ZA200203796B - Butyne diol derivatives. - Google Patents

Butyne diol derivatives. Download PDF

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ZA200203796B
ZA200203796B ZA200203796A ZA200203796A ZA200203796B ZA 200203796 B ZA200203796 B ZA 200203796B ZA 200203796 A ZA200203796 A ZA 200203796A ZA 200203796 A ZA200203796 A ZA 200203796A ZA 200203796 B ZA200203796 B ZA 200203796B
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hydroxy
alkyl
compounds
disorders
substituted
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ZA200203796A
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Martin Bolli
Martine Clozel
Christoph Boss
Walter Fischli
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Actelion Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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 two hetero rings
    • C07D401/04—Heterocyclic 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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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 two hetero rings
    • C07D401/12—Heterocyclic 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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/14—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Description

Butyne Diol Derivatives \5
The present invention relates to novel butyne diol derivatives of the general formula | and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula | and “especially their use as endothelin receptor antagonists.
Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid peptides produced and LL active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332:411. “Endothelins are potent vasoconstrictors and important mediators of cardiac, } renal, endocrine and immune functions (McMillen MA et al.: J Am Coll Surg (1995) 180:621). They participate in bronchoconstriction and regulate ‘neurotransmitter release, activation of inflammatory cells, fibrosis, cell “proliferation and cell differentiation (Rubanyi GM et al.: Pharmacol Rev (1994) '46:328).
Two endothelin receptors have been cloned and characterized in mammals (ETA, ETg) (Arai H et al.: Nature (1990) 348:730; Sakurai T et al.: Nature (1990) 348.732). The ETa receptor is characterized by higher affinity for ET-1 and ET-2 than for ET-3. It is predominant in vascular smooth muscle cells and mediates vasoconstricting and proliferative responses (Ohistein EH et al.:
Drug Dev Res (1993) 29:108). In contrast, the ETg receptor has equivalent affinity for the 3 endothelin isopeptides and binds the linear form of endothelin, tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991) 178:248). This receptor is located in the vascular endothelium and smooth muscles, and is also particularly abundant in lung and brain. The ETg receptor from endothelial cells mediates transient vasodilator responses to
ET-1 and ET-3 through the release of nitric oxide and/or prostacyclin whereas the ETg receptor from smooth muscle cells exerts vasoconstricting actions (Sumner MJ et al.: Brit J Pharmacol (1992) 107:858). ETa and ETg receptors are highly similar in structure and belong to the superfamily of G-protein coupled receptors.
A pathophysiological role has been suggested for ET-1 in view of its increased plasma and tissue levels in several disease states such as hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive heart failure, renal failure, migraine and asthma. As a consequence, endothelin receptor antagonists have been studied extensively as potential therapeutic agents. Endothelin receptor antagonists have demonstrated preclinical and/or clinical efficacy in various diseases such as cerebral vasospasm following subarachnoid hemorrhage, heart failure, pulmonary and systemic hypertension, neurogenic inflammation, renal failure and myocardial infarction.
Today, no endothelin receptor antagonist is marketed yet, several are in : clinical trials. However, these molecules possess a number of weaknesses such as complex synthesis, low solubility, high molecular weight, poor pharmacokinetics or safety problems (e.g. liver enzyme increases).
Furthermore, the contribution of differential ETa / ETg receptor blockade to the clinical outcome is not known. Thus, tailoring of the physicochemical, pharmacokinetic properties and the selectivity profile of each antagonist for a given clinical indication is mandatory. We have discovered a new class of butyne-diol derivatives of the structure below and found that they allow the : specific tailoring described above. : ~The inhibitory activity of the compounds of formula | on endothelin receptors - can be demonstrated using the test procedures described hereinafter:
BN ST
For the evaluation of the potency and efficacy of the compounds of the general formula | the following tests were used: 1) Inhibition of endothelin binding to membranes from CHO cells carrying human ET receptors:
For competition binding studies, membranes of CHO cells expressing human recombinant ET or ET receptors were used. Microsomal membranes from recombinant CHO cells were prepared and the binding assay made as previously described (Breu et al, FEBS Lett 1993; 334:210).
