KR800000906B1 - Process for preparing homophthalimides - Google Patents

Abstract

Antiarrhythmic title compds. (I; R1, R3=H, OMe, R2, R4=H, F, Br, Me, OMe; OEt, iso-propoxy, methylthio, NO2, amino, acetylamino; R5, R6, R7, R8=H, Me, Et, Pr, iso-propyl, Bu, C6H5, p-OMeC6H4, phenylpropyl; A, B=ethylene, 1-methylethylene, propylene, Bu, n-hexyl, C6H5, phenylethyl, phenylpropyl were prepd. Thus, reaction of 19 g(0.1 mol) 4, 4-dimethyl-isochromandion-1, 3 with CH3N(CH2CH2CH2NH2)2 in HO(CH2)2-OH at 180≰C, 4hr gives 65% I(R1, R2, R3, R4=H; R5, R6, R7, R8, R9=Me; A, B=Pr). EC50 and ED50 for I were 5.5 mg/ml and mg/kg in mice, resp.

Description

Manufacturing Method of Homophthalimides

The present invention relates to the following compound of formula (I) having an effective action in the treatment of arrhythmia and a method for preparing acid addition salts thereof.

In the above structural formula

A and B are straight-chain saturated alkylene groups having 2 to 4 carbon atoms optionally substituted with methyl or phenyl groups and may be the same or different.

R ₁ , R ₂ , R ₃ and R ₄ are hydrogen, fluorine, chlorine or bromine, hydroxy, amino, nitro or acetylamino, an alkyl, alkoxy or alkylthio group having 1 to 3 carbon atoms in the alkyl moiety Can be different

R ₅ , R ₆ , R ₇ and R ₈ are alkyl of 1 to 4 carbon atoms optionally substituted with hydrogen, phenyl or methoxyphenyl group, may be the same or different and R ₅ together with R ₆ , R ₇ is R ₈ And a straight chain saturated alkylene group having 2 to 5 carbon atoms and R ₉ is alkyl having 1 to 6 carbon atoms optionally substituted with hydrogen or phenyl.

Preferred compounds according to the invention include compounds in which R ₁ and / or R ₃ are hydrogen or methoxy groups, R ₂ and / or R ₄ is hydrogen, fluorine or bromine, methyl, methoxy, ethoxy, isopropoxy, Compounds which are methylthio, nitro, amino or acetylamino groups, R ₅ , R ₆ , R ₇ and / or R ₈ are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, benzyl, P-methoxybenzyl or phenyl Compounds which are propyl groups and compounds in which R ₅ together with R ₆ or R ₇ together with R ₈ are ethylene, butylene or pentylene groups, A and / or B is ethylene, 1-methyl-ethylene, 1-phenyl Compounds of ethylene, propylene, 1- or 3-methyl-propylene or butylene groups and R ₉ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, n-hexyl, benzyl, phenylethyl or phenylpropyl groups Compounds.

The compound of formula (I) and acid addition salts thereof have pharmacological activity and in particular, arrhythmia treatment.

New compounds of formula (I) are prepared by reacting a homophthalic acid derivative of formula (II) or a corresponding homophthalic acid derivative of formula (IIa) with an amine of formula (III).

In the above structural formula

R ₁ , R ₂ , R ₅ and R ₆ are the same as above

W is oxygen or imino group

X is a halogen atom, hydroxyl or alkoxy group

A, B and R ₉ are the same as above

Y is amino or a group of

R ₃ , R ₄ , R ₇ and R ₈ are the same as above.

The reaction proceeds in the molten state or in the presence of a solvent such as methylene chloride, ethylene glycol or toluene, optionally in the presence of a base such as potassium tert-butoxide, at a temperature of from 0 to 250 ° C., but preferably from 110 to 180 ° C. to be. Particularly preferred is to react with a water separation panel at the boiling point of toluene.

Furthermore, when the compound of formula (II) is reacted with the compound of formula (III), the intermediate product of the following formula (IIb) is separated off and then converted to the desired final product at the reaction temperature indicated above.

In the above structural formula

R ₁ , R ₂ , R ₅ , R ₆ , R ₉ A, B and Y are the same as above.

If at least one of the R ₅ -R ₉ groups is hydrogen or R ₁ -R ₄ is a hydroxy group, obtaining a compound of formula (I) converts it to an alkylated structure of formula (I) by alkylation When at least one of R ₁ -R ₄ is hydrogen, a compound of formula (I) can be converted to a nitro compound of formula (I) by nitration, and the nitrated compound is an amino compound by reduction. Can be converted to acetylation followed by conversion to the corresponding acetylamino amino compound. Alkylation is preferably carried out with the corresponding alkyl halides or dialkylsulfates, which are calcium carbonate, sodium hydroxide, sodium ethoxide or potassium tertiary in a solvent such as ethanol, dimethylformamide, dimethylsulfoxide or hexamethyl-phosphate triamide. It is preferred in the presence of a base such as butoxide and the temperature is 20 to 200 ℃, the preferred temperature is 60 to 160 ℃. Methylated compounds of formula (I) wherein R ₉ is hydrogen can also be methylated by reacting with formaldehyde / formic acid under the boiling point of the reaction mixture.

