RU2104272C1 - Imidazole derivatives, method of their synthesis and pharmaceutical composition decreasing blood pressure - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: imidazole derivatives of the formula: $$$ where $$$ - $$$-alkyl; $$$ - halogen, $$$-alkylthio, $$$-alkoxy; $$$ - CHO, COOH, $$$-alkyl; $$$ means group $$$; $$$ and $$$ are different and mean hydrogen, $$$-alkyl that can contain different substituents, or $$$ and $$$ together with nitrogen atom form $$$-heteroaryl ring and others. The synthesized compounds were used in medicine as hypotensive agents. EFFECT: improved method of synthesis. 9 cl, 8 tbl

Description

 The invention relates to derivatives of azole, to a method for their preparation and to pharmaceutical compositions based on them. From European patent A-28834, 1-benzyl-substituted imidazole derivatives are known, from European patent A-253310 and from European patent A-0401030 imidazole derivatives with the function of diarylcarboxylic acid are known, from pyrazole and triazole derivatives are known from European patent A-323841 and from European A-0409332 discloses triazole derivatives with a diaryl carboxylic acid function, respectively, and European Patent A-324377 discloses imidazole derivatives with a diaryl-tetrazolyl group and their use as angiotis antagonists gasoline-11 receptors.

 In addition, in the patent of Germany And 4010797 (corresponding application US patent N 07 / 679,233) presents substituted azoles that contain a sulfonylurea group.

 New azole derivatives have been found that have a new structure of sulfonylurea, sulfonylurethane or sulfonyl sulfonamide and are highly effective angiotensin-11 receptor antagonists both in vitro and in vivo.

,
или их физиологически переносимые соли.The invention relates to imidazole derivatives of the general formula 1:

,
or their physiologically tolerated salts.

Where
R ¹ - means (C ₂ -C ₇ ) alkyl;
R ² - means halogen, (C ₁ -C ₃ ) -alkylthio, (C ₁ -C ₃ ) -alkoxy;
R ^{2 ′} is CHO, COOH, CH ₂ OH, COO (C ₁ -C ₃ ) alkyl;
R ¹⁵ - means a group: SO ₂ NH-CO-NR ⁶ R ⁹ ,
Where
R ⁶ and R ^{9 are} different and mean hydrogen, (C ₁ -C ₆ ) alkyl, which may be substituted by 1-3 different radicals selected from the series: hydroxyl, phenyl, carboxyl, C ₃ -C ₆ alkynyl, (C ₃ -C ₈ ) -cycloalkylene, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₂ -C ₄ ) alkenyl which may be substituted with phenyl, (C ₁ -C ₃ ) alkoxycarbonyl; (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₆ ) -cycloalkyl - (C ₁ -C ₃ ) -alkyl; phenyl, phenyl - (C ₁ - C ₄ ) alkyl, which may be substituted with 1-2 identical or different radicals selected from the range of trifluoromethyl, methoxy-; (C ₁ -C ₉ ) -heteroaryl, which can be partially or completely hydrogenated, moreover, there may be 1-4 nitrogen atoms or one nitrogen atom and one sulfur atom as a heteroatom, or (C ₁ -C ₉ ) - heteroaryl - ( C ₁ -C ₃ ) alkyl, which may be partially or fully hydrogenated, as a heteroatom may contain one nitrogen atom or one nitrogen atom and one oxygen atom, and which may be substituted by one radical selected from NO ₂ , methyl, oxo;
or R ⁶ and R ⁹ together with a nitrogen atom form a (C ₅ -C ₆ ) heteroaryl ring, which can be partially or completely hydrogenated and contains as a heteroatom one nitrogen atom and one oxygen or sulfur atom, or one nitrogen atom, and the last heteroaryl may be substituted with a (C ₁ -C ₄ ) alkoxycarbonylamino group, or R ¹⁵ is a —SO ₂ NH-CO-OR ^{6 ′} group, where R ^{6 ′} is (C ₁ -C ₆ ) alkyl, which may be substituted by (C ₁ -C ₆ ) alkyl, thienyl, (C ₃ -C ₈ ) cycloalkylene or benzyloxy group, (C ₂ -C ₅ ) alkenyl, which may be substituted by phenyl, (C ₃ -C ₆ ) -alkynyl, (C ₃ -C ₈ ) -cycloalkyl - (C ₁ -C ₃ ) alkyl, phenyl - (C ₁ -C ₄ ) alkyl, or R ¹⁵ represents a group - SO ₂ NH - SO ₂ R ^{6 ″} where R ^{6 ″} - means - N - (C ₁ -C ₄ ) -alkyl ₂ , thienyl or nitrophenyl.

 The invention also relates to imidazole derivatives, which is ethyl-1- [(2'-H-propyl-aminocabonylaminosulfonylbiphenyl-4-yl) methyl] -2-H-butyl-4-methylthioimidazole-5-carboxylate or its physiologically tolerated a salt or 1- [(2'-H-propylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-methylthioimidazole-5-carboxylic acid or a physiologically tolerable salt thereof.

, или их физиологически переносимые соли,
где
R¹ - означает (C₂-C₇)алкил;
R² - означает галоген, (C₁-C₃)-алкилтио, (C₁-C₃)- алкокси;
R^2′ - означает CHO, COOH, CH₂OH, COO(C₁-C₃)алкил;
R¹⁵ - означает группу: SO₂NH-CO-NR⁶R⁹,
где
R⁶ и R⁹ различные и означают водород, (C₁-C₆)алкил, который может быть замещен 1-3 различными радикалами, выбранными из ряда: гидроксил, фенил, карбоксил, (C₃-C₈)-цикло-алкилен, (C₁-C₄)алкоксикарбонил, (C₂-C₄)-алкенил, который может быть замещен фенилом, (C₁-C₃)алкосикарбонилом; (C₃-C₆) алкинил; (C₃-C₈)циклоалкил, (C₃-C₆)-циклоалкил - (C₁-C₃)-алкил; фенил, фенил - (C₁-C₄)-алкил, который может быть замещен 1-2 одинаковыми или различными радикалами, выбранными из ряда трифторметил, метокси-; (C₁-C₉)-гетеоарил, который может быть частично или полностью гидрирован, причем в качестве гетероатома может быть 1-4 атома азота или один атом азота и один атом серы,
или
(C₁-C₉) - гетероарил - (C₁-C₃) алкил, который может быть частично или полностью гидрирован, в качестве гетероатома может содержать один атом азота или один атом азота и один атом кислорода, и который может быть замещен одним радикалом, выбранным из NO₂, метила, оксо;
или
R⁶ и R⁹ вместе с атомом азота образуют (C₅-C₆)-гетероарильное кольцо, которое может частично или полностью гидрировано и содержит в качестве гетероатома один атом азота и один атом кислорода или серы, или один атом азота, причемпоследнийгетероарилможетбытьзамещен(C₁-C₄)-алкоксикарбониламино-группой.Preferably, the invention relates to imidazole derivatives of the general formula 1 according to claim 1:

