Method of producing derivative of [3h]-imidazo-[5,1-alpha]-1,2,3,5-tetrazin-4-none

专利摘要:
Title compds. (I)[R1=halo, C1-4 alkoxy, C3-8 cyclo alkyl, etc.; R2=methyl- or ethyl-carbamoyl were prepd.. Thus, a mixt. contg. 500mg 4[5 -diazo-imidazole-5[4 -carboxamide and 3.0ml methyl iso- cyanate was stirred for 21 days in dark place to give 8-carbamoyl-3- methyl-[3H -imidazo [5,1-d -1,2,3,5-tetrazin-4-one.
公开号:SU1447284A3
申请号:SU823482389
申请日:1982-08-23
公开日:1988-12-23
发明作者:Лант Эдвард；Фрэнкис Грахам Стивенс Малкольм；Стоун Роберт；Роберт Харри Вулдридж Кеннет
申请人:Мэй Энд Бейкер Лимитед (Фирма)；
IPC主号:

专利说明:


The invention relates to the preparation of a new product imidazo-5, 2,3,5on of the general formula
t
N I
, about

where Cc is a methyl, 2-chloroethyl or 2 bromoethyl group, and R is a carbamoyl, methylcarbamoyl or dimethylcarbamoyl group with antitumor activity.
The purpose of the invention is the preparation of new tetrazine derivatives with a new spectrum of biological properties.
Example 1. 8 Carbamoyl-3-methyl-H-imidazr 5,1-aJ-l, 2,3,5-tetrazin-4-one. Compound. BUT,
4 (5.) - Diazoimidazole-5 (h) -carboxymide (500 mg) is suspended in methyl iso cyanate (3.0 ml) and stirred in darkness at ambient temperature for 21 days. The reaction mixture is then diluted with anhydrous diethyl ether and filtered off. The residue is quickly washed with anhydrous methanol, then anhydrous diethyl ether and dried in air, in the dark at room temperature to obtain 8-carbamoyl-3-methyl-3N-imidazo 5, 2, 3,5-tetrazine 4-one in as a light brown microcrystalline solid (198 mg) with mp. 210 ° С (with gas evolution and darkening in the temperature range 160-210 С).
Elemental analysis.
Found,%: C 36.6; H 3.10; N 44.2,
C hfineo
Calculated,%: C 37.1; H 3.09; N 43.3,
Example 2. Connection C.
4 (5) -Diazoimidazole-5 (4) -carboxamide (300 mg) is suspended in anhydrous dichloromethane (10 ml) and 2 chloro-ethylene sciocyanate (1.0 ml) is added, then the reaction mixture is stirred in dark at room temperature within 30 days. The suspension of cream khdaet thus obtained is filtered off, the residue is washed
,
five
five
0
five
Q
five
0
five
anhydrous diethyl ether and dried in the air in the dark to give 8-carbamoyl-3- (2-chlorostil) -3H3-imidazo-5, 2,3,5-tetrazin-4-one (483 mg) in as a cream powder with so pl. 158 С (with strong decomposition). Elemental analysis.
Found,%: C 34.7; H 3.01, N 34.9.
C H ClNeOi Calculated: C34.7; H2.91; N 34.7.
By repeating this procedure, 8-carbamoyl-3- (2-chloroethyl) - 3N-imidazo-5, 2, 3,5-tetrazin-4-one is also obtained in another polymorphic form with m.p. 164-165 seconds (with decomposition).
Example 3. Compound A. Suspension of 4 (5) -diazoimidazole-5 (4) -carboxamide (1.37 g) and ethyl acetate (20 ml) is treated with methyl isocyanate (7.0 g) and stirred in a closed vessel in dark at room temperature for 3 weeks. The resulting solid is filtered and washed with diethyl ether to give 8-carbamoyl-3-methylSNA 3 imidazo-5, 1-aj-1, 2,3,5-tetrazin-4-one (1.9 g) as a solid. . cream color with m.p. 212 С (with gas emission).
This substance is recrystallized from the solvents of the three systems to produce three different products, each of which has a slight difference in the IR spectra. Probably all three products were polymorphic forms of 8-carbamoyl-3-methyl-3N-imidazo-5,1-, 2,3,5-tetrazin-4-one.
(i) Colorless needles obtained from a mixture of acetone - water (3: 1 by volume), viaitc 3410, 3205, 1730, 1758 and 1678, so pl. (with gas).
(ii) White microcrystals are obtained from a mixture of acetone - water (1: 3 by volume), mo, xc 3430, 3200, 1740 and 1675 cm, so pl. 210 ° C (with gas emission: eat).
(j.ii) A granular solid was obtained from hot water, maxs 3450, 3380, 3200, 1742, 1688 and 1640, mp. 215 ° C (s. Gas evolution, darkening at 210 C). Example 4. Compound C. Suspension of 4 (5) -diazoimidazole-5 (4) -carboxamide (1.0 g) in ethyl acetate
