KR100576372B1 - O-thiocarbamoyl-aminoalkanol compounds, their pharmaceutically acceptable salts and process for preparing the same - Google Patents

Abstract

The present invention relates to O-thiocarbamoyl-aminoalkanol compounds and their pharmaceutically acceptable salts, which are rich in racemic or enantiomeric properties, represented by formula (VI), for use in treating the central nervous system. Wherein Ar is a phenyl group represented by formula (I), R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, 1 to 3 Is a member selected from the group consisting of thioalkoxy, nitro, hydroxy and trifluorocarbons of which carbon atoms, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, and R _1, R ₂ , R ₃ , and R ₄ may be the same or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, aliphatic ring compound consisting of 3 to 7 atoms , R ₃ and R ₄ form a ring compound of 5 to 7 atom configuration, such as adjacent N atoms, optionally with one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups With or without more Or contains no further oxygen atoms which are not directly connected, and each of l, m and n is 0 or 1.

O-thiocarbamoyl, Aminoalkanol, Pharmacy, Mammal, Central nervous system

Description

O-thiocarbamoyl-aminoalkanol compounds, pharmaceutically acceptable salts and preparation methods thereof O-thiocarbamoyl-aminoalkanol compounds, their pharmaceutically acceptable salts and process for preparing the same}

The present invention relates generally to novel thiocarbamates of aminoalkanols and pharmaceutically useful salts thereof, which are useful for treating central nervous system diseases. Specifically, the present invention relates to an O-thiocarbamoyl-aminoalkanol compound rich in enantiomeric properties or a racemic mixture thereof and a pharmaceutical useful salt thereof, a method for preparing the same, a composition thereof, and a method for treating a midline nervous system disease. It is about.

Phenylethylamine derivatives belong to the group of therapeutic agents useful for treating central nervous system diseases, and have been mainly used to treat obesity, sleep attacks, minimal brain dysfunction, and mild depression.

Organic thiocarbamates or carbamates have been usefully used to control various central nervous system diseases. For example, US Pat. No. 2,901,501 discloses 1,3-dithiocarbamoyl-1,3-propanediols further substituted at the 2-position with a hydrocarbon-based powder containing an aryl group. J. Am. Chem. Soc., 73, 5779 (1951) introduces 2-methyl-2-propyl-1,3-propanediol dicarbamate and its pharmaceutical activity is described in J. Pharmacol. Exp. Ther., 104, 229 (1952). In addition, many carbamate compounds have been proposed in the prior art as therapeutic agents for central nervous system diseases. For example, US Pat. Nos. 2,884,444 and 2,937,119 disclose carbamates, namely 2-phenyl-1,3-propanediol dicarbamate and isopropylmeprobamate, respectively. It has been found that these compounds can be used very effectively as therapeutic agents for treating central nervous system diseases, especially as antiepileptic and central action muscle relaxants. The development of thiocarbamate or carbamate therapeutics for central nervous system disease has been actively developed and is becoming so.

Recent designs of pharmacologically useful compounds are based on amino acids or derivatives thereof, mainly due to the fact that many of the compounds found in biological systems are derived from amino acids or derivatives thereof.

Intensive and thorough studies have shown that O-thiocarbamoyl-aminoalkanol compounds are pharmaceutically useful compounds for central nervous system diseases, particularly depression and anxiety.

Accordingly, the main object of the present invention is to provide a racemic O-thiocarbamoyl-aminoalkanol compound represented by the following general formula (VI), and a pharmaceutically acceptable salt thereof.

Ar is a phenyl group described as follows.

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor Is a member selected from the group consisting of locarbons, where x is an integer from 1 to 3, wherein R is the same or different when x is 2 or 3. R ₁ and R ₂ may be the same or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, aliphatic ring compound consisting of 3 to 7 atoms, and R ₁ and R ₂ constitutes a cyclic compound of 5 to 7 atoms, such as an adjacent N atom, optionally further comprising or including one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups Or no further inclusion or inclusion of one oxygen atom not directly connected. R ₃ and R ₄ may be the same as or different from each other, and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, and aliphatic ring compound of 3 to 7 atom configuration, and R ₃ and R ₄ form a ring compound of 5 to 7 atom configuration, such as adjacent N atoms, optionally further comprising one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups Or does not include or include one more oxygen atom which is not included or is not directly connected. l, m and n are each 0 or 1.

It is also an object of the present invention to provide O-thiocarbamoyl- (D) -aminoalkanols and pharmaceutically acceptable salts thereof represented by the following formula (VIII): (Alternatively, "D" represents Can be represented by the R-shape at the chiral center of

Wherein Ar is a phenyl group as described below

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor Is a member selected from the group consisting of locarbons, where x is an integer from 1 to 3, wherein R is the same or different when x is 2 or 3. R ₁ and R ₂ may be the same or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, aliphatic ring compound consisting of 3 to 7 atoms, R ₁ And R ₂ , like adjacent N atoms, constitute a cyclic compound of 5 to 7 atoms, optionally further comprising one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or It does not contain, or further contains or does not contain one oxygen atom which is not directly connected. R ₃ and R _{4, which} may be the same or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, and aliphatic ring compound of 3 to 7 atom configuration, R ₃ and R ₄ form a ring compound of 5 to 7 atom configuration, such as adjacent N atoms, optionally further comprising one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups Or does not include or include one more oxygen atom which is not included or is not directly connected. l, m and n are each 0 or 1.

It is also an object of the present invention to provide O-thiocarbamoyl- (L) -aminoalkanols and pharmaceutically acceptable salts thereof represented by the following formula (IX): (Alternatively, "L" is represented by the formula (IX In the chiral center of

Wherein Ar is a phenyl group as described below

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor Is a member selected from the group consisting of locarbons, where x is an integer from 1 to 3, wherein R is the same or different when x is 2 or 3. R ₁ and R ₂ may be the same or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, aliphatic ring compound consisting of 3 to 7 atoms, and R ₁ and R ₂ constitutes a cyclic compound of 5 to 7 atoms, such as an adjacent N atom, and further comprises or does not contain one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or Or may further include or include one oxygen atom not directly connected. R ₃ and R _{4, which} may be the same or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, and aliphatic ring compound of 3 to 7 atom configuration, R ₃ and R ₄ form a ring compound of 5 to 7 atom configuration, such as adjacent N atoms, containing no further nitrogen atoms substituted with substituents selected from the group consisting of hydrogen, alkyl and aryl groups; It may or may not contain one or more oxygen atoms which are not directly connected. Each of l, m and n is 0 or 1.

According to the present invention, racemic or enantiomerically enriched O-thiocarbamoyl-aminoalkanols represented by the formulas (VI), (VIII) and (IX) and pharmaceutically acceptable salts thereof are It may be prepared by the following steps starting with the readily available material represented by the general formula (II):

Wherein Ar is as defined above.

The stereochemistry of the final products (VI, VIII and IX) depends entirely on the stereochemistry of the starting material (II); Starting materials (II) with D-enantiomers only produce product (III) with D-enantiomers, starting materials (II) with L-enantiomers only product (IX) with L-enantiomers do.

The process for the preparation of novel compounds wherein R 3 = R 4 = H or R 4 = H in the general formula (VI) is described in detail below.

First, aminoalkanol (II) is reacted with di-t-butyl dicarbamate to synthesize N-t-butyloxycarbonyl-aminoalkanol represented by the formula (III).

This was then treated with sodium hydride, carbon disulfide and methyl iodide in ether solution followed by amine base (IV) to form O-thiocarbamoyl-Nt-butyloxycarbonyl-amino represented by formula (V). Produces alkanols:

Wherein Ar, R ₁ , R ₂ , R ₃ , R ₄ , l, m and n are as defined above and Boc represents a butyloxy carbonyl radical. This intermediate is then deprotected with aqueous hydrochloric acid. As a result of deprotection, O-thiocarbamoyl-aminoalkanol represented by the formula (VI) is obtained. Without further purification, the compound of formula (VI) can be converted to a pharmaceutically acceptable salt as described above.

This process is summarized as set out in the reaction scheme (I) below.

Details of the reaction conditions shown in Scheme (I) are as follows. In the first step, the concentration of starting material (II) is about 0.005 to 3 moles and di-t-butyl dicarbonate is in the range of about 1.0 to 2.0 equivalents. The aqueous base solution has a pH value between about 7 and 14 and the conversion reaction is carried out at about −10 to 70 ° C. To convert compound (III) to compound (IV), about 1.0 to 2.0 equivalents of sodium hydride and carbon disulfide, and about 1.0 to 2.5 equivalents of methyl iodide are used, and the reaction is about -10 to 70 It is preferable to carry out at ℃. Without purification, the resulting intermediate is treated with 1 to 5 equivalents of amine at -10 to 30 ° C. to yield the compound of formula (V). For this thiocarbamoylation reaction, etheric solvents such as diethyl ether and tetrahydrofuran, or polar aprotic solvents such as dimethylformamide and dimethylsulfoxide are used. Compounds of formula (VI) (0.005 to 3 moles) are neutralized after treatment with 1-12 N aqueous hydrochloric acid at about -10 to 30 ° C.

In Scheme (I), HX represents an acid capable of forming a pharmaceutically useful salt with the base nitrogen atom. Specific examples of anhydrous acids used in the preparation of compound (I) from compound (VI) include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, lactic acid, Gluconic acid, ascorbic acid, maleic acid, aspartic acid, benzene sulfonic acid, methanesulfonic acid, ethane sulfonic acid, hydroxymethane sulfonic acid, hydroxyethane sulfonic acid and the like. Additional salts can be found in “Pharmaceutical Salts” J. Pharm. Sci., 1977; 66 (1): 1-19. This preparation is carried out in a reaction medium exemplified by an ethereal solvent such as THF, an alcoholic solvent such as methanol, an ester solvent such as ethyl acetate, an aromatic solvent, and any compositional combination thereof. Ethereal solvents, including ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether and the like, are recommended as further solutions. The concentration of the compound (VI) is about 0.01 to 5 moles.

