JPH03118380A - Compound having condensed hetero ring - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {A<1> and A<2> are C or N provided that at least one is N; R<1> is H, OH, lower alkoxy, etc.; R<2> and R<3> are H, lower alkyl, aryl or arylalkyl; W is group of formula II (R<6> is H or lower alkyl), -O-, etc.; -B- is group of formula III, etc.; E is group of formula IV [u is 0 or 1; X is -(CH2)n (n is 2-8), etc.; Y and Z are group of formula V (R<8> is H or OH); r and s are 1-3; R<7> is H, lower alkyl, etc.]}. EXAMPLE:4-Ethoxy-5-[3-(4-benzylpiperazin-1-yl)propyl]pyrimido[4,5- b][1,4]thiazin-6(7H)-one dihydrochloride. USE:Central muscle relaxant. PREPARATION:A halogenated compound of formula VI (Hal is halogen) is made to react with a compound of formula VII in the presence of an acid acceptor such as potassium carbonate at 0-60 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a compound having a fused hederocycle that has excellent medicinal effects. More specifically, the present invention relates to a compound having a fused heterocycle having a central muscle relaxing effect.

[Background of the invention and prior art]

Various central muscle relaxants are used to improve muscle tone in conditions such as cervicobrachial syndrome, glenohumeral periarthritis, and low back pain, as well as to treat spastic paralysis associated with cerebrovascular disorders and spinal cord paralysis. There is. However, when used to treat spastic paralysis caused by spinal cord diseases, the effects are either too weak or too strong, resulting in many side effects, and the reality is that there are very few effective drugs. In addition to central muscle relaxants, cerebral circulation and metabolism improving agents, analgesics, and minor tranquilizers are also used, but there are almost no effective drugs. This is probably due to the fact that the pathophysiology of spastic paralysis is largely unknown.

In view of these circumstances, the present inventors have spent many years conducting intensive studies on compounds that have excellent effects on subjective symptoms associated with hypertonic states and are also more effective against spastic paralysis.

As a result, the inventors discovered that pyrimidothiazine derivatives, which will be described later, and the like, which have a structure different from conventional compounds having a muscle relaxing effect, can achieve the desired purpose, and have completed the present invention.

[Structure and effects of the invention]

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

[In the formula, AI and A2 mean the same or different carbon atoms or nitrogen atoms. However, at least one of them is a nitrogen atom.

R1 represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a 1-atomic atom or a lower alkyl group, or a halogen atom.

R2 and R3 mean the same or different hydrogen atoms, lower alkyl groups, aryl groups or arylalkyl groups.

6 W is a group represented by the formula -L- (in the formula, R6 means a hydrogen atom or a lower alkyl group), and the formula -0- (jlj).

or a group represented by formula-3- (in the formula, r] means 0 or an integer of 1 to 2).

means a group represented by

(In the formula, U means 0 or 1. X is the formula (C11□)
A group represented by h- (in the formula, n means an integer of 2 to 8) 2 1 , or a group represented by the formula -(CH2), -C- (in the formula, m means an integer of 2 to 8) means base.

8 Y and Z are the same or different nitrogen atoms or the formula -〇 (in the formula R
8 means a hydrogen atom or a hydroxyl group).

Both r and s mean an integer of 1 to 3.

R7 is (1) a hydrogen atom, (2) a lower alkyl group, [3) the formula -J-K (wherein J is the formula -(Alk), -(in the formula, a means 0 or 1, and Alk is a straight-chain or branched alkylene group having 1 to 6 carbon atoms), a group represented by the formula o-(cH2)b
A group represented by - (in the formula, 1 means O or an integer from 1 to 3), a 3-alkyl group represented by the formula -〇-, and 0 represents an oxygen atom or a sulfur atom R" 0 1 meaning), a group represented by the formula -N-C- (in the formula RIG
means a hydrogen atom or a lower alkyl group, Ω means an oxygen atom or a sulfur atom), or a group represented by the formula -CH
2-[:ll means a group represented by CI+-.

are different hydrogen atoms, halogen atoms, lower alkyl groups,
halogenated lower alkyl group, lower alkoxy group or cyano group) means a lower alkyl group), quaternary alkyl group), cycloalkyl group, furyl group, thienyl group, or a heterocyclic group consisting of a 5- to 6-membered ring containing two nitrogen atoms), (4) Formula -!, -M <In the formula -(CH2)c - (wherein C means an integer of 1 to 3), a group represented by the formula -CH2-CH=CH, a group represented by the formula -(CH2)d-0 (wherein d is an integer of 1 to 3), means an integer) or a group represented by the formula (CH2).-
NH-(CH2) means a group represented by -<where e and f mean integers of 1 to 3). In the above definition of the present invention, R2, R', R',
R5゜R6, R7t R9t RIG, R port 1112
．． The lower alkyl group found in RI3 and 1t14 refers to 1 to 6 straight or branched alkyl groups, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 5ec-butyl group, tert-butyl group, pentyl group (amyl group), impentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1- Methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1
．． l-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, 1.2.2-) dimethylpropyl group, ■-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, etc. Among these, preferable groups include methyl group, ethyl group, propyl group, isopropyl group, and the like.

The lower alkoxy group in the definitions of R1, R11, and RI2 means 6 lower alkoxy groups derived from the above lower alkyl groups such as methoxy group, ethoxy group, and n-propoxy group, and among these, the most preferred group is can include a methoxy group.

Moreover, the halogen atom found in RJIJ+2 specifically means, for example, a chlorine atom, a bromine atom, a fluorine atom, and the like.

The aryl group seen in the definitions of R2 and R3 means, for example, substituted or unsubstituted phenyl group, naphthyl group, etc., and the arylalkyl group means, for example, benzyl group, phenethyl group, etc.

The halogenated lower alkyl group seen in the definition of R11, 1lI2 means a halogenated lower alkyl group derived from the above-mentioned lower alkyl group.

A typical example is a trifluoromethyl group.

A', A2. Although W and B are shown in the above definitions, specifically preferred condensed rings are as follows.

8 B Among the above, the most preferred condensed ring is the pyrimidothiazine ring (1), and the next preferred condensed ring is the pyridinothiazine ring (4).

(0).

The group represented by formula-3- (in the formula, p means O or an integer of 1 to 2) in the definition of IW specifically means a group represented by the following formula.

9 refers to the group represented by 9. Specifically, in terms of the condensed ring in (1) above, it refers to the following two rings.

In the definition of Snake, X is the formula -(CL). -(in the formula, n is 2
means an integer of ~8) or a group represented by the formula -(CH2
), -C- (in the formula, m means an integer of 2 to 8), and as a preferable group, n and m are each preferably 3 to 7, especially n The most preferable case is 3.

6 Y and Z are the same or different nitrogen atoms or the formula -〇 (in the formula R
8 means a hydrogen atom or a hydroxyl group). Moreover, r and s both mean an integer of 1 to 3. Specifically preferred formula % Formula % R7 is as defined above, but preferred groups are as follows.

In (a) to (e) above, a is 0 or 1, b is 0 or an integer of 1 to 3, and ^lk represents a straight or branched alkylene group having 1 to 6 carbon atoms; The most preferred case is when a=1 and Alk is a methylene group, or when b is 1.

RIJ12 means a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, or a cyano group. Among these, it is most preferable when RIJI2 is a hydrogen atom, when R1 is a lower alkoxy group, preferably an ethoxy group or a methoxy group, especially a methoxy group, and when RI2 is a hydrogen atom.

A preferred compound group in the present invention is the following general formula (II
).

In the above general formula (n) (wherein R' and B have the above-mentioned meanings), R1 is most preferably a hydrogen atom or a lower alkoxy group.

Among the lower alkoxy groups, ethoxy and methoxy groups are preferred, with methoxy being the most preferred.

(In the formula, X, Y, r, s, Z, R7, u have the above meanings) is preferable,
In this formula, X is preferably a group represented by -((J12)h- (in the formula, n means an integer of 2 to 8). Regarding Y and Z, both Y and Z are When it is a nitrogen atom, it is preferable that Y is a nitrogen atom and Z is the formula, but the most preferable case is that both Y and Z are nitrogen atoms. r and s are both 1 to 3. Although it means an integer, the most preferable case is when r and s are both 2.Y.

When Z is both a nitrogen atom and r and s are both 2, a piperazine ring is formed.

24 R7 is preferably a group represented by the formula -J-K (in the formula, J has the above-mentioned meaning). In this case, J is the expression −
The most preferred group is (Alk), - (in the formula, Alk and a have the above meanings).

Among these, preferable groups include groups represented by the formula -CH2CH2 CH2-Cl12-, -CH2-CH2-CH2- or -C112-CH-CH2. K is preferably a group represented by the formula R13 having the above meaning.

In the above, the most preferable groups are as follows.

(means alkoxy group) Among lower alkoxy groups, preferred groups =25 include ethoxy group and methoxy group, but
Most preferred is a methoxy group, among which is an 0-methoxy group.

In the present invention, pharmacologically acceptable salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate; for example, acetate, maleate, fumarate, tartrate;
Organic acid salts such as methanesulfonate, benzenesulfonate, toluenesulfonate, or e.g. arginine,
Examples include salts with amino acids such as aspartic acid and glutamic acid.

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

Manufacturing method 1 When u, Z, R' have the above-mentioned meanings), it can be manufactured by the following manufacturing method.

6 X-flaal + (in a series of formulas, A', A', W, B, R',
R', R3, X, Y, Z, r, s.

u and R' have the above-mentioned meanings, and I (al means a \\rogen atom). That is, the halogenide represented by the general formula (III) is converted into the halogenide represented by the general formula (IV) by a conventional method. By condensation with the compound represented by formula (V), the target substance represented by general formula (V) is obtained.

Halogen means chlorine, bromine, iodine, etc.

Preferably, this reaction is carried out in the presence of a deoxidizing agent. Examples of deoxidizing agents include alkali metal carbonates or hydrogen carbonates such as potassium carbonate, sodium carbonate, and sodium hydrogen carbonate, alkali hydroxides such as potassium hydroxide, pyridine, and triethylamine. Examples include bases such as organic amines.

Examples of the solvent used in the reaction include alcohols such as methyl alcohol and ethyl alcohol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, and mixtures 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 a series of formulas, ^', A2. W, B, R',
R2, R', K, Y, Z, r, s.

u and R' have the above-mentioned meanings, Hal means a halogen atom) That is, in the same manner as Production Method 1, the compound represented by the general formula (Vl) is converted to the compound represented by the general formula (■). The compound is subjected to a condensation reaction with a halide to obtain a compound represented by the general formula (V), which is the target substance.

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

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

0 X-fla l (in a series of formulas, AI, 82. III, B, R',
(R2, R3,

Examples of pharmacological experiments (ischemic decapitation) 1. Experimental method Male Wistar rats (300-500 g
Charles River) was used. The rat was fixed in the dorsal position under halothane anesthesia, and the neck was incised. After inserting a tracheal cannula, the esophagus was double ligated and cut. Thereafter, a hole with a diameter of 4 mm was made in the occipital bone using a dental drill, and the dura mater was incised. The basilar artery was ligated with a nylon thread under a surgical microscope, and then the blood flow in both common carotid arteries was blocked with a ligature, and the anesthesia was discontinued.

As the animal recovered from halothane anesthesia, surface lines appeared on its forelimbs, neck, hindlimbs, and wet areas. To measure the surface line = 31-, two enameled wires with a diameter Q and 2 mm were inserted into the biceps brachii muscle of the forelimb to induce bipolar muscle discharge. moreover,
The electromyogram is output to an oscilloscope (VC9, Nihon Kohden) and simultaneously processed by a medical data processing device (ATAC-450, Nihon Kohden), and the firing frequency per unit time is calculated by
- Recorded on a Y plotter (7225^, Hewlett Paracard). The test compound was administered at a dose of 0.1 d per 100 g of body weight through a catheter inserted into the femoral vein.

2. Experimental results It is shown in Table 1.

In Table 1, the minimum effective dose mg/kg, i, v means the minimum concentration at which each test compound, which is a compound of the present invention, relaxes the surface line.

32 Table ■ 33 Table (Continued) 4 Table 1 (Continued) 5 The above pharmacological experimental examples show that the compound of the present invention has a significantly lower effect on rat anemic brain lines (spastic paralysis model) than the control drug eperisone. It was found to have excellent medicinal efficacy.

In addition, representative compounds of the present invention (compounds N01 and No.
, 5), an acute toxicity test was conducted using male Wistar rats, and there were no deaths at an oral dose of 300 mg/kg.

Therefore, the compound of the present invention has an excellent muscle relaxing effect, and based on this effect, it can be used to treat, for example, cerebrovascular disorders, spasticity, spinal palsy, etc.
It is effective in treating and improving spastic paralysis caused by spinal cord diseases such as cervical spondylosis and after-effects of trauma, and in treating and improving muscle tension caused by cervico-shoulder-brachial syndrome, shoulder periarthritis, and low back pain. Furthermore,
Since the compound of the present invention is highly safe as described in G above, the value of the present invention is high.

