JPS6366315B2 - - Google Patents

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 medicaments containing the derivatives. (Prior Art) Acyls derived from saturated or unsaturated aliphatic carboxylic acids containing up to 6 carbon atoms, aromatic carboxylic acids, or aromatic-aliphatic carboxylic acids containing 7 to 10 carbon atoms 8-amino-4-aryl- substituted on the amino group by the group
2-Alkyl-tetrahydro-isoquinoline derivatives are described in GB 1164192. This compound has a central nervous system stimulating effect and a tymoleptic effect. Compounds with a similar structure are described in DE 1670848 and DE1795829. (Structure of the invention) According to this invention, the following general formula () (wherein R represents hydrogen or halogen, and R ⁴
is a lower alkyl group, a halogenated lower alkyl group,
or phenyl lower alkyl group, 4-aryl-2-methyl-
1,2,3,4-Tetrahydro-isoquinoline derivatives and pharmaceutically acceptable acid addition salts thereof are provided. A preferred representative example of the compound represented by the general formula () is 8-(ethoxycarbonylamino)-
4-(p-chlorophenyl)-2-methyl-1,
Mention may be made of 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" means a straight-chain or branched aliphatic group having 1 to 6, especially 1 to 4 carbon atoms, such as methyl, ethyl, n -propyl group, isopropyl group, n-butyl group, isobutyl group, etc. The term "halogen" means fluorine, chlorine, bromine and iodine atoms. The substituent R is preferably attached to the para position of the phenyl ring. Pharmaceutically acceptable acid addition salts of compounds of general formula () can be formed with pharmaceutically acceptable inorganic or organic acids. These salts include mineral acids (e.g. hydrogen halides such as hydrogen chloride or hydrogen bromide, sulfuric acid, phosphoric acid, etc.) or organic acids (e.g. formic acid, acetic acid, propionic acid, lactic acid,
maleic acid, tartaric acid, benzoic acid, salicylic acid, etc.)
It can be formed together with According to the present invention, there is further provided a method for producing a compound represented by the general formula (), which method comprises: (c1) the following general formula (); (wherein R has the meaning given above) A compound represented by the following general formula (), Hlg-COOR ⁴ () (wherein Hlg represents a halogen, preferably chlorine or bromine, and R ⁴ has the above meaning; or (c2) the following general formula () (wherein R and R ⁴ have the meanings given above) is cyclized in the presence of an acid catalyst; and, if desired, the compound of formula () is converted into a pharmaceutically acceptable salt thereof. It is characterized by converting. In the method (c1) of this invention, a compound of general formula () is reacted with a halogenoformiate of general formula (). Preference is given to using compounds of 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 worked up by methods 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 () is extracted with an organic solvent (eg chloroform). The compound of the general formula () used as a starting material can be produced by cyclizing the compound of the following general formula (XI). (wherein R has the meaning given above) Compounds of general formulas () and (XI) are already known (GB 1164192) or can be produced by known methods. In the method (c2) of this invention, the compound of general formula () is ring-closed. This cyclization is carried out by acidic catalysts,
For example, mineral acids (e.g., hydrochloric acid, sulfuric acid, polyphosphoric acid, etc.)
Alternatively, it can be carried out in the presence of a Lewis acid (eg, aluminum chloride, boron trifluoride, zinc chloride, tin chloride, etc.). It can be carried out particularly advantageously in the presence of sulfuric acid as catalyst. The reaction is carried out in an inert organic solvent. Halogenated hydrocarbons (e.g. methylene chloride,
chloroform, etc.) can be used. The reaction temperature depends on the activity of the catalyst and is generally between 0 and 80℃.
The reaction is carried out at The compound of general formula () can be separated by a method known per se. When using sulfuric acid as a catalyst, it is preferred to pour the sulfuric acid solution onto ice, make the reaction mixture basic, and purify the compound of general formula () by extraction with an organic solvent (e.g. chloroform). . The starting material of general formula () can be prepared by reacting a compound of general formula (XI) with a halogenoformiate of general formula ().
