CA2364906C - 4-heterocyclysulfonamidyl-6-methoxy-5-(2-methoxy-phenoxy)-2-pyridyl-pyrimidine derivatives, their preparation and use as endothelin receptor antagonists - Google Patents

4-heterocyclysulfonamidyl-6-methoxy-5-(2-methoxy-phenoxy)-2-pyridyl-pyrimidine derivatives, their preparation and use as endothelin receptor antagonists Download PDF

Info

Publication number
CA2364906C
CA2364906C CA002364906A CA2364906A CA2364906C CA 2364906 C CA2364906 C CA 2364906C CA 002364906 A CA002364906 A CA 002364906A CA 2364906 A CA2364906 A CA 2364906A CA 2364906 C CA2364906 C CA 2364906C
Authority
CA
Canada
Prior art keywords
methoxy
phenoxy
pyridine
pyrimidin
pyridin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA002364906A
Other languages
French (fr)
Other versions
CA2364906A1 (en
Inventor
Volker Breu
Philippe Coassolo
Werner Neidhart
Sebastien Roux
Peter Weiss
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of CA2364906A1 publication Critical patent/CA2364906A1/en
Application granted granted Critical
Publication of CA2364906C publication Critical patent/CA2364906C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10Drugs for genital or sexual disorders; Contraceptives for impotence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/06Antimigraine agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/14Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The compounds of formula (I) wherein R1 is a heterocyclic residue selected form pyridil and thiazolyl, where said heterocyclic residue may optionally b e substituted with lower alkyl or lower alkenyl; and pharmaceutically acceptab le salts thereof, are inhibitors of endothelin receptors and can therefore be used for the treatment of disorders which are associated with abnormal vascular tone and endothelial dysfunction; and the corresponding intermediat es of formulae (III) and (V).

Description

4-HETEROCYCLYSULFONAMIDYL-6-METHOXY-5-(2-METHOXY-PHENOXY)-2-PYRIDYL-PYRIMIDINE
DERIVATIVES, THEIR PREPARATION AND USE AS ENDOTHELIN RECEPTOR ANTAGONISTS
The present invention relates to heterocyclic sulfonamides and their use as medicaments. In particular, the present invention relates to compounds of the formula (I) O
,O
R'~S~NH O~
N \ O \
i N O
NI J
wherein R~ is a heterocyclic residue selected from pyridyl and thiazolyl, where said heterocyclic residue may optionally be substituted with lower alkyl or lower alkenyl;
and pharmaceutically acceptable salts thereof.
The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant.
Furthermore the present invention relates to the use of such compounds for the preparation of medicaments for the treatment or prophyla:cis of disorders which are associated with abnormal vascular tone and endothelial dysfunction.
to The present invention also relates to processes for the preparation of the compounds of formula (I).
In addition, the present invention relates to a method for the prophylactic and/or therapeutic treatment of disorders which are associated with abnormal vascular tone and endothelial dysfunction, which method comprises administering a compound of formula (I) to a human being or an animal.
The sulfonamides of the present invention are inhibitors of endothelin receptors.
They can accordingly be used for the treatment of disorders which are associated with abnormal vascular tone and endothelial dysfunction. EP 0 713 875 discloses sulfonamide compounds as endothelin receptor inhibitors. However, the compounds of the present invention have a high antagonistic potency in vitro and show unexpectedly high plasma levels following oral administration.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term "lower alkyl" refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, ri-butyl, s-butyl, t-butyl and the like.
The term "lower alkenyl" refers to a lower alkyl group containing one or more double bonds) in the alkylene chain.
The term "pharmaceutically acceptable salts" embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, malefic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non-toxic to living organisms. It also includes salts with inorganic or organic bases such as alkali salts like sodium and potassium salts, alkaline earth metal salts like calcium and magnesium salts, N-methyl-D-glutamine salts and salts with amino acids like arginine, lysine and the like.
More particularly, the present invention relates to compounds of the above formula (I), wherein R' is a heterocyclic residue selected from pyridyl and thiazolyl, where said heterocyclic residue may optionally be substituted with lower alkyl or lower alkenyl. The term "lower alkyl" preferably means methyl, ethyl; n-propyl, isopropyl, n-butyl, s-butyl or t-butyl, more preferably methyl, ethyl or isopropyl, still more preferably methyl or isopropyl, most preferably methyl. The term "lower alkenyl" preferably means vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl or 3-butenyl, more preferably vinyl, 1-propenyl, allyl and isopropenyl, most preferably isopropenyl.
Preferred heterocyclic residues in R' are 2-pyridyl and 2-thiazolyl, most preferred is 2-pyridyl. In a preferred embodiment, the heterocyclic residues in Rl are substituted with lower alkyl or lower alkenyl, with lower alkyl being preferred.
Particularly preferred residues R1 are 5-methyl-pyridine-2-yl, 5-isopropyl-pyridine-2-yl, 5-isopropenyl-pyridine-2-yl and 5-methyl-thiazol-2-yl. More preferred are 5-methyl-pyridine-2-yl, 5-isopropyl-pyridine-2-yl and 5-isopropenyl-pyridine-2-yl. Still more preferred are 5-methyl-pyridine-2-yl and 5-isopropyl-pyridine-2-yl. Most preferred is 5-methyl-pyridine-2-yl.
Particularly preferred compounds of formula (I) are 5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide, 5-isopropyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide, 5-isopropenyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide and 5-methyl-thiazole-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide.
More particularly preferred compounds of formula (I) are 5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide and 5-isopropyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide, most preferred is 5-methyl-pyridine-2-sulfonic acid 6-methoxy-5-( 2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl ] -amide.

