前苏联专利SU1731051A3 Method for synthesis of benzothiazole derivatives or theirs acid-additive salt

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专利摘要:
A benzothiazole compound having the formula below and pharmaceutical compositions containing it are disclosed which are effective to inhibit the production of leukotriene. The compounds can be used for the making of medicaments effective against allergy, asthma, affections of the skin, allergic rhinitis and affection of a cardiovascular system, <CHEM> in which R20 is ester or amide and -NR5R6 is amino in variety.
公开号:SU1731051A3
申请号:SU884356028
申请日:1988-06-16
公开日:1992-04-30
发明作者:Абе Синя；Миямото Мицуаки；Танака Масаюки；Акасака Козо；Хаяси Кендзи；Каванара Тецуя；Катаяма Тоси；Сакума Есинори；Сузуки Такеси；Ямацу Исао
申请人:Эйсай Ко., Лтд (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of new biologically active chemical compounds, namely benzothiazole derivatives, or their acid addition salts, which have an anti-asthmatic effect and can be used in medicine.
N- (benzothiazolyl-2) -base amides or M- (benzothiazolyl-2) -N-benzyl amines with anti-allergic activity are known.
A known method for producing N- (benzothiazol-2) -benzamides by reacting the corresponding 2-aminobenzo00
-sh-os-l
where R, 1C and R are, independently of each other, hydrogen, halogen, C-C-alkyl or Cr-C $ -alkanoyl, or two substituents from R ,, R and R are attached to adjacent carbon atoms of the benzene ring and represent a group of atoms, an additional benzene ring;
R is hydrogen, C, -C4 alkyl, C2-C / - alkanoyl, No.- (C -C alkylcarbamoyl or N, N-di (C) alkylcarbamoyl s X is a group -CO- or -CH2-;
Rg independently of one another, hydrogen, C.j-Ј4-alkyl or hydroxy-,,}. alkyl,
or their acid addition salts, which consists in the fact that 2-ammonium benzothiazole of formula II:
I
K4
where Rj, R $ and have the indicated meanings, and R has the meanings indicated for R2, except hydrogen,
68 g of 4-sulfamoyl benzoic acid are suspended in 500 ml of dimethoxyethane. 50 ml of thionyl chloride is added to the suspension and refluxed for 5 hours. Dimethoxyethane, thionyl chloride and hydrogen chloride are distilled off in vacuo in 500 ml of tetrahydrofuran . 50 g of 2-amyo 16-methoxy-4,5i 7-trimethylbenzothiazole is added to the solution obtained.
REID of formula III:
C1-CO exposure to chlorangid-40 and 10 ° ™ pyridine with cooling
solution with ice, then stirred for 1 h at room temperature. The reaction mixture is poured onto ice / water and then extracted with ethyl acetate under acidic conditions in the presence of hydrochloric acid. The organic phase is about
where Ry and Rg have the indicated values,
in the presence of a base, formed
target product, where X means -CO-,
washed with water and then dried over anhydrous magnesium sulphate. The solvent is distilled off and the residue is recrystallized, if necessary, subjected to decomposition from methanol, as a result of which lithium aluminum hydride is formed with 4T, 1 g of the title compound is obtained.
NMR (daso-dg): 2.24 (3N, s); 2.38 (3N, s); 2.52 (ЗН, s); 3.63 (ЗН, s) | 7.49 (2H, shir „s.); 7.89 (2H, d, I 10 Hz); 8.20 (2H, d, 1 10 Hz);
by irradiating the target product, where X is -CH2, and / or the target product, where Rt is methyl, is demethylated by boron tribromide to obtain the desired product, where Rfc is hydrogen, and the target product is isolated in free form or in in the form of an acid addition salt.
55
42.83 (1H, brs).
