JPH0780886B2 - Tricyclic-bonded hydroxyguanidine, method for producing the same, and anticancer composition containing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel tricyclic-linked hydroxyguanidine, its pharmaceutical use and production.

[0002]

Background of the Invention Ribonucleoside reductase is DN
It is an important enzyme involved in A synthesis and cell replication, and is an important target in the development of anticancer agents by suppressing DNA synthesis [Prog. In Drug Res., 1987, 31, 101.]. Initially, it was reported that hydroxyurea and guanidine derivatives act at the site of this enzyme and have antiviral and anticancer activity [Can.
cer Res., 1967, 27, 535.].

Thereafter, it was reported that a hydroxyguanidine derivative having functional groups bound to both the anticancer agent hydroxyurea and the antiviral agent guanidine derivative had anticancer activity and antiviral activity "J. Med. Chem., 1990, 33,". 608.].
However, since this type of compound is hydrophilic and has a low molecular weight, it has a short half-life, rapid metabolic conversion into an inactive form, and spinal cord depression. Hydrophobicity is known to play an important role in binding a substrate or inhibitor to the active site of an enzyme, and the hydrophobic region near the active site of such enzyme is dihydrofolate reductase, guanase, thymidine, phosphorylase, and purine. Found in nucleoside phosphorylase. As a result of careful investigation by the present inventors, the following formula (I)
Based on this finding, we discovered that the tricyclic-bonded hydroxyguanidine shown in Fig. 2 is more stable, hydrophobic, and has important rigid structural properties for exerting the biological activity of both hydroxyurea and guanidine. Completed the invention.

The above references do not indicate or suggest compounds, compositions and uses thereof in connection with the present invention.

[0005]

SUMMARY OF THE INVENTION The present inventors have developed a series of novel compounds having more excellent anticancer activity than hydroxyguanidine derivatives, which are currently recognized to be the most prominent among hydroxyguanidine and hydroxyurea having anticancer activity. As a result of their discovery and as much research as possible, they have discovered that compound (I) suppresses cancer cells more than hydroxyguanidine and hydroxyurea.

The present invention comprises a series of tricyclic linked hydroxyguanidine diamines of formula (I) and pharmaceutically acceptable salts thereof.

[Chemical 7] In the formula, Y represents SO ₂ or C═O;

A is C _2-4 alkylene which may be substituted with one hydroxy; halogen, C _1-4 alkyl, C _1-4
Represents phenyl optionally substituted with one or two substituents selected from alkoxy, mono C _1-4 alkylamino, nitro, amino, trifluoromethyl and cyano;

R ₁ represents hydrogen, C _1-4 alkyl, C _1-4 alkoxy, nitro, amino, trifluoromethyl, cyano or phenyl-lower alkyl;

R ₁ R ₂ together represent C _4-10 alkylene.

The compounds of the present invention may exist as hydrates or stereoisomers, and these hydrates and stereoisomers are naturally included in the scope of the present invention.

The present invention provides a patient with a therapeutically effective amount of Compound (I)
Is also provided to suppress the ribonucleoside reductase activity.

The present invention further provides an antitumor effective amount of compound (I)
The present invention provides a method for treating a tumor patient or controlling tumor growth.

The present invention also provides an antivirally effective amount of a compound.
(I) is administered to provide a method for treating a patient infected with a virus or controlling the virus infection.

[0014]

EXAMPLES Lower alkyl as used in the above definitions includes C _1-6 straight or branched chain alkyl, alkylene includes straight or branched chain alkylene, and halogen refers to fluorine, chlorine, and bromine.

Examples of pharmaceutically acceptable salts include salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, phosphates, salts with organic acids such as acetates, maleates, tartrates, methane. Examples thereof include sulfonates, benzene sulfonates, towene sulfonates, and salts with amino acids such as arginine, aspartic acid and glutamic acid.

Preferred compounds within formula (I) include 10
-N-hydroxy-2,3-dihydroimidazo [1,2
-B] [1,2,4] benzothiadiazine 5,5-dioxide and 11-N-hydroxy-2,3-dihydro-
4H-pyrimido [1,2-b] [1,2,4] benzothiadiazine 6,6-dioxide.