, or their physiologically tolerated salts,
Where
R ¹ - means (C ₂ -C ₇ ) alkyl;
R ² - means halogen, (C ₁ -C ₃ ) -alkylthio, (C ₁ -C ₃ ) - alkoxy;
R ^{2 ′} is CHO, COOH, CH ₂ OH, COO (C ₁ -C ₃ ) alkyl;
R ¹⁵ - means a group: SO ₂ NH-CO-NR ⁶ R ⁹ ,
Where
R ⁶ and R ^{9 are} different and mean hydrogen, (C ₁ -C ₆ ) alkyl, which may be substituted by 1-3 different radicals selected from the series: hydroxyl, phenyl, carboxyl, (C ₃ -C ₈ ) -cycloalkylene , (C ₁ -C ₄ ) alkoxycarbonyl, (C ₂ -C ₄ ) alkenyl which may be substituted with phenyl, (C ₁ -C ₃ ) alkoxycarbonyl; (C ₃ -C ₆ ) alkynyl; (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₆ ) -cycloalkyl - (C ₁ -C ₃ ) -alkyl; phenyl, phenyl - (C ₁ -C ₄ ) -alkyl, which may be substituted with 1-2 identical or different radicals selected from the range of trifluoromethyl, methoxy-; (C ₁ -C ₉ ) -heteroaryl, which can be partially or completely hydrogenated, moreover, as a heteroatom there can be 1-4 nitrogen atoms or one nitrogen atom and one sulfur atom,
or
(C ₁ -C ₉ ) - heteroaryl - (C ₁ -C ₃ ) alkyl, which may be partially or fully hydrogenated, may contain one nitrogen atom or one nitrogen atom and one oxygen atom, and which may be substituted by one a radical selected from NO ₂ , methyl, oxo;
or
R ⁶ and R ⁹ together with a nitrogen atom form a (C ₅ -C ₆ ) heteroaryl ring which can be partially or completely hydrogenated and contains as a heteroatom one nitrogen atom and one oxygen or sulfur atom, or one nitrogen atom, the last heteroaryl being substituted (C ₁ -C ₄ ) -alkoxycarbonylamino group.

,
алкилирует соединением формулы III:

где
V - отщепляемая группа, с получением соединения формулы 1:

,
где
R¹⁵ представляет защитную сульфамидную группу с последующим снятием защитной группы и полученный сульфонамид при необходимости превращают в сульфонилуретаны или сульфонилмочевины или сульфонилсульфонамиды формулы 1.In addition, the invention relates to a method for producing imidazole derivatives of general formula I according to claim 1, characterized in that the compound of formula II:

,
alkylates with a compound of formula III:

Where
V is a leaving group to give a compound of formula 1:

,
Where
R ¹⁵ represents a sulfamide protecting group, followed by deprotection, and the resulting sulfonamide is optionally converted to sulfonylurethanes or sulfonylureas or sulfonyl sulfonamides of the formula 1.

 The invention also relates to a pharmaceutical composition for lowering blood pressure, comprising an active compound and a pharmaceutically acceptable additive, characterized in that as an active compound it contains a compound of imidazole derivatives of formula 1 in an effective amount described above.

 The compounds of the invention of formula (1) have an antagonistic effect on angiotensin-11 receptors and can therefore be used to treat angiotensin-11 dependent hypertension. Other applications are for heart failure, cardioprotection, myocardial infarction, heart hypertrophy, arteriosclerosis, nephropathy, renal failure, and also for vascular diseases of the brain, such as transistor ischemic attacks and cerebral hemorrhage.

 Renin is a proteolytic enzyme from the class of asertyl proteases, which, as a result of various stimuli (volume reduction, sodium deficiency, stimulation of β-receptors) of adjacent agglomerated kidney cells, is secreted into the blood circulation. There he cleaves the decapeptide angiotensin 1 from angiotensinogen isolated from the liver. The latter is converted into angiotensin 11 through angiotenzin converting enzyme (ACE) 11. Angiotensin 11 plays a significant role in the regulation of blood pressure, since it directly increases blood pressure due to angiospasm. Additionally, it stimulates the secretion of the aldosterone from the adrenal gland and thus increases the extracellular fluid volume, which, in turn, increases blood pressure through inhibition of sodium excretion.

Postreceptor actions include, among other things, stimulating the conversion of phosphoinositol (Ca ^{+ 2} release), activating protein kinase C) and helping c-AMP-dependent hormone receptors.

The affinity of the compounds of formula 1 with the angiotensin-11 receptor can be determined by measuring ¹²⁵ J-angiotensin-11- or ³ H-angiotensin-11-displacement of receptors on the membranes of the cattle adrenal glomerulosis zone. For this, the preparation of the membrane is suspended in a buffer solution at pH 7.4.

To prevent the degradation of the radioligand during incubation, aprotinin, a peptidase inhibitor, is added. Additionally, about 14,000 cf isotope indicator with a specific activity of 74 TBq / mmol (sold by Amersham Buchler Braunschweig, Germany) and the amount of receptor protein that binds 50% of the isotope indicator are used. The reaction is started by adding 50 ml of a membrane suspension to a mixture of 100 ml of buffer solution + aprotinin; 50 ml of buffer solution with angiotensin-11 or a receptor antagonist or without angiotensin-11 or a receptor antagonist and 50 ml of an isotopic indicator. After an incubation period of 60 minutes at 25 ^° C, the bound and free radioligand are separated by filtering experiments using Whatmann ^® GFIC filters on a Scatron ^® cell collector.

Non-specific bonds are prevented by treating the filters with 0.3% polyethyleneimine with pH = 10 (Sigma, N 3143). By measuring the radioactivity in a gamma scintillation counter, the intensity of the displacement of the radioligand by the receptor is determined. IC ₅₀ values that indicate the concentration of inhibitor to displace 50% of the ligand are determined by J. Theor. Biol 59,253 (1970). They range from 1.10 ^-4 to 1.10 ^-9 M for the compounds of formula (1).

Alternatively, you can determine the affinity of compounds of formula 1 with an angiotensin-11 receptor by measuring ¹²⁵ J-angiotensin-11- or ³ H-angiotensin-11-receptor displacement from various organs (liver, lung, adrenal gland, brain, etc. .).

For this, the prepared membranes are suspended in an incubation buffer solution (20 mmol Tris, pH 7.4, containing 135 mmol NaCl, 10 mmol KCl, 10 mmol MgCl ₂ , 5 mmol glucose, 0.2% bovine serum albumin and PMSF protease inhibitors 0.3 mmol and bacitration 0.1 mmol) and incubated with radiolabeled angiotensin-11 and with different concentrations of the test compounds for 90 min at 25 ^o C. Then the bound and free radioligand is separated by filtration through a filter with a microglass fiber (GF51, Schleicher - Shiill on a cell collector (SCATR HE).

By measuring the radioactivity associated with the receptor on the filters with a beta or gamma spectrometer, the degree of displacement of the radioligand by the receptor is determined by the tested compounds. The intensity of the radioligand displacement by the receptor due to the tested compounds is indicated by lC ₅₀ , i.e. an inhibitor concentration that displaces 50% of the bound radioligand by the receptor. Calculation of lC ₅₀ values is carried out using PC-software (LIGAND, CA Mepherson 1985, Elsivier-BIOSOFT, 68 Hills Road, Cambridge CB 2 ILA, UK). The lC ₅₀ values measured for compounds of formula (I) lie in the range from 1 • 10 ^-5 to 1 • 10 ^-11 M (cf. the following table 1, which compares lC ₅₀ values for the compounds of the invention).

 Table 1.

