JPH04500815A - 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalene derivative, its production method and its use as a pharmaceutical - 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] 2-amino-7-carbamoyl-1,2,3,4-tetra-11 idronaphthalene Derivatives, their preparation and their use as pharmaceuticals The present invention provides novel 2-amino-7 -Carbamoyl-1,2,3゜4-tetrahydronaphthalene derivative and its production method and its use as a pharmaceutical. 2-amino-7-carbamoyl-1,2 ゜3.4-Tetrahydronaphthalene derivative (2-amino-7-carbamoyltetra Toralin derivative) corresponds to general formula 1.

[In the formula, Rt represents an alkyl group of 01 to C1, Rt is hydrogen, and an alkyl group of C1 to Cat. Alkyl group, C3-C alkenyl group, Cs-Cs (R' is hydrogen, C1-C 4 represents an alkyl group or acyl group, R1 represents an alkyl group of C1 to C, and X represents Hydrogen, hydroxyl group, norogen, C8-C1 alkyl group, ]-]romethyl group C5- It represents a C6 alkoxy group, and n represents an integer of 1, 2, 3, 4.5 or 6. ) and R3 represents hydrogen or a C5-C, alkyl group. ] -R1 is C2 to C1 may be an alkyl group, where R1 is a C9 to C++ alkyl group, or a C3 to C4 alkyl group. Alkenyl group, Cs-C4 alkynyl group, -(CHt), -OR' (R' is water It may be a base, a methyl group, an ethyl group, or an 01-C4 alkylcarbonyl group, n may be an integer of 1.2, 3.4 or 5. ), and R3 is Preferred are compounds of general formula 1 which may be hydrogen, an 01 to C4 alkyl group.

In particular, R1 may be an ethyl group, a propyl group or a butyl group, and R1 may be a C5 ~C7 alkyl group, C1-C1 alkenyl group, Cm ~C4(7)7/I/ Quinyl group, -(CHt), -OR' (R' is methyl group, ethyl group, acetyl group , a trifluoroacetyl group, or an ethylcarbonyl group, where n is 1.2. It may be an integer of 3 or 4. ), R1 is hydrogen, a methyl group, Preference is given to compounds of general formula 1 which may be ethyl or propyl groups.

2-amino-7-carbamoyl-1,2,3,4-tetrahydronaf of the present invention Talen (2-amino-carbamoyltetralin derivative) has at least one It has a carbon atom with a chiral center, and also has several asymmetric centers according to its substitution pattern. Therefore, a wide variety of stereochemical isomers may exist.

As an example, substituted 2-amino-7-carbamoyl tetides of general formulas 1a and ib below: Mention may be made of the isomers of lalin.

The present invention relates to single isomers and mixtures thereof, as well as their corresponding physiological It relates to acid addition salts with inorganic or organic acids suitable for. Preferred acid addition Salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethane Sulfonic acid, toluenesulfonic acid, benzenesulfonic acid, lactic acid, malonic acid, succinic acid Salts with acids, maleic, fumaric, malic, tartaric, citric or benzoic acids It is.

For the purposes of the following, unless otherwise specified, general The following definition applies.

Alkyl groups are usually unbranched or branched carbonized groups having from 1 to 12 carbon atoms. Represents a hydrogen group, preferably a lower alkyl group, and one or more halogen atoms (preferably or fluorine atoms), and they may be substituted with the same type of atoms. may be different. Lower alkyl groups typically have from 1 to about 6 carbon atoms. represents an unbranched or branched hydrocarbon group having Examples include methyl, ethyl ru, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, Neopentyl, hexyl, isohexyl, heptyl, isohbutyl, octyl and and isooctyl groups.

Alkenyl groups usually have 3 to 6 carbon atoms, 1 or more double bonds, preferably It preferably represents a linear or branched hydrocarbon group having l double bonds, and is optionally substituted with multiple halogen atoms (preferably fluorine atoms) They may be of the same type or different atoms. 3 to about 4 carbon sources A lower alkenyl group having one double bond is preferred. 3 or 4 carbon Particularly preferred are alkenyl groups having atoms and one double bond. For example, Lyle, 2-butenyl, 3-butenyl, isopropenyl, pentenyl, isopentene Nyl, hexenyl, isohexenyl, heptenyl, isohebutenyl, octenyl and isooctenyl group.

Alkynyl groups usually have 3 to 6 carbon atoms, preferably 1 or more. represents a straight or branched hydrocarbon group having a triple bond of l. 3 to about 4 charcoal has an elementary atom, has one triple bond, and has a halogen atom, preferably a fluorine atom. , or optionally by multiple halogen atoms which may be the same or different. An optionally substituted lower alkynyl group is preferred. has 3 carbon atoms, l Particularly preferred are alkynyl groups having a triple bond of

By way of example, propargyl and 2-butynyl groups may be mentioned.

The acyl group is usually a benzoyl group or a linear or is an alkylcarbonyl group in which a branched lower alkyl group is bonded to a carbonyl group. , and the alkyl group has one halogen atom, or even if they are the same, they are different. may be optionally substituted with a plurality of halogen atoms. Charcoal below 4 Alkyl groups having elementary atoms are preferred. Examples of these are: can be mentioned. i.e. acetyl, trifluoroacetyl, ethylcarbonyl, Lopylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutyl It has a carbonyl group.

Particularly preferred are alkoxycarbonyl groups having 1 or 2 carbon atoms in the alkyl group. Delicious. Examples include the following alkoxycarbonyl groups. That is, methoxy Carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl There are carbonyl, butoxycarbonyl or isobutoxycarbonyl groups.

The alkoxycarbonyl group can be represented by the following formula, for example.

-COO-alkyl Here, the alkyl group is a straight-chain or branched carbonized group having 1-12 carbon atoms. It is a hydrogen group. Lower alkoxycarbonyl groups having 1 to 6 carbon atoms are preferred. stomach. Particularly preferred are alkoxycarbonyl groups having 1 to 4 carbon atoms in the alkyl group. Delicious. Examples include the following alkoxycarbonyl groups. That is, methoxy Carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl There are carbonyl, butoxycarbonyl or isobutoxycarbonyl groups.

Unless otherwise stated, halogens include fluorine, chlorine, bromine and, to a lesser extent, It represents the inferior form of iodine.

Pharmaceutical properties This novel compound or its physiologically acceptable acid addition salts have useful pharmaceutical properties. It has effects on hypertension, tachycardia, and prolactin secretion, especially on the central nervous system. do. Presynaptic effects of compounds of the invention with simultaneous postsynaptic dopamine antagonism Particular emphasis should be placed on dopamine antagonism.

For example, as a result of examining the influence of presynaptic dopaminergic neurons, the following The effect of the compound on suppressing dopamine synthesis was confirmed.

A Near-carbamoyl-2-(N,N-dipropylamino)-1゜2.3.4- Tetrahydronaphthalene hydrochloride B: 2-(N,N-dipropylamino)-7- Methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride C:2 -(N-allyl-N-propylamino)-7-carbamoyl-1,2,3,4- Tetrahydronaphthalene hydrochloride D: 2-(N-allyl-N-propylamino) -7-Methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride E: 2-(N-butyl-N-propylamino)-7-methylcarbamoyl-1, 2,3,4-tetrahydronaphthalene hydrochloride FNia-methylcarbamoyl-2-(N-phenylethyl-N-propylamino )-l 2,3.4-tetrahydronaphthalene hydrochloride G: 2-(N-butyl-N-propylamino)-7-carbamoyl-1,2,3 ,4-tetrahydronaphthalene hydrochloride (melting point: 221 to 223°C) [In the table below, the initials assigned to the above compounds are used in place of the names of the compounds. The symbols (+) or (-) for optical isomers are added as appropriate.

] Confirmation of inhibition of dopamine synthesis J, R, Walters and R, H, Roth (Na unyn-3cbmiedeberg's Arch, Pharmacol, 296. (1976) 5). For this method, 10/kg of the substance to be investigated was administered subcutaneously to each of 5 animals. 5 minutes have passed After that, it occurs as a result of the blockage of the presynaptic pulse line (pulse 1ine). eliminate the influence of postsynaptic feedback loops on the rate of dopamine synthesis Therefore, 750 μ/kg of γ-butyrolactone was administered intraperitoneally. γ-butyrolact Administration of drugs results in a rapid increase in dopa or dopamine synthesis. Another 5 minutes passed After that, 3-hydroxybenzylhydride was added to suppress the decarboxylation reaction of dopa. Radin hydrochloride 200 μ/kg was administered intraperitoneally. 40 minutes after administration of the study substance , the animals were killed and the striatum was removed. Using HPLC with electrochemical detector The content of dopa was measured (standard substance: dihydroxybenzylamine).

The rate at which the test substance inhibited the accumulation of dopa stimulated by γ-butyrolactone was 'C was determined in comparison with control animals administered 0.9% sodium chloride solution.

The results of this experiment are listed in the table below.

Substance Dosage Comparison with control animals administered NaCl solution (■/kg subcutaneous administration) Dopa accumulation inhibition rate (%) A 10 86 (+)-A Io 90 B 10 73 (+)-81075 (+)-C1083 (+)-01076 (+)-E 10 84 (+)-F 10 85 (+)-G 10 85 Confirmation of postsynaptic dopaminergic effect using MP/TP model Neurotoxin l-meth -4-phenyl-1,2,5,6-titrahydropyridine (MPTP) (J , W. Langston et al., 5science 219. (1 The pharmaceutical properties of 983) 979) make it possible to use it in animal models of Parkinson's disease. It is possible to use

Irreversible neurological symptoms induced extensively in humans and monkeys by MPTP has clinical, pathological, biochemical and pharmaceutical manifestations similar to idiopathic Parkinson's disease. (S, D, Markey et al., Nature 31.1 ．． (1984) 464), the reason for this convincing agreement is that MPTP Brain damage that is destroyed by degenerative processes even in the natural occurrence of Parkinson's disease This is due to the fact that it selectively destroys small groups of dopaminergic neurons in the brain. Ru.