When the compounds of the present invention are used as these medicines, they are administered orally or parenterally, but they are usually administered intravenously, subcutaneously, intramuscularly, etc., or parenterally, such as suppositories or sublingual tablets. administered. The dosage depends on the severity of the symptoms; the age of the patient;
Gender, body weight, sensitivity differences; administration method; administration timing, interval,
It varies depending on the nature, preparation, type of pharmaceutical preparation; type of active ingredient, etc., and is not particularly limited, but it is usually about 0.1 to 500 mg, preferably about 1 to 100 mg, and more preferably 5 to 50 mg per day for adults. This is usually administered in 1 to 4 divided doses a day.

In order to formulate a compound of the present invention, it is prepared into a dosage form such as an injection, a herbal medicine, a sublingual tablet, a tablet, or a capsule by a conventional method in the field of pharmaceutical preparation.

When preparing injections, add pH adjusting agents, buffering agents, suspending agents, solubilizing agents, stabilizers, isotonic agents, preservatives, etc. to the herbal medicine as necessary, and administer intravenously, using a conventional method. It is administered as a subcutaneous or intramuscular injection. At that time, if necessary, it is also possible to freeze-dry it by a conventional method.

Examples of suspending agents include methyl cellulose, polysorbate 80, hydroxyethyl cellulose,
Examples include gum arabic, tragacanth 7 powder, sodium carboxymethyl cellulose, and polyoxyethylene sorbitan monolaurate.

Examples of solubilizing agents include polyoxyethylene hydrogenated castor oil, polysorbate 80. Examples include nicotinic acid amide, polyoxyethylene sorbitan monolaurate, magrogol, and castor oil fatty acid ethyl ester.

In addition, as a stabilizer, for example, sulfite, IJum,
Examples of preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.

〔Example〕

Examples of the present invention will be listed next, but it goes without saying that the present invention is not limited to these.

In addition, the target compound of the present invention is given as an example, and the manufacturing method of the starting material for producing the target compound is also given as a production example prior to the example.

Production Example 1 40 g of 5-day-pyrimide (4,5-b) [:l, 4:]thiazin-6(7H)-one was suspended in 300 g of dimethylformamide, and while stirring, sodium hydride (6
0%) at room temperature. After 1 hour and 20 minutes, the reaction mixture was cooled on ice, and 122 g of dibromopropane was added dropwise over 40 minutes. After the addition was completed, the mixture was stirred at room temperature for 1 hour and 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine 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.

9 ・Melting point (t); 75-77 ・Molecular formula; C22H29N502S ・'H-NMR (CDCl2) δ; 1.91-2.
31 (211,m), 3.31 (211t).

s), 4.03 (211, t), 4.09 (3
H,s)-MS m/e; 317/319 (M+)
Example 1 3.40(2+1 4-methoxy-5-(3-bromopropyl)pyrimide(
4,5-b) 4-ethoxy-5-(3bromopropyl)pyrimide (4,5-b) (1,4J thiazin-6) synthesized in the same manner as [1,4]thiazin-6(78)-one
After reacting 37 g of (7H)-one with 35 g of l-benzyl-piperazine in the presence of 50-triethylamine in dimethylformamide for 12 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography and recrystallized from ethyl acetate. This was converted into a hydrochloride salt according to a conventional method, and 28 g (yield: 56%) of the title compound as colorless crystals was obtained from ethanol-ether.

・Melting point (t); 219-221.5 ・Molecular formula: C
22H29N502S・211C・'H-NMR (CD
Cl2) δ; 1.44 (], t), 1.68 (2
H, u), 2.10-2.50 (1ON, m), 3
．． 4 (2H, s), 3.45 (2H, s), 4
．． 02 (2H, t), 4.50 (2H, q), 7.
24 (5tl, s>, 8.24 (IH, s) -MS m/e; 427 (M”) Example 2 N dihydrochloride 4-methoxy-5-(3-bromopropyl)pyrimide C
4,5-b) 9.54 g of [1,4)thiazine-6(7N)-mene was dissolved in 9.5 g of N-(2-methoxybenzyl)piperazine in the presence of triethylamine in dimethylformamide.
27 g! After reacting overnight, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate-diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, converted into a hydrochloride salt 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 (t); 166-168 (decomposition) ・Molecular formula;
C22H29N503S・2+1CI2 ・'H-NMR (CDCI,) δ; 1.72 (2)
1. q), 2.15 to 2.65 (IOH, m),
3.40 (2H, s), 3.63 (2ft, s)
, 3.80(3)1. s), 3.99(2f(
, t), 4.03(3)1. s), 6.86(
21(,t), 7.24(2H,ddd),
8.26 (IH,s)・MS m/e; 444(
MH”) Example 3 N dihydrochloride 4-methoxy-5-C3-(4-orthomethoxybenzylpiperazin-1-yl)propyl]pyrimide[4,5
-b) [:1.4]thiazine-6(711)-one
Dihydrochloride 1. Add 10% hydrochloric acid-ethyl acetate (10%) and 0.5% water to Ong and heat to reflux. After evaporating the solvent under reduced pressure, the residue was recrystallized from methanol-dichloromethane diethyl ether to give 0.46 g of the title compound as colorless crystals.
(yield 68%).

・Melting point (t"); 144 (decomposition) ・Molecular formula: C2+H2tNsO+S・2+1CI・'
H-NMR (DMSO-66) δ; 1.60-2
．． 60 (12H, m), 6.70-7.40 (4H,
m).

7,85 (18,s) -MS m/e; 430 (M+1)"Example 4 Methoxy (3 Bromopropyl) A Pyrimide C4.5-b]Cl, 4j Thiazine-6
(7H)-one5. 00 g of sodium iodate in aqueous methanol 15. 00 g and stirred overnight. 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.

Obtained 4-methoxy-5-(3bromopropyl)pyrimide [:4.5-b] (1,4)thiazine-6 <7
H)-one-8-oxide in the presence of triethylamine in dimethylformamide (N(2-(methoxybenzyl))
piperazine 1. After 50 g was reacted and stirred for 4 hours, saturated brine was added to the reaction solution, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. 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; C22H29N504S ・'H-NMR (CDCI3) δ; 1,60 ~1
．． 97 (2H, m), 2.00-2.50 (108,
m).

5 3, 52 (21(, s), 3. 58~3
, 82 (4N, m), 3.98~4, 28 (6tl
, m), 6.84 (2H, t), 7.04 ~
7.30 (2/fl, m), 8. 52 (l
tl, s) - MS m/e; 459 (M") Example 5 Synthesis of 46 1.97 g of thiazin-6(7H)-one was dissolved in 20-tetrahydrofuran and 5-dimethylformamide, and dissolved in sodium hydride ( 60% oil disversion)
Add 0.42 g at room temperature under nitrogen atmosphere. After stirring at room temperature for 45 minutes, a solution of 2.58 g of 1,7-dibromohebutane in 5-tetrahydrofuran is added, and the mixture is stirred at room temperature for 6 hours. Saturated brine (25) was added to the reaction solution, and ethyl acetate (1
00mff, 50m1! X 2 ), and the organic layer was washed with 25 parts of water and 25 parts of saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2.
84 g (yield 75.9%) was obtained.

・'H-NMR (CDCl2) δ; 1, 16
~1.94 (1011, m), 3.36 (2H, t,
d=7tlz).

3.43 (2H, s), 3.95 (2H, t, d=7
Hz), 4.06 (3H, s), 8.31 (IH,
s) 7 4-methoxy-5-(7-bromoheptyl)pyrimide obtained with dihydrochloride (a) C4,5-b) [:1. 1.0 g of Uthiazin-6(7H)-one and 0.48 g of 1-benzylpiperazine were dissolved in dimethylformamide 15-
Add 0.68 g of triethylamine and react at 50°C for 6 hours. The reaction solution was diluted with 50% water, extracted with ethyl acetate (50mfX4), and the organic layer was diluted with water and saturated brine (
After washing with 20-X2.20 m water, drying with magnesium sulfate, and evaporating the solvent under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4-methoxy5-[7-(
1.16 g (yield 78.9%) of 4-benzylpiperazin-1yl)heptyl]pyrimide(4,5-b)[1,4)thiazin-6(7H)-one was obtained.

8 to give a hydrochloride salt using a 1:5 method, and recrystallization from ethanol-ethyl acetate gave 1.05 g of the title compound as white crystals.

・Melting point (t); 171-174 ・Molecular formula; C25l13sNsLS・2H[:1・'
H-NMI (CDCl2) δ; 1.00-1. ，
60 (10H, m), 2.08-2.64 (IOH,
m).

3.40 (2H, s), 3.48 (2H, s), 3
．． 92 (2N, t).

4.03 (3H, s), 7.04 (5H, br s)
, 8.28(IH,s)・MS m/e; 469
(M') Example 6 9 4-Methoxy-7,7-dimethyl-5H-pyrimide (4
,5-b) 0.2 g of (1,4:]thiazin-6(7H)-one is suspended in dimethylformamide 3- and 0.043 g of sodium hydride (60%) is added at room temperature with stirring. 20 minutes later dibromopropane 0.355 g
and stirred at room temperature for 12 hours.

Water is added, extracted with ethyl acetate, and the organic layer is washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 2:1) gave the title compound 0.2
1 g (68% yield) was obtained.

・') I-NMR (CDCl2) δ; 1.46 (6
H,s), 1.97-2.3H2H,m), 3.3
750- (2H, t).

3.91-4.14 (5H, m).

8, 37 (1)1. s) Synthesis of salt 4-methoxy-7,7-dimethyl-5-(3bromopropyl)-7,7-dimethylpyrimide C4,5-b) [
1,4:]thiazin-6(7H)-one 0,21 g in dimethylformamide 3mi! Add 0.16 g of 1-(orthomethoxybenzyl)piperazine and 0.3 ml of triethylamine, and stir at room temperature for 18 hours.

Water is added, extracted with ethyl acetate, and the organic layer is washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography 1-(dichloromethane:methanol-95:5),
0.14 g (49% yield) of free base was obtained. The title compound was converted into a hydrochloride salt using a conventional method, and the title compound was obtained as colorless crystals from isopropanol-isopropyl ether.

・Melting point (t); 189-190 ・Molecular formula; C2J3JsOiS・2■C!・'H-NM
R(CDCl2) δ; 1.44 (6H, s), 1
．． 54-1.86 (2H, m), 2.00-2.60
(IOH, m), 3.55 (2) 1. s), 3.8
1 (3H, s).

4.00 (2N, t), 4.05 (3)1. s),
6.76-7.42 (4) 1. m), 8.33 (IH
,s)・MS m/e; 471 (M+) Example 7 2 (a) Cuchlorotoxyxylopyrimidine 9.4 g of 4,6-dichloro-5-nitropyrimidine in 100 ml of methanol! Add 2.6 g of sodium methoxide, and stir 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 obtain 2.8 g of the title compound.

・'H-NMR (CDCl2) δ; 4, 12 (3N
,s), 7.20(ltl,S), 8.56(IH
,s)3 2.5 g of 4-chloro-6-methoxy5-nitropyrimidine obtained in (a) and glycolic acid methyl ester1.
3 g was dissolved in 40 m+' of dimethylformamide, 5.2 g of potassium carbonate was added, and the mixture was stirred at 60°C for 5 hours.

After the reaction, the mixture was poured into dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain the title compound. 93g
Obtained.

・'LNMR (CDC1.) δ; 3, 75 (2H.S), 4.07 (3H, s), 7
．． 21 (IH, s).

8, 35 (IH, S) Dissolve 0.93 g of 2-(4-methoxy-5-nitropyrimidinyl-6-oxy)methyl acetate 4 ester obtained in (b) in 30 ml of methanol,
Add 0.5 g of 10% palladium-carbon (water content 50%) and hydrogenate at room temperature at 3.5 kg/cm2 for 1 hour.
Do minutes. After the reaction is complete, the solid is filtered off and the solvent is distilled off under reduced pressure. The residue was dissolved in 30 liters of ethanol, added with 1-liter of concentrated hydrochloric acid, and heated under reflux for 20 minutes.

After the reaction was completed, the solution was concentrated to about 100 ml, and 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.

・'H-NMR (DMSO-d6) δ; 3.91 (
3H,s), 4.77(2M,s>, 8.03(I
H,s).

10,62 (LH,bs) 0.62 g of 4 methoxyH pyrimide 5 [4,5-b][1,4)oxazin-6(7H)-one obtained in (C) was added to 30 ml of dimethylformamide. Add IJium (dissolved and hydrogenated to 60%) and heat under nitrogen stream for 6 hours.
The mixture was extruded at 0° C. for 2 hours, then returned to room temperature, 5 g of 1,3-dibromopropane was added, and the mixture was further stirred for 2 hours. Pour the reaction solution into water, extract with ethyl acetate, wash with saturated saline, and add anhydrous magnesilla sulfate!・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.

・'H-NMR (CDC1,) δ; 2.17 (2H
, m), 3.38 (2H, t), 4.07 (3H,
s).

4.12 (21, t), 4.69 (2H, s), 8
．． 15(Ift, s) 56 (d) 4-Methoxy-5-(3-bromopropyl)pyrimide(4,5-b) (1,4)oxazin-6(71()-one0. 4 g of N-benzylpiperazine and 0.8 g of N-benzylpiperazine were dissolved in 20-dimethylformamide, 1.2 g of triethylamine was added thereto, and the mixture was left overnight at room temperature.

The reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure. Separation and purification by silica gel column chromatography gave 0.35 g of the title compound. Prepare the hydrochloride using the usual method.

・Melting point (t); 240-244 (decomposition) ・Molecular formula;
Cz+LJsOa・2HC1・'H-NMR (CDCl
2) δ; 1.70 (2H, m), 2.00-2.
50 (1ON, m), 3.45 (2H, S), 4.
02 (38, s), 4.08 (2H, t), 4.6
5 (2H, s), 7.23 (5H, s), 8.1H
1 tl, s)・MS m/e; 397 (M”) Example 8 4-dimethylamino-5-cinnamyl-5,6,7°7
- Synthesis of Chil 4. Glycine ethyl ester hydrochloride 3 in a mixture of 47 g 6-dichloro-5-nitropyrimidine 1 65 g sodium bicarbonate 250 mf diethyl ether and 100 mf water
6 g of an aqueous solution 100- is added dropwise under water cooling. After the dripping is finished,
Stir at room temperature for 7 hours and add chloroform 11. Water 30 (lr
Add 8 mL of organic layer, separate the organic layer, wash with water, and dry with magnesium sulfate. The solid obtained by evaporation of the solvent was recrystallized from dichloromethane-isopropyl ether to give 44 g of N-(4-chloro-5-
Nitropyrimidin-6-yl)glycine ethyl ester was obtained.

Next, this N-(4-chloro-5-nitropyrimidine-6
3.0 g of glycine ethyl ester is dissolved in 40-dimethylformamide, and 2.0-g of a 50% diethylamine aqueous solution is added dropwise under water cooling, followed by stirring for 2 hours while maintaining the temperature at 5°C.

The reaction solution was poured into ice water, and the precipitate was collected by filtration, washed with water, and dried to obtain 3.1 g of the title compound.

◇' H-NMR (CDCI 3) δ; 1.32 (
3)1. t), 3.10 (6t(,s), 4.1~
4.4(48), 8.06(LH,s) 59- N-(4-dimethylamino 5-nitropyrimidin-6-yl)glycine ethyl ester obtained in (a) 3.1
Dissolve g in 50% of tetrahydrofuran and add palladium
Add a catalytic amount of carbon and heat at room temperature under a hydrogen pressure of 3 kg/cm2.
Hydrogenate for an hour.

After the reaction is completed, the catalyst is filtered off, and the mother liquor is concentrated. 3 ml of ethanol 30-1 concentrated hydrochloric acid is added to the resulting residue, and the mixture is treated at room temperature for 30 minutes and at 40° C. for 10 minutes.

The reaction solution was cooled, 100 i of isopropyl ether was added, and the precipitate was collected by filtration, resulting in 4-dimethylamino-5,6,
2.6 g of 7,8-tetrahydropyrimide C4,5-b) pyrazin-6-one hydrochloride were obtained.

Next, this compound was mixed with 18-1 g of dimethylformamide.
18-1H, 0.9 g of sodium hydride rum (60% oil dispersion)
Add and stir at room temperature for 1 hour. Cinnamyl chloride 1.6g
After stirring again at room temperature for 3 hours, the reaction solution was poured into water, extracted with dichloromethane, washed with water, and dried with magnesium sulfate. Add isopropyl ether to the residue after evaporation of the solvent to solidify, collect by filtration, and dry to obtain 2.0 g of the title compound.
I got it.

To prepare the hydrochloride, 10 ml of ethyl acetate dissolved in hydrochloric acid is added to the ethanol solution, and diethyl ether is added to precipitate crystals, which are collected by filtration.

・Melting point (t); 193-196 (decomposition) ・Molecular formula:
C+JIJs0・2+1[:1・'II-NMR(C
DCI3+DMSO-d6) δ; 2.94 (3H,
s), 3.04 (3B, s), 3.86 (2N
, m).

4.60 (2H, d), 5.84 (If (, dt)
, 6.35 (2H, d).

7.20 (5H, s), 7.92 (18, s)・M
S m/e; 309 (M”) Example 9 1-5,6.7.8-Tetrahydropteridine trihydrochloride 1 (4-methoxy-(5H)-6-oxo-5,6,7,
0.475 g of 8-tetrahydropteridine was dissolved in dimethylformamide 30- and HMPA15-, 0.107 g of 60% sodium hydride was added, and the mixture was heated for 55 g under a nitrogen stream.
After stirring at °C for 1 hour, 10 g of 1,3-di2-bromopropane was added while cooling with water, 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 purified by silica gel column chromatography to obtain the title compound. .45 g was obtained.

・' H-NMR (CDCl 3) δ; 2.17 (
2H, m), 3.37 (2H, t), 4.00 (5
ft, s).

4.12 (2tl, t), 5.63 (IH, bs),
7.97(1N,5)N-benzylpiperazine 0.7
g)! j Ethiamine 5g to dimethylformamide 2
Add 0.45 g of 4-methoxy-5-(3-bromopropyl)-6-oxo-5,6°7.8-tetrahydropteridine obtained in (a) and stir at room temperature. Leave overnight. The reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound. Constitute the hydrochloride using the usual method.

・Melting point (t); 203-210 ・Molecular formula: C21H28N602・3ICI・' 1
1-NMR (CDCl3) δ; 1.78 (2N,
m), 2.1-2.4 (IOH, m), 3.45 (
2)1. s), 3.96(5)I, s), 4.03
(2H, t), 7.12 (6H, s), 7.92 (
LH,s)-MS m/e; 396 (M+) [1,4) Thiazin-2(3N)-one dihydrochloride 4 Synthetic 160 g of powdered potassium hydroxide and 500 g of dimethyl sulfoxide were mixed at room temperature. Stir for 30 minutes and add 85 g of N-benzoyl-4-piperiditul (N-benzoyl-4
300 d of a dimethyl sulfoxide solution of -obtained by treating piperidone with sodium borohydride is added, and the mixture is stirred for 20 minutes at room temperature. Next, 68 g of 2-picolyl chloride hydrochloride was added and stirring was continued for 15 hours, then 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 purified using silica gel column Chromadog 5. Separation and purification using Roughy gave 81 g of an oily substance.

This compound was heated under reflux with 200 mf of 25% hydrochloric acid for 1 hour, poured into ice water, the aqueous layer was washed with ethyl acetate, made alkaline by adding aqueous caustic potassium solution, and dichloromethane was added for 3 hours.
Extract times. 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-NMR (CDCl2) δ; 1.2-2.2 (4H), 2.4-2.8 (2N)
, 2.9-3.2 (2H), 3.3-3.7 (
IH), 4.64 (2H, s), 7.0-7.
8 (3tl), 8.46 (IH, br d) (Cl
12) 3-Dr 1H-pyrido[2,3 b] (1,4]thiazin=66 (3H)-one 4.6 g was dissolved in dimethylformamide 150
Add 0.1 g of oil dispersion containing sodium hydride (60%) at room temperature, stir for 30 minutes, and add 17.0 g of 1,3-dibromopropane all at once. After stirring at room temperature for 3 hours, The reaction mixture obtained by pouring into ice water and performing usual post-treatment was purified by silica gel column chromatography to obtain 6.3 g of the title compound.

・') I-NMR (CDC1,) δ; 2.22 (2
tl, dd), 3.40 (2N, t), 3.50 (
2fl, s).

4.08 (2H, t), 7.12 (IH, dd),
7.40 (IH, dd).

8,14 (1N, dd) 67 4-(2-picolyloxy)piperidine obtained in (a) 4
．． Dissolve 6.3 g of 1-(3-bromopropyl)pyrid (2,3-b) [1,4) thiazin-2 (3 days)-one obtained in 7.0 g of dimethylformamide and dilute with triethylamine 6. .2mf! Add and leave at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 5.7 g of the title compound.

Hydrochloride salt (amorphous) can be obtained by passing through the column.

・Molecular formula; C21H26N402S・2+1CI・'
H-NMR (CDC1,) δ; 1.4-2.8 (4
2tl, m), 3.2-3.6 (IH, m).

3.48 (211, s), 3.98 (211, t),
C62 (2H, s).

7.00-7.70 (5H, m), 8.12 (lit
, m), 8.44 (1N, m) -MS m/e; 398 (M+) 8 8.0 g of 2-vinylpyridine and 6.3 g of 4-(2-hydroxyethyl)piperidine were mixed and heated under a nitrogen atmosphere. 80
Heat at ℃ for 10 hours. The reaction mixture is cooled, 100-chloroform is added thereto to form a solution, 5 ml of thionyl chloride is added, and the mixture is left at room temperature for 15 hours. Then, the reaction solution is poured into ice water, made alkaline by adding an aqueous sodium hydroxide solution, and extracted with chloroform. After drying the chloroform layer over magnesium sulfate, the solvent was distilled off, and the resulting mixture was separated and purified by silica gel column chromatography to obtain the title compound 9 as an oil. Obtained Og.

IH-pyrido C2,3-b) was added to a solution of 0.25 g of sodium hydride (oil dispersion containing 60%) and dimethyl sulfoxide 10- treated at 55°C for 1 hour.
, 4) A solution of 1.0 g of thiazin-2(3H)-one in 13 mff of dimethyl sulfoxide was added, stirred for 1 hour, and then DJ-(2-(2pyridyl)ethyl]- obtained in (a) was added.
Add 1.5 g of 1-(2-chloroethyl)piperidine. Thereafter, the mixture was treated in room temperature for 1 hour and at 60°C for 2 hours, poured into ice water, and treated in a conventional manner. The mixture was separated and purified by silica gel column chromatography, and 0.5 g of the title compound was obtained as 0.0 hydrochloride using a conventional method. Ta.

・Melting point (t); 182-184 (decomposition)・'H-
NMR (CDCI 3) δ; 1.1-2.3 (9H
, m), 2.6-3.2 (6H, m), 3.44 (
211, s), 3°98 (2H, br t), 6.
9-7.7 (5H, m).

8.12 (IH, dd>, 8.44 (ltl, br
d) -MS m/e; 3B2 (M+)II (-pyrido C2,3-b) C1,4) Thiazine-2(3)1
) was dissolved in 20-dimethylformamide, 0.35 g of 60% sodium hydride was added, and the mixture was heated at room temperature.
After stirring for 45 minutes under a nitrogen stream, 1.6 g of 1-bendi 1-4-bromoacetylpiperidine was added to 10 ml of dimethylformamide! Add the solution and leave overnight. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain 0.7 g of the title compound. Construct the hydrochloride using the usual method.

・Melting point (t); 171-176 ・Molecular formula; C2゜)122N402s・HCI・'
It-NMR (CDCl2) δ; 2.10-2
．． 60 (4H, m), 3.4 (1-3, 80 (68m)
).

4.65 (211,s), 7.00~7.40 (7H
, m), 8.13 (ltl.

dd) ・MS m/e; 3B2(M”) 2 ■ Heat 25 g of 2-chloro-3-nitropyridine, 7.8 g of ethyl glycole and 35 g of potassium carbonate in 150 ml of dimethylformamide at 60°C for 12 hours. After cooling. ,
Add water to the reaction solution and extract with ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 31.9 g of 2-ethoxycarbonylmethoxy-3-nitropyridine as a pale brown-white oil, which was used in the next reaction without purification.

31.9 g of 2-ethoxycarbonylmethoxy-3-23-tropyridine is dissolved in 200 rd ethanol and stirred with a 10% palladium-carbon catalyst for 18 hours at room temperature in a hydrogen stream (balloon).

After removing the palladium catalyst by passing through Celite and concentrating the mother liquor, 15% ethanol-hydrochloric acid (300%) was added to the residue, and the mixture was heated under heavy reflux for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting pale brown crystals were collected by filtration and washed with isopropyl ether to obtain 16.5 g of the title compound.

・' It-NMR (DMSO-d6) δ; 4.7
9 (211, s), 6.90-7.45 (2H, m>
, 7.79 (IH, dd) IH-pyrido[:2.3-b][1,
4) Oxazin-2(311)-one-hydrochloride 0.8
Dissolve 1 g in 130 g of dimethylformamide and add 0.34 g of sodium hydride (60%) 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 was stirred at room temperature for 12 hours. Water is added, extracted with ethyl acetate, and the organic layer is washed with saturated brine 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.

・'lt-111MR (CDCl2) δ; 1.91
~2.43 (2H, m), 3.49 (2H, t),
4.08 (2H, t), 4.81 (2H, s), ?
, 03(1)1. dd).

7.34(IH,dd), 7.91(IH,dd) Salt Synthesis 5 1-(3-bromopropyl)pyrido obtained in (b) [
2,3-b] o, 4) Dissolve 0.41 g of oxazin-2(3N)one in 6 ml of dimethylformamide,
Add 0.3 g of 4-phenoxypiperidine and 1.2 g of triethylamine, and stir at room temperature for 26 hours. Add water;
After extraction with ethyl acetate and washing the organic layer with saturated brine, the residue was purified by silica gel column chromatography (dichloromethane:methanol-9:1) to obtain 0.31 g (yield 56%) of free base. . It was converted into a hydrochloride salt by a conventional method and crystallized from inpropanol-isopropyl ether to obtain the title compound.

・Melting point (t); 135-140 ・Molecular formula: C2I82SN303・llCl・'H-
NMR (CDCl2) δ; 54-2.86 (12H
, m).

