Endothelin antagonists: n-[[2'-[[(4,5-dimethyl-3-isoxazolyl) amino]sulfonyl]-4-(2-oxazolyl)[1,1'- biphenyl]-2-yl]methyl]- n,3,3-trimethylbutyramide and n-(4,5-dimethyl-3-isoxazolyl)-2'- [(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl ]-4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide and their salts

 

(57) Abstract:

The invention relates to compounds: N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl] -2-yl] methyl]-N,3,3-trimethylbutyramide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide and their pharmaceutically acceptable salts, such as lithium, sodium or potassium salt or a salt with a base, which is an organic amine. These compounds can be used as antagonists of endothelin. The technical result is to provide new compounds which are antagonists of endothelin. 9 C. and 6 C.p. f-crystals, 2 tab.

The scope of the invention

The invention relates to compounds N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl] -2-yl]methyl]-N,3,3-trimethylbutyramide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide and their salts, which are applicable as endothelin antagonists.

Brief description of the invention

Endothelin antagonists, which are compounds capable of, among other things, to inhibit the binding of peptides indotel and congestive heart failure. In addition to increasing the ability of antagonists to inhibit (suppress) endothelin, in the technique continues to seek ways to improve parameters related to the overall in vivo functional activity.

The present invention provides compounds N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N, 3,3-trimethylbutyramide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide and their salts, which help to achieve such improvement. In addition to its high activity proposed endothelin antagonists have exceptional bioavailability in oral administration, the duration of action and predestiny metabolic stability within the digestive tract and, therefore, especially suitable for the treatment-dependent endothelin violations.

Detailed description of the invention

Connection N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl] -2-yl] methyl] -N, 3,3-trimethylbutyramide according to this invention has the following structure:

< / BR>
The compound N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfon-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl] -2-yl]methyl]-N,3,3-trimethylbutyramide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamida included in the scope of this invention and, in particular, those formed by the joining of inorganic or organic bases. Preferred pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts, although applicable also other salts, for example, for the isolation or purification of these compounds.

Preferred alkali metal salts, such as sodium, potassium and lithium salts, alkaline earth metals such as calcium salts and magnesium, and salts with organic bases (for example, organic amines) such as dicyclohexylamine, tert-butylamine, benzathine, N-methyl-D-glutamic and geranamine, and with amino acids, such as arginine, lysine and the like.

Salts according to this invention can be obtained, for example, by the reaction of N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl] -2-yl] methyl] -N, 3,3-trimethylbutyramide or N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamida with a given ion (for example, when interacting with an equivalent number of bases) in the environment (for example, in the environment from which the salt falls, or in an aqueous medium followed by lyophilization).

Above with the Yu inside the gastrointestinal tract, contain 3-isoxazolyl group. As this group can give predestiny metabolic stability in the gastrointestinal tract, the invention also provides new compounds applicable as endothelin antagonists with excellent metabolic stability, the following General formula:

Z*-SO2-NH-(3-isoxazoline group),

where Z* denotes an organic radical (balance), for example unsubstituted or substituted naphthyl, phenyl, biphenyl or a heterocyclic residue (e.g., thiophenyl), and where "3-isoxazoline group" represents an unsubstituted or substituted isoxazoline group with the NH-group in position 3. The preferred "3-isoxazolyl groups are unsubstituted isoxazoles or such, having as substituents alkyl (especially saturated with the number of carbon atoms in the chain from 1 to 12, for example, methyl) and/or halogen (i.e. fluorine, chlorine, iodine and bromine). A number of endothelin antagonists are described in the following documents entered as links in this description in its entirety, especially, but not only, in connection with a particular, those described in these compounds: U.S. patent 5,378,715; U.S. patent 5,514,696; U.S. patent 5,420,123; application U.S. 114,251, filed August 30, 1993 application U.S. 08/692,869, filed July 25, 1996; the application of the U.S. 60/011,974, filed February 20, 1996; the application of the U.S. 60/013,491, filed March 12, 1996; the application of the U.S. 60/015,072, filed April 2, 1996; international application 94/27979; U.S. patent 5,464,853; U.S. patent 5,514,691; EP 601386; EP 633259; U.S. patent 5,292,740; EP 510526; EP 526708; EP 658548; U.S. patent 5,541,186; WO 96/19454; WO 96/19455; EP 713875; WO 96/20177; EP 733626; Japanese patent JP 8059635; EP 682016; English patent GB 2295616; WO 95/26957; U.S. patent 5,571,821; EP 743307 and WO 96/31492; for example, is described, as indicated, the following compounds (entered into this description by reference, as given above): bosentan (Ro 47-0203, Clozel, M., et al., "Pharmacological Characterization of Bosentan, A New Potent Orally Active Nonpeptide Endothelin Receptor Antagonist", The Journal of Pharmacology and Experimental Therapeutics, vol. 270(1), pp.228-235 (1994)); and FA-11,251 of, i.e.:

< / BR>
(IBC international conference on inhibitors of endothelin, Coronado, CA (February 1996 ) and 211 of the national Congress of American Chemical Society, New Orleans, LA (March 1996). These compounds contain sulfonamidnuyu group-SO2-NH-, in which the organic residue linked to the rest of the molecule through sulfonyloxy group. Preferred as the group Z* in the above General formula Z*-SO2-NH-(3-isoxazoline group) according to this invention are related through sulfonyloxy the group of organic residues sainani this invention also provides a method of using these compounds, characterized in that they are administered to treat endothelialised disorders.

The compounds of this invention are antagonists of ET-1, ET-2 and/or ET-3 and applicable for treating conditions associated with elevated levels of ET (e.g., dialysis, trauma or surgery), and all endothelization disorders. They are, therefore, useful as antihypertensive agents. With the introduction of the composition containing one (or a combination) of the compounds according to this invention, the blood pressure of the host mammal (e.g. human) is reduced. They are also applicable if pregnancy-induced hypertension and coma (preeclampsia and eclampsia), acute portal hypertension and hypertension in the side effects of erythropoietin.

The compounds of this invention are also applicable in the treatment of lesions of the kidney cells, kidney glomeruli and mesange, including acute and chronic renal failure, damage to the glomerulus, disorders of the kidney as a consequence of age or as a result of dialysis, nephrosclerosis (especially hypertensive nephrosclerosis), nephrotoxicity (including nephrotoxicity associated with visualizacionslas and the like. Compounds according to this invention can also be applied in the treatment of disorders associated with paracrine and endocrine function.

Compounds according to this invention is also applicable in the treatment of endotoxemia (presence of blood endotoxin or endotoxin bacterial-toxic shock and hemorrhagic shock.

The compounds of this invention are also applicable in hypoxic disease and as an anti-ischemic drug for treatment, for example, ischemia of the heart, kidneys or brain, and reperfusion (e.g., after surgical installation of artificial blood circulation), coronal or cerebral vasospasm and the like.

In addition, the compounds of this invention can also be used as anti-arrhythmia; against angina; against atrial; as anti-asthma drugs; as a means against atherosclerosis and arteriosclerosis; as additives to solutions for cardioplegia in lung machine; as an aid in thrombolytic therapy and as a remedy against diarrhea. Compounds according to this invention can be used in therapeutic treatment infer the Shi); for the treatment of cardiac hypertrophy (e.g., hypertrophic cardiomyopathy); for treatment of primary pulmonary hypertension (e.g., plexogenic or embolic) in adults and newborns pulmonary hypertension caused by congestive heart failure, damage caused by radiation or chemotherapy, or other injuries; for the treatment of vascular disorders of the Central nervous system, such as strike (attack), headache and subarachnoid hemorrhage; in the treatment of behavioral disorders of the Central nervous system; in the treatment of diseases of the gastrointestinal tract, such as ulcerative colitis, Crohn's disease, damage to the mucous of the stomach, ulcerative and ischemic disease of the digestive tract; in the treatment of diseases of the gallbladder and bile ducts, such as cholangitis; in the treatment of pancreatitis; for the regulation of cell growth; in the treatment of benign prostatic hypertrophy; restenosis after angioplasty or other procedures, including transplantation; treatment of congestive heart failure, including inhibition of fibrosis; reduced dilation, changes (correction) and dysfunction of the left ventricle and in the treatment of hepatitis and sudden death. Connection annenih crises of this disease; in the treatment of the harmful effects of the presence of ET-producing tumors, such as hypertension, which is a consequence of hemangiopericytoma; in the treatment of early and running disease and liver damage, including related complications (e.g., hepatotoxicity, fibrosis and cirrhosis); in the treatment of spastic conditions of the urinary tract and/or bladder; in the treatment hepatorenal syndrome; in the treatment of immunological, including vasculitis, diseases, such as lupus, systemic sclerosis, mixed cryoglobulinemia; and in the treatment of fibrosis associated with renal dysfunction, and hepatotoxicity. Compounds according to this invention can be applied in the treatment of metabolic and neurological disorders; cancer; insulin-dependent and non-insulin-dependent diabetes mellitus; neuropathy; retinopathy; maternal respiratory distress syndrome; dysmenorrhea; epilepsy; a bleeding and attack ischemia; bone remodeling (changes); psoriasis and chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, sarcoidosis and eczematoid dermatitis (all types of dermatitis).