Furthermore, the compound of formula (I) according to the present invention can be converted into inorganic or organic acids into pharmaceutically harmless acid addition salts as necessary. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid.

Compounds used as starting materials are obtained according to known methods known in the literature or according to the methods described in the examples. As mentioned above, the compound of formula (I) and acid addition salts thereof have a pharmaceutically effective action, in particular, arrhythmia treatment.

Examples of compounds tested for arrhythmia treatment are as follows.

A = bis [3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine,

B = bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine,

C = bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -bis] -ethylamine,

D = [2- (3,4-Dihydro-7-methoxy-4,4-dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3, 4-dihydro-4,4-dimethyl) -1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine,

E = [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -epi]-[3- (3,4-dihydro- 7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine,

F = bis- [2- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -methylamine,

G = [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro- 4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine,

H = [3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) propyl]-[4- (3,4-dihydro-4 , 4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -butyl] -amine,

I = bis [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolin) -ethyl] -amine,

J = [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[4- (3,4-dihydro- 4,4-Dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -butyl] -amine.

[One. Effect of Mormot's Isolated, Electrically Stimulated Left Heart of the Heart on the Effective Resonance of the Heart]

[Way]

Mormor is killed by striking a neck, regardless of gender. After the incision in the chest, the heart is quickly removed and transferred to Tyrode solution at 37 ° C. Cut the seam and use only the left seam. Electrical stimulation is performed with a glass stimulator S4G, with a spherical wave stimulus for 10 ^-3 seconds and a stimulus of 12V. Shims NaCl 136.8; KCl 2.68; MgCl ₂ 0.2625; NaH ₂ PO ₄ 0.417; NaHCO ₃ 11.9; CaCl ₂ 1.8 (mval / L); It is suspended in a 37 ° C thyroid solution containing 3 g of glucose. The solution is constantly oxidized with 98% oxygen and 2% carbon dioxide. Shrinkage is measured with a force converter and recorded in glass-polygraph (P5).

Sims contract at 0.5 hertz. The maximum heart rate is measured by increasing the stimulus rate by 1 hertz every 10 seconds. The measurement is made three times every 5 minutes before the test drug is added and at 5 and 10 minutes after the addition. The stimulus rate during the measurement time interval is 0.5 Hz. The effect of the drug is calculated by calculating the change in the maximum heart rate for 5 and 10 minutes after adding the drug. Drugs are tested at increasing concentrations to create a dose-response curve to calculate the EC ₅₀ .

[principle]

Peak beats are measured with increasing stimulation rate. When the period between the two stimuli is short, it is a stimulus every second, which corresponds to the post-contraction refractory to the preceding stimulus, and no response occurs for the next stimulus. Thus, the highest heart rate is a measure of the effective refractory, and the compound that reduces the highest heart rate is one that extends the inferiority.

[result]

The next concentration from the dose-response pole is the dose that reduces the highest heart rate by 50%, which is obtained by treating the graph.

[2. Arrhythmia Treatment Effect on Ventricular Fibrillation Induced by Chloroform in Rats]

[Way]

After placing the rat in a saturated area with chloroform gas, the rat is anesthetized 40 minutes later, and the respiratory system is stopped and again gasping after 20 seconds. When breathing is completely suppressed, remove the rat from the presence of chloroform gas, dissecting the chest and quickly cutting the heart to examine cardiac movement. One minute after the incision of the chest, ventricular fibrillation can be seen in almost all animals, or even if it is not present, it can be caused by touching the heart.

Pretreatment with a compound having an arrhythmic treatment reduces the number of animals showing ventricular fibrillation with dose. A dose that reduces the number of animals with ventricular fibrillation by 50% is calculated as a dose-response-curve and the standard error is calculated. Miller, L.C. and Tainter M.L., Proc. Soc. Exp. Biol. Med. 57, 261 (1944).

The experiment uses male rats weighing 20-25 g. Each dose is tested on 10 rats.

The drug is injected intravenously 1 minute before triggering the ventricular fibrillation.

[3. Acute Toxicity Test]

The acute toxicity of the compound in question can be determined using rats after oral or intravenous injection (observation time: 14 days).

LD ₅₀ is calculated from mortality after various doses within the observation time (J. pharmacol. Exp. Therap. 66, 99 (1949).

Therefore, the compound of formula (I) and the pharmaceutical non-toxic salt thereof according to the present invention are particularly suitable for the treatment of arrhythmias of the heart, and the pharmaceutical administration is a conventional pharmaceutical preparation with tablets, coating points, suspensions, suppositories, or stabilizers and other active substances. It can be made into a formulation prepared by mixing arbitrarily. Adult doses range from 25 to 50 mg.

The following examples detail the invention.