The reaction can be carried out in the same manner as method (c1). The compound of general formula () thus obtained is cyclized after separation or preferably without separation. The compound of general formula () obtained as described above can be converted into an acid addition salt with a pharmaceutically acceptable acid. Salt formation can be carried out according to conventional methods. For example, it is preferred to react a compound of general formula () with the corresponding acid in a suitable inert organic solvent. Preferably, the acids are used in equimolar amounts. liberating the compound of general formula () from the pharmaceutically unacceptable salt of the compound of general formula () using a strong base and reacting the free base of general formula () with the corresponding pharmaceutically acceptable acid; Pharmaceutically acceptable acid addition salts can also be prepared by. The novel compounds of general formula () 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. This invention further provides one or more compounds of general formula () or pharmaceutically acceptable salts thereof,
A medicament comprising the present invention is provided, 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, dragee, solution, emulsion, suspension) or parenterally (e.g., injection). can be converted into The medicament may contain conventional inert solid or liquid carriers such as talc, starch, magnesium stearate, magnesium carbonate, calcium carbonate, water, alcohol, polyethylene glycol, and the like. The medicament may also contain conventional pharmaceutical auxiliaries such as wetting agents, disintegrants, flavoring agents, flavor modifiers, etc. The medicament of the invention can be produced by 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. (1) Acute toxicity: administered subcutaneously and after a 96-hour observation period.
Find the LD50 value. (2) Subcutaneous dose inhibiting catalepsy induced by 13 micromoles/Kg of haloperidol in 50% of mice. (3) The lowest intraperitoneal dose that still increases or decreases locomotor activity in mice. (4) Subcutaneous dose inhibiting catalepsy induced by 110 micromoles/Kg of tetrabenazine in 50% of mice. (5) Subcutaneous dose inhibiting ptosis induced by 79 micromoles/Kg of tetrabenazine in 50% of mice. (6) The lowest subcutaneous dose that still inhibits the decrease in rectal temperature induced by administration of 1.6 micromoles/Kg of reserpine. (7) The lowest intravenous dose that still increases blood pressure and blinking in cats. (8) The lowest subcutaneous dose that still induces stereotypy in rats. (9) A dose that induces specific rotational behavior after creating an electrical lesion in the substantia nigra. (10) Dose that induces a significant decrease in prolactin levels 4 days after treatment with 0.073 micromol/Kg oestradiol in rats that had undergone ovariectomy 3 weeks previously. The following test compounds were used. Compound I Product of Example 1 Nomi fensin (Reference Compound)
8-amino-4-phenyl-2-methyl-1,
2,3,4-Tetrahydro-isoquinoline (as described in GB 1164192) The test results are summarized in Table 1 below.

[Table] Acute toxicity data are determined in mice.
Tests (2)-(6) are also performed in mice. Doses are expressed as micromoles/Kg. The therapeutic index TI is
It is expressed as the quotient of LD/ED. In test (3), “+” indicates increased movement;
"-" indicates decreased movement. TBZ stands for tetrabenazine. Tests (7) to (10) were carried out in cats and rats, and doses are given in micromoles/Kg. Tests (2), (8), (9) and (10) are suitable for evaluating the dopamine stimulating effect of the test compound (possibility as an antiparkinsonian agent). Tests (4), (5), (6) and (7) give information on the catecholamine-uptake inhibitory effect (potential as an antidepressant). The reference compound nomifuensin is a well-known antiparkinsonian and antidepressant. The new compound of general formula () does not increase locomotor activity in mice. In contrast, nomifuensin increases locomotor activity. The absence of the amphetamine-like voluntary movement stimulating effect described above is advantageous from a therapeutic point of view. The compound has significant therapeutic properties. Its toxicity is very low, and its activity is higher than that of nomifuensin. That is, in various tests,
The therapeutic index of the compound is approximately 2-6.8 times that of nomifuensin. In comparing the dopamine-type anti-haloperidol test and the anti-tetrabenazine activity specific to antidepressant effects, the following can be said. The quotient of the ED values of compounds column 2 and column 4 is the highest (55:13=4.2). This means that this compound is a relatively more potent antidepressant compared to an antiparkinsonian. The effective oral dosage for humans of the compounds of this invention is 1 to 1000 mg per day. The invention will now be explained in more detail by way of example. However, this does not limit the scope of the invention. Example 1 8-(ethoxycarbonylamino)-4-(p-
Chloro-phenyl)-2-methyl-1,2,3,
Preparation of 4-tetrahydro-isoquinoline 13.1 g (0.047 mol) of 8-amino-4-(p-
Chloro-phenyl)-2-methyl-1,2,3,
6.8 g (0.0625 mol, 6 ml) of a solution of 4-tetrahydro-isoquinoline in 300 ml of anhydrous benzene
of ethyl chloroformate and 60 ml of anhydrous benzene. The reaction mixture is refluxed for 2.5 hours and the benzene is removed in vacuo. 10ml of residue
of water, made basic with 10 ml of concentrated ammonium hydroxide solution and extracted three times with 100 ml portions of chloroform. The chloroform extracts were combined, dried over anhydrous sodium sulfate, and evaporated.