Of the compounds of this invention can be prepared drugs in the and thromboxane receptor; with substances that promote the opening of potassium channels; thrombin inhibitors (such as hirudin and the like); inhibitors of growth factors, such as modulators of PDGF activity; antagonists activating factor thrombocyto (PAF) receptor antagonists angiotensin II (AII); renin inhibitors; angiotensin converting enzyme (ACE) such as captopril, zofenopril, fosinopril, ceronapril, alacepril, enalapril, delapril, pentopril, ginepri (quinapril, ramipril, lisinopril, and salts of these compounds; inhibitors of neutral endopeptidase (NEP); NEP-ACE inhibitors, double action; inhibitors of the HMG COA reductase inhibitor such as pravastatin and mevacor; inhibitors stvalentines; biliary acids, such as questran; calcium channel blockers; activators of potassium channels; beta-adrenergic drugs; antiarrhythmic drugs; diuretics, such as chlorothiazide, dihlotiazid (hydrochlorothiazide), flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlormethiazide, polythiazide or benzothiazin, as well as ethacrynic acid, ticrynafen, oksodolin (chlorthalidone, furosemide, muzolimine, bifenox (bumetanide), triamterene, amiloride is blood clotting, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, the PUK and the complex Antilibanus of plasminogen-activator - streptokinase (APSAC). If you want to cook in a fixed dose, such combination of substances use of the compounds according to this invention at doses described below, and another active agent in the best (optimal) range of doses. Compounds according to this invention can be prepared in the form of the drug with, or be used in conjunction with, antifungal agents and immunosuppressants, such as amphotericin b, cyclosporine, and the like, in order to prevent reduction in glomerular and renal toxicity induced by these compounds. Compounds according to this invention can also be used in combination with hemodialysis.

Compounds according to this invention can be entered in any suitable way, for example oral, or parenteral, various mammalian species, about which it is known that they may be exposed to such diseases, such as man, in effective amounts, such as amounts in the range of doses from about 0.1 to about 100 mg/kg, preferably from about 0.2 to primerno about 5 to about 2000 mg) as a single or 2 to 4 divided daily doses.

The active substance may be used in compositions in the form of a tablet, capsule, solution or suspension containing from about 5 to about 500 mg per standard dose of the compound or mixture of compounds according to this invention or in the form of forms for local application in the healing of wounds (for example, from 0.01 to 5% by weight of compounds according to this invention, from 1 to 5 treatments per day). Compounds according to this invention may be combined appropriately with a physiologically acceptable excipient or carrier, excipient, binder, preservative, stabilizer, Corrigendum and so on , or with the local media, such as Plastibase (gel polyethylene in mineral oil), as is customary in conventional pharmaceutical practice.

Compounds according to this invention can also be applied topically for the treatment of peripheral vascular diseases and in this case they can be in the form of a cream or ointment.

Compounds according to this invention may also be in the form of compositions such as sterile solutions or suspensions for parenteral administration. For example, from about 0.1 to 500 milligrams of the compound in this invention can be combined with a physiologically acceptable excipient, the conventional pharmaceutical practice. The amount of active substance in these compositions or preparations is preferably such that it turns out right dose at the specified interval.

