KR20010108167A - Tetrahydro isoquinolinealkanol derivatives and pharmaceutical compositions containing same - Google Patents

Abstract

The present invention relates to novel 1,2,3,4-tetrahydroisoquinoline carbamate and thiocarbamate derivatives represented by the following formula (I) and pharmaceutically acceptable nontoxic salts thereof. This compound is useful for treating central nervous system diseases, including depression.

Formula I

In the above formula

X ₁ and X ₂ are the same or different from each other and are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, thioalkoxy, halogen, hydroxy, nitro and trifluorocarbon;

Y is a member selected from the group consisting of oxygen and sulfur;

R ₁ is a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and CONHR ', wherein R' is selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl;

R ₂ and R ₃ are the same as or different from each other, and independently a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and cycloalkyl, or R ₂ and R ₃ together with a nitrogen atom bonded thereto are 5 to 7 May form a circular ring;

R ₄ is a member selected from the group consisting of hydrogen or lower alkyl.

Description

Tetrahydro isoquinolinalkanol derivatives and pharmaceutical compositions containing same}

Depression is the primary characteristic of mood or emotional disorders. In the United States, it is estimated that one in ten people suffer from depression for life. There are many useful drug therapies, but current treatments are effective only in 70% of all patients. There is still no proper treatment for the remaining 30%, and therefore newer drug therapies are needed. For this reason, the development of new antidepressants remains a major challenge for pharmacists.

At present, it has been found that hydroxyalkyltetrahydroisoquinoline derived carbamate and thiocarbamate compounds exhibit significant activity against central nervous system models including depression with good toxin profiles.

The present invention relates to pharmaceutically active new compounds and compositions for treating central nervous system diseases including depressive states and cognitive impairment.

The present invention relates to novel 1,2,3,4-tetrahydroisoquinoline carbamate and thiocarbamate derivatives represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

In the above formula, X ₁ , X ₂ , Y, R ₁ , R ₂ , R ₃ and R ₄ are as described below. The present invention, which continues to be studied in the art, provides pharmaceutically active new compounds useful for treating central nervous system diseases including depression. The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient and administering the pharmaceutical composition as a unit to a mammal suffering from central nervous system disease. Also included is a method for treating a mammal suffering from a disease.

In biological analysis, compounds of formula I have been shown to have activity in a central nervous system model including depression and monoamine oxidase (MAO) inhibitory properties. The novel compounds are thus effective for treating subjects with central nervous system diseases, including depression.

The product of the invention is a compound of formula (I) and pharmaceutically acceptable non-toxic salts thereof:

Formula I

In the above formula,

X ₁ and X ₂ are the same or different from each other and are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, thioalkoxy, halogen, hydroxy, nitro and trifluorocarbon;

Y is a member selected from the group consisting of oxygen and sulfur;

R ₁ is selected from the group consisting of hydrogen, alkyl, arylalkyl and CONHR ', wherein R' is selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl;

R ₂ and R ₃ are the same as or different from each other, and independently a member selected from the group consisting of hydrogen, alkyl, arylalkyl and cycloalkyl, or R ₂ and R ₃ together with a nitrogen atom bonded thereto are 5 to 7 members May form a ring;

R ₄ is selected from the group consisting of hydrogen or lower alkyl.

Certain compounds of the invention have one or more chiral centers, each centered in an R or S structure. The present invention includes all enantiomers and diastereomers as well as appropriate mixtures thereof.

Radicals in formula (I) are defined as follows.

The term "alkyl" means a straight or branched hydrocarbon radical having 1 to 8 carbon atoms, and unless specifically stated otherwise, examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl, tert-butyl, n-pentyl, n-hexyl and the like.

The term "halogen" is fluorine, chlorine, bromine and iodine, and more preferred halogens are fluorine and chlorine.

The term "alkoxy" refers to alkyl radicals in which oxygen is attached to molecular moieties, including but not limited to methoxy, ethoxy and propoxy groups.

The term "thioalkoxy" refers to an alkyl radical wherein sulfur is attached to a molecular moiety, including but not limited to thiomethoxy, thioethoxy and thiopropoxy groups.

The term "cycloalkyl" refers to a cyclic group having 3 to 6 carbon atoms, with preferred cycloalkyls being cyclopentyl and cyclohexyl.

The term "aryl" refers to aromatic hydrocarbons such as phenyl, naphthyl and the like and may be unsubstituted or substituted with alkyl such as methyl or ethyl, alkoxy such as methoxy or ethoxy, halogen, NO ₂ and SCH ₃ .

The term "arylalkyl" is as described above for alkyl and aryl. Such groups include, but are not limited to, PhCH ₂ .

The present invention includes pharmaceutically acceptable non-toxic salts of instant product I. Suitable salts are acid addition salts of compounds of formula (I), i.e. salts derived from nontoxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, and the like, as well as nontoxic organic acids such as acetic acid, propionic acid, Salts derived from glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, humeric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, salicylic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like It includes.

Acid addition salts of these basic compounds are obtained by contacting the free base form with a sufficient amount of the desired acid to produce the salt in a conventional manner. The free base can be regenerated by contacting the salt form with the base and separating the free base in a conventional manner.

Preferred embodiments of the invention are compounds according to formula II, wherein Y is oxygen, and pharmaceutically acceptable non-toxic salts thereof:

In the above formula,

X ₁ and X ₂ are the same as or different from each other, and are independently selected from the group consisting of hydrogen, alkyl, alkoxy, thioalkoxy, halogen, hydroxy, nitro and trifluorocarbon;

R ₁ is a member selected from the group consisting of hydrogen, alkyl, arylalkyl and CONHR ', wherein R' is selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl;

R ₂ and R ₃ are the same as or different from each other, and independently a member selected from the group consisting of hydrogen, alkyl, arylalkyl and cycloalkyl, or R ₂ and R ₃ together with a nitrogen atom bonded thereto are 5 to 7 members May form a ring;

R ₄ is a member selected from the group consisting of hydrogen or lower alkyl.

Another preferred embodiment of the invention is a compound according to formula III, wherein Y is sulfur and a pharmaceutically acceptable non-toxic salt thereof:

Wherein X ₁ and X ₂ are the same or different from each other and are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, thioalkoxy, halogen, hydroxy, nitro and trifluorocarbon;

R ₁ is a member selected from the group consisting of hydrogen, alkyl, arylalkyl and CONHR ', wherein R' is selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl;

R ₂ and R ₃ are the same as or different from each other, and independently a member selected from the group consisting of hydrogen, alkyl, arylalkyl and cycloalkyl, or R ₂ and R ₃ together with a nitrogen atom bonded thereto are 5 to 7 members May form a ring;

R ₄ is a member selected from the group consisting of hydrogen or lower alkyl.