Example 1

[Bis- [3-3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) propyl] -methylamine]

19 g (0.1 mole) of 4,4-dimethyl-isochroman-dione-1,3 and 3.6 g (0.025 mole) of bis- (3-aminopropyl) -methylamine in 50 ml of glycol for 4 hours Heat to 180 ° C. After cooling, 150 ml of 10% potassium carbonate solution was added, extracted twice with chloroform of the mixed solution, the chloroform layer was washed twice with water, dehydrated and evaporated. The residue was dissolved in 100 ml of acetone, mixed with 2.9 g of fumaric acid solution in 4 ml of acetone, and concentrated by evaporation to 100 ml. The resulting crystals were suction filtered. After recrystallization from water / charcoal, 8.5 g of a colorless product are obtained with a melting point of 156 to 158 ° C. Yield: 65%

Example 2

[Bis- [3- (3,4-Dihydro-7-methoxy-4,4-dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

22 g (0.1 mole) of 4,4-dimethyl-7-methoxy-isochroman-dione-1,3- and 3.3 g (0.025 mole) bis in 50 ml of glycol in a similar manner to Example 1 The title compound is prepared from-(3-aminopropyl) -amine. Melting Point: 220 ~ 222 ℃

Example 2

[Bis- [3- (3,4-dihydro-6,7-dimethoxy-4, 4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] methylamine]

Water separation of 15 g (0.06 mol) of 4,4-dimethyl-6,7-dimethoxy-isochroman-dione-1,3 and 2.9 g (0.02 mol) of bis- (3-aminopropyl) -methylamine Boil by heating in 200 ml of toluene for 4 hours using a device equipped with a funnel. The solvent is distilled off in vacuo and the residue is purified by silica gel column. Fractions containing the desired product are combined, evaporated and the residue is dissolved in 50 ml of acetone and then mixed with 1.7 g of fumaric acid dissolved in 300 ml of acetone. The solution is concentrated by evaporation to 50 ml volume and ether is added. After about 1 hour, the precipitate is suction filtered and dried.

Yield: 77.2% (11.2 g)

Melting Point (Fumarate): 110 ℃

Example 4

[Bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] amine]

28.5 g (0.15 mol) of 4,4-dimethyl-isochroman-dione-1,3 and 6.5 g (0.05 mol) of bis- (3-aminopropyl)-in 300 ml of toluene in a similar manner to Example 3 Prepared with amines. Hydrochloric acid precipitates in methanol with etheric hydrochloric acid.

Yield: 53.1% (13.6 g)

Melting Point (HCl): 170 to 172 ℃

Example 5

[Bis- [3- (3,4-dihydro-6,7-dimethoxy-4, 4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl] -propyl] amine]

3 g (0.012 mol) of 4,4-dimethyl-6,7-dimethoxy-isochroman-dione-1,3 and 0.72 g (0.0055 mol) of bis- (3 in 150 ml toluene in a similar manner to Example 3 -Aminopropyl) -amine.

Melting Point: 215 ~ 216 ℃ (Recrystallized from Methanol / Acetone)

According to Examples 1 to 5, the following compounds were prepared.

2- (3,4-Dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-di Hydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

Melting Point: 103 ~ 105 ℃

[2- (3,4-Dihydro-4,4-dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3, 4-dihydro-7- Methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] methylamine

Melting Point: 158 ℃

[2- (3,4-Dihydro-4,4-dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3, 4-dihydro-4, 4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] amine

Melting Point (Fumaline): 205 to 206 ℃

Bis- [2- (3,4-dihydro-4,4-dimethyl-1,3-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -amine

Melting Point (Fumarate): 207-208 ℃

Example 6

[Bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] ethylamine]

7.6 g (0.04 mole) of 4,4-dimethyl-isochroman-dione-1,3 and 3.2 g (0.02 mole) of bis- (3-aminopropyl) -ethylamine Heated to reflux for 4 h in 100 ml toluene. The reaction mixture is evaporated, purified by column chromatography on silica gel, and precipitated by forming a salt with an amount of fumaric acid dissolved in acetone / ether.

Yield: 71% (8.8 g)

Melting Point (Fumarate):] 141 to 142 ℃

Example 7

[Bis- [3- (3,4-Dihydro-7-methoxy-4,4-dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -ethylamine]

In a similar manner to Example 6, 8.8 g (0.04 mole) of 4,4-dimethyl-7-methoxy-isochroman-dione-1,3 and 3.2 g (0.02 mole) bis- () in 100 ml of toluene 3-aminopropyl) -ethylamine.

Yield: 51.4 (7 g)

Melting Point: 141 ~ 143 ℃

Example 8

[[3- (3, 4-Dihydro-7-methoxy-4, 4-dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl]-[4- (3,4 -Dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -butyl] -propylamine]

In a manner similar to Example 3, 16.5 g (0.07 mole) of 4,4-dimethyl-7-methoxy-isochroman-dione-1,3 and 4.7 g (0.24 mole) of N- () in 150 ml of toluene Prepared from 3-aminopropyl) -N- (4-aminobutyl) -propylamine.

Yield: 49.2% (7.3 g): viscous oil

analysis :

Calculated Value: C, 69.01% H, 7.66% N, 7.10%

Found: C, 69.00% H, 7.65% N, 7.13%

Example 9

[Bis- [3- (3,4-Dihydro-7-methoxy-4,4-dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -propylamine]

In a manner similar to Example 6, 16.5 g (0.075 moles) of 4,4-dimethyl-7-methoxy-isochroman-dione-1,3 and 4.3 g (0.025 moles) of bis- (in 150 ml of toluene Prepared from 3-aminopropyl) -propylamine.