3,98 (2H, t).

4.14~ 4, 51 (LH, m).

4,80 (2tl, s).

6.74-7.51 (7N, m).

7,89 (LH,cld>・MS m/e; 367(M”) Synthesis of lahydropyrido[2,3 b]pyrazine/dihydrochloride pyrazine 7 2-oxo-1,2,3,4-tetrahydropyride C2
, 3-b) 1.49 g of pyrazine and 30 ml of dimethyl sulfoxide! Dissolve 60% sodium hydride in 0.
After stirring at 65°C for 1 hour and 15 minutes under a nitrogen stream, the reaction mixture was cooled on ice, 30 g of 1,3-dibromopropane was added, and after stirring at room temperature for 4 hours and 30 minutes, it was poured into water and diluted with ethyl acetate. Extract, wash with saturated brine, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain 1.53 g of the title compound.

・'II-NMR (CDCl2) δ; 2.18 (2
H, m>, 3.46 (2H, t), 4.02 (2H
,t).

4.13 (28, s), 5.56 (IH, bs),
6.69 (IH, dd).

7.13 (LH, dd), 7.69 (IH, dd) 8 1-(3-bromopropyl)2-oxo-1,2,3,4,-tetrahydropyride obtained in (a) [ 2,3-
b] 0.5 g of pyrazine and 0.8 g of 4-benzylpiperidine
Dissolve 7 g in 20 g of dimethylformamide, add 2.0 g of triethylamine, and let stand overnight at room temperature. Thereafter, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was 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. Convert it into hydrochloride (amorphous) using the usual method.

・Molecular formula; C22H28N40・2HCI・1H-N
MR (CDCl2) δ; 1.10-2.20 (9H
, m), 2.25-2.90 (411, m) 9 2.70-3.00 (211, m), 2.95 (21
1,t), 3.12(2H,s), 5.83(IH
, br s), 6.61 (IN, dd).

7.00-7.40 (6H, m), 7.69 (IH
, dd) -MS m/e; 364 (M") 8.76 g of 4-benzylpiperidine and 1-1- in the presence of 20-triethylamine in 100 ml of tetrahydrofuran!
Add 12.270 g of chloro-3-iodopropane and stir overnight. Water was added to the reaction solution, extracted with dichloromethane, washed with saturated brine, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
'JJ to obtain 4.48 g (yield 36%) of the title compound as a pale yellow oil.

・'H-NMR (CDCl2) δ; 1.08-2.
60 (13H, m), 2.60-2.96 (2H, m
).

3.94 (211, t), 7.40-7.76 (5H
, m) 2 days-pyrido C4,3-b) [:1.4) Oxazin-3 (4 days)-one 0.81 g was dissolved in 10 ml of dimethylformamide, and sodium hydride 1 (60 %) and stirred for 15 minutes at room temperature. 4-benzyl (1-(
3-Chloropropyl)] Add 15 ml of a solution of 36 g of piperidine in dimethylformamide, and stir at 60°C.
Allow time to react. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then 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 salt according to a conventional method, and recrystallized from methanol-diethyl ether to give the title compound 0 as colorless crystals.
．． 52 g (yield 22%) was obtained.

・Melting point (t); 226-227 (decomposition) ・Molecular formula;
C22) 127N302・2l-ICI・'H-NM
R(CDCl2) δ; 1.10 to 2.04 (91
1,m), 2.28-2.59 (4H,m)2.
72-2.98 (2H, m), 4.00 (211, t
), 4.67(211,s), 6.84(ill,
d), 7.00-7.32 (511, m>.

8, 14 (It(, d), 8.31 (It-1, s
)2-MS m/e; 365(M”) 2■-pyridoC4,3-b) [1,4)thiazine-3
(0.42 g of 4B>-one was dissolved in 10 ml of dimethylformamide, and sodium hydride (6
0%) and stirred for 15 minutes at room temperature. 4-benzyl[1-(3-chloropropyl)]piperidine obtained in Example 15 (a) 0,75 to the reaction solution
A dimethylformamide solution 6-g of the mixture was added, and the mixture was reacted at 60°C for 2 hours and at 80°C for 1 hour.

The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate.

3 After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography, converted into a hydrochloride salt according to a conventional method, and recrystallized from methanol-diethyl ether to obtain 21 g (yield 19%) of the title compound as colorless crystals. Ta.

・Melting point (°C); 213-214 ・Molecular formula: C22H27N30S・2HC1・'H
-NMR (CDCI,) δ; 1.18-2.60
(13H, m), 2.70-3.00 (2H, m).

3.40(2)1. s), 4.06 (2H, t),
6.70-7.36 (6H, m), 8.16 (1) 1
．． d), 8.24(IH,s)-MS m/e;
381 (M+) Example 17 The following compounds were obtained according to the methods described in Examples 1 to 16 above.

(1) 4 ・Molecular formula; C211btNs02s・211CI・'
H-NMR (CDCI, ) δ; 1.68 (2H
, m), 2.0 to 2.4 (10 fl, m), 3
．． 41 (2N, s>, 3.47 (2H, s),
4.01 (2H, t), 4.05 (3H, s),
7.23 (5H, s), 8.25 (IH, s) -
MS m/e; 413 (M") ・Melting point (t); 183 (decomposition) (2) ・Molecular formula: C20H26N602S ・' II-NMR (CDCI,) δ; 1.73
(2N, m), 2.0 to 2.6 (6H, m),
3.42(2)1. s), 3.63(2H,s),
4.02(211,t), 4.07(3H,s
), 7.1 to 7.8 (3H, m), 8.31
(LH,s).

8, 52 (IH, d) -MS m/e; 414 (M+) ・Melting point (°C); 118-120 (3) 21100cmCll=CH-COO11 ・Molecular formula;
C2311+ 1NsO2s ・2C4It-L・'H
-NMR (CDCI+) δ; 1.43 to 1.97 (
4H, m), 2.06-2.7H14H, m).

3.42 (2tl, m), 4.02 (2H, t),
4.08 (3H, s).

7.20 (5H, br, d), 8J2 (IH, s)
・MS m/e; 441 (M”)・Melting point (t)
;198-200 (4) 6 ・Molecular formula; C231129NS[]2S' I, 7
c4H41'14・tNMII (CDCI,)
Cl1.43-1.86 (2f(,m), 1.8
6r ~2.57 (101(, m).

3.13 (211, d), 3.43 (21-1, s)
, 4.03 (2H, t).

4.08(3f(, s>, 6.04~6.67(21
,m), 7.16~7,47 (5H,m),
8.33 (18,s>-145m/e; 439(
M') ・Melting point (t); 1B8~191 (5) ・Molecular formula: C2+H33N=, 02S・2HCI・'
H-NMR (CDCI3) Cl0.9-1.9(1
3ft, m), 1.95-2.50 (12H, m)
.

3.40 (2) l, s), 3.9-4.1 (5N, m
), 826 (IH, s) -MS m/e; 419 (M+) ・Melting point (t); 197-200 (decomposition) 7 ・Molecular formula; C22H29NSO2S・2HC1・'l
(-NMR(CDCI3) Cl1.5-3.0(1
6H,,w>, 3.40(LH,s), 3.8~4
, H5tl, m), 7.0 to 7.3 (5H, m),
8.28(IH,S)-MS m/e; 427(M
”) ・Melting point (tl:); 182-184(7) ・Molecular formula; C,9H2SNSO3S ・211C+-
') I-NMR (CDCI,) Cl1.5-1.9
(2H, m), 2.0-2.6 (IOH, m).

3.40 (2H, s), 3.50 (2H, s), 3
．． 9-4.1 (58, m), 6.14 (III, d
), 6.26 (18, m).

(LH, m), 8.26 (IH, s) - MS m/
e; 403 (M+) ・Melting point (t); 175-176 (decomposition) 7.30 (8) ・Molecular formula: Cl9)125NsO2s2・2HClli'H-NMR (CDC1,) δ; 1.5-
1.9 (2H, m), 2.1-2.6 (IOH, m
).

3.40(28,s>, 3.66(2H,s>,
3.9-4.1 (5H, m), 6.8-6.9 (
2H, m), 7.1-7.2 (IH, m), 8
．． 14(IH,s>・MS m/e; 419(M+
) ・Melting point (t); 190-192 (decomposition) 89 (q) ・+100C-C11=CIl-COO11 ・Molecular formula;
C2□H2eNeO2S-C4+14046'H-NM
R (CDCI,) Cl1.46-1.86 (2H,
m), 2.09-2.54 (108, m) 3.4
3 (2H, s), 3.51 (2H, s), 4.
01 (2H, t).

4.07 (3H, s), 7.402H, d),
7.60 (28, d).

8,92 (IH,s) -MS m/e; 438 (M+) ・Melting point (t); 155-156 0 ・'II-NMR (CDCI3) δ; 1.50-1
．． 86 (211), 2.06-2.48 (8N),
2.20 (2H, t), 3.39 (2Ls),
3.42 (2H, S), 3.98 (2H, t)
, 4.03 (3H, s), 6.72-7.36
(4H).

8, 26 (1tl, s) -MS m/e; 43HM") ・Melting point (t); 190-194 ・%) 100C-CH=CH-COD)I ・Molecular formula;
C21H26FNSO7S-! AC-H-04・'H
-NMR (CDCI 3) δ; 1.57=-1,9
4 (2ft, m), 2.11~2.60 (IOH,
m).

3.42(2)1. s), 3.46(2t(,s)
, 4.00 (2N, t).

4.07 (3H, s), 6°80-7.40 (4)
1. m), 8J2 (III, S) ・MS m/e; 431 (M+)1 ・Melting point (1); 181 ~ 183 ・Molecular formula; C22H29N503S・2HC1・'H-
NMR (CDCI3) δ; 1.67 (2H, m),
2.1~2.6 (10ft, m), 3.40 (2H
,s), 3.78(3H,s), 3.97(2H,
t), 4.04(2t(,s), 6.78(2H,
d), ? , 16(2)1. d), 8.27 (ltl
, s) -MS m/e; 443 (M”) ・Melting point (t:); 195-200 2 ・Molecular formula; C20) 131NSO2S ・211CI
・'H-NMR (CDCI,) δ; 0.9-2
．． 0 (128m).

3, 40 (2H, s), 3.9 (IH, s) -MS m/e; 405 (M”) ・Melting point (t);, 178-181 (decomposition) 2.0-
2.7(11)I,m).

~4. H2N, m>, 8.28・Molecular formula; C
22H26N60゜S・2HC1・'l(-NMR(C
DCI, ) δ; 1.64 (2H, dt), 2.
20 (28, t), 2.04-2.46 (8H, m
), 3.40(2H,s), 3.46(2)1
．． s), 3.98(2)1. t), 4.93(
3H, s), 7.26-7.60 (4H, m).

8,25 (18,s) ・MS m/e; 433 (M”) ・Melting point ('j:); 190-1923- ・Molecular formula: C22H29N503S・2HCI・'
H-NMR (CDCl3) δ; 1.65 (2H,
q>, 2.10 to 2.40 (IOH, m), 3.4
2 (2fl, s), 3.44 (2H, s), 3.8
0 (3H, s), 4.00 (2H, t), 4.
05 (3tl, s), 6.70-6.90 (311,
m).

7.20(ltl,t), 8.3H1tl,s)・
MS m/e; 443 (M+) ・Melting point (t); 1B6~188 ・Molecular formula: C+5H2Js02S・2+1CI・'H
-NMR (CDCIa) δ; 4 1.6-1.9 (2H, m), 2.1-2.6 (1
3H, m).

3.4H2H,s), 3.95-4.10(5H,
m), 8.28 (IH, s) ・MS m/e; 337 (M”) ・Melting point (t)
;184-186 (decomposition)・Molecular formula; L, N50
□S・2H['1・'H-NMR (CDCH3) δ
:0.88(6i(,d,), 1.6~2.5(1
3H, m>, 3.42 (2N, s>, 3.9~
4.2(5tl, m), 8.32(11(,s)・
MS m/e; 379 (M+) ・Melting point (t); 180-183 (decomposition) 5 ・Molecular formula; C2o)H3,NSO□S ・211CI
・' H-NMR (CDCl 3) δ; 1.2-2
．． 0 (1211, m), 2.0-2.9 (1111
, m) 3.41 (2H, s), 3.9-4.1 (5
H, m), 8.28 (IH, s) -MS m/e; 405 (M") ・Melting point (°C); 203-205 (decomposition) ・Molecular formula;
C2゜H26FN502S・2HC1・'H-NMR(
CDC1,) δ; 1.5 to 1.9 (2H, m),
2.0~2.6(1,OH,m>3.40(2H,s
), 3.56 (2H, d), 3.9 ~ 4.1
(58,m>, 6.9~7゜4(4)1.m),
8.26(l)I,s)-MS m/e; 431
(M”)・Melting point ('j:); 188・〜190(
Decomposition) 96 ・Molecular formula: C21H2sN503S ・'H-NMR (CDC) 3) δ; 1.72 (
2H, m>, 2.0 to 2.5 (IOH, m),
3.44(2)1. s>, 4.03(2)1. t)
, 4.08(3)1. s), 7.37 (5t1
．． s), 8.28 (1N, s)・MS m/e;
427 (M”)O Melting point (℃); Amorphous/Molecular formula; C34H2, N5O2S-y2C-H40
-・'H-NMR (CDCI,) δ; 1.49-1
．． 86 (2H, m), 2.06-4.00 (101
1, m).

