2-PYRAZINONE DERIVATIVES FOR THE TREATMENT OF DISEASE OR CONDITION IN WHICH INHIBITION OF NEUTROPHIL ELASTASE ACTIVITY IS BENEFICIAL
First Claim
Patent Images
1. A compound of formula (I) whereinR1 represents hydrogen or C1-C6 alkyl;
- W represents a 5-membered heterocyclic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, wherein at least one of the ring carbon atoms may be optionally replaced by a carbonyl group; and
wherein the heterocyclic ring is optionally substituted by at least one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, CN, OH, NO2, C1-C3 alkyl substituted by one or more F atoms, C1-C3 alkoxy substituted by one or more F atoms, NR10R11, C≡
CR15, CONR16R17, CHO, C2-C4 alkanoyl, S(O)xR18 and OSO2R19;
R14 represents phenyl or a 6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms;
said ring being optionally substituted with at least one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, CN, OH, NO2, C1-C3 alkyl substituted by one or more F atoms, C1-C3 alkoxy substituted by one or more F atoms, NR12R13, C≡
CR30, CONR31R32, CHO, C2-C4 alkanoyl, S(O)pR33 and OSO2R34;
R10, R11, R12 and R13 independently represent H, C1-C6 alkyl, formyl or C2-C6 alkanoyl;
or the group —
NR10R11 or —
NR12R13 together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR26;
R15 and R30 independently represent H, C1-C3 alkyl or Si(CH3)3;
R18, R19, R33 and R34 independently represent H or C1-C3 alkyl;
said alkyl being optionally substituted by one or more F atoms;
R3 represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N;
said ring being optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, cyano, C1-C6 alkoxy, nitro, methylcarbonyl, NR35R36, C1-C3 alkyl substituted by one or more F atoms or C1-C3 alkoxy substituted by one or more F atoms;
R35 and R36 independently represent H or C1-C3 alkyl;
said alkyl being optionally further substituted by one or more F atoms;
R4 represents hydrogen or C1-C6 alkyl optionally substituted with at least one substituent selected from fluoro, hydroxyl and C1-C6 alkoxy;
X represents a single bond, O, NR24 or a group —
C1-C6 alkylene-Y—
, wherein Y represents a single bond, oxygen atom, NR24 or S(O)w; and
said alkylene being optionally further substituted by OH, halogen, CN, NR37R38, C1-C3 alkoxy, CONR39R40, CO2R66, SO2R41 and SO2NR42R43;
or R4 and X are joined together such that the group —
NR4X together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR44;
said ring being optionally substituted by C1-C6 alkyl or NR45R46;
said alkyl being optionally further substituted by OH;
either R5 represents a monocyclic ring system selected fromi) phenoxy,ii) phenyl,iii) a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur,iv) a saturated or partially unsaturated C3-C6 cycloalkyl ring, andv) a saturated or partially unsaturated 4- to 7-membered heterocyclic ring comprising at least one ring heteroatom selected from oxygen, S(O)r and NR20, wherein at least one of the ring carbon atoms may be optionally replaced by a carbonyl group,or R5 represents a bicyclic ring system in which the two rings are independently selected from the monocyclic ring systems defined in ii), iii), iv) and v) above, wherein the two rings are either fused together, bonded directly to one another or are separated from one another by a linker group selected from oxygen, S(O)t or C1-C6 alkylene optionally comprising one or more internal or terminal heteroatoms selected from oxygen, sulphur and NR27 and being optionally substituted by at least one substituent selected from hydroxyl, oxo and C1-C6 alkoxy,the monocyclic or bicyclic ring system being optionally substituted by at least one substituent selected from oxygen, CN, OH, C1-C6 alkyl, C1-C6 alkoxy, halogen, NR47R48, NO2, OSO2R49, CO2R50, C(═
NH)NH2, C(O)NR51R52, C(S)NR53R54, SC(═
NH)NH2, NR55C(═
NH)NH2, S(O)vR21, SO2NR56R57, C1-C3 alkoxy substituted by one or more F atoms and C1-C3 alkyl substituted by SO2R58 or by one or more F atoms;
said C1-C6 alkyl being optionally further substituted with at least one substituent selected from cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkylthio and —
C(O)NR22R23;
or R5 may also represent H;
R20 represents hydrogen, C1-C6 alkyl, C1-C6 alkylcarbonyl or C1-C6 alkoxycarbonyl;
R21 represents hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl;
said alkyl or cycloalkyl group being optionally further substituted by one or more substituents selected independently from OH, CN, C1-C3 alkoxy and CONR59R60;
R37 and R38 independently represent H, C1-C6 alkyl, formyl or C2-C6 alkanoyl;
R47 and R48 independently represent H, C1-C6 alkyl, formyl, C2-C6 alkanoyl, S(O)qR61 or SO2NR62R63;
said alkyl group being optionally further substituted by halogen, CN, C1-C4 alkoxy or CONR64R65;
R41 and R61 independently represent H, C1-C6 alkyl or C3-C6 cycloalkyl;
p is 0, 1 or 2;
q is 0, 1 or 2;
r is 0, 1 or 2;
t is 0, 1 or 2;
w is 0, 1 or 2;
x is 0, 1 or 2;
v is 0, 1 or 2;
R16, R17, R22, R23, R24, R26, R27, R31, R32, R39, R40, R42, R43, R44, R45, R46, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R62, R63, R64, R65 and R66 each independently represent hydrogen or C1-C6 alkyl;
or a pharmaceutically acceptable salt thereof.
