FI97471C - Process for the preparation of 3- (2'-N-benzoylsulfonamido-biphen-4-yl) methyl-5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] pyridine active as an angiotensin II antagonist - Google Patents

Description

97471

Process for the preparation of 3- (2'-N-benzoylsulfonamido-biphen-4-yl) methyl-5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] pyridine active as an angiotensin II antagonist Split from application 902661.

This invention represents a selection invention for the compounds (I) described in FI application 902661, which are useful as angiotensin II antagonists in the treatment of hypertension, heart failure and intraocular pressure.

The compound (I ') of the present invention has particularly advantageous angiotensin II antagonistic properties.

15 The renin-angiotensin system (RAS) plays a key role in the regulation of normal blood pressure and appears to be substantially associated with the development and maintenance of hypertension and heart failure. Angiotensin-II (Ali), an octapeptide hormone, is mainly produced in the blood by the cleavage of angiotensin-I by angiotensin converting enzyme (ACE), which is present in the vascular endothelium of the lungs, kidneys and many other organs. and it is the end product of RAS. Ali is a potent arterial vasoconstrictor whose action is based on its interaction with specific receptors on cell membranes. One possible means of controlling RAS is angiotensin * receptor antagonism. Several AII peptide analogs are known to inhibit the action of this hormone by blocking these receptors from competing, but their • · ».’j *. experimental and clinical applications have been limited by partial agonist activity and lack of oral absorption [M. Antonaccio, Clin ♦ Exp.Hypertens. A4 (1982) 27-46; D.H.P. Streeten and G.H. Anderson, Jr., 35 Handbook of Hypertension, Clinical Pharmacology of Anti- 2 97471 Hypertensive Drugs, ed. S.A. Doyle, Vol. 5, Elsevier Science Publishers, Amsterdam, The Netherlands, 1984, p. 246 -271].

Several non-peptide compounds have recently been described as AII antagonists. Examples of such compounds include those disclosed in U.S. Patent Nos. 4,207,324; 4,340,598; 4,576,958; 4,582,847; and 4,880,804; EP Application Publication Nos. 028,834; 245,637; 253 310; and 291,969; and in A.T. Chiu, et al. 10 [Eur.J.Pharm.Exp.Therap. 157 (1988) 13-21) and P.C. Wong, et al. (J.Pharm.Exp.Therap. 247 (1988) 1-7]. All of the aforementioned U.S. patents, EP-A-028 834 and 253 310 and the other two publications disclose substituted imidazole compounds which are generally bound. EP-A-245 637 discloses 4,5,5,7-tetrahydro-2H-imidazo [4,5-c] pyridine-6-carboxylic acid derivatives and their analogues as antihypertensive drugs. .

The related state of the art is also represented by FI patent applications 902,522, 904,424 and 924,054.

None of the compounds disclosed in the aforementioned U.S. Patent Publications, EP Application Publications, or other publications have the heterobicyclic structure of the compound of this invention.

The present invention relates to a process for the preparation of 3- (2'-N-benzoylsulfonamido-biphen-4-yl) methyl-5,7-dimethyl-2, which is active as an angiotensin II antagonist of formula (I *). -ethyl 3H-imidazo [4,5-b] pyridine and its pharmaceutical. 30 for the preparation of acceptable salts • · · "I CH, N N ch3 (I ·) 35 \ SO2-NH-C0- ^ y 3 97471

Compounds (I ') are prepared according to the invention by reacting a compound of formula (5) CH3 c ^ - <j0i N N ^ Nch3 ch ?.

to react with a reactive derivative of a compound of the formula: O COOH 6 then deprotecting, after which, if desired, the compound (I ') is converted into a pharmaceutically acceptable salt.

The compound of formula I 'can be prepared as described in the following Reaction Scheme 1. Nitroyh-25 diste 7c can be reduced to the corresponding amino compound and; converted to the aromatic diazonium chloride salt, which can then be reacted with sulfur dioxide? copper (2) in the presence of a salt to form the corresponding arylsulfonyl chloride 27 [H. Meerwein, G. Dittmar, R.