The compounds of general formula (I) can be prepared in analogy to known processes or processes described below and summarized in the following schemes 1 and 2:
4,6-Dichloro-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine (described in EP 0 799 209) can be transformed to the intermediate of general formula (III) -according to scheme 1 - on reaction with an appropriate sulfonamide of general formula (II), wherein R' is as defined in claim 1, in a suited solvent such as D1IS0 or DMF
at room temperature or at elevated temperature and in the presence of a suited base such as potassium carbonate.
The corresponding sulfonamides can also be applied in above reaction in form of their pre-formed sodium or potassium salts.
Compounds of formula (III) can be further transformed to compounds of general formula (I) by treatment with sodium methylate in a solvent such as methanol.
Scheme 1 ~~ ~O
CI O O O R'~S~NH O~
y NI \ O I \ R'iS~NH2 N \ O \
I \ N CI / h \ I N"CI I /
N\% N J III
y The heterocyclic sulfonamides of general formula (II) are either already known in the literature, prepared in a manner analogous to established procedures and/or can be derived from corresponding mercapto derivatives in analogy to a known reaction sequence comprising oxidation with Ch in an acidic aqueous medium, such as diluted aqueous HCI, to yield the corresponding sulfonyl chlorides which can be transformed with liquid ammonia or aqueous ammonium hydroxide to the sulfonamides. The corresponding sodium or potassium salts can be obtained on treatment with sodium or potassium alkoxide in an appropriate solvent such as methanol.
Alternatively, compounds of general formula (I) can be prepared - according to scheme 2 - starting from 4-(4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-1-oxide (preparation described in EP 0 799 209) in a reaction sequence analogous to that of scheme l, to give compounds of general formula (V).
Pyridine-N-Oxide reduction of compounds of general formula (V) can be accomplished with a reagent system such as TiCI,~/NaI in analogy to a method described in Chem. Ber. 123, 647 ( 1990), or with a trialkylsilyl chloride (for example, t-butyldimethylsilyl chloride) in the presence of a suited base, such as triethylamine, and with acetonitrile as a solvent. Other methods for pyridine-N-Oxide deoxygenation are l0 known per se and comprise, for example, catalytic hydrogenation or reduction with reducing agents such as trivalent phosphorus compounds or metals in acid.
Scheme 2 ~~ ~O
O O O R'~S~NH O~
O ~ \ R~iS~NHz N \ O \
CI / h \ I N CI ~ /
O r O~N
,O
R'~S~NH O~
i \ O I \
E
\ N O /
J
The intermediates of above formula (III) and formula (V), wherein R' is as defined above l, preferably wherein R1 is 5-methyl-pyridine-2-yl or 5-isopropyl-pyridine-2-yl, and the pharmaceutically acceptable salts thereof are new and are also subject of the present invention.
The inhibitory activity of the compounds of formula (I) on endothelin receptors can be demonstrated using the test procedures described hereinafter:
I. Inhibition of endothelin binding to recombinant human ET-1 receptors expressed in Baculovirus-infected insect cells A cDNA coding for human ETA receptors of human placenta was cloned (M.
Adachi, Y.-Y. Yang, Y. Furuichi and C. Miyamoto, BBRC 180, 1265-1272) and expressed in the Baculovirus-insect cell system. Baculovirus-infected insect cells from a 231 fermenter are centrifuged off (3000 x g, 15 minutes, 4°C) 60 hours after the infection, re-l0 suspended in Tris buffer (5 mM, pH 7.4, 1 mM MgClz) and again centrifuged.
After a further re-suspension and centrifugation the cells are suspended in 800 ml of the same buffer and freeze-dried at -120°C. The cells disintegrate when the suspension in this hypotonic buffer mixture is thawed. After a repeated freeze-drying/thawing cycle the suspension is homogenised and centrifuged (25000 x g, 15 minutes, 4°C).
After suspension 15 in Tris buffer (75 mM, pH 7.4, 25 mM MgCh, 250 mM sucrose) 1 ml aliquots (protein content about 3.5 mg/ml) are stored at -85°C.
For the binding assay, the freeze-dried membrane preparations are thawed and, after centrifugation at 20°C and 25000 g for 10 minutes, re-suspended in assay buffer (50 mM Tris buffer, pH 7.4, containing 25 mM MnCl2, 1 mM EDTA and 0.5% bovine serum 20 albumin). 100 Etl of this membrane suspension containing 70 Ltg of protein are incubated with 50 l,tl of 1''SI-endothelin (specific activity 2200 Ci/mMol) in assay buffer (25000 cpm, final concentration 20 pM) and 100 l.tl of assay buffer containing varying concentrations of test compound. The incubation is carried out at 20°C for 2 hours or at 4°C for 24 hours.
The separation of free and membrane-bound radio- ligands is carried out by filtration 25 over a glass fibre filter. The inhibitory activity of compounds of formula (I) determined in this test procedure is given in Table 1 as the ICso, i.e. as the concentration [nM] which is required to inhibit 50% of the specific binding of lzsI-endothelin.