Another preferred embodiment of the invention is a compound which is enriched in the enantiomer of Formula IV and a pharmaceutically acceptable non-toxic salt thereof:

In the above formula,

X ₁ and X ₂ are the same or different from each other and are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, thioalkoxy, halogen, hydroxy, nitro and trifluorocarbon;

R ₁ is selected from the group consisting of hydrogen, alkyl, arylalkyl and CONHR ', wherein R' is selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl;

R ₂ and R ₃ are the same as or different from each other, and independently a member selected from the group consisting of hydrogen, alkyl, arylalkyl and cycloalkyl, or R ₂ and R ₃ together with a nitrogen atom bonded thereto are 5 to 7 members May form a ring;

R ₄ is a member selected from the group consisting of hydrogen or lower alkyl.

Another preferred embodiment of the invention is an enantiomeric compound of formula V and pharmaceutically acceptable non-toxic salts thereof:

In the above formula

X ₁ and X ₂ are the same or different from each other and are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, thioalkoxy, halogen, hydroxy, nitro and trifluorocarbon;

R ₁ is a member selected from the group consisting of hydrogen, alkyl, arylalkyl and CONHR ', wherein R' is selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl;

R ₂ and R ₃ are the same as or different from each other, and independently a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and cycloalkyl, or R ₂ and R ₃ are 5 to 7 members together with the nitrogen atom bonded thereto; May form a ring;

R ₄ is a member selected from the group consisting of hydrogen or lower alkyl.

Enantiomeric compounds are referred to as compounds in which one enantiomeric form of the compound predominates over the other enantiomeric form. Preferably, one of the enantiomers prevails at least 90%, most preferably at least about 98%.

Central nervous system diseases, ie depression, Parkinson's disease, memory impairment, cognitive impairment, dementia, hyperactivity syndrome, neurodegenerative disorder, attention deficit disorder, schizophrenia, obesity, Alzheimer's disease, panic attack, pain, smoking cessation Provided are compounds of formula (I) suitable for treating a subject with cessation, anxiety, epilepsy, seizures, or withdrawal syndrome.

synthesis

In general, the compounds of the present invention can be prepared as illustrated in Schemes I-III. For illustrative purposes, the case where X ₁ and X ₂ are hydrogen is shown.

In Scheme I, 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (Compound 1) is treated with a nitrogen protecting group such as benzyl chloroformate (CbzCl) to give N-benzyloxycarbonyl-3- Hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (Compound 2) is obtained. Compound 2 is reacted with carbonyl diimidazole (CDI) or phosgene in the presence of an amine base and then subjected to amine decomposition with R ₂ R ₃ NH to give carbamate (Compound 3). Removal of the benzyloxycarbonyl group and nitrogen protecting group is carried out through hydrocracking reaction in the presence of a metal hydride catalyst such as palladium-carbon (Pd-C) to obtain a carbamate product (compound 4). Pharmaceutically acceptable salts of the product, such as the HCl salt, can be obtained by treating the product with HCl. Scheme I represents preparation of the S-type product. Note that the stereochemistry of Compounds 4 and 5 depends on the stereochemistry of Compound 1, the starting material. Starting with Form R starting material yields Form R products.

In Scheme II, 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (Compound 6) is converted to di-tert-butyl dicarbonate or (BOC ₂ O) or 2- (tert-butoxycarbonyl N-BOC protected compound Nt-butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydro treated with a nitrogen protecting group such as oxyimino) -2-phenylacetonitrile (BOC-ON) Isoquinoline (Compound 7) is obtained.

Compound 7 is treated with sodium hydride, carbon disulfide, methyl iodide and the obtained intermediate is treated with amine R ₂ R ₃ NH to give compound 8. The protecting group in compound 8 is deprotected with an aqueous acid such as aqueous hydrochloric acid to give thiocarbamate product 9. Salts are formed by treatment with a pharmaceutically acceptable acid such as HCl to obtain the hydrochloride salt of thiocarbamate product 10.

In Scheme III, (S) -3-hydroxymethyl-N-methyl-1,2,3,4-tetrahydroisoquinoline (Compound 11) was substituted with carbonyl diimidazole (CDI) followed by amine R ₂ R ₃ Treatment with NH yields carbamate product compound 12. In addition, compound 14 can be converted to carbamate compound 15 in a similar manner. (S) -3-hydroxymethyl-N-methyl-1,2,3,4-tetrahydroisoquinoline (Compound 11) was treated with sodium hydride, carbon disulfide and methyl iodide and then amine R ₂ R ₃ Treatment with NH gives thiocarbamate product 13. In a similar manner, compound 14 may also be converted to thiocarbamate compound 16.

Representative compounds of formula (I) are shown in Table 1.

Compound example shape X ₁ , X ₂ Y R ₁ R ₂ R ₃ R ₄ S 6-Cl O Me H H H S H O Et H H H S H O CH ₂ Ph H H H S 7-NO ₂ O H H H H RS 7,8- (Cl) ₂ O H H H H S 6,7- (OMe) ₂ O H H H H S 6-F O H H H H S 6-OMe O H H H H R 6-Cl O Me H H H RS 6-Cl O Me H H H S H O Et Me Me H S H O Et Me Me Me S 6-Cl S Me H H H S H S Et H H H S H S CH ₂ Ph H H H S 7-NO ₂ S H H H H RS 7,8- (Cl) ₂ S H H H H R 6-Cl S Me Me H H RS 6-Cl S Me Me H Me

pharmacy

Preparation: The product (I) of the present invention can be used as an active ingredient in various pharmaceutical compositions in admixture with a pharmaceutically acceptable solid or liquid diluent or carrier. Pharmaceutically acceptable diluents or carriers include all non-toxic substances that are more suitable for oral, intravenous or intramuscular administration when mixed with the products of the present invention. Oral administration is preferred when the compounds of the present invention are used for therapeutic purposes.