(30 ml) is treated with 2-chloroethyl isocyanate (3.3 ml) and the mixture is stirred at room temperature for 6 days. The reaction mixture is then diluted with diethyl ether and the resulting solid is filtered off to give 8-carbamoyl-3- (2-chloroethyl) -3n-imidazo 5, N-methylpiperid-2-ona (3.5) is prepared by methyl isocyanate (and stirred at room temperature in for 4 weeks. Mixture with diethyl ether and semi solid filtered off to obtain 8-carbamoyl-3 methi-imidazo 5, 1-aj-1, 2,3,5-tetraz
1,2,3,5 - tetrazin-4-one (1.6 g) as 10 it (2.38 g) as a colorless solid with mp. 164-165 C (with decomposition).
Elemental analysis.
Found,%: C 34.5; H 2.88; N 34.5; C1 14.6. 15 N 43.10.
, C1
Calculated,%: C 34.65; H 2.91; N 34.65; C1 14.61.
va pale purple color with 202-203 C (with decomposition).
Elemental analysis.
Found,%: C 36.8; H 2.94
C 37, P; H 3
Calculated 43.3.
Example 5. Connection C.
A suspension of 4 (5) -diazoimidazole-5 (4) -carboxamide (5.0 g) in a mixture of dichloromethane (158 ml) and 1-methy-1Pyrrolide-2-one (8.3 ml) is treated with 2-chloroethyl isocyanate ( 16.7 ml) and the mixture was stirred in the dark at room temperature for 14 days. The reaction mixture is then diluted with anhydrous diethyl ether and the resulting solid is filtered off and washed with diethyl ether to give 8 carbamoyl-3- (2-chloroethyl) - | 3N-imidazo {5, l-sQ-l, 2,3,5-tetrazin-4-one (6.3 g) in the form of a solid with a purple hue with mp. 164-165 s (with decomposition). Elemental analysis.
Found,%: C 34.7; H 2.95; N 34.5; C1 14.4.
С Н С1бОг
N
Calculated,%: C 34.65; H 2.91; 34.65; 01 14.61.
Example 6. Connection C.
A suspension of 4 (5) -diazoimidazole-5 (4) -carboxamide (145 g) in ethyl acetate (2175 ml) is treated with 2-chloroethyl isocyanate (478.5 ml) and stirred in the dark for 2 days. The mixture is then filtered out to give 8-carbamoyl-3- (2-chloro-eth1) -3N-imidazo-5,1-a | -1,2,3,5-tetrazin-4-one (250 g) as a solid. peach color with so pl. 166 C.
Example 7. Connection A.
Stirring suspension of 4 (5) - diazoimidazole-5 (4) -carboxamide (2.2 g) in a mixture of dichloromethane (70 ml)
and N-methylpiperid-2 ona (3.5 ml) is treated with methyl isocyanates (7.0 ml) and stirred at room temperature for 4 weeks. The mixture was diluted with diethyl ether and the resulting solid filtered off to give 8-carbamoyl-3 methyl-3N 3 imidazo 5, 1-aj-1, 2,3,5-tetrazin-4one (2.38 g) as a solid.
she (2.38 g) as a solid
N 43,10.
va pale purple color with 202-203 C (with decomposition).
Elemental analysis.
Found,%: C 36.8; H 2.94;
real
m.p.
C 37, P; H 3.14;
five
0
five
0
five
0
five
Calculated 43.3.
The polymorphic form of 8-carbamoyl-.3- Zn1-imidazo-5, 2,3,5-in 4-it is obtained by the color of a solid solid substance with so pl. 200 С
methyl j
The tetrazine -one is obtained by dissolving it in acetonitrile, filtering, concentrating the filtrate to dryness, and triturating the resulting residue with diethyl ether. The product is obtained as an orange (decomposed).
Elemental analysis.
Found,%: C 37.4; H 3.26; N 43.5.
The NMR spectrum of this compound in dimethylsulfoxide B6 is identical to the spectrum of this pale purple solid, but its IR spectrum (KBr disk) showed some difference.
Example 8. Compound D.
A stirred solution of sodium nitrate (0.64 g) in water (4.6 ml) is cooled to 5-10 ° C and at this temperature, the tour is treated dropwise with a solution of 5-amino-4-methylcarbamoylimidazole (1.00 d) in an aqueous solution of acetic acid (Ø, 14.3 ml) for 5 minutes. Stirring is continued at 5-10 ° C for 5 minutes. The dark red solution is then extracted with ethyl acetate (ml) and the combined extracts are dried over magnesium sulfate. The resulting solution contains crude 4 (5) -diazo-5 (4) -methylcarbamoylimidazole, which is unstable and immediately used in the next stage without further purification.
