JP2886570B2 - Compounds having fused heterocycle - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a compound having a condensed heterocycle having an excellent action as a medicament. More specifically, the present invention relates to a compound having a fused heterocycle having a central muscle relaxant action.

[Background of the Invention and Prior Art]

Various central muscle relaxants have been used for improving muscle tone in cervical-shoulder-arm syndrome, shoulder periarthritis, low back pain and the like, and for treating spastic paralysis accompanying cerebrovascular disorder, spastic spinal palsy and the like. However, when used for the treatment of spastic paralysis due to cerebral and spinal cord diseases, the effect is too weak or too strong, causing many side effects, and the number of effective drugs is extremely small. In addition to central muscle relaxants, they are also used as cerebral circulation metabolism improvers, analgesics, minor tranquilizers, etc., but there are few effective drugs. This may be due to the fact that the pathophysiology of spastic paralysis is often unknown.

In view of such circumstances, the present inventors have intensively studied for many years a compound having an excellent effect on subjective symptoms associated with hypertonia and a more effective compound against spastic paralysis. As a result, they have found that a pyrimidothiazine derivative described below having a structure different from that of a conventional compound having a muscle relaxing action can achieve the intended purpose, and have completed the present invention.

[Structure and effect of the invention]

The compound of the present invention is a compound having a condensed heterocycle represented by the following general formula (I) and a pharmaceutically acceptable salt thereof.

(In the formula, A ¹ and A ² represent the same or different carbon atoms or nitrogen atoms, provided that at least one is a nitrogen atom.

R ¹ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a formula (Wherein, R ⁴ and R ⁵ represent the same or different hydrogen atoms or lower alkyl groups) or a halogen atom.

(Wherein R ⁶ represents a hydrogen atom), a group represented by the formula -O-
A group represented by or a formula (Where p represents 0 or an integer of 1 to 2).

-B- is the formula Means a group represented by

E is the formula Ｕ In the formula, u means 1. X is a group represented by the formula — (CH ₂ ) _n — (wherein n represents an integer of 2 to 8); (Wherein m represents an integer of 2 to 8).

Y and Z are the same or different nitrogen atoms or formulas (Wherein R ⁸ represents a hydrogen atom or a hydroxyl group), at least one of which is a nitrogen atom.

 r represents 2, and s represents an integer of 2 to 3.

R ⁷ is: (1) a lower alkyl group, (2) a formula —JK (wherein J is a formula — (AlK) _a — (where a represents 0 or 1 and Alk represents 1 to 6 carbon atoms) linear or branched group represented by alkylene group means a), formula -O- (CH _{2) b} of - (groups represented by b is 0 or an integer of 1 to 3 in the formula),
formula A group represented by the formula (Wherein R ⁹ represents a hydrogen atom or a lower alkyl group, and Q represents an oxygen atom or a sulfur atom). (Wherein R ¹⁰ represents a hydrogen atom or a lower alkyl group;
Means an oxygen atom or a sulfur atom means a) a group represented by, or formula -CH ₂ -CH = CH- group represented by the.

K is the formula (Wherein, R ¹¹ and R ¹² are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group,
A lower alkoxy group or a cyano group); (Wherein R ¹³ represents a hydrogen atom or a lower alkyl group)
A group represented by the formula (Wherein R ¹⁴ represents a hydrogen atom or a lower alkyl group)
A cycloalkyl group, a furyl group, a thienyl group, or a heterocyclic group comprising a 5- to 6-membered ring containing two nitrogen atoms). (3) Formula -LM ( In the formula, L is a group represented by — (CH ₂ ) _c — (where c represents an integer of 1 to 3), a group represented by the formula —CH ₂ —CH ＝ CH—, a formula — (CH ₂ ) _d -O- group represented by (d is an integer of 1 to 3 in the formula), or formula _{(CH 2) e -NH- (CH} 2) f -
(Wherein e and f each represent an integer of 1 to 3). M represents a phenyl group or a heteroaryl group having 1 to 2 nitrogen atoms) and a group represented by｝] In the above definition of the present invention, R ⁴ , R ⁵ , R ⁷ , R ⁹ ,
The lower alkyl group found in R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ is a linear or branched alkyl group having 1 to 6, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group,
Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group (amyl group), isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group,
2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-
Methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group,
2-ethylbutyl group, 1,1,2-trimethylpropyl group,
It means a 1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl group and the like. Among these, preferred groups include a methyl group, an ethyl group, a propyl group, and an isopropyl group.

The lower alkoxy group in the definition of R ¹ , R ¹¹ and R ¹² is
A lower alkoxy group derived from the above lower alkyl group such as a methoxy group, an ethoxy group, and an n-propoxy group is meant. Among them, the most preferred group is a methoxy group.

Further, the halogen atom found in R ¹ , R ¹¹ and R ¹² specifically means, for example, a chlorine atom, a bromine atom, a fluorine atom and the like.

The term “halogenated lower alkyl group” as defined in the definitions of R ¹¹ and R ¹² means a halogenated lower alkyl group derived from the aforementioned lower alkyl group. Typical examples include a trifluoromethyl group and the like.

A ¹ , A ² , W, and B are as defined above, and specific preferred fused rings are as follows.

Among the above, the most preferred condensed ring is the pyrimidothiazine ring of (1), and the second most preferred condensed ring is the pyridinothiazine ring of (4).

Expressions in the definition of W The group represented by (where p represents 0 or an integer of 1 to 2) specifically means a group represented by the following formula.

In the definition of E, X has the formula - (CH _{2) n} - (wherein n is 2
A group or formula represented by the following: (Wherein m represents an integer of 2 to 8), and preferred groups include n and m each of 3 to 7
Is preferable, and the case where n is 3 is most preferable.

Y and Z are the same or different nitrogen atoms or formulas (Wherein R ⁸ represents a hydrogen atom or a hydroxyl group), at least one of which is a nitrogen atom. Also,
r represents 2, and s represents an integer of 2 to 3. Specifically preferred formula The group represented by is shown below.

R ⁷ is as defined above, but preferred groups are as follows.

In the above (a) to (e), a is 0 or 1, and b is 0
Or an integer of 1 to 3 and Alk represents a linear or branched alkylene group having 1 to 6 carbon atoms. Among these, the most preferred case is a = 1 and Alk is a methylene group, or b is 1
Is the case. R ¹¹ and R ¹² represent a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a cyano group. Of these, R ¹¹ and R ¹²
Are most preferably hydrogen atoms, and R ¹¹ is a lower alkoxy group, preferably an ethoxy group, a methoxy group, especially a methoxy group, and R ¹² is a hydrogen atom.

A preferred compound group in the present invention is represented by the following general formula (I
Represented by I).

(Wherein R ¹ and E have the above-mentioned meanings) In the above general formula (II), R ¹ is most preferably a hydrogen atom or a lower alkoxy group. Among lower alkoxy groups, an ethoxy group and a methoxy group are preferred, and a methoxy group is most preferred.

In the definition of E, E is an expression (Wherein X, Y, r, s, Z, R ⁷ and u have the above-mentioned meaning). In the formula, X is preferably a group represented by
- (CH _{2) n} - if (wherein n represents an integer of 2 to 8) a group represented by are preferred. As for Y and Z, when both Y and Z are nitrogen atoms, Y is a nitrogen atom;
Is the expression And Y is a group represented by the formula: It is preferred that Z is a nitrogen atom, but the most preferred is the case where both Y and Z are nitrogen atoms. r is 2, and s is an integer of 2 to 3,
Most preferred is when both r and s are 2.
When both Y and Z are nitrogen atoms and r and s are both 2, it is a case where a piperazine ring is formed.

R ⁷ is preferably a group represented by the formula —JK (wherein J and K have the same meanings as described above). In this case, J is represented by the formula-(Al
k) The group represented by _a- (where Alk, a has the above-mentioned meaning) is most preferred. Among these, preferred groups include those represented by the formulas —CH ₂ —, —CH ₂ —CH ₂ —, CH ₂ —CH ₂ —CH ₂ — or And the group represented by K is the formula (Wherein R ¹¹ and R ¹² have the above-mentioned meanings),
Or expression (Wherein R ¹³ has the meaning described above).

In the above, the most preferred groups are specifically described as follows.

formula (In the formula, Ra represents ^a hydrogen atom or a lower alkoxy group.) Among the lower alkoxy groups, preferred groups include an ethoxy group and a methoxy group, and most preferred is a methoxy group. It is an o-methoxy group.

In the present invention, pharmacologically acceptable salts include, for example, hydrochlorides, hydrobromides, sulfates, inorganic acid salts such as phosphates,
For example, organic acid salts such as acetate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, and toluenesulfonate, or salts with amino acids such as arginine, aspartic acid, and glutamic acid. Can be given.

Although various methods for producing the compound of the present invention are conceivable, typical methods are as follows.

Manufacturing method 1 E is the formula (Wherein X, Y, r, s, u, Z, and R ⁷ have the same meaning as described above), they can be produced by the following production method.

(In the series of formulas, A ¹ , A ₂ , W, B, R ¹ , X, Y, Z, r, s, u, R ⁷ have the above-mentioned meaning, and Hal means a halogen atom.) By condensing the halide represented by the general formula (III) with the compound represented by the general formula (IV) by an ordinary method,
The target substance represented by the general formula (V) is obtained.

 Halogen means chlorine, bromine, iodine and the like.

It is preferable to carry out this reaction in the presence of a deoxidizing agent. Examples of the deoxidizing agent include carbonates or bicarbonates of alkali metals such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, alkali hydroxides such as sodium hydroxide and potassium hydroxide, and organic compounds such as pyridine and triethylamine. Bases such as amines are exemplified.
Examples of the solvent used for the reaction include alcohols such as methyl alcohol and ethyl alcohol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, and a mixture of these with water.

The reaction temperature is from -40 ° C to the boiling point of the solvent, preferably from about 0 to 60 ° C.

Manufacturing method 2 (In the series of formulas, A ¹ , A ₂ , W, B, R ¹ , X, Y, Z, r, s, u, R ⁷ have the above-mentioned meaning, and Hal means a halogen atom.) The compound represented by the general formula (VI) is subjected to a condensation reaction with the halide represented by the general formula (VII) in the same manner as in the production method 1, and the compound represented by the general formula (V) is obtained. A compound.

This reaction is carried out without a solvent or in an organic solvent which does not participate in a reaction selected from benzene, ethanol, xylene, tetrahydrofuran, chloroform, carbon tetrachloride, dimethylformamide and the like, under ice-cooling or at room temperature to heating by a conventional method. The reaction is carried out for several hours underneath. In this case, the reaction is easily carried out by using inorganic salts such as sodium hydrogen carbonate, potassium carbonate, sodium carbonate and caustic soda, or organic bases such as triethylamine, pyridine, pyrimidine and diethylaniline as the dehydrohalogenating agent. proceed.

In the production method 1, the halide represented by the general formula (III) used as a starting material can be produced, for example, by the following method.

(In the series of formulas, A ¹ , A ² , W, R, R ¹ , X, and Hal have the above-mentioned meanings.) In order to elaborate the effects of the compound of the present invention, specific pharmacological experimental examples will be described below. Show.

Example of pharmacological experiment (ischemic decerebrate rigidity) 1. Experimental method Male Wistar rats (300-500 g, Charles River) were used for the experiment. Under halothane anesthesia, the rat was fixed in the dorsal position and the neck was incised. After insertion of the tracheal cannula, the esophagus was double-ligated and cut. Thereafter, a hole having a diameter of about 4 mm was made in the occipital bone with a dental drill, and the dura was incised.
Under a surgical microscope, the basilar artery was ligated with a nylon thread. Subsequently, the blood flow in both common carotid arteries was cut off with the ligature, and then the anesthesia was stopped.

As he recovered from halothane anesthesia, rigidity appeared in the forelimbs, neck, hindlimbs and tail. For the measurement of rigidity, two enamel wires with a diameter of 0.2 mm were inserted into the triceps brachii muscle of the forelimbs to induce myoelectric discharge bipolarly. In addition, the electromyogram is converted to an oscilloscope (VC
-9, Nihon Kohden) and processed by a medical data processor (ATAC-450, Nihon Kohden), and the firing frequency per unit time was recorded on an XY plotter (7225A, Hewlett-Packard). The test compound was administered at 0.1 ml per 100 g of body weight from a catheter inserted into the femoral vein.

2. Experimental results are shown in Table 1.

In Table 1, the minimum effective amount mg / kg, iv means the minimum concentration at which each test compound of the present invention relaxes rigidity.