Typically intended diluents or carriers are solid, liquid and semisolid diluents and carriers such as paraffin, vegetable oils, mannitol, sucrose, glucose or water, saline, glycols and bactericides, and petroleum, animal, plant or synthetic Oils of origin, such as peanut oil, mineral oil and sesame oil. Moreover, the composition can be further enhanced by including other useful ingredients such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, viscosity aids or fragrances.

Dosage: The amount administered depends largely on the condition to be treated and the weight of the subject, but a typical daily dosage may consist of from 0.1 mg to 500 mg of active ingredient per kg of body weight, which may be administered once or several times. The overall preferred daily dosage is in the range of about 0.1 mg to 50 mg of active ingredient per kg of body weight.

Unit Formulations: The compositions of the present invention may be administered parenterally or orally in solid and liquid oral dosage forms, for example tablets, capsules, powders, suspensions, solutions, syrups, sustained release preparations and injectable liquids such as sterile solutions and suspensions. May be administered. As used herein, the term "unit dosage form" refers to physically discrete units administered once or several times, each unit containing a predetermined amount of active ingredient in combination with the required diluent, carrier or excipient.

Solid tablets: Hard tablets are prepared by combining an appropriately ground effective ingredient with a diluent such as starch, sucrose, kaolin or calcium phosphate and a lubricant. Optionally, the composition may contain stabilizers, antioxidants, preservatives, suspending agents, viscosity aids, fragrances, and the like. The composition is pressurized into tablets and a protective coating of shellac, wax, sugar or polymer is added. If desired, further colorants are provided to provide color-coded means for distinguishing different dosages.

Chewing Tablet: This unit dosage form is prepared by combining an active ingredient with a pharmaceutically acceptable orally ingestible solid carrier and gum base. If desired, the composition may further contain fragrances, binders, lubricants and other excipients.

Soft capsules: Soft gelatin capsules are prepared by dissolving the active ingredient together with glycerin and water in a pharmaceutically acceptable oil such as peanut oil, sesame oil or corn oil.

Hard Capsules: Hard gelatin capsules are prepared by mixing the active ingredient with lactose and magnesium stearate and putting the mixture into No. 3 gelatin capsules. If desired, lubricants, such as colloidal silica, may be added to improve flowability and disintegrants or solubilizers may be included to improve the availability of the medicament for injection.

Liquid: Syrups, elixirs and suspensions can be prepared in unit dosage forms so that the composition can be administered in a full amount of teaspoons. Syrups are prepared by dissolving the compound in a moderately fragrant sucrose aqueous solution, while elixirs are prepared by combining an active ingredient with a non-toxic alcoholic excipient. Suspensions are obtained by mixing an active ingredient-containing dry powder in water with a small amount of suspending agents, fragrances, sweeteners such as sugars, and preservatives as necessary.

Parenteral: Suitable unit dosage forms for parenteral administration are prepared by suspending or dissolving the active ingredient in a measurand in a nontoxic liquid excipient suitable for injection such as an aqueous or oily medium and sterilizing the resulting mixture. Alternatively, the effective amount of the measurand may be placed in a vial in a separate amount to sterilize and seal the vial and its contents. If desired, separate vials containing suitable excipients for mixing with the active ingredient may be provided to combine and mix the contents of the two vials just prior to use for administration purposes.

Topical: Powders and other solid unit dosage forms can be used as active ingredients of the invention, talc, bentonite, silicic acid, polyamide powder, animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones. And suitable carriers such as zinc oxide or mixtures thereof.

On the other hand, liquid and semisolid preparations can be prepared in the form of suspensions, solutions, ointments, pastes, creams and gels by combining an active ingredient with carriers such as polyethylene glycol, vegetable oils and mineral oils, alcohols such as isopropanol and the like. In addition to the carrier, the preparation may further include other excipients such as emulsifiers, preservatives, colorants, fragrances, and the like.

Biological Analysis Method

Compounds of formula (I) are valuable for treating a variety of central nervous system conditions.

The head-twitch response of mice is initiated with mimetic drugs of various 5-HTs. Tests include Heal, D.J., Philpot, J. O'Shaughnessy, K.M and Davides, C.L .: The influence of central noradrenergic function of 5-HT-mediated head-twitch responses in mice: Possible implications for the actions of antidepressant drugs. Psychopharmachology 89: 414-420, conducted in a similar manner to the procedure described in 1986.

The head-twitch consisted of a unique rotation of the mouse's head, neck and shoulders. Test drugs or excipients were given by oral gavage. After 30 minutes all animals were pretreated with carbidopa (25 mg / kg ip). After 15 minutes of carbidopa administration, mice were injected with 100 mg / kg ip of L-5-hydroxytryptophan (5-HTP). The animals were then left to stand for 30 minutes and then head-twitch responses were measured at the next 2 minute cycle. To calculate the percent response increase, the head twitch number difference of the drug relative to the head twitch number of the control excipient was divided by the control head twitch and multiplied by 100.

Head-twitch test Example number Dosage (mg / kg, oral) % Response increase 3 One 238 4 15 258 5 3 144 8 One 77 14 8 42

The Behavioral Despair (Forced Swimming) test, a known pharmacological screening method for depression, is described in Porsolt, RD, Bertin, A. and Jalfre, M .: Behavior despair in mice: A preliminary screening test for antidepressants. Arch. Int. Pharmacodyn. Ther. 229: 327-336, similar to the test described in 1977.

Mice were administered intraperitoneally (ip) with test compounds or excipients. After 1 hour each animal was placed in a 1500 mL glass beaker with water at room temperature. Mice were placed in water for 15 minutes and the immobilization observed within the 15 minute test time was recorded. When the mouse head appeared above the surface of the water and floated in water without any movement, it was determined that the mouse was floating. To calculate the percent reduction in immobility time, the immobility time difference of the control excipient relative to the drug immobility time was divided by the immobility time of the control excipient and multiplied by 100.

The day before the test, the rats were pre-swimmed for 10 minutes in a 4000 mL glass cylinder containing 25 ° C. water. On the day of testing, rats were dosed orally (po) with test compounds or excipients. After 1 hour each animal was placed in a glass cylinder and subjected to a 2 minute preliminary test and the immobility recorded for a 4 minute test time. To calculate the percent reduction of immobility time, the immobility time of the control excipient relative to the immobility time of the drug was divided by the immobility time of the control excipient and multiplied by 100.