A solution of 4 (5) -diazo-5 (4) -methylcar bamoylimidazole in ethyl acetate, prepared as described above, is treated with 2 chloroethyl isocyanate (4.3 ml) and left to stand in the dark for 1 day. Then the solution is evaporated at 40 C / 10 mm Hg. and the residue is triturated with petroleum ether (bp 40-60 C) to give an orange gum (4.23 g). This resin is treated with ethyl acetate (50 ml) and filtered, the filtrate is evaporated at 40 C / 10 mm Hg. to give an orange gum (2.94 g). This resin is purified by medium-pressure column chromatography on silica gel, eluting with a mixture of ethyl acetate and acetonitrile (4: 1 by volume) to give 3- (2-chloro ethyl) -8-methyl rbamoyl-3H imidazo 5, i-aj-1 , 2,3,5-tetrazin-4-one (0.81 g) as a solid
purple with so pl. (with decomposition).
Elemental analysis.
Found,%; C 37.3; H 3.58; I am 3.9.
CgHgClNfcO
Calculated
120 122 ° C
 32.7.
Example
C 37.4; H 3.53; 9. Connection N.
(i) A homogeneous mixture of 5-nitro-4-carboic acid (2.0 g) 20 and phosphorus pentachloride (2.67 g) is stirred and heated in oil at 120 ° C for a resulting yellow suspension is evaporated at, 1 mm Hg, in 25 for 30 minutes with obtaining 1.6-bN, YUN, diimidazo (1.5-a; 1
5-6) pyrazin-5,10-dione (1.90 g) A solution of 4 (5) -diazo-5 (4) -dime tilcarbamoylimidazole (1.59 g) In dry ethyl acetate (57 ml) is treated with 2-chloroethyl isocyanate ( 6.36 g) and stirred at room temperature in the dark for 24 hours. Then the solution is evaporated in vacuum at 35 ° C and at the end at 0.5 mm Hg. to remove excess 2-chloroethyl isocyanate. The residual liquid was purified by medium pressure column chromatography on silica gel, eluting with ethyl acetate-acetonitrile (4: 1 by volume) to give 3- (2-chloroethyl 8-dimethylcarbamoyl-3H-imidazo-5 1 in the form of a yellow solid, mp 249-251 C (with decomposition (1 m), 30 (KBG disc)) 1750; that / e 278 (M).
(ii) An aqueous solution of dimethylam (25 wt.%, 60 ml) is cooled to 0 and treated in portions with transfection 1.6-dinitro-5H, YUN-diim 30 (l, 5a: l,) nHpa3HH-5,, 2,3,5-tetrazin-4-one (0.82 g) as colorless crystals with mp. 114-1164,
Elemental analysis.
Found,%: C 39.7; H 3.95; N 80,8.
C, HI, ClNjC
Calculated% N 31.0,
Example 10. Compound I. Mixed suspension 4 (5) - diazoimidazole-5 (4) -carboximide
45
C, 39.9; H 4.10;
50
(6.0 g) at the same temperature. The resulting purple solution is stirred for 2 hours. The solution is ryt at 50 C / 10 mm Hg. and acidified by treating the concentrator with hydrochloric acid to obtain an orange solution. This solution was dissolved with ethyl acetate (7 200 200 ml. The combined extracts were dried over magnesium fath and evaporated with a solid yellow substance (6.6 g). This solid was mixed with toluene (50 ml) and then crystallized from ethyl acetate to obtain 5 ( 4) -nitro-4 (5) -dime bamoylimidazole (2.53 g) in the color of hard crystals with mp 193-195 C
Elemental analysis.
Found,%: C 39.9; H 4.23;
(1.0 g) p hexamethylphosphoramide
(4 ml) is treated with 2-bromo-methyliso-N 30.4,
yata (4.5 ml) and the mixture is stirred (,
in the dark at room temperature (temperature Calculated,%: C 39.1; H 4.38;
within 2 days The reaction mixtureN 30,4,
five
0
then diluted with anhydrous DG-ethylether and the resulting solids; the solid is filtered off and washed with anhydrous distil ether to give 3- (2-bromoethyl) -8-carbamoyl-H3HP-
G P
imidazo-5,1-aJ-1,2, 3,5-tetrazin-4-one (1.17 g) as a colorless solid with mp. 156-157 C (with decomposition).
Elemental analysis.
Found,%: C 29.5; H 2.36; N 29.1; Br 27.3.
Calculated,%: C 29.3; H 2, 46; . N 29.3; Br 27.8.
Example 20 (reference).
(i) A homogeneous mixture of 5-nitroimidazole-4-carboic acid (2.0 g) 0 and phosphorus pentachloride (2.67 g) is stirred and heated in an oil bath at 120 ° C for 1 hour. The resulting yellow suspension at 1 mm Hg, in 5 for 30 min, to obtain 1.6 dinit.-ro-BN, YUN, -diimidazo (1.5-a; 1,
5-6) pyrazin-5,10-dione (1.90 g)