From the above pharmacological experimental examples, it was found that the compound of the present invention has a significantly superior drug effect in rat anemia cerebral rigidity (spastic paralysis model) as compared with eperisone which is a control drug.

In addition, representative compounds of the present invention (compounds No. 1 and No.
An acute toxicity test was performed on male Wistar rats for 5), and no deaths occurred at 300 mg / kg by oral administration.

Therefore, the compound of the present invention has an excellent muscle relaxing action,
Based on its action, for example, cerebrovascular disorders, spastic spinal palsy, cervical spondylosis, treatment and improvement of spastic paralysis due to cerebral and spinal diseases such as trauma sequelae, cervico-shoulder-arm syndrome, shoulder periarthritis,
It is effective in treating and improving muscle tone due to low back pain. Further, as described above, the compounds of the present invention have high safety, and thus the value of the present invention is high.

When the compound of the present invention is used as these medicaments,
It is administered by oral or parenteral administration, but is usually administered by parenteral administration such as intravenous, subcutaneous, intramuscular injections, suppositories or sublingual tablets. The dosage depends on the degree of symptoms; age, sex, weight, and sensitivity difference of the patient;
The timing and interval of administration, the nature of the pharmaceutical preparation, the preparation and the type; vary depending on the type of the active ingredient, and are not particularly limited,
Usually about 0.1 to 500 mg per day, preferably about 1 to 10 per adult
0 mg, more preferably 5 to 50 mg, which is usually administered once to four times a day.

In order to formulate the compound of the present invention, dosage forms such as injections, suppositories, sublingual tablets, tablets, capsules and the like are made by a usual method in the technical field of formulation.

When preparing an injection, a pH adjuster, a buffer, a suspending agent, a solubilizing agent, a stabilizing agent, an isotonic agent, a preservative, etc. are added to the main drug as necessary, and intravenous, Subcutaneous or intramuscular injection. At that time, if necessary, a freeze-dried product can be obtained by a conventional method.

Examples of the suspending agent include, for example, methylcellulose, polysorbate 80, hydroxyethylcellulose,
Examples include gum arabic, powder of trangant, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate and the like.

Examples of the solubilizer include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, magrogol, and castor oil fatty acid ethyl ester.

Further, as a stabilizer, for example, sodium sulfite, sodium metasulfite, ether, etc., as a preservative,
Examples thereof include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like.

〔Example〕

Next, examples of the present invention will be described. However, it is needless to say that the present invention is not limited thereto.

The target compound of the present invention was taken as an example, and a method for producing a starting material for producing the target compound was taken as a production example prior to the example.

Production Example 1 4-methoxy-5- (3-bromopropyl) pyrimido [4,5-b] [1,4] thiazin-6 (7H) one 5H-pyrimido [4,5-b] [1,4] thiazine-6 (7H)
40 g of -one are suspended in 300 ml of dimethylformamide and 10 g of sodium hydroxide (60%) are added at room temperature with stirring. After 1 hour and 20 minutes, the reaction mixture was cooled with ice, and 122 g of dibromopropane was added dropwise over 40 minutes. After dropping, 1 hour at room temperature
Stir for 30 minutes, add water and extract with ethyl acetate. The organic layer is washed with saturated saline and dried over magnesium sulfate.
After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 50 g (yield 77%) of the title compound.

Mp (° C.); 75 to 77 molecular _{formula; C 10 H 12 BrN 3 O} 2 S 1 H-NMR (CDCl 3) δ; 1.91~2.31 (2H, m), 3.31 (2H, t), 3.40 (2H, s ), 4.03
(2H, t), 4.09 (3H, s) MS m / e; 317/319 (M ⁺ ) Example 1 4-ethoxy-5- [3- (4-benzylpiperazyl-
1-yl) propyl] pyrimido [4,5-b] [1,4] thiazin-6 (7H) -one dihydrochloride 4-methoxy-5- (3-bromopropyl) pyrimido [4,5-b] [1,4] thiethoxy-6 (7H) -one Pyrimido [4,5-b] [1,4] thiazin-6 (7H) -one 37
g was reacted with 35 g of 1-benzylpiperazine in the presence of 50 ml of triethylamine in dimethylformamide for 12 hours,
The reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled under reduced pressure. The residue is purified by silica gel column chromatography and recrystallized from ethyl acetate. This was converted into a hydrochloride according to a conventional method to obtain 28 g (yield 56%) of the title compound as colorless crystals from ethanol-ether.

Mp (° C.): 219-221.5 molecular _{formula; C 22 H 29 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.44 (3H, t), 1.68 (2H, tt), 2.10~2.50 (10H , m), 3.4
(2H, s), 3.45 (2H, s), 4.02 (2H, t), 4.50 (2H, q), 7.
24 (5H, s), 8.24 (1H, s) MS m / e; 427 (M ⁺ ) Example 2 4-Methoxy-5- [3- (4-orthomethoxybenzylpiperazin-1-yl) propyl] pyrimid (4,5-
b] [1,4] thiazin-6 (7H) -one dihydrochloride 9.54 g of 4-methoxy-5- (3-bromopropyl) pyrimido [4,5-b] [1,4] thiazin-6 (7H) -one was added to dimethylformamide in the presence of triethylamine in N-
After reacting with 9.27 g of (2-methoxybenzyl) piperazine overnight, the reaction mixture is poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate-diethyl ether. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography, converted into a hydrochloride according to a conventional method, and recrystallized from methanol-diethyl ether to obtain 12.78 g (yield: 82%) of the title compound as colorless crystals.

Melting point (° C.); 166-168 (decomposition) Molecular formula: C ₂₂ H ₂₉ N ₅ O ₃ S · 2HCl ¹ H-NMR (CDCl ₃ ) δ; 3.40 (2H, s), 3.63
(2H, s), 3.80 (3H, s), 3.99 (2H, t), 4.03 (3H, s), 6.
86 (2H, t), 7.24 (2H, ddd), 8.26 (1H, s) MS m / e; 444 (MH ^<+> ) Example 3 4-hydroxy-5- [3- (4-orthomethoxybenzylpiperazine- 1-yl) propyl] pyrimido [4,5
-B] [1,4] thiazin-6 (7H) -one dihydrochloride 4-methoxy-5- [3- (4-orthomethoxybenzylpiperazin-1-yl) propyl] pyrimido [4,5
-B] [1,4] thiazin-6 (7H) -one dihydrochloride 1.0
10 ml of 10% hydrochloric acid-ethyl acetate and 0.5 ml of water are added to 0 g, and the mixture is heated under reflux. After evaporating the solvent under reduced pressure, the residue was recrystallized from methanol-dichloromethane-diethyl ether to obtain 0.46 g (yield 68%) of the title compound as colorless crystals.

Melting point (° C.); 144 (decomposition) Molecular formula: C ₂₁ H ₂₇ N ₅ O ₃ S.2HCl ¹ H-NMR (DMSO-d ₆ ) δ; 1.60 to 2.60 (12 H, m), 6.70 to 7.40 (4 H, m ), 7.85 (1H,
s) MS m / e; 430 (M + 1) ⁺ Example 4 4-methoxy-5- [3- (4-orthomethoxybenzylpiperazin-1-yl) propyl] pyrimido [4,5-
b] [1,4] thiazine-6 (7H) -one-8-oxide 5.00 g of 4-methoxy-5- (3-bromopropyl) pyrimido [4,5-b] [1,4] thiazin-6 (7H) -one was reacted with 15.00 g of sodium periodate in water-containing methanol and stirred overnight. I do. Water is added to the reaction solution, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography. The obtained 4-methoxy-5- (3-bromopropyl) pyrimido [4,5-b] [1,4] thiazine-6 (7
H) -one-8-oxide was allowed to react with 1.50 g of N- (2- (methoxybenzyl) piperazine) in the presence of triethylamine in dimethylformamide. After stirring for 4 hours, a saturated saline solution was added to the reaction solution, and the mixture was extracted with dichloromethane and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.90 g (yield: 12%) of the title compound as a colorless oil.

Molecular _{formula; C 22 H 29 N 5 O} 4 S 1 H-NMR (CDCl 3) δ; 1.60~1.97 (2H, m), 2.00~2.50 (10H, m), 3.52 (2H,
s), 3.58 to 3.82 (4H, m), 3.98 to 4.28 (6H, m), 6.84 (2
H, t), 7.04-7.30 (2H, m), 8.52 (1H, s) MS m / e; 459 (M ⁺ ) Example 5 4-Methoxy-5- [7- (4-benzylpiperazine-
1-yl) heptyl] pyrimido [4,5-b) [1,4] thiazin-6 (7H) -one dihydrochloride (A) Synthesis of 4-methoxy-5- (7-bromoheptyl) pyrimido [4,5-b] [1,4] thiazin-6 (7H) -one 1.97 g of 4-methoxy-5H-pyrimido [4,5-b] [1,4] thiazin-6 (7H) -one in 20 ml of tetrahydrofuran
And dimethylformamide (5 ml), and 0.42 g of sodium hydride (60% oil dispersion) is added at room temperature under a nitrogen atmosphere. After stirring at room temperature for 45 minutes, a solution of 2.58 g of 1,7-dibromoheptane in 5 ml of tetrahydrofuran is added, and the mixture is stirred at room temperature for 6 hours. 25 ml of saturated saline was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml, 50 ml × 2). The organic layer was washed with 25 ml of water and 25 ml of saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.84 g, yield 75.9%). _{^{1 H-NMR (CDCl 3)}} δ; 1.16~1.94 (10H, m), 3.36 (2H, t, d = 7Hz), 3.43 (2H,
s), 3.95 (2H, t, d = 7 Hz), 4.06 (3H, s), 8.31 (1 H, s) (b) 4-methoxy-5- [7- (4-benzylpiperazin-1-yl) heptyl ] Pyrimido [4,5-b] [1,
4] Thiazin-6 (7H) -one dihydrochloride 4-methoxy-5- (7-bromoheptyl) pyrimido [4,5-b] [1,4] thiazine-6 (7) obtained in (a)
H) -one (1.0 g) and 1-benzylpiperazine (0.48 g) were dissolved in dimethylformamide (15 ml), and triethylamine (0.68 g) was dissolved.
And react at 50 ° C. for 6 hours. The reaction solution was diluted with 50 ml of water, extracted with ethyl acetate (50 ml × 4), the organic layer was washed with water and saturated saline (20 ml × 2, 20 ml), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Leave. The residue was purified by silica gel column chromatography, and 4-methoxy-
5- [7- (4-benzylpiperazin-1-yl) heptyl] pyrimido [4,5-b] [1,4] thiazine-6 (7H)
1.16 g (78.9% yield) of -one was obtained.

The resulting compound was converted into a hydrochloride by a conventional method, and recrystallized from ethanol-ethyl acetate to obtain 1.05 g of the title compound as white crystals.

