前苏联专利SU1424736A3 Method of producing substituted derivatives of imidazole or their non-toxic additive salts with acid

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专利摘要:
Compounds of the formula: and in which X is -CH2-, -CH2CH3- or -0- are useful intermediates in the preparation of substituted imidazoles which are antagonists to sedatives and analgesics used in veterinary medicine.
公开号:SU1424736A3
申请号:SU853979907
申请日:1985-11-22
公开日:1988-09-15
发明作者:Йоханнес Карьялайнен Арто；Эйнари Виртанен Раймо；Леена Карьялайнен Аря；Ойва Антеро Куркела Кауко
申请人:Фармос-Ихтюмя Ой (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of new) -substituted imidazole and its non-poisonous salts, which are new efficient and selective antagonists of sb-receptors.
The purpose of the invention is to obtain new compounds with a higher activity than the structural analog,
In the examples below, the chemical shifts in the H and NMR spectra were determined on a Brngker WB 80 DC using the trimethylsilane as the internal standard, from which the chemical shifts were counted (5, ppm). The compounds shown as bases were assayed in deuterated methanol, deuterated acetone or deuterated chloroform, while the values for compounds indicated as chlorohydrates are determined in deuterium oxide or deuterated methanol. Mass spectra were obtained on a Kratos MS 80 Autocouson instrument.
Example 1. 1. Getting 4 (5) - - (2,3-DIHIDRO-2-ETIHL-1-OXI-1H-I.N- den-2-yl) imidazole,
but). Preparation of 4 (5) - (2,3-dihydro--2-ethyl-1-oco-1H-inden-2-yl) imidazole.
2-Acetyl-1-indanone (62.2 g) (Lie- bigs Ann. Chem, 1906, 347, 112) is alkylated with ethyl bromide (41.9 g) in acetone (370 ml) in the presence of sodium carbonate (18, 9 g) with the formation of 2-acetyl-2-ethyl-1-indanone (yield 39.4 g). Acetyl is brominated with bromine (39.4 g) in methanol (390) and condensed to imidaeol by heating in formamide (195 mp) and heated at 170-180 ° C for 4 hours. The reaction mixture is then spontaneously cooled to room temperature and transferred to ice-cold dilute hydrochloric acid. The mixture is washed twice with toluene, the aqueous layer is added with ammonia and extracted several times with ethyl acetate. The combined organic solutions are dried over anhydrous magnesium sulphate and evaporated. The melting point of the resulting reaction product as the base is 126-127 seconds (from ethyl acetate). Output 25.6 g.
with
Yu
15 20 25
Q
35
dp
50
five
at). Preparation of 4 (5) - (2,3-dihydro-2-ethyl-1-hydroxy-1H-inden-2-yl) imidazole.
The carbonyl group of oxo-indene-imidazole (14.5 g) obtained in step a) is reduced to the alcohol group with sodium borohydride (1.21 g) in ethanol (100 nl). The reaction product is a mixture of cis-trans-stereoisomers, the purification of which is carried out by liquid chromatography.
Cis isomer in the form of hydrochloride (mp. 184-185 s): H NMR (80 MHz, MeOH - d4): 0.73 (3N, triplet) i, 86 (2H, multiplet)} 3.36 (2H multiplet); 3.61 (SA, singlet); 5.15 (1H, singlet); 7.06 (1H, doublet) J 7.2-7.4 (4H, multiplet), 8.68 (1H, doublet).
Chlorohydratl trans isomer:
H NMR (80 MHz, MeOH - GHz): 0.80 (GD, triplet); 1.84 (2H, multiplegg); 3.15 (2H, multiplet); 3.24 (SA, singlet); 5.15 (W, singlet); 6.87 (1H, doublet); 7.2-7.4 (4H, multiplet); 8.54 (1H, doublet).
1.2. Preparation of 4 (5) - (2,3-dihydro-2-ethyl-1H-inden-2-sh1) imidazole, (compound 9).
The oxo derivative obtained in step 1.1 of stage a or hydroxyelectric one (12.0 g) obtained in stage c is hydrogenated in a 2N solution of hydrochloric acid in the presence of 10% palladium on carbon at 70 ° C. After termination of the absorption of hydrogen, the reaction mixture is filtered and alkalinized. The reaction product is extracted with methylene chloride, the extract is washed with water, dried and evaporated to dryness. The residue (7.7 g), which is the product of the reaction in the form of a base, is converted to the hydrochloride in ethyl acetate with dry hydrogen chloride. T. pl. 211-215 ° C.
n NMR (8 MHz, CDClj, base): 0.78 (t. 3H) j 1.88 (q. 2H); .3.17 (q., 4H); 6.75 (s. UI); 7.13 (s, 4H); 7.53 (s, 1H); 10.01 (s, 1H).
Using the procedure of Example 1, the following compounds were obtained.
Example 2. 4 (3) - (2,3-Dihydro-1H-inden-2-yl) yldazole (compound 1).
With product A (5) -f2,3-dihydro-1H-inden-2-yl) imide o.t.
displacement chromatography (solvent system: methylene chloride 9.5: 0.5). The resulting 4 (5) - - (2,3-dihydro-1H-inden-2-Sh1) imidazole is converted to its hydrochloride by dissolving the base in ethyl acetate and passing into a solution of dry hydrogen chloride. Add dry ether precipitated hydrochloride.
4 (5) - (2,3-dihydro-1H- -inden-2-yl) imidazole hydrochloride.
MS: 184 (100 M); 183 (71, M-H); 169 (89, M-CH) i 156 (32); 150 (10); 147 (12); 142 (17); 141 (10); 139 (18); 129 (20); 128 (24); 127 (15); 119 (12); 116 (23), 115 (36); 111 (10); 91 (25); 77 (8) 69 (20).
H NMR (80 MHz, MeOH - d,): 2.93 - 3.83 5H, m, H, H and H 7.08-7.27 (4H, m, aromatics); 7.35 (1H, dd. Im-5,4); 8.83 (1H, d, 1 1.37 Hz, im-2).
