, N 6.16

Found: 61.70 6.53 5.23

Example 30

[2-Methyl-3- [4- (3- (2-isobutyloxycarbonylethylamino) -propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

Similarly prepared according to Example 3 from 2-methyl-3- [4- (3-chloropropoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one and β-aminopropionate do.

Yield: 22% of theory (obtained with oxalate)

Melting point: 190-195 ° C. (from acetone)

C ₂₉ H ₃₆ N ₂ O ₉ (556.62)

Calculated Value: C 62.57, H 6.52, N 5.03

Found: 62.90 6.66 5.03

Example 31

[6-Methyl-7- [4- (2-hydroxy-3- (3,4-dimethoxy-phenyl-N-methyl-ethylamino) -propoxy) -phenyl] -1,6-naphthyridine- 5 (6H) -on]

6-methyl-7- [4- (2,3-ethoxypropoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one and 2- (3,4-dimethoxyphenyl) -N Similarly prepared according to example 2 from -methyl-ethylamine.

Yield: 70% of theory (obtained with oxalate)

Melting Point: 85-95 ℃

C ₃₁ H ₃₅ N ₃ O ₉ (593.6)

Calculated Value: C 62.72, H 5.94, N 7.08

Found: 62.22 5.95 6.98

Example 32

[6-Methyl-7- [4- (2-hydroxy-3-isopropylamino-propoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one]

Similarly prepared according to Example 1 from 6-methyl-7- [4- (2,3-ethoxypropoxy) -phenyl] -1,65-naphthyridin-5 (6H) -one and isopropylamine .

Yield: 92% of theory

Melting Point: 135-139 ℃

C ₂₁ H ₂₅ N ₃ O ₂ (367.46)

Calculated Value: C 68.64, H 6.86, N 11.44

Found: 67.03 6.69 11.39

Example 33

[6-Methyl-7- [4- (2-hydroxy-3- (3,4-dimethoxy-ethylamino) -propoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one ]

6-Methyl-7- [4- (2,3-epoxypropoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one and 2- (3,4-dimethoxy-phenyl) -ethyl Similarly prepared according to Example 2 from amines.

Yield: 64% of theory (obtained with oxalate)

Melting Point: 82 95 ℃

C ₄₀ H ₃₃ N ₃ O ₉ (57.60)

Calculated Value: C 62.17, H 5.74, N 7.25

Found: 61.56 5.80 6.32

Example 34

[6-Methyl-7- [4- (2-hydroxy-3- (4-methoxyphenyl-N-methyl-ethylamino) -propoxy) -phenyl] -1,6-naphthyridine-5 (6H )-On]

6-methyl-7- [4- (2,3-ethoxypropoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one and 2- (4-methoxyphenyl) -N-methyl Similarly prepared according to example 2 from ethylamine.

Yield: 61% of theory (obtained with oxalate)

Melting Point: 66 ~ 73 ℃

C ₃₀ H ₃₃ N ₃ O ₈ (563.60)

Calculated Value: C 69.93, H 5.90, N 7.45

Found: 63.94 5.75 7.14

Example 35

[6-Methyl-7- [4- (2-hydroxy-3- (3,4,5-trimethoxy-phenyl-N-methyl-ethylamino) -propoxy)-]-1,6-naphthy Lidin-5 (6H) -one]

6-methyl-7- [4 (2,3-ethoxypropoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one and 2- (3,4,5-trimethoxyphenyl) Similarly prepared according to example 2 from -N-methyl-ethylamine.

Yield: 35.5% of theory (obtained with oxalate)

Melting Point: 87-95 ℃

C ₃₂ H ₃₇ N ₃ O ₁₀ (623.7)

Calculated Value: C 61.63, H 5.98, N 6.74

Found: 61.38 5.84 6.77

Example 36

[6-Methyl-7- [4- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one]

Similarly according to Example 1 from 6-methyl-7- [4- (2,3-ethoxypropoxy) -phenoxy] -1,6-naphthyridin-5 (6H) -one and tertiary butylamine Are manufactured.

Yield: 41% of theory (obtained with oxalate)

Melting Point: 248 ~ 250 ℃

C ₂₄ H ₂₉ N ₃ O ₇ (471.5)

Calculated Value: C 61.04, H 6.20, N 8.91

Found: 60.70 6.42 8.89

Example 37

[6-Methyl-7- [4- (2-hydroxy-3-diethylamino-propoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one]

Similarly prepared according to Example 1 from 6-methyl-7- [4- (2,3-epoxypropoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one and dimethylamine.

Yield: 70% of theory (obtained with oxalate)

Melting Point: 143 ~ 145 ℃

C ₂₄ H ₂₉ N ₃ O ₇ (471.4)

Calculated Value: C 61.14, H 6.20, N 8.91

Found: 61.22 6.25 9.01

Example 38

[6-Methyl-7- [4- (3- (3,4-dimethoxy-phenyl-N-methyl-ethylamino) -propoxy) -phenyl] -1,6-naphthyridine-5 (6H)- On]

6-Methyl-7- [4- (3-chloropropoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one and 2- (3,4-dimethoxyphenyl) -N-methyl- Similarly prepared according to Example 3 from ethylamine.