1 Assignment
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Accused Products
Abstract
The invention provides compounds of formula
wherein R1, R3, R4, R5, R14, X and W are as defined in the specification and optical isomers, racemates and tautomers thereof, and pharmaceutically acceptable salts thereof; together with processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The compounds are inhibitors of human neutrophil elastase.
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Citations
17 Claims
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1. A compound of formula (I)
wherein R1 represents hydrogen or C1-C6 alkyl; -
W represents a 5-membered heterocyclic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, wherein at least one of the ring carbon atoms may be optionally replaced by a carbonyl group; and
wherein the heterocyclic ring is optionally substituted by at least one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, CN, OH, NO2, C1-C3 alkyl substituted by one or more F atoms, C1-C3 alkoxy substituted by one or more F atoms, NR10R11, C≡
CR15, CONR16R17, CHO, C2-C4 alkanoyl, S(O)xR18 and OSO2R19;R14 represents phenyl or a 6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms;
said ring being optionally substituted with at least one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, CN, OH, NO2, C1-C3 alkyl substituted by one or more F atoms, C1-C3 alkoxy substituted by one or more F atoms, NR12R13, C≡
CR30, CONR31R32, CHO, C2-C4 alkanoyl, S(O)pR33 and OSO2R34;R10, R11, R12 and R13 independently represent H, C1-C6 alkyl, formyl or C2-C6 alkanoyl;
or the group —
NR10R11 or —
NR12R13 together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR26;R15 and R30 independently represent H, C1-C3 alkyl or Si(CH3)3; R18, R19, R33 and R34 independently represent H or C1-C3 alkyl;
said alkyl being optionally substituted by one or more F atoms;R3 represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N;
said ring being optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, cyano, C1-C6 alkoxy, nitro, methylcarbonyl, NR35R36, C1-C3 alkyl substituted by one or more F atoms or C1-C3 alkoxy substituted by one or more F atoms;R35 and R36 independently represent H or C1-C3 alkyl;
said alkyl being optionally further substituted by one or more F atoms;R4 represents hydrogen or C1-C6 alkyl optionally substituted with at least one substituent selected from fluoro, hydroxyl and C1-C6 alkoxy; X represents a single bond, O, NR24 or a group —
C1-C6 alkylene-Y—
, wherein Y represents a single bond, oxygen atom, NR24 or S(O)w; and
said alkylene being optionally further substituted by OH, halogen, CN, NR37R38, C1-C3 alkoxy, CONR39R40, CO2R66, SO2R41 and SO2NR42R43;or R4 and X are joined together such that the group —
NR4X together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR44;
said ring being optionally substituted by C1-C6 alkyl or NR45R46;
said alkyl being optionally further substituted by OH;either R5 represents a monocyclic ring system selected from i) phenoxy, ii) phenyl, iii) a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, iv) a saturated or partially unsaturated C3-C6 cycloalkyl ring, and v) a saturated or partially unsaturated 4- to 7-membered heterocyclic ring comprising at least one ring heteroatom selected from oxygen, S(O)r and NR20, wherein at least one of the ring carbon atoms may be optionally replaced by a carbonyl group, or R5 represents a bicyclic ring system in which the two rings are independently selected from the monocyclic ring systems defined in ii), iii), iv) and v) above, wherein the two rings are either fused together, bonded directly to one another or are separated from one another by a linker group selected from oxygen, S(O)t or C1-C6 alkylene optionally comprising one or more internal or terminal heteroatoms selected from oxygen, sulphur and NR27 and being optionally substituted by at least one substituent selected from hydroxyl, oxo and C1-C6 alkoxy, the monocyclic or bicyclic ring system being optionally substituted by at least one substituent selected from oxygen, CN, OH, C1-C6 alkyl, C1-C6 alkoxy, halogen, NR47R48, NO2, OSO2R49, CO2R50, C(═
NH)NH2, C(O)NR51R52, C(S)NR53R54, SC(═
NH)NH2, NR55C(═
NH)NH2, S(O)vR21, SO2NR56R57, C1-C3 alkoxy substituted by one or more F atoms and C1-C3 alkyl substituted by SO2R58 or by one or more F atoms;
said C1-C6 alkyl being optionally further substituted with at least one substituent selected from cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkylthio and —
C(O)NR22R23;or R5 may also represent H; R20 represents hydrogen, C1-C6 alkyl, C1-C6 alkylcarbonyl or C1-C6 alkoxycarbonyl; R21 represents hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl;