The cause of idiopathic Parkinson's disease is MPTP produced in vivo or similar substances. There is a possibility that the compound [S, H, Synder, Nat. ure 311 (1984) 514). MPTP Parkinson's clinical picture Clinical manifestations are probably a result of the unique metabolism of <MPTP, but until now human Other than that, it was only observed in monkeys.

Therefore, the MPTP model that appeared in rhesus macaques is based on a synergistic model with dopamine antagonism. Suitable for testing the effects of post-pushes substances.

For this purpose, approximately 6 μ/kg of MPTP was administered until the following symptoms appeared in the rhesus macaque: (Body weight) The following doses were administered. That is, it becomes immobile and has no access to water and food. exhibits typical flexed posture with inability to speak, and occasional catalepsic symptoms. The limbs become stiff and stiff while the passive movements of clonic spasm occur. cut off This is a symptom.

Drugs such as B-HT920, Levodopa and apomorphine A single intramuscular administration of a long/kg pamine agonist maintains this status picture for 4 to 5 hours. Reduce over time. Then, the above symptoms occur again.

Intramuscular administration of the compound of the present invention (0.1 to 3.0 μ/kg) 1. , Taatoha, MP There was a notable improvement or even reduction in the appearance of the condition in monkeys treated with TP. do not have. Alleviates Parkinson's disease-like symptoms caused by B-HT920 Even antagonism to the effect of B-HT920 0.1■/k While administering 0.1-3.0 mg/kg of the compound of the present invention with g Ghezaru remains in a state of bradykinesia and, in addition, is unable to consume water and food. Not in. This suggests that these substances have postsynaptic dopamine antagonistic effects. It can be concluded that there is.

The results are shown in the table below.

Substance Dose Effect A 3 mg/kg B-HT 920 antagonistic effect 08 3 mg/ kg B-6 antagonistic effect on HT 920 9(+)-B l mg/kg B- Antagonism to HT920 9(+)-C3mg/kg B-HT920 pair Antagonism 0(+)-D 1. mg/kg Antagonism to B-HT 920 The synthesis of the compound of the present invention is 0.1 mg of B-HT920 per 1 kg of body weight. The following synthetic routes were followed, with individual routes described in detail thereafter.

Synthesis method ■ 2,7-Diami2-1,2,3.4-tetrahydrona used as starting material Phthalene (2) can be synthesized by a conventional method, e.g. , separated into two enantiomers using a method via the corresponding tartrate. be able to.

■ The protection of the amino group (R8) required for proceeding with the synthesis can be achieved using the current state of the art. How to know from CM, Bodanszky.

Pr1ciples of Peptide 5ynthesis, Spr inger-Verlag, Berlin1984, page 84; T , W. Greene, Protective Groups in Organic Synthesis ve Groups in Organic 5ynrhesis), Joh n Wiley and Sons, New York N, Y, 1981. page 218~; Houben-Weyl, Methods in Organic Chemistry (M ethoden der organischen Chen+ie), Vo lume B 4゜Georg Thieme verlag, Stuttg art 1983. page 144). Here, Arco oxycarbonyl group (or aralkoxycarbonyl protecting group), especially tert-butyl Protection of the amino group using a toxycarbonyl (BOC) protecting group is preferred.

Type 3 7-amino-2-tert-butoxycarbonyl amine as follows: do-1,2,3,4-tetrahydronaphthalene (in its enantiomeric pure form) optional), for example, a compound that acts as a base, preferably , for example, in the presence of an organic nitrogenous base such as triethylamine in an inert solvent. using a method known per se using tert-butylpyrocarbonate. Can be synthesized. Organic solvents that do not change under the applied reaction conditions are usually Useful as an inert solvent. These preferably include, for example, tetrahydro Ethers such as furan or glycol dimethyl ether (Glyme) are listed. It will be done.

A ■ Selectively protected racemate or R- or S-diamino-1,2 of general formula 3 ,3,4-tetrahydronaphthalene derivatives, preferably racemic or or 5-7-amino-2-tert-butoxycarbonylamide-1,2,3, 4-Tetrahydronaphthalene can be produced using methods known from the current state of the art and A method particularly suitable for the synthesis of acylanilides [C, Ferri, Organic synthesis reaction these>, GeorgThien+e Verlag, Stuttga rt　1978. page 222~) to create the corresponding protected 7- Acylamide-2-amino-1,2,3゜4-tetrahydronaphthalene derivative or 7-acylamido-2-tert-butoxycarbonylamide-1,2, It can be converted to 3,4-tetrahydronaphthalene. These are shown in general formula 4 It is something that

In this case, selectively protected 2,7-cyamitsu I.

2.3.4-Tetrahydronaphthalene derivatives or preferred compounds thereof 7-amino-2-tert-butoxycarbonylamide-1,2,3, Base in an inert solvent with a reactive carboxylic acid derivative of 4-tetrahydronaphthalene Reaction in the presence of is preferred. Reactive carboxylic acid derivatives are generally Carboxylic acid halides and carboxylic acids optionally substituted by halogen atoms It is understood to mean anhydrous. This type of carboxylic acid derivative is known or by known methods [Houben-Weyl, Methods in Organic Chemistry ( Chemie).

Volume ■ and Volume E 5, Georg Thieme Ve rlag, Stuttgart 1952 or 1985). be. In this case, aliphatic carboxylic acid bromide, carboxylic acid chloride or aliphatic Carboxylic acid anhydrides are preferred. Acetate bromide, acetic chloride, acetic anhydride and anhydride Particularly preferred is trifluoroacetic acid.

All normal basic compounds can be used as bases and these are used in base reactions It is suitable for These include, for example, alkali metals or alkaline earth metals. hydroxides, carbonates or alcoholades of the genus, preferably tertiary amines, Particularly preferably triethylamine is used.

For example, hydrocarbons such as Hensen, toluene, xylene or petroleum fractions, or For example, halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride , or preferably diethyl ether, glycol dimethyl ether (Gly me), diglycol dimethyl ether (Diglyme), and particularly preferred Alternatively, organic solvents such as ethers such as tetrahydrofuran are commonly used as inert solvents. used for. These are those that do not change under the reaction conditions.

■ Cleavage of protecting group R8 from the 2-position amino group of tetrahydronaphthalene of general formula 4 can be carried out using methods known from the current state of the art (the protection group type is Depends on the type and is influenced by the chemical stability of the acylanilide partial structure> cT, w, Greene, Protecting Groups in Organic Synthesis, John Wiley and 5ons, New York 1981. page 2 18- ; U, Petersen in Houben-Weyl, Organic Chemistry Method in Chem ie), Volume E 4゜Georg Thieme Verlag, Stuttgart 1983. page 144), from now on, general An acylated 1,2,3,4-tetrahydronaphthalene derivative of formula 5 is obtained.

■ 7-acylamino-2-amino-1,2,3,4-tetrahydrona of general formula 5 Several methods for converting primary amino groups in phthalene derivatives to tertiary amine-1 can also be known from the current state of technology. Tetrahydronaphthalene of general formula 6b Derivatives are those obtained from CG, Spielberger in H ouben-Weyl, Methods in Organic Chemistry rganischen Chemie), volumeXI/1゜Georg Thieme Verlag, Stuttgart 1957. page 24; J, 7-chi (March), Adva, nced Organic Chemistry, 3rd Bdition, John Wileyan d 5ons, New York 1985. page 1153) Here, when R1=R1, alkylation is performed in one step, and R1 and R2 are equal. If not, react an intermediate product of type 6a to synthesize the corresponding tertiary amine 6b. to be accomplished.

In the previous step of this synthesis, a protecting group (R'' = R5) (e.g. benzyl group, etc.) is added to the synthesis stage. It may be necessary to introduce it under certain conditions.

The protecting group that selectively protected the amino group can be cleaved again or with the current technology. A method that can be learned from the level (T, W, Greene).

Protecting Groups in Organic Synthesis, John Wiley and 5ons, New York N, Y.

1981, page 272~ and cited references]. (9→13a→14a or 12→13b of the synthetic routes on page 10) →See 14b).

The alkylation reaction is preferably performed, for example, methyl halide, ethyl halide. , propyl halide, isopropyl halide, butyl halide, halogen benzyl halide, phenethyl halide, 0-methylbenzyl halide, halogen m-methylbenzyl halide, p-methylbenzyl halide, l-halogeno-3-phenyl Alkyl or alkyl such as phenylpropane and l-halogen, /-4-phenylbutane Ralkyl halide or sulfuric acid ester, tosylic acid ester, methanesulfonic acid ester Can be done using ster or trifluoromethanesulfonic acid ester Ru. Halogen or halide here represents chlorine, bromine or iodine.

This type of halide, sulfate ester, methanesulfonate ester, trifluoride Lomethanesulfonic acid ester or tosylic acid ester is known or It can be synthesized by a known method.