3, 43 (2JI, s), 3.75 (1) 1.
s, 020 exchangeable).

4.02 (2H, t), 4.08 (3) 1. s),
8.33(LH,s)-MS m/e; 323
(M") ・Melting point (t); 188-190 ・Molecular formula; C22H2,N502S・2IC+・')
I-NMR (CDCl3) δ; 1.20-2.7
(1(141(), 3.40(21(,S), 3.
56 (2tl, s), 3.97 (2H, t),
4.03 (3H,S), 7.10~7.32 (5
H), 8.25 (LH,s)・US m/e
; 427 (M+) ・Melting point (t); 152-155 2HOOC-CH-CH-COOH 98 ・Molecular formula: CzJ, 11NsO+S・2C,) 1.0
゜・') I-NMR (CDCI3) δ; 1.46~
2.14 (4H, m), 2.40-3.11 (IO
H, m).

3.42 (2H, s), 3.85 (3H, s),
3.95 (2H, s).

3.95 (2t1.t), 4.09 (3H,s>,
6.85-7.56 (4H, m), 8.33 (
1) l, s)-MS m/e; 458 (MH”)・
Melting point (t); 116-118 ・Molecular formula; C22■5sNsO2S・211CI・'
If-NMR (CDCI, ) δ; 0.70-2.6
6 (27H), 3.40 (2H, s), 3.9
7 (2H, t), 4.05 (3) 1. s), 8
．． 26(ltl,s)・US m/e; 433(M
”) ・Melting point ('j:); 185-1889 ・Molecular formula: C20H25NSO2S ・') I-NMR (CDC1,) δ; 1,75 (
2H, m), 2.1 to 2.6 (6H, m), 3
．． 09 (4H, t), 3.43 (2H, s), 3.
8-4.2 (511, m).

6.7-7.0 (3H, m), 7.1-7J (2H,
m), 8.29(l)l,s) ・MS m/e; 399(M") ・Melting point (t); 131-133 ・Molecular formula; C,8H2,N702S 00 ・' II-NMR (CDCI 3 ) δ; 1.73
(2H, m), 2.0 to 2.5 (6H, m),
3.43 (2H, s), 3.69 (4ft, t),
3.8-4. H5H, m).

6.42 (lH, t), 8.22 (2H, d),
8.24(IH,s)-MS m/e; 401(
M") ・Melting point (t); 128-130 ・Molecular formula; C,9H2,N602S ・'H-NMR (CDCI3) δ; 1.77 (2N
, m), 2.1-2.5 (6H, m), 3.4
5(4)1. t), 3.45(2H,s>, 4
．． 09(3)1. s), 4.09 (2H, t),
6.5-6.7 (2N, m), 7.3-7.6 (
IH, m>, 8.13 (LH, cld), 8.
30(IH,s)-MS m/e; 400(M+) ・Melting point (t); 134-137 01 O molecular formula; C23H31NSO3S・21+CI・'
H-NMR (CDCI3) δ; 1.25-1.56
(411, m), 2.16-2.64 (l OH
,m＞.

3.40 (2H, S), 3.56 (28, s),
3.76 (3H, s).

3.95 (2H, t), 4.03 (3H, s),
6.84 (211t).

7.20 (2H, ddd), 8.27 (ltl, s
)-MS m/e; 457 (M”)・Melting point ('C
) ;168~1G! ] (Decomposition) 02 ・'H-NMR (CDCI3) δ; 1.15-1.
64 (6H, m), 2.08-2.64 (IOH,
m).

3.39 (2H, s), 3.55 (2H, s),
3.76 (3H, s).

3.96(2)1. t), 4.02 (3H, s),
6.84 (2H, t).

7.18(28,ddd), 8.28(ill,s
)-MS m/e; 471 (M”) ・Melting point (t); 188-189 (decomposition) ・Molecular formula;
C25l13SNSO3S・211CI・'H-NM
R(CDCI3) δ; 1.08 to 1.58 (8H,
m), 1.98-2.64 (IOH, m).

3.38 (2H, s), 3.56 (2) 1. s),
3.76 (38,s).

3.92(21(,t), 4.01(3H,s),
6.83 (2H, t).

7.18 (2H, ddd), 8.25 (IH, s)
-MS m/e; 485 (M+) ・Melting point (t:); 165-166 (decomposition) 03 ・Molecular formula; C26H37NSO3S・2HCI・'I
I-NMR (CD(:l,) δ; 1.12-1.6
0 (IOH, m), 2.00-2.68 (IOH,
m).

3.40 (2H, s), 3.57 (2H, s),
3.78 (3H, s).

3.93(2)l,t), 4.04(3H,s),
6.83 (28,t).

7.2H2H,ddd), 8.28(IN,s)・
MS m/e; 500 (MH”)・Melting point (t)
;144-145 (decomposition)・Molecular formula: C22H2sN
, 02S・211CI・' H-NMR (CDCI,
) δ; 04 1.30-1.56 (4tl, m), 2.19-2.
36 (2H, m).

2.46 (8H, bs), 3.40 (2) 1. s),
3.48 (211, s).

3.95 (2H, t), 4.04 (3H, s), 7
．． 24 (5H, s>.

8, 27 (LH, s) -MS m/c; 427 (M”) ・Melting point (t); 182-184 (decomposition) ・Molecular formula;
C23■31NsO2S・2+1CI・ )I-11
1MII (CDC+ 3) δ; 1.10-1.6
5 (6H, m), 2.20-2.44 (2N, m).

2, 55 (8t-1, bs), 3.4 (1 (2) f,
s), 3.49 (21(, s).

3.92 (2H, t), 4.03 (3N, s), 7
．． 23 (5H, s>.

8,27<IH,s) -MS m/e; 441 (M”)・Melting point (℃)
;168-169 (decomposition) 105 ・Molecular formula: C24H33NSO2S・211C・′)
I-NMR (CDCI3) δ; 1.10-1.60
(8H, m), 2.20-2.46 (2H, m)
.

2.46 (8H, bs), 3.39 (28, s),
3.49 (2tl, s>.

3.92 (2H, t), 4.02 (3H, s),
7.24 (5H, s).

8, 26 (llt, s) -MS m/e; 455 (Ma ・Melting point (t); 169-170 (decomposition) ・Molecular formula:
C25H37N502s・21iC1・'H-NMR
(CDCI,) δ;06 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 (18,9) -MS m/e; 447 (M”) ・Melting point (t); 195-198 ・HooC-CII=CII-COOH ・Molecular formula: C
23H31NSO3S -C-H-0-・'H-NMR
(CDCI3) δ; 1.00 to 2.94 (16H,
m), 3.29-3.71 (3fl, m).

3.96 (2H, t), 4.07 (3H, m),
4.64 (2H, s).

7.05-7.82 (3H, m), 8.34 (18
, s), 8.52 (l) I, br, d) -MS m/e; 457 (M+) ・Melting point (℃); Amorphous 07 ・Molecular formula: C22H28N, 03S・11C1・'
H-NMR (CDCI 3) δ; 1.38-2.6
6 (12H), 3.40 (2tl, s), 3.
20-3.42 (IH, m), 3.98 (2H, t
), 4.05 (311, s).

4.47 (2tl, s), 7.25 (5H, br,
s), 8.26(LH,s)-MS m/e;
428 (M") ・Melting point (℃); Hygroscopic amorphous ・Molecular formula: C2, H27N503S・2HC1・'
H-NMR (CDCI 3) δ; 1.4 ~ 2.9
(13H, m), 3.42 (2H, s).

4.00 08 (2H, t), 4.07 (3N, s), 4.6
0(2H,s), 7.11(ltl,t), 7
．． 3-7.7 (2 days, m), 8.18 (IH, s)
.

8, 14 (IHd) ・US m/e; 430 (MH”) ・Melting point (℃);
Amorphous・Molecular formula: C22H2゜N50□S・211CI・'
H-NMR ([:DC+3) δ; 1.08-1.8
8 (IIH), 2.15 (2H, dd), 2.
44-2.86 (411), 3.38 (211,s
), 3.98 (2t1.t).

4,03 (3N, s), 7.00 (III,
ddd), 7.05 (IH, dd).

7, 49 (IH, ddd), 8.25 (1N, s
), 8.40 (LH, dd)-MS m/e;
427 (M+) ・Melting point (℃); Amorphous 09 ・Molecular formula: Cl5H22N402S・IIcI・'
H-NMR (CDCI 3) δ; 1,3 - 1.9
(8H, m).

3, 43 (2H, s), 3.9 (18, s) -MS m/e; 322 (M+) ・Melting point (t); Hygroscopic amorphous 2, 0-2.4 (6N, m).

~4. H5H,m), 8.32 ・Molecular formula; C2□H26N402S ・' H-NMR (CDCI 3) δ; 1.6-2
．． 6 (13H, m), 2.6-2.9 (2H, m
).

10 3.43 (2H, s), 4.05 (211, t),
4.09 (3tl, s).

7.0-7.4(5)1. m), 8.30 (IH,
s)-MS m/e; 398 (M") ・Melting point (t); Ill~113 ・Molecular formula: C22H2eN<'02S・'H-NMR
(CDCl2) δ; 1.4-2.0 (9H, m),
2.0-2.3 (28, m).

2.4-2.8 (48, m), 3.42 (211,
s), 3.97 (2H, t), 4.02 (3H,
s), 7.0-7.3 (5H, m).

8,25(IH,s) -MS m/e; 382(M+) ・Melting point (t); 122-125 ・Molecular formula: C221128N-033・'H-NM
R(CDCl2) δ; 1.3-1.9 (7H,
m), 2.0-2.6 (6H, m).

2.7H2H,s), 3.40(2H,s),
4.00 (2+1.t).

4.04 (3H, s), 7.0~7.4 (5H, m
), 8.33(IH,s) ・MS m/e; 428(M+) ・Melting point (t); 127-130 ・Molecular formula; C22t(2sFN4[]2s' I(C
112 ・'H-NMR (CDCl3) δ; 1.4-2
．． 3 (IOH, m), 2.5-2.8 (2H, m>
.

2.9-3.3 (IH, m), 3.44 (2H, s
), 4.05 (211, L), 4.08 (211
,s), 7.08(211,t), 7.9°(2
ft, dd), 8.17 (LH, s)-MS m/
e; 444 (M") Melting point (t); 148-152 ・Molecular formula: C23H28N404S・HC・'H-N
MR (CDCl2) δ; 1.54-3.29 (13
H, m), 3.43 (2H, s), 3.86 (
3H,S), 4.04(2H,t), 4,IH3H
,s), 6.92(28,d), 7.89(2H,
d), 8.33 (IH, s)・MS m/e; 4
56 (M")・Melting point (t); 140-142 ・Hoo [nee C11-CII-CODI+・Molecular formula;
c2. H25pN, o3s'C<It40<・'
H-NMR (CDCl2) δ; 1.29-2.70
(1211, m).

(2H, t), 4.09 (3H, s).

8, 29 (ltl, s) ・MS m/e; 432 (M”) ・Melting point (t); 146-147 3.43 (2H, s), 4.00 6.57-7.00 (4H, m).

・1100cmCII=CI-COO11・Molecular formula:
C21Hz@N403S' C41l-0-4 ・' It-NMR (CDCI,) δ; 1.40
-2.7H12H,m), 3.43(2H,m),
4.04 (2H, t), 4.09 (3H, s)
, 4.19 (IH, br9m) 6.75-7.04
(3H, m), 7.10~? , 42 (2H, m).

8, 33 (ill, s) ・MS m/e; 414 (M”) ・Melting point (t)
;161-162 ・Molecular formula; C2JzJsOiS ・'H-NMR (CDCI 3) δ; 1.6-2
．． 4 (IIH, m>, 2.6-2.9 (2H, m)
.

3.43 (2H, s), 4.04 (28, t), 4
．． 09(3)1. s).

7.0-7.6 (IH, m), 8.28 (IH, s
)-MS m/e; 44 days Ma ・Melting point (t:); 134-136 115 ・Molecular formula: C22H27NSO3S・[IC1・'H
-NMR (CDCI, ) δ; 1.20-2.36 (
IOH), 2.52-2.80 (211).

3.42 (2H, s), 4.00 (2H, t),
4.07 (3H, s).

3.84-4.10 (IH, m), 5.94 (IH
, m), 7.30-7.80 (5H), 8.3
2(IH,s)-MS m/e; 441 (M+)
・Melting point (t); 180-183 ・Molecular formula: C21828N6033・2HCI・'H
-NMR (CDCI3) δ; 6 1.38-2.36 (10 days), 2.52-2.8
0 (2H).

3.43 (2H, s), 4.03 (2fl, t),
3.82-4,16 (IH), 4.09 (:E
, s), 7.40 (IH, ddd), 7.82
(IH, ddd), 7.80-8.02 (IH),
8.16 (LH, dd).

8.33(IH,s>, 8.52(IH,dd)-
MS m/e; 442 (M") ・Melting point (t); 181-184 ・Molecular formula; C24H31NSO3S-HCI・'It
-NMR (CDCI3) δ; 1.06 to 2.76 (
15H), 3.20-3°48 (2 days).