. 30 Gollner, K. Hafner, F. Mensch, and 0. Steifort, Chem. Ber ♦ 90 (1957) 841; A.J. Prinsen and H. Cerfontain, Reports 84] · (1965) 24; E.E. Gilbert, Synthesis 3 (1969) and references cited therein]. The sulfonyl chloride can be reacted with ammonia in aqueous solution or in an inert organic solvent [F.H. Bergheim and W. Baker, J. Amer.

4 97471

Soc. 66 (1944) 1459] or with dry powdered ammonium carbonate [E.H. Huntress and J.S. Autenrieth, J ♦ Amer ♦ Chem ♦ Soc ♦ 63 (1941) 3446; E. H. Huntress and F.H.

Carten, J.Amer.Chem.Soc. 62 (1940) 511] to form a sulfonamide 28 5. Benzyl bromide 30 can be prepared from sulfonamide 28 and then reacted with an alkali metal salt of the heterocyclic compound to form sulfonamide 31. Sulfonamide 31 can also be prepared from aromatic sulfonyl chloride, which can be prepared from arylamine. Acylation of compound 31 using appropriate acyl chlorides (or acyl imidazoles or other acylation reagents) can provide the desired acyl sulfonamides 32.

«1 4 •» * t * · 1 * · / · 4 «t» 1 · 4 0 »0 • 44 • ♦ · * · · ·» 4 · * · t • 0 • ♦ 5 97471

Reaction formula 1 CH 2 CH 2 CH 2 CH, O a O b, y C, 5 Js ^ NO, X ^ SOjCl J \ ^ SO 2 NH 2 Jv ^ OaNHC (CeHj) 3 7c 27 2B 29 / d 10 CH /> ^ SrN * ch, < rHjBr c-3 ^ Sri jfrvc2 «5- + φ XiN. - J ^ aOjHHccCeH,), 15 li) AcOH-HjO 30 CJP \? H3 "AA ^ 2" 5 CH * 3 CH2 20 f ^ il

Jv ^ SOjNHCO # ii 25 a. I) H2 / Pd-C, ii) NaNO2-HCl, iii) SO2, AcOH, CuCl2: * · ': b. NH3 or (NH4) 2CO3

·: · C. (C6H5) 3CC1, Et3N, CH2Cl2, 25 ° C

• · · * d. N-bromosuccinimide

• · I

e. 0COC1 or 0CO-imidazole or other acylation reagent φ 30 (0 = phenyl).

The compound of the present invention forms salts with various inorganic and organic acids and bases, and these salts are also part of the invention. These salts include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth metal salts such as calcium and magnesium salts, salts formed with organic bases; e.g., dicyclohexylamine salts, N-methyl-D-glucamine salts, salts formed with arginine, lysine and the corresponding amino acids. Salts with organic or inorganic acids can also be prepared; e.g. with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid, camphorsulfonic acid. Non-toxic, physiologically acceptable salts are preferred, although other salts are also useful; e.g. to isolate or clean the product.

These salts may be formed by conventional means, such as by reacting the free acid or free base form of the product with one or more equivalents of a suitable base or acid in a solvent or medium in which the salt is insoluble, or in a water-like solvent which is then removed in vacuo. by racket or freeze-drying, or by exchanging the cations of an existing salt for another type of cation in a suitable ion exchange resin.

Angiotensin-II (Ali) is a potent arterial vasoconstrictor that acts by interacting with specific receptors on cell membranes. with receptors. The compounds described in the present invention act as competitive antagonists of Ali at these receptors. To identify α1-antagonists and to determine their efficacy in vitro, .. ·. 30 the following two ligand-receptor binding assays.