Despair test Example number Dose (mg / kg) % Reduction 3 60 (po) 83 18 30 (ip) 33 16 30 (ip) 56 17 30 (ip) 46

In vitro, MAO-A activity was determined by S. Otsuka & Y. Kobayashi. A Radioisotopic Assay for Monoamine Oxidase Determinations in Human Plasma. Biochem. Measured using a rat liver mitochondrial membrane as an enzyme source according to a modified method of Pharmachol. 13: 995-1006 (1964).

Mitochondrial membranes between rats are preincubated with drugs or excipients and subtype selective blockers (300 nM deprenyl for blocking B of MAO) at 100 mM KPO ₄ (pH 7.2), 37 ° C. for 60 minutes. [ ¹⁴ C] Serotonin (45-60 Ci / mmol) is added and incubated for 10 minutes. The reaction is stopped by adding 0.5 ml of 2 M citric acid. The radioactive product is extracted with toluene / ethylacetate fluoride and compared with the control values by scintillation spectrophotometry to confirm the interaction of the test compound with MAO-A.

MAO-A Inhibitory Activity at 10 μM Example number % Inhibition 3 97.7 4 63.9

In addition, the present invention is very valuable in this respect as it has a reduced level of toxicity and a high level of safety.

The results obtained indicate that compounds of formula (I) may cause central nervous system diseases such as depression, Parkinson's disease, memory disorders, cognitive impairment, dementia, hyperactivity syndrome, neurodegenerative disorders, attention deficit disorder, schizophrenia, obesity, Alzheimer's disease, panic attacks It is indicated to be suitable for the treatment of subjects with pain, smoking cessation, anxiety, epilepsy, seizures or withdrawal syndrome.

It is to be understood that the present invention has been described in an illustrative manner and that the terminology which has been used is intended to be in the nature of words of description rather than of limitation. Many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

The following examples illustrate the invention and are not intended to limit the scope in any way.

Example 1

(S) -N-benzyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline

Benzyl chloroformate to a stirred mixture of (S) -3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (10 g) and sodium bicarbonate (15.5 g) in tetrahydrofuran (50 mL) (9.7 mL) was added dropwise at 5 ° C. The reaction was stirred at rt for 2 h, ethyl acetate added, washed with brine and concentrated in vacuo. The obtained concentrate was purified by flash chromatography to give the product (17.9 g) as an oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ: 2.48 (OH), 2.85 & 3.05 (m, 2H), 3.58 (m, 2H), 4.30-4.85 (m, 3H), 5.22 (s, 2H), 7.05 -7.50 (m, 9 H).

Example 2

(S) -N-benzyloxycarbonyl-3-carbamoyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline

Carbonyl diimidazole (0.6 g) to (S) -N-benzyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (1 g) in tetrahydrofuran (5 mL) ) Was added and stirred for 45 minutes. Ammonium hydroxide (30%, 5 mL) was added and stirred overnight, and then the reaction mixture was extracted with ethyl acetate. The extract was washed with water and 0.5 N HCl, concentrated and recrystallized from ethanol to give the product (0.67 g) as a white solid. Melting point 136.0-137.9 ° C.

1 H NMR (300 MHz, DMSO-d ₆ ) δ: 2.75-3.00 (m, 2H), 3.85 (m, 2), 4.30 (m, 1H), 4.60-4.75 (2H), 5.15 (s, 2H), 6.52 (s, 2 H), 7.20-7.40 (m, 9 H).

Example 3

(S) -3-carbamoyloxymethyl-1,2,3,4-tetrahydroisoquinoline

(S) -N-benzyloxycarbonyl-3-carbamoyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline (7 g) in methanol (150 mL) was added 10% palladium-carbon (2.2 hydrogenated at 40 ° C., 40 psi for 1 hour in the presence of g). The mixture was filtered through celite and the filtrate was concentrated and recrystallized from ethanol to give the product (2.99 g) as a solid. Melting point 152-153 ° C.

1 H NMR (300 MHz, DMSO-d ₆ ) δ: 2.38 (s, br, 1H), 2.57 (m, 2H), 2.79 (dd, J = 16.2, 3.8, 1H), 3.12 (m, 1H), 4.07 (m, 4H), 6.80 (s, br, 2H), 7.22 (m, 4H).

[α] _D ²⁵ = -81.6 (c = 1.0, MeOH)

The product was treated with HCl-isopropanol to give product hydrochloride.

Melting Point 203-205 ° C

1 H NMR (300 MHz, DMSO-d ₆ ) δ: 3.10 (m, 2H), 3.74 (m, 1H), 4.33 (s, 4H), 6.73 (s, br, 2H), 7.30 (s, br, 4H ), 10.10 (s, br, 2H).

[α] _D ²⁵ = -46.6 (c = 1.0, MeOH)

Example 4

(R) -3-carbamoyloxymethyl-1,2,3,4-tetrahydroisoquinoline

The title compound was obtained as hydrochloride starting from (R) -3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline. Melting point 214-217 ° C.

Example 5

(RS) -3-carbamoyloxymethyl-1,2,3,4-tetrahydroisoquinoline

Starting with (RS) -3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline, the title compound was obtained as hydrochloride. Melting point 203.7-204.3 ° C .;

1 H NMR (300 MHz, DMSO-d ₆ ) δ: 3.01-3.16 (m, 2H), 3.43 (s, 1H), 4.12-4.35 (m, 4H), 6.69 (s, 2H), 7.12-7.36 (m , 4H), 10.04 (s, br, 2H).

Example 6

(RS) -N-tert-butyloxycarbonyl-3-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline

Di-tert-butyl dicarbonate (37.9 g) was added in portions to 34 g of 1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid and ethyl ester dissolved in 180 mL of dichloromethane. The reaction mixture was stirred for 30 minutes until no gas evolution was observed. The mixture was washed with 200 mL of 0.5 N HCl solution followed by 200 mL of brine. The organic layer was dried over MgSO _{4 and} evaporated in vacuo to give 49.7 g (92%) of the product as a yellow solid.

¹ H NMR (200 MHz, CDCl ₃ ) δ: 7.30-7.15 (bs, 4H), 5.10 (m, 1H), 4.80-4.45 (m, 2H), 4.20-4.00 (2H), 3.25-3.10 (m, 2H), 1.53 (s, 9H), 1.28 (t, 1H), 1.23 (t, 2H).

