Method for producing guanidine derivatives or salts thereof

专利摘要:
A process for the manufacture of the guanidinoheterocyclic derivatives described in European Patent Publications Nos. 60094 and 60697 characterised by formation of the guanidine residue by reaction of the appropriate aryl isourea with the appropriate amine.
公开号:SU1303027A3
申请号:SU833640700
申请日:1983-09-06
公开日:1987-04-07
发明作者:Джеймс Хейлз Нейл；Майкл Мант Деррик
申请人:Империал Кемикал Индастриз Плс (Фирма)；
IPC主号:

专利说明:

The invention relates to methods for producing new guanidine derivatives or its salts, which are histamine H-2 receptor antagonists and can be used in medicine,
The aim of the invention is to synthesize new guanidine derivatives or its salts with improved properties.
Example 1. A mixture of hydrochloric (4-nitrophenyl) -isoo-ureido | -pyrazol-1 -yl valeramide (0.16 g), triethylamine (0.06 ml), 2,2,2-trifluoroethylamine (0.2 g) and acetonitrile (5 ml) is heated under reflux overnight. The solvent is evaporated, and the residue is purified by liquid chromatography on medium pressure on silica gel, using first the CHC1, (MeOH) aqueous ammonia (beats, weight O, IV) 9: 1 as eluant : 0.1 vol / vol / vol and then MeOH to give 0.09 g (70%) of 5- {3- (2,2 (2,2,2-trifluoroethyl) - -guanidino-pyrazole-1-yl-valers - yes, so pl. 130 ° C at recrystallization from Et OAc (ethyl palatate).
The source material can be obtained as follows.
Sodium hydride paste (6.16 g, 61% w / w suspension in liquid paraffin) is added portionwise over 30 minutes to a solution of 3-nitropyrazole (17.4 g) in anhydrous DMF (150 ml) with external ice cooling, to maintain the temperature at 20-30 ° C. The mixture is stirred for 45 minutes, 5-bromovaleronitrile (25 g) is added to the almost clear solution for 30 minutes at 25-30 ° C and the mixture is stirred for 4 hours. Water (450 ml) is added and EtOAc (450 ml), the upper layer is separated, dried (MgSO4) and evaporated under vacuum to an oil, which is a mixture of 5- (3-nitropyrazol-1-yl) -valeronitrile and 5- - (5-nitropyrazol-1-yl) -valeronitrile. The oil is divided into two portions of 15 g each, which are fractionated on a clone of silica gel (diameter 3.5 cm, length 100 cm), eluting at a pressure of 2 atm with a mixture of EtOAc / 60-80 ° petroleum spir (3: 7 v / v ). First, the 1: 5 isomer is eluted, and then the 1: 3 isomer, 5- (3-11titropyrazol-1-yl) -valon eronitrile has mp, 32-33 C,
A solution of 5- (3-nitropyrazol-1-yl) - -valeronitrile (0.2 g) in a concentrate
The mixture was diluted with water (4 ml), alkalinized to pH 10 with 10.8 n sodium hydroxide solution and extracted with EtOAc (ml). The extracts are dried (MpSO) and evaporated under vacuum to a white solid, which is recrystallized from ethanol to obtain 5- (3 nitropyrazol-1-yl) -valeramide, mp, 129-131 C,
A mixture of 5- (3-nitropyrazol-1-yl) -valeramide (3.6 g) and 3% (w / 5 / weight) palladium on carbon (0.54 g) is stirred in isopropanol (20 ml) in hydrogen atmosphere. The temperature is maintained below 40 ° C with external ice cooling. After 4 hours, hydrogen 0 is no longer absorbed,
The mixture is filtered, and the filtrate is evaporated under vacuum to give 5- (3-aminopyrazol-1-yl) -valeride amide as an oil, which is crystallized.
A mixture of hydrochloric 5- (3-α-aminopyrazyl-1-yl) -valeramide obtained in EtOF. with ethereal HC1, followed by evaporation (0.22 g), 4-nitrophenyl cyanate (0.16 g) and acetonitrile (2 ml) was stirred at room temperature overnight. Then another 0.08 g of 4-nitrophenyl cyanate is added, and the mixture is stirred at room temperature overnight. An additional 0.15 g of 4-n-nitrophenyl cyanate and 5 ml of acetonitrile are then added, and the mixture is stirred at room temperature for a long time. The mixture is filtered. The solid solids retained (the mixture is taken up in acetonitrile and dried in air to obtain 0.16 g (42%) of hydrochloric 5- {3- 2- (4-nitrophenyl) - -isoureido-pyrazole-1-yl-valeramide which is used without further purification
NMR in d DMCO: 7.39 (1H doublet);
about
0
five
0
five
0
5.66 (doublet, 1H); 4.03 (quartet, 2H); 3.94 (triplet, 2H); 2.08 (triplet, 2H); 1.6 (multiplet, 4H),
Salt of maleic acid obtained in acetone, so pl. 183-184 S.
Example 2: A mixture of 5- (3-aminopyrazol-1-yl) -valeramide (1.0 g), 1- (4-methylphenyl) -2- (2,2,2-trifluoroethyl) -isourea (2.0 g) and acetonitrile (10 ml) are heated at 80 ° C for 3 days. The mixture is treated twice with 0.5 g portions of hydrochloric 1- (4-methylphenyl) -2- (2,2, 2-trifluoroethyl) -isourea and in 0.5 ml portions of triethylamine and heated at 100 (for 1 day. The solvent is evaporated, and the mixture is purified by liquid chromatography on medium pressure on silica gel, using a mixture of 1: 3 / MeOH / aqueous ammonia (specific weight: 0.88) 19: 1: 0.1 v / v / v as eluant to obtain 0.28 g (17%) of 5- {3- 2- (2,2,2-β-trifluoroethyl) -guanidino-pyrazole-1 - -yl | -valeramide, which is identical to the sample obtained in the example I.
The source material can be obtained as follows.
A mixture of hydrochloride 2,2,2-β-trifluoroethylamine (7.0 g), 4-methyl-phenylpianate and DLP (50 ml) is stirred at room temperature for 4 days. DMF was removed by distillation under reduced pressure. The residue is triturated with ether and filtered to obtain 10.8 g of solid. A portion of this solid (9.5 g) is treated with an excess of saturated sodium bicarbonate solution and extracted with ether. The extract is dried (MgSO4) and evaporated. The resulting solid is triturated with light petroleum ether (b.p. 40-60 C) and filtered to obtain 4.7 g of 1- (4-methi-phenol1) -2- - (2,2,2-trifluoroethyl) - isomureas, so pl. 83-85 C. 4.2 g of this substance is treated with ethereal hydrogen chloride. The mixture is filtered to obtain 4.2 g (39.5%) of the product as the hydrochloride salt, so pl. 180-182 C.
Biological testing.
The compound obtained in Examples 1 and 2 was tested using a test with aminopyridine in comparison with 2-guanidino-4- 2- (2-cyano-3-methyl-gyanidine) ethylthiomethyl-thiazole (compound A). Compound A will provide 50% inhibition at a concentration of 0.057 μm. The corresponding value for the compound of examples 1 and 2 was 0.0036 µm.
The compound obtained in Examples 1 and 2 was administered intravenously to two anaesthetized rats and four conscious mice in doses that, respectively, exceeded the dose (mg / kg) by a factor of ten and a hundred times, which allowed
o 5
0 5 O -

