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US 6,720,322 B2Granted
Butyne diol derivatives
AssigneeActelion Pharamceuticals Ltd.
InventorsMartin Bolli, Christoph Boss, Martine Clozel, Walter Fischli
Life of this patent
Estimating the term…
Abstract
The present invention relates to novel butyne diol derivatives of the general formula I 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 I and especially their use as endothelin receptor antagonists.
Claims10
A compound of the formula I:
- wherein
- R1 represents phenyl;
- mono-, di- or tri-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkenyl, lower alkoxy, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynl, trifluoromethyl, cycloalkyl, or hydroxy-cycloalkyl;
- 2-pyridyl;
- 5-substituted 2-pyridyl substituted with lower alkyl;
- or a five-membered heteroaryl ring containing one or two nitrogen, sulfur or oxygen atoms;
- R1 represents hydrogen;
- lower alkyl;
- phenyl;
- mono-, di- or tri-substituted phenyl substituted with halogen, lower alkyl, lower alkoxy, lower alkyloxy-lower alkyl, or trifluoromethyl;
- or a five-membered heteroaryl ring contatining one or two nitrogen, sulfur or oxygen atoms and which may be mono- or di-substituted with halogen, lower alkyl, lower alkoxy, or tirfluoromethyl, 2-pyrimidyl;
- mono- or di-substituted 2-pyrimidyl substituted with lower alkyl, lower alkoxy, halogen, or trifluoromethyl;
- or a group of the formula, —C(A)—B—Ra,
- wherein
- A represents O or S;
- B represents NH;
- and
- Ra represents lower alkyl;
- cycloalkyl;
- phenyl;
- mono-, di- or tri-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkoxy, or trifluoromethyl;
- or a six-membered heteroaryl ring containing one or two nitrogen atoms and which may be mono- or di-substituted with halogen, lower alkyl, or lower alkyloxy;
- R3 represents phenyl;
- mono-, di- or tri-substituted with lower alkyl, lower alkenyl, lower alkyloxy, trifluoromethyl, halogen, or hydroxy;
- R4 represents hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, lower alkyloxy-lower alkyl;
- phenyl;
- mono- or di-substituted phenyl substituted with halogen, lower alkyl, lower alkoxy, lower alkylene or lower alkenylene or lower alkylenoxy or lower alklenedioxy forming with the phenyl ring a five- or six-membered ring;
- heteroaryl;
- or heterocyclyl;
- and
- X represents oxygen;
- sulfur;
- or a bond;
- and
- pure enantiomers, enantiomerically pure diastereomers, mixtures of diastereomers, diastereomeric recemates, mixtures of diastereomeric racemates and pharmaceutically acceptable salts thereof.
32 more elements
A compounds of formula II:
- wherein
- R2 represents hydrogen;
- lower alkyl;
- phenyl;
- mono-, di- or tri-substituted phenyl substituted with halogen, lower alkyl, lower alkoxy, lower alkyloxy-lower alkyl, or trifluoromethyl;
- or a five-membered heteroaryl ring containing one or two nitrogen, sulfur or oxygen atoms and which may be mono- or di-substituted with halogen, lower alkyl, or lower alkoxy;
- benzyl;
- mono- or di-substituted benzyl substituted with halogen, lower alkyl, lower alkyl, or trifluoromethyl, 2-pyrimidyl;
- mono- or di-substituted 2-pyrimidyl substituted with lower alkyl, lower alkoxy, halogen, or trifluoromethyl;
- or a group of the formula, —C(A)—B—Ra,
- wherein
- A represents O or S;
- B represents NH;
- and
- Ra represents lower alkyl;
- cycloalkyl;
- phenyl;
- mono-, di- or tri-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkoxy, or trifluoromethyl;
- or a six-membered heteroaryl ring containing one or two nitrogen atoms and which may be mono- or di-substituted with halogen, lower alkyl, or lower alkyloxy;
- R4 represent hydrogen, halogen, trifluoromethyl, lower alkyloxy, lower alkylthio, lower alkyloxy-lower alkyl;
- phenyl;
- mono- or di-substituted phenyl substituted with halogen, lower alkyl, lower alkoxy, lower alkylene or lower alkenylene or lower alkylenoxy or lower alkylenedioxy forming with the phenyl ring a five- or six-membered ring;
- heteroaryl;
- or heterocyclycl;
- and
- X represents oxygen;
- sulfur;
- or a bond;
- and
- R5 represents lower alkyl, and
- pharmaceutically acceptable salts of compounds of formula II.
28 more elements
A compound of formula III:
- wherein
- R1 represents phenyl;
- mono-, di- or tri-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynyl, trifluoromethyl, cycloalkyl, or hydroxy-cycloalkyl;
- 2-pyridyl;
- 5-substituted 2-pyridyl substituted with lower alkyl;
- or a five-member heteroaryl ring containing one or two nitrogen, sulfur oxygen atoms;
- R3 represents phenyl;
- mono-, di- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkyloxy, trifluoromethyl, halogen, or hydroxy;
- R4 represents hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, lower alkyloxy-lower alkyl;
- phenyl;
- mono- or di-substituted phenyl substituted with halogen, lower alkyl, lower alkoxy, lower alkylene or lower alkenylene or lower alkylenoxy or lower alkylenedioxy forming with the phenyl ring a five- or six-membered ring;
- heteroaryl;
- or heterocyclyl;
- and
- X represent oxygen;
- sulfur;
- or a bond;
- and
- R6, R7, and R8, each and independently represents hydrogen, lower alkyl, lower alkyloxy, halogen, or trifluoromethyl;
- and
- pharmaceutically acceptable salts thereof.
18 more elements
A compound of formula IV:
- wherein
- R1 represents phenyl;
- mono-, di- or tri-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynyl, trifluoromethyl, cycloalkyl, or hydroxy-cycloalkyl;
- 2-pyridyl;
- 5-substituted 2-pyridyl substituted with lower alkyl;
- or a five-membered heteroaryl ring containing one or two nitrogen, sulfur or oxygen atoms;
- Ra represents lower alkyl;
- cycloalkyl;
- phenyl;
- mono-, di- or tri-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkoxy, or trifluoromethyl;
- or a six-membered heteroaryl ring containing one or two nitrogen atoms and which may be mono- or di-substituted with halogen, lower alkyl, or lower alkyloxy;
- R3 represents phenyl;
- mono-, di- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkyloxy, trifluoromethyl, halogen, or hydroxy;
- R4 represents hydrogen, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, lower alkyloxy-lower alkyl;
- phenyl;
- mono- or di-substituted phenyl substituted with halogen, lower alkyl, lower alkoxy, lower alkylene or lower alkenylene or lower alkylenoxy or lower alklenedioxy forming with the phenyl ring a five- or six-membered ring;
- heteroaryl;
- or heterocyclyl;
- and
- X represents oxygen;
- sulfur;
- or a bond;
- and
- pharmaceutically acceptable salts thereof.
21 more elements
A compound selected from:
- 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-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;
- 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)4-pyrimidinyl]-2-pyridine sulfonamide;
- 5-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-pyrimidinyl]benzene sulfonamide;
- 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide;
- 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide;
- 5-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-pyrimidinyl]-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-morpholin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl 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;
- 2-pyridinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl 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-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide;
- or
- 5-isopropyl-N-[6-(4-methoxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide.
15 more elements
Dependencies are inferred from the claim text.