Example 2. Getting 6 tags- (4-sulfamoylbenzylamino) -4,5, 7-trimethylbenzothiazole
five
The examples below illustrate the invention of
In the examples below and in the tables in the PIR spectra (H-NMR), the signals of active hydrogen, which can be replaced by D20, are omitted,
Example 1 ,, Obtaining 6 labels- (4 sulfamoylbenzamido) -4,5,7- trimethylbenzothiaol
25
CH30
68 g of 4-sulfamoyl benzoic acid are suspended in 500 ml of dimethoxyethane. 50 ml of thionyl chloride is added to the suspension and refluxed for 5 hours. Dimethoxyethane, thionyl chloride and hydrogen chloride are distilled off in vacuo in 500 ml of tetrahydrofuran . 50 g of 2-amyo 6-methoxy-4,5i 7-trimethylbenzothiazole is added to the solution obtained.
NMR (daso-dg): 2.24 (3N, s); 2.38 (3N, s); 2.52 (ЗН, s); 3.63 (ЗН, s) | 7.49 (2H, shir „s.); 7.89 (2H, d, I 10 Hz); 8.20 (2H, d, 1 10 Hz);
42.83 (1H, brs).
Example 2. Getting 6 tags- (4-sulfamoylbenzylamino) -4,5, 7-trimethylbenzothiazole
CH30
38.7 g of lithium aluminum hydride in 1.2 l of tetrahydrofuran are suspended. To the suspension, 41.4 g of 6-methoxy 2- (4-sulfamoylbenzamido) -4,57-trimethyl benzothiazole are added at room temperature with stirring, the mixture is boiled 40 minutes under reflux, the reaction mixture is cooled with ice, then water is added. The precipitate formed is dissolved by adding concentrated hydrochloric acid. A saturated sodium bicarbonate aqueous solution is added thereto to adjust the pH to 4-5, then extract with ethyl acetate.
BUT
he.
jЈ -: nn-sn
N
20.7 g of 6-methoxy-2- (4-sulphamoyl-, benzylaminb) 4,5-trimethylbenzothiazole are suspended in 500 ml of methylene chloride. 200 ml of an i1M solution of boron tribromide in methylene chloride are added to the suspension with stirring at room temperature, then boiled under reflux for 30 minutes. The reaction mixture is allowed to cool, poured into a saturated aqueous solution of sodium bicarbonate for neutralization and extracted with ethyl acetate. The organic phase is washed with water and dried over anhydrous
- -NH- CH2 -O- so 2 H2 -O
19.5 g of 6-hydroxy-2- (4-sulfa moylbenzylamine -4.5, 7-three-methylbenzothiazole) are dissolved in 2 liters of ethanol with heating. Then ethanol is added, containing in a dissolved form hydrogen chloride, and cooled. The crystals formed are filtered off to give 19.5 g of the title compound as white crystals. mp. 210 ° C (decomposition) „
about i
n-cch7 y $ o2sh2
tomo The organic phase is washed with water and dried over anhydrous magnesium sulphate, then the solvent is distilled off. The residue is recrystallized from acetone / methanol to give 20.7 g of the title compound.
H-NMR (flMCO-dg), 8; 2.14 (3N, s); 2.22 (ЗН, s); 2.34 (3N, s); 3.56 (3N, s); 4.58 (2H, d, 1 7 Hz); 7.23 (2H, broad s); 7.47 (2H, d, 1 10 Hz); 7.72 (2H, d, 1 10 Hz); 8.32 (1H, brs, I 7 Hz).
Example 3 Preparation of 6-hydroxy-2- (4-sulfamoyl-benzylamino) -4,5,7-trimethyl-benzothiazole
R
magnesium sulfate. The solvent is distilled off and the resulting crystals are filtered off to obtain 19.5 g of the title compound.
iH-NMR (), Ј: 2.13 (ЗН, s); 2.20 (3N, s); 2.36 (3N, s); 4.57 (2H, d, Hz); 7.24 (2H, brs); 7.50 (2H, d, 1 9 Hz); 7.74 (2H, d, 1 9 Hz); 8.84 (1H, shear); 8.14 (1H, shir, t, I 7 Hz) o
Example 40 Preparation of 6-hydroxy -2- (4-sulfamylbenzinamine) -4,5 7-trimethylbenzothiazole hydrochloride
50 IH-NMR (flMCO-dg) ,: 2.15 (ЗН, s); 2.20 (3N, s); 2.37 (3N, s); 4.84 (2H, brs); 7.56 (2H, d, 1 9 Hz); 7.78 (2H, d, 1 9 Hz).