Table 1.
Compound of example 1 2 3 ICSO [nM] <_ 50 <_ 50 <_ 50 _7_ II. Inhibition of endothelin-induced contractions in isolated rat aorta rings Rings with a length of 5 mm were cut out from the thorax aorta of adult Wistar-Kyoto rats. The endothelium was removed by lightly rubbing the internal surface. Each ring was immersed at 37°C in 10 ml of Krebs-Henseleit solution in an isolated bath while gassing with 95% OZ and 5% CO~. The isometric stretching of the rings was measured. The rings were stretched to a pre-tension of 3 g. After incubation for 10 minutes with the test compound or vehicle cumulative dosages of endothelin-1 were added. The activity of the test compound was ascertained by the observed shift to the right of the dosage-activity curve of endothelin-1 in the presence of different concentrations of antagonist. This shift l0 to the right (or "dose ratio", DR) corresponds to the quotient from the ECSO values of endothelin-1 in the presence and in the absence of antagonist, with the ECso value denoting the endothelin concentration required for a half maximum contraction.
The corresponding pA~ value, which is a measure of the activity of the test compound, was calculated using a computer programme according to the following equation from the "dose ratio" DR for each individual dosage-activity curve.
pA~ = log(DR-1)-log(antagonist-concentration) The ECSO of endothelin in the absence of test compounds is 0.3 nM.
The pA~ values obtained with compounds of formula (I) are given in the following Table 3.
Table 2.
Compound of example1 2 pA2 >_8.0 >_8.0 III. Pharmacokinetics of the endothelin receptor antagonists The pharmacokinetics of the newly synthesised endothelin receptor antagonists were assessed in Wistar rats. The test compounds were dissolved in DMSO at a concentration of 5 mg/mL and administered orally by gavage at a dose of 1 mL/kg body weight corresponding to 5 mg/kg body weight. Two rats were administered per test compound. Blood samples were collected from the retro-orbital sinus at 1 and 5 h post dose in one rat, and at 3 and 7 h post dose in the other rat. In addition a terminal 24 h blood sample was collected from both rats by heart puncture. Blood was collected on _g_ EDTA-NaF. Plasma was derived by centrifugation at 2000 g at +4°C for 15 min. Plasma samples were assayed for active drug related material with a bioassay, based on the binding competition of tested compounds and 1'SI ET-1 on recombinant ETA receptors.
Quantitation of plasma samples was by comparison to a calibration curve build up from control rat plasma spiked with known concentrations of the test compounds.
Selected findings are summarised in the following table:
Table 3.
Test compound Peak concentrationArea under the plasma in of example rat plasma (ng/mL)concentration time curve (ng.h/mL) 1 >_ 1'500 >_ 10'000 _g_ On the basis of their capability of inhibiting endogenous endothelin binding, the compounds of formula (I) can be used as medicaments for the treatment of disorders which are associated with abnormal vascular tone and endothelial dysfunction.
Therefore, the application field of the compounds of formula (I) could be heart failure (acute and chronic), systemic, and pulmonary hypertension, acute ischaemic coronary syndrome, angina pectoris, renal failure (acute and chronic), organ transplant (e.g: liver, heart, kidney), cyclosporin nephrotoxicity, vasospastic disease (subarachnoid haemorrhage but also haemorrhagic and non-haemorrhagic stroke, Raynaud syndrome), peripheral artery occlusive disease, prevention of restenosis after stmt or balloon to angioplasty, septic shock or multiple organ failure as that occurring in intensive care, asthma, chronic obstructive pulmonary disease, gastric and duodenal ulcus, liver cirrhosis, pancreatitis (acute and chronic), inflammatory bowel disease, fibrosis, atheriosclerosis, obesity, glaucoma, prostatic adenoma, migraine, erectile dysfunction, adjunct to cancer therapy as well as other disorders associated with endothelin activities.
The compounds of formula (I) can also be administered in combination with antihypertensive drugs, antiarrhythmics, anti angina, antithrombotic and lipid lowering agents as well as antioxidants.
It will be appreciated that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide prodrug derivatives which are capable of conversion back to the parent compounds in vivo. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of ?5 this invention.
As mentioned earlier, medicaments containing a compound of formula (I) are also an object of the present invention, as is a process for the manufacture of such medicaments, which process comprises bringing one or more compounds of formula (I) and, if desired, one or more other therapeutically valuable substances into a galenical administration form.