five
0
0
50% inhibition of gastric secretion in anesthetized rat. In all animals, which were introduced; these doses, no toxic symptoms were detected.
The aminopyrine test was performed as follows.
Gastric mucosa taken from a New Zealand white rabbit was separated from the underlying rabbit and washed in buffer solution 1 containing, g / l: NaCl 8.007; KS1 0,201; , 0.113; KgHPO 0.204; CaCl2-2H, 0 0.132; MgCl0.101 and glucose 1 adjusted to pH 7.4 with NaOH. This tissue was finely chopped, suspended in buffer 1 and washed three times with buffer 1. The tissue was then suspended in a dispersion medium — collagenase (Sigma Chemical Company, type V, 100 mg) and bovine serum albumin (Miles Laboratories Limited, fraction V, 100 mg) in buffer solution 1 (100 ml); 50 ml of the dispersed medium per 10 g net weight of the tissue was incubated at a temperature and pH of 7.4 (held at this level as a result of continuous control) with stirring in an oxygen atmosphere. After 30 minutes, the tissues were allowed to settle and the supernatant was removed. Fresh dispersion medium was added (50 ml per 10 g net weight of the tissue) and the incubation continued, resulting in 40–60 minutes later the tissue was mainly dispersed into glands and whole cells. The remaining large pieces of fabric were removed by filtration through a nylon mesh. The mixture of glands and cells was collected by centrifugation at and suspended in buffer 1 containing 1% bovine serum albumin (Miles
laboratories lmt., fraction V). And finally, the cells and glands were washed 3 times with buffer solution 1 and suspended in a buffer solution of 2 L-dehydrated D but Els (MEM) butane (500 MP), aprotinin (Sigma Chemical Company, 10 ml) and HEPE S (2- hydroxyethyl) piperazin-2-yl-ethanesulfonic acid (150 g, 20 ml) adjusted to pH 7.4 with NaOH (150 mt1 per 10 g net weight of the fabric). The tissue suspension was stirred under oxygen at 32 ° C for at least 1 h before use. Tissue suspension was incubated
five
together with the test compound and aminopyrin (10 μm) labeled with an atom in the dimethylamino group (0.1 μm / ml) for 20 minutes Amino irin absorption was then stimulated by adding histamine and diesterase inhibitor ICi 63197 to obtain final concentrations of 10 M and 5 10 M, respectively. After 18 minutes, the cell and gland were separated from the incubation medium by filtering the suspension through filters of porous glass with microfiber structure . Cells and glands were quickly (10 s) washed with chilled buffer 1 in a ice bath for three times. Ami
nopirid labeled with an atom
retained in the tissue, measured using a scintillation counter, and the degree of inhibition caused by the absorbed amount of the test compound was calculated using the control sample. The concentration of the test compound, resulting in a 50% inhibition, was then calculated graphically from a series of tests performed at different concentrations.
F
formula of invention
1. A method of producing guanidine derivatives of the general formula
RIP
--m about
n: k-A4-K
HjN H
where R is 2,2,2-trifluoroethyl;
And - tetramethylene,
or their salts, I differ by the fact that isourea of the general formula
Editor N.Egorova Order 1227/57
Compiled by N.Pivnitska Tehred I.Popovich
Corrector
Circulation 372Subscribe
VNISHI USSR State Committee
for inventions and discoveries 113035, Moscow, D-35, Rautska nab. d. 4/5
Production and printing company, Uzhgorod, st. Project, 4
d
ABOUT
n
Isf
 N-A-C-IS
H
where is r,
nitrophenyl,
subjected to interaction with the amine of the General formula
R, NH, in the presence of the solvent, acetonitrile, at the boiling point of the solvent, and isolate the desired product in free form or in the form of a salt.
2. A method of producing guanidine derivatives of the general formula
RI.
H
: 1 about
 C lSl-Clsi-A-C- / - i - hm-l-v; -: P N
five
0
Where
R, 2, 2,2-trifluoroethyl; And - tetramethylene,
or their salts, characterized by the fact that iso-urea of the total form I.
H o-l-nr
with
mules