Unchanged under the reaction conditions or itself as a reactive component in the reaction process All inert organic solvents that do not have any adverse effects are suitable as reaction solvents. Kaka Solvents include methanol, ethanol, propatool or isopropatool. alcohols or halogenated substances that do not themselves act as alkylating agents Hydrocarbons, preferably e.g. fluorinated hydrocarbons, methylene chloride, chloroform or halogenated hydrocarbons such as carbon tetrachloride, particularly preferably diethyl ether. di-n-butyl ether, tert-butyl methyl ether, glycol Dimethyl ether (Glyme), diethylene glycol dimethyl ether (D iglyme), tetrahydrofuran, dioxane, and ethers such as , acid amides such as hexamethylphosphoric triamide or dimethylformamide. be.

It is also possible to use known solvents in mixtures.

Furthermore, when a tertiary amine of general formula 6b is alkylated in two steps, In the second step of the alkylation reaction, dimethylforma was used as the reaction medium. It has been found that using mido can produce special effects.

Also, in the one-step reaction of a primary amine of type 5 to a tertiary amine of type 6b, It was also found that using dimethylformamide as a solvent is effective. won.

This reaction is preferably carried out by e.g. an alkali metal or alkaline earth metal carbonate. It is carried out in the presence of an acid scavenger such as a salt or bicarbonate.

■ Furthermore, the primary amino group of the diamine of general formula 5 can be a suitable aldehyde or ketone. or the corresponding second or corresponding derivatives via reductive amination reactions with suitable derivatives thereof. or can be converted to a tertiary amine. Note that this reductive amination reaction 7-acylamino-2-amino-1,2,3,4-tetrahydronaf of general formula 5 It is influenced by the molar ratio of the carbonyl compound used in the talene.

This reaction can be performed either directly or with a specific Schiff base as an intermediate. Proceed along the following route.

The aldehydes or ketones used as educts are known per se or can be synthesized by a known method [Aldehyde: Houben-Weyl , Methods in Organic Chemistry Chemie), Volume■/l and E5, Georg Thiem eVerlag, Stuttgart 1954 or 1983; Ketone: Houben-Weyl, Methods in Organic Chemistry Organischen Chemie), Volume■/2a and 2b , Georg Thieme Verlag, Stuttgart 197 3 or 1976).

Examples of suitable aldehydes or ketones include, for example, formaldehyde, Acetaldehyde, propionaldehyde, acetone, butyraldehyde, ben Dualdehyde, phenylacetaldehyde, 2-phenylpropionaldehyde , 3-phenylpropionaldehyde, 4-phenylbutyraldehyde, etc. It will be done.

Schiff bases are synthesized in an inert organic solvent, optionally in the presence of a catalyst, and if necessary If so, it is synthesized in the presence of a water scavenger.

In this case, the Suitable inert solvents are inert organic solvents that do not have an adverse effect on the components.

Such solvents preferably include, for example, methanol, ethanol, propatool or alcohols such as isopropanol, or, for example, diethyl ether. tert, tert-butyl methyl ether, di-n-butyl ether, glycol Dimethyl ether (Glyme), diethylene glycol dimethyl ether (D iglyme), tetrahydrofuran, or e.g. Halogenated hydrocarbons such as lomethane, trichloromethane, carbon tetrachloride, or e.g. For example, petroleum fractions, hydrocarbons such as benzene, toluene, xylene, and particularly preferred For example, dimethylformamide, acetamide, hexamethylphosphate triphosphate. Amides such as amides, or carboxylic acids such as formic acid or acetic acid, or , mixtures of the abovementioned solvents may also be mentioned.

Hydrogen acid can optionally be used as a catalyst. Such catalysts preferably include , for example, mineral acids such as hydrochloric acid or sulfuric acid, or optionally fluorine, chlorine, and/or Includes organic carboxylic acids with 1 to 6 carbon atoms optionally substituted with bromine. Ru. Examples of this type of acid are formic acid, acetic acid, trifluoroacetic acid, and trichloroacetic acid. There is acetic acid or propionic acid. For example, methanesulfonic acid, trifluorometa sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc. an alkyl having 1 to 4 carbon atoms which may be optionally substituted with a halogen atom, Sulfonic acids having groups or aryl groups also belong to the group of preferred acids.

The water produced during the reaction can be purified, if necessary, by adding a water scavenger, e.g. phosphorus pentoxide. or preferably removed from the reaction mixture with molecular sieves, or In addition, if the solvent is mixed with the used solvent, the reaction should be carried out during or after the reaction is completed. removed from the reaction mixture, for example by distillation.

The reaction is usually carried out at a temperature ranging from 20°C to the boiling point of each reaction mixture, preferably It is carried out at 20°C to 100°C.

The boiling point of each azeotrope is the opposite of the solvent or solvent mixture used in each reaction. Suitable for azeotropic distillation with water produced during reaction.

The reaction is usually carried out under normal pressure, but may also be carried out under increased pressure or reduced pressure.

For the synthesis of secondary amines, equimolar amounts of 7-acetamido-2-amino-1,2,3 , 4-tetrahydronaphthalene and carbonyl compounds are used. 3rd ami In the synthesis of carbonyl compounds, the carbonyl compound is used in excess.

Schiff salts produced as intermediates in the synthesis of secondary or tertiary amines groups or enamine or iminium salts in water or in alcohols, ethers or or a halogenated hydrocarbon or a mixture thereof in an inert organic solvent. Hydrogenated with hydrogen in the presence of a medium or hydrogenated complex (optionally in the presence of a catalyst) It can be reduced in the body. In this way, the reduction reaction can be carried out in the same reaction medium or in a further solvent. It can also be carried out in a medium or in a further solvent mixture. In the latter case, the first The solvent or solvent mixture used is preferably distilled off.

Raney nickel, palladium, palladium on animal charcoal, platinum and preferably palladium Dium charcoal (containing 10% Pd) is an example of a catalyst used for catalytic reduction with hydrogen.

Boron hydride complexes are preferably used in reductions using hydrides. Hydrogenation Sodium boron is particularly preferably used.

remain unchanged or at least not significantly changed under the chosen reaction conditions; Therefore, all inert organic solvents that do not have an adverse effect on the reaction process are suitable as solvents. are doing. Such solvents include, for example, dimethylformamide or hexamethyl Amides such as phosphoric acid triamide, or, for example, diethyl ether, tert -butyl methyl ethyl, di-n-butyl ether, glycol dimethyl ether ter (e of cry), diglycol dimethyl ether (Diglyme), tet Ni-chills such as hydrofuran and dioxane, and particularly preferably e.g. Alcohols such as , methanol, ethanol, propanol or isopropanol There are many types of tools.

When reducing using hydrogen, the reaction is carried out under known reaction conditions, and for catalytic reduction. [K, Harad a in Patai, rChemistry of carbon-nitrogen double bonds J (The Chem istry of the Carbon-Nitrogen Double Bond).

Interseience Publishers, London 1970 ．． page 276 and cited literature, P, N, Rylander (Ry 1aride r), catalytic hydrogenation with platinum metal (CaLalytieHydrogenati on over PIatinun+Metals), Academic Press, New York 1967, page 123; F, Mo 1ler and R, 5ehrote in Houben-Weyl.

Methods in organic chemistry Chemie).

VolumeXf/1. Gcorg Thieme Verlag, Stu ttgart 1957. page 602; W, S, Emmannon (Em erson), Orgar+ic Reactions, 4 (1949) 174; E, M, Haneock et al., Org, 5yn th,, C011,V (11゜III (1955) 501;, J, C, D Robinsor+ et al., Oig, 5ynth, Co11. Vol, III (1955) 717; D, M, Fulcolum (Maleo lrn) et al., Org, 5ynth, Co11° Vol, IV (196 3) 603),.

The hydrogenation reaction is preferably carried out in methane at 20-50°C, particularly preferably at 20°C. At a temperature of 5-35℃, 0.102-0.816kg/al (0.1-O58Mp a), particularly preferably 0.408 to 0.612 kg/crl (o, 4 to o, It was carried out using palladium charcoal (containing 10% Pd) under hydrogen pressure of a Mpa). Ru.

If the process of the invention is carried out using a hydrogenated complex, an inert solvent is preferred, 2. < using a carboxylic acid amide, particularly preferably dimethylformamide; The amine is reacted with the corresponding rdehyde or tetra in an lbot reaction at a temperature of lOO°C. After the reaction is completed, the solvent is distilled off under reduced pressure, and the residue is dissolved in an organic solvent (preferably 2 or alcohol), and the mixture is dissolved or dispersed in at least equimolar amount of reducing agent (preferably hydride complex, particularly preferably sodium borohydride [7 When the reaction is complete, the mixture is decomposed with water and the reaction product is from the reaction mixture and purify it by appropriate chromatography. It has been established that it is advantageous to isolate or purify by other methods. It has been certified.

■ The synthesis of the compounds of the invention within the framework of a reductive amination reaction (Leukar!-Wallah) reaction route, and is carried out by different synthetic methods. ·)be able to. This Ikkardt-Balak reaction (especially for the synthesis of A tertiary amines) Are suitable. , 6-type reduction)-type 717 reaction conditions are known ( Autorenko! 1ektiv, Organikum, VBBl)eu tseher Verlag der Wissensehaften, Be riin 1986 (, 16ttlCditior+) page 491 ; C, Fu, Tsuno (Ferri), Reaction of organic synthesis (Re’action) der organischen 5yntt+csis), Georg T h1e[i+e　VerJag.

Stuttga 1978. Page 133 and cited documents; F, Mo1l er and R, 5 chroner in Houben-Weyl, Organic Chemistry Method (Metbodender organisehen Chemi e), Volume XI/1. Georg Thieme Verlag .

Stuttgart 1957. page 648).

The tertiary amine of the present invention of general formula 6b can also be obtained by combining the above synthetic methods. Wear.