According to the procedure of Examples 1 to 3, the compounds shown in Table 1 are obtained 14,
An example of a pharmacological experiment.
The effect on leukotriene generation) from pieces of marine lungs
pigs. I.
Do an intravenous injection
guinea pig albumen albumen (dilution 1/10; 0.5 ml / 100 g) to a male Hartley guinea pig (300-350 g) for passive sensitization (sensitizing JIOCTH). After 16 to 18 hours after passive sensitization, blood is removed by circulating Tyrod's solution and the lung is removed. The removed lung is cut into small pieces of 1 mm x 1 mm x 1 mm while cooling the lung with ice. The pieces are washed and suspended 150 mg of the pieces in 1.8 ml. Tyrod's solution, then incubate for 5 minutes at 37 ° C. Add 3 μM there.
The test compounds of the invention are then incubated for 10 minutes. The antigen solution is added there (egg albumin, final concentration 10 µg / ml) and then incubated for another 15 minutes. The mixture is filtered through a nylon mesh. The leukotriene fy (LTSL) is filtered in 100 ml radioimmunoassay (H2A, Kit).
Experimental Results
Table 4 shows the percent inhibition of leukotriene C / j release (LTC) by each compound tested.
The compound number in Table COOT- corresponds to the compound number in the examples and Table. 1 - 30
From the results of the pharmacological experiment given in table 4
R

a2n ° zy
AT 4.
.
de R (, R 4, and independently of each other 45 hydrogen, halogen, Cm-C-alkyl or alkanoyl or two substituents from R ,, R and R 4 are attached to the next 50 carbon atoms of the benzene ring and represent the group atoms supplementing another benzene ring;
hydrogen, C alkyl, C2-Su-alkanoyl, N- (C, -C alkyl) carba
R to
20
,,
I
731051 -8
it is seen that the compounds of the invention inhibit leukotriene production. Therefore, compounds for the use of fertilizers are useful as pharmaceuticals due to their activity in inhibiting the production of leukotriene, effective against diseases that are caused by leukotrienes, especially asthma.
The compounds of the invention can inhibit leukotriene production by inhibiting 5-lipoxygenase and exert their effect when administered orally in the case of an asthma model. Therefore, the compounds of the invention are particularly useful as drugs and prophylactic agents.
In addition, the compounds of the invention have low toxicity and high safety: they do not show serious toxicity when administered alone to oral administration (300 mg / kg) in guinea pigs (Hartley, weight 300 -
350 g)
Therefore, exemplified compounds are useful as a therapeutic composition for inhibiting
15
thirty
leukotriene production by inhibiting 5-lipoxygenase

权利要求:
Claims (1)
[1]
Invention Formula
35 Method for preparing benzothiazole derivatives of formula
moyl or NiN-flHtC-Cf-alkyl) carb amoyl; X is a group --CO-- or Ry and Rg - independently of one another hydrogen, C, kil or hydroxy-C C - alkyl,
their acid addition salts, characterized in that 2 benzothiazole formulas
,
R4 s
91
. Where Rj, Rj and R have the indicated meanings, R has the meanings given for Rg, besides hydrogen, is reacted with the chlorine hydride of the formula
/ R5
N "
eight
where Ry and R have the indicated meanings, in the presence of a base, which forms
3105110
the target product, where X means -CO-, if necessary, is subjected to addition with lithium aluminum hydride to obtain the target product, where X means, and / or the desired product, where methyl, is subjected to demethylation under the action of boron tribromide to obtain the desired product, IQ where R2 is hydrogen, and the target product is isolated in free form or as acid addition salt.
physical and chemical characteristics of benzothiazoles of formula
Rl
sn,
sn.
sn.
sn,
sn.
sn,
sn,
sn,
CH3
CH3
CH3.CHN
CH- / CH-, n
CH3CH3 /
CH-W-in
P
sn,
sn.
sn,
sn.
n
at
I
-CH2CHNGON-SNgSNgON Hydroh-222-225 (DMSO-dg) ,: 2,11 (ЗН, s); 2.20
n..n / 1U “H About 1A flu “hh 11 ft.a
-CH2CH3
-SNgSN2ON
-sngygon
-sng3
Reed
Free base
Hydrochlo-210 REED (decomp.)