Melting point (° C.): 171-174 molecular formula; C ₂₅ H ₃₅ N ₅ O ₂ S · 2HCl ¹ H-NMR (CDCl ₃ ) δ; 1.00-1.60 (10H, m), 2.08-2.64 (10H, m), 3.40 (2H,
s), 3.48 (2H, s), 3.92 (2H, t), 4.03 (3H, s), 7.04 (5
H, brs), 8.28 (1H, s) MS m / e; 469 (M ⁺ ) Example 6 4-methoxy-5- [3- (4-benzylpiperazine-
1-yl) propyl] pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one dihydrochloride (A) Synthesis of 4-chloro-6-methoxy-5-nitropyrimidine 9.4 g of 4,6-dichloro-5-nitropyrimidine is dissolved in 100 ml of methanol, 2.6 g of sodium methoxide is added, and the mixture is stirred at room temperature for 50 minutes. After stirring, the solvent was distilled off under reduced pressure, poured into water, extracted with dichloromethane, and separated by silica gel column chromatography to give the title compound 2.
8 g were obtained. ¹ H-NMR (CDCl ₃ ) δ; 4.12 (3H, s), 7.20 (1 H, s), 8.56 (1 H, s) (b) 2- (4-methoxy-5-nitropyrimidyl-6)
Synthesis of -oxy) acetic acid methyl ester 2.5 g of 4-chloro-6-methoxy-5-nitropyrimidine obtained in (a) and 1.3 g of glycolic acid methyl ester
Was dissolved in 40 ml of dimethylformamide, and potassium carbonate 5.
Add 2 g and stir at 60 ° C. for 5 hours. After the reaction, the reaction solution is poured into diluted hydrochloric acid, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain 0.93 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ; 3.75 (2H, s), 4.07 (3H, s), 7.21 (1H, s), 8.35 (1H,
s) (c) 4-methoxy-5H-pyrimido [4,5-b] [1,4]
Synthesis of Oxazin-6 (7H) -one 0.93 g of methyl 2- (4-methoxy-5-nitropyrimidinyl-6-oxy) acetate obtained in (b) was dissolved in 30 ml of methanol, and 10% palladium-carbon (water-containing) was dissolved.
0.5%), and hydrogenation is performed at 3.5 kg / cm ² at room temperature for 1 hour and 20 minutes. After completion of the reaction, the solid is filtered off and the solvent is distilled off under reduced pressure. The residue is dissolved in 30 ml of ethanol, 1 ml of concentrated hydrochloric acid is added, and the mixture is heated under reflux for 20 minutes. After the reaction is completed, the solution is
The precipitate was collected by filtration, washed with ether, and further dried at 65 ° C. overnight to obtain 0.62 g of the title compound. ^{1 H-NMR (DMSO-d} 6) δ; 3.91 (3H, s), 4.77 (2H, s), 8.03 (1H, s), 10.62 (1H, b
s) (d) Synthesis of 4-methoxy-5- (3-bromopropyl) pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one 4-methoxy-5H-pyrimido obtained in (c) [4,5
-B] [1,4] oxazin-6 (7H) -one -0.62 g was dissolved in dimethylformamide (30 ml), 60% sodium hydride was added, the mixture was stirred at 60 ° C for 2 hours in a nitrogen stream, and then returned to room temperature. 5 g of 1,3-dibromopropane is added and the mixture is further stirred for 2 hours. The reaction solution is poured into water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain 0.8 g of the title compound. _{^{1 H-NMR (CDCl 3)}} δ; 2.17 (2H, m), 3.38 (2H, t), 4.07 (3H, s), 4.12 (2H,
t), 4.69 (2H, s), 8.15 (1H, s) (e) 4-methoxy-5- [3- (4-benzylpiperazin-1-yl) propyl] pyrimido [4,5-b] [1 ,
4] Synthesis of oxazine-6 (7H) -one dihydrochloride 4-methoxy-5- (3-bromopropyl) pyrimido [4,5-b] [1,4] oxazine-6 obtained in (d)
0.4 g of (7H) -one and 0.8 g of N-benzylpiperazine were dissolved in 20 ml of dimethylformamide, and 1.2 g of triethylamine was dissolved.
And leave at room temperature overnight. The reaction solution is poured into water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the ethyl acetate is distilled off under reduced pressure. Separation and purification by silica gel column chromatography gave 0.35 g of the title compound. The hydrochloride is prepared in the usual manner.

Melting point (° C.); 240-244 (decomposition) Molecular formula; C ₂₁ H ₂₇ N ₅ O ₃ .2HCl ¹ H-NMR (CDCl ₃ ) δ; 1.70 (2H, m), 2.00-2.50 (10H, m), 3.45 (2H, s), 4.02
(3H, s), 4.08 (2H, t), 4.65 (2H, s), 7.23 (5H, s), 8.
11 (1H, s) MS m / e; 397 (M ⁺ ) Example 7 4-methoxy-5- [3- (4-benzylpiperidine-
1-yl) propyl] -6-oxo-5,6,7,8-tetrahydropteridine trihydrochloride (A) 4-methoxy-5- (3-bromopropyl) -6
Synthesis of -oxo-5,6,7,8-tetrahydropteridine 0.475 g of 4-methoxy- (5H) -6-oxo-5,6,7,8-tetrahydropteridine was added to 30 ml of dimethylformamide.
And 15% of HMPA, and 0.107 g of 60% sodium hydride was added. After stirring at 55 ° C. for 1 hour under a nitrogen stream, 10 g of 1,3-dibromopropane was added under ice cooling, and the mixture was returned to room temperature and left overnight. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give the title compound (0.45 g). g obtained. _{^{1 H-NMR (CDCl 3)}} δ; 2.17 (2H, m), 3.37 (2H, t), 4.00 (5H, s), 4.12 (2H,
t), 5.63 (1H, bs), 7.97 (1 H, s) (b) 4-methoxy-5- [3- (4-benzylpiperidin-1-yl) propyl] -6-oxo-5,6,7 , 8−
Synthesis of tetrahydropteridine trihydrochloride 0.7 g of N-benzylpiperazine and 5 g of triethylamine are dissolved in 20 ml of dimethylformamide, and the 4-methoxy-5- (3-bromopropyl) -6-oxo-5,6,7,8-tetrahydrofuran obtained in (a) is obtained. Add 0.45 g of pteridine and leave at room temperature overnight. The reaction solution was poured into water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound. It is converted into a hydrochloride by an ordinary method.

Melting point (° C.); 203-210 Molecular formula; C ₂₁ H ₂₈ N ₆ O ₂ .3HCl ¹ H-NMR (CDCl ₃ ) δ; 1.78 (2H, m), 2.1-2.4 (10H, m), 3.45 (2H, s), 3.96
(5H, s), 4.03 (2H, t), 7.12 (6H, s), 7.92 (1H, s) MS m / e; 396 (M ⁺ ) Example 8 1- {3- [4- (2- Picolyloxy) piperidine-
1-yl] propyl} pyrido [2,3-b] [1,4] thiazin-2 (3H) -one dihydrochloride (A) Synthesis of 4- (2-picolyloxy) piperidine 160 g of powdered potassium hydroxide and 500 ml of dimethyl sulfoxide were stirred at room temperature for 30 minutes to give N-benzoyl-
A solution of 85 g of 4-piperidinol (obtained by treating N-benzoyl-4-piperidone with sodium borohydride) in 300 ml of dimethyl sulfoxide is added, and the mixture is stirred at room temperature for 20 minutes. Next, 68 g of 2-picolyl chloride / hydrochloride was added, and the mixture was stirred for 15 hours. The reaction solution was poured into water, extracted twice with dichloromethane, and the organic layer was washed with brine and dried over magnesium sulfate. . After evaporating the solvent, the residue was separated and purified by silica gel column chromatography to obtain 81 g of an oily substance.

The compound is heated under reflux with 200 ml of 25% hydrochloric acid for 1 hour, poured into ice water, the aqueous layer is washed with ethyl acetate, made alkaline by adding an aqueous solution of potassium hydroxide, and extracted three times with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off to obtain 50 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ; 1.2 to 2.2 (4H), 2.4 to 2.8 (2H), 2.9 to 3.2 (2H), 3.3 to
3.7 (1H), 4.64 (2H, s), 7.0 to 7.8 (3H), 8.46 (1H, br
d) (b) 1- (3-bromopropyl) pyrido [2,3-b]
Synthesis of [1,4] thiazin-2 (3H) -one 1H-pyrido [2,3-b] [1,4] thiazine-2 (3H)-
Dissolve 4.6 g of dimethylformamide in 150 ml of dimethylformamide, add 1.1 g of sodium hydroxide (60% oil dispersion) at room temperature, and add 17.0 g of 1,3-dibromopropane all at once to the mixture stirred for 30 minutes. After stirring at room temperature for 3 hours, the mixture was poured into ice water, and the reaction mixture obtained by ordinary post-treatment was purified by silica gel column chromatography to obtain 6.3 g of the title compound. _{^{1 H-NMR (CDCl 3)}} δ; 2.22 (2H, dd), 3.40 (2H, t), 3.50 (2H, s), 4.08 (2H,
t), 7.12 (1H, dd), 7.40 (1H, dd), 8.14 (1H, dd) (c) 1- {3- [4- (2-picolyloxy) piperidin-1-yl] propyl} pyrido [2 , 3-b] [1,4]
Synthesis of thiazine-2 (3H) -one dihydrochloride 4- (2-picolyloxy) piperidine obtained in (a)
4.3 g and 6.3 g of 1- (3-bromopropyl) pyrido [2,3-b] [1,4] thiazin-2 (3H) -one obtained in (b) were dissolved in 70 ml of dimethylformamide, and triethylamine 6.
Add 2 ml and leave at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 5.7 g of the title compound. It can be converted into a hydrochloride (amorphous) by an ordinary method.

Molecular _{formula; C 21 H 26 N 4 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.4~2.8 (12H, m), 3.2~3.6 (1H, m), 3.48 (2H, s), 3.
98 (2H, t), 4.62 (2H, s), 7.00 ~ 7.70 (5H, m), 8.12 (1
H, m), 8.44 (1H, m) MS m / e; 398 (M ⁺ ) Example 9 1- [2- {1- [2- (2-pyridyl) ethyl] piperidin-4-yl} ethyl] Pyrido [2,3-b] [1,4]
Thiazine-2 (3H) -one dihydrochloride (A) N- [2- (2-pyridyl) ethyl] -4- (2
Synthesis of (chloroethyl) piperidine 8.0 g of 2-vinylpyridine and 6.3 g of 4- (2-hydroxyethyl) piperidine are mixed and heated at 80 ° C. for 10 hours under a nitrogen atmosphere. Cool the reaction mixture and add chloroform
100 ml is added to make a solution, 5 ml of thionyl chloride is added, and the mixture is left at room temperature for 15 hours. Then pour the reaction solution into ice water,
The mixture is made alkaline by adding an aqueous sodium hydroxide solution, and extracted with chloroform. After the chloroform layer was dried over magnesium sulfate, the solvent was distilled off, and the obtained mixture was separated and purified by silica gel column chromatography to obtain 9.0 g of the title compound as an oil.

(B) 1- [2- {1- [2-pyridyl) ethyl] piperidin-4-yl} ethyl] pyrido [2,3-b] [1,4]
Synthesis of thiazine-2 (3H) -one dihydrochloride 1H-pyrido [2,3-b] [1,4] thiazin-2 (3H) -one was treated with 0.25 g of sodium hydride (60% oil dispersion) and 10 ml of dimethyl sulfoxide at 55 ° C. for 1 hour. A solution of 1.0 g of dimethyl sulfoxide in 10 ml was added and stirred for 1 hour, and then the N- [2- (2
-Pyridyl) ethyl] -4- (2-chloroethyl) piperidine 1.5 g. Thereafter, the mixture was treated at room temperature for 1 hour and at 60 ° C. for 2 hours, poured into ice water, and the mixture treated in a usual manner was separated and purified by silica gel column chromatography to obtain 0.5 g of the title compound as a hydrochloride in a usual manner.

Melting point (° C); 182 to 184 (decomposition) ¹ H-NMR (CDCl ₃ ) δ;
8 (2H, brt), 6.9 ~ 7.7 (5H, m), 8.12 (1H, dd), 8.44
(1H, brd) MS m / e; 382 (M ⁺ ) Example 10 1- [2- (4-benzylpiperidyl) -2-oxoethyl] pyrido [2,3-b] [1,4] thiazine- 2 (3H)-
On monohydrochloride 1H-pyrido [2,3-b] [1,4] thiazine-2 (3H)-
Dissolve 1.0 g in 20 ml of dimethylformamide, add 0.35 g of 60% sodium hydride, and add
After stirring for 1 minute, a solution of 1.6 g of 1-benzyl-4-bromoacetylpiperidine in 10 ml of dimethylformamide is added, and the mixture is left overnight. The reaction solution was poured into ice water, extracted with ethyl acetate,
After washing with saturated saline, drying over anhydrous magnesium sulfate,
The solvent is distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography to give the title compound (0.7 g).
It is converted into a hydrochloride by an ordinary method.

Mp (° C.); 171 to 176 molecular _{formula; C 20 H 22 N 4 O} 2 S · HCl 1 H-NMR (CDCl 3) δ; 2.10~2.60 (4H, m), 3.40~3.80 (6H, m), 4.65 (2H,
s), 7.00 to 7.40 (7H, m), 8.13 (1H, dd) MS m / e; 382 (M ⁺ ) Example 11 1- [3- (phenoxypiperidin-1-yl) propyl] pyrido [2, 3-b] [1,4] oxazine-2 (3H)-
On monohydrochloride (A) 1H-pyrido [2,3-b] [1,4] oxazine-2
Synthesis of (3H) -one monohydrochloride 25 g of 2-chloro-3-nitropyridine, 17.8 g of ethyl glycolate and 35 g of potassium carbonate are added to dimethylformamide
Heat in 150ml at 60 ° C for 12 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a light brown-white oily 2-ethoxycarbonylmethoxy-3.
-31.9 g of nitropyridine are obtained and used for the next reaction without purification.