Example 10

[[2- (3,4-Dihydro-4,4-dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[2- (3, 4-dihydro-6 , 7-dimethoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -methylamine]

10.4 g (0.1 mol) of sodium hydrogen sulfite solution dissolved in 25 ml of water was added dropwise to 7.5 ml (0.1 mol) of 40% formalin aqueous solution within 15 minutes, and the mixture was warmed to 60 DEG C for 2 hours, and the mixture was 24.6 g (0.1 mole) of 4,4-dimethyl-2- (2-methylamino-ethyl-1,2,3,4-tetrahydro-isoquinoline-dione-1,3.

After heating to 50 ° C. for 2 hours, the mixture is cooled and 4.9 g (0.1 mol) of sodium cyanide solution dissolved in 20 ml of water is added. Thereafter, the reaction mixture was stirred at 50 ° C, cooled, and extracted twice with chloroform. Dehydrate the extract and evaporate. The obtained 26.5 g (0.0977 mol) of oily substance was hydrogenated at 5 atmospheres and 50 DEG C for 7 hours using Ranickel as a catalyst in 200 ml of methanolic ammonia. 28 g of 4,4-dimethyl-2- [N-methyl-N- (2-aminoethyl) -aminoethyl] -1,2,3,4-tetrahydro-isoquinoline- very viscous oily substance Obtain Dion-1,3.

3.75 g (0.015 mole) of 4,4-dimethyl-6,7-dimethoxy-isochroman-dione-1 dissolved in 100 g of toluene in 5.2 g (0.018 mole) of the compound thus obtained in a similar manner to Example 10 React with, 3.

Yield: 51.2% (5.6 g)

Melting Point: 122-123 ℃ (Decomposition)

Example 11

[Bis- [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -methylamine]

5.8 g (0.02 mole) of 4,4-dimethyl-2- [N-methyl-N- (2-aminoethyl) -aminoethyl] -1,2,3 in 100 ml of toluene in a similar manner as in Example 10 , 4-tetrahydro-isoquinoline-dione-1,3.

Yield: 35.5% (3.3 g)

Melting Point: 106 ~ 107 ℃

Example 12

[[2- (3,4-Dihydro-7-methoxy-4,4-dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[2- (3,4 -Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -methylamine]

5.8 g (0.02 mole) of 4,4-dimethyl-2 [N-methyl-N- (2-aminoethyl) -aminoethyl] -1,2,3, in 100 ml of toluene in a similar manner as in Example 10 4-tetrahydro-isoquinoline-dione-1,3 and 6.6 g (0.03 mol) of 4,4-dimethyl-7-methoxy-isocoroman-dione-1,3.

Example 13

[[2- (3,4-Dihydro-7-methoxy-4,4-dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[2- (3,4 -Dihydro-6,7-dimethoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -methylamine]

6.4 g (0.02 mol) 4,4-dimethyl-7-methoxy- [N-methyl-N- (2-aminoethyl) -aminoethyl] -1,2 in 150 ml of toluene in a similar manner as in Example 10 And 3,4-tetrahydro-isoquinoline-dione-1,3 and 5 g (0.02 mole) of 4,4-dimethyl-6,7-dimethoxy-isochroman-dione-1,3.

Yield: 55% (7.3g) Melting Point: 118 ~ 120 ℃

Example 14

[Bis- [2- (3,4-Dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl-ethyl] -methylamine]

In a similar manner to Example 10, 12.8 (0.04 mol) of 4,4-dimethyl-7-methoxy-2- [N-methyl-N- (2-aminoethyl) -aminoethyl] -1 in 200 ml of toluene , 2, 3, 4-tetrahydro-isoquinoline-dione-1, 3 and 13.2 g (0.06 mole) of 4,4-dimethyl-7-methoxy-isochroman-dione-1,3 .

Yield: 37.3% (7.8 g)

Melting Point: 105 ~ 151 ℃ (Recrystallized from Acetone)

Example 15

[Bis- [3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine]

20.8 g (0.1 mole) of α, α-dimethyl-homophthalic acid and 3.6 g (0.025 mole) of bis- (3-aminopropyl) -methylamine are heated to 180 ° C. in 50 ml of glycol for 4 hours. The reaction mixture is cooled, mixed with 150 ml of 10% potassium carbonate solution and extracted with chloroform. The extract is washed with water and dehydrated to evaporate. The obtained residue is dissolved in ether, and hydrochloride is produced by ether hydrochloric acid to precipitate.

Yield: 72.2 (9.5 g)

Melting point (hydrochloride): 80 ℃ or more

Example 16

[Bis- [3- (3,4-dihydro-6,7-dimethoxy-4, 4-dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine]

In a similar manner to Example 3, 3.5 g (0.14 mole) of 4,4-dimethyl-6,7-dimethoxy-isochroman-dione-1,3 and 0.73 g (0.005 mole) bis in 200 ml of toluene It is prepared from-(3-aminopropyl) -methylamine. Hydrochloride is produced with etheric hydrochloric acid and precipitated in ether solution.

Yield: 65% (2.1 g)

Melting point (hydrochloride) 70 ℃ or more

Example 17

[Bis- [3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

Prepared in a similar manner to Example 1 from 19 g of (0.1 mole) 4,4-dimethyl-isochroman-dione-1,3 and 3.3 g (0.025 mole) of bis- (3-aminopropyl) -amine .