Example - lC ₅₀ nM
1 - 5000
2 - 8000
3 - 1100
4 - 1100
5 - 16000
22 - 2000
24 - 800
25 - 1400
29 - 1.1
30 - 2030.0
31 - 153.0
32 - 3,5
33 - 34.0
34 - 1,0
35 - 50.0
36 - 16.0
37 - 1.1
55 - 8.8
56 - 4.6
57 - 1100
58 - 3.0
59 - 1.3
60 - 2.2
61 - 1.1
62 - 3.6
63 - 1.3
64 - 0.5
65 - 1.8
66 - 6.9
67 - 0.91
68 - 12.0
69 - 3.2
70 - 4.4
71 - 2.2
73 - 2.5
76 - 9.5
79 - 5.8
80 - 0.69
81 - 0.79
83 - 0.96
84 - 4.3
85 - 3.9
89 - 1.1
90 - 0.69
92 - 280.0
93 - 3.3
95 - 1.8
98 - 1.4
99 - 26.6
100 - 68.5
101 - 2.4
102 - 2,3
105 - 3.0
107 - 2.5
108 - 0.95
109 - 0.6
110 - 0.5
111 - 2.9
112 - 1.5
113 - 0.3
115 - 0.9
116 - 2.4
117 - 1.2
124 - 1.8
125 - 2.8
127 - 3.0
128 - 5.6
129 - 1.5
134 - 180.0
135 - 5.6
138 - 1.7
139 - 2.8
140 - 8.2
141 - 4.4
144 - 5.3
146 - 40.0
151 - 0.4
152 - 1.5
153 - 0.88
154 - 1.8
155 - 6.0
156 - 4.7
157 - 1.4
159 - 8.7
160 - 0.73
161 - 57.0
162 - 3.9
163 - 3.7
164 - 0.86
165 - 2,3
166 - 1.2
167 - 4.0
168 - 7.0
169 - 2.9
170 - 2.7
171 - 0.7
172 - 0.48
174 - 5.1
179 - 2.6
181 - 1.0
183 - 1.7
185 - 5.9
186 - 6.5
187 - 1.2
190 - 22.0
191 - 21.4
194 - 21.7
195 - 3.0
To determine the antagonistic effect of the compounds of formula (I), their effect on angiotensin-II-induced increase in blood pressure in Spragie-Dawley anesthetized rats can be measured. The drug is Na-thiobarbital Trapanal ^® , trademark Buk Gulden, Germany) at a dose of 100 mg / kg intraperitoneally. Intravenous administration is performed in the jugular vein. Blood pressure is measured in the carotid artery. First, animals are treated with pentoline tartrate (10 mg / kg intramuscularly), so that lower blood pressure (ganglion block) is achieved. ANGII (CIBA hypertensin) is used in a volume of 0.1 ml / 100 g at 10-minute intervals intravenously. The dose is 0.5 μg / kg. The compounds of formula (1) are dissolved in distilled water and used at doses from 0.1 to 1.0 μg / kg intravenously or 10 and 100 mg / kg intraduodenally.

 The compounds of formula (1) are particularly effective in the range of 0.1-100 mg / kg, preferably 0.1-3 mg / kg.

 The invention also relates to pharmaceutical compositions consisting of a compound of formula (1) and other active substances, such as diuretics or non-steroidal anti-inflammatory active substances. The compounds of formula (1) can also be used as diagnostic tools for the renin-angiotensin system.

 The pharmaceutical preparations contain an active amount of the active substance of the formula (1) and, if appropriate, other active substances together with the inorganic or organic pharmaceutical carrier substance used. Application can be carried out through the nose, intravenously, subcutaneously or through the mouth. The dosage of the active substance depends on the type of warm-blooded, on body weight, on age and on the type of application.

 The pharmaceutical preparations of the present invention are prepared by known methods of dissolving, mixing, granulating or pelleting.

 For oral administration, the active compounds are mixed with additives customary for this purpose, such as carrier materials, stabilizers or inert solvents, and are conventionally formulated into suitable administration forms as tablets, dragees, capsules, aqueous, alcoholic or oily suspensions, or aqueous, alcoholic or oil solutions. As inert carriers, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose, magnesium stearyl fumarate or starch, especially corn starch, can be used. In this case, the dosage form can be obtained as dry and wet granules. As oily carrier substances or solvents, for example, vegetable and animal oils such as sunflower oil and fish oil are taken into account.

 For subcutaneous or intravenous use, the active compounds or their physiologically compatible salts, if necessary with the usual substances for this purpose, such as dissolution agents emulsifiers or other auxiliary substances, are given in the form of solutions, suspensions or emulsions. As solvents take into account, for example, water, physiological solution of sodium chloride or alcohols, such as ethanol, propanediol or glycerin, as well as sugar solutions, such as glucose or mannitol solutions, or mixtures of these solvents.

,
a) получение 4'-метилбифенил-2-амина
К 23,9 г (0,112 мол) 4'-метил-2-нитробифенила (R.B. Muller и S.Dugar, Organometallics 1984, 3, 1261) в 50 мл метанола добавляют 3 г никеля Ренея и гидрируют при нормальном давлении при комнатной температуре до поглощения теоретического количества H₂. После этого отделяют катализатор для фильтрования и сгущают фильтрат. Хроматография на SiO₂ (500 г) с EE/HEP (1/6) в качестве растворителя дает 19 г соединения указанного в названии в виде масла (92,5%).List of abbreviations:
DMF - N, N-dimethylformamide
NBS - N-Bromosuccinimide
AIBN - L, L-azobis-isobutyronitrile
EI - shock electron
DCI - Desorption-Chemical Ionization
RT - room temperature
EE - ethyl acetate (EtOAc)
DIP - diisopropyl ether
MTB - methyl tert-butyl ether
mp - melting point
HEP - n-heptane
DME - dimethoxyethane
FAB - atomic bombardment
CH ₂ Cl ₂ - dichloromethane
The invention is illustrated by the following examples:
Example 1. Synthesis of 1 - [(2'-phenylaminocarbonylaminosulfonyl-biphenyl-4-yl) methyl] -2 n-butyl-4-chloro-imidazole-5-carboxaldehyde

,
a) obtaining 4'-methylbiphenyl-2-amine
To 23.9 g (0.112 mol) of 4'-methyl-2-nitrobiphenyl (RB Muller and S. Dugar, Organometallics 1984, 3, 1261), 3 g of Raney nickel are added to 50 ml of methanol and hydrogenated at normal pressure at room temperature to absorption of a theoretical amount of H ₂ . After that, the catalyst for filtration is separated and the filtrate is concentrated. Chromatography on SiO ₂ (500 g) with EE / HEP (1/6) as solvent gives 19 g of the title compound as an oil (92.5%).

Coefficient Rf (EE / HEP 1/4) = 0.3 MS (El) = 183 (M ⁺ )
b) 4 '- methyl biphenyl-2-ammonium hydrochloride
10 g of compound 1a) are dissolved in 50 ml of 6 in HCl and 100 ml of dioxane. Removal of the solvent afforded the title compound, which was used without further purification.

 c) 4 '- methylphenyl-2-sulfonamide.

To a suspension of 31 g (140 mmol) of compound 1b) in 200 ml of 6 N HCl, 7.9 g (114 mmol) of sodium nitrite are added at -10 ^° C, and a clear solution is formed. The latter at 0 ^o C is added to a solution consisting of 200 ml of glacial acetic acid saturated with SO ₂ , 17 g of C and Cl ₂ • H ₂ O and 25 ml of H ₂ O. After that, it is brought to room temperature and stirred for 2 hours at this temperature. Then 250 ml of EE are added, the phases are separated and the organic phase is dried with magnesium sulfate. Condensation gives an oil which is dissolved in 300 ml of acetone. Then add 150 ml of 25% ammonia and stir for 2 hours. Then it is concentrated and 500 ml of EE are added. The EE phase is washed with 1 • H ₂ O, dried on MgSO ₄ and concentrated. Chromatography on SiO ₂ with EE / HEP (1/1) gives the title compound (4.6 g).

Rf (EE / HEP 1/1) = 0.25 MS (DCI) = 248 (M ⁺ + H).

Melting point: 122 ^o C.

d) 4 '- methylbiphenyl-2-N, N-dimethylaminoformylsulfonamide
4.6 g (18.6 mmol) of compound 1c) and 2.5 g (19.3 mmol) of N, N-dimethylformamide dimethyl acetal in 30 ml of DMF are stirred for 2 hours at room temperature, then 100 ml of H ₂ O and the precipitate formed are added. suctioned off and dried in air, whereby 4.2 g of the title compound are obtained.