31.9 g of 2-ethoxycarbonylmethoxy-3-nitropyridine is dissolved in 200 ml of ethanol, and the mixture is stirred for 18 hours at room temperature in a hydrogen stream (balloon) in the presence of a 10% palladium-carbon catalyst. The palladium catalyst was removed by celite filtration, and the mother liquor was concentrated.
Heat to reflux for half an hour. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting light brown crystals were collected by filtration and washed with isopropyl ether to give 16.5 g of the title compound. ^{1 H-NMR (DMSO-d} 6) δ; 4.79 (2H, s), 6.90~7.45 (2H, m), 7.79 (1H, dd) (b) 1- (3- bromopropyl) pyrido [2,3 -B]
Synthesis of [1,4] oxazine-2 (3H) -one 0.81 g of 1H-pyrido [2,3-b] [1,4] oxazin-2 (3H) -one monohydrochloride obtained in (a) was dissolved in 130 ml of dimethylformamide, and sodium hydride (60% )
Add 0.34 g at room temperature. After stirring for 30 minutes, the reaction solution is cooled with ice water and 3.6 g of dibromopropane is added. Thereafter, the mixture is stirred at room temperature for 12 hours. Water is added, the mixture is extracted with ethyl acetate, and the organic layer is washed with saturated saline and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain 0.42 g (yield 36%) of the title compound. _{^{1 H-NMR (CDCl 3)}} δ; 1.91~2.43 (2H, m), 3.49 (2H, t), 4.08 (2H, t), 4.81
(2H, s), 7.03 (1H, dd), 7.34 (1H, dd), 7.91 (1H, dd) (c) 1- [3- (4-phenoxypiperidin-1-yl) propyl] pyrido [2, 3-b] [1,4] oxazine-
Synthesis of 2 (3H) -one monohydrochloride 0.41 g of 1- (3-bromopropyl) pyrido [2,3-b] [1,4] oxazin-2 (3H) -one obtained in (b)
Is dissolved in 6 ml of dimethylformamide, 0.3 g of 4-phenoxypiperidine and 1.2 ml of triethylamine are added, and the mixture is stirred at room temperature for 26 hours. Water was added, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol = 9: 9).
Purification in 1) gave 0.31 g (56% yield) of the free base.
The compound was converted into a hydrochloride by a conventional method, and crystallized from isopropanol-isopropyl ether to give the title compound.

Mp (° C.); 135-140 molecular _{formula; C 21 H 25 N 3 O} 3 · HCl 1 H-NMR (CDCl 3) δ; 1.54~2.86 (12H, m), 3.98 (2H, t), 4.14~4.51 ( 1H,
m), 4.80 (2H, s), 6.74 to 7.51 (7H, m), 7.89 (1 H, dd) MS m / e; 367 (M ⁺ ) Example 12 1- [3- (4-benzylpiperidine-1) -Yl) propyl] -2-oxo-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine dihydrochloride (A) 1- (3-bromopropyl) -2-oxo-1,2,
Synthesis of 3,4-tetrahydropyrido [2,3-b] pyrazine 2-oxo-1,2,3,4-tetrahydropyrido [2,3-
b] 1.49 g of pyrazine are dissolved in 30 ml of dimethyl sulfoxide, 0.42 g of 60% sodium hydride is added, and the mixture is dissolved under a nitrogen stream.
After stirring at ℃ for 1 hour and 15 minutes, the reaction solution was ice-cooled, 30 g of 1,3-dibromopropane was added, the mixture was reacted at room temperature for 4 hours and 30 minutes, poured into water, extracted with ethyl acetate, and washed with saturated saline. And dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
The residue was separated and purified by silica gel column chromatography to obtain 1.53 g of the title compound. _{^{1 H-NMR (CDCl 3)}} δ; 2.18 (2H, m), 3.46 (2H, t), 4.02 (2H, t), 4.13 (2H,
s), 5.56 (1H, bs), 6.69 (1H, dd), 7.13 (1H, dd), 7.69
(1H, dd) (b) 1- [3- (4-benzylpiperidin-1-yl) propyl] -2-oxo-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine. Synthesis of dihydrochloride 1- (3-bromopropyl) -2- obtained in (a)
Dissolve 0.5 g of oxo-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine and 0.87 g of 4-benzylpiperidine in 20 ml of dimethylformamide, add 2.0 g of triethylamine and leave at room temperature overnight . Then, pour the reaction solution into water,
The mixture is extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain 0.51 g of the title compound. It is converted into a hydrochloride (amorphous) by an ordinary method.

Molecular _{formula; C 22 H 28 N 4 O} · 2HCl 1 H-NMR (CDCl 3) δ; 1.10~2.20 (9H, m), 2.25~2.90 (4H, m), 2.70~3.00
(2H, m), 2.95 (2H, t), 3.12 (2H, s), 5.83 (1H, br
s), 6.61 (1H, dd), 7.00 to 7.40 (6H, m), 7.69 (1H, dd) MS m / e; 364 (M ⁺ ) Example 13 4- [3- (4-benzylpiperidine-1) -Yl) propyl] pyrido [4,3-b] [1,4] oxazine-3 (2H)
-One dihydrochloride (A) 4-benzyl- [1- (3-chloropropyl)]
Synthesis of piperidine Tetrahydrofuran 1 in 8.76 g of 4-benzylpiperidine
12.27 g of 1-chloro-3-iodopropane is allowed to act in the presence of 20 ml of triethylamine in 00 ml and stirred overnight. Water was added to the reaction solution, and the mixture was extracted with dichloromethane, washed with saturated saline, and the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (4.48)
g (36% yield). _{^{1 H-NMR (CDCl 3)}} δ; 1.08~2.60 (13H, m), 2.60~2.96 (2H, m), 3.94 (2H,
t), 7.40-7.76 (5H, m) (b) 4- [3- (4-benzylpiperidin-1-yl) propyl] pyrido [4,3-b] [1,4] oxazine-
Synthesis of 3 (2H) -one dihydrochloride 2H-pyrido [4,3-b] [1,4] oxazine-3 (4H)
0.81 g of -one was dissolved in 10 ml of dimethylformamide, and 0.135 g of sodium hydride (60%) was added at 0 ° C.
Stir for 15 minutes at room temperature. The reaction liquid obtained in (a) was added to the reaction mixture.
Benzyl- [1- (3-chloropropyl)] piperidine
1.36 g of dimethylformamide solution (15 ml) is added and reacted at 60 ° C. for 2 hours. The reaction solution is poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, and the organic layer is washed with water and saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography, and converted into a hydrochloride according to a conventional method.
Recrystallization from diethyl ether gave the title compound as colorless crystals (0.52 g, yield 22%).

Mp (℃); 226~227 (decomposition) Molecular _{formula; C 22 H 27 N 3 O} 2 · 2HCl 1 H-NMR (CDCl 3) δ; 1.10~2.04 (9H, m), 2.28~2.59 (4H, m) , 2.72 ~ 2.98
(2H, m), 4.00 (2H, t), 4.67 (2H, s), 6.84 (1H, d), 7.
00 to 7.32 (5H, m), 8.14 (1H, d), 8.31 (1 H, s) MS m / e; 365 (M ⁺ ) Example 14 4- [3- (4-benzylpiperidin-1-yl) Propyl] pyrido [4,3-b] [1,4] thiazine-3 (2H)-
On dihydrochloride 2H-pyrido [4,3-b] [1,4] thiazine-3 (4H)-
Dissolve 0.42 g of ON in 10 ml of dimethylformamide,
At 0 ° C., 0.075 g of sodium hydride (60%) is added, and the mixture is stirred at room temperature for 15 minutes. To the reaction solution, 6 ml of a dimethylformamide solution containing 0.75 g of 4-benzyl- [1- (3-chloropropyl)] piperidine obtained in (a) of Example 15 was added.
The reaction is carried out at 80 ° C. for 2 hours and at 80 ° C. for 1 hour. The reaction solution is poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, and the organic layer is washed with water and saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography, converted into a hydrochloride according to a conventional method, and recrystallized from methanol-diethyl ether to obtain 0.21 g of the title compound as colorless crystals (19% yield). Was.

Mp (℃); 213~214 molecular _{formula; C 22 H 27 N 3 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 1.18~2.60 (13H, m), 2.70~3.00 (2H, m), 3.40 (2H ,
s), 4.06 (2H, t), 6.70 ~ 7.36 (6H, m), 8.16 (1H, d),
8.24 (1H, s) MS m / e; 381 (M ⁺ ) Example 15 The following compounds were obtained according to the method described in Examples 1 to 14 above.