Yield: 58.1% (8.6 g)

Melting Point: 216 ° C (Recrystallized from Methanol)

Example 18

[Bis- [3- (3,4-Dihydro-7-methoxy-4, 4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

In a similar manner to Example 3, 33 g (0.15 mole) of 4,4-dimethyl-7-methoxy-isochroman-dione-1,3 and 6.5 g (0.05 mole) of bis- (3 in 30 ml of toluene -Aminopropyl) -amine.

Yield: 64% (18.3 g)

Melting Point: 151 ~ 152 ℃

Example 19

[[2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro-4 , 4-dimethyl-1,3-dioxo-2) 1H) -isoquinolyl) -propyl] -amine]

1.9 g of 4,4-dimethyl-isochroman-dione-1,3 and 4.7 g of 3- (2-amino-ethylamino) -propylamine were heated to 160 ° C. in 50 ml of ethylene glycol for 2 hours. Do it. After cooling, the mixture is diluted with water, extracted with chloroform several times, the chloroform layer is washed with water and evaporated. The residue is treated with acetone and fumarate is produced as fumaric acid in acetone and precipitated in this solution.

Yield: 90% (20.8 g)

Melting Point (Fumarate): 205-206 ℃

Example 20

[[3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-[4- (3,4-dihydro-4 , 4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl-butyl] -amine]

In a similar manner to Example 23, it is prepared from 9.5 g of 4,4-dimethyl-isochroman-dione-1,3 and 3.1 g of 4- (3-amino-propylamino) -butylamine.

Yield: 79% (9.6 g)

Melting Point (Fumarate): 90-95 ℃

Example 21

[Bis- [2- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl-ethyl] -amine]

In a similar manner to Example 23, it was prepared from 9.5 g of 4,4-dimethyl-isochroman-dione-1,3 and 2.1 g of bis- (2-amino-ethyl) -amine.

Yield: 80% (9 g)

Melting Point (Fumarate): 207-208 ℃

Example 22

[Bis- [2- (3,4-dihydro-4-methyl-4-ethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -amine]

In a similar manner to Example 19, it is prepared from 3.9 g of 4-methyl-4-ethyl-isochroman-dione-1,3 and 0.79 g of bis- (2-aminoethyl) -amine. Hydrochloride is produced with etheric hydrochloric acid and precipitated in acetone.

Yield: 35% (1.7 g)

Melting Point (Hylori): Above 260 ℃

analysis :

Calculated Value: C, 65.67 H, 6.69 N, 8.20 Cl, 6.92

Found: C, 65.20 H, 6.60 N, 7.95 Cl, 6.78

5.8 g of [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro -4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -ammonium-fumarate was dissolved in 100 ml of dimethylformamide and 2.8 g of potassium carbonate and 1.85 g of 2- Mix with phenyl-ethyl bromide and heat reflux for 4 hours. Distilled dimethylformamide, extracted with chloroform and purified by silica gel (eluent: chloroform / acetone = 19: 1). Obtain a colorless oil.

Yield: 55% (3.1 g)

analysis :

Calculated Value: C, 74.31 H, 6.95 N, 7.43

Found: C, 74.10 H, 7.06 N, 7.41

Example 23

[[3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-[4- (3,4-dihydro-4 , 4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -2-butyl] -amine]

4.9 g of [4- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -2-butyl]-(3-aminopropyl) -amine (Methyl- [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -ketone and 1,3-diamino-propane Prepared by reduction in the presence of palladium / charcoal) is heated to 160 ° C. for 2 hours with 5.2 g of 4,4-dimethyl-isochroman-dione-1,3. The product was purified by column chromatography on silica gel (eluant: initially pure chloroform, then gradually increasing the amount of acetone until the chloroform / acetone ratio reached 9: 1). Fumarate is precipitated in the same manner as described in Example 23.

Yield: 18% (1.7 g)

Melting Point (Fumarate): 231 ~ 232 ℃

Example 24

[Bis- [3- (2,4-Dihydro-4,4-dimethyl-7-isopropyloxy-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

4.32 g of 4,4-dimethyl-7-isopropyloxy-isochroman-dione-1,3 and 0.66 g of bis- (3-amino-propyl) -amine were prepared using a device equipped with a water separation panel. Boil in 100 ml of toluene for 1 hour. Toluene is evaporated and the residue is purified by silica gel (eluent: chloroform / ethanol = 19: 1). Fumarate is obtained in the same manner as described in Example 19.

Yield: 11% (1.2 g)

Melting Point (Fumarate): 171-173 ° C

Example 25

[Bis- [3- (3,4-Dihydro-4,4-dimethyl-7-bromo-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

In a similar manner to Example 24, it is prepared from 4.02 g of 4,4-dimethyl-7-bromo-isochroman-dione-1,3 and 0.66 g of bis- (3-aminopropyl) -amine.

Yield: 4.5% (0.5 g)

Melting Point (Fumarate): 214-216 ℃

Example 26

[Bis- [3- (3,4-dihydro-4,4-dimethyl-7-fluoro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

Prepared in a similar manner to Example 24 from 1.8 g of 4,4-dimethyl-7-fluoro-isochroman-1,3-dione and 0.38 g of bis- (3-aminopropyl) -amine.