The assay was performed in 200 uL 50 mM Tris/HCI buffer, pH 7.4, including 25 mM MnCl,, 1 mM EDTA and 0.5% (w/v) BSA in polypropylene microtiter plates. Membranes containing 0.5 ug protein were incubated for 2 h at 20°C with 8 pM ['®I)ET-1 (4000 cpm) and increasing concentrations of unlabelled antagonists. Maximum and minimum binding were estimated in samples without and with 100 nM ET-1, respectively. After two h, the membranes were filtered on filterplates containing GF/C filters (Unifilterplates from Canberra
Packard S.A. Zirich, Switzerland). To each well, 50 uL of scintillation cocktail was added (MicroScint 20, Canberra Packard S.A. Zurich, Switzerland) and the filter plates counted in a microplate counter (TopCount, Canberra Packard
S.A. Zurich, Switzerland).
All the test compounds were dissolved, diluted and added in DMSO. The assay was run in the presence of 2.5% DMSO which was found not to interfere significantly with the binding. ICs; was calculated as the concentration of antagonist inhibiting 50 % of the specific binding of ET-1. For reference compounds, the following ICs values were found: ET, cells: 0.075 nM (n=8) for ET-1 and 118 nM (n=8) for ET-3; ETz cells: 0.067 nM (n=8) for . \ ET-1 and 0.092 nM (n=3) for ET-3.
The ICs values obtained with compounds of formula | are given in Table 1
Table 1:
Compound of ICsolnM]
ETa ETs © Exampetg 26 17
Example 2¢ 126 44
Example 3e 22 1520
Example 4d 53 2030
Example 5b 38 635
Example 9d 16 49
Example 11d 49 97
Example 18 79 36 :
Example 19 112 45
Example 21 230 44
Example 58 7 123
Example 70 94 375
Example 71 13 28
Example 72 1 42
Example 81 1 197
Example 84 2 241
Example 89 13 1140
Example 94 13 107 2) Inhibition of endothelin-induced contractions on isolated rat aortic rings (ETa receptors) and rat tracheal rings (ETg receptors):
The functional inhibitory potency of the endothelin antagonists was assessed by their inhibition of the contraction induced by endothelin-1 on rat aortic rings (ETa receptors) and of the contraction induced by sarafotoxin S6c on rat i . WO 01/46156 PCT/EP00/12743 tracheal (ETs receptors). Adult Wistar rats were anesthetized and ] exsanguinated. The thoracic aorta or trachea were excised, dissected and cut in 3-5 mm rings. The endothelium/epithelium was removed by gentle rubbing of the intimal surface. Each ring was suspended in a 10 ml isolated organ bath filled with Krebs-Henseleit solution (in mM; NaCl 115, KCI 4.7, MgSO, 1.2, KHoPO4 1.5, NaHCO; 25, CaCl, 2.5, glucose 10) kept at 37°C and gassed with 95% O, and 5% CO,. The rings were connected to force transducers and isometric tension was recorded (EMKA Technologies SA,
Paris, France). The rings were stretched to a resting tension of 3 g (aorta) or 2 g (trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6c (trachea) were added after a 10 min incubation with the test compound or its vehicle.
The functional inhibitory potency of the test compound was assessed by calculating the concentration ratio, i.e. the shift to the right of the ECs induced by different concentrations of test compound. ECs is the concentration of endothelin needed to get a half-maximal contraction, pA; is the negative logarithm of the antagonist concentration which induces a two- fold shift in the ECs value.
The pA; values obtained with compounds of formula | are given in Table 2.
Table 2:
Compound of PR aortic rings trachea
Example 4d 7.15 5.89
Example 9d 7.11 6.47
Example 11d 7.05 7.03
Example 19 <5 7.62
Example 58 7.57
Example 59 7.70
Example 72 7.70 ]
Example 81 7.56
Example 84 8.11
Because of their ability to inhibit the endothelin binding, the described compounds can be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portal hypertension and pulmonary hypertension. They can also be used for atherosclerosis, prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to endothelin.