6b: R’4H, R24H7: R’ヰH, R2kiH■ The acyl group is cleaved to form a derivative with an additional aniline-based amino functional group. . A diamine of general formula 7 is obtained from this reaction.

Hydrolysis of arylamides of this type is known, for example for compounds of general formula 6b. carried out by reacting a rubonic acid amide with an alkali metal hydroxide or an acid. CF, Moeller in Houben-Weyl.

Methods in organic chemistry Chemie).

Volume XI/1. Georg Thieme Verlag, St uttgart 1957. page 927~ and page 934~; R, M, Herbst et al., Org, 5ynLh.

Co11. Vol, U (1943) 491; P, E, Fanta ) et al., Org, 5ynth,.

Co11. Vol. m (1955) 66).

Reaction with dilute mineral acids under boiling conditions, especially hydrolysis using 2N hydrochloric acid, is preferred. In this case, the corresponding hydrochloride is immediately formed in the lbot reaction and is present in the reaction mixture. The reaction solvent and volatile components of are distilled off (preferably under reduced pressure) and then the organic solvent Slurry the hydrochloride in (preferably alcohol, particularly preferably ethanol) This is then filtered and then dried to produce a reaction that can separate the hydrochloride. preferable.

■ The 2-amino-2-cyanotetralin derivative can be synthesized by a method known per se. (Organikum, Deutscher l/erlag der W issenschaften, 17th Edition, Berlin 1988 Page 547; 7 T-Gel Practical Organic Chemistry Text (Vogel 's Textbook of Practical Organic Chem istry), 4th Edition, Longman, London 1978゜page 703), i.e. Type 7 2,7- protected as appropriate Jiami Two 1. 2. 3. 4-tetrahydronaphthalene derivative, for example , reacted using potassium cyanide in the presence of copper cyanide (0), the so-called It can be carried out through the Sandmeyer reaction route.

When carrying out the process of the invention, diazonium salts are usually produced as intermediate products that can be separated. to be accomplished. However, it is advantageous to carry out this reaction without separating this intermediate. That's what I found out.

This reaction requires water, methanol, ethanol, propatool or isocarbons. Alcohols such as propatool, or formamide or dimethylform Amides such as amides are suitable as inert solvents, with water being the preferred solvent.

Mineral acids such as sulfuric or phosphoric acid are usually used as acids, with sulfuric acid being preferred. but However, it is also possible to use mixtures of these acids.

Also, alkali metal cyanide such as sodium cyanide or potassium cyanide Usually used as a nitrile source, potassium cyanide is preferably used.

This reaction is usually carried out at -10°C to +50°C (preferably -5°C to +50°C). Performed over a temperature range.

This reaction is usually carried out at normal pressure, but it can also be carried out under elevated or reduced pressure. [For example, 0.51-5.1 kg/al (0.5-5 bar)].

In the method of the present invention, usually, first, a nitrite aqueous solution is mixed with 2-aminotetate in a sulfuric acid aqueous solution. larin, and then the reaction solution is treated with an alkali metal cyanide, preferably a cyanide. This is done by treating with potassium and copper(I) cyanide. cyan It is optional whether or not the chemical steel (I) is used after being dissolved in water. Usually, the front Salt does not separate.

The final treatment of the reaction is usually carried out using an aqueous ammonia solution or an alkali metal solution. by neutralizing the reaction mixture using hydroxides or carbonates; The thus obtained FIJ-base is extracted and reacted with the corresponding acid. Therefore, the target salt can be obtained from this extract.

On the other hand, the corresponding amide of type 9 was prepared in the presence of methanesulfonic acid and a small amount of water. 2-Amino-7-diatu 1,2,3,4-tetrahydronaphthalene derivative 8 can be obtained by further reacting. On the other hand, cyano compound 8 is When hydrolyzed using acid, the corresponding tetralin carboxylic acid derivative of type 10 You get a body. However, the nitrile group can be hydrolyzed to form an aminocarbonyl group. It is also possible to use other strong mineral acids suitable for production. Addition of nitrile The water splitting reaction is performed using CP, N, and 7-ampagnon, which are known per se from the current state of the art. (Compagnon) et al., Ann.

Alternatively, water is used as the solvent. The reaction takes place from 0°C to the boiling point of the reaction mixture. It is carried out at a range of temperatures and under normal pressure. 20°C to 120°C is preferred.

XI The tetralin carboxylic acid derivative IO can be prepared by methods known in the literature [J. Marc h), Advanced Organic Chemistry, 3rd Ed ition, New York N, Y, 1985. page 388 and [Reference] [Reference] The conversion of tI (C ferri-(Fe rri), Organic Synthesis L: 1) Reaction (Reaction) ischen 5ynthesis), Georg ThiemeVerla g, Stuttgart 1978. Page 192 and cited documents; O rganicum.

Deutscher Verlag der Wissensehaften, 17th Edition, Berlin1988 page 422. J. , S., Pizey, 5 synthetic Reagents.

Volume, 321. Wiley, New York N, Y, 1 974].

Subsequent reaction of the resulting acid halide or acid chloride with a primary amine results in the formation of a Corresponding acid amide 12 force <? CC is humiliated, Ferrill Reaction of organic synthesis 5ynthesis), Georg Thieme Verlag, Stutt gart 1978. Page 223 and cited references]. The reaction is carried out in an inert solvent. Then, he was attacked by Yuko J.

In this case, the inert solvent is usually a solvent that does not undergo -C conversion under the reaction conditions. child These preferably include diethyl ether, tetrahydrofuran, nooxane or or ethers such as glycono-1-nodimethyl ether, or t-, di-nocene Hydrocarbons such as petroleum distillates, tolu, xylene, or methane chloride Halogenated hydrocarbons such as carbon tetrachloride are listed. Ru. It is also possible to use mixtures of these solvents.

Type +1 acid l\light or acid chloride 1z amino acid (well, qualified, -20 °C to +100 °C, preferably (performed at -20 °C to +50 °C and normal pressure -1000 °C) .

X■ From the amine group at the 2-position of the tetrahydronaphthalene of general formula 9 or 12, The cleavage of the protecting groups R, S (R'' = R5) depends on the type of protecting group and the carbamoyl moiety. Although it is affected by the chemical stability of the structure, it is possible to use methods known from the current state of the art. [T, W, Greene, organic synthesis] Protecting Groups, John Wileyand 5oz, New York 1 981. page 218 ~; U, Petersen in Houb en-Weyl, Methods in Organic Chemistry Nischen Chemie).

VolumeE 4, Georg Thieme Verlag, Stu ttgart 1983. page 14), 1 of general formula 13a or 13b , 2,3,4-tetrahydronaphthalene derivatives are obtained. For example, amino group from compounds of types 9 and 12 using a pencil group as a protecting group. The cleavage of can be carried out by catalytic reduction using a palladium catalyst, This produces type 13a tetrahydronaphthalene.

13a 14a X■ As explained in ■ and ■, 2-amino-1,2, of general formula 14a or 14b, Converting the secondary amino group in the 3,4-tetrahydronaphthalene derivative to a tertiary amine A number of methods are known from the current state of the art to convert , a tetrahydronaphthalene derivative of general formula 14a or 141) is produced ( G.

Spielberger in Tlouben-Weyl, *In Mechanical Chemistry method (Methodender organischen Chemie), Volume XI/L Georg Thieme Verlag.

Stuttgar mouth 957. page 24 ;, L March , Advanced Organic Chemistry, 3rd Editi on, John Wiley and 5ons, New York 1985 ゜page　1153　). In this case, the reducing agent for the reductive amination reaction is The acid amide group must be selected so that it is not attacked [J, 7-Chi (March), Advanced Organic Chemist ry, 3rd Edition, John Wiley and 5ons, N ew York N, Y, 1985. page 1095).

On the other hand, the alkylation reaction preferably includes, for example, methyl, ethyl, propyl, Sopropyl, butyl, allyl, propargyl, benzyl, phenethyl, 0-methy Rubenzyl, m-methylbenzyl, p-methylbenzyl, O-methoxybenzyl , m-methoxybenzyl or p-methoxybenzyl halide, l-no\rogeno -3-phenylpropane, l-halogeno-3-phenyl-2-propene, l-ha Logeno-4-phenylbutane, 1-/% Logeno-3-(p-chlorophenyl)propylene Ropane, (2-haloethyl)methyl ether, l-halogen-3-methoxypro Pan, (2-)10ethyl)methylsulfide, (2-haloethyl)phenyls Rufide, (3-halopropyl)methyl sulfide, methyl halopropionate, p-(2-haloethyl)methoxybenzene, p-(2-/\loethyl)toluene , (2-haloethyl)-3,4-dimethoxybenzene, (2-haloethyl)-3 -chlorobenzene, (2-haloethyl)-2,4-dichlorobenzene, (2-) \loethyl)-3゜5-dichlorobenzene or (2-halogeno-1-methylethyl) chill) benzene, etc. (here, halogen or halide refers to chlorine, bromine or iodine). an alkyl or aralkyl halide or a sulfuric acid ester derived as appropriate ster, tosylate, methanesulfonate or trifluorometa carried out using sulfonic acid esters.

This type of halide, sulfate ester, trifluoromethanesulfonate ester or tosylate esters are known or can be synthesized by known methods. Ru. Here, for example, those having free phenolic hydroxyl groups or carboxylic acid groups, etc. When introducing a polyfunctional substituent, for example, a pair such as an ether or an ester, The corresponding protected derivatives thereof are first introduced. These ethers or Esters etc. can be processed in subsequent steps, e.g. by ether or ester decomposition. Alternatively, it is converted by hydrolysis into the required derivative in a conventional manner. Gakaruta For example, l-bromo-2-(4-methoxyphenyl)ether derivatives include Mention may be made of Ru.

