KR800001703B1 - Manufacturing Method of Homophthalimides - Google Patents

Abstract

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Description

Manufacturing Method of Homophthalimides

The present invention relates to the following formula (I) compound 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, nitropo is acetylamino, 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 having 1 to 4 carbon atoms optionally substituted with hydrogen, phenyl or methoxyphenyl group and may be the same or different and R ₅ together with R ₆ , R ₇ together with R ₈ A straight chain saturated alkylene group having 2 to 5 carbon atoms,

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, insoluble or bromine, methyl, methoxy, ethoxy, isopropoxy methyl Compounds which are thio, 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 phenylpropyl groups Phosphorus compounds and compounds wherein 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-ethylene And R ₉ are hydrogen, methyl ethyl, propyl, isopropyl, butyl, n-hexyl, benzyl, phenylethyl or phenylpropyl groups .

Structural Formula (I) compounds and their acid salts have pharmaceutical activity, particularly arrhythmia treatment.

A new compound of formula (I) is prepared by reacting a carbonyl compound of formula (II) in the presence of a reducing agent 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

D is a saturated alkylene group having 1 to 3 carbon atoms optionally substituted with a methyl group.

R ₁₀ is hydrogen, methyl or phenyl group

R ₉ is the same as above

E is hydrogen or a group of the following structural formula.

From here

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

This reaction, including reduction, proceeds at a temperature of 0 to 100 ° C. but preferably at a temperature of 40 to 80 ° C. in the presence of a solvent such as ethanol, methanol / ammonia, ethanol, ethyl acetate or dioxane. The reduction is carried out as hydrogen, for example in the presence of palladium / charcoal at a hydrogen pressure of 5 atmospheres, in the presence of a hydrogenation catalyst such as hydrogen or a metal hydride complex salt such as naphtha brohydride.

A compound of formula (I) wherein at least one of the groups R ₅ -R ₉ is hydrogen or RR ₄ is a hydroxy group can be converted according to the invention to a compound of formula (I) which is alkylated by alkylation. Obtaining a compound of formula (I) wherein at least one of R ₁ -R ₄ is hydrogen can convert this compound to a nitro compound of structure (I) by nitration, and the nitrated compound is converted to an amino compound by reduction. And then acetylated to convert to the corresponding acetylamino amino compound.

The alkylation is preferably carried out with the corresponding alkyl halide or dialkylsulfate and in a solvent such as ethanol, dimethylformamide, dimethylsulfoxide or hexamethyl-phosphate triamide, calcium carbonate, sodium hydroxide, sodium ethoxide or potassium 3 Presence of a base such as a but-butoxide is preferred and the temperature is from 20 to 200 ° C. but the preferred temperature is from 60 to 160 ° C.

The methylated compound 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.

The 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 structural formula (I) compound and its acid salts have a pharmaceutically effective action, in particular arrhythmia.

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) -propyne] -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-1,34-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine,

E = [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl]-[3- (3,4-ethyldihydro-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- (8,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -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,

1.Isolation of Mormort on the Effective Incompatibility of the Electrically Stimulated Left Heart 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 at 37 ° C. Cut the seam and use only the left seam. Electrical stimulation is carried out with a glass stimulator S4G, with a spherical shape for 10 ^-3 seconds and a stimulus of 12V. Shim 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 on a glass-plygraph (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 stimulation 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 the drug is added. Drugs are tested at increasing concentrations to create a dose-response curve to calculate EC ₅₀ .

[principle]

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

[result]

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

2. Effect of Arrhythmia on Chloroform-Induced Ventricular Fibrillation in Rats

[Way]

After placing the rat in a saturated area with chloroform gas, the rat is anesthetized 40 seconds later, and the respiratory system stops, and again, gasping 20 seconds later. When breathing is completely suppressed, the rat is removed from the presence of chloroform gas, incised to the chest, and quickly struck the heart to investigate 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. Doses that reduce the number of animals with ventricular fibrillation by 50% are calculated as dose-response-curve and estimate standard error. [Reference: Miller. L. C. and Tainter, M. L., ProC. Soc. Exp. Biol. Med. 57, 261 (1944)]

Experiments use 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

Acute toxicity of the compound in question can be determined using oral or intravenous mice. (Observation time: 14 days)

LD ₅₀ is calculated from the mortality rate after administration of several doses within the observation time. (See J. Pharmacol. ExP. Therap. 96, 99 (1949)).