The compounds can be administered orally, rectally, parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually or as ophthalmic preparation or administered as aerosol.
Examples of applications are capsules, tablets, oral administered . suspensions or solutions, suppositories, injections, eye-drops, ointments or aerosols/nebulizers.
Preferred applications are intravenous, intra-muscular, eye drops or oral administrations. The dosage used depends upon the type of the specific active ingredient, the age and the requirements of the patient and the kind of \ application. Generally, dosages of 0.1 — 50 mg / kg body weight per day are considered. The preparations with compounds can contain inert or as well pharmacodynamically active excipients. Tablets or granules, for example, could contain a number of binding agents, filling excipients, carrier substances or diluents.
The present invention relates to butyne diol derivatives of the general formula l,
Oo 0
WY
RY NH
X
: ~ . OY R® general formula I
PP
R N 0]
OR; wherein
R' represents phenyl; mono-, di- or tri-substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylen or lower alkenylen or lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl; heterocyclyl; five membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen atoms which may be mono- or di-substituted with halogen, lower

Claims (11)

\ Claims EPO-BERLIN 5-700
1. Compounds of the formula Oo O \V4 rR SNH X ~ I oN R® general formula I ML = R N (0) ~~ | OR; oo wherein } R' represents phenyl; mono-, di- or tri-substituted ‘phenyl substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, six-membered-ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower : alkynyl, lower—alkyloxy-lower—alkyl, lower—alkyloxy-lower—alkyloxy, trifluoromethyl, triflueremethoxy, cycloalkyl, hydroxy-cycloalkyl; heterocyehy; atkyl-lower-alkexy-hydrexy-lower-alkyl-halegen-trifluoromethyl; 2-pyridyl; 5- substituted 2-pyridyl substituted with lower alkyl, lower-alkexy,-benzyl; mono - AMENDED SHEEY J
A trifluoromethyl triflucromethoxy,—eyclealkyl—hydroxy-cycloatkyd;, five membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen atoms; aryk-heteroans; ~~ 5 R?represents hydrogen; lower alkyl; trifluoromethyl; phenyl; mono-, di- or tri- substituted phenyl substituted with pheryl, halogen, hydroxy, lower alkyl, lower-alkenyh-lower-alkynyl, lower alkoxy, loweralkenyloxylower-alkynyloxy, hydroxy-loweralkenyl-hydroxy-lower-alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower-alkylexy, trifluoromethyl, trifluoromethoxy, sycloalky—hydroxy- eycloalkyl:-heterosyehy; five membered heteroaryl rings containing one or two . nitrogen, sulfur or oxygen atoms which may be mono-or di-substituted with halogen, lower alkyl, lower alkoxy; benzyl; mono-, di- or tri-substituted benzyl R 15 substituted with phenyl, halogen, hydroxy, lower alkyl, lower-alkenyi, lower alkynyl, lower alkoxy, lower—alkenyloxy—lower-atkynyloxy;,—lower—alkylon—of Le five: . | | ring, hyd loth alkenyl—hydroxy-lower—alkynyl, trifiuoromethyl, triflucromethoxy, sycloatkyl hydroxy-eyelealkey; 2-pyrimidyl; mono- or di-substituted 2-pyrimidyl substituted with lower alkyl, lower alkoxy, hydroxylower—alkyl, halogen, trifluoromethyl, five—membered—hetereard—rings—containing—ene—or—twe pitrogen;-sulfur-or-oxygen-atoms; aryl-hetereary-heteroeyely; a group of the formula -C(A)-B-R? wherein A represents O or S; B represents NH ora-bend; and | oo R? represents lower alkyl; cycloalkyl; trifluoromethyl; phenyl; mono-, di- or tri- substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl, AMENDED SHEET