Example 7

(S) -N-methyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline

Lithium aluminum hydride (4.7) in a solution of (S) -N-butyloxycarbonyl-3-ethoxycarbonyl-1,2,3,4-isoquinoline (12 g, 39.3 mmol) dissolved in 120 mL of tetrahydrofuran. g, 3.0 eq) was added carefully at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and refluxed for 1 hour. After cooling, the reaction mixture was poured into ice little by little and the resulting solution was filtered through 200 mL of brine and then brine. The volatiles in the filtrate were evaporated in vacuo and the residue was extracted (dichloromethane, 200 mL × 3). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated. The residue was crystallized in Et ₂ O to give 5.10 g (73.2%) of product as a white solid.

¹ H NMR (200 MHz, CDCl ₃ ) δ: 7.20-6.96 (m, 4H), 3.90-3.50 (m, 4H), 2.80 (m, 1H), 2.82-2.70 (m, 3H), 2.39 (3H) .

Example 8

(S) -3-carbamoyloxymethyl-N-methyl-1,2,3,4-tetrahydroisoquinoline

Starting with (S) -N-methyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline, the product was obtained as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 2.30 (s, 3H), 2.68-2.95 (m, 3H), 3.43-3.80 (m, 2H), 3.84-4.19 (m, 2H), 6.63- 6.82 (m, 2 H), 6.94-7.30 (m, 4 H).

Hydrochloride

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 2.64 (s, 3H), 2.70 (m, 2H), 2.82-3.16 (m, 2H), 3.91-4.41 (m, 4H), 6.76 (s, br, 2H), 7.00-7.35 (m, 4H).

Example 9

N-tert-butyloxycarbonyl-3-ethoxycarbonyl-3-methyl-1,2,3,4-tetrahydroisoquinoline

Potassium hexamethyldisilazine in 20 g (65.5 mmol) of N-tert-butyloxycarbonyl-3-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline dissolved in 150 mL of anhydrous tetrahydrofuran. (KHMDS, 42.5 mL, 1.3 eq) was added at -78 ° C under N ₂ atmosphere. The reaction mixture was stirred for 30 minutes and MeI (3.0 mL, 3.0 eq) was added at -78 ° C, stirred for 30 minutes at -78 ° C, and for 3 hours at room temperature.

The reaction mixture was poured into 1N HCl (300 mL) and then poured into brine (600 mL). The volatiles were evaporated in vacuo and extracted with dichloromethane (300 mL × 3). After evaporation of the solvent the residue was dissolved in 250 mL of aqueous tetrahydrofuran (tetrahydrofuran: H ₂ O = 3: 1) and refluxed overnight in the presence of NaBH ₄ (2.0 g) to reduce only the unmethylated starting material. The mixture was added to 1N HCl (100 mL), after evaporation of the volatiles, extracted with dichloromethane (200 mL × 2), washed with brine (200 mL) and concentrated and column-chromatography (SiO ₂ , hexanes: EtOAc = 10: Purification with 1) gave 18.7 g of the product (89.4%) as a yellow liquid.

¹ H NMR (200 MHz, CDCl ₃ ) δ: 7.30-6.95 (m, 4H), 4.73-4.54 (m, 1H), 4.42 (d, 1H), 4.32-3.95 (m, 2H), 3.13 (d, 1H), 2.79 (d, 1H), 1.45 (s, 9H), 1.41 (s, 3H), 1.20 (t, 3H).

Example 10

(RS) -3-hydroxymethyl-3-methyl-N-methyl-1,2,3,4-tetrahydroisoquinoline

N-tert-butyloxycarbonyl-3-ethoxycarbonyl-3-methyl-1,2,3,4-tetrahydroisoquinoline (10 g) is dissolved in 100 mL of tetrahydrofuran and lithium aluminum hydride (3.42 g) was added carefully at 0 ° C. and the mixture was stirred for 30 minutes. Next, it was refluxed for 3 hours and the reaction mixture was poured into ice little by little. The mixture was acidified to pH 1 with 2 N HCl (2000 mL) and filtered over Celite 545. The volatiles in the resulting clear solution were evaporated in vacuo and 100 mL of brine was added followed by extraction with dichloromethane (100 mL × 3). The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give the product (5.98 g) as a yellow solid.

¹ H NMR (200 MHz, CDCl ₃ ) δ: 7.18-6.90 (m, 4H), 3.90 (d, 1H), 3.79 (d, 1H), 3.75 (d, 1H), 3.13 (d, 1H), 2.80 (bs, 1 H), 2.34 (s, 3 H), 0.94 (s, 3 H).

Example 11

(RS) -3-carbamoyloxymethyl-3-methyl-N-methyl-1,2,3,4-tetrahydroisoquinoline

The product was obtained as a white solid starting with (RS) -3-hydroxymethyl-3-methyl-N-methyl-1,2,3,4-tetrahydroisoquinoline.

¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 7.38-7.20 (m, 4H), 6.77 (bs, 2H), 4.64-4.07 (m, 4H), 3.35-3.10 (m, 2H), 2.90- 2.73 (m, 3 H), 1.50 (s, 1 H), 1.23 (s, 2 H).

Example 12

N-tert-butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline

3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (13.9 g), 2- (t-butyloxycarbonyloxyimino) -2-phenylacetonitrile in tetrahydrofuran (150 mL), The mixture of triethylamine (10.4 mL) was stirred for 3 hours. The mixture was chromatographed on silica gel to give the product (19.6 g) as a yellow viscous oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ: 1.49 (s, 9H), 1.97-2.13 (m, 2H), 3.06 (m, 1H), 3.51 (s, 2H), 4.29-4.94 (m, 3H) , 7.00-7.27 (m, 4 H).

Example 13

N-tert-butyloxycarbonyl-3-thiocarbamoyloxymethyl-1,2,3,4-tetrahydroisoquinoline

Sodium hydride (60% in mineral oil) in N-tert-butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (9 g) dissolved in tetrahydrofuran (200 mL), 1.64 g) was added at 0 ° C. Stir for 50 minutes, add carbon disulfide (2.5 mL) and stir for 1 hour more. Methyl iodide (2.55 mL) was added and after 2 hours ammonium hydroxide (28% solution, 10.4 mL) was added. After stirring overnight, brine was added, extracted with methylene chloride and the extract was concentrated to give the product (5.6 g) as a solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 1.41 (s, 9H), 2.75-2.98 (m, 1H), 3.00 (m, 1H), 4.10-4.41 (m, 4H), 7.18 (s, 4H), 8.46 (s, 1 H), 8.82 (s, 1 H).

