JPS5942369A - Isoquinoline derivative, manufacture and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention This invention relates to novel 4-aryl-2-methyl-1,2
, 3,4-tetrahydro-isoquinoline derivatives, methods for producing the derivatives, and pharmaceuticals containing the derivatives.

(Prior Art) From saturated or unsaturated aliphatic carbanoic acids containing up to 6 carbon atoms, aromatic carbanoic acids, or aromatic-aliphatic carbenoic acids containing from 7 to 10 carbon atoms 8-amino-4-aryl-2-alkyl-tetrahydro-isoquinoline derivatives substituted with diamino radicals by derivatized acyl groups are described in GB 1 164 192. This compound has central nervous system stimulating effects and tymoleptic eff.
ect). Compounds with a similar structure are described in DE 1670848 and DE1795829.

(Structure of the Invention) According to the present invention, the following general formula (1) % formula % (wherein R represents hydrogen, a lower alkyl group or halodane, and X represents the following general formula, -(CI (2) n-NRR, -NH
-R3 or -OR' (wherein R1 and R2 are the same or different and represent hydrogen or a lower alkyl group, or ul and R2 together with the adjacent nitrogen atom to which they are bonded) taken together to form a 5- or 6-membered saturated heterocycle, where the heterocycle is optionally further substituted with an oxygen or sulfur atom, or optionally with a lower alkyl group; may contain some imino groups); n is 1, 2.3 or 4
is an integer; R3 represents a lower alkyl group or an optionally substituted phenyl group; and R4
represents a lower alkyl group, a halodanated lower alkyl group, or a phenyl lower alkyl group;
, 3,4-tetrahydro-isoquinoline derivatives, and pharmaceutically acceptable acid addition salts thereof.

A preferred subgroup of compounds represented by general formula (I) includes the following general formula (IA), HN-Co-(CH2)n-NR'R2 (wherein R, R
1, R2 and n have the meanings given above.

Preferred representative examples of formula (IA) include 8-(
ethylamino-acetylamino)-4-(p-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline, 8-(n-butylamino-acetylamino)-4-(p-chlorophenyl) -2-methyl-1
, 2,3,4-tetrahydro-isoquinoline, 8-(ethylamino-acetylamino)-4-(p-tolyl)-
2-Methyl-1,2,3,4-tetrahydro-isoquinoline and 8-(n-butylamino-acetylamino)-
Mention may be made of 4-(p-tolyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline, as well as their pharmaceutically acceptable acid addition salts.

Other subgroups fK of the compound represented by the general formula (1) include compounds represented by the following general formula (rB), in which R and R3 have the above-mentioned meanings.

A preferred representative example of the compound represented by the general formula (IB) is 8-(n-butyl-carbamoylamino)-4-
(p-chlorophenyl)-2-methyl-1,2,3,4
-tetrahydro-isoquinoline, and 8-(n-butyl-carbamoylamino)-4-(p-tolyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline. Mention may be made of addition salts.

Other subgroups of the compounds represented by the general formula (I) include the following general formula (IC): Contains compounds.

A preferred representative example of the compound represented by the general formula (IC) is 8-(ethoxylic water), diamino-4-(p-
Mention may be made of chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline and its pharmaceutically acceptable acid addition salts. This compound and its salts have particularly advantageous pharmaceutical properties.

In this specification, the term "lower alkyl group" refers to 1 to
means a straight-chain or branched G aliphatic group having 6, especially 1 to 4 carbon atoms, such as methyl, ethyl, n-
These include globyl group, inglovir group, 'n-butyl group, isodityl group, and the like. The term "heguran" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. R and R
However, the 5- or 6-membered saturated heterocycle formed together with the adjacent nitrogen atom to which they are bonded is, for example, a pyrrolidino group, a piperidino group, a morpholino group, a thiomorpholino group, a piperazino group or an N-substituted A hiherazino group (for example, an N-alkylpiperazino group or an N-benzylpiperazino group, such as an N-methyl bicylindrical group). n
is preferably 1 or 2. The substituent R is preferably attached to the para position of the phenyl ring.

R3 as an optionally di-substituted phenyl group is
There can be one or more identical or different substituents.

Pharmaceutically acceptable acid addition salts of compounds of general formula (1) can be formed with pharmaceutically acceptable inorganic or organic acids. These salts can be used with mineral acids (e.g. hydrogen chloride or hydrogen bromide, hydrogen halides, sulfuric acid,
phosphoric acid, etc.) or organic acids (for example, formic acid, acetic acid, !lobionic acid, lactic acid, maleic acid, tartaric acid, benzoic acid, salicylic acid, etc.).

According to the present invention, there is further provided a method for producing a compound represented by the general formula (I), which comprises: (,) In order to produce the compound represented by the general formula (IA), (II), HN-CO-(CH2)n-1
(1g (wherein R and n have the above-mentioned meanings and Hlg represents a halogen) or a compound thereof represented by the following general formula (6)%
or (b) producing a compound represented by the general formula (IB) above; (bl) The compound represented by the following general formula (It/), 2 (wherein, R has the above-mentioned meaning) is converted into the following general formula (V), R3-NC
O(V) (wherein R3 has the meaning given above) is reacted with an isocyanate; Alternatively, (c) to produce a compound represented by the above general formula (IC), (cl) a compound represented by the above general formula (IV),
The following general formula (■), Hl g -C0OR' (■) (in the formula H
1g represents a halogen, preferably chlorine or bromine, and R4 has the meaning given above; or (d.

(c2) cyclizing a compound represented by the following general formula (■) (wherein R and R4 have the meanings given above); and, if desired, converting the compound of formula (D) into a pharmaceutically acceptable It is characterized by converting it into salt.

In the method (,) of this invention, a compound of general formula Φ) or a salt thereof is reacted with an amine of general formula (2) or a salt thereof. This reaction is preferably carried out in an inert organic solvent. As reaction medium it is preferably possible to use aliphatic alcohols, especially methanol or ethanol. The reaction is carried out at an elevated temperature, preferably at the boiling point of the reaction mixture.

The starting materials of general formula (II) and @) can also be used in the form of their acid addition salts (eg hydrochlorides).

The reaction mixture can be worked up in a manner known per se. For example, the product can be separated by distilling off the solvent and extracting with an organic solvent.

The starting material of general formula (II) is the following general formula (XI), (
(wherein R has the meaning given above) can be prepared in two ways from compounds of the formula:

According to the first method, the compound of the general formula (X) is converted into a compound of the general formula (IV), which is converted into the compound of the general formula (X), Hlgl-(CH2)n-co- Hlg (X
) (wherein Hlg has the meaning given above and R1g'
represents a halide, preferably chlorine).

The cyclization of the compound of general formula (X[) is carried out in an inert organic solvent. Halodanated hydrocarbons (eg methylene chloride, chloroform, etc.) can be used as reaction media. The reaction can be carried out in the presence of an acidic catalyst. Mineral acids such as sulfuric acid, polyphosphoric acid or polyphosphoric esters can be used for this purpose. The reaction can be easily carried out at low temperatures, for example 0-5°C.

The compound of the general formula (It/) thus obtained and the general formula ■
The reaction of ω-8 with the ω-8-acid halide can be carried out in an inert organic solvent. Preference is given to using aromatic hydrocarbons (eg benzene, toluene, xylene, etc.) as reaction medium. The reaction can advantageously be carried out at elevated temperatures, preferably at the boiling point of the reaction mixture. The reaction is
It can be carried out in the presence of an acid binder (eg, a tertiary organic base such as trimethylamine, quinoline, etc.).

The compound of formula (II) can be separated from the reaction mixture by known methods (eg, filtration, crystallization, etc.).

The crude compound of 2ω) can be used directly without purification to prepare the compound of general formula (1).

According to another method, the starting material of general formula al) is obtained by reacting a compound of general formula (XI) with an ω-halodanoic acid halide of general formula IX), hereinafter referred to as loan (in the formula,
υ can be produced by cyclizing a compound represented by (R, Hlg and n have the above-mentioned meanings).

The reaction of the compounds of general formulas (XI) and (X) can be carried out by the general formula (
This reaction can be carried out in a manner similar to the reaction of compounds (2) and (X). This can be carried out in the same manner as for the cyclization of the compound of the general formula (DO) and the ring closure of the compound of the general formula (XI).

Compounds of general formulas (It/) and (XI) are already known (UK Patent No. 1,164,192) or can be produced by known methods.

In the method (bl) of this invention, the general formula (mV)
is reacted with an isocyanate of general formula (V). The reaction is carried out in an inert organic solvent.

Preference is given to using aromatic hydrocarbons (eg benzene, toluene, xylene, etc.) as reaction medium.