Yield: 5.8% (0.31 g)

Melting Point (Fumarate): 234 ~ 236 ℃

Example 27

[Bis- [3- (3,4-dihydro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] amine]

In a similar manner to Example 30, it is prepared from 2.44 g of isochroman-1,3-dione and bis- (3-amino-propyl) -amine. Hydrochloride is precipitated in acetone with etheric hydrochloric acid.

Yield: 2.5% (0.17 g)

Melting Point (HCl): 135-140 ℃

Example 28

[Bis- [3- (3,4-Dihydro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine]

In a similar manner to Example 24, it is prepared from 15 g of isochroman-1,3-dione and bis- (3-aminopropyl) -methylamine. Hydrochloride is precipitated in acetone with etheric hydrochloric acid and recrystallized from ethanol.

Yield: 32% (13.8 g)

Melting point (hydrochloride): 202 to 205 ° C

Example 29

[[3- (3, 4-Dihydro-4, 4-dimethyl-7-methylthio-1, 3-dioxo-2 (1H) -isoquinolyl) propyl]-[3- (3,4- Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

3.03 g of [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-(3- according to the method of example 23; 2.36 g of 4,4-dimethyl-7-methylthio-isochroman-dione-1,3 with amino-propyl) -amine. Hydrochloride is precipitated in acetone with etheric hydrochloric acid.

Yield: 8.1% (6.45 g)

Melting point (hydrochloride): 116 ℃ (from 74 ℃ semi-melting)

Example 30

[[3- (3,4-Dihydro-4,4-dimethyl-7-hydroxy-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl]-[3- (3,4 -Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine]

2.4 g of ethyl-2,2-dimethyl-2- (2-carboxy-4-hydroxyphenyl) -acetate and 3 g of [3- (3,4-dihydro-4,4-dimethyl-1,3- Dioxo-2 (1H) -isoquinolyl) -propyl- (3-amino-propyl) -methylamine is heated to 160 ° C. for 1.75 h in 20 ml of ethylene glycol. Ice water is added and the mixture is extracted with chloroform. After evaporation, the residue is purified by silica gel (eluent: chloroform / ethanol = 19: 1) and the hydrochloride is precipitated in acetone with etheric hydrochloric acid.

Yield: 64% (3.4 g)

Melting Point: 107 ℃ (Reaction from 69 ℃)

Example 31

[Bis- [3- (3,4-Dihydro-4-methyl-4-benzyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

In a similar manner as in Example 19, 4 g of 4-methyl-4-benzyl-isochroman-dione-1,3 and 0.79 g of bis- (3-aminopropyl) -amine were prepared.

Yield: 38% (2.1 g)

Melting Point (Fumarate): 170-172 ℃

Example 32

[Bis- [3- (3,4-Dihydro-4-methyl-4n-butyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

In a similar manner to Example 19, it is prepared from 2.75 g of 4-methyl-4-n-butyl-isochroman-dione-1,3 and 0.62 g of bis- (3-aminopropyl) -amine.

Yield: 25 (1 g)

Melting Point (Fumarate): 141 ~ 143 ℃

Example 33

[[3- (3,4-Dihydro-4,4,6-trimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-[3- (3,4-dihydro -4,4-Dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

3.03 g of 3- (3,4-dihydro-4,4-dimethyl-1,3 and dioxo-2 (1H) -isoquinolyl) -propyl] -3 (aminopropyl) in a similar manner to Example 19 ) And 2.04 g of 4,4,6-trimethyl-isochroman-dione-1,3.

Yield: 5.7% (0.3 g)

Melting point (hydrochloride): 203 ° C (half-melt from 145 ° C)

Example 34

[[3- (3,4-Dihydro-4-methyl-4- (4-methoxy-benzyl) -1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-[3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) propyl] -amine]

2.4 g of 4-methyl-4- (4-methoxy-benzyl) -isochroman-dione-1,3 (methyl 2-methyl-2- (2-methoxycarbonyl-phenyl) -3- (4 -Methoxy-phenyl) -propionate prepared by alkaline saponification followed by dehydration) and 3 g of [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) ) -Isoquinolyl) -propyl]-(3-amino-propyl) -amine was dissolved in 50 ml of methylene chloride and mixed. After standing at room temperature for 0.5 hours, the solvent is evaporated and the remaining amide is closed by heating to 180 ° C. for 0.75 hours. Fumarate is precipitated with acetone.

Yield: 39% (2.2 g)

Melting Point (Fumarate): 144 ℃ (Decomposition)

Example 35

[[3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -2-propyl]-[3- (3, 4-dihydro -4,4-dimethyl-1,3-dioxo-2 (1H-isoquinolyl) -propyl] -amine]

In a similar manner as in Example 23, [3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -2-propyl]-(3-amino -Propyl) -amine and 4,4-dimethyl | isochromen-dione-1,3.

Melting Point (Fumarate): 168 to 169 ℃

Example 36

[[3- (3,4-Dihydro-4-methyl-4- (3-phenylpropyl) -1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-[3- (4 , 4-dimethyl-1,3-dioxo-3,4-dihydro-2 (1H) -isoquinolyl) -propyl] -amine]

In a similar manner to Example 34, 3 g of 4-methyl-4- (3-phenyl-propyl) -isochroman-dione-1,3 and 3.1 g of [3- (3,4-dihydro-4,4 -Dimethyl-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl]-(3-aminopropyl) -amine.