A second method of preparing novel compounds in which R ₃ and R ₄ in the formula (VI) is not hydrogen will be described in detail below.

First, aminoalkanol (II) is reacted with sodium hydride, carbon disulfide and methyl aodide in an ethereal solution to produce xanthate which is treated with an amine base (VI) to form O- Produces thiocarbamoyl-aminoalkanols.

Formula VI

Wherein Ar, R ₁ , R ₂ , R ₃ , R ₄ , l, m and n are as defined above. Without further purification, the compound of formula (VI) can be converted into a pharmaceutically acceptable salt as described above.

The procedure is summarized as set out in reaction scheme (II) below.

Details of the reaction conditions shown in Scheme (I) are as follows. In the first step, to convert compound (II) to compound (VI), sodium hydride and carbon disulfide in the range of about 1.0 to 2.0 equivalents, and about 1.0 to 2.5 equivalents of methyl iodide are used. The reaction is preferably carried out at about -10 to 70 ℃. Without purification, the resulting intermediate is treated with 1 to 5 equivalents of amine at -10 to 30 ° C. to yield the compound of formula (VI). For this thiocarbamoylation reaction, etheric solvents such as diethyl ether and tetrahydrofuran, or polar aprotic solvents such as dimethylformamide and dimethylsulfoxide are used. Compounds of formula (VI) (0.005 to 3 moles) are neutralized after treatment with 1-12 N aqueous hydrochloric acid at about -10 to 30 ° C.

In Scheme (II), HX represents an acid capable of forming a pharmaceutically useful salt with the base nitrogen atom.

A third method for preparing novel compounds wherein R 1 = R 3 = R 4 = H or R 1 = R 4 = H in formula (VI) will be described in detail below.

First, N- (t-butyloxycarbonyl) -aminoalkanol (III) is reacted with isothiocyanate (VII) to form N- (t-butyloxycarbonyl) -O- represented by the formula (V). Produces thiocarbamoyl-aminoalkanols.

Formula V

Wherein Ar, R ₁ , R ₂ , R ₃ , l, m and n are as defined above and Boc represents a t-butyloxy carbonyl radical. This intermediate is then deprotected with aqueous hydrochloric acid. As a result of deprotection, O-thiocarbamoyl-aminoalkanol (VI) represented by Example (VI) is obtained. Without further purification, the compound of formula (VI) can be converted into a pharmaceutically acceptable salt as described above.

The procedure is summarized as set out in Reaction Scheme (III) below.

Details of the reaction conditions shown in Scheme (III) are as follows. In a second step, the concentration of starting material (III) is about 0.005 to 3 moles and isothiocyanate (VII) ranges from about 1.0 to 2.0 equivalents. This conversion reaction is carried out at about 30 to 110 ° C. For this thiocarbamoylation reaction, ethereal solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, or aromatic solvents such as benzene and toluene can be used, and dichloromethane and chloroform Halogenated hydrocarbons such as are preferred. Compounds of formula (VI) (about 0.005 to 3 moles) are neutralized after treatment with 1 to 12 N aqueous hydrochloric acid at about −10 to 30 ° C.

In the formula (VI) a fourth method of preparing new compounds wherein R ₃ and R ₄ are not hydrogen and R ₁ is hydrogen will be described in detail below.

First, aminoalkanol (II) is reacted with isothiocyanate (VIII) in a halogenated hydrocarbon solvent to produce O-thiocarbamoyl-aminoalkanol represented by formula (VI):

Formula VI

Wherein Ar, R ₁ , R ₂ , R, l, m and n are as defined above. Without further purification, the compound of formula (VI) can be converted into a pharmaceutically acceptable salt as described above.

The procedure is summarized as set out in Reaction Scheme (IV) below.

Representative examples of compounds (VI), (VIII) and (IX) in Schemes I, II, III and IV are shown in Table 1:

Examples of compounds (VI), (VIII) and (IX) of Schemes I, II, III and IV Rx R ₁ R ₂ R ₃ R ₄ Rx R ₁ R ₂ R ₃ R ₄ H H H H H H Me Me H H H H Me H H H Et Et H H H H Et H H H H i-Pr H H H H n-Pr H H H H n-Bu H H H H c-Pr H H H H c-Hex H H H H n-Oct H H H H C ₆ H ₅ H H H H benzyl H H H H oFC ₆ H ₅ H H H H COOEt H H H - H H H H H H H - H H o-F - Me H H p-Cl H H H H m-F H H H H p-Cl H Me H H p-F H H H H p-MeS H H H H p-OH H H H H p-MeO H H H H 3,4- (HO) ₂ H H H H M, p- (Cl) ₂ Me Me H H 3,4- (MeO) ₂ H H H H 3,4-(OH) ₂ Me Me H H H H Me Me H H H i-Pr Me Me p-F H Me Me H p-HO H H Me Me H H Me i-Pr H H H Me Me Me m-F H H i-Pr H p-MeO H H Me Me H H COOEt benzyl H p-Cl H Me benzyl H

For use in therapeutic drugs to treat pain, depression, anxiety, epilepsy, seizures, dementia, and Parkinson's disease, the compounds of the present invention are administered to a patient in a dosage of about 0.7 to 7,000 mg per day, alone or as a pharmaceutically acceptable excipient. do. For a normal person having a weight of about 70 kg, the dosage is converted to a daily dosage of about 0.01 to 100 mg per kg body weight. However, the dosage used varies depending on the condition of the patient, the severity of the patient's condition, and the activity of the compound. Determination of the optimal dosage for a particular condition must be determined clinically and is within the skill of the art.

In using the compounds of the present invention to treat diseases and disorders of the central nervous system, particularly depression, it is preferred to administer the compounds orally. Since the compound is well absorbed orally, there is no need to rely on parenteral administration. For oral administration of females, compound (I) is preferably mixed with pharmaceutical excipients. The ratio of excipient to compound of formula (I) is not critical to expressing the effect of the drug on the central nervous system and can vary considerably depending on whether the composition is filled into capsules or made into tablets. In tabletting, various edible pharmaceutical excipients or mixtures thereof can be used. For example, a suitable excipient is a mixture of lactose, dibasic calcium phosphate, and / or corn starch. Other pharmaceutically acceptable ingredients may be further added, including lubricants such as magnesium stearate.

In addition to the compounds of formula (I), compositions comprising them are within the scope of the present invention. Moreover, the present invention encompasses the use of compound (I) and / or said composition.

As described above, it has been observed that the compounds represented by formula (I) are useful for the prevention and treatment of central nervous system diseases including pain, depression, anxiety, epilepsy, seizures, dementia and Parkinson's disease.

The therapeutic use of the compounds as antidepressants required in the present invention has been demonstrated by the "Forced Swimming Test", a known pharmacological test method for depression and the results are shown in Table II below.

The method presented by Porsolt et al. (1997) was used. The test compound was administered orally (peroral po) and intraperitoneally (ip) to mice (species CD-1), and after one hour the mice were filled with 1500 mL glass filled with water (20-23 ° C.) up to 5 cm. Fall into a beaker (16.5 cm deep, 13.0 cm diameter). Mice were kept in this water for 15 minutes and the quiescent period observed within the 15 minute test period was recorded. Mice were considered to be floating if they floated in the water with only the movement necessary to keep their head above the water.

compound Dose (mg / kg) Inhibition rate (% reduction)

i.p. (30 mg / kg) p.o. (30mg / kg) 41.6-

i.p. (30 mg / kg) p.o. (30mg / kg) 51.2-

i.p. (30 mg / kg) p.o. (30mg / kg) 30.5 25.6

i.p. (30 mg / kg) p.o. (30mg / kg) 30.6 38.1

i.p. (30 mg / kg) p.o. (30mg / kg) 31.4 23.4

i.p. (30 mg / kg) p.o. (30mg / kg) 54.9 50.8

i.p. (30 mg / kg) p.o. (30mg / kg) 44.2 29.2

The therapeutic use of the compounds as anticonvulsants required by the present invention has been demonstrated in the "Maximal ElectroShock (MES)" test, a well-established pharmacological test for testing anticonvulsants for partial seizures and the results are shown in Table III. Is shown in.

The process adopted in the MES test for anticonvulsants is as follows. Compound dosage solutions are prepared in saline and administered orally to subjects, ie mice (CD-1 species). After a predetermined time, a maximum electric shock through the corneal electrode was applied to the mouse using a model 11A Shocker from IITC Life Science, 0.2 seconds at 50 mA-60 Hz. When maximal electric shock was applied, the absence of stiff extension of the hind limb was considered to provide evidence of protection by anticonvulsants. The medium 50% effective amount (ED50) was determined using three different doses in at least six mice in each group. Compounds with low ED 50 values are more potent as anticonvulsants.

compound MES (IP, 30 mg / kg) or ED50 MES (po, 30 mg / kg) is ED50

ED50 = 29.0 (O.5h) ED50 = 188.8 (0.5h)

ED50 = 20.9 (1h) 3/3 (0.5h)

ED50 = 24.7 (1h)

ED50 = 41.8 (0.5h) ED50 = 152.0 (0.5h)

ED50 = 31.5 (1h) ED50 = 82.5 (0.5h)

1/3 (4.0h)

The invention will be better understood in the following examples, which are set forth for illustration only and are not intended to limit the invention.