The reaction is preferably carried out with heat, preferably at the boiling point of the reaction mixture.

The reaction mixture can be worked up by methods known per se. For example, the solvent is evaporated and the residue is purified by chromatographic methods.

Starting materials of general formula (IV) can be prepared by cyclization of compounds of general formula (XI).

In the method (b2), the compound of general formula (■) is ring-closed. This cyclization is carried out in the presence of an acidic catalyst. For this purpose, mineral acids (for example sulfuric acid, polyphosphoric acid, etc.) or Lewis acids (for example boron trifluoride, aluminum chloride, zinc chloride, tin chloride, etc.) can be used. Sulfuric acid is a particularly preferred acidic catalyst. The reaction is carried out in an organic solvent, preferably a halodanated hydrocarbon (eg methylene chloride, chloroform, etc.). The reaction temperature depends on the activity of the catalyst.

When using sulfuric acid as a catalyst, low temperatures, e.g. 0-6°C
The reaction can be carried out quickly and easily.

The reaction mixture can be further worked up in a manner known per se. If sulfuric acid is used as a catalyst, the dispersible reaction mixture is ice-cooled, the reaction mixture is made basic, and the product is separated by extraction.

Halodanized hydrocarbons (eg chloroform) can advantageously be used as extractants.

Starting materials of general formula (Vl) can be prepared by reacting compounds of general formula (XI) with isocyanates of general formula (V). This reaction is the result of this invention (
It is carried out in the same manner as the method of bl).

In the method (cl) of the present invention, a compound of general formula (■) is reacted with an octoformate of general formula (■). Preference is given to using compounds of the general formula (■) in which Hlg is chlorine. The reaction is carried out in an inert organic solvent. Aromatic hydrocarbons (eg benzene, toluene, xylene, etc.) can advantageously be used as reaction medium. The reaction can advantageously be carried out at elevated temperatures, especially at the boiling point of the reaction mixture. The reaction can also be carried out without using a solvent. Preferably, the reaction is carried out in the presence of an acid binder such as a tertiary amine, such as triethylamine or quinoline.

The reaction mixture can be further worked up in a manner known per se. For example, the reaction mixture is evaporated, the residue is made basic (eg with ammonium hydroxide) and the target compound of general formula (1) is extracted with an organic solvent (eg chloroform).

The compound of general formula V) used as a starting material can be produced by cyclizing the compound of general formula (XI).

In the method (c2') of this invention, the general formula (■
) The cyclization is carried out using acidic catalysts, such as mineral acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, etc.) or Lewis acids (
For example, it can be carried out in the presence of aluminum chloride, boron trifluoride, zinc chloride, tin chloride, etc.). It can be carried out with particular advantage in the presence of sulfuric acid as catalyst.

The reaction is carried out in an inert organic solvent. Halodanated hydrocarbons (eg methylene chloride, chloroform, etc.) can be used as reaction media. The reaction temperature depends on the activity of the catalyst, and the reaction is generally carried out at 0 to 80°C.

The compound of general formula (1) can be separated by a method known per se. When using sulfuric acid as a catalyst, dilute the sulfuric acid solution with ice to make the reaction mixture basic;
Then, it is preferable to purify the compound of general formula (1) by extraction with an organic solvent (for example, chloroform).

The starting material of general formula (■) can be prepared by reacting a compound of general formula (X[) with a chlorohalo-noformate of general formula (■).

The reaction can be carried out in the same manner as in method (cl).

The compound of general formula (■) thus obtained is cyclized after separation or preferably without separation.

The compound of general formula (I) obtained as described above can be converted into an acid addition salt with a pharmaceutically acceptable acid. Formation of the salt can be carried out according to conventional methods. For example, it is preferred to react the compound of general formula (1) with the corresponding acid in a suitable inert organic solvent. Preferably, the acids are used in equimolar amounts. The compound of general formula (1) is liberated from the pharmaceutically unacceptable salt of the compound of general formula (1) using a strong base, and the compound of general formula (I
Pharmaceutically acceptable acid addition salts can also be prepared by reacting the free base of ) with the corresponding pharmaceutically acceptable acid.

The novel compounds of general formula (1) and their pharmaceutically acceptable acid addition salts have useful pharmacological properties and have particularly valuable central nervous system effects. The compounds of this invention are particularly useful as active ingredients in antidepressants and antiparkinson drugs.

The invention further provides a medicament comprising one or more compounds of general formula (1) or pharmaceutically acceptable salts thereof together with suitable inert pharmaceutical carriers and/or excipients.

The medicament of this invention can be formulated as a dosage form suitable for oral administration (e.g., tablet, capsule, pill, coated pill, sugar-coated agent, solution, emulsion, suspension) or parenterally (e.g., injection). can be converted into The drug may contain conventional inert solid or liquid carriers (e.g., talc, starch, magnesium stearate, magnesium carbonate, calcium carbonate, water, alcohol, yf?+):rf rangelicol, etc.). I can do it. Pharmaceuticals include commonly used pharmaceutical adjuvants (e.g. wetting agents, disintegrants, flavoring agents, flavor improvers, etc.)
can be made to contain.

The medicament of this invention can be manufactured by 1) methods known per se in the pharmaceutical industry.

(Effect of the invention) The pharmacological activity of the compound of this invention is measured as follows.

(Acute toxicity: After subcutaneous administration and 96-hour observation period,
Find the D50 value.

(2) Caterpillar induced by 13 micromol/kg of haloperidol! Subcutaneous doses that inhibit C. in mice at 50q6.

(3) The lowest intravenous dose that still increases or decreases locomotor activity in mice.

(4) A subcutaneous dose of 110 micromol/9 that inhibits tetrabenazine-induced catallegia in 50% of mice.

(5) 79 micromol/kg subcutaneous dose inhibiting tetrabenazine-induced ptosis in 50 mice.

(6) The lowest subcutaneous dose that still inhibits the decrease in rectal temperature induced by administration of 1.6 μmol/9 reserpine.

(7) The lowest intravenous dose that still increases collapse pressure and blinking in cats.

(8) The lowest subcutaneous dose that still induces permanent opening in rats.

(9) A dose that induces specific rotational behavior after producing an electrical lesion in the punctum.

0 in rats that had undergone ovariectomy 13 weeks prior.
．． The dose that induces a significant decrease in the levels of prolactin after 4 days of treatment with 0.073 micromoles/kg of oestradiol.

The following test compounds were used.

Compound A Product Compound of Example 4 Compound B Product Compound of Example 8 C Product Compound D of Example 10 Product Compound D of Example 11 Product Compound E of Example 17 Product Compound F of Example 18 Product Compound G of Example 13 H Product Compound Construction of Example 12 Product Nomifensin of Example 20 (Reference Compound) 8-Amino-4-phenyl-2-monomethyl-1,2,3,4-tetrahydro-isoquinoline (as described in British Patent No. 1164192) The test results are summarized in Table 1 below.

(43) Part 1 Acute density data are determined in mice.

Tests (2)-(6) are also performed in mice. Doses are expressed as micromoles/kllF. Treatment index TI
is expressed as the quotient of LD/ED.

In test (3) "+" indicates increased movement, "-"
indicates a decrease in movement. TBZ represents tetrabenazine.

Tests (7) to (10) were conducted on cats and rats,
Doses are given in micromoles/kg.

Test f2), (s), (91 and (10) are
Suitable for evaluating the dopamine stimulating effect of test compounds (anti-
(Possibility as a drug). Test (4), (
5), (6) and (power gives information on the catecholamine-uptake inhibitory effect (potential as an antidepressant).

The reference compound nomifensine is a well-known antiparkinsonian and antidepressant.

The new compounds of general formula (I) do not increase locomotor activity in mice. In contrast, nomifensine increases locomotor activity. The absence of the aforementioned amphetamine-like voluntary movement stimulating effects is advantageous from a therapeutic point of view.

Compound C outperforms nomifensine in three tests. Compound Rimo also shows higher activity than nomifensine in some tests and a more favorable therapeutic index in antireserpine tests. Compounds G and H exhibit very high activity and a good therapeutic index. Compound IH has remarkable therapeutic properties. Its toxicity is very low, and its activity is higher than that of nomifensine. That is, in various tests, the therapeutic index of the compound was about 2 to 6.8 higher than that of nomifensine.
It's double.

In comparing the dopamine-type anti-halo-4-ridol test and the anti-tetrabenazine activity specific to antidepressant effects, the following can be said.

The quotient of ED[ in column 2 and column 4 of compound engineering is the highest (55:
13=2.4). This means that this compound is a relatively more potent antidepressant compared to antiparkinsonian agents. This quotient is Nomifensine (1,6)
, compound D (1,8), compound E (2,7) and compound F (1,7).