The residue is then recrystallized twice from ethanol.
Thus, 7.3 g (yield 45.6%) of the title compound are obtained as white crystals. Melting point 155℃. Analysis: C ₁₉ H ₂₁ ClN ₂ O ₂ (344.845) Calculated value (%): C = 66.19 H = 6.14 N = 8.12 Cl = 10.28 Measured value (%): C = 66.79 H = 5.89 N = 8.42 Cl = 10.56 Example 2 8-(ethoxycarbonyl-amino)-4-(p
-chloro-phenyl)-2-methyl-1,2,
Preparation of 3,4-tetrahydro-isoquinoline-hydrochloride 7.3 g (0.0212 mol) of the base prepared according to Example 1 are suspended in 50 ml of ethanol and 10 ml of ethanol saturated with hydrogen chloride are added with cooling. The mixture is clouded by adding 200 ml of ether and complete precipitation of the product is achieved by rubbing the walls of the flask. The precipitated product is collected and washed with ether.
8.1 g (yield almost 100%) of the title compound are obtained as a white powder. Melting point 145-150℃. Analysis: C ₁₉ H ₂₂ Cl ₂ N ₂ O ₂ (381.30) Calculated value (%): C = 59.85 H = 5.82 N = 7.35 Cl = 18.60 Cl ^- = 9.30 Measured value (%): C = 59.74 H = 6.06 N =7.17 Cl=18.54 Cl ^- =9.21 Example 3 Preparation of 8-(ethoxycarbonylamino)-4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline 5.5 g (0.023 mol) of 8-amino -4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline in a solution of 50 ml of anhydrous benzene.
3.4 g (0.031 mol) of ethyl chloroformate and
Add a solution with 30 ml of anhydrous benzene. The reaction mixture is heated to boiling for 3 hours and the benzene is removed in vacuo. The residue was dissolved in 5 ml of water and made basic by adding 30% aqueous sodium hydroxide solution.
Then extract three times with 50 ml of chloroform each time.
The chloroform extracts are combined, dried over sodium sulfate and evaporated. The residue is washed with cold ethanol and recrystallized from ethanol to give 3.0 g (37.5% yield) of the title compound as white crystals. Melting point: 178℃. Analysis: C ₁₉ H ₂₂ N ₂ O ₂ (346.86) Calculated value (%): C = 73.84 H = 7.15 N = 9.02 Measured value (%): C = 73.96 H = 7.51 N = 8.95 Example 4 8-(Ethoxycarbonyl Preparation of 2.6 g (0.01 mol) of N-(2-amino-benzyl)-1-phenyl-2-methyl-amino -1-
Dissolve the ethanol in 30 ml of ether. Add 0.79 g (0.01 mol) of anhydrous pyridine to this solution,
After that, while stirring vigorously, 1.3g (0.012mol)
of ethyl chloroformate is added, cooled and the reaction is carried out 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 portions of ether, the combined ether extracts are dried over anhydrous sodium sulphate and evaporated in vacuo. Thus, 2.8 g of N-[2-(ethoxycarbonylamino)-benzyl]-1-phenyl-2-methyl-
Amino-1-ethanol is obtained as a yellow-white oil. This material can be further cyclized without purification. 2.8 g of the oily residue obtained according to the previous paragraph was dissolved in 40 ml of dichloromethane and, with cooling and stirring, at 5-6° C., the solution was poured into 15.4 ml of concentrated sulfuric acid during 0.5 h. do. The reaction mixture was stirred at this temperature for a further 20 min and 60 min.