• · · V. '.' Receptor binding assay using rabbit «· · *. aorttamembraanivalmistetta:

Three frozen rabbit aortas (obtained from Pel-Freeze Biologicals) were suspended in 5 mM Tris-35 in 0.25 M sucrose, pH 7.4 buffer (50 ml), homogenized and centrifuged. The mixture was filtered through gauze, after which the supernatant was centrifuged at 20,000 rpm for 30 minutes at 4 ° C. The pellet thus obtained was resuspended in 30 ml of 50 mM Tris-5 mM MgCl 2 buffer containing 0.2% bovine serum albumin and 0.2 mg / ml Bacitration, after which 100 assay tubes could be prepared from the slurry. Screened samples were determined in duplicate. To the membrane preparation (0.25 ml) was added 125 I-Sar1Ile8-angioten-10-sine-yl (obtained from New England Nuclear) (10 microliters; 20,000 scintillations / min) with or without the addition of a test sample, followed by incubated at 37 ° C for 90 minutes. The mixture was then diluted with ice-cold 50 mM Tris-0.9% NaCl, pH 7.4 15 (4 mL) and filtered through a glass fiber filter (GF / B Whatman diameter 2.4 "). The filter was soaked in scintillation fluid (10 mL). , after which the radioactivity was counted using a Packard 2660 Tricarb liquid scintillation counter The efficacy of potential Ali antagonists as AII antagonists was measured by the inhibitory concentration of such a compound that displaced 50% of the specifically binding 125 I-Sar1Ile8 angiotensin-II .

The IC50 value of the compound of the invention in the experiment described above was 0.16 nM, which represents a considerably better activity compared to the compounds described in FI patent application 902661 on average.

• · · ·

Receptor assay using bovine adrenal cortex preparation. . ·. The bovine adrenal cortex was chosen as the 30 ΑΙΙ receptor source. The weighed tissue (0.1 g is required for 100 assay tubes *) was slurried in Tris.HCl (50 mM), pH 7.7 buffer and homogenized. The homogenate was centrifuged at 20,000 rpm for 15 minutes. The Su-35 splenatant was discarded and the pellets resuspended in buffer [Na 2 HPO 4 (10 mM) -NaCl (120 mM) -disodium EDTA (5 mM) with phenylmethanesulfonyl fluoride (PMSF) (0.1 mM)]. (Compound screening is usually performed using parallel assays). 3H-Angiotensin-II (50 mM) (10 microliters) was then added to the membrane-5 preparation (0.5 ml) with or without the addition of a test sample, after which the mixture was incubated at 37 ° C for 1 hour. The mixture was then diluted by the addition of Tris buffer (4 ml), filtered through a glass fiber filter (GF / B 10 Whatman diameter 2.4 "). The filter was soaked in eluent (10 ml), after which the radioactivity was counted using a Packard 2660 Tricarb - As a measure of the efficacy of potential β-antagonists as Ali antagonists, the inhibitory concentration of such a compound that displaced 50% of the total binding 3H-angiotensin-II (IC50) was used.

The antihypertensive effects of a compound of the invention can be evaluated using the methodology described below: Male Charles River Sprague-Dawley rats (300-375 g) were anesthetized with methohexital (Brevital; 50 mg / kg i, p.) And PE 205 was placed in the trachea. -putkika-phenyl. A stainless steel destructive rod of the central nervous system of the experimental animal (thickness 1.5 mm, length 150 25 mm) was inserted into the right eye socket and downwards: the spine. Rats were immediately placed on a Harvard rodent ventilator (respiration rate 60 beats per minute, volume 1.1 cm 3/100 g body weight). The right carotid artery was ligated, both the left and right circulatory nerves. 30 was cut and a PE 50 «· ·!” I tubular cannula was placed in the left carotid artery for drug administration, and body temperature was maintained. at 37 ° C with a thermostatically controlled heating pad impulse from a rectal temperature sensor. The animals were then given atropine 35 (1 mg / kg i.v.) and 15 minutes later propranolol li 9 97471 (1 mg / kg i.v.). After 30 minutes, an angiotensin II or other agonist was administered intravenously every 30 minutes, recording an increase in diastolic blood pressure before and after administration of the drug or vehicle.