NMR (2, MHz, MeOH - 64): 36.8 (OFR, d., Cr); 39.71 (2 t., C and C,); 115.96 (d, im- 5 (4)) - ,. 125.32 (2 days, aromatics); 127.86 (2d., Aromatics); 134.85 (d., Im-2); 138.76, (s. Im -4 (5)); 142.42 (2c., Cg and C,).
Example 4 (5) -dihydrobenzfuran-2-yl-imidazole (compound 2).
Toluene-isopropanol is crystallized from the mixture and then converted into its hydrochloride in the mixture of isopropanol-ether. Received 1.3 g of product with so pl. f77-178 c.
MS: 186 (46%) i 186 (13%) - 170 (15%) j 169 (100%); 159 (5%); 158 (8%); 157 (7%) -, 146 (16%): 142 (43%), 131 (11%); 136 (20%); .10S (10%).
EXAMPLE 4 4 (5) - (2,3-dihydro-5-methyl-1H-inden-2-yl) imidazole (compound 4). M.p. (HC1) 171-175 ° C.
H NMR (80 MHz, CDClj, base): 2.3 (s., 3N); 2.8-3.8 (m, 5H); 6.78 (s, 1H); 7-7.1 (m, 3N); 7.5 (s, 1H), 9.9 (s, 1H).
EXAMPLE 5 4 (5) - (2,3-Dihydro-2-ethyl-5-methyl-1H-inden-2-yl) imidazole (compound 10).
M.p. 54-57 C (base).
MS: 226 (40%); 211 (12%); 197 (100%); 182 (7%); 128 (12%); 98 (17%); 84 (15%).
PRI me R 6. 4 (5) - (1,2,3,4-Tetrahydronapht-2-yl) imidazole (compound 11).
Sufa 4 (5) - (1,2,3,4-tetrahydroneft-2-yl) imidazole c. base is purified by pressure chromatography
five
0
0
five
fia (solvent system: methylene chloride-methanol 9.5: 0.5). M.p. hydrochloride 4 (5) - (1,2,3,4-tetrahydronaphth-2-yl) imidazole 168-177 ° C.
MS: 198 (100, M); 197 (64); 183 (31) -, 170 (22); 169 (30); 130 (22); 129 (18); 128 (23); 117 (16); 116 (10); 115 (30); 104 (77); 103 (23) -, 98 (12); 95 (12) -, 91 (16); 82 (30); 81 (15).
n NMR (80 MHz, MeOH - S 1.66- 2.46 (2H, m, - CHjCH CH); 2.86-3.13 (5H, m, 2xA CHj and -CHjCHCHj), 7.12 (4H, s., Aromatics). 7.34 (.1H, m., Im-5 (4)), 8.85 (1H, d, l 1.54 Hz, im-2).
With NMR (20 MHz, MeOH - d): 29.23 (OFR, t.) 29.63 (t.); 32.53 (d); 35.5 (t.); 115.84 (d); 126.89 (d); 127.19 (d); 129.92 (2d.); 134.7 (d.), 135.43 (s.); 136.52 (s); 139.45 (s.).
Example 7. 4 (5) - (2,5-Dihydro-2-methyl-1H-inden-2-yl) imidazole (compound 8).
Purification of the crude base by pressure chromatography (methylene chloride-methanol 9.75: 0.25) afforded the pure product. M.p. bases 167-170 ° C.
4 (5) - (2,3-dihydro-2-methyl-1H-indide-2-yl) imidazole, base.
MS: 198 (44, M); 197 (13, M – H); 183 (100, M-CH,) i 129 (14); 128 (18); 115 (22); 91 (28); 77 (11).
n NMR (80 MHz, CDCl1): 1.48 (3N, s, CH,) AB quartet: 5d 298, HC 3.32, 39 Hz (4H, 2xCHP; 6.78 (W, s., im 54), 7.16 (4H, s., Aromatics); 7.54 (1H, s., Im-2); 8.74 (1H, s., W).
EXAMPLE 8 4 (5) - (5-Bromo-2,3-β-dihydrobenzfuran-2-yl) imidazole (compound 3).
The crude product is dissolved in warm water, the insoluble material is filtered off, the filtrate is alkalinized with sodium hydroxide, and the precipitated precipitate is filtered off. The resulting product is converted into a mixture of isopropanol-ether in its hydrochloride, so pl. 187-188 seconds
The pharmacological activity of the proposed compounds was determined by the following methods.
oil-Antagonism in vitro, g oij -Antagonism was detected using isolated, electrically-stimulated conclusions of the vessels (Mars-hali et al. - Bg. I. Pharmac., 1978, 62, 147, 151). In this model, "t, -aro5
0
five
0
nist (detomidine) blocks an electrically stimulated muscle contraction and the effect of op.2 of the antagonist is seen when it is introduced before introducing the agonist and determining the value of the pL. EZ No. 2542 738 respectively).
In order to obtain information on selectivity with respect to oi, - and antagonist receptor receptors, its ability to inhibit or stimulate ot receptors with the help of isolated rat anal muscle was revealed. In this case, the control compounds were phenylephrine - known about (α-agonist and prazosin - known with (h antagonist. To determine α-antagonism, phenyl-frin caused muscle contraction and the pA value of the compound under study was determined. Effect of oi, α-agonist effect at D values (negative logarithm of the molar concentration of the compound causing 50% of the maximum reduction).
The results are shown in Table. one .
The central cx blocking effect of the tested, in vivo compounds is revealed using two methods. As is well known, C-antagonists induce contraction of the pupil (Mydriasis) in rats, and this effect is transmitted through the, -receptors of the central nervous system. An anesthetized rat was given a standard dose of detomidine intravenously. Then increased doses of the test antagonist are administered intravenously and a change in pupil contraction caused by detomidine is detected. The value of AU is determined, i.e. dose, a 50% change.
The results are shown in Table. 2
The c4g Antagonism in the central nervous system revealed based on the antagonist's ability to inhibit detomidine-induced sedation in mice, which was carried out by measuring the increase in sleep time (the effect of barbiturate) caused by detomidine. The action of detomidine is known to be transmitted by activating the C-receptor. Action antagonist may be
was revealed by its administration before administration of dethomidine (150 mg / kg v. b.). The results are shown in Table. 3