3.42 (2H, s), 3.99 (2H, t),
3.90-4.10 (LH), 4.07 (311
,s), 7.34(5H,m), 8.32(I
H, S) -MS m/e; 469 (M”)・Melting point ('j:
); 165-16917 ・Molecular formula; C2°H26N40□S ・'H-NMR (CDCI3) δ; 1.00-2.
50 (IIH, m), 2.70-2.99 (2H, m
>.

3.40 (2H, s), 3.54 (2H, s), 3
．． 92 (2H, t).

4.04 (3N, s), 7.25 (5B, s), 8
．． 28(IH,s)-MS m/e; 412(M+
) ・Melting point (t); 151-152 (53) ・Molecular formula: C23H29NSO3S ・'H-NMR (CDCI, ) δ; 18 1.57-2.00 (2H, m>, 2.08-2.
69 (10H, m).

3.13 (2H, cl), 3.73 (IH, d),
4.16 (3H, s).

4.16 (2H, t), 4.21 (IH, d),
6. '00~6.62 (2H, m), 7.11~
7.43 (5H, m), 8.62 (LH, s)・M
S m/e; 456 (MH”)・Melting point (℃); Amorphous・C00H-CH=CH-COOI-1・Molecular formula; C
2J3+N502S-C4H404・'H-NMR(
CDCl 3) δ; 1.44 (38, t), 1
．． 69 (2H, m>, 2.0 to 2.6 (IOH, m
), 3.12 (2N, d), 3.42 (2H,
s).

4.03 (2H, t), 4.53 (28, q),
6.0-6.5 (2 fl, m), 7.0-7.4
(5H, m), 8.15 (LH, S)・MS m/
e; 453 (M”) ・Melting point (t); 188-189 19 ・Molecular formula; C23H31N503S・2HCIO' H
-NMR (CDCI 1) δ; 1.43 (3H, t
), 1.65(2)1. m), 2.0 to 2.7
(IOH, m), 3.4N2! (,s) 3.55
(2)! , s).

3.77 (3H, s), 4.03 (211, t),
4.47 (2H,q).

6.7-7.4 (4) 1. m), 8.23 (IH,
s)-MS m/e; 457 (M') ・Melting point (℃); Amorphous ・HooC-C11=C)I-[:0011-120= ・Molecular formula; C201427NSO2S2' C41
'+404・') I-NMR (CDC13) δ;1
．． 45 (3N, t), 1.65 (2H, m),
2.0-2.6 (IOH, m), 3.41 (2H, s
>, 3.68(2)1. s).

4.03 (2N, t>, 4.49(2)1.q),
6.8~7.0 (2N, m), 7.1~7.2
(1)1. m), 8.24(IH,s)-MS m/
e; 433 (M”) ・Melting point (t); 186-188 ・Molecular formula; C2+H2GN, 02S-HCI・'H-
NMR (DMSO-d6) δ; 1.1-2.2 (7
H, 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 (IN, s).

10, 0-10.6 (II, bs) ・MS m/e; 298 (M”) 21 ・Melting point (℃); Amorphous ・Molecular formula; C22H2JsO2S・2HCI・' H
-NMR (DMSO-66) δ; 1, 70-=2.
29 (2H, m).

7, 26-7.63 (5H, m).

'MS m/e; 426 (Ml(')・Melting point (t)
;222 (decomposition) 6.14-7.09 (2H, m).

8.00 (IH, S) ・Molecular formula; Cz2H:+5Ns02S・2110・'
LNMR (DMSO-66) δ; 22 0.8-2.0 (17H, m), 2.7-3.2 (
4H, m).

3.2-3.8 (10 fl, m), 3.8-4. H
2H, m) 7, 85 (IH, s) -US m/e; 434 (MH”)・Melting point (t)
;201-204 ・Molecular formula; C2oLsNs02S H2HCI6'
It-NMR (DMSO-66) δ: 1.7-2.
H2)1. m), 2.7-3.8 (14H, m).

3.9-4. H2)! , m), 7.3-7.5 (3
H, m).

7.5-7.8 (2ft, m), 7.96 (IH,
s)-MS m/e; 400 (MH+)・Melting point (℃
) ; Amorphous 23- ・Molecular formula: C21) 126N403S-HCI・')
l-NMR (CDCl2) δ; 1.6-2.2 (6
H, m), 2.6-3.0 (6H, m) 2.6-3
．． 0 (2H, m), 3.37 (2H, S), 4.
17 (211, t), 7.0-7.4 (5H, m>
, 7.77 (IH, s>-MS m/e; 41
4(M+) ・Melting point (t); 215-220 (decomposition) ・Molecular formula;
C20H31NSO2S ・2HCl・' H-NM
R(D20) δ; 24 0.9-2.3 (131(), 3.0-4. HI
6H).

(IH,S) -MS m/e; 405 (iA")・Melting point ('j:
); 1B3~185 (decomposition) 8.02 ・Molecular formula; self 8823NSO□S2・2HC]・' H
-NMR (D20) δ; 1.9-2.3 (2H), 3.1-3.4 (2N)
, 3y59(211,s), 3.70(IOH
), 4.00 (211,t), 7.13 (IH
, dd), 7.3 (18, d), 7.62 (I
t(, d), 8.01 (LH, S) -MS m/e; 405 (M+) Melting point ('j:); 228-230 (decomposition) 19
Bow- ・Molecular formula; C, 9H23NSO2S・2HC1・'H
-NMR (DMSO-c16) δ; 1.8-2.2
(2fl, m), 2.9, 3.9 (12H, m),
3.9-4.2 (2H, m>, 6.7-7.1
(3H, m), 7.1-7.3 (2tl, m)
, 7.96 (IH,s)-MS m/e; 3
85 (M) ・Melting point (t); 215-218 (decomposition) O molecular formula:
C1-H22N602S・2HCI・'H-NMR(
DMSO-d6) δ; 1.8-2.2 (2H, m)
, 2.9-3.4 (6H, m).

4 26 ~ 3.9 (6H, m), 3.9 ~ 4.2 (28, m
＞, 6.95(1N, t＞, 7.32(11(
, d), 7.8-8.1 (2H, m).

11.0-11.7 (IH, bs) -MS m/e; 386 (M+) ・Melting point (t); 221-225 (decomposition) ・Molecular formula:
C+J2+NtO2S・2 anal 1・'H-NMR (DM
SO-d6) δ; 1.8 to 2.2 (2H, m),
2.9-4.2 (16 fl, m).

6.71(1N,t), 7.92(II(,s),
8.37(2)1. d)-MS m/e; 38
7 (M+) ・Melting point (t); 224-227 (decomposition) 27 ・Molecular formula: C2J3oNsO3・3HC1・'H-N
MR (CDCI+) δ; 1.50 (2H, m),
1.9-2.5 (1ON, m), 2.96 (6)
1. s), 3.1-3.5 (6tl, m), 7
．． 18 (5H, s).

8,09 (LH,s) -MS m/e; 426 (M') ・Melting point (tl:); 187-191 ・Molecular formula: C
23H3□N602S・3HCI・')l-NMR(C
DC1,) δ; 1.20 to 1.69 (2H, m),
1.94-2.57 (IOH, m).

2.98 (6N, br, s), 3.26-4.43
(98, m>.

6.70-7.42 (4N, m), 8.16 (18
,S)-MS m/e; 456 (M") ・Melting point (t); 195-19B 28 ・Molecular formula; C21H25CIN40S-HCI・'H
-NMR (CDCl2) δ; 10-2.7 (15H
, m), 3.48 (2N, s), 4.10 (2
H, t), 7.0 to 7.4 (5H, m), 8.
44(ltl,s)-MS m/e; 416/41
8 (M")・Melting point (t); 182-184 (decomposition)・Molecular formula; C2+H2JCIN<025'H
Cl6'H-NMR (CDCl2) δ: 1.4-2
．． 6 (12H, m>, 3.2-3.4 (IH, m)
.

3.50 (28, s), 4.12 (2ft, t),
4.44 (2N, s).

90 6.8-7.4 (4H, m), 8.44 (IH, s
)・MS m/e; 4'l/453 (M”)・Melting point (℃); Hygroscopic amorphous・Molecular formula; l:aoH24clNs02s・2fl
C1-')l-NMR (CDCl2) δ; 1.5
~2.7 (2H, m), 3.40 (IH, m),
3.45 (2H, s), 4.18 (2H, t),
4.76 (2H, s).

7.5-7.8 (3N, m), 8.4-8.5 (2
11, m)・MS m/e; 433/435 (
M+)・Melting point (t); 191-194 30・Molecular formula; C2+HisCIN402S' HCl
0'HNMR (CDCI3) δ; 1.4-2.6 (12i, m), 3.2-3.4 (
IH, m).

3.48 (2H, s), 4.12 (2H, t),
4.48 (28,s).

7, 28 (5ft, s), 8.24 (1N, s
)-MS m/e; 432/434 (M+), melting point ('j:); 198-200 (decomposition), molecular formula;
C2oH23FCINSO3・211C+・'H-N
RIR (CDCI,) δ; 1.51-1.9H2H
, m), 2. OO~2.40 (1ON, m).

3.41 (2tl, m), 3.49 (2H, m),
4.13 (2H, t).

6, 86-7.35 (4H, m), 8.48
(IH,s)・MS m/e; 435/437(M
+)・Melting point (t); 196-198 (decomposition)-13
1 ・Molecular formula; C201130CIN50S ・211C
I·'H-NMR (CDCI3) δ; 0.6-1.
9 (13H, m), 1. ．． 9-2.5 (12H, m
).

3.49 (2H, s), 4. lN211. t),
8.44(III,s)-MS m/e; 423
/425 (M″″)・Melting point (t); 229-231
(Decomposition) Molecular formula: C20H24C]N5O5・2ft
CIH-NMR (CDCI3) δ; 1.79 (2H, m>, 2.1 - 2.4 (101
1, m), 3.52 (2N, s), 3.55 (
2H,s), 4.18(2H,t), 7.30
32 (5H,s>, 8.48(IH,s)-MS m/
e; 417/419 (M”)・Melting point ('C);
207-213 O molecular formula: Ct+H2eCIN50°S・211CI
・'H-NMR (CDCI 3) δ; 1.57~
1.86 (2ft, m), 2.06~2.49 (1
08, 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 (LH, s) ・MS m/e; 447/449 (M") ・Melting point (
t) ;1B9~191 ・Molecular formula; C2oH2, FCIN50S + 211
CI・'H-NMR (CDCI3) δ; 1.5-1
．． 9 (2H, m), 2.0-2.5 (IOH, m).

3.48 (2H, s), 3.52 (2H, s), 4
．． 10 (2H, t).

6.8-7.4 (4H, m), 8.42 (IH, s
)・MS m/e; 435/437 (M”)・Melting point (t); 1B5-187 (decomposition)・Molecular formula: C2
0H23FCINSO3・2tlCI・'H-NMR(
CDC1,,) δ; 1.46 to 1.94 (2H, m
), 2.00-2.43 (1ON, m).

3,44(211,s), 3.50(2H,s>,
4.14 (2tl, t).

6, 77-7.37 (4H, m), 8.48
(Ill, s)・MS m/e; 435/437
(M'')・Melting point (t:); 1B8~190 34-・Molecular formula: C21H24C]N50□S -HCI・
' I (-NMR (CDCI 3) δ: 1.3-2
．． 7 (12H, m), 3.50 (2H, s),
3.9-4.0 (IN, m), 4.16 (2tl,
t), 7.3-7.8 (5H, m).

8,50 (IH,s) ・MS m/e; 445/447 (M+) ・Melting point (
t) ;195-196 ・Molecular formula; C2(lH22FclN402s-HCI
・' ) I-NMR (CDCl 3) δ; 1.4 ~
2.7 (128, m), 3.48 (2H, s).

4.0 35 4.3 (311, m), 6.7~7.1 (4H, m
).

-MS m/e; 436/438 (M')・Melting point (
t); 192-194 (decomposition) 8, 44 (IH, s
) ・Molecular formula; C2DH29NSO8・2HCI・'H-
NMR (CDCI3) δ; 1.83 (2tl, m)
, 2.2-2.6 (IOH, m), 3.49 (2H
,s), 3.55(2)1. s), 4.02(
2H,t), 7.27(5H,s), 8.49
(IH,s), 8.63(IH,s)-MS m/
e; 383 (M”) ・Melting point ('C); 246-249 (decomposition) 36 ・Molecular formula; C2QI1.l1150S ・2+1CI
Re'H-NMR (CDCI 3) δ; 0.6~
2.0 (1311, m), 2.16 (2N, d),
2.2-2.5 (IOH, m), 3.57 (2H, s
>, 4.05 (2H, t).

8.55(IH,s), 8.68(IH,s)-M
S m/e; 389 (M+) ・Melting point (t); 260-265 (decomposition) ・Molecular formula;
C21) 127NSO2S・28C]・')I-NM
R(C[HCI3) δ; 1.84(2H,q),
2.20-2.60 (IH, m), 3.52 (4H,
s), 3.77 (3H, s), 3.98 (2H, t
l 6.84 (2H, t), 7.20 (2+1.dd
d), 8.44 (IH,S) 8,60 (IH,s) ・MS m/e; 413 (M') ・Melting point (t); 105-106 (decomposition) 37 ・Molecular formula; C23HsaN<D2S'IIC:1
・'H-NMR (CDCI3) δ; 1.0 to 1.9
(IOH, m), 2.0-2.8 (8H, m>.