Thus, the present invention provides new uses and new connections, data in the present description, and pharmaceutical compositions containing them. This invention is particularly (mainly) includes methods of treatment endothelialised disorders in mammals, which (means) are in the introduction to the mammal an effective therapy endothelization disorder number of compounds according to this invention. This invention is also particularly (mostly) covers a pharmaceutical composition for the treatment endothelialised disorders containing compounds according to this invention in amounts effective for this purpose, and a physiologically acceptable excipient or carrier. The connection according to this invention can, for example, be used in the methods or pharmaceutical compositions according to this invention one (as such), in combination with one or more other compounds of this invention and/or in combination with at least another (with another active agent, for example and the a (ACE, ACE) inhibitor of double-acting neutral endopeptidase NEP-ACE, a diuretic or cardiac glycoside, or other means listed above.

In the methods according to this invention is similar to (e) other (s) active (e) agent(s) may(can) be administered before, simultaneously with or after administration of the compound (s) according to this invention. In the pharmaceutical compositions according to this invention is similar to (e) other (s) active (e) agent(s) may come together with the compound (s) of this invention or to be entered separately, as described above for the methods according to this invention.

In particular, the preferred methods and compositions for the treatment of hypertension, especially hyporeninemic hypertension (e.g., such as described in application U.S. 60/035,825, filed January 30, 1997, J. E. Bird, called "a Method of preventing or treating hyporeninemic hypertension by administration of endothelin antagonist or pulmonary hypertension, in particular, primary pulmonary hypertension; benign prostate hypertrophy; migraine; lesions of the kidney cells, kidney glomeruli and mesange; endotoxemia; ischemia; atherosclerosis; restenosis; subarachnoid hemorrhage and l)[1,1'-biphenyl] -2-yl]methyl]-N,3,3-trimethylbutyramide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide and their salts can be obtained by methods such which are described in European patent application N 702,012 and the application of the U.S. N 08/754,715, filed November 21, 1996, and/or methods presented in the experimental part of this description. The invention is additionally illustrated by the following working examples, which represent preferred forms of embodiment of the present invention. These examples are intended to be as illustrating, rather than limiting the invention.

EXAMPLE 1

Obtaining N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutyramide

A. Hydrochloride 4,5-dimethyl-3-isoxazolin

To 1,1-dimethylethylamine ether (4,5-dimethyl-3-isoxazolyl)carbamino acid (25,0 g, 117,79 mmol, obtained as described Konoike, T. et al., Tet. Lett., 37, 3339-3342 (1996)), placed in the flask, add 100 ml of 4N Hcl in dioxane. The mixture is stirred at room temperature for 5 hours and concentrated to obtain indicated in the title this stage of the product in the form of a solid substance, which is used in the next stage without additional purification.

C. 2-Bromo-N-(4,5-dimethyl-3-isoxazolyl)benzosulfimide

To a mixture of a solid obtained in Stage A, and 4-dimethylaminopyridine (1.44 g, 11,78 mmol) in ü stirred at 40oWith over 6.5 hours and concentrated. The residue is dissolved in 300 ml of methanol ("Meon"), add 1000 ml of 3% aqueous solution of NaHCO3and the mixture was concentrated in vacuo to remove most of the Meon. The solid residue is filtered off and the aqueous filtrate is acidified to pH 1 with 6N Hcl at 0oWith, and extracted with ethyl acetate ("tO", 2400 ml). The extract was washed with 100 ml 1N HCl, 100 ml of N2O and 100 ml of brine, dried and concentrated to obtain indicated in the title this stage of the product (34,32 g, ~95% purity, yield 84% in two stages). Rf=0,57, silica gel, 1:1 hexane/tO.

C. 2-Bromo-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzosulfimide

To the product obtained in Stage (32.60 high. g, 102,78 mmol) in 343 ml of dimethylformamide ("DMF") at 0oTo add portions of NaH (60% in mineral oil, is 4.93 g, 123,34 mmol). After stirring at room temperature for 30 minutes the mixture is cooled in a bath with a mixture of ice and salt (-15oC) and added dropwise within 20 minutes 2-methoxyethoxymethyl (16.0 g, 128,48 mmol). The reaction mixture was stirred in a bath with a mixture of ice and salt for 20 minutes and then at room temperature for 1.5 hour. Add to the reaction mixture of 1400 ml of a mixture 1:1 hexane/tO. Organic is the gel using a mixture of 2.5:1 hexane/tO and get marked in the title of this stage, the product (32,12 g, 75%) as oil.