Example 1

O-thiocarbamoyl-N- (t-butyloxycarbonyl)-(DL) -phenylalaninol

In a 500 mL flask equipped with a magnetic stirrer, N- (t-butyloxycarbonyl)-(DL) -phenylalaninol (0.051 mol, 13.6 g) was dissolved in 200 mL THF at 0 ° C. and NaH (0.061 mol) , 1.47 g) was added. The reaction mixture was stirred at 캜 for 1 h, then CS ₂ (0.061 mol, 4.66 g) was added. After stirring for 40 min at 0 ° C, MeI (0.061 mol, 8.69 g) was added to the reaction mixture. After stirring for 2 hours at room temperature, 5 N NH ₄ OH (0.090 mol, 18.0 mL) was added for 6 hours. The reaction was stopped by adding water to the resulting solution. The organic layer was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated in vacuo to give a solid. It was recrystallized in n-hexane and diethyl ether solution to give O-thiocarbamoyl-N- (t-butyloxycarmonyl)-(DL) -phenylalaninol: yield 80%.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.35 (s, 9H), 2.65-2.98 (m, 2H), 4.05-4.25 (br, 1H), 4.33-4.43 (m, 2H), 4.62-4.83 (br, 1H), 6.25 (s, 1H), 6.58 (s, 1 H), 7.01-7.42 (m, 5 H).

Example 2

O-thiocarbamoyl-N- (t-butyloxycarbonyl)-(L) -phenylalaninol

Instead of N- (t-butyloxycarbonyl)-(DL) -phenylalaninol, except using N- (t-butyloxycarbonyl)-(L) -phenylalaninol as starting material In the same manner as in Example 1, 1.90 g of the title compound was obtained. The yield was 79%.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.38 (s, 9H), 2.72-2.95 (m, 2H), 4.01-4.28 (br, 1H), 4.30-4.48 (m, 2H), 4.62-4.83 (br, 1H), 6.22 (s, 1H), 6.67 (s, 1 H) 7.08-7.39 (m, 5 H).

Example 3

O-thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol

In a 500 mL flask equipped with a magnetic stirrer, N- (t-butyloxycarbonyl)-(D) -phenylalaninol (0.040 mol, 10.05 g) was dissolved in 200 mL THF at 0 ° C. and NaH (0.048 mol) , 1.15 g) was added.

The reaction mixture was stirred at 캜 for 1 h, then CS ₂ (0.048 mol, 3.65 g) was added. After stirring for 40 min at 0 ° C, MeI (0.048 mol, 3.65 g) was added to the reaction mixture. After stirring for 2 hours at room temperature, 5 N NH ₄ OH (0.090 mol, 18.0 mL) was added for 6 hours. The reaction was stopped by adding water to the resulting solution. The organic layer was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated in vacuo to give a solid. This was recrystallized in n-hexane and diethyl ether solution to give O-thiocarbamoyl-N- (t-butyloxycarmonyl)-(D) -phenylalaninol: yield 78%.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.45 (s, 9H), 2.77-3.01 (m, 2H), 4.01-4.28 (br, 1H), 4.30-4.51 (m, 2H), 4.60-4.83 (br, 1H), 6.25 (s, 1H), 6.55 (s, 1H), 7.11-7.51 (m, 5H)

Example 4

O- (N-methyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol                 

Methylamine was used as the reactant instead of NH ₄ OH and the process of Example 3 was repeated to yield 2.33 g of the title compound. Yield 75%.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.45 (s, 9H), 2.68-2.98 (m, 2.5H), 3.12 (d, 1.5H), 4.06-4.28 (br, 1H), 4.31-4.55 (m, 2H), 6.35 (br, 0.5H) , 6.65 (br, 0.5H), 7.05-7.48 (m, 5H).

Example 5

O- (N-cyclopropyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol

Cyclopropylamine was used as the reactant instead of NH ₄ OH and the process of Example 3 was repeated to yield 2.49 g of the title compound. A yield of 74% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 0.51-0.98 (m, 4H), 1.45 (s, 9H),

2.68-3.05 (m, 3H), 4.05-4.82 (m, 4H), 6.42 (br, 0.5H), 6.82 (br, 0.5H), 7.05-7.48 (m, 5H).

Example 6

O- (N-octyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol

N-octylamine was used as the reactant instead of NH ₄ OH and the process of Example 3 was repeated to yield 3.34 g of the title compound. A yield of 78% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 0.89 (t, 3H), 1.02-1.78 (m, 21H), 2.68- 3.02 (m, 2H), 3.25 (q, 1H), 3.52 (q, 1H), 4.01-4.82 (m, 4H), 6.45 ( br, 0.5H), 6.95 (br, 0.5H), 7.05-7.48 (m, 5H).

Example 7

O- (N-isopropyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol

Using isopropylamine as the reactant instead of NH ₄ OH and repeating the procedure of Example 3 yielding 3.0 g of the title compound. Yield of 80% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.12-1.65 (m, 15H), 2.72-2.955 (m, 2H), 4.05-4.55 (m, 3H), 4.65 (br, 1H), 6.15 (br, 0.5H), 6.52 (br, 0.5H), 7.05-7.48 (m, 5H)

Example 8

O- (N-dimethyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol

Dimethylamine was used as the reactant instead of NH ₄ OH and the process of Example 3 was repeated to yield 2.56 g of the title compound. A yield of 67% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.45 (s, 9H), 2.78-2.98 (m, 2H), 3.12 (s, 3H), 3.38 (s, 3H), 4.18-4.52 (m, 3H), 4.58-4.74 (br, 1H), 7.10- 7.38 (m, 5H)

Example 9

O- (N-morpholino) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol

Morpholine was used as the reactant instead of NH ₄ OH and the process of Example 3 was repeated to yield 2.97 g of the title compound. Yield 75%.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.45 (s, 9H), 2.68-2.98 (m, 2H), 3.55-3.92 (m, 6H), 4.01-4.75 (m, 6H), 7.05-7.48 (m, 5H)

Example 10

O- (N-methyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D)-(o-fluoro) phenylalaninol

N- (t-butyloxycarbonyl)-(DL) -phenylalaninol and N- (t-butyloxycarbonyl)-(DL)-(o-fluoro) phenylalaninol instead of NH ₄ OH Was used as the starting material and methylamine as the reactant and the procedure of Example 1 was repeated to yield 1.01 g of the title compound. A yield of 60% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.35 (s, 9H), 2.72-3.15 (m, 5H), 4.01-4.28 (br, 1H), 4.30-4.52 (m, 2H), 4.58-4.83 (br, 1H), 6.42 (s.1H), 6.71 (s, 1H), 6.98-7.32 (m, 5H)

Example 11

O-thiocarbamoyl-N- (t-butyloxycarbonyl)-(DL)-(p-chloro) phenylalaninol

N- (t-butyloxycarbonyl)-(DL)-(p-chloro) phenylalaninol is used as a starting material instead of N- (t-butyloxycarbonyl)-(DL) -phenylalaninol The procedure of Example 1 was repeated to yield 3.0 g of the title compound. A yield of 62% was obtained.

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 1.32 (s, 9H), 2.62-2.82 (m, 2H), 3.79- 4.01 (br, 1H), 4.03-4.42 (m, 3H), 6.98-7.42 (m, 5H), 8.25 (s, 1H), 8.65 (s, 1 H).

Example 12

O-thiocarbamoyl-N- (t-butyloxycarbonyl)-(D)-(t-butyloxycarbonyloxy) phenylalaninol

N- (t-butyloxycarbonyl)-(D)-(t-butyloxycarbonyloxy) phenylalaninol instead of N- (t-butyloxycarbonyl)-(D) -phenylalaninol Use as starting material and repeat the procedure of Example 3 to yield 2.9 g of the title compound. Yield of 60% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.18-1.75 (m, 18H), 2.78-3.01 (m, 2H), 4.11-4.25 (m, 1H), 4.35-4.51 (m, 2H), 4.65-4.85 (m, 1H), 6.22 (br, s .1 H), 6.66 (br, s, 1 H), 7.02-7.35 (m, 4H).

Example 13

O- (N-dimethyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D)-(m, p-dichloro) phenylalaninol

N- (t-butyloxycarbonyl)-(D)-(m, p-dichloro) phenylalaninol as a starting material instead of N- (t-butyloxycarbonyl)-(D) -phenylalaninol And the procedure of Example 3 was repeated to yield 3.0 g of the title compound. A yield of 62% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.28-1.42 (m, 9H), 2.69-2.88 (m, 2H), 3.11 (d, 3H), 3.37 (d, 3H), 4.09-4.28 (m, 1H), 4.35-4.51 (m, 2H), 4.61-4.81 (m, 1 H), 7.01-7.41 (m, 3 H).

Example 14

O- (N-ethoxycarbonyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol

In a 100 mL flask equipped with a magnetic stirrer, N- (t-butyloxycarbonyl)-(D) -phenylalaninol (0.013 mol, 3.3 g) was dissolved in 50 mL of chloroform at room temperature and ethoxycarbonyl Isocyanate (0.014 mol, 1.7 mL) was added. The reaction mixture was heated at reflux for 6 hours and cooled to room temperature. Water was added to the resulting solution to stop the reaction. The organic layer was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated in vacuo to give a solid. It was recrystallized from a solution mixture of n-hexane and diethyl ether to give 2.56 g of O- (N-ethoxycarbonyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol. Generated. A yield of 56% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.18-1.61 (m, 12H), 2.82-3.08 (m, 2H), 4.22-4.38 (m, 3H), 4.45 (d, 2H), 5.01 (d, 1H), 7.02-7.45 (m, 5H), 8.25 (s, 1 H).