On the other hand, this quotient is low in the case of compounds G and H, which have stronger anti-dominic and antiparkinsonian activities.

The invention will now be explained in more detail by way of example. However, this does not limit the scope of the invention.

5.3 g (0,015 mol) of 4-phenyl-8-(chloro-acetyl-amine)-2-methyl-1,2,3,
4-Tetrahydroisoquinoline-hydrochloride, 1
A mixture of 5 m/(10.4 g, 0.32% l) of ethylamine and 50 rnl of ethanol is reacted for 5 hours at 60° C. in a bomb tube. The reaction mixture was evaporated and the residual oil (7,19) k was triturated with 50 ml of water and then 47)
The mixture is made basic by adding 30 ml of 30% aqueous sodium hydroxide solution while stirring and cooling. This mixture is extracted 10 times with elooml portions of ether. The ether solution is dried over anhydrous sodium sulfate and evaporated. Triturate the oily residue with whole petroleum ether. Thus, 4.3g (0,013
3 mol) of crude 8-(ethylamino-acetyl-amino)
-4-7enyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline is obtained as a yellow-white powder.

The base '1 thus obtained is dissolved in 30 ml of ethanol and a solution of 1.6 g (0,238 mol) of maleic acid and 15 mA! of ethanol is added. The precipitated product 1+' is taken. Thus 5. 2 g of the title compound are obtained, melting point 169° C. Recrystallization from ethanol at 50 mA! gives 4.7 g (yield 71.2 g) of the pure title compound, melting point 170° C.

Analysis: C24H2, N304 (439,515) Direct calculation (9)): C=65.60 I (=6.65 N
=9.56 measurement [%): C=65.38 H=6.
74N = 9.62 (48) The melting point of 8-(ethylamino-acetylamino)-4-phenyl-2-methyl-1,2,3,4-tetrahydro-in quinoline base is 111 °C (benzene and petroleum ether). mixture).

Analysis: C2oH25N30 (323,439) calculated value part): C=74.27 H=7.79 N=12.
99 measurement value part): C=74.41 FI=7.97
The N=13.13 starting material is prepared as follows.

31.9 g (0.09 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline-maleate K dissolved in 200 ml of water (D, dissolved in 500 ml of ether) Gold is added and the mixture is made basic by adding 150 m/ml of 30% aqueous sodium hydroxide solution with cooling and stirring.The ether phase is separated and the aqueous layer is basified three more times.
Extract with 00 ml of ether. - The combined ether solution is dried over anhydrous sulfuric acid (IJ) and evaporated in vacuo (25° C./20 Torr). The yellow oily residue (22,5F) was dissolved in 600 mJ of anhydrous benzene and 7.6 ml (11,4 g 10.101
A solution of 1 mol) of chloroacetyl chloride and 49 ml of anhydrous sodium chloride is added dropwise with stirring. The reaction mixture is refluxed for 2 hours and cooled. The precipitated product is filtered off and washed three times with 60 ml portions of anhydrous benzene and three times with 70 ml portions of anhydrous ether.

32 g of white powder are obtained. Melting point 217°C (decomposed).

Recrystallized from 230 nrl of ethanol and 25.41
The target compound (yield: 81 cm) was obtained as a white powder. Melting point: 222°C (decomposition).

Analysis: C48H2oCt2N20 (M= 351.
278) Calculation (W@): C=61.54 a=s
, 74 N=7.97Cz=20.19Cz-=1
0.09 measured value): C=61.23 H=5.66
N=8.0OC1=20.41. Ct-=10.
The 17 starting material can also be prepared as follows.

3.12 g (0,012 mol) of N-(2-amino-benzyl)-1-phenyl-2-methylamino-1-ethanol were dissolved in 70 ml of anhydrous ether (49), followed by 0.95 g ( 0,012 mol) of anhydrous pyridine is added and this is followed by vigorous stirring and heating at 3-6°C.
1.62 g (0.0144 mol) of chloro-acetyl-chloride are added to the solution while cooling on ice.

The yellow-white reaction mixture containing the precipitate is stirred at room temperature for 30 minutes, poured into ice water at 100 mA' and extracted three times with 100 ml portions of ether. The ether solution is dried over anhydrous sodium sulfate for 30 minutes and evaporated in vacuo without heating. The crude N-chloroacetyl compound thus obtained is cyclized as it is.

The oily product obtained according to the previous section is dissolved in 30 ml of dichloromethane, filtered and poured into 20 ml of concentrated sulfuric acid. The reaction mixture is stirred at 0-3° C. for 15 minutes, after which stirring is continued for an additional 20 minutes.

Pour the reaction mixture onto ice and add 200 m
Extract 4 times with 1f chloroform. The organic phase is dried over all anhydrous sodium sulfate and evaporated in vacuo. Thus 3. An orange powder of OI is obtained. This product i
, 3 times with 3 Qd of ether (50). Thus, 2.3. A beige powder of p is obtained. 1 by recrystallization from ethanol
．． 6.9 (yield 42.4) of 4-phenyl-8-(chloro-acetyl-amine)-2-methyl-1,2,3,
4-Tetrahydro-isoquinoline is obtained as a white powder. Melting point: 240°C (decomposed).

Analysis: C48H4, CAN20 (N=314.81
7) Calculated value (%): C=68.67 H=6.0
8 N=8.90C1=11.26 Measured value): C=68.42 H=5.95 N=
8.96 Ct=11.12 1.5 g (0,00475 mol) of the above base are suspended in 5 d of ethanol, then 5 ml of ether saturated with hydrogen chloride are added under heating, and this solution is diluted by adding ether. cloudiness 9 occurs. The precipitated product is filtered under cooling. Thus, 1.59 (yield 38.
2%) of 4-phenyl-8-(chloroacetylamine)
-2-Methyl-1°2.3.4-tetrahydro-isoquinoline-hydrochloride is obtained as a white powder. Melting point 2
22°C (decomposition).

Produced 4.27 g (0,0122 mol) of 4-phenyl-8-
(chloro-acetyl-amino)-2-methyl-1,2,
3,4-Tetrahydro-isoquinoline-hydrochloride, 50ml ethanol and 15mlc10.4g, 0
．． A mixture of 176 mol) of isozolohylamine is heated to the boil for 5 hours. The reaction mixture was evaporated and a viscous residue (6.5 g)'t100 mA! of water and make the solution basic by adding 10 ml of 30% sodium hydroxide solution with stirring and cooling. 5 with ether of 200+++ At in the aqueous phase.
Extracted twice and the combined ether solutions were dried over anhydrous sodium sulfate and evaporated in vacuo. The yellow oily residue (4,4,!i') is dissolved in 5 omt of ethanol and a solution of 3.5.9 (0.03 mol) of maleic acid and 10 ml of ethanol is added with stirring.

The precipitated product was filtered with cooling, washed twice with 1 r) ml of ethanol to obtain C69 ft), and 4
Recrystallize from 5 ml of ethanol. Thus 5.3
g of simalate salt is obtained. Melting point: 170°C.

Dissolve the above simalate in 30 mA' water and
, add 100 ml of ether. The above solution is made basic by adding 30 ml of aqueous sodium hydroxide solution with stirring and cooling. The ether phase is separated and the aqueous phase is extracted twice with 100 ml of ether and twice with 5 Qm/! of ether.-
The combined ether extracts are dried over anhydrous sodium sulfate and the ether is evaporated in vacuo. In this way, 3.
15 g (9.35 mmol) of crude base are obtained. Melting point 89
℃. This crude base k was dissolved in 47 ml of ethanol,
and 1.19 (9.45 mmol) of maleic acid and 3
Add solution with 0 ml ether. White powder (4,
1 g) was obtained, and this was recrystallized from 40 ml of ethanol to obtain 3.45 g (yield: 62.6 g) of the title compound. Melting point: 134°C.

Analysis: C2, N3. N305 (N=453.543
) Calculated value ←): C=66.22 F(=6.89
N=9.29 Measured value (a): C=66.23 N=
7.03 N=9.33 free base forms yellow-white crystals from a mixture of benzene and petroleum ether. Melting point 9
1℃.