Specific examples of aldehydes or ketones suitable for reductive amination reactions include, for example: , formaldehyde, acetaldehyde, propionaldehyde, acetone, but Tinogeldehyde, acrolein, propargylaldehyde, benzaldehyde, Phenylacetaldehyde, 2-phenylpropionaldehyde, 3-phenyl Propionaldehyde, 3-buenyl acrolein (cinnamaldehyde), 4 -Phenylbutyraldehyde, methoxyacetaldehyde, phenoxyacetoa aldehyde, benzyloxyacetaldehyde, 3-methoxypropionaldehyde methylmercaptoacetaldehyde, 3-methylmercaptopropional Dehyde, (3,4-dichlorophenyl)acetaldehyde, 4-methoxyphenyl acetaldehyde, (3,4-dimethoxyphenyl)acetaldehyde and ( 3,5-dimethoxyphenyl)acetaldehyde.

Furthermore, the compounds of the invention may be prepared starting from a secondary amine as the amine component, e.g. for example, by any other reaction, such as via a Michael! reaction. It can also be synthesized. Specific examples of reaction materials suitable for these other synthetic methods include: For example, there are derivatives of acrylic acid, methacrylic acid, or crotonic acid (C, Ferri.

Reactions of organic synthesis 5 synthesis), G.

Thieme Verlag, Stuttgart 1978. page 173 and cited documents, M, B.

Gasc et al., Tetrahedron 39. (1983) 7 03; H. Pines et al., “Ba5ecatalysed Re actions of Hydrocarbons and RelatedC ”, Academic Press, New York N, Y, 1977, page 423; M, S, Gibson in Patai , rThe Chesnistry of the Am1 no Group''), Interscience, New York N, Y , 1968. Page 61～].

The tertiary amine of general formula 14a or 14b of the present invention can be obtained by combining the above synthesis methods. It can also be obtained by

The following examples illustrate the invention and do not limit it. .

The prefixes (+)/(-) in front of the substance names in the synthesis examples indicate the names of these compounds. However, similar to the dextrorotatory optical isomer, the levorotatory optical isomer is also This means that it can also be carried out with mixtures of or the corresponding racemates.

Example 12,7-diami2-1,2,3.4-tetrahydronaphthalene ena separation of antimers Methanol/water mixture (95:5) 11 to 2.7-cyami2 1.2, 3.4- Dissolve 81.0 g (0.5 mol) of tetrahydronaphthalene and heat to 50°C. Ta. At this temperature, L-(+)-tartaric acid dissolved in 200-methanol was added. . The crystals precipitated after a short period of time were filtered with suction, and each time a 300-ml methanol/water mixture was added. A combined solution (95:5) was added and boiled three times, and recrystallized once from water. Next, the alcohol The salt salt was dispersed in 70° of water and treated with 33 g (0.6 mol) of potassium hydroxide. , and extracted twice using 70 liters of tetrahydrofuran each time. Magnesium sulfate After drying the organic phase using vacuum, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure at 0.06 mmHg (0.08 hPa).

C+)-2,7-diami2-1,2.3.4-tetrahydronaphthalene is colorless Obtained as crystals.

Yield: 9.7g (12%) Melting point: 33-34℃ Boiling point: 108-110℃ (-)-enantiomer via a similar route using R-(-)-tartaric acid. - obtained.

Yield: 9.8g (12%) Melting point = 33-34℃ Boiling point: 108-110℃ In the following examples, (+)-2,7-diamitwo 1. 2. 3゜4-tetraha Hydronaphthalene or (-)-2,7-diamitwo 1. 2. 3. 4-te Pure enantiomeric compounds each using trahydronaphthalene as a starting material I prepared things.

Example 2 (+)/(-)-7-amino-2-tert-butoxycarbonyla Mido-1,2,3,4-tetrahydronaphthalene (+)/(・-)-2,7-diami2-1,2,3.4-tetrahydronut 20 g (0.12 mol) of tanone and 17.1 ml (0.12 mol) of triethylamine mol) in 250 ml of anhydrous tetrahydrofuran. 28.71 nI (0.12 mol) of t-butylpyrocarbonate was dissolved in anhydrous tetrahydride. A solution dissolved in 140 ml of Lofuran was added dropwise at -10''C. Stir for 30 min at 10 °C and then leave until the temperature of the reaction solution reaches room temperature. Ta. The solvent was distilled off under reduced pressure, the residue was dissolved in 500 ml of ethyl acetate, and water was added each time. Washed twice using 100ml. The organic phase was then dried with magnesium sulfate The solvent was then distilled off under reduced pressure, and the residue was recrystallized from diethyl ether.

Yield: 25g (80%) Melting point: 119-121℃ Example 3 (+)/(-)-7-acetamido-2-tert-butoxycarbo Nylamide-1,2,3,4-tetrahydronaphthalene 7-amino-2-tert-butoxycarboxylic acid in 120 J of anhydrous tetrahydrofuran Nylamide-1,2,3,4-tetrahydronaphthalene 25g (95 mmol ) and triethylamine (14.5 m/(100 mmol)) and the solution was It was treated with 9.9 m/(105 mmol) of acetic anhydride at room temperature. The mixture was heated at room temperature for 1 The mixture was stirred for an hour and then 450 d of ice water was added. The precipitated crystals were filtered with suction and mixed with water 2. 00ml, washed with acetone 35- and diethyl ether 6o-, and dried. It was dried by circulating air in the container until the weight became constant.

Yield: 25.9g (93%) Melting point = 193-195℃ Example 4 (+)/(-)-7-acetamido-2-amino-1°2, 3.　 4-Tetrahydronaphthalene hydrochloride 7-aceto° in 300 Tnl of ethanol Amido-2-tart-butoxycarbonylamide-1,2,3,4-tetraha 50 g (0.16 mol) of idronaphthalene were suspended. Add HCI gas to the suspension. was vigorously introduced for about 10 minutes. The temperature rose to 70'C. The suspension was cooled to room temperature. The precipitated crystals were filtered with suction and diluted once with 100% acetone and diethyl ethyl ether. Rinse once with Tel 100-, then dry in a dryer while circulating air under normal pressure. It was dried at room temperature and then at 80°C until constant weight.

Yield: 36g (91%) Melting point: 260℃ Example 5 (+),/(-)-7-acetoTmido = 2-propylamino-1,2 ,3,4-tetrahydronaphthalene hydrochloride (alkylated) Tetra T: To Franc 900nn! Ni (+) / (-) -7-Architoa 83. 8 g (0.41 mol) and 75.13 g (0.61 mol) of propyl bromide were dissolved. treated with 84 g (0.84 mol) of potassium hydrogen carbonate and heated at reflux temperature for 7 hours. Shimata. Next, 75.6 g (0.6 mmol) of odoriferous 4-propyl was added, and the boiling point The mixture was heated again for 7 hours. After cooling to room temperature for 1,000 minutes, filter the filtrate under reduced pressure. The mixture was concentrated to 500 mff of water, treated with 5004 (-) over acetic acid, and washed with 500 mff of water. organic The phase was dried with 1 ml of sulfuric acid (7 g) , the residue was treated with a mixture of methane chloride and methanol (80:20), C', ShiiJ Kagel (particle size 0.063-0.2mm)! -7 tograph i = f [yzo;.

After separating with 1 matogran and E, the eluate was dissolved in concentrated HF7 under reduced pressure, and the residue was dissolved in concentrated HF7. 62. The reaction in r-thyl ether with a solution of hydrochloric acid. It precipitates as salt, which is taken off and placed in a dryer.While air is circulated, the weight is reduced. is constant (Gonaruma 1.'Dry 7', l:, 5 yield @: 43.4g (38%) Hight l1j3-phthalene hydrochloride Dimethi, Rua I-, Lumamide 80Jl (+) / () -7-7-Seto r-F-2-propyl amide, / l, 2,3,4 tetol\ide O-1 monophthalate 7 g (24.8 mmol) of ren hydrochloride and 2.8 g (93 mmol) of butyl bromide mol) and treated the solution with potassium bicarbonate log(100 mmol). 1. The solution was cooled to room temperature and filtered, and the filtrate was removed under reduced pressure. Concentrate to the bottom, treat with 250ml of water, and add 200Wl of ethyl acetate for each time. It was used and extracted twice. The combined organic extracts were purified using magnesylanosulfate. The mixture was dried, the desiccant was removed by filtration, and the mixture was concentrated under reduced pressure for 2 hours. Convert the residue into methylene chloride Silica gel (particle size 0.06 3-0.2 city) and was subjected to 1.1 madography.

After separation by chromatography, the eluate was concentrated under reduced pressure, and the residue was Reaction with hydrochloric acid solution in ethyl ether precipitates the title compound as the hydrochloride salt. This was collected by filtration and dried until the weight I became constant.

Yield: 5.5g (6’/%) Melting point: 208-...211)℃ Example 7 (+'min, / (-) -7 acetoa::・'・;:N, N-ditech 1 ゛Luminor 1. ), 3.4-”7-lano-1-hydronaphthalene hydrochloride (hydrogen 7-2P-hi1-a to the metapool'1iotnl Mido-2-amino-192゜3.4-1,000 Tora♂ Idroner, I Clen 6.5g ( 32 mmol) and 71'! h　Flude and dissolve F22g (500ml) Saze, Nonorapaji rum charcoal (10%)? , 2 gF treatment. Store the solution in an auto-cooker. In the L node, hydrogen pressure 5.1 m/cffl (500 kPa), 1 at 30°C Hydrogenation was carried out for 8 hours. The product was filtered with suction through silica gel (2, the solvent was removed under reduced pressure) The residue was then treated with 5 LJ of diethyl: , wash twice using 60 i of water each time. Using ``Ygnesium sulfate'' The organic phase was dried for 12 hours, the desiccant was filtered (1°7 tJa) and the residue was concentrated under reduced pressure (knee). Silica gel, ゛particle size 0063~0.2+r+mouth) with chromatography J (mobile phase 4 acetate nib/l/meta 7,·'-l; 80:20).