The tricyclic linked hydroxyguanidine (I) can be prepared by methods and techniques well known and recommended by those skilled in the art.

A suitable method for preparing compound (I) comprises the following steps: (a) the following formula

[Chemical 8] In the formula, A represents a compound represented by the following formula

[Chemical 9] In the formula, X is a halogen, and R is a C _1-4 alkyl or benzyl.

(B) The following formula obtained in step (a)

[Chemical 10] In the formula, A and R have the same meanings as described above, and a compound represented by

[Chemical 11] In the formula, R ₁ , R ₂ and Y have the same meanings as described above, and Z is a halogen.

(C) The following formula obtained in step (b)

[Chemical 12] In the formula, A, R, R ₁ , R ₂ and Y have the same meanings as described above, and the compound represented by the formula is treated with a reducing agent, preferably zinc powder.

Compound (VI) is the key intermediate chosen for the synthesis of Compound (I), and by appropriate operation, the reduction of the nitro group on the benzene ring with zinc powder is stopped with hydroxyamine rather than amine. can do. Next, the nitrogen atom of hydroxyamine undergoes nucleophilic substitution with the alkylthio group to give compound (I).

To synthesize compound (VI), compound (IV) obtained by reacting compound (II) with compound (III) is converted to compound (V).
The resulting compound (VI) is reduced with the nitro group and cyclized.

In step (a), compound (II) is commercially available or can be obtained by treating a diamino compound with carbon disulfide in the presence of a base. A salt of compound (IV) is obtained by treating this compound (II) with compound (III) in the presence or absence of a base. Compound (II) Compound (II
Alkylation with I) can use any solvent that does not interact with the reactants. Suitable examples of the solvent include chloroform, dichloromethane, ether, DMF and the like.

In step (b), compound (IV) and compound
The reaction of (V) is carried out in the presence of a base such as triethylamine, pyridine, DBU, DBN, etc. However, in the absence of the base, a salt of compound (VI) can be obtained. Any inert solvent can be employed as long as it does not adversely affect the reaction. Suitable examples of the solvent include alcohol, chloroform, dichloromethane, ether, DMF and the like. The reaction is usually in the presence of a base,
Perform at room temperature for 1 hour, or reflux for 2 hours in the absence of base.

The reduction reaction of compound (VI) in step (c) is carried out with an acid such as acetic acid in a salt-ice cold bath. The reaction is usually completed in 1 hour. Since the crude product separated from the reaction mixture is complexed with 1 equivalent of zinc, the crude product is dissolved in ethanol and treated with 0.1 M EDTA to obtain the desired product.

The developed compound (I), its salts and hydroxyguanidines have very strong activity against various cancer cells (ED ₅₀ against KB, Colo 205, Hela, Hep-2
(1.1 mg / ml) and very high stability, it is useful for cancer and virus treatment.

Next, the effect of the compound of the present invention will be shown by the following in vitro anticancer assay. In vitro anti-cancer analysis by MTT method. Cells were taken from an experimental culture and 5% fetal bovine serum in a 96-well plate,
At 37 ° C in RPMI-1640 medium supplemented with 1 mM glutamine and antibiotics (penicillin, streptomycin)
After culturing in a CO ₂ incubator, the cell suspension was digested and dispersed with trypsin, 3 × 10 ³ cells were inoculated into each well of 0.18 mL medium, 0.02 mL of the drug was added, and the cells were cultured for 4 days. After removing the culture solution, 0.1 mg of 3-4,5-dimethylthiazole-2,5-diphenyltetrazolium bromide (MTT) was added to each well and incubated for 4 hours. 0.2 mL of DMSO was added to each well. Add, stir for 10 minutes, and then adjust the optical density of each hole with Titertek Multiskan.
Using a plate reader, the measurement wavelength was 545 nm and the reference wavelength was 690 nm. The absorbance of the dosed cells was calibrated with untreated control values, the results are shown in Table 1-2.