Analysis: C2, ■27N30 Calculated value (4): C=74.74 N=8.07
N=12.45 Measured value (a): C=74.6811=
8.21 N=12.493.5 g (0.01 mol) of 4-phenyl-8-(chloro-acetylamino)-
2-Methyl-1゜2.3.4-tetrahydro-isoquinoline-hydrochloride, 50 ml of ethanol and U 1
A mixture of 0 ml (7.3'l, 0.1 mol) of butylamine is refluxed for 5 hours. The reaction mixture is evaporated in vacuo and the residue is washed ten times with 5'□ ml portions of anhydrous ether. The ether washings are evaporated to dryness in vacuo, the remaining eloml is stirred with benzene and the benzene is evaporated, and this is repeated three times. Thus 3.3. !
17 yellow oil is obtained. This oil is dissolved in 30 ml of ethanol and a solution of 1.2 g (0.01 mol) of maleic acid and 1 Q ml of ethanol is added. Precipitation (2
, 9 g, melting point 172° C.) is recrystallized from ethanol. There are thus obtained 2.39 (yield 49.2) of the pure title compound. Melting point: 174°C.

Analysis: C26H33N305 (N=467.57'
) Calculated value (%): C=66.79 N=7.11
N=8.99 Measured value (a): C=66.80 N=
7.10 N=9.247, O,! i'(o, o2 mol) of 4-phenyl-8-(chloro-acetylamino)-
2-Methyl-1゜2.3.4-tetrahydro-in quinoline-hydrochloride, 10 mg ethanol and 2
ornl! A mixture of (17.0 g, 0.24 mol) of pyrrolidine is refluxed for 5 hours. The above solution was prepared by evaporating the reaction mixture in vacuo, dissolving the remainder in a mixture of 1.00 me water and 100 ml of ether, and adding 30 ml of 30% aqueous sodium hydroxide solution with cooling and stirring. Makes basic.

The phases are separated, the aqueous phase is extracted five times with 'tloo*rl portions of ether, the organic phase is dried over anhydrous sodium sulfate, clarified over activated charcoal and evaporated. The residue is 10 (1
Dissolved in +l of warm ethanol, 6.6g ((1,057
mol) of maleic acid and 4 Qml of ethanol is added. The product is precipitated by adding 1000+++ l of ether. The sticky solid simalate salt kloOml is dissolved in water and the simalate solution is made basic by adding 60 ml of 30% sodium hydroxide in water with cooling and stirring. water phase k 20
Extract once with 0 nrl of ether and four times with 100 ml of ether. The ether phases are combined, dried over anhydrous sodium sulfate and clarified over activated charcoal. The ether is evaporated, the residue washed with a mixture of total ether and petroleum ether. Thus, 5.4 g (0,015
4 mol) (7) 4-phenyl-2-me IF-8-
(Pyrrolidino-acetylamino)-1,2,3,4-tetrahydro-isoquinoline is obtained as white crystals.

Melting point: 130°C.

The free base 'Th thus obtained is suspended in 100 ml of ethanol and a solution of 3.6 g (0.0315 mol) of maleic acid and 36 ml of ethanol is added.

After dissolving the salt, the solution is diluted with 150 ml of ether and the precipitated product is filtered with cooling to give 9 g of product, which is recrystallized from ethanol and ether. This gives 7.39 (yield 2.9%) of the title compound. Melting point: 120°C.

Analysis: C3oH3, N30. (N=581.62) Calculated value (a): C=61.95 N=6.07 N=
7.22 suppression] Fixed value (%): C=61.64 N=6
．． 40 N=6.93 free base forms white crystals with a melting point of 130°C.

Analysis: C22H27N30 Calculated value (%): C=75.61 N=7.81
N=12.02 Measured value (%): C=75.77 FI
=8.02 N=12.16 Example 5.4-phenyl-2-
Methyl-8-(piperi 4.3 g (0,0122 mol) of 4-phenyl-8-(chloro-acetylamino)-2-
Methyl-1゜2.3.4. -tetrahydro-isoquinoline-hydrochloride, 70ml ethanol and 15ml
1 (12,9,9,0,15 mol) of piperidine is refluxed for 5 hours. The reaction mixture was evaporated and the residue
1 in water, and with cooling and stirring 15
The solution is made basic by adding ml of 30% aqueous sodium hydroxide solution. The aqueous solution is extracted once with 200 ml of benzene and four times with 100 ml of nobenzene, the benzene extracts are combined, dried over anhydrous sodium sulphate and evaporated. Oily residue (5,69)
Dissolve in 50 ml of ethanol and add 3.59 (
A solution of 0.08 mol) of maleic acid and 10 ml of ethanol is added. 5.9. ! ? ) and recrystallized from ethanol. Thus, 5.09 of the simalate salt is obtained.

Dissolve simalate f in 30 ml of water and add 1
The solution is made basic by adding 00 mA' of ether and, with stirring and cooling, 10 rnl of hydroxide.

Phase separation is carried out and the aqueous phase is extracted once with 100 mA' of ether and twice with 50 ml of ether. The ethereal phases are combined, dried over anhydrous sodium sulfate and evaporated. 3.2 g (0,0085 mol) of 4-phenyl-2-mef-s-(piperidino-acetyl-amino)-1,2,3,4-tetrahydro-isoquinoline are thus obtained as a yellow-white product. .

The free base ' thus obtained is dissolved in 38 ml of ethanol and 2.03 g (0.0175 mol) of maleic acid are added. Dilute this solution f2Qrnl with ether. The precipitated product is filtered while cooling.

The white powder (4,1,9) is recrystallized from ethanol. The title compound is thus obtained with a yield of 3.55 IC (61%). This product has a non-specific and sloppy melting point.

Analysis: C31H37N30. (M=609.66
) Calculated value): C=62.51 H=6.26
N=7.05 Measured value (%): C=62.28 H=
6.29 The analytical data for N-7,2° oil base are as follows.

Analysis"23"29N30 Calculated value part): C=75.99 I(=8.04
N=11.56 measurement rate (%): C=75.60 H=
8.08 N=11.677g (0.02 mol) of 4-
Phenyl-8-(chloro-acetylamine)-2-methyl-1,2°3.4-tetrahydro-isoquinoline-hydrochloride, 70 ml (D
A mixture of 20,0,9,0,23 mol) of morpholine is refluxed for 5 hours. The reaction mixture was evaporated in vacuo, leaving a residue of 200+ liters of water and 200 m7! of sodium hydroxide in a mixture with ether and add 30 ml of an aqueous solution of 30 ml of sodium hydroxide, phase separation is carried out and the aqueous phase is
Extract 4 times with 0 ml portions of ether. - Dry the combined ether solutions over anhydrous sodium sulfate and evaporate. The oily residue (6.7 g) is dissolved in 100 ml of ethanol and 30 ml of methanol are added. The precipitated product is filtered while cooling. Beige cimalic acid tm (1o, 7.1Th dissolved in 100% water, made the solution basic by adding 60 ml of 35% aqueous sodium hydroxide solution and once with 200 ml of ether and once with 100 ml of ether) Extract 4 times. Combine the ethereal phases, dry over anhydrous sulfuric acid, clarify with activated charcoal, and dry. The ether is evaporated, dried and the residue is recrystallized from a mixture of ether and petroleum ether. In this way, 5.1g (0
, 014 mol) white crystals of 4-phenyl-2-methyl-
8-(morpholino-acetylamine)-1,2,3,4
-Tetrahydro-isoquinoline is obtained. Melting point: 120°C.

Dissolve the above free base in 7o7nl of ethanol and 3.3. ! A solution of i' (0,0284 mol) of maleic acid and 30 ml of ethanol is added. 1 solution
Dilute with 5 ml of ether. The precipitated crystals are completely cooled and filtered. 8.0 g of white powder is obtained.

Recrystallization from ethanol gives 6.9 g (58% yield) of the title compound as white crystals. Melting point 17
6°C (decomposition).

Analysis: C3oH,5N,01o (M=597.62
) Calculated value part): C=60.29 H=s, c+o
N=7.03 measurement #L(a): C=60.11H
= 5.83 N = 7.02 Base C. From ether-petroleum ether, white crystals with a melting point of 120°C are formed.

Analysis: C22H27N302 Calculated value (%): C=72.30 H=7.45
N=11.50 Measured value (%): C=72.45 H
=7.49 N=11.58 Preparation of ate 4.89 (0,013 mol) of 4-phenyl-8-(
3'-chloro-propionyl)-amino-2-methyl-
1,2,3,4-tetrahydro-isoquinoline-hydrochloride, 50 Tnl of ethanol and 15 ml (10
, 49,0,23 mol) of ethylamine is heated in a tempeh tube at 60° C. for 5 hours. The reaction mixture was evaporated, a yellow oily residue 'fr: triturated with 50 ml of water, the solution was made basic by adding 20 ml of 30% aqueous sodium hydroxide solution and 1o
oml! Extract 5 times with 5 portions of benzene and 3 times with 200 ml portions of benzene.

Combine the organic phases and add anhydrous sulfuric acid) l) Dry with a ram;
Then evaporate in vacuum. 3.5 g of a yellow-white powder (0.01'04 mol of crude base) are thus obtained.