Example 15

O- (N-ethoxycarbonyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(L) -phenylalaninol

Example 14, using N- (t-butyloxycarbonyl)-(L) -phenylalaninol as starting material instead of N- (t-butyloxycarbonyl)-(D) -phenylalaninol The procedure was repeated to yield 3.4 g of the title compound. A yield of 64% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.18-1.48 (m, 12H), 2.85-3.01 (m, 2H), 4.22-4.32 (m, 3H), 4.45 (d, 2H), 5.01 (d, 1H), 7.12-7.35 (m, 5H), 8.28 (s, 1 H).

Example 16

3-N- (t-butyloxycarbonyl) amino-3-phenyl-1-O-((N-methyl) thiocarbamoyl) propanol

3-N- (t-butyloxycarbonyl) amino-3-phenyl-1-propanol as starting material instead of N- (t-butyloxycarbonyl)-(DL) -phenylalaninol and NH ₄ OH And using methylamine as a reactant and repeating the procedure of Example 1 to 3-N- (t-butyloxycarbonyl) amino-3-phenyl-1-O-((N-methyl) thiocarbamoyl) propanol Got it. Yield of 70% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.18-1.48 (m, 9H), 2.68-32.92 (m, 3H), 3.02 (d, 2H), 4.01-4.18 (m, 1H), 4.29-4.48 (m, 2H), 4.85-4.92 (m, 1H ), 6.81 (br, 0.4 H),

7.05-7.31 (m, 5H), 7.42 (br, 0.6H)

Example 17

3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-O- (thiocarbamoyl) propanol

Example using 3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-propanol as starting material instead of N- (t-butyloxycarbonyl)-(DL) -phenylalaninol The procedure of 1 was repeated to obtain 3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-O-((N-methyl) thiocarbamoyl) propanol. A yield of 66% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.42 (s, 9H), 3.21-3.40 (m, 2H), 3.55-3.68 (m, 1H), 4.50-4.70 (m, 3H), 6.20 (bs, 1H), 6.42 (bs, 1H), 7.20- 7.40 (m, 5 H).

Example 18

3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-O-((N-methyl) thiocarbamoyl) propanol

3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-propanol as starting material instead of N- (t-butyloxycarbonyl)-(DL) -phenylalaninol and NH ₄ OH And using methyl amine as reactant and repeating the procedure of Example 1 to obtain 3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-O-((N-methyl) thiocarbamoyl) propanol. Got it. A yield of 92% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.40 (9H), 2.89 (1H), 3.06 (H), 3.13-3.45 (2H), 3.45-3.72 (1H), 4.40-5.80 (2H), 6.30-6.70 (1H), 7.10-7.40 (5H).

Example 19

3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-O- (N-dimethyl) thiocarbamoyl) propanol

3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-propanol as starting material instead of N- (t-butyloxycarbonyl)-(DL) -phenylalaninol and NH ₄ OH And using dimethyl amine as reactant and repeating the procedure of Example 1 to 3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-O-((N-dimethyl) thiocarbamoyl) propanol Got it. A yield of 65% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 1.41 (s, 9H), 3.01 (s, 3H), 3.33 (3, 3H), 3.20-3.45 (m, 2H), 3.60 (m.1H), 4.55-4.70 (m, 3H), 7.20-7.40 ( m, 5H).

Example 20

O-N- (methyl) thiocarbamoyl-N-dimethyl- (D) -phenylalaninol

Example 3 using N-dimethyl-D-phenylalaninol as starting material and dimethyl amine as reactant instead of N- (t-butyloxycarbonyl)-(D) -phenylalaninol and NH ₄ OH The process of was repeated to yield 3.52 g of the title compound. A yield of 92% was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz), ppm (δ); 2.35 (s, 7.6H), 2.65-2.82 (m, 1.4H), 2.85-3.18 (m, 3H), 4.25-4.59 (m, 2H), 6.55 (br, 0.76H), 6.75 (br, 0.14H ), 6.98-7.32 (m. 5 H).

Example 21

O-thiocarbamoyl- (DL) -phenylalaninol hydrogen chloride

In a 100 mL flask equipped with a magnetic stirrer, O-thiocarbamoyl-N- (t-butyloxycarbonyl)-(DL) -phenylalaninol obtained in Example 1 was dissolved in 40 mL of THF and 6 N 20 mL of aqueous hydrochloric acid solution was added. The reaction mixture was stirred at rt for 8 h and then neutralized with saturated aqueous potassium carbonate solution. The organic layer was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated in vacuo to yield a yellow liquid. It was dissolved in 30 mL of THF at 0 ° C. and hydrochloric anhydride was added to give the desired white precipitate. To this was added 30 mL of anhydrous diethyl ether to maximize precipitation. As a result, 1.32 g of the title compound was produced. Yield 82%.

Melting Point: 181.3-181.6 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.78-3.18 (m, 2H), 3.78-4.02 (m, 1H), 4.15 (dd, 1H), 4.37 (dd, 1H), 7.08-7.45 (m, 5H), 8.38 (br, 4H), 9.02 ( s, 1H).

Example 22

O-thiocarbamoyl- (L) -phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O-thiocarbamoyl-N- (t-butyloxycarbonyl)-(L) -phenylalaninol as starting material to produce the title compound.

Melting Point: 173.2-173.6 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.78-3.15 (m, 2H), 3.58-3.82 (br, 1H), 4.15 (dd, 1H), 4.35 (dd, 1H), 7.02-7.43 (m, 5H), 8.45 (br, 4H), 9.01 ( s, 1H).

Example 23

O-thiocarbamoyl- (D) -phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O-thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol as starting material to produce the title compound.                 

Melting Point: 181.5-181.7 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.78-3.22 (m, 2H), 3.58-3.82 (br, 1H), 4.08-4.48 (m, 2H), 7.12-7.58 (m, 5H), 8.45 (br, 4H), 9.05 (s, 1H).

Example 24

O- (N-methyl) thiocarbamoyl- (D) -phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O- (N-methyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol as starting material to produce the title compound.

Melting Point: 178.1-179.5 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.75-3.25 (m, 5H), 3.65-3.95 (br, 1H), 4.11-4.55 (m, 2H), 7.18-7.61 (m, 5H), 7.48 (br, 3H), 9.25 (dd, 1H).

Example 25

O- (N-cyclopropyl) thiocarbamoyl- (D) -phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O- (N-cyclopropyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol as starting material to produce the title compound. .

Melting point: 180-181 ℃

₁ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 0.45-0.91 (m, 4H), 2.80-3.26 (m, 3H), 3.62-3.92 (m, 1H), 4.15-4.61 (m, 2H), 7.18-7.58 (m, 5H), 8.45 (br, 3H ), 9.45 (dd, 1 H).

Example 26                 

O- (N-octyl) thiocarbamoyl- (D) -phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O- (N-octyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol as starting material to produce the title compound.

Melting point: 123-124 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 0.89 (t, 3H), 1.12-1.68 (m, 14H), 2.78-3.35 (m, 4H), 3.75 (br, 1H), 4.01-4.82 (m, 4H), 7.05-7.48 (m, 5H), 8.52 (br, 3 H), 9.32 (dd, 1 H).

Example 27

O- (N-isopropyl) thiocarbamoyl- (D) -phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O- (N-isopropyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol as starting material to produce the title compound. .

Melting point: 200.1-201 ℃

₁ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 1.05-1.45 (m, 6H), 2.82-3.22 (m, 2H), 3.62-3.92 (m, 1H), 4.05-4.55 (m, 3H), 7.18-7.58 (m, 5H), 8.45 (br, 3H ), 9.25 (t, 1 H).

Example 28

O- (N-dimethyl) thiocarbamoyl- (D) -phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O- (N-dimethyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol as starting material to produce the title compound.

Melting Point: 185.6-186.4 ℃                 

₁ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.75-3.55 (m, 7H), 3.99 (br, s, 1H), 4.12-4.58 (m, 2H), 7.11-7.58 (m, 5H), 8.65 (br, 3H).

Example 29

O- (N-morpholino) thiocarbamoyl- (D) -phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O- (N-morpholino) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol as a starting material to produce the title compound. It was.

Melting point: 202-203 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.78-3.18 (m, 2H), 3.38-4.08 (m, 11H), 4.18-4.53 (m, 2H), 7.18-7.48 (m, 5H), 8.41 (br, 3H).

Example 30

O-thiocarbamoyl- (D)-(p-hydroxy) phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O-thiocarbamoyl-N- (t-butyloxycarbonyl)-(D)-(pt-butyloxycarbonyl) phenylalaninol as a starting material and the title compound was prepared. Generated.

Melting Point: 173.8-175.4 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.68-3.18 (m, 2H), 3.38-3.81 (m, 1H), 3.90-4.51 (m, 2H), 6.45-7.22 (m, 4H), 8.35 (br, 3H), 9.01 (s, 1H), 9.41 (s, 1 H).

Example 31                 

O- (N-dimethyl) thiocarbamoyl- (D) -phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O- (N-dimethyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D)-(m, p-dichloro) phenylalaninol as starting material To give the title compound.

Melting Point: 189.7-190.3 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.82-3.48 (m, 8H), 3.72-3.94 (m, 1H), 4.25-4.59 (m, 2H), 7.32 (d, 1H), 7.52-7.75 (m, 2H), 8.35 (br, 3H).