Yield: 45% of theory (obtained with oxalate)

Melting Point: 167-170 ℃

C ₃₁ H ₃₅ N ₃ O ₈ (577.6)

Calculated Value: C 64.46, H 6.11, N 7.27

Found: 64.45 6.16 7.05

Example 39

[6-Methyl-7- [4- (3- (4-methoxyphenyl-methyl-ethylamino) -propoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one]

6-Methyl-7- [4- (3-chloropropoxy) -phenyl] -1,6-naphthyridin-5 (6H) -one and 2- (4-methoxyphenyl) -N-methyl-ethylamine From Similar according to Example 3.

Yield: 45% of theory (obtained with oxalate)

Melting Point: 188 ~ 190 ℃

C ₃₀ H ₃₃ N ₃ O ₇ (547.6)

Calculated Value: C 65.80, H 6.07, N 7.67

Found: 66.72 5.85 7.74

Example 40

[2-Methyl-3- [4- (3- (4-methoxyphenyl-N-methyl-ethylamino) -propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one]

2.5 g (5 m mol) of 2-methyl-3- [4-3- (4-methoxyphenylethyl-N-methylamino) -propoxy) -acetophenyl] -5-methoxy-benzoic acid in a closed container To 25 ml of methylamine. Excess methylamine was distilled off after heating to 50 degreeC for 3 hours, and the obtained crude product was filtered by the silica gel column (particle size: 0.2-0.5 mm, eluent: chloroform: methanol = 19: 1). The residue obtained after evaporation is dissolved in acetone and precipitated by addition of hydrochloric acid on ether with hydrogen chloride.

Yield: 1.4 g (25.6% of theory) (obtained by hydrochloride)

Melting point: 226 to 228 ° C. (from acetone / ether)

C ₃₀ H ₃₅ ClN ₂ O ₄ (523.07)

Calculated Value: C 68.88, H 6.75, N 5.36 Cl 6.78

Found: 68.43 6.82 5.39 6.73

Example 41

[2-Methyl-3- [4- (3- (3,4-methoxyphenyl-N-methyl-ethylamino) -propoxy) -phenyl] -7-methoxy-isoquinoline-1 (2H)- On]

The reaction temperature is 200 ° C. from 2- [4- (3- (3,4-dimethoxy-phenyl-ethyl-N-methyl-amino) -propoxy) -acetophenyl] -5-methoxy-benzoic acid and methylamine And similarly prepared according to Example 40.

Yield: 31.6% of theory (obtained from hydrogen chloride)

Melting Point: 157-159 ° C. (from Acetone)

C ₃₁ H ₁₇ ClN ₂ O ₅ (553.09)

Calculated Value: C 67.32 H 6.74 N 5.07 Cl 6.41

Found: 67.14 6.71 5.12 6.37

Example A

Tablets containing 100 mg of 2-methyl-3- [4- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one

[Manufacturing method]

The active ingredient and lactose are homogeneously wetted with an aqueous solution of polyvinylpyrrolidone and then passed through the screen. After drying, the particles are mixed with the remaining ingredients and the mixture is compressed by conventional methods to form a tablet.

Example B

Containing 150 mg 2-methyl-3- [4- (2-hydroxy-3-isopropyl-amino-propoxy) -phenyl] -6,7-dimethoxy-isoquinolin-1 (2H) -one

[suppository]

[Manufacturing method]

The active ingredient is added to the dissolved suppository mass with stirring, suspended and the liquid mixture is poured into a cooled suppository.

Example C

50 mg of 2-methyl-3- [4- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl] -7-methoxy-isoquinolin-1 (2H) -one

[Manufacturing method]

The mixture is prepared from the coated tablet cores as described in Example A and then coated with sugar and gum arabic.

Example D

5 ml containing 250 mg 2-methyl-3- [4- (2-hydroxy-3-isopropylamino-propoxy) -phenyl] -6,7-dimethoxy-isoquinolin-1 (2H) -one Suspension of

[Manufacturing method]

Benzoic acid ester, glycerin, and carboxymethylcellulose are dissolved in water heated to 70 ° C with stirring. The solution is cooled to room temperature, the active ingredient is added with stirring and homogeneously dispersed. Sucrose is added and dissolved, and the sorbitol solution and the flavor suspension are stirred and evacuated.

Claims (1)

The aminoalkoxyphenyl of formula (I) characterized in that the propoxyphenyl derivative of formula (II) reacts with the amine of formula (III) or the carboxylic acid or derivative thereof of formula (IV) reacts with the amine of formula (V) Method for producing a derivative or acid addition salt thereof.

Wherein A is a mono-, di- or tri-substituted phenyl group with a lower alkoxy group, an amino- and / or nitro group or a pyridyl group, R ₁ is a hydrogen atom or a lower alkyl group and R ₂ is from 1 to 6 Linear or branched alkyl groups having carbon atoms or linearly saturated alkylene groups optionally substituted by hydroxy groups and having 1 to 4 carbon atoms. Wherein the alkylene group is terminally substituted by an amino group, a carboalkoxy group having 2 to 6 carbon atoms, a phenyl or phenoxy group (a mono-, di- or tri-substituted group by lower alkyl and / or alkoxy group) . R ₃ is a hydrogen atom or a hydroxy group, R ₄ is a hydrogen atom, a lower alkyl or alkoxy group, R ₅ is a hydrogen atom or a lower alkyl group, n is 0, 1 or 2 and X is a nucleophilic exchange such as a halogen atom Or an oxygen atom together with R ₃ .