l~ -The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out rectally, for example using suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally, using for example injectable solutions.
Furthermore, administration can be carried out sublingually or as opthalmological preparations or as an aerosol, for example in the form of a spray.
For the preparation of tablets, coated tablets, dragees or hard gelatine capsules the l0 compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, dragees or hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof.
Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid or liquid polyols etc.; according to the nature of the active ingredients it may however be the case that no excipient is needed at all for soft gelatine capsules.
For the preparation of solutions and syrups, excipients which may be used include for example water, polyols, saccharose, invert sugar and glucose.
For injectable solutions, excipients which may be used include for example water, alcohols, polyols, glycerine, and vegetable oils.
For suppositories, and local or percutaneous application, excipients which may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols.
The pharmaceutical compositions may also contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, coating agents or antioxidants. As mentioned earlier, they may also contain other therapeutically valuable agents.
It is a prerequisite that all adjuvants used in the manufacture of the preparations are non-toxic.
Preferred forms of use are intravenous, intramuscular or oral administration, most preferred is oral administration. The dosages in which the compounds of formula (I) are administered in effective amounts depend on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of application. In general, dosages of about 0.01-10 mg/kg body weight per day come into consideration.

The following Examples shall illustrate preferred embodiments of the present invention but are not intended to limit the scope of the invention. Of the abbreviations used therein, MeOH signifies methanol, AcOEt signifies ethyl acetate, DMF
signifies dimethylformamide, RT signifies room temperature, HPLC signifies high performance liquid chromatography, TLC signifies thin layer chromatography, ISN signifies Ion Spray Mass Spectrometry - negative mode, EI signifies Electron Impact Mass Spectrometry and M signifies molecular mass.
Example 1 a) To a solution of 6.9 g sodium in MeOH (300 ml) were added 14.52 g of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide at RT and the mixture was refluxed for S days until completion of the reaction according to TLC analysis. The reaction mixture was concentrated in vacuo to half its volume upon which the crude reaction product precipitated as a sodium salt. It was filtered off by suction and dried in a high vacuum. The solid was dissolved in water, which was then made acidic by addition of acetic acid. The precipitating free sulfonamide was extracted into Me2Ch. The organic layer was dried over Mg~S04, concentrated on a rotary evaporator, and the crystalline solid that had formed was filtered off. It was then dried in a high vacuum for 12 h at 120 °C to give the desired 5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as white crystals.
Melting point 225-226 °C. ISN mass spectrum, m/e 478.2 (M-1 calculated for C~~H~,N50;S,: 478).
C~3H~,NSOSS1: Calc: C 57.61; H 4.41; N 14.61; S 6.69. Found: C 57.56; H 4.38;
N 14.61; S 6.83 Preparation of the starting material:
b) 11.3 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine and 19.66 g of 5-methylpyridyl-2-sulfonamide potassium salt (preparations described in EP 0 799 209) were dissolved in DMF (255 ml) under argon. The solution was stirred for 2 h at 40°C until completion of the reaction according to TLC analysis.
The reaction mixture was cooled to RT and the solvent removed in a high vacuum. The residue was suspended in water (850 ml), acetic acid (85 ml) was added and the mixture was stirred for 30 minutes at RT. The solid that precipitated was collected by filtration and dried in a high vacuum at 60 °C for 16 h to give 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as yellow crystals.
Melting point 177-179 °C. ISN mass spectrum, m/e 482.2 (M-1 calculated for C~ZH18C1NSO;S1: 482).
Example 2 a) In analogy to example la), from 5-isopropyl-pyridine-2-sulfonic acid[6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide and NaOMe, there was obtained 5-isopropyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-pyridin-4-yl-pyrimidin-4-yl]-amide as slightly yellow crystals. Melting point 195-197 °C.
ISN mass spectrum, m/e 506.2 (M-1 calculated for C~SH~SNSOSS1: 506).
C~jH~iN505S,: Calc: C 59.16; H 4.96; N 13.80; S 6.32. Found: C 58.99; H 4.90;
N 13.83; S 6.37 Preparation of the starting material:
b) In analogy to example lb), from 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine and 5-isopropylpyridyl-2-sulfonamide potassium salt (preparation described in EP 799 209) there was obtained 5-isopropyl-pyridine-2-sulfonic acid[6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as a brown crystalline solid.
Example 3 a) A solution of 0.156 g of 5-isopropenyl-pyridine-2-sulfonic acid [6-methoxy-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-amide in acetonitrile (2 ml) was treated at RT with 0.025 ml TiCl4 followed by 0.135 g of sodium iodide and then stirred at RT for 20 h. Additional 0.1 ml of TiCI:~ were added, the mixture was refluxed for 1 h and then further 0.1 ml of TiCl4 were added and refluxing was continued for 3 h to complete the reaction according to HPLC analysis. The reaction mixture was cooled to RT, concentrated on rotary evaporator, the residue taken up in AcOEt, which was washed with water, dried over NaS04 and finally removed in vacuo. The residue was purified by preparative thin layer chromatography, with AcOEt/MeOH: 9/1 as solvent system, to give the desired 5-isopropenyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as a light yellow solid.
ISN mass spectrum, m/e 504.2 (M-1 calculated for Cz5H23NsO;S,: 504).