Example 32

O- (N-methyl) thiocarbamoyl- (DL)-(o-fluoro) phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O- (N-methyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(DL)-(o-fluoro) phenylalaninol as starting material and The title compound was produced.

Melting Point: 169.6-170.2 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.78 (dd, 3H), 2.85-3.22 (m, 2H), 3.62-3.81 (m, 1H), 4.18 (dd, 1H), 4.46 (dd, 1H) 6.98-7.48 (m, 4H), 8.45 (br , 3H), 9.20 (dd, 1H).

Example 33

O-thiocarbamoyl- (DL)-(p-chloro) phenylalaninol hydrogen chloride                 

The procedure of Example 21 was carried out using O-thiocarbamoyl-N- (t-butyloxycarbonyl)-(DL)-(p-chloro) phenylalaninol as starting material to produce the title compound.

Melting Point: 187.5-187.7 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.82-3.15 (m, 2H), 3.62-3.82 (m, 1H), 4.18 (dd, 1H), 4.39 (dd, 1H) 7.18-7.49 (m, 4H), 8.45 (br, 4H), 9.01 (s , 1H).

Example 34

O- (N-ethoxycarbonyl) thiocarbamoyl- (D) -phenylalaninol hydrogen chloride

The procedure for Example 21 was carried out using O- (N-ethoxycarbonyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(D) -phenylalaninol as a starting material and the procedure of Example 21 to obtain the title compound. Generated.

Melting Point: 157-157.8 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 1.22 (t, 3H), 2.78-3.18 (m, 2H), 3.82 (br, 1H), 4.22 (q, 3H), 4.58 (dd, 1H) 7.18-7.45 (m, 5H), 8.42 (br, 3H ), 11.78 (s, 1 H).

Example 35

O- (N-ethoxycarbonyl) thiocarbamoyl- (L) -phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O- (N-ethoxycarbonyl) thiocarbamoyl-N- (t-butyloxycarbonyl)-(L) -phenylalaninol as starting material and the procedure of Example 21 was carried out. Created.

Melting Point: 144.4-145.0 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 1.22 (t, 3H), 2.78-3.18 (m, 2H), 3.62-3.92 (m, 1H), 3.95-4.38 (m, 3H), 4.42-4.62 (m, 1H), 7.02-7.45 (m, 5H ), 8.42 (br, 3 H), 11.85 (s, 1 H).

Example 36

3-amino-3-phenyl-1- (O- (N-methyl) thiocarbamoyl) propanol hydrogen chloride

The procedure of Example 21 was carried out using 3-N- (t-butyloxycarbonyl) amino-3-phenyl-1-O- (N-methyl) thiocarbamoyl) propanol as starting material to give the title compound. It was.

Melting Point: 182.1-182.4 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.71-3.12 (m, 3H), 3.22-3.48 (m, 2H), 3.75-3.95 (m, 1H), 4.18-4.62 (m, 2H), 7.25-7.62 (m, 5H), 8.25 (br, 3H) ), 9.20 (d, 1 H).

Example 37

3-amino-2-phenyl-1- (O-thiocarbamoyl) propanol hydrogen chloride

The procedure of Example 21 was carried out using 3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-O- (thiocarbamoyl) propanol as starting material to produce the title compound.

Melting Point: 189.5-190.0 ℃                 

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 3.05-3.50 (m, 3H), 4.35-4.55 (m, 2H), 7.30 (s, 5H), 7.95 (bs, 3H), 8.53 (s, 1H), 8.85 (s.1H).

Example 38

3-amino-2-phenyl-1- (O- (N-methyl) thiocarbamoyl) propanol hydrogen chloride

The procedure of Example 21 was carried out using 3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-O-((N-methyl) thiocarbamoyl) propanol as starting material and the title compound was prepared. Generated.

Melting Point: 95.0-96.0 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.60 (d, 0.6H), 2.86 (d, 2.4H), 3.07-3.48 (m, 3H), 4.39-4.63 (m, 2H), 7.37 (s, 5H), 8.10 (bs, 3H), 9.15 ( bs, 0.2H), 9.30 (bs, 08H)

Example 39

3-amino-2-phenyl-1- (O- (N-dimethyl) thiocarbamoyl) propanol hydrogen chloride

The procedure of Example 21 was carried out using 3-N- (t-butyloxycarbonyl) amino-2-phenyl-1-O-((N-dimethyl) thiocarbamoyl) propanol as starting material and the title compound was prepared. Generated.

Melting point: 164.1-164.6 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.98 (s, 3H), 3.22 (s, 3H), 3.30- 3.60 (m, 3H), 4.53 (m, 2H), 7.37 (m, 5H), 8.13 (bs, 3H)

Example 40

O- (N-methyl) thiocarbamoyl-N-dimethyl- (D) -phenylalaninol hydrogen chloride

The procedure of Example 21 was carried out using O- (N-methyl) thiocarbamoyl-N-dimethyl- (D) -phenylalaninol as starting material to produce the title compound.

Melting Point: 152.5-152.7 ℃

¹ H-NMR (DMSOd ₆ , 200 MHz), ppm (δ); 2.55-3.15 (m, 9H), 3.15-3.45 (m, 2H), 3.75-4.02 (m, 1H), 4.15-4.71 (m, 2H), 7.05-7.58 (m, 5H), 9.25-9.65 (m , 1H), 11.05 (br, 1H)

The present invention has been described in an illustrative manner, and the terminology used herein is to be construed as being illustrative in nature rather than limiting.

Many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that the invention may be practiced within the scope of the appended claims unless specifically stated.

Claims (88)

O-thiocarbamoyl-aminoalkanol compounds represented by the following general formula (VI), rich in racemic or enantiomeric properties, and pharmaceutically acceptable salts thereof: Formula VI

(VI) In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , A lower alkyl, aryl having 1 to 8 carbon atoms, an aliphatic ring compound composed of 3 to 7 atoms, R ₁ and R ₂ is a ring of 5 to 7 atoms, such as adjacent N atoms One constituting the compound, optionally further comprising or not containing one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or not directly connected Without further with or a small atom, R ₃ and R ₄ are the same or be different, and independently are hydrogen, 1 to 8 Ali patik membered ring of the lower alkyl, aryl, and 3 to 7 atomic structure of carbon atoms with each other Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups R, m, and n are each 0 or 1, wherein R, in the compound of formula VI is zero or one, with or without one further substituted nitrogen atom or one or more oxygen atoms not directly connected This hydrogen, _one of R ₁ and R ₂ is hydrogen and the other is phenyl, except for compounds in which R ₃ and R ₄ are hydrogen, l is 1, m and n are 0 and pharmaceutically acceptable salts thereof . The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 1, wherein R in formula (VI) is hydrogen. The compound of claim 1, wherein in formula (VI), R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, of 3 to 7 atom configuration Is selected from the group consisting of aliphatic ring compounds, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as adjacent N atoms, and optionally selected from the group consisting of hydrogen, alkyl and aryl groups Does not contain or further comprise one additional nitrogen atom substituted with a substituent, or Or further comprising or without one oxygen atom not directly connected, R ₃ and R ₄ may be the same or different from each other and independently represent hydrogen, lower alkyl of 1 to 8 carbon atoms and 3 to 7 atoms Selected from the group consisting of an aliphatic ring compound of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, and optionally, hydrogen, alkyl and aryl groups O-thiocarbamoyl-aminoalkanol compounds, characterized in that they do not contain or comprise one additional nitrogen atom substituted with a substituent selected from the group or do not contain one or more oxygen atoms not directly linked; Its pharmaceutically acceptable salts. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 1, wherein x in Formula (VI) is 1. O-thiocarbamoyl- (D) -aminoalkanol compounds and pharmaceutically acceptable salts thereof, rich in enantiomeric properties, represented by the following formula (VIII): Formula VIII

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , A lower alkyl, aryl having 1 to 8 carbon atoms, an aliphatic ring compound composed of 3 to 7 atoms, R ₁ and R ₂ is a ring of 5 to 7 atoms, such as adjacent N atoms Constituting the compound, optionally further comprising or not comprising one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or Or further comprising or without one oxygen atom not directly connected, R ₃ and R ₄ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, and 3 to 7 Selected from the group consisting of an aliphatic ring compound of 4 atom configuration, R ₃ and R ₄ , like adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally hydrogen, alkyl and aryl Does not contain or include one additional nitrogen atom substituted with a substituent selected from the group consisting of groups or does not include one or more oxygen atoms not directly connected, and l, m and n are each 0 or 1 . 6. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 5, wherein R in formula (VIII) is hydrogen. The compound of claim 5, wherein in formula (VIII) R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, of 3 to 7 atom configuration Is selected from the group consisting of aliphatic ring compounds, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as adjacent N atoms, and optionally selected from the group consisting of hydrogen, alkyl and aryl groups R ₃ and R ₄ may be the same as or different from each other and independently, or they may not include or contain one additional nitrogen atom substituted as a member, or further include or do not include one oxygen atom that is not directly connected. as selected from the group consisting of Ali patik membered ring of hydrogen, lower alkyl, and 3 to 7 atoms composed of 1 to 8 carbon atoms, R ₃ and R ₄ are adjacent to the N atom To form a ring compound of 5 to 7 atom configuration, optionally comprising one or more additional nitrogen atoms substituted by a member selected from the group consisting of hydrogen, alkyl and aryl groups or not directly connected O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it does not contain one or more oxygen atoms. 6. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 5, wherein x in formula (VIII) is 1. O-thiocarbamoyl- (L) -aminoalkanol compounds and their pharmaceutically acceptable salts, enriched in enantiomeric nature, represented by the following formula (IX): Formula IX