3.56 (2H, s), 3.92 (2H, t),
7.15 (511, s).

8.27 (LH, s), 8.57 (III, s) -
MS m/e; 426 (M") ・Melting point (℃); Amorphous ・Molecular formula; C22H34NSO3・28C]・'tN
MR (CDCI3) δ: 38 0.6 to 1.9 (17t(, m>, 2.0 to 2.6
(12ft, m).

3.6H2H,s), 3.98(2H,t),
8.36(LH,s>.

8,70 (LH,s) -MS m/e; 417 (MH")・Melting point ('j
:) ;245-248 (decomposition)・Molecular formula: C21
H26N40S-HCI・'It-NMR (CDCI,
) δ; 1.0 to 2.1 (9H, m), 2.21
(2H, t), 2.53 (2H, d), 2.6
~2.9 (2H, m), 3.56 (2H, s).

3.99 (2H, t), 7.0-7.4 (5N, m
), 8.48 (IH, s), 8.64 (1N,
s)-MS m/e; 382 (M") ・Melting point (t); 1B4~185 39 ・Molecular formula: C21H25FN402S-HCI・'
H-N&lR (CDCI,) δ; 1.4-2.4
(IOH, m>, 2.5-2.8(2)1.m).

3.41 (IH, m>, 3.58 (2H, s>,
4.05(2t(,t).

4.48 (2H, s), 7.01 (2H, t),
7.30(2)1. dd).

8, 53 (1) 1. s), 8.68 (IH, s)
-MS m/e; 416 (M+) ・Melting point (t); 155-160 ・Molecular formula; C20H25N502S -2) ICI・
') l-NMR (CDC1,) δ; 1.5-2.5
(108, m), 2.5-2.8 (2H, m).

3.38 (2H, s), 3.50 (LH, m), 3
．． 60 (2H, s).

4.03 (2ft, t), 4.63 (2N, s),
7.1-7.8 (3H, m), 8.3-8.5 (2H
, m), 8.62 (18, s>-MS m/e;
399 (M") ・Melting point (℃); Amorphous ・Molecular formula: C21H26N402S 'HCl-'
H-NMR (CDCI, ) δ; 1.3-2.6 (6
H, m), 2.0-2.7 (6H, m), 2.76
(2H, s), 3.57 (2H, s), 4. Old (2
H, t), 7.23 (5N, m), 8.48 (l)
I, S), 8.63(1)1. s)・MS m/e
; 398 (M") ・Melting point (t); 185-190 ・Molecular formula; C22) 1211N404.1 (CI・'
H-NMR (CDCI3) δ: 1.5-1.9 (2
H, m), 2.0 to 2.7 (IOH, m>2.7
3 (2fl, s), 3.9~4.2 (5ft, m>
, 4.67(2H,s>, 7.0~7.3(5
H,m), 8.14(LH,s)-MS m/e
; 412 (M') 0 melting point (°C); amorphous, molecular formula; self all + 6 to "102, HCI, '
H-NMR (1 CDC) δ; 42 4.00 (3H, s), 4.04 (2H, s),
4.80 (2H, d).

6.06 (IH, dt), 6.50 (IH, d),
7.20(5)1. m).

? , 94 (1)1. s) ・US m/e; 296 (M+) ・Melting point (℃); 185-188 (decomposition) ・Molecular formula;
C20H26N60 ・3tlCI・'H-NMR(
CDCl2) δ; 1.6-2.0 (2N, m),
'2.2-2.7 (1ON, m).

3.51 (2H, s), 3.96 (2H, t),
4.23(2)1. s).

? , 25 (6H, s), 8.02 (IH, s),
8.21(18,s)・MS m/e; 306(
M”) ・Melting point (tl:); 202-205 (decomposition) 43 ・Molecular formula; C, 5H ・'H-NMR (CDCl 3) 4, 30 (2H, s).

6, 58 (LH, d).

8, 24 (LH, s) -MS m/e; 284 (M+) Melting point (°C); 193 3FN, O.HCI δ; 4.66 (2) 1. d), 6.08 (IH, dt)
.

6.8-7.4 (4N, m), 7.94 (IH).

~195 (decomposition) ・Molecular formula: C21H26N402S・2H['ll・
'H-NMR (CDCI,) δ; 1.5-2.
9 (12H, m), 3.3-3.5 (ltl, m)
.

44 3, 50 (2H, s), 3.98 (2tl, t
), 4.52 (2H, s).

7.0 to 7.5 (4N, m), 8.10 (IH,
m), 8.48 (2tlm) -MS m/e; 398 (M+) ・Melting point (t); Hygroscopic amorphous ・Molecular formula: C2□H28N-023・2HCI・'H
-NMR (CDCl3) δ1.08-2.16 (
IIH, m), 2.32 (2H, t), 2.6
2-2.96 (4H, m), 3.48 (2H, s)
, 3.96 (2N, t).

6.92-7.24 (3N, m), 7.47 (IH
, dd), 7.52 (IH, dd), 8.09
(IH, dd), 8.43 (III, dd)-MS
m/e; 396 (M”) ・61 points (t); Hygroscopic amorphous = 145 ・Molecular formula; C21H26N402S・211CI・'H
-NMR (CDCl2) δ; 1.68 (2H, dd
), 2.00-2.52 (411, m), 2.
93 (2tl, s>, 2.80-3.36 (6H,
m), 3.47 (2H, s).

3.98(2)1. t), 6.56 (Ift, br
), 7.00-7.24 (3H, m), 7.5
4(ltl, dd>, 7.61(IH, dd).

8.09 (LH, dd), 8.34 (IH, dd)
-MS m/e; 398 (M+) ・Melting point (℃); Hygroscopic amorphous 46 ・Molecular formula: C22H27N3O3-HCI・tNM
R (CDCI 3) δ; 1.1-2.2 (9H, m
), 2.3-2.6 (4tl, m).

2.7-3.1<2H, m), 3.42<28. s)
, 3.95 (2H, t), 6.9-7.3 (6H,
m), 7.49 (IH, dd).

8, 10 (LH, dd) ・MS m/e; 381 (M”) 0 melting point (°C);
Amorphous/Molecular formula: CzJ2<FJs02S HHCI/'
)l-NMR (CDC13) δ ・1.5-2
．． 9 (12H, m>, 3.48 (28, s), 3.
98 (2N, t), 4.33 (Ift, m), 6.
86(2H,d), 6.9-7.2(it(,m),
7.3-7.6 (3H, m), 8.11 (IH, d
cl) -MS m/e; 451 (M'')47 ・Melting point (1); Amorphous ・Molecular formula; C22H27N302S-tlcl・'H
-NMR (CDCI3) δ; 1.1 to 2.0 (6N
, m), 2.05-2.8 (8H, m) 3.45 (
2H, s), 3.95 (2H, t), 6.9~
7.6(7)1. m), 8.10(IH, dd)-
MS m/e; 397 (M") ・Melting point (℃); Amorphous ・Molecular formula; C21826N, O3-HC148 0'H-NMR (CDCI,) δ; 1.1-2.2
(7H, m), 2J ~2.6 (2tl, m),
2.70 (2H, d), 2.7-3.3 (4H,
m), 3.43 (3H,S).

3.96 (2H, t), 6.9-7.3 (3) 1.
m>, 7.4-7.7 (2H, m), 8.12
(Ift, dd), 8.45 (IH, dd) - MS
m/e; 382 (M") ・Melting point (℃); Amorphous ・Molecular formula: C, 51t2.N, O3-HCI・' H
-NMR (CDCI 3) δ; 1.2-2.0 (I
OH, m>, 2.1-2.5 (4H, m).

3.47 (2H, s), 3.95 (2H, t),
7.10(1)l, dd).

7.45 (IH, dd), 8.07 (1)1.
dd)-MS m/e; 291 (M”)・Melting point (
°C); Amorphous 49 ・Molecular formula; C21826N40□S・2HCIO'H
-NMR (CDCI3) δ; 1.3 to 2.4 (10
tl, m), 2.5-2.8 (2tl, m>3.3
9(1)1. m), 3.48(2H,s>, 3
．． 97(2)1. t).

4.52 (2H, s), 7.0-7.3 (2H, m
), 7.4-7.7 (2H, m), 8.10 (
IH, dd), 8.3 to 8.6 (2H, m) -MS m/e; 398 (M") ・Melting point (℃); Amorphous 50 ・'H-NMR (CDCI3) δ; 0.9 to 2.1
(11) 1), 2.2-2.9 (811), 3
．． 44 (2H, s), 3.92 (2tl, t),
6.9-7.6 (5H).

8.06 (1N, dd), 8.3-8.5 (III
)-MS m/e; 410 (M”) ・Melting point (t); Hygroscopic amorphous ・Molecular formula: C+ 8822NSOS・2HCI・'H
-NMR (CDC13) δ; 1.5 to 3.0 (13
tl), 3.46 (2H, s), 4.00 (2
H, t), 6.76 (IH, s), 7.0~7
．． 7(3)1).

8, 17 (IH, dd) -US m/z; 358 (M") ・Melting point (t); 179-180 = 151 ・Molecular formula; C21fhsN50□S・2ICI・')I
-NMR (CDCI, ) δ; 1.5-3.0 (13
H, m>, 3.56 (2) 1. s), 3.8~
4.2(3)1. m), 7.0 to 8.2 (7H, m
), 8.50 (IH, m>-MS m/e; 4
11 (M+)・Melting point (℃); Oil molecular formula: Cl3814N40S・2HC1'H-NM
R (CDC1,) δ; 1.86-2.29 (2H, m), 3.54 (2H
,s), 4.09 (4H, 2xt), 6.97
(11-1,br,s), 7.06-7.2952 (3)1. t), 7.51 (18, br, s).

-MS m/e; 273 (MH)”・Melting point (tl
:);168-1708,26 (IH,t) ・Molecular formula: C+5LsLO□5-)HCI・'H-
NMR (CDCI3) δ: 1.94-2.31 (2
H, m), 3.52 (2H, s), 3.99 (
2H,t), 4.16(21(,t), 6.7
0-7.51 (7H, m).

8, 08 (ltl, br, d) -MS m/e; 300 (M+) ・Melting point (°C): 115-117 53 ・Molecular formula; self 6H ・'H-NMII (CDCI*> 3,52 (2H,s).

6, 55 (IH, d).

(18, da) -MS m/e; 266 (M”)・Melting point (°C)
;170 4N20S-HCI δ; 4.70 (2H, d), 6.17 (IH, dt).

7.0-7.6 (7)1. m) 8.20-173 ・Molecular formula; C2, H25N, O3, ・HCI・'H-
NMR (CDCI3) δ; 1.6-2.0 (2tl
, m), 2.3-2.6 (6H, m), 3.4
8 (2H, s), 3.6-3.9 (411, m),
3.98(2)1. t).

6.9-7.5 (8H, m>, 8.16 (LH, m
)-MS m/e; 427 (M+) ・Melting point (t); Hygroscopic amorphous 54 ・Molecular formula; C17)12ON40s -28C1・'
)I-NMII(CI)CI, ) δ; 1.7-2.
0(2)1), 2.5-3.1(6H), 3.
48 (2H, s), 4.0 (1 (2) 1.t),
7.0-7.7(5)1).

8.10(III, dd), 8.04(1)1. d
d)・MS m/e; 328 ・Melting point (℃); Molecular formula of hygroscopic amorphous O; C20H23FN40S ・2+1CI・
'H-NMR (CDCI,) δ; 1.6-2.0 (
2tl, m), 2.1-2.7(4)1. m).

2.8 55 ~3.2 (2H, m), 3.46 (2H, s),
3.97 (2H, t).

6.6-7.2 (4H, m), 7.41 (2H, d
), 8.07 (18, dd) ・MS m/e; 386 (M”) ・Melting point (t); 185-190 ・Molecular formula: [:181(22NBO3・28CIQ'
) I-NMR (CDC1a) δ; 1.7-2.0 (
2N), 2.2-2.5 (611), 3.50
(2H, s), 3.6-3.9 (4H), 4.
00 (2H, t).

6.44 (LH, t), 7.10 (IH, dd),
7.47 (IH, dd).

8.10 (ill, dd), 8.23 (2H, d)
-MS m/e; 370 (M+) ・Melting point (tl:); 172-178 (decomposition) 56- ・Molecular formula; (:, 9H23N50S ・2) IC+・
') I-NMR (CDCI3) δ; 1.7-2.0
(2H), 2.3-2.6 (6H), 3.3-3.
6 (6H), 4.00 (2tl, t), 6.5~6
．． 7 (211).

7.10 (Ill, dd), 7.3-7.6 (2N)
, 8.10 (2H, dd) -MS m/e; 369 (M") ・Melting point (t); 195-198 (decomposition) ・Molecular formula;
Cl5)122N40s・2HC]・H-NMR
(CDCI3) δ; 1.75 (211, m),
2.27 (311, s), 2.2-2.6 (IOH
, m), 3.42 (28, s>, 3.95 (2
11,t).