The compounds of formula (I ') have been found to have excellent in vivo potency and long duration of action as an angiotensin II receptor antagonist compared to the compounds known from FI patent applications 902 661, 902 511, 904 424 and 924 054. In addition, compound (I ') does not form harmful metabolites.

The compound of the invention is useful in the treatment of hypertension. It is also valuable for keeping acute and chronic heart failure in the hal-15 castle. The compound may also be expected to be useful in the treatment of secondary hypersecretion of aldosterone, primary and secondary hypersecretion of aldosterone, primary and secondary hypertension of the lungs, renal failure, renal failure, renal failure and renal disease, renal disease, renal failure , urinary incontinence of proteins associated with primary kidney disease, treatment of end-stage renal disease, renal transplant therapy and the like, renal hypertension, left ventricular failure, rheumatoid arthritis, diabetes mellitus, and retinal disease in the treatment of the disease, in the cavity hyperclasia and in the minimization of the arterial hardening process. The use of a compound of this invention in these and similar disorders will be apparent to those skilled in the art.

• · · *. The compound of this invention is also useful for treating elevated intraocular pressure and enhancing blood flow to the retina, and may be administered to patients in need of such treatment in typical pharmaceutical compositions such as tablets, capsules, injections, and the like, as well as topical drugs. as inserts, gels and the like. Pharmaceutical compositions for the treatment of intraocular pressure would typically contain from about 0.1% to 15% by weight, preferably from 0.5% to 2% by weight of a compound of this invention.

The compound of the invention can be formulated into pharmaceutical compositions in a known manner.

The following examples illustrate the preparation of a compound of formula I1.

Abbreviations used in the synthetic scheme: 15 DMF dimethylformamide NBS N-bromosuccinimide AIBN azo (bis) isobutyronitrile TFA trifluoroacetic acid THF tetrahydrofuran 20 CDI carbonyldiimidazole a · · • · • · · · · · · · · • »> · 1 •» · • · · 11 97471

General synthesis scheme (for Examples 1-3)

Br Tr T

I JL en m. ^ \ N ^^ S09NHBu

Step 1 2 Step ^ 2 | J 1. NaNOp, HAc / HCr, t-BuNH2, CH2Cl2

2. S09, CuCl J

^ RT. 12h, 84%

x X fS

+ iT ^) Pd (PPh3) 2Cl2

Ao V <ln. ^ - so9nhbu I DMF, 90 ° C, rT 2

SnMe3 6 h, 70% (I I Phase 3

Preparation of tin reagent NBS, AIBN

Step 5 CCl 4 'reflux ^ ^ 4 h, 78% jCO- [Step 6 SO 2 NHBu * ---—

: ··: = Χλ ^ fTs ° 2NHBU

··· w k.

··· ’· step 7 h DMF, 50 ° c '3h wax / Anisole * · * * ^ RT, 8 h, 76% 91% i! Xv Xx> -