Wherein Ar is a phenyl group as described below,

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , Lower alkyl having 1 to 8 carbon atoms, aliphatic ring compound having 3 to 7 atoms, and R ₁ and R ₂ constitute a ring compound having 5 to 7 atoms, such as adjacent N atoms. Further comprises or does not further comprise one additional nitrogen atom, optionally substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or Or may further comprise or comprise one oxygen atom which is not directly linked, and R ₃ and R ₄ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, and 3 to Selected from the group consisting of 7-membered aliphatic ring compounds, wherein R ₃ and R ₄ form a ring compound of 5 to 7 membered atoms, such as adjacent N atoms, consisting of hydrogen, alkyl and aryl groups It may or may not include one additional nitrogen atom substituted with a substituent selected from the group consisting of, or may not include one or more oxygen atoms not directly connected, and l, m and n are each 0 or 1 . 10. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 9, wherein R in formula (IX) is hydrogen. The compound of claim 9, wherein in formula (IX), R is hydrogen, R ₁ and R ₂ may be the same or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, and aliphatic ring compound of 3 to 7 atoms, and R ₁ and R ₂ constitutes a cyclic compound of 5 to 7 atoms, such as an adjacent N atom, and further includes or does not include one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or Or may further comprise or comprise one oxygen atom which is not directly linked, and R ₃ and R ₄ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms and 3 to 7 atoms as selected from the group consisting of Ali patik membered ring configuration, R ₃ and R ₄ is a bar, which can form a cyclic compound of 5 to 7 atoms with the adjacent N atom as configurations O-thiocarba, characterized in that it does not contain or contain one additional nitrogen atom substituted with a substituent selected from the group consisting of alkyl and aryl groups or does not contain one or more oxygen atoms not directly linked Moyl-aminoalkanol compounds and pharmaceutically acceptable salts thereof. 10. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 9, wherein x is 1 in the formula. An O-thiocarbamoyl-aminoalkanol compound rich in racemic or enantiomeric properties and a pharmaceutically acceptable salt thereof represented by the following general formula (X). Formula X

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , A lower alkyl, aryl having 1 to 8 carbon atoms, an aliphatic ring compound composed of 3 to 7 atoms, R ₁ and R ₂ is a ring of 5 to 7 atoms, such as adjacent N atoms One constituting the compound, optionally further comprising or not containing one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or not directly connected Without further with or a small atom, R ₃ and R ₄ are the same or be different, and independently are hydrogen, 1 to 8 Ali patik membered ring of the lower alkyl, aryl, and 3 to 7 atomic structure of carbon atoms with each other Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or comprise one more oxygen atom not directly connected. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof of claim 13, wherein R in formula (X) is hydrogen. The compound of claim 13, wherein in formula (X) R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, of 3 to 7 atom configuration Is selected from the group consisting of aliphatic ring compounds, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as adjacent N atoms, and optionally selected from the group consisting of hydrogen, alkyl and aryl groups R ₃ and R ₄ may be the same as or different from each other and independently, or they may not include or contain one additional nitrogen atom substituted with a substituent, or further include or do not include one oxygen atom not directly connected thereto. Hydrogen, lower alkyl having 1 to 8 carbon atoms, and an aliphatic ring compound having 3 to 7 atoms in composition, wherein R ₃ and R ₄ are selected from adjacent N atoms; To form a ring compound of 5 to 7 atom configuration, optionally comprising one or more additional nitrogen atoms substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or not directly connected O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it does not contain one or more oxygen atoms. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 13, wherein in formula (X), x is 1. O-thiocarbamoyl- (D) -aminoalkanol compounds and their pharmaceutically acceptable salts, enriched in enantiomeric nature, represented by the formula (XI): Formula XI

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , A lower alkyl, aryl having 1 to 8 carbon atoms, an aliphatic ring compound composed of 3 to 7 atoms, R ₁ and R ₂ is a ring of 5 to 7 atoms, such as adjacent N atoms One constituting the compound, optionally further comprising or not containing one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or not directly connected Further comprising or without an oxygen atom, R ₃ and R ₄ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, and an aliphatic ring compound of 3 to 7 atom configuration Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or comprise one more oxygen atom not directly connected. 18. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 17, wherein R in formula (XI) is hydrogen. 18. The compound of claim 17, wherein in formula (XI) R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, of 3 to 7 atom configuration Selected from the group consisting of aliphatic ring compounds, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as adjacent N atoms, and optionally from the group consisting of hydrogen, alkyl and aryl groups R ₃ and R ₄ may be the same as or different from each other and may be independent of, or further include, one or more additional nitrogen atoms substituted with selected substituents, or no further one or more oxygen atoms, which are not directly linked. with as being selected from the group consisting of Ali patik membered ring of hydrogen, lower alkyl, and 3 to 7 atoms composed of 1 to 8 carbon atoms, R ₃ and R ₄ are adjacent to the N atom To form a ring compound of 5 to 7 atom configuration, optionally comprising one or more additional nitrogen atoms substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or not directly connected O-thiocarbamoyl-aminoalkanol compounds and pharmaceutically acceptable salts thereof, containing or not containing one more oxygen atom. 18. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 17, wherein x in Formula (XI) is 1. O-thiocarbamoyl- (L) -aminoalkanol compounds and their pharmaceutically acceptable salts, enriched in enantiomeric nature, represented by the following formula (XII): Formula XII

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , Lower alkyl, aryl having 1 to 8 carbon atoms, aliphatic ring compound consisting of 3 to 7 atoms, R ₁ and R ₂ are cyclic compounds of 5 to 7 atoms, such as adjacent N atoms Optionally comprising one further nitrogen atom which is substituted or not further substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or is not directly connected Without further with or a small atom, R ₃ and R ₄ are the same or be different, and independently are hydrogen, 1 to 8 Ali patik membered ring of the lower alkyl, aryl, and 3 to 7 atomic structure of carbon atoms with each other Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or comprise one more oxygen atom not directly connected. 22. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 21, wherein R in formula (XII) is hydrogen. 22. The compound of claim 21, wherein in formula (XII) R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, and 3 to 7 atom configurations Is selected from the group consisting of an aliphatic ring compound, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as an adjacent N atom, and optionally from the group consisting of hydrogen, alkyl and aryl groups. R ₃ and R ₄ may be the same as or different from each other and may be independent of each other, further including or not including one additional nitrogen atom substituted with a selected substituent, or further including or not including one oxygen atom not directly connected to each other. Is selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, and aliphatic ring compound of 3 to 7 atom configuration, wherein R ₃ and R ₄ are adjacent N members. Form a ring compound of 5 to 7 atom configuration, such as, optionally comprising one or more additional nitrogen atoms substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or directly O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it does not contain one or more unconnected oxygen atoms. 22. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 21, wherein x in formula (XII) is 1. O-thiocarbamoyl-aminoalkanol compounds enriched in racemic or enantiomeric nature and represented by formula (XIII): Formula XIII

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , A lower alkyl, aryl having 1 to 8 carbon atoms, an aliphatic ring compound composed of 3 to 7 atoms, R ₁ and R ₂ is a ring of 5 to 7 atoms, such as adjacent N atoms One constituting the compound, optionally further comprising or not containing one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or not directly connected Without further with or a small atom, R ₃ and R ₄ are the same or be different, and independently are hydrogen, 1 to 8 Ali patik membered ring of the lower alkyl, aryl, and 3 to 7 atomic structure of carbon atoms with each other Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or contain one more oxygen atom not directly connected. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 25, wherein R in formula (XIII) is hydrogen. The compound of claim 25, wherein in formula (XIII), R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, and 3 to 7 atoms It is selected from the group consisting of an aliphatic ring compound of the configuration, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as adjacent N atoms, and is optionally composed of hydrogen, alkyl and aryl groups R ₃ and R ₄ may be the same as or different from each other, further including or not including one additional nitrogen atom substituted with a substituent selected from the group, or further including or not including one oxygen atom not directly connected thereto. And are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, and aliphatic ring compound of 3 to 7 atom configuration, wherein R ₃ and R ₄ are adjacent N Forming a ring compound of 5 to 7 atom configuration, such as an atom, optionally comprising one or more additional nitrogen atoms substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or directly O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it does not contain one or more unconnected oxygen atoms. 26. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 25, wherein x in formula (XIII) is 1. O-thiocarbamoyl- (D) -aminoalkanol compounds and their pharmaceutically acceptable salts, enriched in enantiomeric nature, represented by the following formula (XIV):

(XIV) In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , Lower alkyl, aryl having 1 to 8 carbon atoms, aliphatic ring compound consisting of 3 to 7 atoms, R ₁ and R ₂ are cyclic compounds of 5 to 7 atoms, such as adjacent N atoms Optionally comprising one further nitrogen atom which is substituted or not further substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or is not directly connected Without further with or a small atom, R ₃ and R ₄ are the same or be different, and independently are hydrogen, 1 to 8 Ali patik membered ring of the lower alkyl, aryl, and 3 to 7 atomic structure of carbon atoms with each other Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or comprise one more oxygen atom not directly connected. 30. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 29, wherein R in formula (XIV) is hydrogen. 30. The compound of claim 29, wherein in formula (XIV) R is hydrogen, and R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, and 3 to 7 atom configurations Is selected from the group consisting of an aliphatic ring compound, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as an adjacent N atom, and optionally, a group consisting of hydrogen, alkyl, and aryl groups R ₃ and R ₄ may be the same as or different from each other, further including or not further comprising one additional nitrogen atom substituted with a substituent selected from as independently selected from the group consisting of Ali patik membered ring of hydrogen, lower alkyl, and 3 to 7 atoms composed of 1 to 8 carbon atoms, R ₃ and R ₄ are adjacent N Form a ring compound of 5 to 7 atom configuration, such as, optionally comprising one or more additional nitrogen atoms substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or directly O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it does not contain one or more unconnected oxygen atoms. 30. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 29, wherein x in formula (XIV) is 1. O-thiocarbamoyl- (L) -aminoalkanol compounds and their pharmaceutically acceptable salts, enriched in enantiomeric nature, represented by the following formula (XV): Formula XV