D. N-(4,5-Dimethyl-3-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide

To a solution of the product obtained at Stage (22,16 g, 52,85 mmol), in 264 ml of tetrahydrofuran ("THF") at -95oWith add n-utility ("n-BuLi", 2M solution in pentane, 29,07 ml, 58,14 mmol). The mixture was stirred at -95oC for 10 minutes, add trimethylboron (6,59 g, 63,42 mmol) and stirred at -78oC for 15 minutes. Remove the cooling bath and the mixture is slowly brought to room temperature and stirred at room temperature for 0.5 hour. The mixture is then cooled to 0oC and added dropwise to 100 ml of 3N Hcl. After stirring for 30 minutes, the mixture is extracted with CH2CL2(300 ml, 100 ml). The combined organic extracts washed with brine, dried and concentrated to obtain 2-borono-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzosulfimide resin.

2-borono-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)-methyl]benzosulfimide and 2-bromo-5-(2-oxazolyl)benzaldehyde (13,32 g, 58,14 mmol, obtained as described in example 21 European application N 702,012), in 264 ml of toluene and 132 ml of 95% ethanol ("EtOH") add 106 ml of a 2M aqueous solution of CA is argon at 85oC for 4 h, cooled and diluted with 250 ml EtOAc. The organic layer is separated and washed with 100 ml of N2O and 50 ml of brine, dried and concentrated. The remainder chromatographic on silica gel using a mixture of 1:1 hexane/tO and get marked in the title of this stage, the product (16,95 g, 62,7% in two stages) in the form of a colourless resin.

1H NMR (CDCl3d 1,89 (s, 3H), of 2.28 (s, 3H), of 3.28 (s, 3H), 3.43 points (m, 2H), 3,60 is 3.76 (m, 2H), 4,40-4,59 (m, 2H), 7,28-8,68 (m, N), 9,76 (s, 1H).

E. N-(4,5-Dimethyl-3-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide

To the product obtained in Stage D (16,95 g, 33,14 mmol), 414 ml 95% EtOH add 414 ml 6N Hcl. The mixture is refluxed for 55 minutes and poured onto 800 g of ice. After maturation for 2 hours, separate the white precipitate by filtration to obtain indicated in the title this stage of the product (13,17 g, yield 92%).

Rf(silica gel)=0,31 (5% methanol in CH2CL2).

F. N-(4,5-Dimethyl-3-isoxazolyl)-2'-[(methylamino)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide

To the product obtained in Stage E (12,91 g of 30.48 mmol) and molecular sieves 3A in 305 ml of CH2Cl2add acetic acid ("Asón", 4,58 g, 76,20 mmol) and then added methylamine (8,03 M mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with 700 ml of CH2Cl2and 100 ml Meon and filtered through celite. The filtrate is washed with 150 ml of N2Oh, dried and concentrated. The residue is triturated with ethyl ether (50 ml, 30 ml, 30 ml). Azeotropic distillation with a mixture of CH2CL2-heptane (several times) leads to marked in the title of this stage the product is in a solid gray color, which is used in the next stage without additional purification.

1H NMR (Dl3/CD3D 3: 1) (d) to 1.83 (s, 3H), 2.13 and (s, 3H), 2,71 (s, 3H), a 3.87-4,27 (m, 2H), 7,11-8,09 (m,N).

G. N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)-[1,1'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutane

To the product obtained in Stage F, 300 ml of CH2CL2at 0oWith add triethylamine (6,17 g, 60,96 mmol) and stirred for 5 minutes. To the mixture is added dropwise within 10 minutes, tert-butylcatechol (398 g, 29,57 mmol). The reaction mixture was stirred at 0oC for 10 minutes and at room temperature for 1 hour. Add 100 ml of 10% aqueous solution of NaHSO4. The aqueous layer was extracted with 100 ml of CH2CL2. The combined organic extracts washed the mixture of 60:40:1 hexane/EtOAc/AcOH and get marked in the title of this example, the product (13,10 g, 80% in two stages) in a solid white color. Melting point=120-128o(Amorphous).

New intermediate compounds obtained in the stages D, E and F of the above example 1, the title of which is given in the title of these stages, also claimed in this invention. Called in stages E and F products may themselves find use as endothelin antagonists for the treatment of endothelialized disorders.

EXAMPLE 2

In vivo functional activity of N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl] -2-yl]methyl]-N,3,3-trimethylbutyramide

Excellent functional activity in vivo indicated in the title compounds (including bioavailability, efficacy and duration of action and metabolic stability) was demonstrated as follows.