’/, “After separation by 7 Matogra-74- treatment, reduce the eluate and add A to the bottom. contracted, (+) / (-) a.humanamide-2-N,N-diethylamino-1 + 2 + 3 + 4-Atra l'S Hydronaphta i horn with etheric hydrochloric acid The crystals were converted to hydrochloride by using a Dry in a container until it reaches a constant weight of 1 kg.

Yield・　i,　’/　g　(18%) Melting point -265℃ Examples) Lumino! , 2,3.4-tetrahydronaphthalene hydrochloride (+)/(-)-7-a7F amide 2-(N-butyl-N-propyla Mi,))-1,2,3,4-tetrahydronaphthalene hydrochloride 1.5 g (4, 4 mmol) was heated with 30-2N HCl at reflux temperature for 2 hours at t-0, then the The solution was concentrated under reduced pressure, the residue was treated with 20 ml of ethanol, and the C crystals were filtered with suction. , wash with ethanol and circulate air in a dryer until the weight becomes constant. Dry.

Yield: 1.1g (75%) Melting point: 167℃ or higher Example 9 (+)/(-)-7-dia2-(N,N-dipropylami, ri- 1,2,3,4-tetrahydronaphthalene 7--/'mi/-2- (N, N-dipropyl 7mi/)-1,2,3゜4-6 24.6 g (0.1 mol) of hydronaphthalene was added to 5 ml of water (1 m/and concentrated sulfuric acid). In a solution dissolved in 12,5-, add 8,5 g of sodium nitrite to 5 LJ of water. The dissolved solution was poured at -5°C to .0°r'. The mixture was heated at -5°C for 3 The reaction was allowed to proceed for 0 minutes.

Next, the reaction mixture was diluted with 20 l of water cooled to -5°C. 40 g (0.6 mol) of potassium and 20 g (0.2 mol) of copper cyanide <1) Dissolved f, treated with solution, the mixture foamed vigorously 1.,-. The emission of scum has stopped. After that, the mixture was stirred for an additional 30 minutes at room temperature. Using 400J of Monia water, make the solution 400 mA of acetic acid every time! using.

'Extracted 1-3 times, combined, washed with 50 oy of water, dried, After removing the desiccant, concentrate under reduced pressure ゛F 1+'7':. Distill the residue under high vacuum Ta.

Yield: 20.2g (79%) Boiling point: 132°C (0.06 Torr) Same as Example 9. The compound was synthesized.

(+)/(-)-2-(N-benzyl N propylamino)-7-cyano l,2,3.4-tetrahydronaphthalene Yield, 58% Boiling point: 180-185℃ (0.75X I O-” Torr (l O-3mb ar):1 Example 10 (+)/(-)-7-carbamoyl-2-(N,N-dipropyla (mino)-1,2,3,4-tetrahydronaphthalene hydrochloride 7-dia2-2-(N,N-dipropylamino)-1,2,3°4-tetrahy 3.0 g (12 mmol) of dronaphthalene was added to 18 ml of methanesulfonic acid and water. The reaction mixture was heated at 110° C. for 1 hour. cool down Then, pour the reaction mixture onto ice and evaporate using concentrated ammonia solution. Made potassium-based. Extract twice using 100% ethyl acetate each time and combine them. The solution was washed with 100 - of water, dried and concentrated under reduced pressure. the remaining base Dissolved in acetone and precipitated the hydrochloride using ethereal hydrochloric acid.

Yield: 3.0%, (81%) Melting point: 251-253℃ The following compound was synthesized in the same manner as in Example IO.

(2R)-7-carbamoyl-2-(N,N-dipropylamino)-1,2,3 ,4-tetrahydronaphthalene hydrochloride yield: 78% Melting point: 255℃ [α]D,. =(+)76.7°・(C=1; methanol)(2S)-7-ka rubamoyl-2-(N,N-dipropylamino)-1,2,3,4-tetrahydr Dronaphthalene hydrochloride yield: 79% Melting point: 252-254℃ [αID,. =-71,9° (C=l; methanol) (+)/(-)-2-( N-benzyl-N-propylamino)-7-carbamoyl-1,2,B,4-te Trahydronaphthalene hydrochloride Yield: 65% Melting point: 142-144℃ Example 11 (+)/(-)-7-hydroxycarbonyl-2-(N,N-dip Lopylamino')-1,2,3,4-tetrahydronaphthalene hydrochloride 7-cya2-2-(N,N-dipropylamino)-1,2,3゜4-tetraha 8.1 g (31.5 mmol) of idronaphthalene was treated with concentrated hydrochloric acid 15.01R1. The mixture was heated under reflux for 8 hours. The reaction mixture was then concentrated under reduced pressure and the residue It was treated with Setone 100- and the crystals thus precipitated were filtered with suction. The result obtained The crystals were washed three times with 30° of cold water, once with 50° of acetone, and diethyl ether; Next, it was dried at 50° C. in a dryer.

Yield: 6.2g (63%) Melting point: 223-226℃ Example 2 Example 122-(N,N-dipropylamino)-7-methylcarbamoyl-1 ,2,3,4-tetrahydronaphthalene hydrochloride 7-hydroxycarbonyl-2-(N,N-dipropylamino)-1,2,3 , 5 g (16 mmol) of 4-tetrahydronaphthalene hydrochloride was added to thionyl chloride 1 ．． 8d (24 mmol) and heated under reflux for 30 minutes with moisture removed. Then, Excess thionyl chloride was distilled off under reduced pressure, and 100 rIIl of dichloroethane was added to the residue. Ta. The solution was cooled to 0°C, and methylamine was added to 300 ml of anhydrous tetrahydrofuran. A solution containing 36 g (1.1 mol) of I added. The mixture was further reacted at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. and remove the residue with 150 g of potassium carbonate solution (20 g of Kt Cow in 150 d of water). Processed. The mixture was extracted three times using 150 m/l of ethyl acetate each time, The combined organic extract phases were washed using 1501 nl of water and dried after removal of the desiccant. , concentrated under reduced pressure. The remaining base was dissolved in acetone and treated with ethereal hydrochloric acid. The hydrochloride was precipitated.

Yield: 4.6g (88%) Melting point: 222-224℃ The following compound was synthesized in the same manner as in Example 12.

7-Ethylcarbamoyl-2-(N,N-dipropylamino)-1,2,3,4 -Tetrahydronaphthalene hydrochloride yield: 92% Melting point: 195-196℃ (+)-2-(N,N-dipropylamino)-7-methylcarbamoyl-1,2 ,3,4-tetrahydronaphthalene hydrochloride Yield: 75% Melting point: 233-235℃ [α] J o = + 73.5° (C = 1; methanol) (-) -2-(N , N-dipropylamino)-7-methylcarbamoyl-1,2,3,4-tetra Hydronaphthalene hydrochloride Yield: 71% Melting point: 233-235℃ [a] D10=-73,6° (C=l; methanol) Example 13 (2R) -7-methylcarbamoyl-2-propylamino-1,2,3,4-tetrahy Dronaphthalene hydrochloride (2R)-7-carbamoyl-2-(N-benzyl-N- propylamino)-It 2.3.4-tetrahydronaphthalene 28.5 g ( 85 mmol) and treated with 4 g (10%) of palladium on charcoal. The reaction solution In the autoclave, hydrogen pressure 5.1 kg/cnr (5b ar), temperature 20 Hydrogenation was carried out at ℃ for 5 hours.

Hydrogen absorption ended when the calculated amount of hydrogen was consumed. Suction through silica gel The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure.

Dissolve the remaining base in ethanol and precipitate the hydrochloride using ethereal hydrochloric acid. Ta.

Yield: 15.4g (68%) Melting point: 242-244℃ [α]D,. =(+)70.7° (C=1; methanol) Same as Example 13 The following compound was synthesized.

(2R)-7-carbamoyl-2-propylamino-1,2゜3.4-tetraha Idronaphthalene hydrochloride yield: 73% Melting point: 244-246℃ [α]DI. =-68,9° (C=1; methanol) (+)/(-)-7- Carbamoyl-2-propylamino-1,2,3,4-tetrahydronaphthalene Hydrochloride yield: 97% Melting point: 255-257℃ (+)-7-Methylcarbamoyl-2-propylamino-1゜2.3.4-tet Lahydronaphthalene hydrochloride yield: 91% Melting point; 245-247°C [α]Dt. =+60.5° (C=l; methanol) Example 14 (2R)- 2-(N-allyl-N-propylamino)-7-carbamoyl-1,2,3,4 -Tetrahydronaphthalene hydrochloride (2R)-7-carbamoyl-2-propylamino-1,2゜31,4-tetra Hydronaphthalene hydrochloride 7.3 g (27 mmol), allyl bromide 6.4 J (7 4 mmol) and 5.6 g (41 mmol) of potassium carbonate were added to 73 m/m of dimethyl The mixture was stirred at 35° C. for 4 hours in diformamide. Then C1 the reaction mixture was concentrated under reduced pressure. The residue was treated with 200 μm of water and 150 μl of ethyl acetate each time. use and extracted twice. , '\XJ book, extract phase and water! Wash at 00mA’C and dry. 1.Remove the desiccant, then concentrate again.Residue =:, - Recrystallize once from the base, then dissolve the purified base merpa in a var, l, - precipitate the monohydrochloride using hydrochloric acid, t,''.