Example 14

3-thiocarbamoyloxymethyl-1,2,3,4-tetrahydroisoquinoline

N-tert-butyloxycarbonyl-3-thiocarbamoyloxymethyl-1,2,3,4-tetrahydroisoquinoline (5.6 g) suspended in methanol (20 mL) 6 N HCl 10 in methanol mL was added. After 6 hours, ether (30 mL) and isopropyl ether (10 mL) were added, cooled to 0 ° C. and filtered to afford the product (3 g) as hydrochloride. Melting point 167.6-168.2 ° C.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 2.85-3.11 (m, 2H), 3.74-3.95 (m, 1H), 4.20-4.38 (m, 1H), 4.45-4.62 (m, 1H), 7.02-7.39 (m, 4H), 8.92 (s, 1H), 9.10 (s, 1H), 9.66-10.1 (s, 1H).

Example 15

(RS) -N-methyl-3-methyl-3- (N-methylthiocarbamoyloxymethyl) -1,2,3,4-tetrahydroisoquinoline

To 25 mL of a dichloromethane solution containing 1.0 g (5.64 mmol) of (RS) -3-hydroxymethyl-3-methyl-N-methyl-1,2,3,4-tetrahydroisoquinoline, NaH (60% in oil) ) Was added. The mixture was stirred for 15 minutes and MeNCS (495 mg, 1.2 eq) dissolved in 10 mL of dichloromethane was added. The mixture was stirred for 2 hours and the reaction was quenched by addition of 1N HCl. The mixture was basified with saturated Na ₂ CO ₃ (20 mL) and extracted with dichloromethane (50 mL × 2). After evaporation in vacuo and concentration, the residue was purified by column-chromatography (SiO ₂ , hexanes: EtOAc = 1: 1.1). The product was dissolved in 30 mL of tetrahydrofuran and treated with HCl methanol (0.5N). The volatiles were evaporated in vacuo and the residue was washed with Et ₂ O (20 mL × 2) to afford the product as a yellow viscous gum.

¹ H NMR (200 MHz, 60 ° C., DMSO-d ₆ ) δ: 9.3 (bs, 1H), 7.36-7.12 (m, 4H), 4.75-4.25 (m, 5H), 3.05-2.65 (m, 7H) , 2.55 (s, 1 H), 1.35 (s, 2 H).

Example 16

(S) -3- (N-methylthiocarbamoyloxymethyl) -1,2,3,4-tetrahydroisoquinoline

To 50 mL of dichloromethane solution containing (S) -3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (4.53 g, 27.75 mmol) di-tert-butyl dicarbonate (5.45 g, 25.0 mmol, 0.9eq) was added and the reaction mixture was stirred for 2 hours until no gas bubble was observed. The reaction mixture was washed with 0.5 N HCl (50 mL) followed by brine (50 mL) to remove residual starting material. After drying over MgSO ₄ and filtration, the dichloromethane mixture was evaporated to afford crude (S) -N-tert-butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline. . Crude N-tert-butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline was redissolved in 100 mL of tetrahydrofuran. NaH (60%, 1.22 g) was added to the solution several times at 0 ° C. and stirred at room temperature for 30 minutes, then MeNCS (2.23 g) was added and the mixture was stirred at room temperature for 2 hours. Brine (50 mL) was added to the mixture to quench the reaction and the volatiles were evaporated in vacuo, then extracted with dichloromethane (50 mL × 2) and the combined layers were dried (MgSO ₄ ), filtered and evaporated. The resulting material was chromatographed on SiO ₂ with a hexane-EtOAc (4: 1) mixture to give (S) -N-tert-butyloxycarbonyl-3- (N-methyl-thiocarbamoyloxymethyl) -1,2 7.07 g (81.8%) of, 3,4-tetrahydroisoquinoline were obtained. This material was dissolved in THF (30 mL) and 10 mL of concentrated HCl was added to the solution. After 1 hour, 5 mL of concentrated HCl was added and stirred for another 1 hour until the reaction was complete. The reaction mixture was diluted with 30 mL of water and the volatiles were evaporated. During evaporation the desired product precipitated out as a white solid. The solid was filtered and dried to give the product (4.8 g) as hydrochloride.

¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 10.5-9.7 (m, 2H), 9.30 (s, 1H), 7.23 (s, 4H), 4.90 (m, 2H), 4.38 (s, 2H) , 3.15-3.00 (m, 2H), 2.95 (d, 2H), 2.80 (1H).

Example 17

(S) -3- (N-methyl-thiocarbamoyloxymethyl) -N- (anilinocarbonyl) -1,2,3,4-tetrahydroisoquinoline

(S) -3- (N-methylthiocarbamoyloxymethyl) -1,2,3,4-tetrahydroisoquinoline (1.0 g, 4.94 mmol) dissolved in 20 mL of dichloromethane was dissolved with PhNCO (1.0 g). Combined and stirred for 24 h at room temperature. The reaction mixture was evaporated and the crude product was purified by column chromatography (SiO ₂ , hexanes: EtOAc = 3: 2) to give the product (1.7 g) as a white solid.

¹ H NMR (200 MHz, CDCl ₃ ) δ: 7.78 (s, 1H), 7.58-7.42 (m, 2H), 7.35-6.85 (m, 7H), 6.70 (s, 1H), 4.90-4.50 (m, 4H), 4.20-3.90 (m, 1 H), 3.25-2.75 (m, 5H).

Example 18

(S) -3- (N-methylthiocarbamoyloxymethyl) -N-methyl-1,2,3,4-tetrahydroisoquinoline

(S) -N-methyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (2.0 g, 11.3 mmol) was dissolved in 20 mL of dichloromethane and NaH (60% in oil, 452 mg, 1.0 eq) ) Was added at 0 ° C. and stirred for 30 minutes under N ₂ atmosphere. MeNCS (850 mg, 1.03eq) dissolved in 10 mL of dichloromethane was added to the reaction mixture and stirred overnight. The reaction mixture was evaporated and the residue was purified by column chromatography (SiO ₂ , hexanes: EtOAc = 1: 2). The purified product was dissolved in Et ₂ O and acidified to pH = 1 with 3N HCl. The solvent was evaporated and the white solid obtained was washed with Et ₂ O (50 mL × 3) to give 2.4 g (74.4%) of product.