(A) Bioavailability

Male individuals of rats (n= 3) on an empty stomach gave a single dose of the test (denoted in the title) connection or intravenously (10 mmol/kg as a 10-minute infusion) or orally via a stomach tube (20 mmol/kg). The media were propylene glycol in the case of intravenous and PEG-400 for oral administration. After organisations in the plasma, and calculated the area under the curve AUCg(µm x h) was 31,32,9 and 72,817,3 for intravenous and oral administration, respectively. As normalized by dose AUC valuesgfor intravenous and oral administration were not statistically different, the size of the bioavailability of this compound after oral administration was determined approximately 100%.

(B) Vazopressornye test

(i) Intravenous injection of big ET-1 in conscious rats with normal blood pressure leads to a temporary increase in the mean arterial pressure, which may be weakened by the receptor antagonist ETAND.

Rats Sprague-Dawley before and 5 minutes after intravenous injection of doses of the test (denoted in the title) connection (0,01 mmol/kg (n= 10), 0,03 mmol/kg (n=10) and 0.1 mmol/kg (n=3)) was rapidly injected large volumes ("bolus-injection) human big ET-1 (1 nmol/kg, intravenously; media: 1% Tween 80 5% Panso3). The maximum Pressor response (spikes) were compared in order to determine the degree of inhibition caused by the test compound. The dose of the test compound that causes 50% inhibition (suppression) vasoconstrictor (Pressor) response to big ET-1 (ED503) rats Sprague-Dawley (n=3) was administered before and after 15, 105 and 195 minutes after dose 3 mmol/kg of the test (denoted in the title) connection. The peak values of the Pressor response was compared in order to determine the degree of inhibition caused by the test compound in these time intervals. The results demonstrate both the efficacy and duration of action of the tested compounds are presented in table.1.

(C) Predestina metabolic stability in the gastrointestinal tract

In vitro

The contents of the caecum of rats was quickly placed in a cold degassed potassium phosphate buffer (50 mm, pH 7.4, was purged with nitrogen for at least 30 minutes). Each tank (die) for cultivation (incubation) contained about 0.1 g slabokislogo content/ml. Test (denoted in the title), the compound was added to the die to a temperature in the form of a solution in bicarbonate buffer. Temperature control was performed with 200 μm of the test compounds was mixed with acetonitrile in the ratio of 1 is the PMC YMC-ODS AQ (4,6150 mm, 3 microns) with a gradient elution with ammonium acetate/acetonitrile and determined at 270 nm. The percentage of the test (denoted in the title) compounds that remain intact (i.e., metabolites were not observed after incubation with the homogenate of the contents of the caecum of rats for 1 hour, was 100%.

In vivo

Rats, in which the bile ducts entered cannula, hungry during the night. Test (denoted in the title), the compound was administered in the form of a solution in 5% sodium bicarbonate (approximately 8 mg/ml, 29 mg/kg) orally via gastric tube. The homogenate content of the gastrointestinal tract were prepared in 3 volumes of water and added equal volume of acetonitrile. Test the connection identified by LC-MS/MS and quantitatively determined by LC-UV at column YMC-ODS AQ (4,6150 mm, 3 microns) with a gradient elution system ammonium acetate/acetonitrile and detection at 270 nm. The percentage of remaining intact test (denoted in the title) connection (i.e., metabolites were not observed in the gastrointestinal tract of rats after 9 hours after an oral dose was 100%.

EXAMPLE 3

Obtaining N - (4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-d'-(hydroxymethyl)-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide

To the solution indicated in the title of Stage D of example 1 product (0,37 g, from 0.76 mmol) in 10 ml Meon at room temperature is added sodium borohydride (0.035 g, of 0.93 mmol) and the mixture is stirred for 2 hours. A clear solution is then concentrated to 5 ml and diluted with 100 ml of water, and the aqueous solution extracted with 3100 ml EtOAc. The combined organic extract is then washed once with water, dried and evaporated to obtain 0.36 g (95%) indicated in the title this stage of the product in the form of a colourless resin.

Rf(silica gel)=0,32 (5% methanol in CH2Cl2).