A lower alkenyl, lower-alkynyl, lower alkoxy, loweralkenyloxy-lower-alkynyloxy;
alkyloxy-lower-alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, —hydroxy- halogen, —lower—alkyl, lower alkoxy, trifluoromehiyl—trifluoromethoxy; six membered heteroaryl rings containing one or two nitrogen atoms which may be mono-, di- or tr-substituted with halogen, lower alkyl, lower akyloxy, trifluoromethyl; } R® represents hydrogen—ewer—alkyl, phenyl; mono-, di- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower—alkynyl, lower ] 15 alkyloxy, amino,—lower—alkylamino—amine-lower—alkyl, trifluoromethyl, trifluoromethoxy, halogen, lower—alkyithio, hydroxy, hydroxy-lower—alkyl; hydroxy-hydroxy-lower-atkyl-cyano-carboxy,
R* represents hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, lewer—alkylthio-lower—alkyl—hydroxy-lower—alkyl, lower alkyl- oxy-lower alkyl, hydroxy-lower-atkyl-exy-loweralkyl—amino-loweratkyl lower alkyl-amino-lewer—alkyl—amino,—lower—alkyl-amino,—di-lower—alkyl-amine, phenyl; mono-, di- or tri-substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylen or lower alkenylen or lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six- membered ring, lower—alkeny—lower—alkenyioxy,——trifluoremethyl;
andoxy—aryl-lower-atkyl; heteroaryl; heterocyclyl,
AMENDED SHEgT oF 15:11-2001
JURE El ae — Enea pees X represents oxygen; sulfur; NH or a bond; and pure enantiomers, enantiamerically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and pharmaceutically acceptable salts thereof.
2. Compounds of formula | wherein R', R?, and R* are as defined in claim 1, and wherein R® represents phenyl; mono substituted phenyl substituted with lower alkyl, lower alkyloxy, trifluoromethyl, triflucremethoxy, halogen; X represents oxygen or a single bond, : and pharmaceutically acceptable salts thereof.
3. Compounds of formula ll o. 9 AY or T X R® = NTR ge : formula II 4 = R N 0] Op wherein R?, R® R* and X are as defined in formula | in claim 1, and R® represents lower alkyl, and pharmaceutically acceptable salts of compounds of formula Il. AMENDED sppgy gan ir £ ERE ee I RAVER 15:11-2001
) Flu a, aaa a Gag he a
4. Compounds of formula lll : 0 0 \ RT X NTO ge formula III . ZF : R N 6} ~~
. . 0 N R® . . N Pa i. . 5 R® wherein R', R3, R*, and X are as defined in formula I in claim 1, : and R%, R’, and R®, each and independently represents hydrogen, lower alkyl, lower—alkenyl, lower—alkynyl, lower alkyloxy, lower—alkenyloxy—lower alkymylexy, halogen, trifluoromethyl, rifluoromethoxylower-atkyithio; and pharmaceutically acceptable salts thereof.
5. Compounds of formula IV AMENDED SHEET
. ’ 0, © WY NY oo XN I R® formula IV Pp oo R NT, 0
~~. TT I wherein R, R3, R* R? and X are as defined in formula | above, and pharmaceutically acceptable salts thereof.
6. Compounds of formula | wherein R', R? R* and X are as defined in claim , 1, and wherein R? represents lower alkyl, and pharmaceutically acceptable salts thereof.