Molecular formula; C ₂₁ H ₂₇ N ₅ O ₂ S · 2HCl ¹ H-NMR (CDCl ₃ ) δ; 1.68 (2H, m), 2.0 to 2.4 (10H, m), 3.41 (2H, s), 3.47
(2H, s), 4.01 (2H, t), 4.05 (3H, s), 7.23 (5H, s), 8.
25 (1H, s) MS m / e; 413 (M ⁺ ) Melting point (° C); 183 (decomposition) Molecular _{formula; C 20 H 26 N 6 O} 2 S 1 H-NMR (CDCl 3) δ; 1.73 (2H, m), 2.0~2.6 (6H, m), 3.42 (2H, s), 3.63 (2
H, s), 4.02 (2H, t), 4.07 (3H, s), 7.1 ~ 7.8 (3H, m),
8.31 (1H, s), 8.52 (1H, d) MS m / e; 414 (M ⁺ ) Melting point (C); 118-120 Molecular _{formula; C 23 H 31 N 5 O} 2 S · 2C 4 H 4 O 4 1 H-NMR (CDCl 3) δ; 1.43~1.97 (4H, m), 2.06~2.71 (14H, m), 3.42 (2H,
m), 4.02 (2H, t), 4.08 (3H, s), 7.20 (5H, br.d), 8.32
(1H, s) MS m / e; 441 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 23 H 29 N 5 O} 2 S · 1.7C 4 H 4 O 4 1 H-NMR (CDCl 3) δ; 1.43~1.86 (2H, m), 1.86~2.57 (10H, m), 3.13 (2H ,
d), 3.43 (2H, s), 4.03 (2H, t), 4.08 (3H, s), 6.04 ~
6.67 (2H, m), 7.16-7.47 (5H, m), 8.33 (1H, s) MS m / e; 439 (M ⁺ ) Melting point (C); 188-191 Molecular _{formula; C 21 H 33 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 0.9~1.9 (13H, m), 1.95~2.50 (12H, m), 3.40 (2H,
s), 3.9-4.1 (5H, m), 8.26 (1H, s) MS m / e; 419 (M ⁺ ) Melting point (° C); 197-200 (decomposition) Molecular _{formula; C 22 H 29 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.5~3.0 (16H, m), 3.40 (1H, s), 3.8~4.1 (5H, m), 7.
0-7.3 (5H, m), 8.28 (1H, s) MS m / e; 427 (M ⁺ ) Melting point (C); 182-184 Molecular _{formula; C 19 H 25 N 5 O} 3 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.5~1.9 (2H, m), 2.0~2.6 (10H, m), 3.40 (2H, s), 3.
50 (2H, s), 3.9 ~ 4.1 (5H, m), 6.14 (1H, d), 6.26 (1H,
m), 7.30 (1H, m), 8.26 (1H, s) MS m / e; 403 (M ⁺ ) Melting point (° C); 175-176 (decomposition) Molecular _{formula; C 19 H 25 N 5 O} 2 S 2 · 2HCl 1 H-NMR (CDCl 3) δ; 1.5~1.9 (2H, m), 2.1~2.6 (10H, m), 3.40 (2H, s), 3 .
66 (2H, s), 3.9 ~ 4.1 (5H, m), 6.8 ~ 6.9 (2H, m), 7.1 ~
7.2 (1H, m), 8.14 (1H, s) MS m / e; 419 (M ⁺ ) Melting point (° C); 190-192 (decomposition) Molecular _{formula; C 22 H 26 N 6 O} 2 S · C 4 H 4 O 4 1 H-NMR (CDCl 3) δ; 1.46~1.86 (2H, m), 2.09~2.54 (10H, m), 3.43 (2H,
s), 3.51 (2H, s), 4.01 (2H, t), 4.07 (3H, s), 7.41 (2
H, d), 7.60 (2H, d), 8.92 (1H, s) MS m / e; 438 (M ^<+> ) Melting point ([deg.] C); Molecular formula; C ₂₁ H ₂₆ FN ₅ O ₂ S · 2HCl ¹ H-NMR (CDCl ₃ ) δ; 1.50 to 1.86 (2H), 2.06 to 2.48 (8H), 2.20 (2H, t), 3.3
9 (2H, s), 3.42 (2H, s), 3.98 (2H, t), 4.03 (3H, s),
6.72-7.36 (4H), 8.26 (1H, s) MS m / e; 431 (M ⁺ ) Melting point (C); 190-194 Molecular _{formula; C 21 H 26 FN 5 O} 2 S · 3 / 2C 4 H 4 O 4 1 H-NMR (CDCl 3) δ; 1.57~1.94 (2H, m), 2.11~2.60 (10H, m), 3.42 ( 2H,
s), 3.46 (2H, s), 4.00 (2H, t), 4.07 (3H, s), 6.80-
7.40 (4H, m), 8.32 (1H, s) MS m / e; 431 (M ⁺ ) Melting point (C); 181-183. Molecular _{formula; C 22 H 29 N 5 O} 3 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.67 (2H, m), 2.1~2.6 (10H, m), 3.40 (2H, s), 3.78
(3H, s), 3.97 (2H, t), 4.04 (2H, s), 6.78 (2H, d), 7.
16 (2H, d), 8.27 (1H, s) MS m / e; 443 (M ⁺ ) Melting point (C); Molecular _{formula; C 20 H 31 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 0.9~2.0 (12H, m), 2.0~2.7 (11H, m), 3.40 (2H, s),
3.9-4.1 (5H, m), 8.28 (1H, s) MS m / e; 405 (M ⁺ ) Melting point (° C); 178-181 (decomposition) Molecular _{formula; C 22 H 26 N 6 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.64 (2H, dt), 2.20 (2H, t), 2.04~2.46 (8H, m), 3.40
(2H, s), 3.46 (2H, s), 3.98 (2H, t), 4.03 (3H, s), 7.
26-7.60 (4H, m), 8.25 (1H, s) MS m / e; 438 (M ⁺ ) Melting point (C); 190-192 Molecular _{formula; C 22 H 29 N 5 O} 3 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.65 (2H, q), 2.10~2.40 (10H, m), 3.42 (2H, s), 3.44
(2H, s), 3.80 (3H, s), 4.00 (2H, t), 4.05 (3H, s), 6.
70-6.90 (3H, m), 7.20 (1H, t), 8.31 (1H, s) MS m / e; 443 (M ⁺ ) Melting point (C); 186-188 Molecular _{formula; C 15 H 23 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.6~1.9 (2H, m), 2.1~5.6 (13H, m), 3.41 (2H, s), 3.
95-4.10 (5H, m), 8.28 (1H, s) MS m / e; 337 (M ⁺ ) Melting point (° C); 184-186 (decomposition) Molecular _{formula; C 18 H 29 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 0.88 (6H, d), 1.6~2.5 (13H, m), 3.42 (2H, s), 3.9~
4.2 (5H, m), 8.32 (1H, s) MS m / e; 379 (M ⁺ ) Melting point (° C); 180-183 (decomposition) Molecular _{formula; C 20 H 31 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.2~2.0 (12H, m), 2.0~2.9 (11H, m), 3.41 (2H, s),
3.9-4.1 (5H, m), 8,28 (1H, s) MS m / e; 405 (M ⁺ ) Melting point (° C); 203-205 (decomposition) Molecular formula; C ₂₁ H ₂₆ FN ₅ O ₂ S · 2HCl ¹ H-NMR (CDCl ₃ ) δ; 1.5 to 1.9 (2H, m), 2.0 to 2.6 (10H, m), 3.40 (2H, s), 3.
56 (2H, d), 3.9 ~ 4.1 (5H, m), 6.9 ~ 7.4 (4H, m), 8.26
(1H, s) MS m / e; 431 (M ⁺ ) Melting point (° C); 188-190 (decomposition) Molecular _{formula; C 21 H 25 N 5 O} 3 S 1 H-NMR (CDCl 3) δ; 1.72 (2H, m), 2.0~2.5 (10H, m), 3.44 (2H, s), 4.03
(2H, t), 4.08 (3H, s), 7.37 (5H, s), 8.28 (1H, s) MS m / e; 427 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 22 H 29 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.20~2.70 (14H), 3.40 (2H, s), 3.56 (2H, s), 3.97
(2H, t), 4.03 (3H, s), 7.10 ~ 7.32 (5H), 8.25 (1H,
s) MS m / e; 427 (M ^<+> ) Melting point ([deg.] C); 152-155. Molecular _{formula; C 23 H 31 N 5 O} 3 S · 2C 4 H 4 O 4 1 H-NMR (CDCl 3) δ; 1.46~2.14 (4H, m), 2.40~3.11 (10H, m), 3.42 (2H,
s), 3.85 (3H, s), 3.95 (2H, s), 3.95 (2H, t), 4.09 (3
H, s), 6.85-7.56 (4H, m), 8.33 (1H, s) MS m / e; 458 (MH ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 22 H 35 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 0.70~2.66 (27H), 3.40 (2H, s), 3.97 (2H, t), 4.05
(3H, s), 8.26 (1H, s) MS m / e; 433 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 20 H 25 N 5 O} 2 S 1 H-NMR (CDCl 3) δ; 1.75 (2H, m), 2.1~2.6 (6H, m), 3.09 (4H, t), 3.43 (2
H, s), 3.8-4.2 (5H, m), 6.7-7.0 (3H, m), 7.1-7.3
(2H, m), 8.29 (1H, s) MS m / e; 399 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 18 H 23 N 7 O} 2 S 1 H-NMR (CDCl 3) δ; 1.73 (2H, m), 2.0~2.5 (6H, m), 3.43 (2H, s), 3.69 (4
H, t), 3.8 ~ 4.1 (5H, m), 6.42 (1H, t), 8.22 (2H, d),
8.24 (1H, s) MS m / e; 401 (M ⁺ ) Melting point (° C); 128-130 Molecular _{formula; C 19 H 24 N 6 O} 2 S 1 H-NMR (CDCl 3) δ; 1.77 (2H, m), 2.1~2.5 (6H, m), 3.45 (4H, t), 3.45 (2
H, s), 4.09 (3H, s), 4.09 (2H, t), 6.5 ~ 6.7 (2H, m),
7.3 to 7.6 (1H, m), 8.13 (1H, dd), 8.30 (1H, s) MS m / e; 400 (M ⁺ ) Melting point (° C); 134 to 137 Molecular _{formula; C 23 H 31 N 5 O} 3 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.25~1.56 (4H, m), 2.16~2.64 (10H, m), 3.40 (2H,
s), 3.56 (2H, s), 3.76 (3H, s), 3.95 (2H, t), 4.03 (3
H, s), 6.84 (2H, t), 7.20 (2H, ddd), 8.27 (1H, s) MS m / e; 457 (M ⁺ ) Melting point (° C); 168-169 (decomposition) Molecular _{formula; C 24 H 33 N 5 O} 3 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.15~1.64 (6H, m), 2.08~2.64 (10H, m), 3.39 (2H,
s), 3.55 (2H, s), 3.76 (3H, s), 3.96 (2H, t), 4.02 (3
H, s), 6.84 (2H, t), 7.18 (2H, ddd), 8.28 (1H, s) MS m / e; 471 (M ⁺ ) Melting point (° C); 188-189 (decomposition) Molecular _{formula; C 25 H 35 N 5 O} 3 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.08~1.58 (8H, m), 1.98~2.64 (10H, m), 3.38 (2H,
s), 3.56 (2H, s), 3.76 (3H, s), 3.92 (2H, t), 4.01 (3
H, s), 6.83 (2H, t), 7.18 (2H, ddd), 8.25 (1H, s) MS m / e; 485 (M ⁺ ) Melting point (° C); 165-166 (decomposition) Molecular _{formula; C 26 H 37 N 5 O} 3 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.12~1.60 (10H, m), 2.00~2.68 (10H, m), 3.40 (2H,
s), 3.57 (2H, s), 3.78 (3H, s), 3.93 (2H, t), 4.04 (3
H, s), 6.83 (2H, t), 7.21 (2H, ddd), 8.28 (1H, s) MS m / e; 500 (MH ⁺ ) Melting point (° C); 144-145 (decomposition) Molecular _{formula; C 22 H 29 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.30~1.56 (4H, m), 2.19~2.36 (2H, m), 2.46 (8H, b
s), 3.40 (2H, s), 3.48 (2H, s), 3.95 (2H, t), 4.04 (3
H, s), 7.24 (5H, s), 8.27 (1H, s) MS m / e; 427 (M ⁺ ) Melting point (° C); 182-184 (decomposition) Molecular _{formula; C 23 H 31 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.10~1.65 (6H, m), 2.20~2.44 (2H, m), 2.55 (8H, b
s), 3.40 (2H, s), 3.49 (2H, s), 3.92 (2H, t), 4.03 (3
H, s), 7.23 (5H, s), 8.27 (1H, s) MS m / e; 441 (M ⁺ ) Melting point (° C); 168-169 (decomposition) Molecular _{formula; C 24 H 33 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.10~1.60 (8H, m), 2.20~2.46 (2H, m), 2.46 (8H, b
s), 3.39 (2H, s), 3.49 (2H, s), 3.92 (2H, t), 4.02 (3
H, s), 7.24 (5H, s), 8.26 (1H, s) MS m / e; 455 (M ⁺ ) Melting point (° C); 169-170 (decomposition) Molecular _{formula; C 23 H 37 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 0.6~1.9 (17H, m), 2.0~2.6 (12H, m), 3.42 (2H, s),
3.95 (2H, t), 4.04 (3H, s), 8.29 (1H, s) MS m / e; 447 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 23 H 31 N 5 O} 3 S · C 4 H 4 O 4 1 H-NMR (CDCl 3) δ; 1.00~2.94 (16H, m), 3.29~3.71 (3H, m), 3.96 (2H,
t), 4.07 (3H, m), 4.64 (2H, s), 7.05-7.82 (3H, m),
8.34 (1H, s), 8.52 (1H, br.d) MS m / e; 457 (M ⁺ ) Melting point (℃); Amorphous Molecular _{formula; C 22 H 28 N 4 O} 3 S · HCl 1 H-NMR (CDCl 3) δ; 1.38~2.66 (12H), 3.40 (2H, s), 3.20~3.42 (1H, m),
3.98 (2H, t), 4.05 (3H, s), 4.47 (2H, s), 7.25 (5H, b
rs), 8.26 (1H, s) MS m / e; 428 (M ⁺ ) Melting point (℃); Hygroscopic amorphous Molecular _{formula; C 21 H 27 N 5 O} 3 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.4~2.9 (13H, m), 3.42 (2H, s), 4.00 (2H, t), 4.07
(3H, s), 4.60 (2H, s), 7.11 (1H, t), 7.3 ~ 7.7 (2H,
m), 8.18 (1H, s), 8.14 (1H, d) MS m / e; 430 (MH ⁺ ) Melting point (℃); Amorphous Molecular _{formula; C 22 H 29 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.08~1.88 (11H), 2.15 (2H, dd), 2.44~2.86 (4H),
3.38 (2H, s), 3.98 (2H, t), 4.03 (3H, s), 7.00 (1H, dd
d), 7.05 (1H, dd), 7.49 (1H, ddd), 8.25 (1H, s), 8.40
(1H, dd) MS m / e; 427 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 21 H 26 N 4 O} 2 S 1 H-NMR (CDCl 3) δ; 1.6~2.6 (13H, m), 2.6~2.9 (2H, m), 3.43 (2H, s), 4.
05 (2H, t), 4.09 (3H, s), 7.0 ~ 7.4 (5H, m), 8.30 (1H,
s) MS m / e; 398 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 22 H 28 N 4 O} 2 S 1 H-NMR (CDCl 3) δ; 1.4~2.0 (9H, m), 2.0~2.3 (2H, m), 2.4~2.8 (4H,
m), 3.42 (2H, s), 3.97 (2H, t), 4.02 (3H, s), 7.0-7.
3 (5H, m), 8.25 (1H, s) MS m / e; 382 (M ⁺ ) Melting point (C); 122-125 Molecular _{formula; C 22 H 28 N 4 O} 3 S 1 H-NMR (CDCl 3) δ; 1.3~1.9 (7H, m), 2.0~2.6 (6H, m), 2.71 (2H, s), 3.4
0 (2H, s), 4.00 (2H, t), 4.04 (3H, s), 7.0 ~ 7.4 (5H,
m), 8.33 (1H, s) MS m / e; 428 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 22 H 25 FN 4 O} 2 S · HCl 1 H-NMR (CDCl 3) δ; 1.4~2.3 (10H, m), 2.5~2.8 (2H, m), 2.9~3.3 (1H,
m), 3.44 (2H, s), 4.05 (2H, t), 4.08 (2H, s), 7.08 (2
H, t), 7.90 (2H, dd), 8.17 (1H, s) MS m / e; 444 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 23 H 28 N 4 O} 4 S · HCl 1 H-NMR (CDCl 3) δ; 1.54~3.29 (13H, m), 3.43 (2H, s), 3.86 (3H, s), 4.04
(2H, t), 4.11 (3H, s), 6.92 (2H, d), 7.89 (2H, d), 8.
33 (1H, s) MS m / e; 456 (M ⁺ ) melting point ([deg.] C); Molecular _{formula; C 21 H 25 FN 4 O} 3 S · C 4 H 4 O 4 1 H-NMR (CDCl 3) δ; 1.29~2.70 (12H, m), 3.43 (2H, s), 4.00 (2H, t) , 4.09
(3H, s), 6.75-7.00 (4H, m), 8.29 (1H, s) MS m / e; 432 (M ⁺ ) Melting point (C); 146-147 Molecular _{formula; C 21 H 26 N 4 O} 3 S · C 4 H 4 O 4 1 H-NMR (CDCl 3) δ; 1.40~2.71 (12H, m), 3.43 (2H, m), 4.04 (2H, t) , 4.09
(3H, s), 4.19 (1H, br.m), 6.75-7.04 (3H, m), 7.10-
7.42 (2H, m), 8.33 (1H, s) MS m / e; 414 (M ⁺ ) Melting point (C); 161-162 Molecular _{formula; C 22 H 27 N 5 O} 3 S 1 H-NMR (CDCl 3) δ; 1.6~2.4 (11H, m), 2.6~2.9 (2H, m), 3.43 (2H, s), 4.
04 (2H, t), 4.09 (3H, s), 7.0 ~ 7.6 (1H, m), 8.28 (1H,
s) MS m / e; 441 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 22 H 27 N 5 O} 3 S · HCl 1 H-NMR (CDCl 3) δ; 1.20~2.36 (10H), 2.52~2.80 (2H), 3.42 (2H, s), 4.
00 (2H, t), 4.07 (3H, s), 3.84 ~ 4.10 (1H, m), 5.94 (1
H, m), 7.30-7.80 (5H), 8.32 (1H, s) MS m / e; 441 (M ⁺ ) Melting point (C); 180-183 Molecular formula; C ₂₁ H ₂₆ N ₆ O ₃ S · 2HCl ¹ H-NMR (CDCl ₃ ) δ; 1.38 to 2.36 (10H), 2.52 to 2.80 (2H), 3.43 (2H, s), 4.
03 (2H, t), 3.82 ~ 4.16 (1H), 4.09 (3H, s), 7.40 (1H,
ddd), 7.82 (1H, ddd), 7.80 ~ 8.02 (1H), 8.16 (1H, d
d), 8.33 (1H, s), 8.52 (1H, dd) MS m / e; 442 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 24 H 31 N 5 O} 3 S · HCl 1 H-NMR (CDCl 3) δ; 1.06~2.76 (15H), 3.20~3.48 (2H), 3.42 (2H, s), 3.
99 (2H, t), 3.90-4.10 (1H), 4.07 (3H, s), 7.34 (5H,
m), 8.32 (1H, s) MS m / e; 469 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 22 H 28 N 4 O} 3 S 1 H-NMR (CDCl 3) δ; 1.00~2.50 (11H, m), 2.70~2.99 (2H, m), 3.40 (2H,
s), 3.54 (2H, s), 3.92 (2H, t), 4.04 (3H, s), 7.25 (5
H, s), 8.28 (1H, s) MS m / e; 412 (M ⁺ ) Melting point (° C); 151-152 Molecular _{formula; C 23 H 29 N 5 O} 3 S 1 H-NMR (CDCl 3) δ; 1.57~2.00 (2H, m), 2.08~2.69 (10H, m), 3.13 (2H,
d), 3.73 (1H, d), 4.16 (3H, s), 4.16 (2H, t), 4.21 (1
H, d), 6.00 ~ 6.62 (2H, m), 7.11 ~ 7.43 (5H, m), 8.62
(1H, s) MS m / e; 456 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 24 H 31 N 5 O} 2 S · C 4 H 4 O 4 1 H-NMR (CDCl 3) δ; 1.44 (3H, t), 1.69 (2H, m), 2.0~2.6 (10H, m) , 3.12
(2H, d), 3.42 (2H, s), 4.03 (2H, t), 4.53 (2H, q), 6.
0-6.5 (2H, m), 7.0-7.4 (5H, m), 8.15 (1H, s) MS m / e; 453 (M ⁺ ) Melting point (C); 188-189 Molecular _{formula; C 23 H 31 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.43 (3H, t), 1.65 (2H, m), 2.0~2.7 (10H, m), 3.41
(2H, s), 3.55 (2H, s), 3.77 (3H, s), 4.03 (2H, t), 4.
47 (2H, q), 6.7 to 7.4 (4H, m), 8.23 (1H, s) MS m / e; 457 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 20 H 27 N 5 O} 2 S 2 · C 4 H 4 O 4 1 H-NMR (CDCl 3) δ; 1.45 (3H, t), 1.65 (2H, m), 2.0~2.6 (10H, m ), 3.41
(2H, s), 3.68 (2H, s), 4.03 (2H, t), 4.49 (2H, q), 6.
8-7.0 (2H, m), 7.1-7.2 (1H, m), 8.24 (1H, s) MS m / e; 433 (M ⁺ ) Melting point (C); 186-188 Molecular _{formula; C 21 H 26 N 4 O} 2 S · HCl 1 H-NMR (DMOS-d 6) δ; 1.1~2.2 (7H, m), 2.3~3.1 (6H, m), 3.0~3.5 (2H,
m), 3.57 (2H, s), 3.8-4.1 (2H, m), 7.0-7.4 (5H,
m), 7.92 (1H, s), 10.0 to 10.6 (1H, bs) MS m / e; 298 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 22 H 27 N 5 O} 2 S · 2HCl 1 H-NMR (DMOS-d 6) δ; 1.70~2.29 (2H, m), 6.14~7.09 (2H, m), 7.26~7.63
(5H, m), 8.00 (1H, s) MS m / e; 426 (MH ⁺ ) Melting point (° C); 222 (decomposition) Molecular _{formula; C 22 H 35 N 5 O} 2 S · 2HCl 1 H-NMR (DMOS-d 6) δ; 0.8~2.0 (17H, m), 2.7~3.2 (4H, m), 3.2~3.8 (10H,
m), 3.8-4.1 (2H, m), 7.85 (1H, s) MS m / e; 434 (MH ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 20 H 25 N 5 O} 2 S · 2HCl 1 H-NMR (DMOS-d 6) δ; 1.7~2.1 (2H, m), 2.7~3.8 (14H, m), 3.9~4.1 (2H,
m), 7.3-7.5 (3H, m), 7.5-7.8 (2H, m), 7.96 (1H, s) MS m / e; 400 (MH ⁺ ) Melting point (℃); Amorphous Molecular formula; C ₂₁ H ₂₆ N ₄ O ₃ S · HCl ¹ H-NMR (CDCl ₃ ) δ; 1.6 to 2.2 (6H, m), 2.6 to 3.0 (6H, m), 2.6 to 3.0 (2H,
m), 3.37 (2H, s), 4.17 (2H, t), 7.0-7.4 (5H, m), 7.7
7 (1H, s) MS m / e; 414 (M ⁺ ) Melting point (° C); 215-220 (decomposition) Molecular _{formula; C 20 H 31 N 5 O} 2 S · 2HCl 1 H-NMR (D 2 O) δ; 0.9~2.3 (13H), 3.0~4.1 (16H), 8.02 (1H, s) MS m / e; 405 (M ⁺ ) Melting point (° C); 183-185 (decomposition) Molecular _{formula; C 18 H 23 N 5 O} 2 S 2 · 2HCl 1 H-NMR (D 2) δ; 1.9~2.3 (2H), 3.1~3.4 (2H), 3.59 (2H, s), 3.70 (1