5-6) pyrazin-5,10-dione (1.90 g)
in the form of a yellow solid with so pl. 249-251 C (with decomposition (1 m), (KBG disc) 1750; that / e 278 (M).
(ii) An aqueous solution of dimethylamine (25 wt.%, 60 ml) is cooled to 0–5 ° C and treated with portions while moving 1,6-dinitro-5H, YUN-diimide-30 (l, 5a: l,) nHpa3HH-5, 10dio
Mr. (6.0 g) at the same temperature. The resulting purple solution is stirred for 2 hours. The solution is evaporated at 50 C / 10 mm Hg. and then acidified by treatment with concentrated hydrochloric acid to obtain an orange solution. This solution is extracted with ethyl acetate (7 “200 ml), the combined extracts are dried over magnesium sulfate and evaporated to give a yellow solid (6.6 g). This solid was triturated with toluene (50 ml) and then recrystallized from ethyl acetate to give 5 (4) -nitro-4 (5) -dimethylcarbamoylimidazole (2.53 g) as a yellow crystal, m.p. 193-195 S.
Elemental analysis.
Found,%: C 39.9; H 4.23;
N 30.4,
(Lii) A solution of 5 (4) -nitro-4 (5) -di. Methylcarbamoylnmidazole (1.62 g) in dry dimethylformamide (3-2 ml) is treated with platinum oxide (0.32 g) and shaken in an atmosphere of hydrogen at atmospheric pressure and room temperature. After 3 hours, the hydrogen uptake is complete (710 ml). The mixture is treated with activated carbon and filtered through diatomaceous earth. The dark brown filtrate is evaporated at 50 C / 0.1 mm Hg. and the resulting residue is triturated with diethyl ether-ipOM to give crude 5 (A) -amino-L (5) -dimethylcarbamoylimidazole (1.75 g) as a dark brown dress with
1595 cm
crystalline 179-181 ° c) (KBr disk) NMR in dimethyl sulphoxide-Dg; singletons at 3.2 and 7.0 Sj, which still contain an admixture of colloidal platinum and which are used in the next stage of additional purification.
(N) A stirred solution of sodium nitrate (0.79 g) in water (5.7 ml) is cooled to 5-10 ° C and treated dropwise at this temperature with a solution of 5 (4) -amino-4 (5) -dimethylcarbamoyl imidazole (1.75 g) in aqueous acetic acid (Ø, 17.6 ml) for ... 5 min. The resulting solution is extracted with ethyl acetate (ml), the combined extracts are dried over magnesium sulphate and evaporated at 30 ° C / 10 mm Hg. to obtain 4 (5) -diazo-5 (4) -dimethylcarbamosh1 Imidazole (1.59 g) as orange crystals with m.p. 101-103 C (with decomposition).
Elemental analysis.
Found,%: C 42.6; H 4.17; N 41.4.
Calculated,%: C43,6; H4.27; N 42.4.
The activity of the new compounds (A, I, C, D, H) against TLX5 type lymphoma implanted in mice is illustrated in Table 1.
The activity of compound C against various tumors implanted in mice is illustrated in Table 2.
10 tumor cells of the species L 1210 were implanted intraperitoneally in BDFj mice per day. Mice were treated on the first day by intrabrugline administration of compound C dissolved in 10% dimethylsulfoxide. In peanut oil (0.1 ml), and then as indicated in table 2.
10 tumor cells of the P388 species were intraperitoneally implanted in BDF mice, on O day. Then, the compound was treated with compound C according to the indicated method.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the derivative of Zn-imidazo-5, 2,3,5-tetrazine 4-one of the general formula
B
Have
 R,
ABOUT
Where
R,
RO
-2-chloroethyl or 2-bromoethyl;
-carbamoyl, methylcarbamoyl or dimethylcarbamoyl,
characterized in that the compound of the general formula
J (
/ H ©
-R2 N2
where Rj has the indicated values, it is reacted at a temperature of from ambient to 30 ° C and in the presence of light with an isocyanate of the general formula
R, NCO,
where R, has the indicated meanings.
Table 1
Optimal dose, mg / kg, administered 3 days after implantation
A I C
160 160 40
D n
40 40
Mice after 60 days. remained alive, not further explored
Table 2
Survival time compared with control
157% 137%
All 5 treated mice continued to live for 60 days after implantation.
" Also