7. ~ 156 Compounds according to anyone of the claims 1 to 6 selected from the group consisting of oo 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(0-methoxyphenoxy)-2-(4- pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4- - pyridyl)-4-pyrimidinyl}-benzene sulfonamide ; | APAENDED SHEET | oo
S-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4- pyridyl)-4-pyrimidinyi]-2-pyridine sulfonamide S-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4- pyrimidinyl}-2-pyridine sulfonamide 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4- pyrimidinyflbenzene sulfonamide S-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(0-methoxyphenoxy)-2-(N- morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide S-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4- pyrimidinyl]-2-pyridine sulfonamide S-isopropyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5- (o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide 4-tert.-butyl-N-[6-(4-(2-pyrimidinyloxy)-2-butynyloxy)-5-(o- methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidi-nyl]-benzene sulfonamide 4-tert.-butyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5- (o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl}-benzene sulfonamide 2-pyridinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5- ) (2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2- methoxy-phenoxy)-2-methyl-pyrimidin-4-yloxy]-but-2-ynyl ester phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2- methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy}-but-2-yny ester 2-pyridinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5- (2-methoxy-phenoxy)-2-(N-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester
25 . 2-pyridinyl-carbamic acid 4-[6-(S-methyl-pyridine-2-sulfonylamino)-5-(2- methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyi ester 4-pyrazinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5- (2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester 4-tert.-butyl-N-[6-(4-methoxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-2- (2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide 5-isopropyl-N-[6-(4-methoxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2- (N-morpholino)-4-pyrimidinyl}-2-pyridine sulfonamide AMENDED SHEET oo dna RE RE Bday a Lee er
8. Pharmaceutical compositions for the treatment of disorders which are associated with a role of endothelin, especially circulatory disorders such as hypertension, ischaemia, vasospasm and angina pectoris and proliferative disorders such as cancer, containing a compound of any one of claims 1 to 7 and usual carrier materials and adjuvants.
9. Pharmaceutical compositions for the treatment of disorders which are associated with a role of endothelin, such as migraine, asthma or inflammatory disorders, containing a compound of any one of claims 1 to 7 and usual carrier materials and adjuvants. ,
10. The compounds of any one of the claims 1 to 7 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, . 15 especially circulatory disorders such as hypertension, ischaemia, vasospasm and angina pectoris, proliferative disorders such as cancer, migraine and . inflammatory disorders. : .
11. The compounds of any one of the claims 1 to 7 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, and require mixed ETa and ETpg blocking for treatment.
12. The compounds of any one of the claims 1 to 7 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, and require selective ET blocking for treatment.
13. The compounds of any one of the claims 1 to 7 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, and require selective ETg blocking for treatment.
14. The use of one or more compounds of any one of claims 1 to 7 as active ingredients for the production of pharmaceutical compositions for the
. ‘ PCT/EPO0/12743 treatment of disorders associated with a role of endothelin, especially circulatory disorders such as hypertension, ischaemia, vasospasm and angina pectoris and proliferative disorders such as cancer.
15. The use of one or more compounds of any one of claims 1 to 7 as active ingredients for the production of pharmaceutical compositions for the treatment of disorders associated with endothelin activities, such as migraine, asthma or inflammatory disorders.
16. A process for the manufacture of pharmaceutical compositions for the treatment of disorders associated with a role of endothelin containing one or more compounds as claimed in any one of claims 1 to 7 as active ingredients which process comprises mixing one or more active ingredient with pharmaceutically acceptable excipients in a manner known per se.
17. Use of the compounds of any one of the claims 1 to 7 in the manufacture of a medicament for the treatment of disorders which are associated with a role of endothelin, and require mixed ET, and ETg blocking.
18. Use of the compounds of any one of the claims 1 to 7 in the manufacture of a medicament for the treatment of disorders which are associated with a role of endothelin, and require selective ET, blocking.
19. Use of the compounds of any one of the claims 1 to 7 in the manufacture of a medicament for the treatment of disorders which are associated with a role of endothelin, and require selective ETg blocking.
20. The invention as hereinbefore described. AMENDED SHEET rr i i ; “ PCT/EPOO/12743 -85-
21. A compound according to any one of claims 1 to 6, substantially as herein described and illustrated.
22. A composition according to claim 8 or claim 9, substantially as herein described and illustrated. /
23. Use according to claim 14 or claim 15 or claim 17 or claim 19, substantially as herein described and illustrated.
24. A process according to claim 16, substantially as herein described and illustrated.
25. A new compound; a substance or composition for a new use in a method of treatment; a new use of a compound according to any of claims 1 to 7; a new composition; or a new process of manufacturing compositions, substantially as herein described. = AMENDED SHEET
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