\ __ .... Step 8 _ SOnNHCOR

so2nh2--7 I \ 1

[I \ I Method A U JL

RCOC1 || ^ 1 | I pyridine or (I λ

kv ^ 5 '* Method B

RCOOH, CDI, THF I

R = phenyl 12 97471

Example 1 3 - {[2 '- (Aminosulfonyl) -1,11-biphenyl-4-yl] methyl} -5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] pyridine Preparation 5 Step 1: Preparation of 2-bromobenzenesulfonyl chloride To concentrated hydrochloric acid (300 mL), which was stirred, was added 2-bromoaniline (Aldrich; 125 g, 0.727 mol) in glacial acetic acid (125 mL). The resulting light brown precipitate 10 was cooled to -10 ° C. A solution of sodium nitrite (59.5 g, 0.789 mol) in water (100 mL) was added at such a rate that the temperature remained below -5 ° C. After the addition was complete, the mixture was stirred at -10 ° C for 45 minutes. Meanwhile, glacial acetic acid (750 ml) was blown into sulfur dioxide to give a saturated solution (about 60 min). Copper (I) chloride (18.3 g, 0.185 mol) was added. Sulfur dioxide was blown into the mixture until it turned blue or blue-green. The copper chloride-sulfur dioxide mixture was cooled to 20 ° C and the ice bath was then removed. The diazonium salt mixture was added in two portions. The resulting green precipitate was stirred for 60 minutes, after which it was poured into ice water (4 L). A brown oil formed which solidified. The aqueous layer was removed by decantation and the remaining solid was dissolved in diethyl ether (1 L). The aqueous phase was extracted with diethyl ether (3 x 2 L).

The combined organic phase was washed with saturated sodium bicarbonate (3 x 4 L) until slightly basic, dried (magnesium sulfate) and the solvent removed under reduced pressure to give 2-bromobenzene. nisulfonyl chloride (152.6 g, 82%) as brown crystals; t 1 H-NMR (300 MHz, CDCl 3): δ 8.21 (m, 1H), 7.85 (m, 1H), 7.58 (m, 2H).

Step 2: Preparation of 2-bromobenzene (t-butyl) sulfonamide 35

To a solution of 2-bromobenzenesulfonyl chloride (352 g, 1.40 mol) in dichloromethane (6 L) and 13 97471 stirred under nitrogen at room temperature was added dropwise over 1 hour t-butylamine (Aid-rich; 367 mL, 3, 49 mol). The mixture was stirred at room temperature for 4 hours, the t-butylamine hydrochloride precipitate was removed by filtration and the filtrate was evaporated to give 2-bromobenzene (t-butylamine) sulfonamide (404 g, 99%) as a light brown solid; 1 H-NMR (300 MHz, CDCl 3): δ 8.18 (d, J = 8.5 Hz, 1H), 7.73 d, J = 8.5 Hz, 1H), 7.50-7, 35 (m, 2H), 5.11 (s, 1H, NH), δ 1.20 (s, 9H).

Step 3: Preparation of p-tolyltrimethyltin

To trimethyltin chloride (546 g, 2.79 mol) stirred in tetrahydrofuran (4000 mL) and kept under nitrogen at -10 ° C was added dropwise a solution of p-tolyl-15 magnesium bromide (Aldrich; 1.0 M solution in diethyl ether, 4 1, 4 mol) keeping the temperature below -5 ° C (about 4 h). The suspension was allowed to slowly warm to room temperature over 12 hours, after which saturated ammonium chloride solution (1 L) was added followed by sufficient water (ca. 1 L) to dissolve the precipitate. The solution was extracted with diethyl ether-hexane (1: 1, 1x41, 3x21). The combined organic solution was washed with saturated sodium chloride solution and dried (magnesium sulfate), and the solvents were removed under reduced pressure. Flash chromatography (silica gel, 5% ethyl acetate in hexane) afforded a pale yellow oil which contained white 4,4'-dimethylbiphenyl crystals which were removed. by filtration to leave p-tolyltrimethyltin (containing a small amount of 4,4'-dimethylbiphenyl) (711.3 g, 100%); 1 H-NMR (300 MHz, CDCl 3): δ 7.40 (d, j = 7.7 Hz, 2 h), 7.19 (d, j = 7.7 Hz, 2 h), '1' ' 2.34 (s, 3H), 0.30 (s, 9H).