Yield: 52% (3.7 g)

Melting Point (Fumarate): 158-163 ℃

Example 37

[Bis- [3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

0.2 g of 2,4,4-trimethyl-1,2,3,4-tetrahydro-isoquinoline-dione-1,3 was substituted with 0.3 g of [3- (3,4-dihydro-4,4-dimethyl -1, 3-dioxo-2 (1H) -isoquinolyl) -propyl]-(3-amino-propyl) -amine was heated to 160 ° C. for 4 hours and the reaction mixture was purified by silica gel column. (Eluent: chloroform / methanol = 9: 1). Hydrochloride is precipitated in methanol with etheric hydrochloric acid.

Yield: 29% (0.15 g)

Melting Point (HCl): 170 to 172 ℃

Example 38

[Bis- [3- (1,2,3,4-tetrahydro-1,3-dioxo-isoquinolin-4-spirocyclopentan-2-yl) -propyl] -methylamine]

In a similar manner to Example 34, 0.85 g of isochroman-4-spirocyclopentane-dione-1,3 and 0.24 g of bis- (3-amino-propyl) -methylamine are prepared.

Yield: 2.9% (0.07 g)

Melting Point (HCl): 127-132 ℃

Example 39

[[2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro-4 , 4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-(2-phenylethyl) -amine]

5.8 g of [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro -4,4-Dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -ammonium-fumarate was dissolved in 100 ml of dimethylformamide and 2.8 g of calcium carbonate and 1.85 g of 2- Mix with phenyl-ethyl bromide and reflux for 4 hours. After evaporating dimethylformamide, water is added and the mixture is extracted with chloroform, extracted and purified by silica gel (eluant: chloroform / acetone = 19: 1). Obtains a colorless oily substance.

Yield: 55% (3.1 g)

Calculated Value: C, 74.31 H, 6.95 N, 7.43

Found: C, 74.10 H, 7.06 N, 7.41

Example 40

[Bis- [3- (3,4-dihydro-4,4-diethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine]

2.35 g bis- [3- (3,4-dihydro-1,3-dioxo-2 (1H) -isoquinolyl-propyl] -methylamine-hydrochloride and 5.42 g ethyl iodide in 100 ml ethanol Heat and reflux and add 1.08 g of sodium hydroxide solution dissolved in 10 ml of water dropwise, stir the mixture further at 60 ° C for 1.5 hours, evaporate the solvent and add water, extract the mixture with ethyl acetate. After purification by column (eluent: chloroform / ethanol = 19: 1) hydrochloride is precipitated in acetone with etheric hydrochloric acid.

Yield: 5.8% (0.17 g)

Melting point (hydrochloride): 135 to 140 ° C (reaction state from 70 ° C)

Example 41

[[3- (3,4-Dihydro-4,4-dimethyl-7-ethoxy-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-[3- (3,4 -Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine]

1.3 g of [3- (3,4-Dihydro-4,4-dimethyl-7-hydroxy-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-[3- (3 , 4-dihydro-4,4-dimethyl-1,3-2 (1H) -isoquinolyl) -propyl] -methylamine was dissolved in 10 ml of anhydrous ethanol and added to 0.06 g of sodium solution dissolved in 10 ml of anhydrous ethanol. Mix with 0.42 g ethyl iodide. The mixture is refluxed for 0.5 h, the same amount of ethyl iodide is added and refluxed again for 0.5 h. The product is purified by silica gel column (eluent: chloroform / ethanol = 25: 1) and the hydrochloride is precipitated in acetone with etheric hydrochloric acid.

Yield: 35% (0.5 g)

Melting point (hydrochloride): 45 ℃ or more

Example 42

[Bis- [3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -n-hexyl-amine]

2.6 g bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine in a similar manner to Example 39 And 1 g of n-hexylbromide.

Yield: 50% (1.7 g)

Melting Point (Fumarate): 137 to 138 ° C

Example 43

[Bis- [3- (1,2,3,4-tetrahydro-1,3-dioxo-isoquinolyl-4-spirocyclohexan-2-yl) -propyl] -methylamine]

In a similar manner to Example 40, 3.6 g of bis- [3- (3,4-dihydro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine and 4.0 g of 1 , 5-dibromopentane.

Yield: 2.6% (0.12 g)

Melting point (hydrochloride): 183 to 185 ° C

Example 44

[Bis- [3- (3,4-Dihydro-4-isopropyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine]

In a similar manner to Example 40, 4.7 g of bis- [3- (3,4-dihydro-1,3-dioxo-2 (1H) -isoquinolyl-propyl] -methylamine and 3.05 g of isopropyl Prepared from bromide.

Yield: 2.2% (0.12 g)

Melting point (hydrochloride): 204-206 degreeC

Example 45

[Bis- [3- (1,2,3,4-tetrahydro-1,3-dioxo-isoquinolin-4-spirocyclopropan-2-yl) -propyl] -methylamine]

In a similar manner to Example 35, 3.6 g of bis- [3- (3,4-dihydro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine and 3.3 g of 1 , 2-dibromoethane is prepared.