[0028]

[Equation 1]

[0029]

[Table 1]

[0030]

[Table 2]

Example 1 2-Benzylthio-2-imidazolidine Hydrobromide 2-Mercaptoimidazolidine (10 g, 98 mmo)
l) was mixed with 200 ml of methanol, benzyl bromide (23 ml, 100 mmol) was added, refluxed in an oil bath, 1 hour later, evaporated in vacuo, the obtained oil was taken up in 10 ml of methanol, and 206 ml of ether was added. Was added to obtain 2-benzylthio-2-imidazolidine hydrobromide (26.2 g, 98%). The analytical sample was recrystallized from acetone. mp 172-175 ° C (de
c), ¹ H-NMR (100 MHz, DMSO-d6
): Δ 3.86 (s, 4H, CH2), 4.59 (s,
2H, CH2), 7.31-7.41 (m, 5H, Ar-
H), 10.27 (brs, NH, HBr), ms: m /
z 273 (M ⁺ ), elemental analysis, C ₁₀ H ₁₃ N ₂ SBr
(273.29) calculated: C, 43.95, H, 4.79;
N, 10.25. Found: C, 44.01, H, 4.81;
N, 10.13.

Example 2 1- (2-Nitrobenzenesulfonyl) -2-benzylthioimidazolidine 2-Benzylthio-2-imidazolidine hydrobromide (6.2 g, 22.7 mmol) was added to 150 m of dichloromethane.
1 and triethylamine (8 ml, 57 mmol), stirred at room temperature for 1 hour and then evaporated in vacuo, 25 ml of methanol and 50 ml of water were added to the obtained white solid, the white solid was collected by filtration and recrystallized from methanol. , 1-
(2-Nitrobenzenesulfonyl) -2-benzylthioimidazolidine Thio-2-imidazolidine (8.2 g, 9
6%) was obtained. mp 112 ° C (dec), ¹ H-NM
R (100 MHz, DMSO-d6): δ 3.91
(S, 4H, CH2), 4.26 (s, 2H, CH2),
7.29 (s, 5H, Ar-H), 7.90-8.04 (m,
4H, Ar-H); ¹³ C-NMR (25 MHz, DMS
O-d6): δ 35.80, 45.53, 49.45, 53.
32, 124.69, 127.09, 128.14, 128.7
3,129.08,132.77,135.41,136.4
1, 147.54, 153.63; elemental analysis, C ₁₆ H ₁₅ N ₃
0 ₄ S ₂ (377.43) calculated: C, 59.92, H, 4.
00; N, 11.10. Measured value: C, 50.72, H, 3.8
3; N, 10.97.

Example 3 10-N-hydroxy-2,3-dihydroimidazo [1,2-b] [1,2,4] benzothiadiazine
5,5-dioxide