Step 4: Preparation of 41-methylbiphenyl-2-t-butylsulfonamide 2-Bromobenzene (t-butyl) sulfonamide (407.7 g, 1.395 mol), p-tolyltrimethyltin (711.3 g, 2.79 mol), 14 97471 bis (triphenylphosphine) palladlum (II) chloride (Aldrich; 49 g, 0.07 mol) and dimethylformamide (4 L) were heated with stirring under nitrogen at 90 ° C for 3 hours. The mixture was cooled to room temperature and then filtered through a pad of diatomaceous earth, which was washed with diethyl ether. The filtrate was poured into water (15 L) and extracted with diethyl ether (3x41, 2x21). The combined organic phase was washed with water (3 x 4 L) and dried (magnesium sulfate), and the solvent was removed under reduced pressure. The residue was stirred in hot hexane (1 L) (to remove excess tin reagent) for 1 hour, after which it was cooled in an ice bath. The mixture was filtered and the light brown solid was washed with hexane. Flash chromatography (silica gel, hexanes containing 0, 5, and 10% ethyl acetate; the solid was dissolved in as little dichloromethane as possible for column loading) afforded 4'-methylbiphenyl-2-t-butylsulfonamide (221 g, 52%). ) as an off-white solid; 1 H-NMR (300 MHz, CDCl 3): δ 8.16 (d, J = 7.9 Hz, 1H), 7.60 - 7.37 (m, 4 H), 7.36 - 7.24 (m, 3H), 3.57 (s, 1H, NH), 2.42 (s, 3H), 0.99 (s, 9H).

Step 5: Preparation of 4'-bromomethylbiphenyl-2-t-butylsulfonamide

To a solution of 4'-methylbiphenyl-2-t-but-25-sulfonamide (100 g, 0.33 mol) in tetrachloromethane; (8 L) and stirred under nitrogen at room temperature, N-bromosuccinimide (47 g, 0.269 mol) and • α, α'-azoisobutyronitrile (0.55 g, 3.3 mmol) were added. The green mixture was stirred at reflux for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to dryness. Flash chromatography (silica gel, hexane containing 0, 5 and 10% ethyl acetate followed by dichloromethane; the residue was dissolved in as little dichloromethane as possible for column application) gave the product as 4'-methyl-biphenyl- 2-t-butylsulfonamide (19.4 g, 19% starting material) and 4'-bromomethylbiphenyl-2-t-butylsulfonamide (96.8 g, 77%) as off-white crystals; 1 H-NMR (300 MHz, CDCl 3): δ 8.17 (dd, J δ 7.5 and 1.6 Hz, 1H), δ 7.68 - 7.45 (m, 6 H), δ, 31 (dd, J = 7.5 and 1.6 Hz, 1H), 4.55 (s, 2H), 3.52 (s, 1H, NH), 1.00 (s, 9H) .

Step 6: St (4'-tert-butylaminosulfonyl) -1H-biphenyl-4-yl] methyl} -5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] Preparation of pyridine 10 To a suspension of sodium hydride (60% oil dispersion, Aldrich; 9.38 g, 0.235 mol) in dimethylformamide (11) and stirred under nitrogen at room temperature was added 5,7-dimethyl-2-ethyl 3H-imidazo [4,5-b] pyridine (41.4 g, 0.236 mol). The mixture was heated at 50 ° C for 1 hour, then cooled to room temperature. A solution of 4'-bromomethylbiphenyl-2-t-butylsulfonamide (100 g, 0.262 mol) in dimethylformamide (11) was added dropwise over 30 minutes, and the mixture was then stirred at 50 ° C for 4 hours. After cooling to room temperature, the brown solution was poured into ice water (15 L) and extracted with diethyl ether (2 x 4 L, 2 x 2 L). The combined organic phase was washed with water (4 L) and saturated sodium chloride solution (41) and dried (magnesium sulfate), and the solvent was removed under reduced pressure. Flash-chromatography. treatment (silica gel, ethyl acetate-hexane, 1: 1; * * followed by dichloromethane; the residue was dissolved in as little dichloromethane as possible to apply to the column) gave the product 3 - {[2 '- ((t (butyl-amino) sulfonyl) -1,1'-biphenyl-4-yl] methyl} -5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] pyridine (77, 8 g, 69%): as off-white crystals; 1 H-NMR (300 MHz, CDCl 3): δ 8.15 (dd, J = 7.8 and 1.5 Hz, 1H), 7.58 - 7.41 (m, 4 H), 7.30 - 7.16 (m, 3H), 6.91 (s, 1H), 5.52 (s, 2H), 3.48 (s, 1H, 35 NH), 2.83 (q, J = 7.6 Hz, 2 H), 2.64 (s, 3 H), 2.59 (s, 16 97471 3 H), 1.36 (t, J * 7.6 Hz, 3 H), 0 .94 (s, 9H); MS (FAB): 477 (M + H), 246 (C 13 H 12 NO 2 S).