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the substituted imidazole derivatives of the general formula
0
five
five
where r
- hydrogen or lower C4-C4-alkyl X -, -0-;
, H, CH, or Hal, N. CH ,.
f 5
Or their non-toxic
with acids
by that
additive salts, characterized in that the compound of the general formula
ABOUT
1 9 11t
TO,
R
С-СНз. R o
have the indicated values,
35
subjected to halogenation and subsequent interaction of the obtained compound of general formula III
About R.
R
..Hal
40
45
ABOUT
where X, R (-R have the indicated meanings with formamide, obtaining a composition of general formula IV
2
Kyt
H
where X, R, -R have the indicated meanings,
which is either hydrogenated in the presence of Pd / C as a catalyst to form a compound of general formula I, or reacted with NaBH to form a compound of formula V OH
where X, R | -R, have the indicated meanings, followed by hydrogenation with
using Pd / C.
ij-Antagonism in vivo.
Idazoxan
synthetic compound
Table 1
6lit2
100
-20 -60 -100 Not measured
editor I.Rybchenko
Compiled by G.Zhukova Tehred M. Khodanych
Order 4699/58
Circulation 370
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
10 Table 3
-five
-thirty
-60
-70 -85
Proofreader I. Muska
Subscription

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NZ214258A|1989-02-24|

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IE852929L|1986-05-23|

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

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