Add to g of ice. The mixture is made basic with 30% aqueous sodium hydroxide solution while cooling and stirring and extracted six times with 80 ml portions of chloroform. The organic phases are combined, dried over anhydrous sodium sulphate and evaporated in vacuo. Thus 2.3g
A yellowish white solid is obtained. After recrystallization from ethanol, 2.0 g (64.5% yield) of the title compound are obtained.
Melting point: 174℃. Example 5 Preparation of 8-(butoxycarbonyl-amino)-4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline 2.4 g (0.01 mol) of 8-amino-4-phenyl-2-methyl A solution of -1,2,3,4-tetrahydro-isoquinoline and 100 ml of anhydrous benzene is mixed with a solution of 1.4 g (0.012 mol) of butyl chloroformate and 10 ml of anhydrous benzene, and the reaction mixture is Heat to boiling point. 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 20 ml portions of benzene and extracted 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℃. Analysis: C ₂₁ H ₂₆ N ₂ O ₂ (M = 338.454) Calculated value (%): C = 75.43 H = 6.63 N = 8.37 Measured value (%): C = 75.19 H = 6.44 N = 8.57 Example 6 8-( β-chloroethoxycarbonyl-amino)
-4-phenyl-2-methyl-1,2,3,4
Preparation of -tetrahydro-isoquinoline 3.5 g (0.015 mol) of 8-amino-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline was dissolved in 100 ml of anhydrous benzene.
1.28 g (0.016 mol) of anhydrous pyridine is added and a solution of 2.14 g (0.015 mol) (β-chloro-ethyl)-chloro-formiate and 10 ml of anhydrous benzene is stirred and cooled at room temperature. Add dropwise. The reaction mixture was stirred at room temperature for 1 hour,
Pour into 50 ml of ice-cold water, separate the organic phase and extract the aqueous phase with three 30 ml portions of benzene. The combined organic solutions are dried over anhydrous sodium sulfate and evaporated in vacuo to yield 4.5 g of a pale yellow material. By recrystallizing this product twice from ethanol, 2.7 g (52% yield)
The title compound is obtained as white crystals. Melting point 154℃. Analysis: C ₁₉ H ₂₁ ClN ₂ O ₂ (M = 344.845) Calculated value (%): C = 66.18 H = 6.14 N = 8.12 Cl = 10.28 Measured value (%): C = 66.29 H = 6.24 N = 8.10 Cl = 10.38 Example 7 8-(benzyloxycarbonyl-amino)-4
Preparation of -phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline 4.6 g (0.02 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline Dissolve in 100 ml of anhydrous benzene. To this solution is added 6.2 g of 90% benzyloxycarbonyl chloride (5.2 ml, 0.03 mol).