[Chemical 13] 1- (2-nitrobenzenesulfonyl) -2-benzylthio-2-imidazolidine (3.0 g, 7.96 mmol)
Was dissolved in 80 ml of acetic acid, 2.5 g of zinc powder was added over 30 minutes in an ice bath and evaporated in vacuo. 15 ml of ethanol was added to the obtained oil, and excess acetic acid was removed by vacuum evaporation at 50 ° C. The resulting white solid was collected by filtration, dissolved in 20 ml of ethanol and 5 ml of 0.1M EDTA.
By treatment with 10-N-hydroxy-2,3-dihydroimidazo [1,2-b] [1,
2,4] benzothiadiazine 5,5-dioxide (yield, 78%) was obtained. Also, from the filtrate, 2,3-dihydro-
1H-imidazo [1,2-b] [1,2,4] benzothiadiazine 5,5-dioxide (yield, 14%) was obtained. However, if the reaction time is extended to 2 days,
-Dihydro-1H-imidazo [1,2-b] [1,2,
4] benzothiadiazine 5,5-dioxide (yield,
83%) was additionally produced. 10-N-hydroxy-
2,3-dihydroimidazo [1,2-b] [1,2,
4] Benzothiadiazine 5,5-dioxide: mp
195 ° C, ms: m / z 239 (M ⁺ ), 223 (M ⁺
-16); ¹ H-NMR (300 MHz, DMSO-d
6): δ 3.85 (p, 2H, CH2), 3.97 (p,
2H, CH2), 7.25 (t, 1H, J = 7.7Hz, A
r−H), 7.47 (d, 1H, J = 8.6 Hz, Ar−
H), 7.75 (p, 1H, Ar-H), 7.83 (d, 1
H, Ar-H); ¹³ C-NMR (75 MHz, DMSO
-D6): δ44.01, 511.11, 113.41, 120.
70, 122.28, 122.72, 135.16, 138.5
3,149.59; Elemental _{analysis, C 9 H 9 N 3 0} 3 S (23
9.25) Calculated: C, 45.18, H, 3.79; N, 17.
56. Found: C, 45.18, H, 3.81; N, 17.4.
8.2,3-Dihydro-1H-imidazo [1,2-b]
[1,2,4] benzothiadiazine 5,5-dioxide: mp 267 ° C., ms: m / z 223 (M ⁺ ),
166, 158; ¹ H-NMR (300 MHz, DMS
O-d6): δ3.57 (t, 2H, J = 7.9 Hz, CH
2), 4.03 (t, 2H, J = 7.9Hz, CH2), 7.
17 (t, 2H, J = 8.2Hz, Ar-H), 7.57
(T, 1H, J = 7.8 Hz, Ar-H), 7.78 (d,
1H, J = 7.8Hz, Ar-H), 8.23 (s, 1H,
NH); ¹³ C-NMR (75 MHz, DMSO-d6
): Δ39.55, 41.78, 122.46, 122.8
7, 123.34, 125.51, 134.94, 146.3
7,155.10; Elemental _{analysis, C 9 H 9 N 3 0} 2 S (22
3.24) Calculated: C, 48.42, H, 4.06; N, 18.
82. Found: C, 48.78, H, 4.03; N, 18.9.
5.

Example 4 2-benzylthio-1,4,5,6-tetrahydro-2
-Pyrimidine hydrobromide In the same manner as in Example 1, 2-benzylthio-1,4,
5,6-Tetrahydro-2-pyrimidine hydrobromide was obtained, yield 97%. The analytical sample was recrystallized from acetone. mp 152 ° C .; ¹ H-NMR (100 MHz,
DMSO-d6): δ 1.78 (t, 2H, J = 5.6H
z, CH2), 3.34 (t, 4H, J = 5.8Hz, 2C
H2), 4.58 (s, 2H, CH2), 7.34 (s, 5
H, Ar-H), 9.98 (brs, 2H, NH + HB
r); ms: m / z 206 (M ⁺ ); elemental analysis, C ₁₁
H ₁₅ N ₂ SBr (287.31) Calculated: C, 45.99,
H, 5.26; N, 9.75. Measured value: C, 46.16, H,
5.29; N, 9.75.

Example 5 1- (2-Nitrobenzenesulfonyl) -2-benzylthio-4,5, -dihydro-6H-pyrimidine hydrobromide In the same manner as in Example 2, 1- (2-nitrobenzene Sulfonyl) -2-benzylthio-4,5, -dihydro-6
H-pyrimidine hydrobromide was obtained, yield 97%. The analytical sample was recrystallized from ethanol. mp 85 ° C
(Dec); ¹ H-NMR (100 MHz, DMSO-
d6): δ1.83 (m, 2H, CH2), 3.48 (m,
2H, CH2), 3.54 (m, 2H, CH2), 4.05
(S, 2H, CH2), 7.20 (s, 5H, Ar-
H), 7.81-8.00 (m, 4H, Ar-H); ¹³ C-
NMR (25 MHz, DMSO-d6): δ22.50,
35.39, 46.05, 46.35, 124.69, 126.7
0, 127.97, 128.55, 129.79, 131.6
6, 132.60, 135.00, 136.81, 145.2
5, 156.96; ms: m / z 391 (M ⁺ ); elemental analysis, C ₁₆ H ₁₇ N ₃ O ₄ S ₂ (391.46) calculated:
C, 52.16, H, 4.38; N, 10.74. Measured value:
C, 52.14, H, 4.42; N, 10.93.