The crude base thus obtained was dissolved in 35 ml of ethanol,
and 1.2 g (0,010 mol) of maleic acid and 5
Add solution with ml methanol. 100mJ of solution
dilute with ether and cool.

Count the precipitated products. This product (4, tl) is recrystallized from ethanol. In this way, 2.8 g (yield 4
7.4%) of the title compound as white crystals. Melting point: 162°C.

Analysis: C25H31N305 (N=453.54)
Calculated value part): C=66.22 N=6.89 N=
9.29 measurements [(%): C=66.13 N=7.0
7 N=9.47 starting material can be prepared as follows.

39 g (0.11 mol) of 8-amino-4-phenyl-
200 mA for 2-methyl-1,2,3,4-tetrahydro-isoquinoline-maleate! Dissolved in water and 500+++A! Add ether. The solution is made basic by adding 150 ml of a 30% aqueous IJ solution with cooling and stirring. The ether phase is separated and extracted three times with 300 mJ of ether from the aqueous phase. - The combined ether solutions are dried over anhydrous sodium sulfate and evaporated in vacuo. Yellow oily residue (
24,3 g) in 600 m/m of anhydrous benzene and a solution of 14,2 g (0,112 mol) of 3-chloro-propionic acid in 50 m1 of benzene was added within 20 minutes and the reaction mixture Boil for 2 hours.

The mixture is cooled and the precipitated product is collected, washed with ether and air dried. In this way, a white powder of 32I is obtained. The product is recrystallized from ethanol while diluting with 50 ml of hot ether. Thus, 22
．． 5. The target compound was obtained as white crystals with a yield of 60.4%. Melting point: 220°C (decomposed).

Analysis: C1, H22N20C12 (N=365.30
5) Calculated value (a): C=62.47 I(=6.
07 N=7.67C1=19.63 Ct-=9.8
1 Measured value ←): C=62.72 N=6.17 N=
7.68C/! ,=19.33 C4-=9.604.
8 g (0,013 mol) of 4-phenyl-8-(3'-
Chloro-zolopionyl)-amino-2-methyl-1,2
, 3,4-tetrahydro-isoquinoline-hydrochloride, 50 ml of ethanol and 15 mA! (10,4,
! ? , 0.176 mol) of isopropylamine is refluxed for 5 hours, after which time the reaction mixture is evaporated in vacuo. The residue is dissolved in 5 Q ml of water, the solution is made basic by adding 20 ml of 30% aqueous sodium hydroxide with cooling and stirring, and extracted 6 times with tsom portions of benzene. The benzene solution is dried over anhydrous sodium sulfate and evaporated in vacuo. The white oily residue (5.3 g) is dissolved in 50 ml of ethanol and 1.5 g (0.013 mol) of maleic acid are added. Solution i50mA! Dissolved in ether and cooled,
kW of precipitated product is taken. White powder (5,6,!7) i Recrystallized from ethanol. Thus, 5°Og (77.2% yield) of the title compound is obtained as white crystals. Melting point: 158°C.

Analysis: C26H33N30. (M=467.57) Calculated value (%): C=66.79 N=7.11 N=
8.99 Measured value (%): C=66.77 N=7.3
2 Preparation of N=8.93 maleate 4.89 (0,013 mol) of 4-phenyl-8-(
3'-chloro-propionyl)-amino-2-methyl-
1,2,3,4-tetrahydro-inquinoline-hydrochloride 150 ml of ethanol and 15++ J (11
,O,! i', 0.15 mol) of butylamine is refluxed for 5 hours. The reaction mixture is evaporated in vacuo, the residue is suspended in 50 ml of water, basified by adding 20 ml of 30% aqueous sodium hydroxide solution and extracted with 150 ml portions of ether twice. The ether solutions are combined, dried over anhydrous sulfuric acid, and vacuum dried. Colorless oily residue (5,3,9
)'t:6 (11 dissolved in ethanol and 1.3
g (0.0112 mol) of maleic acid.

solution'! Dilute with rloOml ether and cool. The precipitated product is collected (particularly 5.6 g) and recrystallized from ethanol. In this way, 4.5 g (yield 71
．． 8%) of the title compound as white crystals. melting point 14
7℃.

Analysis: C27H3, N30. (M-481,60) Calculated value (9)): C=67.34 N=7.33 N=8
．． 72 measured value (support): C=67.49 H-=7
6o N = 8.677.6 g of 8-(chloro-acetyl)-amino-4-(p-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline-hydrochloride, 100 ml of Ethanol and 40ml
A mixture of (27,89, o, 6x mol) of ethylamine is heated in a Dempe tube at 60°C for 5 hours. The reaction mixture is evaporated, the yellow oily residue is suspended in 50 ml of water and made basic by adding 3 Q ml of 30% aqueous sodium hydroxide solution and extracted with ether. The ether solution is dried over anhydrous sodium sulfate and evaporated. A yellow oil of 8.19 was thus obtained, which was dissolved in a total of 30 ml of ethanol and 5 ml of
2.39 (0.02 mol) of maleic acid in 1 ml of ethanol. Dilute solution f with 40 ml of ether. The precipitated product kF is collected, dried to obtain 10 g of product, and recrystallized from ethanol.

6.2 g (yield 65.2%) of the title compound are thus obtained as white fine crystals. Melting point: 189°C (decomposed).

Analysis: C24I (28C2N305 (N=473.9
6) Calculation @<1): C=60.82 N=5.9
5 C1=7.48 measurement (direct (%): C=60.
98 F (=6.04 ct=r, 56 starting material can be prepared as follows.

10.9 g (0.04 mol) of crude 8-amino-4-(I
;-chloro-phenyl)-2-methyl-1,2°314
-tetrahydro-in 5.4 g (0,047 mol, 3.5 m/
) of chloroacetyl chloride in 30 ml of anhydrous benzene is added with stirring. After the addition is complete, the reaction mixture is heated to the boil for 2.5 hours. The mixture is cooled and the precipitated product is separated, washed with benzene, acetone and ether T, and dried. Thus, 14
g (90.9% yield) of 8-(chloro-acetyl)-amino-4-(p-chloro-phenyl)-2-methyl-1
, 2,3,4-tetrahydro-inquinoline-hydrochloride as a white powder. Melting point: 220°C (decomposed).

Analysis: C,8f(,,C63N20 (N=384.
7) Calculated value [stock]: C=56.05 N=4.
96 N=7.26 C1=27.25 C1-=9.
08 Measured value (A): C=56.21 I(=5.12
N=7.42C1=27.32 C1-=9.12
6.2 g (0,016 mol) of 8-(chloro-acetyl)-7mi/-4-(p-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-hydrochloro Y, 120 ml of ethanol and 29 d(1
4.78 g, 0.2 mol) of a mixture of butylamine,
Reflux for 5 hours. The reaction mixture was evaporated in vacuo, the residue was dissolved in 50 ml of water and, with cooling and stirring, 30 qb of 25 ml of sodium hydroxide.
Make basic using an aqueous solution. Mixture t, 150mA1
Extract six times with each portion of benzene, combine the benzene solutions, dry over anhydrous sodium sulfate, and evaporate the solvent.

The yellow residue (7.3 g) is dissolved in 200 ml of ethanol and a solution of 1.99 (0.064 mol) maleic acid and 5 m, l ethanol is added. solution'k
Dilute with 400 ml of ether and collect the precipitated product (7 g
) is the number of houses. Melting point: 152°C. This is recrystallized from ethanol to obtain 4.6 g (yield 57.5%) of the title compound as white fine crystals. Melting point: 154°C.

Analysis: C26H, CtN305 (M = 502.01
8) Calculated value (a): C=62.21 N=6.4
3 N=8.37Ct=7.06 Measured value (%): C=62.36 I(=6.70
N=8.38C1=7.04 Example 12.8-(ethylamino-acetyl-amino)-2
-Methyl-4-(p-tolyl)-1,2,3° Preparation 5.2.9 (0,0145 mol) of 8-(chloro-acetyl)-amino-2-methyl-4-(p-tolyl) )−
1,2,3,4-tetrahydro-isoquinoline-hydrochloride, 100 ml of ethanol and 30 ml (20
, 8 g, 0.45 mol) of ethylamine is heated in a Dempe tube at 70° C. for 5 hours. The reaction mixture was evaporated and an orange oily residue was dissolved in 1 x 5 Q ml of ethanol and 1.8 g (0.01555 mol)
of maleic acid. solution'! Dilute in portions with 150 ml of ether, cool, and remove the precipitated product ThF and wash with a mixture of acetone and ether. 5.7 g of product are obtained as a white powder. Melting point 157
°C (decomposition). This is recrystallized from a mixture of ethanol and ether to give 4.3 g (66% yield) of the title compound. Melting point: 176°C (decomposed).