The reaction mixture is decomposed with 150 ml of water and made basic by adding 30% aqueous sodium hydroxide solution while cooling on ice. Separate the benzene phase,
The aqueous phase was then extracted twice with 150 ml of benzene,
And let it evaporate. The residue is stirred with 150 ml of ether, cooled, the precipitated product is taken up and washed with cold ether to give 4.7 g of a pale yellow powder. Melting point 142-146℃. Recrystallization from ethanol gives 3.6 g (49% yield) of the title compound as white crystals. Melting point 147-148
℃. Analysis: C ₂₄ H ₂₄ N ₂ O ₂ (M = 372.474) Calculated value (%): C = 77.39 H = 6.49 N = 7.50 Measured value (%): C = 77.50 H = 6.78 N = 7.70 2.4 g (0.0064 mol) ) of the above base is suspended in 70 ml of ether and a solution of 0.75 g (0.0064 mol) maleic acid and 5 ml of ethanol is added with stirring. The reaction mixture is stirred for 10 minutes and cooled to 0°C. The precipitated product was taken, washed with a mixture of ethanol and ether, then washed with ether, and recrystallized from ethanol to give 2.4 g (79% yield) of 8-(benzyloxycarbonyl). -amino)-4-phenyl-2-methyl-1,2,3,4-tetrahydro-
Isoquinoline-maleate is obtained as a white powder. Melting point 166-167℃. Analysis: C ₂₈ H ₂₈ N ₂ O ₆ (M = 488.544) Calculated value (%): C = 68.84 H = 5.98 N = 5.73 Measured value (%): C = 68.76 H = 5.95 N = 5.82

Claims (1)

[Claims] First-order general formula () (wherein R represents hydrogen or halogen, and R ⁴
is a lower alkyl group, a halogenated lower alkyl group,
or phenyl lower alkyl group, 4-aryl-2-methyl-1,
2,3,4-tetrahydro-isoquinoline derivatives and pharmaceutically acceptable acid addition salts thereof. 2 8-(ethoxycarbonylamino)-4-(p
-chloro-phenyl)-2-methyl-1,2,3,
4-Tetrahydro-isoquinoline and its pharmaceutically acceptable acid addition salts. 4-Tetrahydro-isoquinoline and its pharmaceutically acceptable acid addition salts. 3 8-(ethoxycarbonylamino)-4-(p
-chloro-phenyl)-2-methyl-1,2,3,
An acid addition salt of the derivative according to claim 2, which is 4-tetrahydro-isoquinoline-hydrochloride. 4 General formula () (wherein R represents hydrogen or halogen, and R ⁴
is a lower alkyl group, a halogenated lower alkyl group,
or phenyl lower alkyl group, 4-aryl-2-methyl-1,
In the method for producing a 2,3,4-tetrahydro-isoquinoline derivative and a pharmaceutically acceptable acid addition salt thereof, the following general formula (), (wherein R has the above meaning) A compound represented by the following general formula (), Hlg-COOR ⁴ () (wherein Hlg represents halogen and R ⁴ has the above meaning , ), optionally converting the compound of formula () into a pharmaceutically acceptable salt. 5 8-(ethoxycarbonylamino)-4-(p
-chloro-phenyl)-2-methyl-1,2,3,
In preparing 4-tetrahydro-isoquinoline and its hydrochloride, starting materials of formulas () and () are used, where R is a chlorine atom in the para position, ^R4 is an ethyl group and Hlg is a halogen, If desired, the 8-(ethoxycarbonylamino)-4-(p-chloro-phenyl)-2 thus obtained
-Methyl-1,1,3,4-tetrahydro-isoquinoline is converted into hydrochloride.Claim 4
The method described in section. 6 The following general formula () (wherein R represents hydrogen or halogen, and R ⁴
is a lower alkyl group, a halogenated lower alkyl group,
or phenyl lower alkyl group, 4-aryl-2-methyl-1,
In the method for producing a 2,3,4-tetrahydro-isoquinoline derivative and a pharmaceutically acceptable acid addition salt thereof, the following general formula () in the presence of an acid ^catalyst ; and, if desired, converting the compound of formula () into its pharmaceutically acceptable salt. A method characterized by: 7 8-(ethoxycarbonylamino)-4-(p
-chloro-phenyl)-2-methyl-1,2,3,
In preparing 4-tetrahydro-isoquinoline and its hydrochloride, starting materials of formula () in which R is a chlorine atom in the para position and R ⁴ is an ethyl group are used, and the 8-tetrahydro-isoquinoline thus obtained is optionally used.
7. A process according to claim 6 for converting (ethoxycarbonylamino)-4-(p-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline into the hydrochloride salt. 8 The following general formula () (wherein R represents hydrogen or halogen, and R ⁴
is a lower alkyl group, a halogenated lower alkyl group,
or phenyl lower alkyl group, 4-aryl-2-methyl-1,
Containing at least one 2,3,4-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. An antidepressant consisting of 9 The following general formula () (wherein R represents hydrogen or halogen, and R ⁴
is a lower alkyl group, a halogenated lower alkyl group,
or phenyl lower alkyl group, 4-aryl-2-methyl-1,
Containing at least one 2,3,4-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. An anti-Parkinson's drug consisting of