Rf (EE / HEP 1/1) 00.2 MS (DCI) = 303 (M ⁺ + H).

 e) 4'-bromomethylbiphenyl-2-N, N-dimethylamino-formylsulfonamide.

To 2.76 g (13.5 mmol) of compound 1d) and 2.4 g of NBS (13.5 mmol) in 50 ml of chlorobenzene was added 150 mg of benzoyl peroxide. After 4 hours, it is concentrated under reflux, 50 ml of EE are added and the EE phase is washed with 1 x 10% Na ₂ SO ₃ solution and 1 x H ₂ O. After drying with Na ₂ SO _{4, it is} concentrated and chromatographed on SiO ₂ —1 , 2 g of the title compound.

Rf (EE / HEP 2/1) = 0,23 MS (DCl) = 381, 383 (M ^{+ +} H)
f) 2 - n-butyl-4-chloro-5-formyl-imidazole
To 20 g (0.106 mol) of 2-n-butyl-4-chloro-5-hydroxymethylimidazole (prepared according to European Patent A 253 310) in 350 ml of glacial acetic acid, 305 ml of a 1 molar solution are slowly added at 10-15 ^° C ( NH ₄ ) ₂ Ce (NO ₃ ) ₆ in H ₂ O. After 2.5 hours at room temperature, the pH was adjusted with 2 and KOH to 4 (20 ^o C during addition of the base). It was then extracted 4 x with 500 ml of CH ₂ Cl ₂ and the combined organic extracts were washed with 3 x 300 ml of a saturated aqueous solution of NaHCO ₃ , dried with Na ₂ SO ₄ and concentrated to give the title compound as a colorless solid (18 g, 92 %).

Melting point: = 90 ^o C
Rf (DIP / MTV 1/1) = 0.5
g) 1- [(2'-N, N-dimethylaminoformylsulfonamidobiphenyl-4-yl) methyl] -2 n-butyl-4-chloro-imidazole-5-carboxaldehyde.

690 mg (1.98 mmol) of compound 1e), 370 mg (1.98 mmol) of compound 1f) and 270 mg (1.98 mmol) of potassium carbonate are stirred in DMF (10 ml) at room temperature for 2 hours. After this, add 50 ml of EE and washed 2 times with H ₂ O. The organic phase is dried (a ₂ O ₄ ) and concentrated. Chromatography on SiO ₂ with EE / HEP (2/1) as solvent gives the title compound (380 mg; 40%).

Rf (EE / HEP 2/1) = 0,15 MS (DCl) = 487 (M ^{+ +} H)
h) 1- [(2'-sulfonamidobiphenyl-4-yl) methyl] -2-n-butyl-4-chloroimidazole-5-carboxaldehyde, 280 mg (0.58 mmol) of compound 1g) in 7 ml of methanol and 14 ml of H ₂ O is mixed with 110 mg (2.88 mmol) of sodium hydroxide and heated for 4 hours to a boil. After cooling to room temperature, pH was adjusted to about 6 with 4 and HCl and extracted 3 × with 30 ml of EE, dried on the EE phase (Na ₂ SO ₄ ) and concentrated to give 190 mg of the title compound.

Rf (EE / HEP 3/1) = 0.45 MS (DCl) = 432 (M ⁺ + H).

 i) 1 - [(2'-phenylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl] -2'-butyl-4-chloro-imidazole-5-carboxaldehyde.

730 mg (1.69 mmol) of compound 1) is heated in 10 ml of phenylisocyanate to 80 ^° C. After 4 hours, it is concentrated and chromatographed on SiO ₂ (solvent EE / HEP (2/1), whereby 400 mg of the title compound is formed.

Rf (EE / HEP 2/1) = 0.15 MS (DCI) = 551 (M ⁺ + H).

 Alternative preparation of compound id (4'-methyl-2-N, N-dimethylaminoformylsulfonamide).

K 11 g (37.9 mmol)
2-N, N-dimethylaminoformylsulfonamidobromobenzene (obtained from 2-bromaniline analogously to 1b - 1d); 1 g of triphenylphosphine, 8 g of Na ₂ CO ₃ in 150 ml of toluene and 40 ml of H ₂ O are added under argon atmosphere, first 420 mg of Pd (OAc) ₂ and then 5.66 g (41.9 mmol) of 4-tolylboronic acid in 100 ml of ethanol. Then heated for 4 hours to a boil. Then it is concentrated and taken up in 500 ml of ethyl acetate and 500 ml of H ₂ O. The resulting precipitate is filtered off and characterized as the title compound. The acetic acid ester phase was separated, dried (Na ₂ SO ₄ ) and concentrated. Chromatography on SiO ₂ with ethyl ester of acetic acid gives another part of the title compound (only 7.6 - 66%).

 Alternative preparation of 2-bromobenzenesulfonamide (similar to intermediate step 1c).

In 4.7 g of 2-bromothiophenyl in 60 ml of H ₂ O is introduced at 0-10 ^o C for 30 min gaseous Cl ₂ . Then it is stirred for 30 minutes at 0 ^° C. and then, without cooling, air is blown through the solution for 30 minutes. After adding 60 ml of acetone and re-cooling to 0 ^° C., 10 ml of a saturated NH ₄ OH solution are slowly added. After another 30 minutes, the pH of the solution was adjusted with 4 N HCl to a value of 3 and product filtration was obtained.

 Yield 4.5 g (77%).

Melting point = 190-191 ^o C.

 Example 3. The synthesis of 1- [(2 '-n-propylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl] -2 n-butyl-4-chloroimidazole-5-carboxaldehyde was carried out analogously to example 1.

.Rf (EE) = 0.6 MS (FAB) = 517 (M ⁺ + H)

.

,
a) 1- [(2'-этоксикарбониламиносульфонилбифенил-4-ил)-метил] -2- n-бутил-4-хлоро-имидазол-5-карбоксальдегид.Example 3. Synthesis of 1- (2'-pyridyl-2-aminocarbonylaminosulfonylbiphenyl-4-yl) methyl -2-n-butyl-4-chloroimidazole-5-carboxaldehyde

,
a) 1- [(2'-ethoxycarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-chloro-imidazole-5-carboxaldehyde.

To 1.1 g (2.5 mmol) of compound Ih) and 0.78 g (5.6 mmol) of potassium carbonate in 20 ml of dry DME was added 0.48 ml (5.1 mmol) of chloroformic acid ethyl ester. After 1 h, cool to room temperature and mix with 50 ml of 10% KH ₂ PO ₄ solution. After extraction with EE, it is dried with Na ₂ SO ₄ and concentrated. Chromatography on SiO ₂ with EE / HEP (2/1) as solvent gives 840 mg of the title compound. Rf (EE / HEP 2/1 = 0.32 MS (DCI) = 504 (M ⁺ + H).

 b) 1-1 (2'-pyridyl-2-aminocarbonylaminosulfonylbiphenyl-4-yl) methyl -2-n-butyl-4-chloro-imidazole-5-carboxaldehyde.

150 mg (0.3 mmol) of compound 3a) and 28.5 mg (0.3 mmol) of 2-aminopyridine are heated in 8 ml of dry toluene for 2 hours to boil. It is then concentrated and chromatographed on SiO ₂ (solvent EE), whereupon 34 mg of the title compound are formed.

Rf (EE / methanol 10/1) = 0.4 MS (FAB) = 552 (M ⁺ +1).

.The compounds of examples 4 to 39 can be synthesized analogously to example 3. (see table. 2)
These compounds have the following general formula (A)

.

 Example 40. Synthesis of 1 - [(2'-phenylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-chloro-5-hydroxymethylimidazole.