Preparation of the starting material:
b) To a solution of 5-isopropyl-pyridine-2-sulfonamide potassium salt (synthesis described in EP 799 209) in water ( 10 ml) were added 1.2 g of KMn04 at RT and the mixture was then refluxed for 30 minutes. The mixture was cooled to RT, acidified with diluted HCl and the product was extracted into AcOEt. The organic layer was washed with water, dried over Na~SO~ and concentrated in vacuo to give (5-(1-hydroxy-1-methyl-ethyl))-pyridine-2-sulfonic acid amide as yellow oil. EI mass spectrum, m/e (M calculated for: C8H1~NZO~S 216).
c) A solution of 0.1 g of (5-( 1-hydroxy-1-methyl-ethyl))-pyridine-2-sulfonic acid amide in CF3CO~H (2 ml) was refluxed for 20 h. The solvent was then removed in vacuo to give 5-isopropenyl-pyridine-2-sulfonic acid amide as a white solid which was essentially pure. EI mass spectrum, m/e 198 (M calculated for CBH,oNzO~S: 198).
The corresponding potassium salt was prepared from the sulfonamide on treatment with potassium t-butylate in MeOH.
d) In analogy to example lb), from 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-1-oxide (synthesis described in EP 799 209) and 5-isopropenyl-pyridine-2-sulfonic acid amide potassium salt, there was obtained 5-isopropenyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-( 1-oxy-pyridin-4-yl)-pyrimidin-4 yl]-amide as a light yellow solid. ISN mass spectrum, m/e 524.3 (M-1 calculated for C=~H=~C1N;OSS: 524).
e) In analogy to example la), from 5-isopropenyl-pyridine-2-sulfonic acid [6-?5 chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-amide and sodium methoxide there was obtained 5-isopropenyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-amide as a light yellow solid. ISN mass spectrum, m/e 520.2 (M-1 calculated for C25H23~s06S: 520).
Example 4 a) A suspension of 0.4 g of 5-methyl-thiazole-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-amide in acetonitile (5 ml) was treated subsequently with 1.12 ml of triethylamine and 1.243 g of t-butyldimethylsilyl chloride at RT. The mixture was stirred 5 minutes at RT, its pH adjusted to neutral (by addition of trietylamine), and then heated to reflux for 60 h. The reaction mixture was cooled to RT and concentrated on a rotary evaporator. The residue was taken up in CH~CI~, which was subsequently washed with acetic acid and water. The organic layer was dried over MgSO~ and the solvent removed in vacuo. The residue was applied to a silica gel column with AcOEt/MeOH: 4/1 as eluent. Combination of the purified fractions and concentration in vacuo gave the desired 5-methyl-thiazole-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as a beige crystalline solid.
15N mass spectrum, m/e 484.2 (M-1 calculated for CZiHI9NSO5Sl: 484).
Preparation of the starting material:
b) 2.23 g of 5-methylene-thiazolidine-2-thione (preparation described in:
Liebigs Ann. Chem., 1985, 58-64) were dissolved in 36% aqueous HCl ( 150 ml), cooled to -20°C
and Ch was bubbled through the solution for 0.5 h while keeping its temperature below -20°C. Ether (400 ml cooled to -15°C) was then added and after stirring for 5 minutes the layers were separated. The organic layer was treated with liquid NH3 (200 ml) and the mixture allowed warming slowly to RT. The solvent was removed in vacuo to give 5-methyl-thiazole-2-sulfonic acid amide as an off-white solid. EI mass spectrum, m/e 178 (M calculated for C4H6N~OzS~: 178).
The corresponding potassium salt was prepared from the sulfonamide on treatment with potassium t-butylate in MeOH.
c) In analogy to example lb), from 5-methyl-thiazole-2-sulfonic acid amide potassium salt, and 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-1-oxide there was obtained 5-methyl-thiazole-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-( 1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-amide as a light yellow solid. ISN mass spectrum, m/e 504 (M-1 calculated for C~°H16C1N505Sz: 504).
d) In analogy to example la), from 5-methyl-thiazole-2-sulfonic acid (6-chloro-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin--1-yl]-amide and sodium methoxide there was obtained 5-methyl-thiazole-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-amide as a light yellow solid.
ISN mass spectrum, m/e 500.1 (M-1 calculated for CZ,H,9C1NSO6S~: 500).