0H), 4.00 (2H, t), 7.13 (1H, dd), 7.3 (1H, d), 7.62
(1H, d), 8.01 (1H, s) MS m / e; 405 (M ⁺ ) Melting point (° C); 228-230 (decomposition) Molecular _{formula; C 19 H 23 N 5 O} 2 S · 2HCl 1 H-NMR (DMSO-d 6) δ; 1.8~2.2 (2H, m), 2.9,3.9 (12H, m), 3.9~4.2 (2H,
m), 6.7 to 7.1 (3H, m), 7.1 to 7.3 (2H, m), 7.96 (1H, s) MS m / e; 385 (M) Melting point (° C); 215 to 218 (decomposition) Molecular formula; C ₁₈ H ₂₂ N ₆ O ₂ S · 2HCl ¹ H-NMR (DMOS-d ₆ ) δ; 1.8 to 2.2 (2H, m), 2.9 to 3.4 (6H, m), 3.4 to 3.9 (6H,
m), 3.9-4.2 (2H, m), 6.95 (1H, t), 7.32 (1H, d), 7.8
~ 8.1 (2H, m), 11.0 ~ 11.7 (1H, bs) MS m / e; 386 (M ⁺ ) Melting point (℃); 221-225 (decomposition) Molecular formula; C ₁₇ H ₂₁ N ₇ O ₂ S · 2HCl ¹ H-NMR (DMOS-d ₆ ) δ; 1.8 to 2.2 (2H, m), 2.9 to 4.2 (16H, m), 6.71 (1H, t), 7.
92 (1H, s), 8.37 (2H, d) MS m / e; 387 (M ⁺ ) Melting point (° C); 224-227 (decomposition) Molecular _{formula; C 22 H 30 N 6 OS} · 3HCl 1 H-NMR (CDCl 3) δ; 1.50 (2H, m), 1.9~2.5 (10H, m), 2.96 (6H, s), 3.1~
3.5 (6H, m), 7.18 (5H, s), 8.09 (1H, s) MS m / e; 426 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 23 H 32 N 6 O} 2 S · 3HCl 1 H-NMR (CDCl 3) δ; 1.20~1.69 (2H, m), 1.94~2.57 (10H, m), 2.98 (6H, b
rs), 3.26-4.43 (9H, m), 6.70-7.42 (4H, m), 8.16
(1H, s) MS m / e; 456 (M ^<+> ) Melting point ([deg.] C); Molecular formula; C ₂₁ H ₂₅ ClN ₄ OS · HCl ¹ H-NMR (CDCl ₃ ) δ; 1.0 to 2.7 (15H, m), 3.48 (2H, s), 4.10 (2H, t), 7.0 to
7.4 (5H, m), 8.44 (1H, s) MS m / e; 416/418 (M ⁺ ) Melting point (° C); 182-184 (decomposition) Molecular formula; C ₂₁ H ₂₂ FClN ₄ O ₂ S · HCl ¹ H-NMR (CDCl ₃ ) δ; 1.4 to 2.6 (12H, m), 3.2 to 3.4 (1H, m), 3.50 (2H, s), 4.
12 (2H, t), 4.44 (2H, s), 6.8 ~ 7.4 (4H, m), 8.44 (1H,
s) MS m / e; 451/453 (M ⁺ ) Melting point (° C); hygroscopic amorphous Molecular _{formula; C 20 H 24 ClN 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.5~2.7 (2H, m), 3.40 (1H, m), 3.45 (2H, s), 4.18 (2
H, t), 4.76 (2H, s), 7.5 ~ 7.8 (3H, m), 8.4 ~ 8.5 (2H,
m) MS m / e; 433/435 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 21 H 25 ClN 4 O} 2 S · HCl 1 H-NMR (CDCl 3) δ; 1.4~2.6 (12H, m), 3.2~3.4 (1H, m), 3.48 (2H, s), 4.
12 (2H, t), 4.48 (2H, s), 7.28 (5H, s), 8.24 (1H, s) MS m / e; 432/434 (M ⁺ ) Melting point (° C); 198-200 (decomposition) Molecular formula; C ₂₀ H ₂₃ FClN ₅ OS · 2HCl ¹ H-NMR (CDCl ₃ ) δ; 1.51 to 1.91 (2H, m), 2.00 to 2.40 (10H, m), 3.41 (2H,
m), 3.49 (2H, m), 4.13 (2H, t), 6.86-7.35 (4H, m),
8.48 (1H, s) MS m / e; 435/437 (M ⁺ ) Melting point (° C); 196-198 (decomposition) Molecular _{formula; C 20 H 30 ClN 5 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 0.6~1.9 (13H, m), 1.9~2.5 (12H, m), 3.49 (2H, s),
4.11 (2H, t), 8.44 (1H, s) MS m / e; 423/425 (M ⁺ ) Melting point (° C); 229-231 (decomposition) Molecular _{formula; C 20 H 24 ClN 5 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 1.79 (2H, m), 2.1~2.4 (10H, m), 3.52 (2H, s), 3.55
(2H, s), 4.18 (2H, t), 7.30 (5H, s), 8.48 (1H, s) MS m / e; 417/419 (M ⁺ ) Melting point (° C); Molecular formula; C ₂₁ H ₂₆ ClN ₅ O ₂ S · 2HCl ¹ H-NMR (CDCl ₃ ) δ; 1.57 to 1.86 (2H, m), 2.06 to 2.49 (10H, m), 3.48 (2H,
s), 3.52 (2H, s), 3.80 (3H, s), 4.12 (2H, s), 6.80 ~
7.32 (4H, m), 8.45 (1H, s) MS m / e; 447/449 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 20 H 23 FClN 5 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 1.5~1.9 (2H, m), 2.0~2.5 (10H, m), 3.48 (2H, s), 3.
52 (2H, s), 4.10 (2H, t), 6.8 ~ 7.4 (4H, m), 8.42 (1H,
s) MS m / e; 435/437 (M ⁺ ) Melting point (° C); 185-187 (decomposition) Molecular formula; C ₂₀ H ₂₃ FClN ₅ OS · 2HCl ¹ H-NMR (CDCl ₃ ) δ; 1.46 to 1.94 (2H, m), 2.00 to 2.43 (10H, m), 3.44 (2H,
s), 3.50 (2H, s), 4.14 (2H, t), 6.77 ~ 7.37 (4H, m),
8.48 (1H, s) MS m / e; 435/437 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 21 H 24 ClN 5 O} 2 S · HCl 1 H-NMR (CDCl 3) δ; 1.3~2.7 (12H, m), 3.50 (2H, s), 3.9~4.0 (1H, m), 4.
16 (2H, t), 7.3-7.8 (5H, m), 8.50 (1H, s) MS m / e; 445/447 (M ⁺ ) Melting point (C); 195-196 Molecular _{formula; C 20 H 22 FClN 4 O} 2 S · HCl 1 H-NMR (CDCl 3) δ; 1.4~2.7 (12H, m), 3.48 (2H, s), 4.0~4.3 (3H, m), 6.
7-7.1 (4H, m), 8.44 (1H, s) MS m / e; 436/438 (M ⁺ ) Melting point (° C); 192-194 (decomposition) Molecular _{formula; C 20 H 25 N 5 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 1.83 (2H, m), 2.2~2.6 (10H, m), 3.49 (2H, s), 3.55
(2H, s), 4.02 (2H, t), 7.27 (5H, s), 8.49 (1H, s), 8.
63 (1H, s) MS m / e; 383 (M ⁺ ) Melting point (° C); 246-249 (decomposition) Molecular _{formula; C 20 H 31 N 5 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 0.6~2.0 (13H, m), 2.16 (2H, d), 2.2~2.5 (10H, m),
3.57 (2H, s), 4.05 (2H, t), 8.55 (1H, s), 8.68 (1H,
s) MS m / e; 389 (M ^<+> ) Melting point ([deg.] C); 260-265 (decomposition) Molecular _{formula; C 21 H 27 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.84 (2H, q), 2.20~2.60 (10H, m), 3.52 (4H, s), 3.77
(3H, s), 3.98 (2H, t), 6.84 (2H, t), 7.20 (2H, ddd),
8.44 (1H, s), 8.60 (1H, s) MS m / e; 413 (M ⁺ ) Melting point (° C); 105-106 (decomposition) Molecular _{formula; C 23 H 30 N 4 O} 2 S · HCl 1 H-NMR (CDCl 3) δ; 1.0~1.9 (10H, m), 2.0~2.8 (8H, m), 3.56 (2H, s), 3.
92 (2H, t), 7.15 (5H, s), 8.27 (1H, s), 8.57 (1H, s) MS m / e; 426 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 22 H 34 N 5 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 0.6~1.9 (17H, m), 2.0~2.6 (12H, m), 3.61 (2H, s),
3.98 (2H, t), 8.36 (1H, s), 8.70 (1H, s) MS m / e; 417 (MH ⁺ ) Melting point (° C); 245-248 (decomposition) Molecular formula; C ₂₁ H ₂₆ N ₄ OS · HCl ¹ H-NMR (CDCl ₃ ) δ; 1.0 to 2.1 (9H, m), 2.21 (2H, t), 2.53 (2H, d), 2.6 to 2.
9 (2H, m), 3.56 (2H, s), 3.99 (2H, t), 7.0 ~ 7.4 (5H,
m), 8.48 (1 H, s), 8.64 (1 H, s) MS m / e; 382 (M ⁺ ) Melting point (° C); Molecular _{formula; C 21 H 25 FN 4 O} 2 S · HCl 1 H-NMR (CDCl 3) δ; 1.4~2.4 (10H, m), 2.5~2.8 (2H, m), 3.41 (1H, m), 3.
58 (2H, s), 4.05 (2H, t), 4.48 (2H, s), 7.01 (2H, t),
7.30 (2H, dd), 8.53 (1H, s), 8.68 (1H, s) MS m / e; 416 (M ⁺ ) Melting point (C); 155-160 Molecular _{formula; C 20 H 25 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.5~2.5 (10H, m), 2.5~2.8 (2H, m), 3.38 (2H, s), 3.
50 (1H, m), 3.60 (2H, s), 4.03 (2H, t), 4.63 (2H, s),
7.1 ~ 7.8 (3H, m), 8.3 ~ 8.5 (2H, m), 8.62 (1H, s) MS m / e; 399 (M ⁺ ) Melting point (℃); Amorphous Molecular _{formula; C 21 H 26 N 4 O} 2 S · HCl 1 H-NMR (CDCl 3) δ; 1.3~2.6 (6H, m), 2.0~2.7 (6H, m), 2.76 (2H, s), 3.5
7 (2H, s), 4.01 (2H, t), 7.23 (5H, m), 8.48 (1H, s),
8.63 (1H, s) MS m / e; 398 (M ⁺ ) Melting point ([deg.] C); Molecular _{formula; C 22 H 28 N 4 O} 4 · HCl 1 H-NMR (CDCl 3) δ; 1.5~1.9 (2H, m), 2.0~2.7 (10H, m), 2.73 (2H, s), 3.
9 ~ 4.2 (5H, m), 4.67 (2H, s), 7.0 ~ 7.3 (5H, m), 8.14
(1H, s) MS m / e; 412 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 20 H 26 N 6 O} · 3HCl 1 H-NMR (CDCl 3) δ; 1.6~2.0 (2H, m), 2.2~2.7 (10H, m), 3.51 (2H, s), 3.
96 (2H, t), 4.23 (2H, s), 7.25 (6H, s), 8.02 (1H, s),
8.21 (1H, s) MS m / e; 306 (M ⁺ ) Melting point (° C); 202-205 (decomposition) Molecular _{formula; C 21 H 26 N 4 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.5~2.9 (12H, m), 3.3~3.5 (1H, m), 3.50 (2H, s), 3.
98 (2H, t), 4.52 (2H, s), 7.0 ~ 7.5 (4H, m), 8.10 (1H,
m), 8.48 (2H, m) MS m / e; 398 (M ⁺ ) Melting point (° C); hygroscopic amorphous Molecular _{formula; C 22 H 28 N 4 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.08~2.16 (11H, m), 2.32 (2H, t), 2.62~2.96 (4H,
m), 3.48 (2H, s), 3.96 (2H, t), 6.92 to 7.24 (3H, m),
7.47 (1H, dd), 7.52 (1H, dd), 8.09 (1H, dd), 8.43 (1
H, dd) MS m / e; 396 (M ⁺ ) Melting point (° C); hygroscopic amorphous Molecular _{formula; C 21 H 26 N 4 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.68 (2H, dd), 2.00~2.52 (4H, m), 2.93 (2H, s), 2.80
~ 3.36 (6H, m), 3.47 (2H, s), 3.98 (2H, t), 6.56 (1H,
br), 7.00-7.24 (3H, m), 7.54 (1H, dd), 7.61 (1H, d
d), 8.09 (1H, dd), 8.34 (1H, dd) MS m / e; 398 (M ⁺ ) Melting point (° C); hygroscopic amorphous Molecular _{formula; C 22 H 27 N 3 OS} · HCl 1 H-NMR (CDCl 3) δ; 1.1~2.2 (9H, m), 2.3~2.6 (4H, m), 2.7~3.1 (2H,
m), 3.42 (2H, s), 3.95 (2H, t), 6.9 ~ 7.3 (6H, m), 7.4
9 (1H, dd), 8.10 (1H, dd) MS m / e; 381 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 22 H 24 F 3 N} 3 O 2 S · HCl 1 H-NMR (CDCl 3) δ; 1.5~2.9 (12H, m), 3.48 (2H, s), 3.98 (2H, t), 4.33
(1H, m), 6.86 (2H, d), 6.9 ~ 7.2 (1H, m), 7.3 ~ 7.6 (3
H, m), 8.11 (1H, dd) MS m / e; 451 (M ⁺ ) Melting point (℃); Amorphous Molecular _{formula; C 22 H 27 N 3 O} 2 S · HCl 1 H-NMR (CDCl 3) δ; 1.1~2.0 (6H, m), 2.05~2.8 (8H, m), 3.45 (2H, s), 3.
95 (2H, t), 6.9 ~ 7.6 (7H, m), 8.10 (1H, dd) MS m / e; 297 (M ⁺ ) Melting point (℃); Amorphous Molecular formula; C ₂₁ H ₂₆ N ₄ OS · HCl ¹ H-NMR (CDCl ₃ ) δ; 1.1 to 2.2 (7H, m), 2.3 to 2.6 (2H, m), 2.70 (2H, d), 2.7
~ 3.3 (4H, m), 3.43 (3H, s), 3.96 (2H, t), 6.9 ~ 7.3
(3H, m), 7.4-7.7 (2H, m), 8.12 (1H, dd) 8.45 (1H, d
d) MS m / e; 382 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 21 H 26 N 4 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.3~2.4 (10H, m), 2.5~2.8 (2H, m), 3.39 (1H, m), 3.
48 (2H, s), 3.97 (2H, t), 4.52 (2H, s), 7.0 ~ 7.3 (2H, s
m), 7.4-7.7 (2H, m), 8.10 (1H, dd), 8.3-8.6 (2H,
m) MS m / e; 398 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 23 H 30 N 4 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 0.9~2.1 (11H), 2.2~2.9 (8H), 3.44 (2H, s), 3.92
(2H, t), 6.9 ~ 7.6 (5H), 8.06 (1H, dd), 8.3 ~ 8.5 (1
H) MS m / e; 410 (M ⁺ ) Melting point (° C); hygroscopic amorphous Molecular _{formula; C 18 H 22 N 5 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 1.5~3.0 (13H), 3.46 (2H, s), 4.00 (2H, t), 6.76 (1
H, s), 7.0-7.7 (3H), 8.17 (1H, dd) MS m / e; 358 (M ^<+> ) Melting point ([deg.] C); Molecular _{formula; C 21 H 25 N 5 O} 2 S · 2HCl 1 H-NMR (CDCl 3) δ; 1.5~3.0 (13H, m), 3.56 (2H, s), 3.8~4.2 (3H, m), 7.
0-8.2 (7H, m), 8.50 (1H, m) MS m / e; 411 (M ⁺ ) Melting point (° C); oil Molecular formula; C ₂₁ H ₂₅ N ₅ OS ₂ .HCl ¹ H-NMR (CDCl ₃ ) δ; 1.6 to 2.0 (2H, m), 2.3 to 2.6 (6H, m), 3.48 (2H, s), 3.6
~ 3.9 (4H, m), 3.98 (2H, t), 6.9 ~ 7.5 (8H, m), 8.16
(1H, m) MS m / e; 427 (M ⁺ ) Melting point (℃); Hygroscopic amorphous Molecular _{formula; C 20 H 23 FN 4 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 1.6~2.0 (2H, m), 2.1~2.7 (4H, m), 2.8~3.2 (2H,
m), 3.46 (2H, s), 3.97 (2H, t), 6.6 ~ 7.2 (4H, m), 7.4
1 (2H, d), 8.07 (1H, dd) MS m / e; 386 (M ⁺ ) Melting point (° C); 185-190 Molecular _{formula; C 18 H 22 N 6 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 1.7~2.0 (2H), 2.2~2.5 (6H), 3.50 (2H, s), 3.6~3.
9 (4H), 4.00 (2H, t), 6.44 (1H, t), 7.10 (1H, dd), 7.
47 (1H, dd), 8.10 (1H, dd), 8.23 (2H, d) MS m / e; 370 (M ⁺ ) Melting point (° C); 172-178 (decomposition) Molecular _{formula; C 19 H 23 N 5 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 1.7~2.0 (2H), 2.3~2.6 (6H), 3.3~3.6 (6H), 4.00
(2H, t), 6.5-6.7 (2H), 7.10 (1H, dd), 7.3-7.6 (2
H), 8.10 (2H, dd) MS m / e; 369 (M ^<+> ) Melting point ([deg.] C); 195-198 (decomposition) Molecular _{formula; C 15 H 22 N 4 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 1.75 (2H, m), 2.27 (3H, s), 2.2~2.6 (10H, m), 3.42
(2H, s), 3.95 (2H, t), 7.04 (1H, dd), 7.38 (1H, d),
8.07 (1H, d) MS m / e; 306 (M ⁺ ) Melting point (° C); 204-208 (decomposition) Molecular _{formula; C 21 H 26 N 4 OS} · 2HCl 1 H-NMR (CDCl 3) δ; 1.75 (2H, m), 2.1~2.7 (10H, m), 3.46 (4H, s), 3.95
(2H, t), 6.9 ~ 7.3 (6H, m), 7.42 (2H, d), 8.06 (1H, d
d) MS m / e; 382 (M ⁺ ) Melting point (° C); 231-236 (decomposition) Molecular _{formula; C 20 H 25 N 5 OS} · 3HCl 1 H-NMR (CDCl 3) δ; 1.6~2.0 (2H), 2.2~2.7 (10H), 3.48 (2H, s), 3.64
(2H, s), 3.98 (2H, t), 7.0 ~ 7.7 (5H), 8.10 (1H, d
d), 8.48 (1H, br.d) MS m / e; 383 (M ⁺ ) Melting point (° C); hygroscopic amorphous Molecular formula; C ₂₁ H ₂₇ N ₅ OS · 3HCl ¹ H-NMR (CDCl ₃ ) δ; 1.6 to 2.0 (2H), 2.2 to 3.1 (14H), 3.50 (2H, s), 4.00
(2H, t), 6.9 ~ 7.6 (5H), 8.10 (1H, dd), 8.3 ~ 8.5 (1
H) MS m / e; 397 (M ^<+> ) Melting point ([deg.] C); 165-167 (decomposition) Molecular _{formula; C 21 H 26 N 4 O} 3 S 1 H-NMR (CDCl 3) δ; 1.44~2.82 (12H), 3.35~3.68 (1H, m), 3.35~3.68 (1
H, m), 3.49 (2H, s), 3.97 (2H, t), 4.73 (2H, s), 7.00
-7.60 (5H), 8.02-8.24 (2H) MS m / e; 415 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 21 H 26 N 4 O} 3 S 1 H-NMR (CDCl 3) δ; 1.34~2.94 (12H, m), 3.23~3.63 (1H, m), 3.79 (1H,
d), 4.11 (2H, t), 4.28 (1H, d), 4.65 (2H, s), 7.06-
7.97 (5H, m), 8.40 (1H, dd), 8.51 (1H, br.d) MS m / e; 415 (M ⁺ ) Melting point (℃); Amorphous Molecular _{formula; C 22 H 27 N 3 O} 2 · HCl 1 H-NMR (CDCl 3) δ; 1.14~2.04 (9H, m), 2.24~2.40 (4H, m), 2.68~2.99
(2H, m), 3.92 (2H, t), 4.78 (2H, s), 6.94 (1H, dd),
7.04 to 7.30 (5H, m), 7.40 (1H, dd), 7.84 (1H, dd) MS m / e; 365 (M ⁺ ) Melting point (° C); 198 to 199 (decomposition) Molecular _{formula; C 22 H 27 N 3 O} 3 · HCl 1 H-NMR (CDCl 3) δ; 1.12~2.68 (13H, m), 2.74 (2H, s), 3.94 (2H, s), 4.77
(2H, s), 6.94 (1H, dd), 7.22 (5H, bs), 7.38 (1H, d
d), 7.88 (1H, dd) MS m / e; 381 (M ⁺ ) melting point (° C); 94-95 (decomposition) Molecular formula; C ₂₂ H ₂₄ F ₃ N ₃ O ₃ .HCl ¹ H-NMR (CDCl ₃ ) δ; 1.56 to 2.80 (12H, m), 3.96 (2H, t), 4.20 to 4.46 (1H,
m), 4.78 (2H, s), 7.90 (2H, d), 6.94 (1H, dd), 7.36
(1H, dd), 7.46 (2H, d), 7.86 (1H, dd) MS m / e; 435 (M ⁺ ) Melting point (℃); Hygroscopic amorphous Molecular _{formula; C 20 H 24 N 4 O} 3 · 2HCl 1 H-NMR (CDCl 3) δ; 1.5~2.9 (12H), 3.96 (2H, t), 4.78 (2H, s), 5.0~5.2
(1H), 6.5-7.6 (5H), 7.84 (1H, dd), 8.05 (1H, dd) MS m / e; 369 (MH ⁺ ) Melting point (° C); oil Molecular _{formula; C 21 H 26 N 4 O} 3 · 2HCl 1 H-NMR (CDCl 3) δ; 1.2~2.9 (12H, m), 3.47 (1H, m), 3.95 (2H, t), 4.63
(2H, s), 4.76 (2H, s), 6.8-7.2 (2H, m), 7.2-7.4 (2
H, m), 7.60 (1H, dd), 7.84 (1H, dd), 8.43 (1H, d) MS m / e; 382 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 22 H 25 F 3 N} 4 O 2 · 2HCl 1 H-NMR (CDCl 3) δ; 1.6~2.9 (12H, m), 3.94 (2H, t), 4.12 (2H, s), 4.37
(1H, m), 5.82 (1H, bs), 6.64 (1H, dd), 6.89 (2H, d),
7.19 (1H, d), 1.45 (2H, d), 7.70 (1H, d) MS m / e; 434 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 22 H 27 N 3 O} 3 · 2HCl 1 H-NMR (CDCl 3) δ; 1.1~2.6 (12H, m), 2.73 (2H, s), 3.98 (2H, t), 5.64
(2H, s), 6.82 (1H, d), 7.20 (5H, s), 8.10 (1H, d), 8.
26 (1H, s) MS m / e; 381 (M ⁺ ) Melting point (° C); amorphous Molecular formula; C ₂₁ H ₂₆ N ₄ O ₃ .3HCl ¹ H-NMR (CDCl ₃ ) δ; 1.6 to 2.9 (12H, m), 3.49 (1H, m), 4.03 (2H, t), 4.65
(2H, s), 4.69 (2H, s), 6.86 (1H, d), 7.15 (1H, t), 7.
3 to 7.8 (2H, m), 8.17 (1H, d), 8.33 (1H, s), 8.49 (1H,
d) MS m / e; 382 (M ⁺ ) Melting point (° C); amorphous Molecular _{formula; C 21 H 26 N 4 O} 2 · 3HCl 1 H-NMR (CDCl 3) δ; 1.80 (2H, m), 2.2~2.6 (10H, m), 3.44 (2H, s), 3.95
(2H, t), 4.60 (2H, s), 6.76 (1H, d), 7.19 (5H, s), 8.
09 (1H, d), 8.26 (1H, s) MS m / e; 366 (M ⁺ ) melting point (C); 197-203 Molecular _{formula; C 15 H 22 N 4 O} 2 · 3HCl 1 H-NMR (CDCl 3) δ; 1.84 (2H, m), 2.27 (3H, s), 2.3~.2.6 (10H, m), 4.00
(2H, t), 4.65 (2H, s), 6.83 (1H, d), 8.11 (1H, d), 8.
29 (1H, s) MS m / e; 290 (M ⁺ ) mp (° C);