n
where R, has the indicated meanings; Rj is nitrophenyl;
subject 35 formula
interaction with the amine
about
HjN-Q-A-C-x
1SI
n
in the presence of acetonitrile solvent at 80-100 ° C, and the target product is isolated in free form or as a salt.
Proofreader A.Zimokosov

权利要求:
Claims (2)
[1]
Claim
1. The method of obtaining derivatives of .guanidine of the General formula where - 2,2,2-trifluoroethyl; A is tetramethylene, or their salts, characterized in that the isourea of the general formula where R ₂ is nitrophenyl is reacted with an amine of the general formula where, in the presence of a solvent, acetonitrile at the boiling point of the solvent, the desired product is isolated in free form or in the form of salt.
[2]
2. The method of obtaining guanidine derivatives of the general formula ^R1 > o r = nII N. Ν-Λ-Ο-χ η ₂ ν ^ν η
R, - 2,2,2-trifluoroethyl;
A - tetramethylene, their salts, otlichayuschiytem that isourea total Forge claim ₄
H has the indicated meanings;
- nitrophenyl;
are reacted with an amine of the formula or:
Η ₂ Ν - ^ - Α-Ιχ ^Η in the presence of a solvent - acetonitrile at 80-100 ° С and the target product is isolated in free form or in the form of a salt.

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引用文献:

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RU2608109C2|2010-11-05|2017-01-13|Синомикс, Инк.|Compounds useful as trpm8 modulators|CA1233818A|1981-03-09|1988-03-08|David J. Gilman|Guanidine derivatives as histamine h-2 receptorantagonists|

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IN158869B|1981-03-18|1987-02-07|Ici Plc|GB8401751D0|1984-01-24|1984-02-29|Ici Plc|Guanidine derivatives|

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JP4746528B2|2006-12-06|2011-08-10|株式会社マスカワ|gasket|

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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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GB8225509|1982-09-07|

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