Example A
Tablets containing the following ingredients can be produced in a conventional manner:
Ingredients m~per tablet Compound of formula (I) 10.0 - 100.0 Lactose 125.0 Corn starch 75.0 Talc 4.0 Magnesium stearate 1.0 Example B
Capsules containing the following ingredients can be produced in a conventional manner:
Ingredients m~per capsule Compound of formula (I) 25.0 Lactose 150.0 Corn starch 20.0 Talc 5.0 Example C
Injection solutions can have the following composition:
Compound of formula (I) 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Water for injection ad 1.0 ml .. . WO 00/52007 PC'T/EP00/01660 xam a D
500 mg of compound of formula (I) are suspended in 3.5 ml of Myglyol 812 and 0.08 g of benzyl alcohol. This suspension is filled into a container having a dosage valve.
5.0 g of Freon 12 are filled into the container under pressure through the valve. The Freon is dissolved in the Myglyol-benzyl alcohol mixture by shaking. This spray container contains about 100 single doses which can be applied individually.
* trademark

Claims (16)

Claims
1. A compound of formula (I) wherein R1 is a heterocyclic residue selected from pyridyl and thiazolyl, where said heterocyclic residue may optionally be substituted with lower alkyl or lower alkenyl;

and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, wherein R1 is pyridyl, optionally substituted with lower alkyl or lower alkenyl.
3. A compound according to any of claims 1-2, wherein R1 is pyridyl, optionally substituted with lower alkyl.
4. A compound of claim 1, selected from the group consisting of:
5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide, 5-isopropyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide, 5-isopropenyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide and 5-methyl-thiazole-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide.
5. A compound of any of claims 1-2, selected from the group consisting of 5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide, 5-isopropyl-pyridine-2-sulfonic acid (6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide and 5-isopropenyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide.
6. A compound of any of claims 1-3, selected from the group consisting of:
5-methyl-pyridine-2-sulfonic acid (6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide and 5-isopropyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide.
7. The compound of any of claims 1-3, which is:
5-methyl-pyridine-2-sulfonic acid (6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide.
8. A pharmaceutical composition comprising a compound of any one of claims 1-7 and a pharmaceutically acceptable carrier and/or adjuvant.
9. A pharmaceutical composition according to claim 8, additionally comprising any active compounds selected from antihypertensive drugs, antiarrhythmics, anti angina, antithrombotic and lipid lowering agents as well as antioxidants.
10. The use of a compound as defined in any of claims 1-7 for the preparation of medicaments containing a compound as defined in any of claims 1-7 for the treatment or prophylaxis of disorders which are associated with abnormal vascular tone and endothelial dysfunction.
11. A use of a compound as defined in any of claims 1-7 for the treatment or prophylaxis of disorders which are associated with abnormal vascular tone and endothelial dysfunction.
12. A process for the preparation of the compounds described in any one of claims 1-7, which process comprises:

a) reacting 4,6-dichloro-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine with an appropriate sulfonamide of the general formula (II) ~~~~~~~~~(II) wherein R1 is as defined in claim 1, in a suitable solvent in the present of a suited base, followed by further treatment with sodium methylate in methanol, or b) reacting 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-1-oxide with an appropriate sulfonamide of the general formula (II) ~~~~~~~~~(II) wherein R1 is as defined in claim 1, in a suitable solvent in the present of a suited base, followed by further treatment with sodium methylate in methanol and pyridine-N-oxide reduction.
13. The compounds of formula (III) ~~~~~~~~~(III) wherein R1 is as defined in claim 1.
14. The compounds of formula (V) wherein R1 is as defined in claim 1.
15. Compounds according to any of claims 1-7, whenever prepared by the process of claim 12.
16. Compounds according to any of claims 1-7 for the treatment of diseases which are associated with abnormal vascular tone and endothelial dysfunction.
CA002364906A 1999-03-03 2000-02-28 4-heterocyclysulfonamidyl-6-methoxy-5-(2-methoxy-phenoxy)-2-pyridyl-pyrimidine derivatives, their preparation and use as endothelin receptor antagonists Expired - Lifetime CA2364906C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP99104306 1999-03-03
EP99104306.8 1999-03-03
PCT/EP2000/001660 WO2000052007A1 (en) 1999-03-03 2000-02-28 4-heterocyclysulfonamidyl-6-methoxy-5-(2-methoxy-phenoxy)-2-pyridyl-pyrimidine derivatives, their preparation and use as endothelin receptor antagonists

Publications (2)

Publication Number Publication Date
CA2364906A1 CA2364906A1 (en) 2000-09-08
CA2364906C true CA2364906C (en) 2006-01-10

Family

ID=8237697

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002364906A Expired - Lifetime CA2364906C (en) 1999-03-03 2000-02-28 4-heterocyclysulfonamidyl-6-methoxy-5-(2-methoxy-phenoxy)-2-pyridyl-pyrimidine derivatives, their preparation and use as endothelin receptor antagonists

Country Status (30)

Country Link
US (2) US6417360B1 (en)
EP (1) EP1185525B1 (en)
JP (1) JP3488203B2 (en)
KR (1) KR100478798B1 (en)
CN (1) CN1342158B (en)
AR (1) AR044720A1 (en)
AT (1) ATE353325T1 (en)
AU (1) AU756738B2 (en)
BR (1) BR0008717A (en)
CA (1) CA2364906C (en)
CY (1) CY1108002T1 (en)
CZ (1) CZ300324B6 (en)
DE (1) DE60033280T2 (en)
DK (1) DK1185525T3 (en)
ES (1) ES2280198T3 (en)
HK (1) HK1044943B (en)
HR (1) HRP20010630B1 (en)
HU (1) HUP0200080A3 (en)
ID (1) ID30484A (en)
IL (1) IL145051A0 (en)
MA (1) MA26776A1 (en)
NO (1) NO320809B1 (en)
NZ (1) NZ513671A (en)
PL (1) PL198815B1 (en)
PT (1) PT1185525E (en)
RS (1) RS50109B (en)
RU (1) RU2201928C1 (en)
TR (1) TR200102562T2 (en)
WO (1) WO2000052007A1 (en)
ZA (1) ZA200107157B (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY140724A (en) 2000-07-21 2010-01-15 Actelion Pharmaceuticals Ltd Novel arylethene-sulfonamides
US20020184047A1 (en) * 2001-04-03 2002-12-05 Plotnick Michael A. Universal ad queue
EP1454625A1 (en) * 2003-03-06 2004-09-08 Speedel Development AG Pyridylsulfonamidyl-pyrimidines for the treatment of diabetic nephropathies
EP1595880A1 (en) * 2004-05-13 2005-11-16 Speedel Pharma AG Crystalline forms of a pyridinyl-sulfonamide and their use as endothelin receptor antagonists
CN101257947A (en) * 2005-09-12 2008-09-03 斯皮德尔药品公司 Pyridylsulfonamidyl-pyrimidines for the prevention of blood vessel graft failure
US20100022568A1 (en) * 2006-04-13 2010-01-28 Actelion Pharmaceeuticals Ltd. Endothelin receptor antagonists for early stage idiopathic pulmonary fibrosis
EP1938812A1 (en) * 2006-12-22 2008-07-02 Speedel Pharma AG Pharmaceutical composition using aliskiren and avosentan
WO2010011868A2 (en) * 2008-07-23 2010-01-28 Auspex Pharmaceuticals Pyridine sulfonamide modulators of endothelin-a-receptor
US20180022710A1 (en) 2015-01-29 2018-01-25 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
KR101936054B1 (en) 2017-06-23 2019-01-11 한국과학기술연구원 Anti-inflammatory 6-phenoxypyrimidine derivatives, process for their preparation and pharmaceutical composition containing them
WO2023111299A1 (en) 2021-12-17 2023-06-22 Idorsia Pharmaceuticals Ltd Clazosentan disodium salt, its preparation and pharmaceutical compositions comprising the same