Example 6 11-N-hydroxy-2,3-dihydro-4H-pyrimido [1,2-b] [1,2,4] benzothiadiazine 6,6-dioxide

[Chemical 14] In the same manner as in Example 3, 1- (2-nitrobenzenesulfonyl) -2-benzylthio-4,5, -dihydro-6.
Using H-pyrimidine hydrobromide, 11-N-hydroxy-2,3-dihydro-4H-pyrimido [1,2-
b] [1,2,4] benzothiadiazine 6,6-dioxide, yield 30%, and 1,2,3,4-tetrahydropyrimido [1,2-b] [1,2,4] A benzothiadiazine 6,6-dioxide yield of 10% was obtained, provided that
When the reaction was performed for 2 days, only the latter was obtained with a yield of 62%. 11-
N-hydroxy-2,3-dihydro-4H-pyrimido [1,2-b] [1,2,4] benzothiadiazine
6,6-dioxide: mp180-182 ° C ms: m /
z 253 (M ⁺ ), 237 (M ⁺ -16), 172;
¹ H-NMR (300 MHz, DMSO-d6): δ
1.83-1.97 (m, 2H, CH2), 3.43 (t, 2)
H, J = 5.6Hz, CH2), 3.79 (t, 2H, J =
5.6Hz, CH2), 7.22 (t, 1H, J = 7.5H
z, Ar-H), 7.56 (d, 1H, J = 8.4Hz, A
r-H), 7.67-7.85 (m, 2H, Ar-H); ¹³
C-NMR (75 MHz, DMSO-d6): δ21.3
6, 39.88, 41.84, 114.40, 121.32, 1
21.85,134.59,138.50,141.46; Elemental _{analysis, C 10 H 11 N 3 O} 3 S (253.28) Calculated: C,
47.42, H, 4.38; N, 16.59. Measured value: C, 4
7.50, H, 4.24; N, 164.54.1, 2, 3, 4-
Tetrahydropyrimido [1,2-b] [1,2,4] benzothiadiazine 6,6-dioxide: mp245-
248 ° C., ms: m / z 237 (M ⁺ ), 209, 1
72, 155; ¹ H-NMR (300 MHz, DMSO
-D6): δ 1.95 (m, 2H, CH2), 3.28
(T, 2H, J = 5.8Hz, CH2), 3.80 (t, 2
H, J = 5.5Hz, CH2), 7.07 (t, 2H, J =
7.9 Hz, Ar-H), 7.52 (t, 1H, Ar-
H), 7.64 (d, 1H, J = 7.7Hz, Ar-H),
8.05 (brs, 1H, NH, D ₂₀ exchangeable); ¹³ C
-NMR (75 MHz, DMSO-d6): δ21.6
4, 38.95, 41.95, 120.78, 120.97, 1
22.86, 1241.11, 133.79, 145.02, 14
8.83; Elemental _{analysis, C 10 H 11 N 3 O} 2 S (237.28)
Calculated: C, 50.62, H, 4.67; N, 17.71. Found: C, 50.41, H, 4.36; N, 17.53.

Example 7 1- (2-Nitrobenzoyl) -2-benzylthioimidazolidine 2-benzylthio-2-imidazolidine hydrobromide (6 g, 22 mmol) was added to 150 ml of dichloromethane.
Mixed with triethylamine (7 ml, 50 mmol)
Was added to form a transparent solution, 2-nitrobenzoyl chloride (4 g, 22 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
Stir for 2 hours, evaporate in vacuo, and add ethanol to the resulting solid.
5 ml and 50 ml of water were added, and the obtained white solid was collected by filtration and recrystallized from ethanol to obtain 7.2 g of the desired product.
(96%) was obtained. mp 131 ° C., ¹ H-NMR (3
00 MHz, DMSO-d6): δ 3.63 (brs,
2H, CH2), 3.86 (t, 2H, CH2), 4.23
(S, 2H, CH2), 7.32-7.41 (m, 5H, A
r-H), 7.76 (t, 2H, Ar-H), 7.90
(T, 2H, Ar-H), 8.24 (d, 1H, Ar-
H), ms: m / z 341 (M ⁺ ), elemental analysis, C _{17
H 15 N 3 O 3 S H} 2 O (359.40) Calculated: C, 5
9.81, H, 4.43; N, 12.31. Found: C, 59.
73, H, 4.49; N, 12.29.