Therefore, the compound of formula (I) according to the present invention and its pharmaceutical non-toxic salts are particularly suitable for the treatment of arrhythmias of the heart, and the pharmaceutical administration is a conventional pharmaceutical preparations such as tablets, coated tablets, suspensions, suppositories, or stabilizers. It can be made into a formulation prepared by mixing arbitrarily. The single dose for adults is 25-50 mg.

The following examples detail the invention.

Example 1

[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

a) 4.4-dimethyl-2- (4-aminobutyl) -1,2,3,4-tetrahydro-isoquinoline-1,3-dione

2.56 g of 4,4-dimethyl-2- (3-cyano-propyl) -1,2,3,4-tetrahydro-isoquinoline-1,3-dione (4,4-dimethyl-1,2, Prepared from 3,4-tetrahydro-isoquinoline-1,3-dione and 4-chlorobutyl acid nitrile) was dissolved 50 ml of methane in a solution of ammonia and 1 g of Raney-Nickel at 50 ° C and 5 atmospheres. , Reduce for 2 hours.

The reaction mixture is diluted with water, acidified and extracted with chloroform. The aqueous layer is alkaline, extracted with chloroform and the chloroform layer is evaporated. The residue is used in the next reaction without purification.

b) [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

1.5 g of 4,4-dimethyl-2- (4-aminobutyl-1,2,3,4-tetrahydro-isoquinoline-1,3-dione and 1.35 g: 81 to 82 ° C. 4,4-dimethyl -1,2,3,4-tetrahydro-isoquinoline-1,3-dione and chloroacetaldehyde-diethylacetal were prepared by acidic soaping in 100 ml of ethanol and 10 at 50 ° C and 5 atmospheres. Hydrogenate in the presence of 0.3 g of 10% palladium / charcoal over time.

The product is purified by column chromatography on silica gel (eluent: chloroform / acetone = 19: 1) and converted to fumarate. Yield: 41% (1.4 g)

Melting Point (Fumarate): 181 to 182 ° C

Example 2

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

5.2 g of methyl- [2- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1A) -isoquinolyl) -ethyl] -ketone with 100 ml of methanol and 5 Hydrogenated with ml of methanolic ammonia in the presence of palladium / charcoal for 5 hours at 70 캜 and 5 atmospheres. The product was purified by silica gel (eluent: chloroform first, then gradually increasing the amount of acetone until the ratio of chloroform / acetone reached 19: 1). Fumarate is precipitated with acetone.

Yield: 18% (11 g)

Melting Point (Fumarate): 188 to 189 ° C

Example 3

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

0.7 g of 1,2,3,4-tetrahydro-4,4-dimethyl-2- (2-amino-2-phenyl-ethyl) -isoquinoline-dione-1,3 in a similar manner to Example 1b) And 0.6 g of 3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propionaldehyde. The product is a colorless oily substance. Yield: 22% (0.3 g)

analysis :

Calculated Value: C 73.71, H 6.55, N 7.82

Found: C 72.90, H 6.94, N 7.61

The following compounds were prepared according to the methods of Examples 1 to 3.

[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

Melting Point (HCl): 116 ℃

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

Melting point (fumarate): 141 to 143 ° C

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

Melting Point: 156 to 158 ° C

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

Melting point (hydrochloride): 170 to 172 ° C

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

Melting Point (Fumarate): 141 to 142 ° C

[2- (3,4-Dihydro-7-ethoxy-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

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 ℃

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

Melting Point: 106 to 107 ° C

[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 (Fumarate): 205 to 206 ° C

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

Melting Point (Fumarate): 90-95 ° C

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

Melting Point (Fumarate): 207 to 203 ° C

Example 4

[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 potassium carbonate and 1.85 g of 2 Mix with petyl-ethylbromide and reflux for 4 hours. After evaporating dimethylformamide, nfdm is added, the mixture is extracted with chloroform and purified by silica gel. (Gluent: chloroform / acetone = 19: 1) A colorless oily substance is obtained.

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 5

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

100 ml of 2.35 g of bis- [3- (3,4-dihydro-1,3-dioxo-2 (1H) -isozonolyl) -propyl] -methylamine-hydrochloride and 5.42 g of ethyl iodide Heat reflux in ethanol and add 1.08 g of sodium hydroxide solution in 10 ml of water. The mixture was stirred at 60 ° C. for 1.5 hours more, the solvent was then evaporated off and water was added. The mixture is extracted with ethyl acetate. After silica gel was purified by a packed column (eluant: chloroform / ethanol = 19: 1), hydrochloride was 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 6

[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]-0.06 g sodium dissolved in 10 ml anhydrous ethanol by dissolving methylamine in 10 ml anhydrous ethanol Add to solution and 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 hydrochloride is precipitated in acetone with etheric hydrochloric acid.