100 mg (0.18 mmol) of compound 1) was dissolved in 5 ml of ethanol and mixed at room temperature with 10 mg (0.27 mmol) of sodium borohydride. After 20 hours, add 10 ml of a 5% sodium bisulfate solution and extract 3x with EE. The organic phase is dried with Na ₃ SO ₄ and concentrated. Chromatography on SiO ₂ with EE / HEP (3/1) gives 55 mg of the title compound.

Rf (EE / HEP 3/1) = 0.25 MS (DCI) = 553 (M ⁺ + H).

 The compounds (see formula B) of examples 41-54 are synthesized analogously to example 40 from the compounds of examples 2,3 and 16-27 (table. 3).

.Example 55. Preparation of 1- [(2'-allylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-chloro-imidazole-5-carboxaldehyde

.

730 mg (1.69 mmol) of compound Ih) is heated in 10 ml of allyl isocyanate to 80 ^° C. After 4 hours, it is concentrated and chromatographed on SiO ₂ (solvent EE / HEP (2/1) to obtain 400 mg of the title compound.

Rf (EE / HEP 2/1) = 0,15 MS (FAB) = 515 (M ^{+ +} H)
Example 56. Preparation of 1 - [(2'-allylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-methylthio-imidazole-5-carboxylic acid.

,
a) Сложный этиловый эфир 2-амино-2-циано-уксусной кислоты.

,
a) Ethyl 2-amino-2-cyano-acetic acid ethyl ester.

To 35 g (0.246 mol) of 2-cyano-glyoxylic acid 2-oxime-ethyl ester in 350 ml of H ₂ O and 280 ml of saturated sodium bicarbonate solution at room temperature, 119 g of sodium dithionite are added in portions (15 min). Then heated for 1 h to 35 ^o C; then saturated with NaCl and extracted with 5 x dichloromethane. After drying with calcium chloride, the organic phase is concentrated. 11.8 g of the title compound are obtained as an oil.

Rf (CH ₂ Cl ₂ / CH ₃ OH 9/1) = 0.6
b) 2-Cyano-2-n-butylcarbonylaminoacetic acid ethyl ester.

In 3.6 g (28.09 mol) of compound 56a) and 50 ml of dry CH ₂ Cl ₂ and 2.3 ml (28.09 mmol) of pyridine are instilled at -5 ^o C to 0 ^o C 3.39 ml ( 28.09 mmol) of valeroil chloride in 5 ml of CH ₂ Cl ₂ . Then stirred for 1 h at room temperature. Then the organic phase is washed with 3 x H ₂ O and 1 x saturated NaCl solution, dried with calcium chloride and concentrated.

 Crystallization from DIP gives 1.7 g of the title compound.

Rf (CH ₂ Cl ₂ / CH ₃ OH 9/1) = 0.35.

Melting point: 87 ^o C.

 c) Z-amino-2-n-butylcarbonylamino-methylthiacrylic acid ethyl ester.

 To 2.9 g (13.67 mmol) of compound 56 b) and 0.19 ml (1.36 mmol) of triethylamine and 60 ml of absolute ethanol, 2 ml (27.26 mmol) of condensed methyl mercaptan was added at room temperature. After 3 days, another 0.5 ml of methyl mercaptan is added. After another 24 hours at room temperature, another 0.5 ml of methyl mercaptan and 0.19 ml of triethylamine are injected and stirred for another 24 hours at room temperature. The solvent was then removed and the residue crystallized from DIP, whereby 2.4 g of the title compound were formed.

Rf (CH ₂ Cl ₂ / EE 4/1) = 0.3.

Melting point: 120 ^o C.

 d) 2-n-Butyl-4-methyl-imidazole-5-carboxylic acid ethyl ester.

In 4.17 g (20.0 mmol) of phosphorus pentachloride in 20 ml of CH ₃ Cl _2, 2.44 g (20.0 mmol) of 4-dimethylaminopyridine in 12 ml of CH ₂ Cl _{2 are} instilled at -78 ^° C. After 5 minutes, 2.42 g (10.0 g mmol) of compound 56c are instilled into 25 ml of CH ₂ Cl ₂ . Then brought to room temperature and diluted with 30 ml of CH ₂ Cl ₂ . After 2 hours, while cooling with ice, 300 ml of a 1N sodium bicarbonate solution was added and stirred for 1 hour. Then the phases were separated, the aqueous phase was extracted with 3 × EE and the combined organic phases were dried using calcium chloride. Chromatography on SiO ₂ with CH ₂ Cl ₂ / EE 9/1).

Rf (CH ₂ Cl ₂ / EE 9/1) = 0.6 MS (DCI) = 243 (M ⁺ + H)
e) 1 - [(2'-Sulphonamidobiphenyl-4-yl) methyl] -2-n-butyl-4-methylthio-imidazole-5-carboxylic acid ethyl ester.

To 1.35 g (2.5 mmol) of 1- (2'-dimethylaminoformylsulfonamidobiphenyl-4-yl) methyl -2-n-butyl-4-methylthio-imidazole-5-carboxylic acid ethyl ester obtained from Example 56d ) and Example 1e), as in Example 1g), add 15 ml of concentrated HCl to 30 ml of methanol. After 20 minutes with reflux, it was cooled to room temperature and a pH value of 5-6 was established using a 2 N NaOH solution. It is then extracted with 3 x 100 ml of EE, the organic extracts are dried with Na ₂ SO ₄ and concentrated, and the title compound is obtained as a foam, which is used without further purification for the next reaction step.

Rf (EE / HEP 1/1) = 0.2 MS (FAB) = 488 (M ⁺ + H)
f) The title compound 56 is obtained as a result of 120 mg of 1- [(2'-allylaminocarbonylamino-sulfonyl-biphenyl-4-yl) methyl] -2-n-butyl-4-methylthioimidazole-5-carboxylic acid ethyl ester acid (obtained analogously to example 55) in 10 ml of ethanol and 1 ml of 2 n sodium hydroxide solution is stirred 4 for at room temperature. After this is concentrated, H ₂ O is added and pH = 4 is set with 1 N HCl, the title compound precipitated and separated by filtration.

,
a) Сложный этиловый эфир 1-[(2'-этоксикарбониламиносульфонилбифенил-4-ил)-метил] -2-n-бутил-4-метилтиоимидазол-5-карбоновой кислоты.Rf (EE / MeOH 10/1) = 0.1 MS (FAB) = 543 (M ⁺ + H)
Example 57. Synthesis of 1 - [(2'-pyridiethyl-2-aminocarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-methylthioimidazole-4-carboxylic acid

,
a) 1 - [(2'-Ethoxycarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-methylthioimidazole-5-carboxylic acid ethyl ester.

1.21 g (2.5 mmol) of compound 56e) and 0.78 g (5.6 mmol) of potassium carbonate in 20 ml of dry DME are heated to boiling and 2.48 ml (5.1 mmol) of chloroformate ethyl ester are added acids. After 1 h, cool to room temperature and mix with 50 ml of 10% KH ₂ PO ₄ solution. After extraction with EE, it is dried with Na ₂ SO ₄ and concentrated. Chromatography on SiO ₂ with EE / MEP (2/1) as solvent gives 840 mg of the title compound.

Rf (EE / HEP 2/1) = 0,5 MS (DCI) = 559 (M ^{+ +} H)
b) 1 - [(2'-Pyridylethyl-2-aminocarbonyl-aminosulfonylbiphenyl-4-yl) methyl] - 2-n-butyl-4-methylthioimidazolo-5-carboxylic acid ethyl ester 168 mg (0.3 mmol) Compounds 57 a) and 37 mg (0.3 mmol) of 2- (2-aminoethyl) -pyridine are heated in 8 ml of dry toluene for 2 hours to boil. It is then concentrated and chromatographed on SiO ₂ (solvent EE), whereupon 34 mg of the title compound are formed.