Analysis: C25H31N305 (N=453.546
) Calculation @ (%): C=66.20 N=6.89
N=9.26 measured value (support): C=66.10 f
(=7.39 N=9.25 The starting material is obtained as follows.

7.69 (0.03 mol) of 8-amino-2-methyl-
4-(p-)lyl)-1,2,3,4-tetrahydro-
In a solution of isoquinoline and 100 ml of anhydrous benzene,
4.059 (0,035 mol, 2.7 mQ chloro-
A solution of ethyl chloride and 30 rrLl of anhydrous benzene is added dropwise with stirring. The reaction mixture is heated to the boil for 5 hours and cooled. The precipitated product was filtered, washed with ether, and dried to give 10.1 g (92.6% yield) of 8-(chloro-acetyl)-amino-2.
-Methyl-4-(p-)lyl)-1,2,3,4-tetrahydro-isoquinoline-hydrochloride is obtained as a white powder. Melting point: 228°C (decomposed).

Analysis: C1, H22Ct2N20 (M=365.3) Calculation rim (%): C=62.47 N=6.07
N=7.67Ct=19.41 CL-=9.7
0 measurement value (%): C=62.69 N=6.45 N
= 7.58 C1 = 19.64 C1- = 9.73 Production 4.9.9 (0,0135 mol) of 8-(chloro-acetyl)-amino-2-methyl τp-tolyl)-1,2
, 3,4-tetrahydro-inquinoline-hydrochloride, 3001d of ethanol and 20 mA' (14,7
8, @s 0.12 mol) O butyl 7mine mixture,
Boil for 5 hours. The reaction mixture is evaporated to dryness, the residue is dissolved in 50 ml of water and basified by adding 25 ml of 30% aqueous sodium hydroxide solution with cooling and stirring. The mixture is extracted five times with 150 ml of ether, the organic layers are combined, dried and the bath is removed in vacuo. Yellow-white oily residue f5
Q ml of ethanol and 1.6 g (0
,0148 mol) of maleic acid.

Add 50 m of ether to the mixture. After cooling, 6 g (yield 92
．． 0%) of the title compound as a white powder.

Melting point: 172°C (decomposed).

Analysis: C27H3C27H35N305(,6) calculation 1
Direct@)): C=67.34 N=7.33 N=
8.73 measurement 1 straight obtuse): C=67.6011=7.5
0 N = 8.473.6 g (0.015 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydro-inquinoline, 1.17 g (0.0165 mol)
A mixture of 40 moles of ethyl incyanate and 40 moles of anhydrous benzene is refluxed for 2 hours. The reaction mixture was evaporated in vacuo, the residue was dissolved in 4 oml of chloroform, the solution was subjected to column chromatography on silica gel, and 250 g of chloroform containing 10% ethanol and 25 g of chloroform containing 20 g of ethanol were added.
Use l to produce m one after another. - Evaporate the combined eluates and treat the residue (3, 8, 9) with petroleum ether. 3.5 in 1 ta/-71/ of 60 ml of solid product
g (0.029 mol) of maleic acid. Dilute the reaction mixture with 200 ml of ether and cool. Precipitated product 'cP taken 5.0
g of product are obtained which is recrystallized from a mixture of ethanol and ether to obtain 4.5 g of the title compound.

Melting point 137-139°C (decomposition). Recrystallization from ethanol gives 3.7 g (yield 77 g) of pure title compound. Melting point: 140°C (decomposed).

Analysis” 23H2□N505 (425,49) calculated value (
%): C=64.93 N=6.40 N=9.
88 measured value): C=65.13 N=6.49 N
=9.92 Preparation The procedure of Example 14 is followed except that n-propylisocyanate is used instead of ethyl isocyanate. 3.5. ! 9 (yield: 53.0 V) of the title compound is obtained as yellow-white crystals. Melting point: 149-150°C.

Analysis: C24H29N305 (439,515) Calculated value (e): C=65.59 N=6.65 N=9
．． 56 Measured value (%): C=65.80 N=7.0
8 N = 9.48 produced 1.9 as in the method of Example 4 except that n-butyl isocyanate is used instead of ethyl isocyanate.
g (yield 42 g) of the title compound is obtained as a white powder.

Melting point: 145°C (decomposed).

Analysis: C25H31N305 (453,54) calculation unit): C=66.20 N=6.89 N=9.
26 measurements (direct (%): C=66.32 K=6.3
7 Production of N=9.44 maleate The use of 8-amino-4-(p-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline and n-butyl isocyanate as starting materials 7.89 (yield 3
The title compound (2) is obtained as a yellow-white powder. Melting point 13
4°C (decomposition).

Analysis: C25H3oCtN305 (487,99) Calculated value (%): C=61.53 N=6.20 N=
8.61C1=7.27 Measuring box (A): C=60.97 I (=6.30 N
=8.64C1=7.51 Using 8-amino-2-methyl-4-(p-tolyl)-1,2,3,4-tetrahydro-isoquinoline and n-butyl-isocyanate as starting materials Example 1 except
8.4 g (yield: 41.5%) of the title compound was obtained as a yellowish-white powder in the same manner as in method 4. Melting point: 169°C (decomposed).

Analysis: C25H3oCtN305 (487,99) Calculated value (%): C=66.79 N=7.11 N=
8.99 Measured value (%): C=66.30 N=7.3
0 N=8.895.29 (0.02 mol) of N-(
2-amino-benzyl)-1-phenyl-2-methyl-
A mixture of amino-11-ethanol, 2.29 (0,022 mol) n-butyl-isocyanate and i'ooml anhydrous benzene is refluxed for 2 hours, after which time the reaction mixture is evaporated in vacuo. 7.2 g of an oil consisting of N-(2-(butyl-carbamoyl-amino)-benzylco-1-phenyl-2-methyl-amino-1-ethanol) is obtained, which solidifies on standing.

Crude product obtained according to the previous section 7.2 g'Fr: 100
ml of methylene chloride and the solution was heated at 2-6°C for 4 hours.
4.4 ml of concentrated sulfuric acid was added dropwise within 5 minutes, and the reaction mixture f was stirred for 0.5 h at 6°C, lubricated with 100 g of ice and basified with 30% aqueous sodium hydroxide solution. and extracted four times with 100 mA' each of chloroform. - The combined chloroform extracts are dried over anhydrous sodium sulfate and evaporated in vacuo. 5.4 g of yellow-white solid gold are obtained. The product is dissolved in 30 ml of ethanol and 2.159 (0.0235 mol) of maleic acid are added. The reaction mixture is diluted in portions with fi=300 mA' of ether, cooled, and the precipitated product is taken off and recrystallized from a mixture of ethanol and ether.

6.0. The title compound of j9 (yield 61.6%) is obtained.

Melting point: 145°C. The white powder thus obtained is identical to the product of Example 16.

Preparation 13.1.10.047 mol) of 8-amino-4-(p
-chloro-phenyl)-2-methyl-1,2゜3.4-
A solution of tetrahydro-isoquinoline and 300 ml of anhydrous benzene (6.8 IC0,0625 mol, 6 ml)
of ethyl chloroformate) is mixed with a solution of 0 mJ of anhydrous benzene. The reaction mixture is refluxed for 2.5 hours and the benzene is removed in vacuo. The residue is dissolved in tloml water, made basic with 10 ml of concentrated ammonium hydroxide solution and extracted three times with 100 ml portions of chloroform. The chloroform extracts are combined, dried over anhydrous sodium sulfate, evaporated, and the residue is recrystallized twice from ethanol. In this way, 7.3 g (yield 45.6
%) of the title compound as white crystals. Melting point 155℃
.

Analysis: C1, H21CtN202 (344,845) Calculated value (%): C=66.19 H=6.14 N
=8.12C1=10.28 Measurement accuracy (%): C=66.79 f(=5.89
N=8.42Ct=10.56 Example 21.8-(ethoxycarbonyl-amino)-Example 20
7, 3.9 (0,0212 mol) of base k, prepared according to the method, are suspended in 50 ml of ethanol and 16 mt2 of ethanol saturated with chlorinated ice cream are added with cooling.

Add 200ml of ether until the mixture becomes cloudy.
complete precipitation of the product by stirring and rubbing the walls of the flask. The precipitated product 'f-F is collected and washed with ether. 8.1 g (yield f1 almost 100%) of the title compound are obtained as a white powder. Melting point: 145-150°C.