Yield 6/% Melting point: 23:3 to 235℃ [alD,,o=-8i,i'''<c=i;Mekno--ru) Example i,i , :: Compound 1 was synthesized in the same manner.

(-) -2-(N--,Fs/l,-N Propyl'7F:#))-゛ l-Pfluvail 1.2.3.4-6' l-Rabide [Konafukushi/Soshio acid salt Yield 62% Melting point, 228-233°C [α) Dto=-s　o, 1' (C=1; methanol) (+)/　(-)-'! -CulverCyl-2-(Nu-thyl-N-propylamine/'')-1,2,3, 4-tetrahydronaphthate/',, hydrochloride Yield: 72% Melting point: 168-170℃ (10)-2-(N allyl-N nia' lobilani))-l-methylcarbamo E'lu! , 2.3.4-Lahydronaphthalene hydrochloride Yield 72% Melting point: 223-225℃ f:a]Dto-"+83.9' (C=l; methanol) (+-) -2(N-butyl-N-propylamide, ))-7-methylcarbamoyl 1,2 ゜3.4-Tetrahydronatsuta 1-non hydrochloride Yield: 84% Melting point: 100° ('', hereinafter L (decomposition) [α11),. -+-70,9° (C・-i; methanol) c+>-7-, Nobulume J Lupamoyl-2-(rIJ-)1. Nilethyl N-bu [J Birua )-1,2,:3,4　,r)U/A idronabutalone hydrochloride Yield, 69% Melting point: 80℃ or higher (decomposition) [α)D! . Pa 4-50.5° (C=t; methanol) Example 15 (-1- )-2-(N-methoxycarponyl-1-N-propylamide,,')-7 Chilcarbamoyl l.

2, 3. 4-7'-Torahydronaphthalene hydrochloride (2S) 2-propyl ami7no7-methylcarbamoyl-1゜2.3.4-teto-lahydroJ-f 1.5 g (5.3 mol) of talen hydrochloride and 1.4 g of potassium carbonate were added to 15+n/! Dissolved in acrylic acid, treated with F/l pml and heated to 50 °C. Ta. Add 3136 methyl acrylate to the mixture every 9 hours. The reaction mixture was heated for an hour and concentrated, and the residue was dissolved in 50 ml of water. 2 and extracted twice with C using ether 50+J each time. 3 combined organic The extract phase was dried i2, concentrated and transferred to a short silica gel column (approximately 5 g of silica gel and acetic acid). The residue was filtered through 200 ml of ethyl. Concentrate a reasonable stream and Precipitating I hydrochloride using hydrochloric acid, two I8? Amount: l, 4g = 71% Melting point: 65℃ or higher (decomposition) [α]D2o=+66.8° (C-=-1; methanol) One or more of the present invention A pharmaceutical product containing one or more compounds together with a non-toxic, inert, pharmaceutically suitable excipient. Pharmaceutical preparations, or pharmaceutical preparations of the present invention consisting only of active ingredients are also part of the invention, as are the methods of preparing these formulations.

Pharmaceutical formulations to which are formulated to contain a medium dose (rlosage unit) Also, it is part of the present invention, which means that the preparation contains original ingredients in a dilute form, For example, it exists in the form of tablets, dragees, capsules, pills, suppositories, ampules, etc. The content of the active ingredient in the preparation is 1 medicinal ffl (single). This means that it is equivalent to a fraction or several times of the amount (dosage). The unit drug The dose may be, for example, 1.2.3 or 4 times the 1 dose, or 1/2 of the 1 dose. - can include l/3 or l/4. The dosage is preferably one Contains the active ingredient to be administered by application, usually in full, half, or half the daily dosage. It contains the active ingredient equivalent to one-third or one-fourth of an amount.

A non-toxic, inert, pharmaceutically suitable excipient is a solid, semi-solid or liquid diluent, filler, etc. It is understood to mean fillers and all other formulation auxiliaries.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions are preferred. It is mentioned as a new pharmaceutical preparation. Tablets, dragees, capsules, tablets and granules are , (a) For example, starch, lactose, sucrose, crucose, mannitol and fillers and extenders such as silicic acid, (b) e.g. carboxymethyl cellulose, Binders such as alginate, gelatin, polyvinylpyrrolidone, (C) e.g. humectants such as lucerol, (d) e.g. agar-agar, calcium carbonate and charcoal; activators such as sodium chloride, (e) dissolution retarders such as paraffin; ) For example, absorption enhancers such as quaternary a)/Moniu 1, salts, (g) For example, Wetting agents such as Leco-L, E-nosodearic acid glycerin-1', λ-chill, etc. (g) Examples Adsorbents such as kaolin and benthite, and (i) e.g. λ6, talc 1 5 people Calcium tearate and Stem 71. i phosphoric acid mag screw fy7. Erasure, etc. and solid poly to mixtures of substances, in addition to the usual excipients (:, single active ingredient or multiple active ingredients.

Tablets, dragees, capsules, tablets, and granules may contain opacifying agents as appropriate. Conventional 21-tenong agents and sheathing agents can be applied, and only a single active ingredient or Ta1! A plurality of active ingredients, if appropriate, by delayed means alone or preferably (7) or in the intestinal tract. It can also be configured to emit in a fixed area, and the polymer material warps the wax. It can be used as an example of an embedding composition.

The active ingredient or active ingredients may optionally be present in one or more excipients as described above. Agent C is microencapsulated. I can also talk to L.

Suppositories may be made of, for example, polyethylene glycol, fats [such as cocoa butter and high Stell (for example, mo], -alcohol and C+i-fatty acid, Stell) or Mixtures of these substances] may be combined with a single active ingredient, either water-soluble or water-insoluble. It may also contain in addition to one or more active ingredients.

Solutions and emulsions can be prepared using water, ethyl alcohol, isopropyl alcohol, charcoal, etc. Ethyl acid, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene Recall, l,3-butylene glycol, dimethylformamide, oil [especially cottonseed] oil, peanut oil, corn seed oil, olive oil, castor oil and sesame oil], Lycerol, glycerol formal, tetrahydrof Fatty acid esters of lyal alcohol, polyethylene glycol and sorbitan, conventional excipients such as solvents, solubility promoters and emulsifiers, or mixtures of these substances; may be present in addition to a single active ingredient or multiple active ingredients.

The solutions and emulsifiers are also sterile and blood isotonic (b) for parenteral application. 1 sotonic form).

Suspending agents include liquid diluents such as water, ethyl alcohol, propylene glycol, etc. agents, such as ethoxylated isostearyl alcohol, polyoxyethylene Sorbitol and sorbitan esters, fine quality cellulose, aluminum Mumetahydroxide, bentonite, agar-agar and tragacanth or this It may also contain conventional excipients, such as suspending agents, such as mixtures of these substances.

The above formulations may also contain colorants, preservatives, flavoring agents and additives such as peppermint oil and spices. Taste improvers such as potash oil and sweeteners such as saccharin may also be included.

The therapeutically active compounds are preferably present in the above-mentioned pharmaceutical formulations in an amount of about 0.1 to 99% of the total amount. ．． It should be present in a concentration of 5% by weight, preferably 0.5-95% by weight.

The above-mentioned pharmaceutical formulations may also contain, in addition to the compounds of the invention, further pharmaceutically active ingredients. It can also contain a component.

The preparation of the above-mentioned pharmaceutical preparations may include, for example, a single active ingredient or multiple active ingredients. It is carried out in a conventional manner by a known method such as mixing with a single excipient or multiple excipients. be able to.

The above formulations may be administered orally, rectally or parenterally (intravenously, intramuscularly, subcutaneously). can be done. Examples of formulations suitable for treatment are injections, solutions and suspensions.

Generally, in order to obtain the desired effect, one or more active ingredients of the invention may be combined with The total amount per 24 hours is about 0.5 to about 500, preferably 5 to 100 ■/kg It is advantageous from a human medical point of view to administer the amount (as appropriate, in several doses). It turned out to be.

1 dosage of the single active ingredient or active ingredients of the invention, preferably about 1 ~80, particularly preferably 3 to 30 μ/kg. However However, it may be necessary to deviate from this dosage and the duration or duration of administration may or interval, as well as the type and weight of the patient being treated, the type of illness and severity of symptoms, It may be necessary to do so in relation to the type of formulation and type of drug administration. Ru.

Therefore, it may be sufficient to treat with lower amounts of active ingredients than those listed above. On the other hand, it may sometimes be necessary to exceed the amounts of active ingredient mentioned above. any expert We also use our expertise to determine the optimum dosage and method of administration of the active ingredient required in each case. It can be easily determined on the basis of

The following formulation examples are illustrative of the invention and are not intended to limit it.

1. Tablets This tablet contains the following ingredients:

Active ingredient of formula l 0.020 part Stearic acid 0.010 part Dextrose 1.890 parts Total amount: 1.920 copies Dispensing: The materials were mixed in a known manner and the mixture was pressed into tablets. Each tablet weighs 1 ．． It weighed 92 g and contained 20 μg of active ingredient.

2. Ointment This ointment consists of the following ingredients:

Active ingredient of formula l 50■ Neribas ointment [commercial product Scherax] ] was added to make 10g.

Dispensing: The active ingredient is ground with 0.5 g of ointment base and the remaining base is added to 1.5 g of ointment base. Gradually add 0g and mixed well to form an ointment. An ointment with a concentration of 0.5% was obtained. in base The distribution of active ingredients was examined by microscopic observation.