Step 7: 3 - {[2 '- (Aminosulfonyl) -1,1'-biphenyl-4-yl] methyl} -5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] pyro- 5 Preparation of ridine

To a solution of 3 - {[2 '- ((t-butylamino) sulfonyl) -1,1'-biphenyl-4-yl] methyl} -5,7-dimethyl-2-ethyl-3H-imidazo [4 .5-b] pyridine (77.8 g, 0.163 mol) in trifluoroacetic acid (1200 ml) and stirred under nitrogen at room temperature was added anisole (20 ml). The orange solution was stirred at room temperature for 16 hours and then the solvent was removed under reduced pressure to leave a brown oil which was dissolved in dichloromethane (1 L). The solution was washed with saturated sodium hydrogen carbonate solution until basic.

The solution was evaporated to dryness to leave a yellow solid. The solid was slurried in dichloromethane (250 ml) and then filtered to give a white solid (64.5 g). The solid was dissolved in ethyl acetate (1300 mL) while heating, and the solution was filtered and then concentrated to half its volume. After cooling in an ice bath, the crystals were filtered off, washed with cold ethyl acetate and dried (41.3 g). The filtrate was concentrated to half its volume and re-cooled in an ice bath.

*. . The resulting crystals were separated by filtration, washed cold • · ·:; ethyl acetate and then dried (10.9 g). The two batches of crystals were combined, slurried in hexane (250 ml) and then filtered and dried to give 3 - {[2 '- (aminosulfonyl) -1.1. 1-Biphenyl-4-yl] methyl} -5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] pyridine (51.5 g, 75%) as white crystals; 1 H-NMR (400 MHz, CDCl 3); Δ 8.11 (dd, J = 8.0 and 1.3 Hz, 1H), 7.53 (dt, J = 7.5 and 1.4 Hz, 1H), 7.46 (dt, J = 7.8 and 1.4 Hz, 1H), 35 7.38 (m, 2 H), 7.25 (m, 1H), 7.18 (d, J = 8.3 Hz, 2 H ), li 17 97471 6.88 (s, 1H), 5.51 (s, 2H), 4.32 (s, 2H, NH), 2.82 (q, J = 7.6 Hz, 2 H), 2.61 (s, 3 H), 2.54 (s, 3 H), 1.32 (t, J = 7.6 Hz, 3 H), 0.94 (s, 9 H) ; MS (FAB): 421 (M + H), 246 (C 13 H 12 NO 2 S).

5 Example 2

General Methods 3 - {[2 '- (aminosulfonyl) -1,1'-bi-phenyl-4-yl] methyl} -5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] pyridine for acylation (preparation of acylsulfonamides)

10 Method A

To a solution of 3 - {[2 '- (aminosulfonyl) -1,1'-biphenyl-4-yl) methyl} -5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] pyridine (0.178 mmol) in pyridine (1 mL) and stirred under nitrogen at room temperature was added the appropriate acid chloride (0.893 mmol). The mixture was stirred at room temperature for 2-12 hours, after which saturated sodium dihydrogen phosphate solution (15 ml) was added. The mixture was extracted with ethyl acetate (4 x 20 mL). The combined organic phase was washed with saturated sodium chloride solution and dried (magnesium sulfate), and the solvent was removed under reduced pressure. Flash chromatography (silica gel, methanol-dichloromethane-ammonia) gave the desired acylsulfonamide in 10-80% yield.