C. 2'-(methyl bromide)-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide

To a solution of the product obtained at Stage A (0,37 g to 0.72 mmol) in 5 ml of DMF in 5oWith added triphenylphosphine (0,283 g at 1.08 mmol) and chetyrehhloristy carbon (0,358 g at 1.08 mmol) and the mixture is stirred for 5 hours. Then the solution was diluted with 100 ml of water, and the aqueous solution extracted with 3100 ml EtOAc. The combined organic extract is then washed once with water, dried and evaporated. Thus obtained residue chromatographic on 20 g of silica gel using a mixture of 2:1 hexane : tO obtaining 0,285 g (69%) indicated in the title of this stadon

Into the flask containing the hydrochloride 1,1-dimethylethylene ether 3,3-dimethyl-2-oxo-1-pyrrolidinecarbonyl acid (0.5 g, 2.34 mmol, obtained as described in J. Chem. Res. (Synopsis), 414-415 (1993)), add lN HCl in ether (15 ml) and the mixture is stirred over night. Then the solution is evaporated and the residue is dried in vacuum to obtain 0.26 g (98%) indicated in the title this stage of the product as a pale yellow resin, which solidifies upon standing.

D. N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-N-[[2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide

To a solution of the product obtained at Stage (by 0.055 g, 0.49 mmol) in 3 ml DMF added NaH (60% suspension in mineral oil, 0,019 g, 0.49 mmol) and the mixture is stirred at room temperature in an argon atmosphere for 5 minutes. Then add the product obtained in Stage (0.14 g, 0.24 mmol) and the mixture stirred at room temperature overnight. In a separate flask stirred for 10 minutes additionally 0,0275 g (0.25 mmol) of the product obtained at Stage S, and 0.01 g (0.25 mmol) of sodium hydride in 1 ml of DMF and the mixture is then added to visaelectron solution, and the reaction mixture was stirred an additional 3 hours. The mixture is then poured to 100 the t obtain 0.16 g (100%) is indicated in the title this stage of the product in the form of a colourless resin.

Rf(silica gel)=0,24 (5% methanol in CH2CL2).

E. N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide

To a solution of the product obtained in Stage D (of) 0.157 g, 0.25 mmol) in 2 ml of acetonitrile add trimethylchlorosilane (of) 0.157 g, 1,45 mmol) and modesty sodium (0.15 g, 1,45 mmol) and the mixture is stirred at room temperature for 1 hour. Add additional portion of trimethylchlorosilane (0,078 g, 0,726 mmol) and sodium iodide (0.075 g, 0,726 mmol) and the mixture is stirred additionally for 1 hour. The mixture is diluted with 20 ml of 1% aqueous sodium thiosulfate solution and extracted 312 ml of EtOAc. The combined organic extract is washed once with water, dried and evaporated. The residue is purified using preparative reverse-phase HPLC on a column of 30x500 mm ODS S10 using 70% solvent B (90% Meon, 10% N2Oh, 0,1% triperoxonane acid ("TFA") and 30% solvent A (10% Meon, 90% H2O WITH 0.1% TFA). The appropriate fractions are collected and neutralized with an aqueous solution of sodium bicarbonate to pH 7 and concentrated to 10 ml and Then the solution is acidified to pH 4 using aqueous solution of sodium bisulfate and the white solid filtered off and dried the floor with the -117o(Amorphous).

New intermediate compounds obtained in stages a, b and D above example, also claimed in this invention.

EXAMPLE 4

An alternative method of obtaining N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamida

A. 4-[[[2'-[[(4,5-Dimethyl-3-isoxazolyl)amino] sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]amino]-2,2-dimethylbutanoate acid

To the product obtained in stage E of example 1 (2.00 g, 4,72 mmol), 3-carboxy-3-methylbutylamine chloride (1,58 g of 9.45 mmol, obtained as described in J. Chem. Res. (S)., 414-415 (1993)) and molecular sieves 3A in 47 ml of CH2Cl2add Asón of 0.85 g, 14,17 mmol) and then add sodium acetate (0,775 g of 9.45 mmol).

The mixture is stirred for 10 minutes and add triacetoxyborohydride sodium (3.00 g, 14,17 mmol). The reaction mixture was stirred at room temperature for 1 hour and 40 minutes, diluted with 100 ml of CH2Cl2and filtered through celite. The filtrate is washed with 230 ml of N2About 30 ml of brine, dried and concentrated to obtain a residue containing indicated in the title of the product.