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

US5260291A|1981-08-24|1993-11-09|Cancer Research Campaign Technology Limited|Tetrazine derivatives|

---

RU2462466C1|2011-06-24|2012-09-27|Автономная Некоммерческая Организация "Научно-Исследовательский Центр Биотехнологии Антибиотиков И Других Биологически Активных Веществ "Биоан"|Substituted azolo[1,2,4,5]tetrazines - inhibitors of antibacterial serine-threonine protein kinases|DE2932305C2|1979-08-09|1990-03-22|Guenter Prof. Dr. 6900 Heidelberg De Ege|GB2125402B|1982-08-17|1985-11-13|May & Baker Ltd|New tetrazine derivatives|

---

FR2531958B1|1982-08-17|1986-10-31|May & Baker Ltd|NEW DERIVATIVES|

---

US4517182A|1983-05-24|1985-05-14|Warner-Lambert Company|3--4-oxopyrazolo-[5,1-d]-1,2,3,5-tetrazine-8-carboxamide composition|

---

GB8616125D0|1986-07-02|1986-08-06|May & Baker Ltd|Compositions of matter|

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US8481503B2|2009-03-06|2013-07-09|Merck Sharp & Dohme Corp.|Combination cancer therapy with an AKT inhibitor and other anticancer agents|

---

CN102803264A|2009-06-23|2012-11-28|法米诺克斯有限公司|3-substituted-8-substituted-3h imidazo[5,1-d][1,2,3,5-tetrazin-4-one compounds and their use|

---

US20140271657A1|2011-10-12|2014-09-18|Children's Medical Center Corporation|Combinatorial compositions and methods of treating hemoglobinopathies|

---

AU2017233898A1|2016-03-15|2018-11-01|Oryzon Genomics, S.A.|Combinations of LSD1 inhibitors for use in the treatment of solid tumors|

---

KR101847342B1|2017-05-08|2018-04-11|센텍코리아|Wearable body fat burning measurement device|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB8125791|1981-08-24|LV930621A| LV5511A3|1981-08-24|1993-06-19|Ú3H¾-imidazo-u5,1-a¾-1,2,3,5-tetrazin-4-one derivative yield|