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 475/02 C07D 475/02 475/06 475/06 498/04 513/04 381 513/04 381 383 383 383 498/04 112T ( 72) Inventor Mitsutsugu Ueno 3-22-7 Namiki, Tsukuba, Ibaraki Prefecture Corp. Namiki G-102 (72) Inventor Kunizo Higurashi 758, Tsukuba City, Ibaraki Prefecture (72) Inventor Tetsu Nagato 4-10, Kasuga, Tsukuba City, Ibaraki Prefecture ―20 Sejour Kasuga 201 (72) Inventor Ichiro Yoshida 2-23-5 Mekuso Gakuen, Tsukuba City, Ibaraki Prefecture 204-23 (72) Inventor Kazuo Tanaka 1-6-2 Takezono, Tsukuba City, Ibaraki Prefecture 901-503 ( 72) Inventor Akihiko Suyama 470-25 Nendo, Kashiwa-shi, Chiba Pref. 914 Windsor Im Kitakashiwa Garden 914 (72) Inventor Takaki Kagaya 4-10-20 Kasuga, Tsukuba, Ibaraki Prefecture 4-10-20 Sejour Kasuga 205 (72) Inventor Mariko Koshi 3322-7 Kashiwada-cho, Ushiku City, Ibaraki Prefecture (72) Inventor Isao Saito 670-63, Hirooka, Tsukuba City, Ibaraki Prefecture (72) Inventor Kiyomi Yamazu 1-8-14 Takezono, Tsukuba City, Ibaraki Prefecture 906-313 (56) References JP-A-61-40264 (JP, A) JP-A-60-166674 (JP, A) USSR patent invention 534073 (SU, A) USSR patent invention 562982 (SU, A) (58) Fields investigated (Int.Cl. ⁶ , DB name) C07D 475/04 C07D 475/02 C07D 475/06 C07D 498/04 C07D 513/04 A61K 31/495 A61K 31/505 A61K 31/54 A61K 31/55