Fr (EE) = 0.15 MS (FAB) = 636 (M ⁺ + H)
c) The title compound 57 was prepared in a similar manner to 56 f).

Rf (EE / MeON 5/1) = 0.1 MS (FAB) = 608 (M ⁺ + H)
Similarly, as described in example 57, you can synthesize the compounds of the following table. 4.

These compounds have the formula (C)
Compounds of the following table. 5 can be synthesized analogously to example 57.

 These compounds have the following formula (D).

Пример 150. Получение 1-{[(2'-бензоилоксикарбониламиносульфонил)-бифенил-4-ил]-метил} -2-n-бутил-4-хлоро-имидазол-5-карбальдегида.

Example 150. Preparation of 1 - {[(2'-benzoyloxycarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2-n-butyl-4-chloro-imidazole-5-carbaldehyde.

.

.

The title compound 150 was prepared by heating 215 mg (0.5 mmol) of the compound lh), 71.3 ml (0.5 mmol) of chloroformic acid benzyl ester and 70 mg (0.5 mmol) of K ₂ CO ₃ in 10 ml of DMF ( anhydrous) 1.5 hours with phlegm. Then it is concentrated, 100 ml of EE are added and washed with 1 x 40 ml of NaHSO ₄ solution and NCl solution. The organic phase is dried over Na ₂ SO ₄ and rotated. Chromatography with MBT gives 120 mg (42%) of the title compound 150 T. pl. = 56 ^o C.

Rf (MTC) = 0.20 MS (FAB) = 566 (M ⁺ + H)
Compounds of the following table. 6 can be synthesized analogously to example 150 or 57a.

 These compounds have the following formula (E).

,
Пример 178. Получение сложного этилового эфира 1-[(2'-диметилсульфамоиламиносульфонил-бифенил-4-ил)-метил-] 2-n-бутил-4-метилтио-имидазол-5-карбоновой кислоты

.

,
Example 178. Obtaining the ethyl ester of 1 - [(2'-dimethylsulfamoylaminosulfonyl-biphenyl-4-yl) methyl-] 2-n-butyl-4-methylthio-imidazole-5-carboxylic acid

.

The title compound 178 was obtained by heating 244 mg (0.5 mmol) of compound 56 e), 108 ml (1.0 mmol) of sulfamoyl chloride and 140 mg (1.0 mmol) of K ₂ CO ₃ in 10 ml of DMF (anhydrous) for 5 days with phlegm. Dilute with 50 ml of EE and wash with 50 ml of KHSO ₄ / H ₂ SO ₄ (pH = 1.0). The organic phase is dried over Na ₂ SO ₄ and rotated. Chromatography with EE gives 69 mg (23%) of a colorless oil.

Rf (EE) = 0.15 MS (FAB) = 617 (M ⁺ + Na)
Example 179. Preparation of 1- [1- (2'-dimethylsulfamoylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-methylthio-imidazole-5-carboxylic acid.

.

.

50 mg (84 mmol) of the title compound of Example 178 and 0.84 ml of 1 N NaOH were dissolved in 3 ml of ethanol and stirred for 2 days at room temperature. Ethanol was distilled off, 5 ml of H ₂ O was added and pH = 2 was adjusted with HCl. The precipitate was washed with 2 x 1 ml of water and dried in vacuo. Obtain 33 mg (70%) of a colorless powder.

Rf (EE / methanol 5: 1) = 0.11 MS (FAB) = 567 (M ⁺ + H).

.Example 180. Ethyl ester of 1 - [(2'-allyloxycarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-methyl-imidazole-5-carboxylic acid

.

244 mg (0.5 mmol) of compound 56 e), 106 ml (1.0 mmol) of chloroformic acid allyl ester and 140 mg (1.0 mmol) of K ₂ CO _{3 are} refluxed for 1 hour. Then add 50 ml of a 10% solution of KHSO ₄ and extract 3 x 50 ml of EE. The organic phase was dried over Na ₂ SO ₄ and evaporated. Chromatography with 1: 1 MTB / DIP gives 115 mg (40%) of a colorless oil.

Rf (MTB / DIP 1: 1) = 0.15 MS (FAB): 572 (M ⁺ + H).

 Example 181. Synthesis of 1 - [(2'-allyloxycarbonylaminosulfonyl-biphenyl-4-yl) methyl] -2-n-butyl-4-methylthio-imidazole-5-carboxylic acid.

 95 mg (0.17 mmol) of compound 180 are saponified, as in Example 179. 30 mg (33%) of a colorless foam are obtained.

Rf (EE / MeOH 10: 1) = 0.1 MS (FAB) = 544
Example 182 1 - [(2'-Benzyloxycarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-methylthio-imidazole-5-carboxylic acid ethyl ester

.

.

 The title compound is synthesized analogously to example 180.

Rf (MTB-DIP 1: 1) = 0.15 MS (FAB) = 622 (M ⁺ + H).

.Example 183. 1 - [(2 '-Benzyloxycarbonylaminosulfonyl-biphenyl-4-yl) methyl] -2-n-butyl-4-methylthio-imidazole-5-carboxylic acid

.

 The title compound is synthesized analogously to example 181.

,
a) 1-[2'-сульфонамидобифенил-4-ил)-метил] -2-n-бутил-4-метоксиимидазол-5-карбальдегид.Rf (EE / MeOH 10: 1) = 0.1 MS (FAB) - 594 (M ⁺ + H)
Example 184. 1- {[2'-allylaminocarbonylaminosulfonyl] biphenyl-4-yl-methyl} -2-n-butyl-4-methoxy-imidazole-5-carbaldehyde

,
a) 1- [2'-sulfonamidobiphenyl-4-yl) methyl] -2-n-butyl-4-methoxyimidazole-5-carbaldehyde.

215 mg (0.5 mmol) of compound lh) and 1.5 mol of 1 N NaOH are boiled in 10 ml of methanol for 19 hours under reflux. Then methanol is rotated, pH = 2 is adjusted with NaHSO ₄ solution and extracted with 3 x 50 ml of EE. The organic phase is dried over Na ₂ SO ₄ and rotated. Chromatography with MTB / DIP (1: 1) gives 170 mg (80%) of the title compound, melting point: = 189 ^° C.

Rf (MTB / DIP 1: 1) = 0.19 MS (DCI) = 426 (M ⁺ + H).

 b) The title compound 184 is obtained by boiling 150 mg (0.35 mmol) of compound 184 a) and 3 ml of allyl isocyanate for 5 hours under reflux. Then rotate and chromatograph with EE. 60 mg (34%) of a colorless foam are obtained.

Rf (EE) = 0.34 MS (FAB) = 511 (M ⁺ + H).

.Example 185. 1 - {[(2'-ethoxycarbonylaminosulfone) biphenyl-4-yl] methyl} -2-n-butyl-4-methoxy-imidazole-5-carbaldehyde

.

1.0 g (2.34 mmol) of compound 184 a) is dissolved in 50 ml of acetone (anhydrous) and 560 mg of K ₂ CO _{3 are} added. Heated to reflux, then 0.45 ml of chloroformic acid ethyl ester is slowly injected at this temperature. Heated for another 4 hours with phlegm, then rotate. Using a solution of NaHSO _{4, it is} acidified to pH = 2, then extracted with 3 x 100 ml of EE. Dry over Na ₂ SO ₄ , then rotate and chromatograph with MTB / DIP / HOAc (15:83: 2). The resulting oil can be crystallized with diethyl ether. Obtain 550 mg of colorless crystals with a melting point of 134 ^o C.

Rf (MTB) = 0.24 MS (FAB) = 500 (M ⁺ + H)
Example 186. 1 - {[(2'-Benzyloxycarbonylaminosulfonyl) biphenyl-4 -] - methyl} -2-n-butyl-4-methoxy-imidazole-5-carbaldehyde.