Analysis: C,,I(22Ct2N20□(381,30
) Calculated value (%): C=59.85 H=5.82
N=7.35Ct=18.60 Ct-=9.30 Measured value (%): C=59.74 H=6.06 N=7
．． 17C1 = 18.54 C1- = 9.21 (83) Preparation of lahydroin quinoline 5.5 g (0,023 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydro I-solution K of -isoquinoline and 50- anhydrous benzene 3.4
g (0,031 mol) of ethyl chloroformate and 30
Add a solution of ml of anhydrous benzene. The reaction mixture was
Heat to boiling for an hour and remove benzene in vacuo. The residue is dissolved in 25 ml of water, made basic by adding 30 ml of aqueous YL sodium hydroxide, and extracted three times with 50 ml portions of chloroform. The chloroform extracts are combined, dried over sodium sulfate and evaporated.

3. by washing the residue with cold ethanol and recrystallizing from ethanol. The title compound is obtained as white crystals (O1 yield: 37.5%). Melting point: 178°C.

Analysis: C,,) (22N202 (346,86”) calculated value←): C=73.84 H=7.15 N=
9.02 measurement @ (a): C=73.96 K=7.5
1 N=8.95fH3,8-(ethoxycarbonylamine)-4-phenyl-2-methyl-1,2,3,4-
N-(2-Amino-benzyl)-1-phenyl-2-methyl-amino- of Tet2.6 jj (n, 01 mol)
1-Ethanol f3 Dissolve in Qml of ether.

To this solution was added 0.79 g (0.01 mol) of anhydrous pyridine, followed by 13 g (0.01 mol) of anhydrous pyridine with vigorous stirring.
Add 2 moles of ethyl chloroformate, cool and carry out the entire reaction at 15°C. The reaction mixture containing a white precipitate is stirred at room temperature for 330 minutes and poured into 30 ml of ice-cold water. The aqueous phase is extracted three times with 100 ml of ether, and the combined ether extracts are dried over anhydrous sodium sulfate and evaporated in vacuo. 2.8 g of N-[2-(ethoxycar?nylamino)-benzylco-1-phenyl-2-methyl-amino-1-ethanol are thus obtained as a yellow-white oil. This material can be further cyclized without purification.

The oily residue of 2,8.9 obtained according to the previous section was dissolved in 4 Q ml of dichloromethane and, with cooling and stirring, added to the above solution in 15.4 ml of concentrated sulfuric acid at 5-6° C. for 0.15 hours. Inject into. The reaction mixture is stirred at this temperature for a further 20 minutes and then basified with a 30% aqueous solution of IJ (hydrogenated with cooling and stirring) and poured into 80 ml portions of chloroform. Extract twice. The organic phases are combined, dried over anhydrous sodium sulphate and evaporated in vacuo. 2.3 g of a yellow-white solid are thus obtained. After recrystallization from ethanol 2.0 g (yield 64.5%) of the title compound are obtained. Melting point: 174°C.

A solution of 2.4 g (0.01 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydro-inquinoline and 100 d of anhydrous benzene is dissolved in 1.4
g (0,012 mol) of butyl chloroformate and 1o
ml of anhydrous benzene and the reaction mixture is heated to boiling for 2 hours.

After cooling, the mixture was diluted with 50 ml of ice-cold water, the pH was adjusted to 9 by adding concentrated ammonium hydroxide solution, the benzene phase was separated and extracted twice with 2 Q ml of benzene and with anhydrous sodium sulfate. Drying and evaporation in vacuo give 3.6 g of an orange oil. The product is recrystallized twice from ethanol to give 1.8 g (52.9% yield) of the title compound as a white powder.

Melting point: 106°C.

Analysis: C21H26N202 (N=338.454
) Calculated value (a): C=75.43 F(=6.63
N=8.37 Measured value (%): C=75.19 N=
6.44 N = 8.573.5 g (0,015 mol) of 8-diminnow 2-methyl-4-phenyl-1,2,3,
1.28 g (0,016 mol) of 4-tetrahydro-inquinoline 'lr100 mA' dissolved in anhydrous benzene
of anhydrous pyridine and 2.14.9 (0,01
A solution of 5 mol) of (β-chloro-ethyl)-chloroformate and 10 ηl of anhydrous benzene is added dropwise at room temperature with stirring and cooling. The entire reaction mixture is stirred for 1 hour at room temperature, poured into 50 ml of ice-cold water, the organic phase is separated and the aqueous phase is extracted three times with 3 Q ml of benzene. The combined organic solutions are dried over anhydrous sodium sulfate and evaporated in vacuo to give 4.5 g of a pale yellow material. This product is recrystallized twice from ethanol to obtain 2.7.9' (52% yield) of the title compound as completely white crystals. Melting point: 154°C.

Analysis: C4, H21C1N202 (M=344.84
5) Calculated value (a): C=66.18 f(=6.
14 N=8.12C1=10.28 Measured value (%): C=66.29 N=6.24 N
=8.10Ct=10.38 4.6g (0.02mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline't is fermented into 100ml of anhydrous benzene. . To this solution is added 6.29 90% benzyloxycarbonyl chloride (5.2 liters, 0.03 mol). The reaction mixture 'e is decomposed with 15 Qml of water and, while cooling on ice, hydroxylated and made basic by adding 30 ml of aqueous ice solution. The benzene phase is separated and the aqueous phase is extracted with two 150 ml portions of benzene and evaporated. The residue is stirred with 150 ml of ether, cooled, the precipitated product is separated and washed with cold ether to give 4.7 g of a pale yellow powder. Melting point 1
42-146℃. Recrystallization from ethanol gives 3.6 g (yield: 49%) of the title compound as a white product. Melting point 147-148°C.

Analysis: C24H2C24H24N202 (,474) Calculated value (%): C=77.39 I (=6.49
N=7.50 measurement straight part): C=77.50 N=6.
78 N=7.702.4. ! i' (0,0064 mol) of the above base ff:, 70 m1 (1') Ni 7
- Suspend L, (:' Lte 0.75 g (0,00
A solution of 64 mol) of maleic acid and 5 ml of ethanol is added with stirring. The reaction mixture was stirred for 1o min.
and cool to 0°C. The precipitated product was collected, washed with a mixture of ethanol and ether, then washed with ether, and recrystallized from ethanol. -(benzyloxycarbonyl-amino)-4-phenyl-2-methyl-1
, 2,3,4-tetrahydro-isoquinoline-maleate as a white powder. Melting point: 166-167°C.

Analysis: C28H2C28H28N2o6 (,544) Calculated value (%): C=68.84 F (=5.98
N=5.73 measured value dull): C=68.76 f(=
5.95 N=5.82 or less margin (89) Continued on page 1 0 Inventor Marton Huekete Budapest, Hungary 2 Huo Utsza 49 0 Inventor Marjit Doda Budapest, Hungary 2 Lajos Utsza 24 0 Inventor András Selej Budapest, Hungary 14 Susanto B. Utsza 14 0 Inventor Béla Kanis Kerepěszá Eperzięsi Utsza, Hungary 3 0 Inventor Ercebet Toto Budapest, Hungary 13 Petnehazy Utsza 29 0 Inventors: Maria Horvat, Budapest, Hungary 19 Trudy Utsza 1 (90) 0 Inventors: Sándor Manyai, Budapest, Hungary 11 Vlastzuló Utsza 38 0 Inventors: Frygies Gyorzheny, Budapest, Hungary 12 Kusersz Utsza 23- 25 0 Inventor Gyorgy Vaszovics Budapest, Hungary 16 Kujileki Utsa 17

Claims (1)