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , A lower alkyl, aryl having 1 to 8 carbon atoms, an aliphatic ring compound composed of 3 to 7 atoms, R ₁ and R ₂ is a ring of 5 to 7 atoms, such as adjacent N atoms One constituting the compound, optionally further comprising or not containing one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or not directly connected Without further with or a small atom, R ₃ and R ₄ are the same or be different, and independently are hydrogen, 1 to 8 Ali patik membered ring of the lower alkyl, aryl, and 3 to 7 atomic structure of carbon atoms with each other Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or comprise one more oxygen atom not directly connected. 34. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 33, wherein R in formula (XV) is hydrogen. The compound of claim 33, wherein in formula (XV), R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, and 3 to 7 atoms It is selected from the group consisting of an aliphatic ring compound of the configuration, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as adjacent N atoms, and is optionally composed of hydrogen, alkyl and aryl groups or do more with or one of more of the nitrogen atom substituted with a substituent selected from the group, or without further with or one oxygen atom not directly linked to, R ₃ and R ₄ are the same or different and as being selected from the group consisting of a Ali patik membered ring of hydrogen, lower alkyl of 1 to 8, and 3 to 7 atoms composed of carbon atoms independently, R ₃ and R ₄ are adjacent N Form a ring compound of 5 to 7 atom configuration, such as, optionally comprising one or more additional nitrogen atoms substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or directly O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it does not contain one or more unconnected oxygen atoms. 34. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 33, wherein x in formula (XV) is 1. O-thiocarbamoyl-aminoalkanol compounds enriched in racemic or enantiomeric nature and represented by the formula (XVI): Formula XVI

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , A lower alkyl, aryl having 1 to 8 carbon atoms, an aliphatic ring compound composed of 3 to 7 atoms, R ₁ and R ₂ is a ring of 5 to 7 atoms, such as adjacent N atoms One constituting the compound, optionally further comprising or not containing one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or not directly connected Without further with or a small atom, R ₃ and R ₄ are the same or be different, and independently are hydrogen, 1 to 8 Ali patik membered ring of the lower alkyl, aryl, and 3 to 7 atomic structure of carbon atoms with each other Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or comprise one more oxygen atom not directly connected. 38. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 37, wherein R in formula (XVI) is hydrogen. 38. The compound of claim 37, wherein in formula (XVI), R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, and 3 to 7 atoms It is selected from the group consisting of an aliphatic ring compound of the configuration, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as adjacent N atoms, and is optionally composed of hydrogen, alkyl and aryl groups R ₃ and R ₄ may be the same as or different from each other, further including or not including one additional nitrogen atom substituted with a substituent selected from the group, or further including or not including one oxygen atom not directly connected thereto. and as being selected from the group consisting of a Ali patik membered ring of hydrogen, lower alkyl of 1 to 8, and 3 to 7 atoms composed of carbon atoms independently, R ₃ and R ₄ are adjacent N Form a ring compound of 5 to 7 atom configuration, such as, optionally comprising one or more additional nitrogen atoms substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or directly O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it does not contain one or more unconnected oxygen atoms. 38. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof of claim 37, wherein x in formula (XVI) is 1. O-thiocarbamoyl- (D) -aminoalkanol compounds and their pharmaceutically acceptable salts, enriched in enantiomeric nature, represented by the following formula (XVII): Formula XVII

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , A lower alkyl, aryl having 1 to 8 carbon atoms, an aliphatic ring compound composed of 3 to 7 atoms, R ₁ and R ₂ is a ring of 5 to 7 atoms, such as adjacent N atoms One constituting the compound, optionally further comprising or not containing one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or not directly connected Further comprising or without an oxygen atom, R ₃ and R ₄ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, and an aliphatic ring compound of 3 to 7 atom configuration Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or comprise one more oxygen atom not directly connected. 42. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 41, wherein R in formula (XVII) is hydrogen. The compound of claim 41, wherein in formula (XVII) R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, and 3 to 7 atom configurations Is selected from the group consisting of an aliphatic ring compound, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as an adjacent N atom, and optionally, a group consisting of hydrogen, alkyl, and aryl groups R ₃ and R ₄ may be the same as or different from each other, further including or not further comprising one additional nitrogen atom substituted with a substituent selected from as independently selected from the group consisting of Ali patik membered ring of hydrogen, lower alkyl, and 3 to 7 atoms composed of 1 to 8 carbon atoms, R ₃ and R ₄ are adjacent N Form a ring compound of 5 to 7 atom configuration, such as, optionally comprising one or more additional nitrogen atoms substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or directly O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it does not contain one or more unconnected oxygen atoms. 42. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 41, wherein x in formula (XVII) is 1. O-thiocarbamoyl- (L) -aminoalkanol compounds and pharmaceutically acceptable salts thereof, enriched in enantiomeric nature, represented by the following formula (XVIII): Formula XVIII

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , A lower alkyl, aryl having 1 to 8 carbon atoms, an aliphatic ring compound composed of 3 to 7 atoms, R ₁ and R ₂ is a ring of 5 to 7 atoms, such as adjacent N atoms One constituting the compound, optionally further comprising or not containing one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or not directly connected Without further with or a small atom, R ₃ and R ₄ are the same or be different, and independently are hydrogen, 1 to 8 Ali patik membered ring of the lower alkyl, aryl, and 3 to 7 atomic structure of carbon atoms with each other Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or comprise one more oxygen atom which is not directly linked. 46. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof of claim 45, wherein R in formula (XVIII) is hydrogen. The compound of claim 45, wherein in formula (XVIII), R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, and 3 to 7 atoms It is selected from the group consisting of aliphatic ring compounds of the configuration, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as adjacent N atoms, optionally, a group consisting of hydrogen, alkyl and aryl groups R ₃ and R ₄ may be the same as or different from each other, further including or not further comprising one additional nitrogen atom substituted with a substituent selected from Independently hydrogen, lower alkyl of 1 to 8 carbon atoms, and aliphatic ring compound of 3 to 7 atom configuration, wherein R ₃ and R ₄ are adjacent N Forming a ring compound of 5 to 7 atom configuration, such as an atom, optionally comprising one or more additional nitrogen atoms substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or directly O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it contains or does not contain one or more unconnected oxygen atoms. 46. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 45, wherein x in formula (XVII) is 1. O-thiocarbamoyl-aminoalkanol compounds enriched in racemic or enantiomeric nature and represented by the general formula (XIX): Formula XIX

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , A lower alkyl, aryl having 1 to 8 carbon atoms, an aliphatic ring compound composed of 3 to 7 atoms, R ₁ and R ₂ is a ring of 5 to 7 atoms, such as adjacent N atoms One constituting the compound, optionally further comprising or not containing one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or not directly connected Further comprising or without an oxygen atom, R ₃ and R ₄ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, and an aliphatic ring compound of 3 to 7 atom configuration Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or comprise one more oxygen atom not directly connected. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 49, wherein R in formula (XIX) is hydrogen. The compound of claim 49, wherein in formula (XIX) R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, and 3 to 7 atoms It is selected from the group consisting of an aliphatic ring compound of the configuration, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as adjacent N atoms, and is optionally composed of hydrogen, alkyl and aryl groups R ₃ and R ₄ may be the same as or different from each other, further including or not including one additional nitrogen atom substituted with a substituent selected from the group, or further including or not including one oxygen atom not directly connected thereto. and as being selected from the group consisting of a Ali patik membered ring of hydrogen, lower alkyl of 1 to 8, and 3 to 7 atoms composed of carbon atoms independently, R ₃ and R ₄ are adjacent N Form a ring compound of 5 to 7 atom configuration, such as, optionally comprising one or more additional nitrogen atoms substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or directly O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it does not contain one or more unconnected oxygen atoms. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 49, wherein x in formula (XIX) is 1. O-thiocarbamoyl- (D) -aminoalkanol compounds and pharmaceutically acceptable salts thereof, rich in enantiomeric properties, represented by the following formula (XX): Formula XX

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , Lower alkyl, aryl having 1 to 8 carbon atoms, aliphatic ring compound consisting of 3 to 7 atoms, R ₁ and R ₂ are cyclic compounds of 5 to 7 atoms, such as adjacent N atoms Optionally comprising one further nitrogen atom which is substituted or not further substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or is not directly connected Without further with or a small atom, R ₃ and R ₄ are the same or be different, and independently are hydrogen, 1 to 8 Ali patik membered ring of the lower alkyl, aryl, and 3 to 7 atomic structure of carbon atoms with each other Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or comprise one more oxygen atom not directly connected. 55. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 53, wherein R in formula (XX) is hydrogen. 54. The compound of claim 53, wherein in formula (XX) R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, and 3 to 7 atom configurations Is selected from the group consisting of an aliphatic ring compound, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as an adjacent N atom, and optionally from the group consisting of hydrogen, alkyl and aryl groups. R ₃ and R ₄ may be the same as or different from each other and may be independent of each other, further including or not including one additional nitrogen atom substituted with a selected substituent, or further including or not including one oxygen atom not directly connected to each other. with as being selected from the group consisting of Ali patik membered ring of hydrogen, lower alkyl, and 3 to 7 atoms composed of 1 to 8 carbon atoms, R ₃ and R ₄ are adjacent to N source To form a ring compound of 5 to 7 atom configuration, such as optionally comprising one or more additional nitrogen atoms substituted with substituents selected from the group consisting of hydrogen, alkyl and aryl groups or directly O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it contains or does not contain one or more unsubstituted oxygen atoms. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 53, wherein x in formula (XX) is 1. O-thiocarbamoyl- (L) -aminoalkanol compounds and their pharmaceutically acceptable salts, enriched in enantiomeric nature, represented by the following formula (XXI): Formula XXI