[Example 8] 10-N-hydroxy-2H, 3H-tetrahydroimidazo [2,1-b] quinazolin-5-one

[Chemical 15] 1- (2-Nitrobenzoyl) -2-benzylthioimidazolidine (3 g, 8.8 mmol) was mixed with 60 ml of acetic acid, zinc powder (2 g, 31 mmol) was added in an ice bath, and the mixture was stirred for 30 minutes and allowed to come to room temperature. After raising the temperature and stirring for another 30 minutes, the zinc powder was filtered, the filtrate was evaporated in vacuo, 5 ml of acetone and 25 ml of ether were added to the obtained oil, and the obtained crude solid (1.71 g, 96%) was chromatographed. (Silica gel, 1.5 × 21 cm, chloroform / methanol = 8/2), pure target product (0.74 g, 42%)
Got mp 230 ° C., ¹ H-NMR (400 MH
z, DMSO-d6): δ 3.77 (m, 2H, CH2
), 4.05 (m, 2H, CH2), 4.33 (brs,
1H, OH), 7.17 (t, 1H, J = 7.8Hz, Ar
-H), 7.45 (d, 1H, J = 8.3Hz, Ar-
H), 7.67 (t, 1H, J = 7.8Hz, Ar-H),
7.84 (d, 1H, J = 7.8Hz, Ar-H), ms:
m / z 203 (M ⁺ , 85%), 187 (M ⁺ -1)
6,100%), 159. Elemental analysis, C ₁₀ H ₉ N ₃ O ₂
Calculated S H ₂ O: C, 54.30, H, 5.01; N, 1
8.99. Found: C, 54.03, H, 4.95; N, 18.
74.

Example 9 1- (2-Nitrobenzoyl) -2-benzylthio-
4,5-Dihydro-6H-pyrimidine hydrobromide In the same manner as in Example 2, 1- (2-nitrobenzoyl)
2-Benzylthio-4,5-dihydro-6H-pyrimidine hydrobromide was obtained, yield 97%. The analytical sample was recrystallized from ethanol. mp 100 ° C (de
c); ¹ H-NMR (400 MHz, DMSO-d6
): Δ 1.82 (s, 2H, CH2), 2.50 (t,
2H, CH2), 3.56 (m, 2H, CH2), 4.02
(S, 2H, CH2), 7.23 (s, 5H, Ar-
H), 7.60 (d, 1H, J = 7.3 Hz, Ar-H),
7.71 (t, 1H, J = 6.8Hz, Ar-H), 7.75
(D, 1H, J = 1.7 Hz, Ar-H), 7.83 (t,
1H, J = 6.8 Hz, Ar-H), 8.21 (d, 1H,
J = 7.3 Hz, Ar-H); ¹³ C-NMR (100.4 M
Hz, DMSO-d6): δ22.50, 35.34, 44.
80, 46.41, 124.72, 126.78, 127.9
1, 128.14, 128.89, 131.00, 131.7
7, 134.89, 137.22, 144.90, 149.4
7, 166.13; ms: m / z 355 (M ⁺ ); elemental analysis, C ₁₈ H ₁₇ N ₃ S ₃ (355.41) calculated: C, 6
0.83, H, 4.82; N, 11.82. Found: C, 60.
83, H, 4.90; N, 11.87.