Active ingredient of formula l 50■ Neribas ointment (commercial product Scherax) ) was added to make 10 g.

Dispensing: Grind the active ingredient with 0.5 g of cream base and gradually add the remaining base in 1.0 g increments. It was prepared using a mortar and a pestle. A cream with a concentration of 0.5% was obtained. in the base The distribution of the active ingredient in the formula 1.0 is observed under a microscope. Sodium chloride 45.0■ Water was injected to make it 5.0d.

Dispensing: the active ingredient is dissolved at its own pH or suitably at a pH of 5.5 to 6.5; Sodium chloride was added as an isotonic agent. The resulting solution was mixed with pyrogen (Naruma). The filtrate was filled into ampoules under sterile conditions, then sterilized and sealed. . The ampoules contain 1, 5 and 10 kg of active ingredient.

5. Fully open Each full opening contains the following ingredients:

Active ingredient of formula l 1.0 part Cacao butter 1200.0 parts Carnuba wax 5.0 parts Preparation: Melted together with cocoa butter and carnuba wax. Add the active ingredient at 45°C until complete. The mixture was stirred until completely dispersed. Pour this mixture into a mold of appropriate size. The resulting whole thing was wrapped appropriately.

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Claims (1)

[Claims] 1. 2-amino-7-carbamoyl-1,2,3,4-tetrahydride of general formula 1 Lonaphthalene (2-amino-7-carbamoyltetralin), its enantiomers -, mixtures of enantiomers, their racemates, and their acid addition salts. ▲There are mathematical formulas, chemical formulas, tables, etc.▼1 [In the formula, R1 may represent a C1-C8 alkyl group, R2 is hydrogen, C1-C8 12 alkyl group, C3-C8 alkenyl group, C3-C6 alkynyl group, - (CH2)m-OR4, -(CH2)m-SR4, -(CH2)m-COOR5 , ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R4 represents hydrogen, a C1 to C4 alkyl group, or an acyl group, and R5 represents a C1 to C8 alkyl group. May represent an alkyl group, X is hydrogen, hydroxyl group, halogen, C1 to C6 alkyl group. may represent a C1-C6 alkoxy group, a halomethyl group, a C1-C6 alkoxy group, and n is 1, 2, It may represent an integer of 3, 4, 5 or 6. ), R3 is hydrogen, C It may also represent a 1-C6 alkyl group. ]2. R1 is a C1 to C6 alkyl group may be represented, R2 is a C1 to C10 alkyl group, a C3 to C4 alkenyl group, C3-C4 alkynyl group, -(CH2)a-OR4 (R4 is hydrogen, methyl group, May represent an ethyl group, a C1-C4 alkylcarbonyl group, and n is 1,2,3 , 4 or 5 may be represented. ), R3 is hydrogen, C1-C 2-amino-7-carbamoyl-1 of general formula 1, which may represent an alkyl group of 4 , 2,3,4-tetrahydronaphthalene (2-amino-7-carbamoyltet) larin), its enantiomers, mixtures of enantiomers, their racemates and their acid addition salts. 3. R1 may be an ethyl group, propyl group or butyl group, and R2 is C3-C 7 alkyl group, C3-C4 alkenyl group, C3-C4 alkynyl group, -( CH2) m-OR4 (R4 is a methyl group, ethyl group, acetyl group, trifluorocarbon It may be a cetyl group or an ethylcarbonyl group, and n is an integer of 1, 2, 3 or 4. It may be. ), and R3 is hydrogen, methyl group, ethyl group or 2-amino-7-carbamoyl-1,2,3 of general formula 1 which may be a lopyl group ,4-tetrahydronaphthalene (2-amino-7-carbamoyltetralin) , their enantiomers, mixtures of enantiomers, their racemates, and their acid addition salts. 4. (+)/(-)-7-carbamoyl-2-(N,N-dipropylamino)- 1,2,3,4-tetrahydronaphthalene, its enantiomers, enantiomers mixtures of mers, their racemates, and their acid addition salts. 5. (+)/(-)-2-(N,N-dipropylamino)-7-methylcarbamo yl-1,2,3,4-tetrahydronaphthalene, its enantiomer, ena mixtures of antithiomers, their racemates, and their acid addition salts. 6. General formula 8 as intermediate compound ▲There are mathematical formulas, chemical formulas, tables, etc.▼(3) (In the formula, R1 and R2 are the definitions of claim 1. It has the same meaning as righteousness. ) of 2-amino-7-cyano-1,2,3,4-tet lahydronaphthalene. 7. A medicament characterized by containing the compound according to any one of claims 1 to 5. drug formulation. 8. Use of a compound according to any one of claims 1 to 5 as a medicament. 9. In the preparation of pharmaceutical preparations for the treatment of diseases based on abnormalities of the dopaminergic system. 6. Use of a compound according to any one of claims 1 to 5. 10. General formula 1 ▲There are mathematical formulas, chemical formulas, tables, etc.▼1 2-Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalene A manufacturing method having the following characteristics. a) R1 and R2 have the same meaning as defined in claim 1, and R3 represents hydrogen; In cases where R 1 and R2 have the same meaning as defined in claim 1 (except for hydrogen) ( R2 may be a protecting group). ] (+) or (-)-2,7-diamino- 1,2,3,4-tetrahydronaphthalene was converted into copper cyanide (I) by a method known per se. ) with an alkali metal cyanide in the presence of the general formula 8 obtained. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(8) 2-amino-7-cyano-1,2, 3,4-tetrahydronaphthalene derivative in the presence of water under reaction conditions known per se. was reacted with an acid (methanesulfonic acid is preferred as the acid) to give the general formula 9. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(9) 2-amino-7-carbamoyl-1 , 2,3,4-tetrahydronaphthalene derivative, the protecting group (R2=R5) If it exists, cut it and the resulting general formula 13a ▲ Numerical formula, chemical formula, table, etc. There is a tetralin derivative of (13a) with the general formula 15 R2-Y (15) [In the formula, Y is halogen, sulfuric acid residue, tosylic acid residue, methanesulfonic acid residue, halo Represents a methanesulfonic acid residue or other group that can be substituted with an amino group, R2 is a group having the same meaning as defined in claim 1 (except when it is hydrogen). ] alkylating agent, known per se, in an inert solvent or in a mixture of inert solvents. React under appropriate reaction conditions (presence or absence of a base is optional), and first protect If there is a protected group, deprotect it and synthesize a different acid addition salt. to convert it into the corresponding acid addition salt by reacting with the different acid, or or The tetrahydronaphthalene derivative of general formula 13a is converted to the tetrahydronaphthalene derivative of general formula 16 ▲There are mathematical formulas, chemical formulas, tables, etc.▼(16) (In the formula, R is hydrogen or an alkyl group. and -CHR'R''=R2, and R2 has the same meaning as defined in claim 1. have ) with a carbonyl compound under reductive conditions in an inert solvent (the catalyst is (It is optional whether the group is present or not), and if there is a previously protected group, this is deprotected. However, when synthesizing a different acid addition salt, the final product is synthesized by reacting with the different acid. to separate; b) R1 and R2 have the same meaning as defined in claim 1, and R3 is defined in claim 1 In cases where it has the same meaning as the definition of (except for hydrogen), general formula 7 ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (7) (+) or (-) -2,7-dia Mino-1,2,3,4-tetrahydronaphthalene is cyanated by a method known per se. General formula 8 obtained by reacting with alkali metal cyanide in the presence of copper (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(8) 2-amino-7-cyano-1,2, 3,4-tetrahydronaphthalene derivative in the presence of an acid under reaction conditions known per se. Hydrolyzed, general formula 10 ▲There are mathematical formulas, chemical formulas, tables, etc.▼The carboxylic acid derivative of (10) and the tetra The phosphoruscarboxylic acid derivative is combined with an acid halide, particularly preferably using a method known per se. Converted to acid chloride of general formula 11, then converted to acid chloride of general formula 17H2NR3 (17) [In the formula, R3 has the same meaning as defined in claim 1 (except when it is hydrogen) . ] is reacted with the amine under known reaction conditions to form the general formula 12▲mathematical formula, chemical formula, table. etc. ▼Give the corresponding acid amide of (12), and the resulting 2- of general formula 12 Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalene derivative If a protective group (R2=R5) exists, it is cleaved, and the resulting general formula 13b▲There are mathematical formulas, chemical formulas, tables, etc.▼The tetralin derivative of (13b) is generally Formula 15 R2-Y(15) [In the formula, Y is halogen, sulfuric acid residue, tosylic acid residue, methanesulfonic acid residue, halo Represents a methanesulfonic acid residue or other group that can be substituted with an amino group, R2 is a group having the same meaning as defined in claim 1 (except when it is hydrogen). ] alkylating agent, known per se, in an inert solvent or in a mixture of inert solvents. React under appropriate reaction conditions (presence or absence of a base is optional), and first protect If there is a protected group, deprotect it and synthesize a different acid addition salt. to convert it into the corresponding acid addition salt by reacting with the different acid, or or The tetrahydronaphthalene derivative of general formula 13a is converted to the tetrahydronaphthalene derivative of general formula 16 ▲There are mathematical formulas, chemical formulas, tables, etc.▼(16) (In the formula, R is hydrogen or an alkyl group. and -CHR'R''=R2, and R2 has the same meaning as defined in claim 1. have ) with a carbonyl compound under reductive conditions in an inert solvent (the catalyst is (It is optional whether the group is present or not), and if there is a previously protected group, this is deprotected. However, when synthesizing a different acid addition salt, the final product is synthesized by reacting with the different acid. to separate.