¹ H NMR (200 MHz, CDCl ₃ ) δ: 7.17-6.90 (m, 4H), 6.70 (bs, 1H), 4.75-4.45 (m, 2H), 3.86 (d, 1H), 3.63 (d, 2H) , 3.10-2.70 (m, 5 H), 2.45 (s, 1 H).

Example 19

N- (t-butyloxycarbonyl) -3-methoxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

To a suspension of O, O'-dimethyl-DOPA methyl ester (2.5 g, 9.1 mmol) in 35 mL of dichloromethane was added anhydrous formaldehyde in 15 mL of dichloromethane followed by BF ₃ .Et ₂ O (836 μL). Anhydrous formaldehyde was prepared by extracting 2.5 mL of aqueous formaldehyde with dichloromethane (5 mL × 3) and drying over Na ₂ SO ₄ . The reaction mixture was refluxed overnight and the reaction mixture was poured into saturated Na ₂ CO ₃ solution (30 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in 50 mL of dichloromethane and stirred overnight with 2.68 g of Boc ₂ O. After evaporation of the volatiles in vacuo, the residue was purified by column chromatography (SiO ₂ , hexanes: EtOAc = 2: 1) to give the product (2.5 g, 75%).

¹ H NMR (200 MHz, 60 ° C., CDCl ₃ ) δ: 6.58 (s, 2H), 4.62 (d, 1H), 4.39 (d, 1H), 3.80 (s, 6H), 3.59 (s, 3H), 3.07 (m, 2 H), 1.45 (s, 9 H).

Example 20

N-methyl-3- (N-methylcarbamoyloxymethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

N- (t-butyloxycarbonyl) -3-methoxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.77 g, 4.8 dissolved in 48 mL of tetrahydrofuran) mmol) was combined with lithium aluminum hydride (231 mg, 1.25 eq) at 0 ° C. and the mixture was stirred for 75 minutes until the reaction was complete. The reaction mixture was poured into ice and the mixture was filtered over celite. The volatiles in the filtrate were evaporated in vacuo and the resulting mixture was extracted with dichloromethane (50 mL × 3) and dried over Na ₂ SO ₄ .

The combined organic layers were concentrated to 30 mL and carbonyl diimidazole (940 mg) was added to the mixture and stirred for 10 minutes followed by MeNH ₂ (10 mL). After stirring overnight, the mixture was extracted with dichloromethane (30 mL × 3), 30 mL of brine was added, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (hex: EtOAc = 3: 1) to give 1.44 g of material. The BOC group in this material was deprotected by methanolic HCl treatment to give the product hydrochloride (0.80 g) as a pale yellow solid.

¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 9.80-9.45 (m, 2H), 7.05-7.03 (m, 1H), 6.85 (s, 1H), 6.80 (s, 1H), 4.43-4.15 ( m, 5H), 3.80 (s, 6H), 2.98-2.82 (m, 2H), 2.62 (d, 3H).

Example 21

N-methyl-3-hydroxymethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

A method similar to that of Example 10 was carried out from N- (t-butyloxycarbonyl) -3-methoxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline starting material To give the title compound as a hydrochloride salt.

¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 6.85-6.75 (m, 2H), 4.50-4.05 (m, 3H), 3.95-3.37 (m, 10H), 3.20-2.85 (m, 4H), 2.75-2.65 (m, 1 H).

Example 22

N-methyl-3- (N-methylthiocarbamoyloxymethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

Starting from N-methyl-3-hydroxymethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline to give the title compound as a hydrochloride salt.

¹ H NMR (200 MHz, D ₂ O) δ: 6.85-6.73 (m, 2H), 4.85-4.50 (m, 3H), 4.50-4.05 (m, 2H), 3.73 (s, 6H), 3.20-2.75 (m, 7 H), 2.60-2.45 (m, 1 H).

Claims (55)