I
-CH2CHNGON Free 101-102 base
Free 272-275 base
-J s
j. Y} V l y I t y. L. Y y) 4, V
(ZN, s); 2.36 (ZN.c); 3.13 (4H, t, 1 6 Hz); 1.18 (4H.I 6 Hz); t, 80 (2H, c); 7.56 (2H, d, I. 9 Hz); 7.71 (2H, d, 1 9 Hz)
(CDC1,), 8: 1.09 (6H, 1 8 Hz); 2.19 (ЗН, s); 2.25 (ЗН); 2.4d HZN.c); 3.17 (1H, kV, 1 - 8 Hz); 4.56 (2H, s); 7.36 (2H, 1 “9 Hz); 7.64 (2H, d, 1 9 Hz)
(DMSO-d), S: 2.14 (3N, s); 2.18 (3N, s); 2.36 (ZN.c); 2.78 (2H, I - 7 Hz), 3.33 (2H, t, 1 7 Hz). 5 4.56 (2H, d, 1 - 6 Hz), 7.50 (2H, d, I - 9 Hz), 7, L8 (2H, d, 1 - 9 Hz)
(DMSO-y6), Y: 2.15 (ЗН, s), 2.20
(3H, c) v 2.38 (3N, s); 4.81 (2H,
with); 7.56 (2H, d, 1 - 9 Hz); 7.78 (2H, d, 1 - 9 Hz)
JJJMCO-d5), $: I, f6 (6H, d, 1 - 8 Hz); 1.28 (6H, d, 1 - 8 Hz); 3.20 - 3.70 (2H, m); 4.90 (2H, s); 7.28 (1H, s); 7.61 (2H, d, 1. 10Tz); 7.84 (2H, d, 1 - 10 Hz)
(DMSO-e1b), $: 1.12 (b.d, Ya8 Hz); 1.26 (6H, d, 1 - 8 Hz); 3.10 (4H.I - 6 Hz); 3.30 - 3.60 (6H, m) 4.58 (2H, d, 1 - 6 Hz); 6.98 (1H, s) 7.48 (2H, d, 1 - 10 Hz); 7.70 (2H, D, 1 - 10 Hz)
(DMSS-a): 4.76 (2H, cJ; - 70 (1H, d, 1 - 10 Hz, 3 Hz); 7.06 (1H, D, 1 3 Hz); 7.20 (1H , d, 1 .10 Hz); 7.54 (2H, d, 1 Yu Hz); 7.81 (2H, d, 1 - 10 Hz).
ghz
CH3, CH3U
sn,
CH3, BUT
: snsn,
sn.
sn,
sn sn sn sn sn
CH3
but
/
CH-.
SK3SN,
sixteen
sn.
CH3
Wmx}
SNZ T K2
he sn3ch
CH3-C-CH3X
Hh
ri rtsn
nSN
sn,
Hydrochloride- 168 "170 REED
Free base (decomp.)