.

.

 Example 186 is synthesized analogously to example 185.

Rf (MTB) = 0.16 MS (FAB) = 562 (M ⁺ + H)
Example 187. Ethyl ester of 1 - {[(2'-benzylaminocarbonylaminosulfonyl-biphenyl-4-yl] methyl} -2-n-butyl-imidazole-5-carboxylic acid.

.

.

A catalytic amount of Pd / C was added to 150 mg (0.24 mmol) of the compound of Example 73 dissolved in 50 ml of MeOH and 5 ml of HOAc. The mixture was stirred in an H ₂ atmosphere for 12 hours at room temperature. Then the mixture is rotated and chromatographed with EE. 30 mg (22%) of a colorless foam are obtained.

Rf (EE) = 0.42 MS (FAB) = 575 (M ⁺ + H)
Example 188. Ethyl ester of 1 - {[(2-ethoxycarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2-n-butyl-imidazole-5-carboxylic acid.

.

.

 About 300 mg of Raney nickel is added to 300 mg (0.5 mmol) of compound 57 a) dissolved in 10 ml of E OH. Heated for 10 hours and with phlegm, add the remaining 200 mg per Raney nickel and again heated for 5 hours with phlegm. The catalyst is filtered off and the solvent is rotated. The residue was chromatographed with MTB to give 50 mg (18%) of a colorless foam.

Rf (EE) = 0.27 MS (FAB) = 514 (M ⁺ + H).

 Example 189. Ethyl ester of 1- [(2 '- {2-thienylsulfonylamino-sulfonyl} biphenyl-4-yl) methyl] -2-n-butyl-4-methylthiodazole-5-carboxylic acid.

.

.

244 mg (0.5 mmol) of the sulfonamide of Example 56 e) was dissolved in 10 ml of diethylene glycol dimethyl ether (anhydrous). Then 346 mg (2.5 mmol) of K ₂ CO ₃ and 81 mg (0.5 mmol) of 2-thienylsulfonyl chloride are added. It is heated for 2 hours under reflux, then the cooled reaction mixture is poured into 50 ml of a 50% NaHSO ₄ solution and extracted with 3 x 50 ml of EE. Dry over Na ₂ SO ₄ , rotate and chromatograph with EE. Obtain 310 mg of pale yellow crystals, melting point = 120 - 122 ^o C.

Rf (EE) = 0.24 MS (FAB) = 634 (M ⁺ + H)
Example 190. 1- [2 '{2-thienylsulfonylaminosulfonyl} biphenyl-4-yl) methyl] -2-n-butyl-4-methylthio-imidazole-5-carboxylic acid.

.

.

 The saponification of the ethyl ester of Example 189 is carried out analogously to Example 56 f).

Rf (EE / MeOH 5: 1) = 0.13 MS (FAB) = 606 (M ⁺ + H).

 Compounds of the following table. 7 can be synthesized analogously to example 189 or analogously to example 190 (or 56 f).

 These compounds have the following formula F).

.

.

 Example 195. Ethyl ester of 1 - [(2'-methylaminocarbonylaminosulfonyl-biphenyl-4-yl) methyl] -2-n-butyl-4-methylthio-imidazole-5-carboxylic acid.

In an autoclave to 1 g of the sulfonylcarbamate from example 57 a) in 50 ml of toluene at 80 ^o C is introduced for 5 min melamine. It is then heated for 8 hours to 80 ^° C. After this it is concentrated in vacuo and the residue is chromatographed on silica gel (EE / n-HEP 2/1), whereby the title compound is obtained as an amorphous powder.

Rf (EE / n-HEP 2/1) = 0.1 MS (PAB) = 545 (M ⁺ + H).

 Similarly, as in example 195 or in example 56f), you can synthesize the compounds of the following table. 8 (the compound of Example 195 is also shown).

 These compounds have the formula C.

.

.

An example of the production of salt (dipotassium salt of the compound according to example 106):
2-Butyl-4- (methylthio) -1 - ((2 '- ((((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl) methyl) -1H salt -imidazole-5-carboxylic acid
To a cooled (3-5 ^° C) suspension of the compound of Example 105 (2 g, 3.5 mmol) in ethanol (40 ml) was added dropwise 6N KOH (2.3 ml, 13.8 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 72 hours. The crude precipitate was filtered off, washed with 96% ethanol, and 1.92 g (89%) of 2-butyl-4- (methylthio) -1 - ((2 '- (( ((propylamino) -carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl) methyl) -1H-imidazole-5-carboxylic acid as colorless crystals of dipotassium salt: so pl. > 260 ^o C; Elemental analysis (C ₂₆ H ₃₀ K ₂ N ₄ O ₅ S ₂ ), C, H, N, S;
¹ H NMR (D ₂ O) 0.77 (t, 2H), 1.31 (m, 4H), 1.58 (m, 2H), 2.47 (s, 3H), 2.72 (t, 2H), 2.80 (m, 2H), 5.63 (s, 2H), 7.05-7.32 (AA'BB ', 4H), 7.25 (d, 1H), 7.56 ( m, 2H); 9.04 (d, 1H); MS (FAB) m / e 621 (M + 1).

 The action of the dipotassium salt of 2-butyl-4- (methylthio) -1 - ((2 '- ((((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl) methyl) -1H -imidazole-5-carboxylic acid (HR720) for systolic blood pressure in hypertensive rats with low sodium intake.

 The experiment is performed on hypertensive dogs (Beagle, 15-21 kg) of each gender. A few months before the experiment and during anesthesia, the two kidneys of the dogs are wrapped with cellophane (Page method). The second operation is performed to introduce a radio telemetry device (Data Sciences, Mn) for registering blood pressure. 17 hours before the experiment, furosemide (Hoechst) was administered at a dose of 10 mg / kg with subcutaneous injection and 1 hour before the drug, it was administered intravenously at a dose of 10 mg / kg in order to increase plasma activity by approximately 6 times. With gastric administration, empty capsules are administered to the control group and HR720 at a dose of 3 mg / kg to the experimental group. Systolic arterial blood pressure is recorded within 30 hours after administration with an interval of 2 hours.

Example 1. Preparation of funds for oral administration:
1000 tablets each containing 20 mg of 2-n-butyl-1 - [(2 'n-propylamino-carbonylamino-sulfonyl-biphenyl-4-yl) methyl] - 4-methylthio-imidazole-5-carboxylic acid are prepared using following aids:
2-n-butyl-1- [(2'n-propylaminocarbonylaminosulfonyl-biphenyl-4-yl) methyl] - 4-methylthio-itidazole-5-carboxylic acid - 20.0 g
Corn Starch - 140.0 g
Gelatin - 7.5 g
Microcrystalline cellulose - 2.5 g
Magnesium Stearate - 2.5 g
2-n-butyl-1- [2'n-propylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl] -4-methylthio-imidazole-5-carboxylic acid and corn starch are mixed with an aqueous solution of gelatin. The mixture is dried and ground to obtain a granulate. Microcrystalline cellulose and magnesium stearate are mixed with granulate. 1000 tablets are pressed from the obtained granulate, each tablet containing 20 mg of the angiotensin II receptor antagonist.

 Example 2. Analogously to example 1, 1000 tablets are prepared, each of which contains 3 mg of 2-n-butyl-1- [(2'-n-propylaminocarbonylaminosulfonyl-biphenyl-4-yl) methyl] -4-methylthioimidazole-5-carboxylic acid wherein 3 g of this compound are used in the composition shown in Example 1.