said alkyl or cycloalkyl group being optionally further substituted by one or more substituents selected independently from OH, CN, C1-C3 alkoxy and CONR59R60;R37 and R38 independently represent H, C1-C6 alkyl, formyl or C2-C6 alkanoyl; R47 and R48 independently represent H, C1-C6 alkyl, formyl, C2-C6 alkanoyl, S(O)qR61 or SO2NR62R63;
said alkyl group being optionally further substituted by halogen, CN, C1-C4 alkoxy or CONR64R65;R41 and R61 independently represent H, C1-C6 alkyl or C3-C6 cycloalkyl; p is 0, 1 or 2; q is 0, 1 or 2; r is 0, 1 or 2; t is 0, 1 or 2; w is 0, 1 or 2; x is 0, 1 or 2; v is 0, 1 or 2; R16, R17, R22, R23, R24, R26, R27, R31, R32, R39, R40, R42, R43, R44, R45, R46, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R62, R63, R64, R65 and R66 each independently represent hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 16, 17)
6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylic acid methylamide; 6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylic acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide; 6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylic acid ethylamide; 6-[1-(4-cyano-phenyl)-1H-1,2,3-triazol-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydro-pyrazine-2-carboxamide; tert-butyl 2-[[6-[2-(4-cyanophenyl)pyrazol-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazine-2-carbonyl]amino]acetate; 6-[3-(4-chloro-phenyl)-3H-[1,2,3]triazol-4-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylic acid methylamide; 6-[2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylic acid methylamide; 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-(2-methoxyethyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide; 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-(2-hydroxy-1,1-dimethylethyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide; 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide; 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide; 6-[1-(6-cyanopyridin-3-yl)-1H-pyrazol-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide; 6-[1-(6-cyanopyridin-3-yl)-1H-pyrazol-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide; 6-[1-(5-cyanopyridin-2-yl)-1H-pyrazol-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide; 6-[1-(5-cyanopyridin-2-yl)-1H-pyrazol-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide; and 2-[[6-[2-(4-cyanophenyl)pyrazol-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazine-2-carbonyl]amino]acetic acid; and pharmaceutically acceptable salts of any one thereof.
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9. A process for the preparation of a compound of formula
(I) or a pharmaceutically acceptable salt thereof as defined in claim 1 which comprises, (a) reacting a compound of formula (II) wherein L1 represents a leaving group and R1, R3, R14 and W are as defined in claim 1, with a compound of formula wherein X, R4 and R5 are as defined in claim 1; - or
(b) reacting a compound of formula (IV) wherein Hal represents a halogen atom and X, R1, R3, R4 and R5 are as defined in claim 1, with a nucleophile R14—
W-M wherein R14 and W are as defined in claim 1 and M represents an organo-tin or organo boronic acid group;
or(c) when W represents thiazolyl or oxazolyl, reacting a compound of formula (V) wherein X, R1, R3, R4, R5 and R14 are as defined in claim 1, with thiourea or formamide respectively; and optionally after (a), (b) or (c) carrying out one or more of the following; converting the compound obtained to a further compound of the invention forming a pharmaceutically acceptable salt of the compound.
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10. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 or claim 8 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
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15. A method of treating, or reducing the risk of, a disease or condition in which inhibition of neutrophil elastase activity is beneficial which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1.
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16. A method of treating, or reducing the risk of, an inflammatory disease or condition which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1.
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17. The method according to claim 15 or claim 16, wherein the disease or condition is adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma including refractive asthma, rhinitis, psoriasis, ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis, systemic inflammatory response syndrome (SIRS), chronic wound, cancer, atherosclerosis, peptic ulcers, Crohn'"'"'disease, ulcerative colitis or gastric mucosal injury.
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11-14. -14. (canceled)
Specification