Yield: 3% (0.05 g)

Melting Point (HCl): 192 ~ 196 ℃

Example 46

[Bis- [3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-(3-phenylpropyl) -amine]

1.8 g of 3-phenyl-bromopropane and 0.96 g of sodium hydroxide solution dissolved in 20 ml of water were added in small portions at 2.56 g of bis- [3- (3,4-dihydro-4,4-dimethyl-1. To a hydrochloride solution of, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine. After 16 hours, the mixture was added to water, extracted with ethyl acetate, evaporated, and the residue was purified by silica gel. (Eluate: chloroform / ethanol = 19: 1) Hydrochloride is precipitated in ethyl acetate with etheric hydrochloric acid.

Yield: 4.2% (0.13 g)

Melting Point (HCl): 135 ℃

Example 47

[Bis- [3- (3,4-Dihydro-4,4-dimethyl-7-acetamino-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine]

3.25 g Bis- [3- (3,4-Dihydro-4,4-dimethyl-7-amino-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine-tri The hydride is suspended in 70 ml of acetic anhydride and stirred at room temperature for 2 hours. The mixture was added to ice, made ammonia, extracted with chloroform, evaporated, and the residue was purified by column chromatography using silica gel (eluant: chloroform / methanol = 9: 1).

Hydrochloride is precipitated in ethanol with etheric hydrochloric acid and recrystallized from isopropanol.

Yield: 54% (1.8 g)

Melting Point (HCl): 175 ℃

Example 48

[Bis- [3- (3,4-Dihydro-4,4-dimethyl-7-amino-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine]

5.3 g bis- [3- (3,4-dihydro-4,4-dimethyl-7-nitro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylammonium-knight Dissolve the rate in 100 ml of methanol, add 10 ml of methanolic hydrochloric acid and 0.6 g of 10% palladium / charcoal and reduce the mixture at 5 atmospheres of hydrogen pressure and room temperature. The catalyst is suction filtered, the solvent is removed and the residue is treated with water. The solution is extracted with methylene chloride, ammonia and extracted with methylene chloride again. The methylene chloride layer is evaporated, the residue is dissolved in ethanol and the trichloride is precipitated with etheric hydrochloric acid.

Yield: 63% (3.25 g)

Melting Point (Trihydrochloride): 225 ℃

Example 49

[Bis- [3- (3,4-Dihydro-4,4-dimethyl-7-nitro-2 (1H) -isoquinolyl) -propyl] -methylamine]

50 g fuming 5 g of bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylammonium-fumarate Add nitric acid at -20 to -30 ℃ and stir at -25 ℃ for 40 minutes. The solution is added to ice and the precipitated nitrate is suction filtered.

Yield: 100% (5.3 g)

Melting Point (Nitrate): 135 ℃

Example 50

[Bis- [3- (3,4-Dihydro-4,4-dimethyl-7-nitro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

10 g bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine in a similar manner to Example 53 It is prepared from hydrochloride.

Yield: 83% (10.2 g)

Melting Point (Nitrate): 197 ℃

Example 51

[Bis- [3- (3,4-Dihydro-4,4-dimethyl-7-amino-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine]

Bis- [3- (3,4-Dihydro-4,4-dimethyl-7-nitro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-in a similar manner to Example 48 Prepared from ammonium-nitrate.

Yield: 41% (1 g) (monohydrochloride)

Melting Point (monohydrochloride): 300 ℃ or higher (reaction state from 285 ℃)

Example 52

[Bis- [3- (3,4-Dihydro-4,4, -dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -benzylamine]

5.12 g bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine in a similar manner to Example 46 Hydrochloride and 1.75 g of benzyl bromadi are prepared using the base sodium epoxide.

Yield: 65% (3.7 g)

Melting Point: 108 ℃

Claims (1)

Reacting a homophthalic acid derivative of the following structural formula (II) or a corresponding homophthalic acid derivative of the following structural formula (IIa) with an amine of the following structural formula (III) and optionally at least one of the R ₅ -R ₉ groups is hydrogen or R ₁ Alkylation of a product wherein at least one of -R ₄ is a hydroxy group to form the corresponding alkylated compound or nitration of a product wherein at least one of R ₁ -R ₄ is hydrogen and then reduction of the initro compound to the corresponding amino compound A process for the preparation of a compound of formula (I) and acid addition salts thereof, characterized in that for converting to and acetylating this amino compound to convert it to the corresponding acetylamino compound.

In the above structural formula A and B is a straight chain saturated alkylene group having 2 to 4 carbon atoms optionally substituted with methyl or phenyl group and may be the same or different from each other, R ₁ , R ₂ , R ₃ and R ₄ are hydrogen, fluorine, chlorine Or bromine, hydroxy, amino, nitro or acetyl amino group, alkyl, alkoxy or alkylthio group having 1 to 3 carbon atoms, which may be the same or different and R ₅ , R ₆ , R ₇ and R ₈ are hydrogen, optionally phenyl or is an alkyl group having 1 to 4 carbon atoms substituted with methoxy perspective phenyl, be the same or different from one another and R ₅ together with R _6, R ₇ is R ₈ and with 2 to 5 carbon atoms of straight-chain saturated alkylene, and R ₉ is hydrogen Or alkyl having 1 to 6 carbon atoms optionally substituted with phenyl, W is an oxygen or amino group, X is a halogen, hydroxy or alkoxy group and Y is an amino or the following structural group.