[Claims] 1. The following general formula (1) % formula % (wherein R represents hydrogen, a lower alkyl group, or halodane, and X represents the following general formula, -(CI(2)n -NR' R2,
--N together with adjacent nitrogen atoms constitute a 5- or 6-membered saturated heterocycle, where the heterocycle optionally further contains an oxygen or sulfur atom, or optionally a lower alkyl group. ): n is 1.2', 3 or 4
is an integer of: R3 represents a lower alkyl group or an optionally substituted phenyl group; and
R4 represents a lower alkyl group, a halodanated lower alkyl group, or a phenyl lower alkyl group, 4-aryl-2-methyl-1,2,3,
4-Tetrahydro-isoquinoline derivatives and pharmaceutically acceptable acid addition salts thereof. (wherein R, R1, R2 and n have the same meanings as stated in claim 1) and pharmaceutically acceptable derivatives thereof according to claim 1. Acid addition salts. 3. The derivative according to claim 1, represented by the following general formula (IB), (wherein R and R have the same meanings as stated in claim 1), and Pharmaceutically acceptable acid addition salts thereof. 4. The compound according to claim 1, represented by the following general formula (IC): Derivatives and pharmaceutically acceptable acid addition salts thereof. 5.8-(ethylamino-acetylamino)-4-(p
-chloro-phenyl)-2-methyl-1,2,3,4-
Tetrahydro-isoquinoline and its pharmaceutically acceptable acid addition salts, 8-(n-butylamino-acetylamino)-4-(p-chloro-phenyl)-2-methyl-1
, 2,3,4-tetrahydro-isoquinoline and its pharmaceutically acceptable acid addition salts, 8-(ethylamino-acetylamino)-4-(p-)lyl)-2-methyl-1
, 2,3,4-tetrahydro-isoquinoline and its pharmaceutically acceptable acid addition salts, or 8-(n-butylamino-acetylamino)-4"(p-tolyl)-2-methyl-1,2, 6.8-(n- butyl-carbamoylamino)-4-(
p-chloro-phenyl)-2-methyl-1,2,3,4
-tetrahydro-isoquinoline and its pharmaceutically acceptable acid addition salts, or 8-(n-butyl-carbamoylamino)-4-(p-tolyl)-2-methyl-1,2,
3,4-tetrahydro-isoquinoline and its pharmaceutically acceptable acid addition salts. amino)-4-(p-
chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoly and its pharmaceutically acceptable acid addition salt, and the derivative according to claim 4, and its pharmaceutically acceptable acid addition salt. Acid addition salts. 8. The derivative according to claim 7, wherein the 8-(ethoxycarbyl is nylamino)-4-(p-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline-hydrochloride. Acid addition salts of. 9, the following general formula (I) -co-x (wherein R represents hydrogen, a lower alkyl group or halodane, and X represents the following general formula, -(CH2)n-NR'R2, - N
H-R' or -OR (wherein R and R are the same or different), hydrogen or a lower alkyl group, or R1 and R2 together with the adjacent nitrogen atom to which they are bonded taken together to form a 5- or 6-membered saturated heterocycle, the heterocycle optionally being further substituted with an oxygen or sulfur atom, or optionally with a lower alkyl group; -bs): n is an integer of 1, 2.3 or 4;
: R31d represents a lower alkyl group, or an optionally substituted phenyl group; and R represents a lower alkyl group, a halodanated lower alkyl group, or a phenyl lower alkyl group. ,
) 4-aryl-2-methyl-1,2,3,
A method for producing a 4-tetrahydro-isoquinoline derivative and a pharmaceutically acceptable acid addition salt thereof, comprising (,) the following general formula (IA), (wherein R, R', R2 and n have the same meanings as above) In order to produce a derivative represented by the following general formula (II), HN-Co-(Cf(2)n-f(Ig(7)), where R and n have the above meanings, and Hlg represents halogeno), or a salt thereof, as the following general 2〇, NH
R'a2(III) (in which Hl and R2 have the above-mentioned meanings) is reacted with an amine or a salt thereof; or, (b) the following general formula (IB), HN-Co-NH -R3 (wherein R and R3 have the above-mentioned meanings), (bl) the following general formula (I
V), (8) NH2 (wherein R has the above-mentioned meaning) A compound represented by the following general formula (V), R'-NC
O(V) (in which R3 has the above meaning); or (b2) the following general formula (M), with the following blank space (wherein R and R3 have the above meaning); ) having the meaning; or alternatively, (c) cyclizing a compound represented by the following general formula (
IC), HN-COOR4 (wherein R and R have the above meanings), (cl) the following general formula (M)
, (wherein R has the above-mentioned meaning) A compound represented by the following general formula (■), Hl g
-C0OR' (■) (in the formula 1 (1g represents a halogen and R4 has the above meaning,
): or (c2) cyclizing a compound represented by the following general formula (■) (11) (wherein R and R4 have the above-mentioned meanings): ; and, if desired, converting the compound of formula (I) into its pharmaceutically acceptable salt. 10. The method according to claim 9, wherein the reaction (a) is carried out at a high temperature. 11. The method according to claim 9 or 10, wherein the reaction (a) is carried out in an inert organic solvent. 12. The method according to claim 11, wherein an aliphatic alcohol is used as the reaction medium. 13, R represents a chlorine atom or a methyl group at the para position,
For producing a derivative of formula (IA) in which R is hydrogen, R is an ethyl group or n-(12) butyl group, and n is 1, R, R, R and n has the meaning given above and Hlg is halogen
The method according to claim 9, using the starting materials of and @). 14. The method according to claim 9, wherein the reaction of (bl) is carried out in an aromatic hydrocarbon as a solvent. 15. The method according to claim 14, wherein benzene is used as the reaction medium. 16. The method according to claim 9, 14 or 15, wherein the reaction of (bl) is carried out at high temperature. 17. The method according to claim 9, wherein the ring-closing reaction of (b2) is carried out in the presence of an acidic catalyst. 18. The method according to claim 17, wherein a mineral acid or a Lewis acid is used as the acidic catalyst. 19. Claim 18 using sulfuric acid as a catalyst
The method described in section. 20. The method according to claim 19, wherein the reaction is carried out at 0°C to 6°C. 21, R represents a methyl group or a chlorine atom at the para position,
When producing a derivative of formula (IB) in which R represents an n-butyl group, use the formula (IV) in which R and R3 have the above meanings.
), (V) and (M). 22. The process according to claim 9, wherein in the reaction of (cl), a compound of formula (■) in which T (Ig is chlorine) is used as a starting compound. 23. The reaction is carried out in the presence of an acid binder. 24. The method according to claim 23, in which the reaction is carried out in an aromatic hydrocarbon. 24. The method according to claim 23, in which triethylamine or quinoline is used as the acid binding agent. 25. The method according to claim 9 or any one of claims 22 to 24. 26. The method according to claim 9 or any one of claims 22 to 25, in which the reaction is carried out at a high temperature. 27. The method according to claim 9, in which the cyclization reaction of (c2) is carried out in the presence of an acid catalyst. 28. The method according to claim 27, in which a mineral acid or a Lewis acid is used as a catalyst. Method. 29. Claim 28 using sulfuric acid as a catalyst
The method described in section. 30. The method according to claim 9 or any one of claims 27 to 29, wherein the reaction (c2) is carried out in the presence of a halodanized hydrocarbon. 31. The method according to claim 30, wherein the reaction is carried out at 0°C to 80°C. 32.8-(ethoxycarbnylamino)-4-(p-
In producing chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline and its hydrochloride, R is NoJ? (Formula (IV) in which R4 is an ethyl group at the chlorine atom at the position) (Ig is a halodane)
, (■) and (■) and optionally the 8-(ethoxycarbnylamino)-
4-(p-chloro-phenyl)-2-methyl-1,2,
Converting 3,4-tetrahydro-isoquinoline to hydrochloride (15) The method according to claim 9 or any one of claims 22 to 31. 33, the following general formula (I) (wherein R represents hydrogen, a lower alkyl group or a halogen, and X is the following general formula, -(CH2)n-NR1R2, -N
)(-R3 or -〇R' (wherein, R1 and R2 are the same or different and represent hydrogen or a lower alkyl group, or R1 and R2 are the adjacent groups to which they are bonded) Together with the nitrogen atom, it constitutes a 5- or 6-membered saturated heterocycle, where this heterocycle (16) may further contain an oxygen atom or a sulfur atom, or a lower alkyl group in some cases. ); n is 1.2.3
or an integer of 4; R3 represents a lower alkyl group or an optionally substituted phenyl group; and R4 is a lower alkyl group, a halodanated lower alkyl group,
4-aryl-2-methyl-1,2,3,
A medicament comprising at least one 4-tetrahydro-isoquinoline derivative or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, and further comprising a suitable conventional inert non-toxic pharmaceutical carrier and/or excipient. °“-Mullet (1) Side, bottom 1 white (in the formula, R represents hydrogen, a lower alkyl group, or halodane, and X is the following general formula, -(CH2)n-NR1R2, -N
H-R3 or -0R4 [wherein R1 and R2 are the same or different and represent hydrogen, hydrogen or a lower alkyl group, or R and R together with the adjacent nitrogen atom to which they are bonded] taken together to form a 5- or 6-membered saturated heterocycle, the heterocycle optionally being further substituted with an oxygen or sulfur atom, or optionally with a lower alkyl group; (may contain groups): n is an integer of 1.2.3 or 4;
R3 represents a lower alkyl group or an optionally substituted phenyl group; and R4 represents a lower alkyl group, a halodated lower alkyl group, or a phenyl lower alkyl group. 4-aryl-2-methy, represented by 1,2,3.
Production of a medicament, characterized in that at least one 4-tetrahydro-isoquinoline derivative or a pharmaceutically acceptable acid addition salt thereof is mixed with a suitable conventional inert non-toxic pharmaceutical carrier and/or excipient. Method.