Yield: 35% (0.5 g)

Freezing point (hydrochloride): 45 ℃ or more

Example 7

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 4 And 1 g of n-hexylbromide.

Yield: 50% (1.7 g)

Melting Point (Fumarate): 137 to 138 ° C

Example 8

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

In a manner similar to Example 5, 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 9

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

4.7 g bis- [3-3,4-dihydro-1,3-dioxo-2 (1H) -isoquinolyl-propyl] -methylamine and 3.05 g isopropyl bromide in a similar manner to Example 5 Is prepared from.

Yield: 2.2% (0.12 g)

Melting point (hydrochloride): 204-206 degreeC

Example 10

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

3.6 g of bis- [3- (3,4-dihydro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine in a similar manner to Example 5 2-dibromoethane is prepared.

Yield: 1.3% (0.05 g)

Melting point (hydrochloride): 192 to 196 ° C

Example 11

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 70 캜 to 2.56 bis- [3- (3,4-dihydro-4,4-dimethyl-1, Hydrochloric acid solution of 3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine is added. After 16 hours, the mixed solution was added to water, extracted with ethyl acetate and evaporated. The obtained 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 12

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

3.25 g of 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 teloform, evaporated, and the residue was purified by column chromatography using silica gel (eluent: chloroform / methanol = 9: 1).

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

Yield: 54% (1.8 g)

Melting Point (HCl): 175 ℃

Example 13

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

5.3 g of bis- [3- (3,4-dihydro-4,4-dimethyl-7-nitro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylammonium-knight The rate is dissolved in 100 ml of methanol, 10 ml of methanolic hydrochloric acid and 0.6 g of 10% palladium / charcoal are added, and the mixture is reduced 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 and ammonia is extracted again with methylene chloride. The methylene chloride layer is evaporated and the residue is taken up in ethanol and the trichloride is precipitated with etheric hydrochloric acid.

Yield: 63% (3.25 g)

Melting Point (Trihydrochloride): 225 ℃

Example 14

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

50 g of 5 g of bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylammonium-fumarate Add fuming nitric acid at -20 to -30 ℃ and stir at -25 ℃ for 40 minutes.

The solution is added and the precipitated nitrate is suction filtered.

Yield: 100% (5.3 g)

Melting Point (Nitrate): 135 ℃

Example 15

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

10 g of bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine in a similar manner to Example 14 It is prepared from hydrochloride.

Yield: 83% (10.2 g)

Melting Point (Nitrate): 197 ℃

Example 16

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 13 Prepared from -ammonium-nitrate.

Yield: 41% (1 g) (hydrochloride)

Melting point (hydrochloride): 300 ℃ or higher (reaction state from 285 ℃)

Example 17

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

5.12 g of bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine in a similar manner to Example 11 Hydrochloride and 1.7 g of benzyl bromide are prepared using sodium ethoxide as the base.

Yield: 65% (3.7 g)

Melting Point: 108 ℃

Claims (1)

Following structural formula Ⅱ) carbonyl a carbonyl compound characterized by then reacting the amine and a reducing agent under the presence of the structural formula (Ⅲ) and if necessary at least one R ₅ -R ₉ wherein at least one of hydrogen, or R ₁ -R ₄ in the group of Alkylating the product of which is a hydroxy group to form the corresponding alkylated compound, or nitrating the product wherein at least one of R ₁ -R ₄ is hydrogen, and then reducing the nitro compound to convert to the corresponding amino compound A process for preparing a compound of formula (I) and acid addition salts thereof by acetylating an amino compound to convert it into a corresponding acetylamino compound.

Wherein A and B are straight chain saturated alkylene groups of 2 to 4 carbon atoms, optionally substituted with methyl or phenyl groups, and may be the same or different, and R ₁ , R ₂ , R ₃ and R ₄ are hydrogen, fluorine, Chlorine or bromine, hydroxy, amino, nitro or acetylamino 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 substituted with phenyl or methoxyphenyl, alkyl having 1 to 4 carbons, which may be the same or different, R ₅ together with R ₆ , R ₇ together with R ₈ straight-chain saturated alkylene having 2 to 5 carbons, R ₉ is hydrogen or alkyl having 1 to 6 carbon atoms optionally substituted with phenyl, D is straight-chain saturated alkylene having 1 to 3 carbon atoms optionally substituted with methyl group, R ₁₀ is hydrogen, methyl or phenyl group, E is hydrogen Or a group of the following structural formulas.