Rf(silica gel)=0,06 (CH2CL2: methanol 10:1).


The rest obtained at stage A, is dissolved in 50 ml of CH2CL2and add 1,3-diisopropylcarbodiimide (775 mg, 6,14 mmol). The reaction mixture was stirred at room temperature for 1 hour and diluted with 50 ml of CH2CL2, washed with 30 ml of N2About 30 ml of brine, dried and concentrated. The remainder chromatographic on silica gel using a mixture of 50:50:1 hexane/tO/Asón with the receipt indicated in the title of this example product (1.47 g, 60% in two stages) in the form of solid white, p. pl. 206-208o(tO/N2O).

New intermediate compound obtained in stage a above example, also claimed in this invention. This intermediate connection itself can be used as an endothelin antagonist for the treatment of endothelialized disorders.

EXAMPLE 5

In vivo functional activity of N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamida

Excellent in vivo functional activity of the test (denoted in the title) compounds (including bioavailability, efficacy and duration of action and metabolic stability) prodem is, is predelli that the bioavailability of the test compound is approximately 78%.

(B) Vazopressornye test

Using the method given in Example 2(B)(i) determined that the dose of the test (denoted in the title) of a compound that causes 50% inhibition (suppression) vasoconstrictor (Pressor) response to big ET-1 (ED50), is approximately 0.01 to mcmol/kg

The effectiveness and duration of action of the tested compounds is demonstrated by the results shown in the table. 2, which are obtained by applying the method described in example 2(B)(ii).

(C) Predestina metabolic stability in the gastrointestinal tract

Using the methods described in example 2(C), have the following stability test (denoted in the title) connection.

In vitro

The number of the test (denoted in the title) compounds that remain intact after incubation with the homogenate of the contents of the caecum of rats for 1 hour, was 100%.

In vivo

The number of the test (denoted in the title) compounds that remain intact in the gastrointestinal tract of rats after 9 hours after an oral dose of a substance, the l] -2-yl] methyl] -N, 3,3-trimethylbutane or its salt.

2. Connection on p. 1, which is N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl] -N,3,3-trimethylbutane or its pharmaceutically acceptable salt.

3. Connection on p. 1, which is N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl] -N,3,3-trimethylbutane.

4. Connection on p. 1, which is a pharmaceutically acceptable salt of the compounds, such as lithium, sodium or potassium salt or a salt with a base, which is an organic amine.

5. The Union, representing N-(4,5-dimethyl-3-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide.

6. The Union, representing N-(4,5-dimethyl-3-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide.

7. The Union, representing N-(4,5-dimethyl-3-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide.

8. The compound N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide or salt.

9. The connection shall yl)[1,1'-biphenyl]-2-sulfonamide or its pharmaceutically acceptable salt.

10. Connection on p. 8, which is N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide.

11. Connection on p. 8, which is a pharmaceutically acceptable salt of the above compound, such as lithium, sodium or potassium salt or a salt with a base, which is an organic amine.

12. The Union, representing N-(4,5-dimethyl-3-isoxazolyl)-2'-(hydroxymethyl)-N-[(2-methoxyethoxy)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide.

13. The Union, which represents 2'-(methyl bromide)-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide.

14. The Union, representing N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -N-[(2-methoxyethoxy)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide.

15. The Union, representing 4-[[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl] -2-yl] methyl]amino]-2,2-dimethylbutanol acid.

 

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The invention relates to a new method of obtaining isoxazolidinone the compounds of formula (II) in which R represents an optionally substituted aromatic hydrocarbon group or its salt, by reacting the compounds of formula (1) or its salt with the compound of the formula (2) in the presence of an inorganic base in an aqueous solvent with getting aspartates the compounds of formula (3), which interacts with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of base followed by heating for decarboxylation to obtain the compounds of formula (4), to which is added p-toluensulfonate acid to obtain oxazolidinedione derivative of the formula (5)which then restores the tetrahydrofuran in the presence of NaBH4and methanol to obtain oxazolidinones the compounds of formula (6) and its further interaction with methylchloride in the presence of triethylamine to obtain methanesulfonate derivative of the formula (7), which interacts with the compound of the formula (8) in the presence of potassium carbonate to obtain benzylidene derivative of the formula (9), which is further restored in an atmosphere of hydrogen for the floor is warping with obtaining the compounds of formula (11)
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