Claims (2)

(57) [Claims] (1) General formula [In the formula, A ¹ and A ² represent the same or different carbon atoms or nitrogen atoms. However, at least one is a nitrogen atom. R ¹ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a formula (Wherein, R ⁴ and R ⁵ represent the same or different hydrogen atoms or lower alkyl groups) or a halogen atom. W is the formula (Wherein R ⁶ represents a hydrogen atom), a group represented by the formula -O-
A group represented by or a formula (Where p represents 0 or an integer of 1 to 2). -B- is the formula Means a group represented by E is the formula Ｕ In the formula, u means 1. X is a group represented by the formula — (CH ₂ ) _n — (wherein n represents an integer of 2 to 8); (Wherein m represents an integer of 2 to 8). Y and Z are the same or different nitrogen atoms or formulas (Wherein R ⁸ represents a hydrogen atom or a hydroxyl group), at least one of which is a nitrogen atom. r represents 2, and s represents an integer of 2 to 3. R ⁷ is: (1) a lower alkyl group, (2) a formula —JK (wherein J is a formula — (AlK) _a — (where a represents 0 or 1 and Alk represents 1 to 6 carbon atoms) linear or branched group represented by alkylene group means a), formula -O- (CH _{2) b} of - (groups represented by b is 0 or an integer of 1 to 3 in the formula),
formula A group represented by the formula (Wherein R ⁹ represents a hydrogen atom or a lower alkyl group, and Q represents an oxygen atom or a sulfur atom). (Wherein R ¹⁰ represents a hydrogen atom or a lower alkyl group;
Means an oxygen atom or a sulfur atom means a) a group represented by, or formula -CH ₂ -CH = CH- group represented by the. K is the formula (Wherein, R ¹¹ and R ¹² are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group,
A lower alkoxy group or a cyano group); (Wherein R ¹³ represents a hydrogen atom or a lower alkyl group)
A group represented by the formula (Wherein R ¹⁴ represents a hydrogen atom or a lower alkyl group)
A cycloalkyl group, a furyl group, a thienyl group, or a heterocyclic group comprising a 5- to 6-membered ring containing two nitrogen atoms). (3) Formula -LM ( In the formula, L is a group represented by — (CH ₂ ) _c — (where c represents an integer of 1 to 3), a group represented by the formula —CH ₂ —CH ＝ CH—, a formula — (CH ₂ ) groups represented by _d -O- (d is an integer of 1 to 3 in the formula), or formula _{- (CH 2) e -NH- (} CH 2) f
-(Wherein e and f mean an integer of 1 to 3). M represents a phenyl group or a heteroaryl group having 1 to 2 nitrogen atoms), a group represented by｝, and a compound having a condensed heterocyclic ring represented by the formula: Physically acceptable salts. 2. A central muscle relaxant comprising, as an active ingredient, the compound having a fused heterocycle according to claim 1 or a pharmacologically acceptable salt thereof.