156-157
Free base
HydroLo-218-220 REED
(HMCO-ds), Ј: 1.24 (6H, / - ,, 1 7 Hz); 2.13 (3N, s); 2.36 (ZN.c); 3.30 (1H, m) :, 4.76 (2H, s); 7.50 (2H, d, 1 10 Hz); 7.74 (2H, d, 1 10 Hz)
(DNSO-Ј6) ,: 2.24 (6H, s); 4.90 (2H, o), 7.19 (1H, s); 7.60 (2H, d, I 10 Hz); 7.80 (2H, d, 1 10 Hz)
(DMSO-a6), Ј: 1.34 (6H, d, 1 8 Hz); 3.5 - 3.7 (1H, m), 4.65 (2H, d, 1 6 Hz), 7.2 - 7.4 (2H, m), - 7.54 (2H, d, 1 10 Hz), 7.75 (2H, d, 1 10 Hz) 8.0 - 8.3 (2H, m)
(DMSO-s16), 8-: 1.28 (ZN, d, 1 8 Hz), 2.14 (ZN.s); 2.38 (3N, s); 4.58 (2H, d, 1 8 Hz); 5.08 (1H, m); 7.48 (2H, d, 1 10 Hz); 7.76 (2H,
d, 1 10 Hz)
(DMSO-dg): 2.22 (ZN.s), 2.50
(ZN.c); 2.72 OH, s); 4.68 (2H, d,
I 8 Hz); 7.63 (2H, d, 1 10 Hz); 7.86 (2H, d, 1 10 Hz)
(flMCO-d6),: 1.94 (6H, s); 2.02 (ЗН, s); 4.49 (2H, d, 1 7 Hz); 7.32 (2H, d, 1 10 Hz); 7.56 (2H, d, 1 10 Hz)
(DMSO-dj): 1,22 (9H, s); 1.32 (ЗН, s); 4.58 (2H, s); 7.6 - 7.9 (4H, m)
-j
w
U1
Table 2 4 n-chemical characteristics of benzothiazoles formula
CH3
Up to l
1 P tt-CH-H J pV2 CH xxx 1G
SNS
sn3cho sn3-ЈсСН3Х
Free base
sn
CH,
h
about
sh-4
Free base
about
CHj-O-e- -snz, S
22 Hydrochloride
CH3X
Reed
ABOUT
i-MH- (U
Free base
24
З-СНз-КН-С

36-V237
(flMGO-d6),: 1.52 (9H, s) 1.96 (ЗН, s); 2.01 (ЗН, с) 2.34 (ЗН. S); 4.58 (2 .. Hz); 7.46 (2H, D, Hz), 7.72 (2H, d, Hz)
(flMCO-d6), ff: 1.30 (6H, d, Hz); 2.00 (3N, s); 2.08 (ЗН, s); 2.38 (3N, s); 3.00 (1H, m); 4.52 (2H, d, Hz); 7.50 (2H, d, 1.
10 Hz); 7.74 (2H, d, 1
10 Hz)
(), 8: 2.06 (ЗН, с) 2.12 (ЗН, с); 2.11 (6H, c) 4.62 (2H, s); 7.27 (2H, d, 1 8, Hz); 7.98 (2H, d, 1 - “8 Hz); 7.42 (2H, d, 1-10 Hz); 7.74 (2H, d, 1 10 Hz)
(flMCO-d6), 5: 2.03 (ЗН, s); 2.22 (ЗН, s); 2.38 (3N, s); 2.92 (ЗН, s); 3.10 (ЗН, s); 4.81 (2H, s); 7.56 (2H, d, I 10 Hz); 7.80 (2C, d, 1 10 Hz)
(flMGO d €) ,: 2.01 (ZN, s); 2.08 (ЗН, s); 2.34 (3N, s); Z, 63 (ZN, d, 1 4.5 Hz); 4.60 (2H, d, 1 6 Hz); 7.46
, (2H, d, 1 10 Hz); 7.70 (2H, d, 1 10 Hz)
(DMSO-f: 1.08 (3N, t, I Hz); 2.01 (3N, s); 2.08 (3N, s); 2.31 (3N, s); 3.04 (2H, c); 4.60 (2H, d, 1 6 Hz); 7.44 (2H, d, 1 "10 Hz); 7.70 (2H, d, 1 10 Hz)
17
Physico-chemical characteristics of benzothiazoles
25С1
HO Jv $ v
vg
26-tTf I;
Hvl w.
jOC -TO-oi JBp 2
Compound No.
five
6
7
eight
9
26
27
1731051 18
Table3
HC1
188A.290
142I45
142I45
p Hjj-HCl (decomposition)
(flMGO d6) ,,: 4.68 (2H, c), 7.36 (1H, c), 7.56 (2H, d, I 10 Hz)
(DMSO-d6): 4.64 (2H, s), 7.44 (d, L 10 Hz), 7.50 (1H, s)
(dmso-a6), 8:
4.44 (2H, s), 6.50 (1H, s), 7.41 (2H, d, I 10 Hz), 7.73 (2H, d, I 10 Hz)
Table4
The effect of inhibiting the test compound at a dose of 3 | UM,%
62
44 46 70 37 31 32

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

JP15098787|1987-06-17|

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