7.04 (Ill, dd), 7.38 (Ill, d
), 8.07 (ill, d)・MS m/e;
306 (M+) ・Melting point ('C); 204-208 (decomposition) ・Molecular formula; C2+LJnllS・2NCI・'H-NMR (C
DC1,) δ; 1.75 (21(, m), 2.
1 ~ 2.7 (1 (Ill, m), 3.46 (4H
,s), 3.95(211,t), 6.9~7
．． 3 (6H, m).

7.42(2+1.d), 8.06(I)I, dd
)-MS m/e; 382 (+,!”)・Melting point (t
); 231-236 (minute 8 + 7) 58 ・Molecular formula; CaoH2sNsO3'38C1・'H
-NMR (CDCl2) δ; 1.6-2.0 (2H
), 2.2-2.7 (IOH), 3.48 (2
N, s), 3.64 (2tl, s), 3.98
(2ft, t), 7.0-7.7 (5H), 8
．． 10 (IH, dd), 8.48 (LH, br, d
)-MS m/e; 383 (M') ・Melting point (℃); Hygroscopic amorphous ・Molecular formula: C2+HzJsO3・3HC1・' H-
NMR (CDCI 3) δ: 1.6-2.0 (2H
), 2.2-3. H14H).

3.50 59 (2)1. s), 4.00 (2N, t), 6.
9-7.6 (5H).

8.10(11(,dd), 8.3~8.5(1N
)・MS m/e; 397 (M”)・Melting point (t:); 165-167 (decomposition)・Molecular formula; C2,I (26N, 03S-'H-NMR (CDC
l2) δ: 1.44-2.82 (12tl),
3.35-3.68 (IH, m).

3.35-3.68 (LH, m), 3.49 (2H
,s>, 3.97(2)1. t), 4.73(
2H, s), 7.00-7.60 (5H).

8.02-8.24 (2H) ・MS m/e; 415 (MH+) 0 melting point (℃)
;Amorphous=160 (119) ・Molecular formula: C21H28N403S ・'H-NMR (CDC1,) δ; 1.34-2.
94 (12H, m), 3.23-3.63 (IH,
m).

3.79 (IH, d), 4. IH2nd, t),
4.28 (E, d).

4.65 (2H, s), 7.06~7.97 (5t
l, m>, 8.40 (IH, dd), 8.51
(IH,br,d)-MS m/e; 415(M”
) ・Melting point (℃); Amorphous ・Molecular formula; C2□H27N302・HCI1 ・'H-NMR (CDCl2) δ; 1.14-2.
04(9)1. m), 2.24-2.40 (4H,
m).

2.68-2.99 (2N, m), 3.92 (2N
,t), 4.78(2H,s), 6.94(1
N, dd), 7.04-7.30 (5H, m),
7.40(1)1. dd), 7.84 (1)1.
dd)-MS m/e; 365 (M”) ・Melting point (t); 198-199 (decomposition) ・Molecular formula;
C2J2J30: +・l-lCl・'II-NMR (C
DCl2) δ; 1.12 to 2.68 (1311, m
), 2.74 (211,s), 3.94 (28
,s), 4.77(2H,s), 6.94(L
H, dd).

7.22(5)1. bs), 7J8 (18, dd)
, 7.88(l)l, dd)-MS m/e;
381 (Ma ・Melting point (t); 94-95 (decomposition) 62 O molecular formula: C2JzJJ3oa ・HCI')I
-NMR (CDCl3) δ; 1.56-2.80
(12)1. m), 3.96(2)1. t), 4.
20-4.46 (18, m), 4.78 (2H, s)
, 7.90 (2H, d).

6.94 (Ill, cld), 7.36 (IH, dd
), 7.46 (211, d).

7,86 (IH, dd) -MS m/e; 435 (M") ・Melting point (℃); Hygroscopic amorphous ・Molecular formula: CzoLJ403・2HC]163 ・1H-NMR (CDCI3) δ; 1.5-2 .9
(12H), 3.96 (21+, t), 4.7
8 (2H, s), 5.0-5.2 (111),
6.5-7.6 (5H).

7, 84 (IH, dd), 8.05 (IH, dd)
・MS m/e; 3690J)+1・Melting point (℃);
Oily/Molecular formula; C2, H26N403/2HCI/'II
-NMR (CDC1,) δ; 1.2 ~ 2.9 (1
2)1. mn, 3.47 (III, n+), 3
．． 95 (2H, t), 4.63 (2N, s),
4.76 (2H, s), 6.8-7.2 (2H, m
), 7.2~7.4(2N, m>, 7.60(
IH, dd), 7.84 (lit, dd), 8
．． 43(IH,d)-MS m/e; 382(M+
) ・Melting point (℃); Amorphous 64 ・Molecular formula; C22H25F, N, D, ・2HCI・
'H-NMR (CDCI 3) δ; 1.6~
2.9 (12H, m), 3.94 (28, t), 4
．． 12 (2N, s), 4.37 (IH, m), 5.
82 (LH, bs).

6.64 (IH, dd), 6.89 (2N, d),
7.19 (E, d).

1.45 (21 (, d), 7.70 (III, d) -
MS m/e; 434 (M”)・Melting point (℃); Amorphous・Molecular formula: C22H27N303・2HC]・'H
-NMR (CDCI3) δ; +Rζ − 1,1 to 2.6 (12H, m), 2.73 (2H,
s), 3.98 (2H, t), 5.64 (2H, s
), 6.82 (IH, d), 7.20 (5B, s
), 8.10(1)1. d), 8.26 (E, s)
-MS m/e; 381 (M') 0 melting point (°C);
Amorphous/Molecular formula; C, sHa+N30□・2HC1・')
I-NMR (CD(: l,) δ; 1.2-1.
8 (6H, m), 1.90 (211, m), 2.1~
2.5 (61 (, m), 3.97 (2H, t), 4
．． 64 (2H, s), 679 (IH, d), 8.0
9(1N, d), 8.27(ill, s)-MS m
/e; 291 (M+) ・Melting point (t:); 180-183 (decomposition) 166- ・Molecular formula; C2,826N-03・3HC]・'H-
NMR (CDCl2) δ; 1.6-2.9 (12H
,+n), 3.49(IH,m), 4.03(
2fl,t), 4.65(2H,s), 4.6
9 (2H, s), 6.86 (IH, d), 7.
15 (IH, t), 7.3-7.8 (2H, m).

8.17 (LH, d), 8.33 (IH, s>,
8.49 (Iff d)・MS m/e; 382
(M") ・Melting point (℃); Amorphous ・Molecular formula: C2+LJ40°・3HC]・'II-N
MR (CDCl2) δ; 1.80 (2H, m>,
2.2-2.6 (IOH, m), 3.44 (2H
,S), 3.95(2H,t), 4.60(2
H,s), 6.76(ltl,d), 7.19
(511,s>, 8.09(IH,d), 8.
26(IH,S) -MS m/e; 366(M") ・Melting point (℃); 197-203 ・Molecular formula; Self-5H22N402・311C+・'H-N
MR (CDCl2) δ: 1.84 (28, m),
2.27 (3H, s), 2.3~2.6 (108
, m), 4.00 (2H, t), 4.65 (2
H,s).

6.83 (IH, d), 8.11 (IH, d),
8.29(1N,s)・MS m/e; 290(
M") ・Melting point (t); 258-262

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, A^1 and A^2 mean the same or different carbon atoms or nitrogen atoms. However, at least one of them is a nitrogen atom. R^1 is a hydrogen atom, hydroxyl group, lower alkoxy group, formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^4 and R^5 mean the same or different hydrogen atoms or lower alkyl groups) means the group or halogen atom shown. R^2 and R^3 mean the same or different hydrogen atoms, lower alkyl groups, aryl groups or arylalkyl groups. W is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^6 in the formula
means a hydrogen atom or a lower alkyl group), a group represented by the formula -O-, or a formula ▲ Numerical formula, chemical formula, table, etc. ▼ (where p is 0 or an integer from 1 to 2) means a group represented by -B- means a group represented by the formula ▲A mathematical formula, a chemical formula, a table, etc. are available, or a group represented by the formula ▲A mathematical formula, a chemical formula, a table, etc. are available. E is a hydrogen atom or a formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, u means 0 or 1. ) or a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, m means an integer from 2 to 8). Y and Z are the same or different nitrogens It means a group represented by an atom or formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^8 means a hydrogen atom or a hydroxyl group). Both r and s mean an integer from 1 to 3. R^7 is: (1) hydrogen atom, (2) lower alkyl group, (3) formula -J-K (wherein J is the formula -(Alk)_a- (in the formula, a means 0 or 1) , Alk means a linear or branched alkylene group having 1 to 6 carbon atoms), a group represented by the formula -O-(CH_
2)_b- (in the formula, b means 0 or an integer from 1 to 3)
There are groups and formulas represented by ▲ Numerical formulas, chemical formulas, tables, etc. There are groups and formulas represented by ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^9 means a hydrogen atom or a lower alkyl group, and Q means an oxygen atom or a sulfur atom), a group represented by the formula ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1^0 means a hydrogen atom or a lower alkyl group, Q means an oxygen atom or a sulfur atom), or a group represented by the formula -CH_2
-CH=CH- means a group represented by -CH=CH-. K is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1 in the formula
^1, R^1^2 are the same or different hydrogen atoms, halogen atoms, lower alkyl groups, halogenated lower alkyl groups,
lower alkoxy group or cyano group), formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula R^1
^3 means a hydrogen atom or a lower alkyl group), formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula R
^1^4 means a hydrogen atom or a lower alkyl group), a cycloalkyl group, a furyl group, a thienyl group, or a heterocyclic group consisting of a 5- to 6-membered ring containing two nitrogen atoms ), (4) a group represented by the formula -L-M (wherein L is -(CH_2)_c- (in the formula, c means an integer of 1 to 3), a group represented by the formula -CH_2-CH= C
A group represented by H-, a group represented by the formula -(CH_2)_d-O- (in the formula, d means an integer of 1 to 3), or a group represented by the formula -(CH_2)_e-NH-(CH_2)_f - means a group represented by (in the formula, e and f mean integers of 1 to 3). M means a phenyl group or a heteroaryl group having 1 to 2 nitrogen atoms) A compound having a fused heterocycle represented by Physically acceptable salt. 2 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A^1 and A^2 mean the same or different carbon atoms or nitrogen atoms. However, at least one of them is a nitrogen atom. R^1 is a hydrogen atom, hydroxyl group, lower alkoxy group, formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^4 and R^5 mean the same or different hydrogen atoms or lower alkyl groups) means the group or halogen atom shown. R^2 and R^3 mean the same or different hydrogen atoms, lower alkyl groups, aryl groups or arylalkyl groups. W is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^6 in the formula
means a hydrogen atom or a lower alkyl group), a group represented by the formula -O-, or a formula ▲ Numerical formula, chemical formula, table, etc. ▼ (where p is 0 or an integer from 1 to 2) means a group represented by -B- means a group represented by the formula ▲A mathematical formula, a chemical formula, a table, etc. are available, or a group represented by the formula ▲A mathematical formula, a chemical formula, a table, etc. are available. E is a hydrogen atom or a formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, u means 0 or 1. ) or a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, m means an integer from 2 to 8). Y and Z are the same or different nitrogens It means a group represented by an atom or formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R^8 means a hydrogen atom or a hydroxyl group). Both r and s mean an integer from 1 to 3. R^7 is: (1) hydrogen atom, (2) lower alkyl group, (3) formula -J-K (wherein J is the formula -(Alk)_a- (in the formula, a means 0 or 1) , Alk means a linear or branched alkylene group having 1 to 6 carbon atoms), a group represented by the formula -O-(CH_
2)_b- (in the formula, b means 0 or an integer from 1 to 3)
There are groups and formulas represented by ▲ Numerical formulas, chemical formulas, tables, etc. There are groups and formulas represented by ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^9 means a hydrogen atom or a lower alkyl group, and Q means an oxygen atom or a sulfur atom), a group represented by the formula ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1^0 means a hydrogen atom or a lower alkyl group, Q means an oxygen atom or a sulfur atom), or a group represented by the formula -CH_2
-CH=CH- means a group represented by -CH=CH-. K is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1 in the formula
^1, R^1^2 are the same or different hydrogen atoms, halogen atoms, lower alkyl groups, halogenated lower alkyl groups,
lower alkoxy group or cyano group), formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula R^1
^3 means a hydrogen atom or a lower alkyl group), formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula R
^1^4 means a hydrogen atom or a lower alkyl group), a cycloalkyl group, a furyl group, a thienyl group, or a heterocyclic group consisting of a 5- to 6-membered ring containing two nitrogen atoms ), (4) a group represented by the formula -L-M (wherein L is -(CH_2)_c- (in the formula, c means an integer of 1 to 3), a group represented by the formula -CH_2-CH= C
A group represented by H-, a group represented by the formula -(CH_2)_d-O- (in the formula, d means an integer of 1 to 3), or a group represented by the formula -(CH_2)_e-NH-(CH_2)_f - means a group represented by (in the formula, e and f mean integers of 1 to 3). M means a phenyl group or a heteroaryl group having 1 to 2 nitrogen atoms) A compound having a fused heterocycle represented by the following or a drug thereof A central muscle relaxant whose active ingredient is a physiologically acceptable salt.