Example 3. Gelatin capsules, each of which contains 20 g of 2-n-butyl-1 - [(2'-n-propylaminocarbonylaminosulfonyl-biphenyl-4-yl) methyl] -4-methylthio-imidazole-5-carboxylic acid the following mixture:
2-n-butyl-1 - [(2'-n-propylaminocarbonylaminosulfonyl-biphenyl-4-yl) methyl] -4-methylthio-imidazole-5-carboxylic acid - 20 mg
Potassium Stearate - 1 mg
Lactose - 124 mg
Example 4. Analogously to example 3 and using 3 mg of biologically active substance, gelatin capsules are prepared, each of which contains 3 mg of 2-n-butyl-1 - [(2'-n-propylaminocarbonylaminosulfonyl-biphenyl-4-yl) methyl] - 4-methylthio-imidazole-5-carboxylic acid.

Example 5. Preparation of a solution for injection:
2-n-butyl-1 - [(2'-n-propylaminocarbonylaminosulfonyl-biphenyl-4-yl) methyl] -4-methylthio-imidazole-5-carboxylic acid 1 g
Methylparaben - 5 g
Propylparaben - 1 g
Sodium Chloride - 25 g
Water for injection - 5 l
2-n-butyl-1 - [(2'-n-propylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl] -4-methylthio-imidazole-5-carboxylic acid, preservatives and sodium chloride are dissolved in 3 L of water for injection, then adding water for injection up to 5 liters. Sterile filtration of the solution is carried out, aseptically poured into pre-sterilized bottles closed with sterilized rubber caps. Each bottle contains 5 ml of solution.

Claims (9)

1. Imidazole derivatives of the general formula I

or their physiologically tolerated salts,
where R ¹ C ₂ C _{7 is} alkyl;
R ^{2 is} halogen, C ₁ -C ₃ -alkylthio, C ₁ -C ₃ -alkoxy;
R ^{2 ′} - CHO, COOH, CH ₂ OH, COOC ₁ C ₃ -alkyl;
R ^{1 5} group SO ₂ NH-CO-NR ⁶ R ⁹ , where R ⁶ and R ^{9 are} different hydrogen, C ₁ C ₆ -alkyl, which may be substituted by 1 3 different radicals selected from the series hydroxyl, phenyl, carboxyl, C ₃ C ₈ -cycloalkylene, C ₁ - C ₄ alkoxycarbonyl, C ₂ C ₄ alkenyl which may be substituted with phenyl, C ₁ C ₃ alkoxycarbonyl, C ₃
C ₆ -alkynyl, C ₃ C ₈ -cycloalkyl, C ₃ - C ₆ -cycloalkyl-C ₁ C ₃ -alkyl, phenyl, phenyl-C ₁ -C ₄ -alkyl, which may be substituted by 1 2 identical or different radicals, selected from the range of trifluoromethyl, methoxy, C ₁ - C ₉ heteroaryl, which may be partially or completely hydrogenated, and as a heteroatom there may be 1 4 nitrogen atoms or one nitrogen atom and one sulfur atom, or C ₁ C ₉ heteroaryl -C ₁ - C ₃ alkyl which may be partially or totally hydrogenated, as a heteroatom can contain one nitrogen atom or one nitrogen atom and one oxygen atom, and otorrhea may be substituted with one radical selected from NO _2, methyl, oxo, or R ⁶ and R ⁹ together with the nitrogen atom form a C ₅ C ₆ -geteroarilnoe ring which may be partially or fully hydrogenated and contains as a heteroatom one nitrogen atom and one oxygen or sulfur atom, or one nitrogen atom, the last heteroaryl may be substituted with a C ₁ -C ₄ alkoxycarbonylamino group, or R ^{1 5} -SO ₂ NH-CO-OR ^{6 ′} group, where R ^{6 ′} is C ₁ C ₆ alkyl which may be substituted by C ₁ - C ₆ alkoxy, thienyl, C ₃ C ₈ -tsikloalkilenom or benzyloxy, C ₂ C ₅ alkenyl, koto th can be substituted by phenyl, C ₃ C ₆ alkynyl, C ₃ - C ₈ -cycloalkyl-C ₁ C ₃ -alkyl, phenyl-C ₁ - C ₄ alkyl, or R ¹ group ⁵ -SO ₂ NH-SO ₂ -OR ^{6 ″} , where R ^{6 ″} is N- (C ₁ C ₄ ) ₂ -alkyl, thienyl or nitrophenyl.  2. The derivative of claim 1, which is ethyl 1- [2'-H-propyl-aminocarbonylaminosulfonylbiphenyl-4-methyl] -2-H-butyl-4-methylthiomidazole-5-carboxylate or a physiologically tolerated salt thereof.  3. The derivative of claim 1, which is 1 - [(2'-H-propylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-H-butyl-4-methylthioimidazole-5-carboxylic acid or a physiologically tolerated salt thereof. 4. Imidazole derivatives of the general formula I according to claim 1

or their physiologically tolerated salts,
where R ¹ C ₂ C _{7 is} alkyl;
R ^{2 is} halogen, C ₁ -C ₃ -alkylthio, C ₁ -C ₃ -alkoxy;
R ^{2 ′} is CHO, COOH, CH ₂ OH, COOC ₁ C ₃ alkyl;
R ^{1 5} group SO ₂ NH-CO-NR ⁶ R ⁹ , where R ⁶ and R ^{9 are} different hydrogen, C ₁ C ₆ -alkyl, which may be substituted by 1 3 different radicals selected from the series hydroxyl, phenyl, carboxyl, C ₃ C ₈ -cycloalkylene, C ₁ - C ₄ alkoxycarbonyl, C ₂ C ₄ alkenyl which may be substituted with phenyl, C ₁ C ₃ alkoxycarbonyl, C ₃
C ₆ -alkynyl, C ₃ C ₈ -cycloalkyl, C ₃ - C ₆ -cycloalkyl-C ₁ C ₃ -alkyl, phenyl, phenyl-C ₁ -C ₄ -alkyl, which may be substituted by 1 2 identical or different radicals, selected from the range of trifluoromethyl, methoxy, C ₁ - C ₉ heteroaryl, which may be partially or completely hydrogenated, and as a heteroatom there may be 1 4 nitrogen atoms or one nitrogen atom and one sulfur atom, or C ₁ C ₉ heteroaryl -C ₁ - C ₃ alkyl which may be partially or totally hydrogenated, as a heteroatom can contain one nitrogen atom or one nitrogen atom and one oxygen atom, and otorrhea may be substituted with one radical selected from NO _2, methyl, oxo, or R ⁶ and R ⁹ together with the nitrogen atom form a C ₅ C ₆ -geteroarilnoe ring which may be partially or fully hydrogenated and contains as a heteroatom one nitrogen atom and one oxygen or sulfur atom or one nitrogen atom, wherein the last heteroaryl may be substituted with a C ₁ -C ₄ alkoxycarbonylamino group. 5. The method of obtaining imidazole derivatives of General formula I according to claim 1, characterized in that the compound of formula II

alkylate with a compound of formula III

where V is a leaving group,
to obtain the compounds of formula I

where R ^{15 ′ is a} sulfamide protecting group,
followed by deprotection, and the resulting sulfonamide, if necessary, is converted to sulfonylurethanes, or sulfonylureas, or sulfonyl sulfonamides of the formula I.  6. A pharmaceutical composition that lowers blood pressure, comprising an active compound and a pharmaceutically acceptable additive, characterized in that as the active compound it contains compounds of formula I according to claim 1 in an effective amount.  7. The composition according to claim 6, characterized in that as an active compound it contains a compound of formula I according to claim 2 in an effective amount.  8. The composition according to claim 6, characterized in that as an active compound it contains a compound of formula I according to claim 3 in an effective amount.  9. The composition according to claim 6, characterized in that as the active compound it contains a compound of the formula I according to claim 4 in an effective amount. Priority on points:
01/04/91 according to claims 5 and 6;
06/27/91 according to claim 1.

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