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1064965C (en) * 1994-11-25 2001-04-25 弗·哈夫曼-拉罗切有限公司 Novel sulfonamides compound and its use as medicine
CA2162630C (en) 1994-11-25 2007-05-01 Volker Breu Sulfonamides
US5837708A (en) 1994-11-25 1998-11-17 Hoffmann-La Roche Inc. Sulphonamides
TW313568B (en) 1994-12-20 1997-08-21 Hoffmann La Roche
EP0897914B1 (en) 1997-08-19 2004-05-26 F. Hoffmann-La Roche Ag Process for the preparation of 2,5-disubstitued pyridines
TWI284642B (en) * 1999-01-18 2007-08-01 Hoffmann La Roche Novel heterocyclic sulfonamides

Also Published As

Publication number Publication date
HUP0200080A3 (en) 2003-01-28
KR20010102480A (en) 2001-11-15
NO20014224D0 (en) 2001-08-31
US6521631B2 (en) 2003-02-18
WO2000052007A1 (en) 2000-09-08
CZ300324B6 (en) 2009-04-22
RU2201928C1 (en) 2003-04-10
TR200102562T2 (en) 2002-02-21
AR044720A1 (en) 2005-10-05
HUP0200080A2 (en) 2002-06-29
DK1185525T3 (en) 2007-06-04
HRP20010630A2 (en) 2002-08-31
AU3161100A (en) 2000-09-21
IL145051A0 (en) 2002-06-30
PL351794A1 (en) 2003-06-16
CZ20013108A3 (en) 2002-02-13
KR100478798B1 (en) 2005-03-24
YU62801A (en) 2004-07-15
NO20014224L (en) 2001-08-31
NO320809B1 (en) 2006-01-30
US20020137933A1 (en) 2002-09-26
PT1185525E (en) 2007-05-31
HRP20010630B1 (en) 2010-08-31
JP2002538156A (en) 2002-11-12
ZA200107157B (en) 2002-11-29
RU2001126348A (en) 2004-03-20
CN1342158A (en) 2002-03-27
CA2364906A1 (en) 2000-09-08
ID30484A (en) 2001-12-13
ES2280198T3 (en) 2007-09-16
CN1342158B (en) 2012-06-06
US6417360B1 (en) 2002-07-09
BR0008717A (en) 2001-12-26
MA26776A1 (en) 2004-12-20
CY1108002T1 (en) 2013-09-04
EP1185525A1 (en) 2002-03-13
HK1044943A1 (en) 2002-11-08
DE60033280T2 (en) 2007-11-22
AU756738B2 (en) 2003-01-23
NZ513671A (en) 2003-04-29
ATE353325T1 (en) 2007-02-15
JP3488203B2 (en) 2004-01-19
EP1185525B1 (en) 2007-02-07
DE60033280D1 (en) 2007-03-22
PL198815B1 (en) 2008-07-31
RS50109B (en) 2009-03-25
HK1044943B (en) 2013-03-22

Similar Documents

Publication Publication Date Title
US6242601B1 (en) Heterocyclic sulfamides
TWI411437B (en) 4-pyrimidinesulfamide derivative
CA2364906C (en) 4-heterocyclysulfonamidyl-6-methoxy-5-(2-methoxy-phenoxy)-2-pyridyl-pyrimidine derivatives, their preparation and use as endothelin receptor antagonists
JP4769460B2 (en) New sulfamides
EP1309564B1 (en) Arylethene-sulfonamides, their preparation and their use as endothelin antagonists
AU2001281970A1 (en) Arylethene-sulfonamides, their preparation and their use as endothelin antagonists
JP4769418B2 (en) Novel alkanesulfonamides
MXPA01008783A (en) 4-heterocyclysulfonamidyl -6-methoxy-5 -(2-methoxy-phenoxy) -2-pyridyl -pyrimidine derivatives, their preparation and use as endothelin receptor antagonists
WO2002083650A1 (en) Novel sulfonylamino-pyrimidines
EP1322624B1 (en) Arylalkane-sulfonamides having endothelin-antagonist activity
WO1996006088A1 (en) Benzothiazolesulfonamide derivative having terminal cycloalkyl group and medicinal use thereof

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry

Effective date: 20200228