In the formula, Ar is a phenyl group described as follows

Wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy of 1 to 3 carbon atoms, thioalkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluor A member selected from the group consisting of carboxyl, x is an integer of 1 to 3, R is the same or different when x is 2 or 3, R ₁ and R ₂ may be the same or different from each other and independently hydrogen , A lower alkyl, aryl having 1 to 8 carbon atoms, aryl, an aliphatic ring compound composed of 3 to 7 atoms, R ₁ and R ₂ is a ring of 5 to 7 atoms, such as adjacent N atoms One constituting the compound, optionally further comprising or not containing one additional nitrogen atom substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups, or not directly connected Further comprising or without an oxygen atom, R ₃ and R ₄ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, and an aliphatic ring compound of 3 to 7 atom configuration Selected from the group consisting of R ₃ and R ₄ , such as adjacent N atoms, form a ring compound of 5 to 7 atom configuration, optionally with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups It does not contain or contain one further substituted nitrogen atom or does not contain or comprise one more oxygen atom not directly connected. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 57, wherein R in formula (XXI) is hydrogen. 58. The compound of claim 57, wherein in formula (XXI), R is hydrogen, R ₁ and R ₂ may be the same or different from each other and independently hydrogen, lower alkyl of 1 to 8 carbon atoms, and 3 to 7 atoms It is selected from the group consisting of an aliphatic ring compound of the configuration, R ₁ and R ₂ constitute a ring compound of 5 to 7 atoms, such as adjacent N atoms, and is optionally composed of hydrogen, alkyl and aryl groups R ₃ and R ₄ may be the same as or different from each other, further including or not including one additional nitrogen atom substituted with a substituent selected from the group, or further including or not including one oxygen atom not directly connected thereto. and as being selected from the group consisting of a Ali patik membered ring of hydrogen, lower alkyl of 1 to 8, and 3 to 7 atoms composed of carbon atoms independently, R ₃ and R ₄ are adjacent N Form a ring compound of 5 to 7 atom configuration, such as, optionally comprising one or more additional nitrogen atoms substituted with a substituent selected from the group consisting of hydrogen, alkyl and aryl groups or directly O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof, characterized in that it does not contain one or more unconnected oxygen atoms. 58. The O-thiocarbamoyl-aminoalkanol compound and pharmaceutically acceptable salt thereof according to claim 57, wherein x in formula (XXI) is 1. A process for preparing the compound of formula (VI) as defined in claim 1, wherein the aminoalkanol of formula (II) is reacted with di-t-butyl dicarbonate to represent Nt-butyloxycarb represented by formula (III). O-thiocarba represented by formula (V) is synthesized by treating carbonyl-aminoalkanol, treating it with sodium hydride, carbon disulfide and methyl iodide in an ethereal solution and then with an amine compound of formula (IV) To yield moyl-Nt-butyloxycarbonyl-aminoalkanol, Deprotecting it with aqueous hydrochloric acid solution to produce O-thiocarbamoyl-aminoalkanol represented by the formula (VI).

(II)

(III) HNR ₁ R (IV)

(V)

(VI) Wherein Ar, R ₁ , R ₂ , R ₃ , R ₄ , l, m and n are as defined in claim 1, and Boc represents a t-butyloxy carbonyl radical. 62. The process of claim 61, wherein the compound of formula (VI) is converted to a pharmaceutically acceptable salt of formula (I) without further purification. Formula I

In the above formula, HX is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleic acid, aspartic acid, Benzene sulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxymethane sulfonic acid, and hydroxyethane sulfonic acid. A process for preparing the compound of formula (VI) as defined in claim 1, wherein in the formula (II), R ₃ and R ₄ are not hydrogen and aminoalkanols are dissolved in an ethereal solution with sodium hydride, carbon disulfide and methyl A method of producing O-thiocarbamoyl-aminoalkanol represented by formula (VI) by reacting with an amide and treating with an amine compound of formula (IV).

(II) HNR ₁ R ₂ (IV)

(VI) 64. The process of claim 63, wherein the compound of formula (VI) is converted to a pharmaceutically acceptable salt of formula (I) without further purification. Formula I

In the above formula, HX is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleic acid, aspartic acid, Benzene sulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxymethane sulfonic acid, and hydroxyethane sulfonic acid. A process for preparing a compound of formula (VI) as defined in claim 1, wherein the aminoalkanol with R ₁ = H in formula (II) is reacted with di-t-butyl dicarbonate to formula (III) O-thiocarbamoyl-Nt- represented by the formula (V) by synthesizing the indicated Nt-butyloxycarbonyl-aminoalkanol and then treating with an isothiocyanate compound of formula (VII) in a halogenated hydrocarbon solution. A method of producing butyloxycarbonyl-aminoalkanol, which is deprotected with aqueous hydrochloric acid solution to produce O-thiocarbamoyl-aminoalkanol represented by the formula (VI).

(II)

(III) R ₂ NCS (VII)

(V)

(VI) Wherein Ar, R ₁ , R ₂ , R ₃ , R ₄ , l, m and n are as described above, and Boc represents a t-butyloxy carbonyl radical. 66. The process of claim 65, wherein the compound of formula (VI) is converted to a pharmaceutically acceptable salt of formula (I) without further purification. Formula I

In the above formula, HX is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleic acid, aspartic acid, Benzene sulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxymethane sulfonic acid, and hydroxyethane sulfonic acid. A process for preparing a compound of formula (VI) as defined in claim 1, wherein the isothio of formula (VII) in a halogenated hydrocarbon solution of aminoalkanol wherein R ₃ and R ₄ in formula (II) A method of reacting with a cyanate compound to produce O-thiocarbamoyl-aminoalkanol represented by formula (VI).

(II), R ₂ NCS (VII)

(VI) 68. The process of claim 67, wherein said compound of formula (VI) is converted to a pharmaceutically acceptable salt of formula (I) without further purification. Formula I

In the above formula, HX is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleic acid, aspartic acid, Benzene sulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxymethane sulfonic acid, and hydroxyethane sulfonic acid. 62. A process for preparing the compound of formula (VIII) according to claim 61, wherein (D) -aminoalkanol is used. 64. A process for preparing the compound of formula (VIII) according to claim 63, wherein (D) -aminoalkanol is used. 66. A process for preparing the compound of formula (VIII) according to claim 65, wherein (D) -aminoalkanol is used. 67. A process for preparing the compound of formula (VIII) according to claim 67, wherein (D) -aminoalkanol is used. 62. A process for preparing the compound of formula (IX) according to claim 61, wherein (L) -aminoalkanol is used. 64. A process for preparing the compound of formula (VIII) according to claim 63, wherein (L) -aminoalkanol is used. 66. A process for preparing the compound of formula (VIII) according to claim 65, wherein (L) -aminoalkanol is used. 67. A process for preparing the compound of formula (VIII) according to claim 67, wherein (L) -aminoalkanol is used. A pharmaceutical composition for treating central nervous system diseases comprising a compound of formula (VI) of claim 1 or a pharmaceutically acceptable salt thereof and a nontoxic pharmaceutically acceptable carrier or diluent thereof. A pharmaceutical composition for treating central nervous system diseases, comprising a compound of formula (VIII) of claim 5 or a pharmaceutically acceptable salt thereof and a non-toxic pharmaceutically acceptable carrier or diluent thereof. A pharmaceutical composition for treating central nervous system diseases comprising a compound of formula (IX) of claim 9 or a pharmaceutically acceptable salt thereof, together with a nontoxic pharmaceutically acceptable carrier or diluent thereof. A method of treating a mammal, except for a human suffering from said central nervous system disease, comprising administering an effective amount of the compound of claim 1 to a mammal, except for a human suffering from a central nervous system disease. A method of treating a mammal, except for a human suffering from central nervous system disease, comprising administering to the mammal, except for a human suffering from central nervous system disease, the compound of claim 5 in an effective amount for central nervous system administration. A method of treating a mammal, except for a human suffering from central nervous system disease, comprising administering an effective amount of the compound of claim 9 to a mammal, except for a human suffering from central nervous system disease. A compound selected from the group consisting of O-thiocarbamoyl- (DL) -phenylalaninol, O-thiocarbamoyl- (D) -phenylalaninol, and O-thiocarbamoyl- (L) -phenylalaninol ; And nontoxic pharmaceutically acceptable salts thereof. O-thiocarbamoyl- (D) -phenylalaninol; And nontoxic pharmaceutically acceptable salts thereof. O-thiocarbamoyl- (L) -phenylalaninol; And nontoxic pharmaceutically acceptable salts thereof. A method of treating a mammal, except for a human suffering from central nervous system disease, comprising administering an effective amount of the compound of claim 83 to a mammal, except for a human suffering from central nervous system disease. A method of treating a mammal, except for a human suffering from central nervous system disease, comprising administering an effective amount of the compound of claim 84 to a mammal, except for a human suffering from central nervous system disease. A method of treating a mammal, except for a human suffering from central nervous system disease, comprising administering an effective amount of the compound of claim 85 to a mammal, except for a human suffering from central nervous system disease, in a central nervous system effective amount.