25 Method B

*. . To a solution containing the appropriate carboxyl • · ·; acid (0.476 mmol) in dry tetrahydrofuran (1 mL) and kept under nitrogen at room temperature, 1,1'-carbonyldiimidazole (Aldrich; 0.476 mmol) was added.

The pale yellow solution was heated at 50 ° C for 2 hours. after which it was cooled to room temperature. A solution of 3 - {[2 '- (aminosulfonyl) -1,1'-biphenyl-4-yl] methyl} -5,7-dimethyl-2-ethyl-3H-imidazo [4] was added dropwise. , 5-b) pyridine (0.119 mmol) and 1,8-diat-35 sabicyclo [5.4.0] undec-7-ene (0.354 mmol) in tetrahydrofuran (2 mL), and the pale yellow solution was then heated to 50 ° At C for 2-24 hours. The solution was poured into 5% aqueous citric acid (10 mL). The mixture was extracted with ethyl acetate (4 x 20 mL). The combined organic phase was washed with water and saturated sodium chloride solution and dried (magnesium sulfate), and the solvent was removed under reduced pressure. Flash chromatography (silica gel, methanol-dichloromethane-ammonia) afforded the desired acylsulfonamide in 10-90% yield.

Example 3 3 - {[2 '- (Benzoylaminosulfonyl) -1,1'-biphenyl-4-yl] methyl} -5,7-dimethyl-2-ethyl-3H-imidazo (4.5 -b] preparation of pyridine (compound 1 ')

The title compound was prepared by acylation of 3 - {[2 '- (aminosulfonyl) -1,1'-biphenyl-4-yl] methyl} -5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] ] pyridine benzohexa-Posta using the acyl imidazole obtained as described in Method B of Example 2. Yield: 87% (white crystalline substance); mp. 230-231 ° C. 1 H-NMR (400 MHz, CD 3 OD-CDCl 3, 1: 3): δ 8.26 (dd, 1H), 7.66-7.54 (m, 2H), 7.49-7, 40 (m, 3H), 7.29-7.19 (m, 5H), 7.03-6.98 (m, 3H), 5.53 (s, 2H), 2.85 ( q, J = 7.6 Hz, 2 H), 2.62 (s, 3 H), 2.59 (s, 3 H), 1.33 (t, J = 7.6 Hz, 3 H); MS (FAB): 526 (M + H).

• • · • · · • • • • <• · 1 · • »· • · · · · # · • · · ·

II

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Claims (4)

A process for the preparation of 3- (2'-N-benzoylsulfonamido-5-biphen-4-yl) methyl-5,7-dimethyl-2-ethyl-3H-imidazole of the formula (I ') which is active as an angiotensin II antagonist. To prepare [4,5-b] pyridine and its pharmaceutically acceptable salts CH3 C2H5 · "^ N N ch3 (i ·) so2-nh-co- ^ y characterized in that: a compound of formula (5) ™ CH, 20 I 3 caXjU N N / Nch3 ch2 ^ s. To react with a reactive derivative of a compound of the formula: Q-COOK 35 - after which the protecting groups are removed, after which, if desired, the compound (I ') is converted into a pharmaceutically acceptable salt. 97471 For the preparation of 3- (2'-N-benzoylsulfonamidobiphen-4-yl) methyl-5,7-dimethyl-2-ethyl-3H-imidazo-5 [4,5-b] pyridine, vilken har formeln (I1) and an active angiotensin II antagonist, and a pharmaceutically acceptable carrier, CH3 NN ^ ch, (I ·) <*> / - \ li so2-nh-co-T y 15 ιό kännetecknat därav, att en förening med formeln (5) 20 ^ H3 1f H en CH2 ^ s. 25 More than S, ° 2NH2 st «t“ “f · · 30 omsätts med ett reactivt derivat av en förening, som har * ·« W ί formeln: _ (/ VcOOH 35 the holding of the farm (I ') account for the pharmaceutical product on the site.