Compounds rich in racemates or enantiomers represented by the following formula (I) and pharmaceutically acceptable non-toxic salts thereof: Formula I In the above formula, X ₁ and X ₂ are the same or different from each other and are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, thioalkoxy, halogen, hydroxy, nitro and trifluorocarbon; Y is a member selected from the group consisting of oxygen and sulfur; R ₁ is a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and CONHR ', wherein R' is selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl; R ₂ and R ₃ are the same as or different from each other, and independently a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and cycloalkyl, or R ₂ and R ₃ together with a nitrogen atom bonded thereto are 5 to 7 May form a circular ring; R ₄ is a member selected from the group consisting of hydrogen or lower alkyl. The compound of claim 1, wherein R ₁ and R ₄ are both hydrogen. The compound of claim 1, wherein R ₁ , R ₄ , X ₁ and X ₂ are all hydrogen. The compound of claim 1, wherein R ₁ , R ₂ , R ₃ and R ₄ are all hydrogen. 2. The compound of claim 1, wherein R ₄ is hydrogen and X ₁ and X ₂ are members selected from the group consisting of hydrogen, alkyl, and halogen. A pharmaceutical composition for treating central nervous system diseases, comprising a therapeutically effective amount of the compound of claim 1 as an active ingredient and a pharmaceutically acceptable carrier. 7. The composition of claim 6, wherein the central nervous system disease to be treated is depression. A method for the treatment of a mammal with a central nervous system disease, comprising administering an effective amount of the compound of claim 1 to a mammal with a central nervous system disease. The method of claim 8, wherein the central nervous system disease is depression. A compound according to claim 1 represented by the following formula (II) and a pharmaceutically acceptable nontoxic salt thereof. Formula II In the above formula, X ₁ and X ₂ are the same or different from each other and are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, thioalkoxy, halogen, hydroxy, nitro and trifluorocarbon; R ₁ is a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and CONHR ', wherein R' is selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl; R ₂ and R ₃ are the same as or different from each other, and independently a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and cycloalkyl, or R ₂ and R ₃ together with a nitrogen atom bonded thereto are 5 to 7 May form a circular ring; R ₄ is a member selected from the group consisting of hydrogen or lower alkyl. The compound of claim 10, wherein R ₁ and R ₄ are both hydrogen. The compound of claim 10, wherein R ₁ , R ₄ , X ₁ and X ₂ are all hydrogen. The compound of claim 10, wherein R ₁ , R ₂ , R ₃ and R ₄ are all hydrogen. A pharmaceutical composition for treating central nervous system diseases, comprising a therapeutically effective amount of the compound of claim 10 as an active ingredient and a pharmaceutically acceptable carrier. 15. The composition of claim 14, wherein said central nervous system disease to be treated is depression. A method for the treatment of a mammal with a central nervous system disease, comprising administering an effective amount of the compound of claim 10 to a mammal with a central nervous system disease. The method of claim 16, wherein the central nervous system disease is depression. A compound according to claim 1 represented by the formula (III) and a pharmaceutically acceptable non-toxic salt thereof. Formula III In the above formula, X ₁ and X ₂ are the same or different from each other and are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, thioalkoxy, halogen, hydroxy, nitro and trifluorocarbon; R ₁ is a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and CONHR ', wherein R' is selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl; R ₂ and R ₃ are the same as or different from each other, and independently a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and cycloalkyl, or R ₂ and R ₃ are 5 to 7 members together with the nitrogen atom bonded thereto; May form a ring. 19. The compound of claim 18, wherein R ₁ and R ₄ are both hydrogen. 19. The compound of claim 18, wherein R ₁ , R ₄ , X ₁ and X ₂ are all hydrogen. 19. The compound of claim 18, wherein R ₁ , R ₂ , R ₃ and R ₄ are all hydrogen. A pharmaceutical composition for treating central nervous system diseases, comprising a therapeutically effective amount of the compound of claim 18 as an active ingredient and a pharmaceutically acceptable carrier. The composition of claim 22, wherein the central nervous system disease to be treated is depression. A method for treating a mammalian suffering from central nervous system disease, comprising administering an effective amount of the compound of claim 18 to a mammalian suffering from central nervous system disease. The method of claim 24, wherein the central nervous system disease is depression. Enantiomeric compound according to claim 1 represented by the formula (IV) and a pharmaceutically acceptable non-toxic salt thereof. Formula IV In the above formula, X ₁ and X ₂ are the same or different from each other and are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, thioalkoxy, halogen, hydroxy, nitro and trifluorocarbon; R ₁ is a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and CONHR ', wherein R' is selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl; R ₂ and R ₃ are the same as or different from each other, and independently a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and cycloalkyl, or R ₂ and R ₃ are 5 to 7 members together with the nitrogen atom bonded thereto; May form a ring; R ₄ is a member selected from the group consisting of hydrogen or lower alkyl. 27. The compound of claim 26, wherein R ₁ and R ₄ are both hydrogen. 27. The compound of claim 26, wherein R ₁ , R ₄ , X ₁ and X ₂ are all hydrogen. 27. The compound of claim 26, wherein R ₁ , R ₂ , R ₃ and R ₄ are all hydrogen. 27. The compound of claim 26, wherein R ₄ is hydrogen and X ₁ and X ₂ are members selected from the group consisting of hydrogen, alkyl or halogen. A pharmaceutical composition for treating central nervous system disease, comprising a therapeutically effective amount of the compound of claim 26 as an active ingredient and a pharmaceutically acceptable carrier. 32. The composition of claim 31, wherein the central nervous system disease to be treated is depression. A method for treating a mammalian disease with central nervous system disease, comprising administering an effective amount of the compound of claim 26 to a mammalian disease with central nervous system disease. 34. The method of claim 33, wherein the central nervous system disease is depression. (S) -3-carbamoyloxymethyl-1,2,3,4-tetrahydroisoquinoline and its pharmaceutically acceptable non-toxic salts. A pharmaceutical composition for treating central nervous system diseases, comprising a therapeutically effective amount of the compound of claim 35 as an active ingredient and a pharmaceutically acceptable carrier. 37. The composition of claim 36, wherein said central nervous system disease to be treated is depression. A method for treating a mammalian suffering from central nervous system disease, comprising administering an effective amount of the compound of claim 35 to a mammalian suffering from central nervous system disease. 39. The method of claim 38, wherein the central nervous system disease is depression. The enantiomer-rich compound according to claim 1 represented by the following formula (V) and a pharmaceutically acceptable nontoxic salt thereof. Formula V In the above formula, X ₁ and X ₂ are the same or different from each other and are independently a member selected from the group consisting of hydrogen, alkyl, alkoxy, thioalkoxy, halogen, hydroxy, nitro and trifluorocarbon; R ₁ is a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and CONHR ', wherein R' is selected from the group consisting of hydrogen, alkyl, arylalkyl and aryl; R ₂ and R ₃ are the same as or different from each other, and independently a member selected from the group consisting of hydrogen, alkyl, arylalkyl, and cycloalkyl, or R ₂ and R ₃ are 5 to 7 members together with the nitrogen atom bonded thereto; May form a ring; R ₄ is a member selected from the group consisting of hydrogen or lower alkyl. 41. The compound of claim 40, wherein R ₁ and R ₄ are both hydrogen. 41. The compound of claim 40, wherein R ₁ , R ₄ , X ₁ and X ₂ are all hydrogen. 41. The compound of claim 40, wherein R ₁ , R ₂ , R ₃ and R ₄ are all hydrogen. A pharmaceutical composition for treating central nervous system diseases, comprising a therapeutically effective amount of the compound of claim 40 and a pharmaceutically acceptable carrier as an active ingredient. 45. The composition of claim 44, wherein the central nervous system disease to be treated is depression. A method for the treatment of a mammal with a central nervous system disease, comprising administering an effective amount of the compound of claim 40 to a mammal with a central nervous system disease. 47. The method of claim 46, wherein the central nervous system disease is depression. (S) -3-carbamoyloxymethyl-1,2,3,4-tetrahydroisoquinoline, (R) -3-carbamoyloxymethyl-1,2,3,4-tetrahydroisoquinoline, And (RS) -3-carbamoyloxymethyl-1,2,3,4-tetrahydroisoquinoline. A method for the treatment of a mammal with central nervous system disease, comprising administering an effective amount of the compound of claim 48 to a mammal with central nervous system disease. 50. The method of claim 49, wherein the central nervous system disease is depression. The agent for the treatment of diseases in which monoamine oxidase inhibition is effective, comprising the compound of claim 1 as an active ingredient. The agent for the treatment of diseases in which monoamine oxidase inhibition is effective, comprising the compound of claim 10 as an active ingredient. An agent for treating diseases, comprising the compound of claim 26 as an active ingredient, wherein monoamine oxidase inhibition is effective. A disease treating agent, comprising the compound of claim 35 as an active ingredient, wherein monoamine oxidase inhibition is effective. The agent for the treatment of diseases in which monoamine oxidase inhibition is effective, comprising the compound of claim 40 as an active ingredient.