Example 10 11-N-hydroxy-2H, 3H-pyrimide [2,1
-B] quinazoline-6 (4H) -one

[Chemical 16] 1- (2-nitrobenzoyl) -2-benzylthio-
4,5-Dihydro-6H-pyrimidine hydrobromide (3.
(0 g, 8.44 mmol) and 60 ml of acetic acid, zinc powder (2.0 g, 31 mmol) was added in an ice bath and stirred for 20 minutes. After warming to room temperature and stirred for 30 minutes, the zinc powder was filtered. Then, the filtrate was evaporated in vacuo, 20 ml of ethanol was added to the obtained oil, and the mixture was evaporated in vacuo several times to remove acetic acid. Finally, the obtained oil was dissolved in 20 ml of ethanol, and the mixture was left to stand in a refrigerator to give a solid. Are collected by filtration. The resulting crude solid (1.32 g, 72%) was added with 0.1M EDTA.
It was recrystallized from a mixed solution of 15 ml of ethanol and 15 ml of water in the presence of 3 ml of 11-N-hydroxy-2H,
3H-pyrimido [2,1-b] quinazoline-6 (4H)
0.51 g (96%) of on were obtained. mp 252 ℃, ¹
H-NMR (400 MHz, DMSO-d6): δ 1.
95 (m, 2H, CH2), 3.41 (m, 2H, CH2)
), 3.96 (t, 2H, CH2), 7.23 (t, 1)
H, Ar-H), 7.74 (t, 1H, Ar-H), 7.8
7 (d, 1H, Ar-H), 7.96 (d, 1H, Ar-
H); ms: m / z 217 (M ⁺ , 100%), 20
1 (M ⁺ -16, 25%), 200 (M ⁺ -17, 50)
%). Elemental _{analysis, C 11 H 11 N 3 0} 2 H 2 O (235) Calculated: C, 56.16; H, 4.71 ; N, 17.86. Found: C, 56.03; H, 4.90; N5 17.87.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical indication location A61K 31/55 C07D 513/04 373 375 381 (72) Inventor Chang-Ling Fan Taiwan, Tao Yang, Tashi, Yuan Rin Road, Section 2, Number 425 (72) Inventor Chahu Chen, Taiwan, Taipei, Wusin Street, Lane 336, Number 27

Claims (1)

[Claims] 1. The following formula (I): Wherein Y represents S O _2; A represents an optionally C _2-4 alkylene <br/> les emissions be substituted with one hydroxy; R ₁ is hydrogen, C _1-4 alkyl, C _1-4 Alkoxy, nitro, amino, trifluoromethyl, cyano or phenyl
-Representing lower alkyl; R _{1 and} R ₂ together represent C _4-10 alkylene; or a tricyclic-bonded hydroxyguanidine diamine or a pharmaceutically acceptable salt thereof. 2. A pharmaceutical composition for treating tumor, which comprises an antitumor effective amount of the compound (I) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable carrier is added thereto. 3. The compound is 10-N-hydroxy-2,3
-The compound of claim 1 which is dihydroimidazo [1,2-b] [1,2,4] benzothiadiazine 5,5-dioxide. 4. The compound is 11-N-hydroxy-2,3.
-Dihydro-4H-pyrimido [1,2-b] [1,2
, 4] Benzothiadiazine 6,6-dioxide. 5. (a) The following formula: In the formula, A has the same meaning as in claim 1, and a compound represented by the following formula: In the formula, X is a halogen, and R is a C _1-4 alkyl or a compound represented by benzyl is reacted; (b) The following formula: In the formula, A and display the same meaning as in claim 1, R is as defined formula 3
Means table to formula ## STR5 ## The compounds shown in, In the formula, R ₁ , R ₂ and Y have the same meanings as in claim 1,
Z represents a halogen, and is reacted with a compound represented by, and (c) the following formula: In the formula, A, R ₁ , R ₂ and Y have the same meanings as in claim 1.
And, R as defined tables to A of 3, in salt compounds represented - an ice bath, compound of claim 1 is treated with a reducing agent in acid production method (I). 6. The method according to claim 5 , wherein the reducing agent is zinc powder.