Author: claimsbot

1. A medicament comprising an EP4 receptor antagonist and a PDE4 inhibitor of formula 1
wherein:
X is SO or SO2;
R1 is H, C1-6-alkyl;
R2 is H or a group selected from C1-10-alkyl and C2-6-alkenyl, each optionally substituted by one or more groups selected from halogen and C1-3-fluoroalkyl or optionally substituted by one or more groups selected from OR2.1, COOR2.1, CONR2.2R2.3, SR2.1, SO\u2014R2.1, SO2\u2014R2.1, C6-10-aryl, a het, a hetaryl, a mono- or bicyclic C3-10-cycloalkyl, CH2\u2014NR2.2R2.3, and NR2.2R2.3, each optionally be substituted by one or more groups selected from OH, halogen, OR2.1, oxo, CF3, CHF2, CH2F, C1-6-alkyl, C1-6-alkanol, C6-10-aryl, COOR2.1, CH2\u2014NR2.2R2.3, and NR2.2R2.3,
wherein R2.1 is H or a group selected from C1-6-alkyl, C1-6-alkanol, C1-3-haloalkyl, mono- or bicyclic C3-10-cycloalkyl, C6-10-aryl-C1-6-alkylene, mono- or bicyclic hetaryl-C1-6-alkylene, het-C1-6-alkylene, C3-10-cycloalkyl-C1-6-alkylene, a mono- or bicyclic C6-10-aryl, a hetaryl, and a het, each optionally substituted by one or more groups selected from OH, O\u2014(C1-3-alkyl), halogen, C1-6-alkyl, and C6-10-aryl,
wherein R2.2 and R2.3 are independently H or a group selected from C1-6-alkyl, mono- or bicyclic C3-10 cycloalkyl, C6-10-aryl-C1-6-alkylene, hetaryl-C1-6-alkylene, mono- or bicyclic C6-10-aryl, het, hetaryl, CO\u2014NH2, CO\u2014NHCH3, CO\u2014N(CH3)2, SO2\u2014(C1-C2-alkyl), CO\u2014R2.1, and COOR2.1, each optionally substituted by one or more groups selected from OH, halogen, C1-6-alkyl, C6-10-aryl, and COOR2.1,

wherein
het is a three- to eleven-membered, mono- or bicyclic, saturated or partly saturated, optionally annellated or optionally bridged heterocyclic group, which contains 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O,
hetaryl is a five- to eleven-membered, mono- or bicyclic, optionally annellated heteroaryl, which contains 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O, and
cycloalkyl is saturated or partly saturated, or

R2 is a mono- or polycyclic C3-10 cycloalkyl optionally singly or multiply bridged by C1-3-alkyl groups and which is optionally substituted by a group selected from branched or unbranched C1-6-alkanol, C1-3-fluoroalkyl, C1-3-alkylene-OR2.1, OR2.1, COOR2.1, SO2\u2014NR2.2R2.3, het, C6-10-aryl, C1-6-alkyl, C6-10-aryl-C1-6-alkylene, hetaryl-C1-6-alkylene, mono- or bicyclic C3-10 cycloalkyl, and NR2.2R2.3, each optionally substituted by one or more groups selected from OH, OR2.1, oxo, halogen, CF3, CHF2, CH2F, C1-6-alkyl, C6-10-aryl, and NR2.2R2.3, or
R2 is a mono- or polycyclic C6-10-aryl optionally substituted by OH, SH, or halogen or by one or more groups selected from OR2.1, COOR2.1, NR2.2R2.3, CH2\u2014NR2.2R2.3, C3-10-cycloalkyl, het, \u2014C1-6-alkyl, C1-3-fluoroalkyl, C6-10-aryl-C1-6-alkylene, het-C1-6-alkylene, hetaryl-C1-6-alkylene, C6-10-aryl, SO2\u2014CH3, SO2\u2014CH2CH3, and SO2\u2014NR2.2R2.3, each optionally substituted by one or more selected from OH, OR2.1, CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C1-6-alkyl, C6-10-aryl, and NR2.2R2.3, or
R2 is a group selected from het and hetaryl, each optionally substituted by one or more groups selected from halogen, OH, oxo, CF3, CHF2 and CH2F or by one or more groups selected from OR2.1, C1-3-alkylene-OR2.1, SR2.1, SO\u2014R2.1 and SO2\u2014R2.1, COOR2.1, COR2.1, C1-6-alkanol, C3-10-cycloalkyl, C6-10-aryl, C1-6-alkyl, C6-10-aryl-C1-6-alkylene, hetaryl-C1-6-alkylene, het, hetaryl, C1-3-alkylene-OR2.1, and NR2.2R2.3, each optionally substituted by one or more groups selected from OH, OR2.1, oxo, halogen, CF3, CHF2, CH2F, C1-6-alkyl, C6-10-aryl, and NR2.2R2.3, or
wherein
NR1R2 together are a heterocyclic four- to seven-membered ring optionally bridged, which contains 1, 2, or 3 heteroatoms selected from N, O, and S and which is optionally substituted by one or more groups selected from OH, OR2.1, C1-3-alkylene-OR.1, oxo, halogen, C1-6-alkyl, C6-10-aryl, COOR2.1, CH2\u2014NR2.2\u2014COO\u2014R2.1, CH2\u2014NR2.2\u2014CO\u2014R2.1, CH2\u2014NR2.2\u2014CO\u2014CH2\u2014NR2.2R2.3, CH2\u2014NR2.2\u2014SO2\u2014C1-3-alkyl, CH2\u2014NR2.2\u2014SO2\u2014NR2.2R2.3, CH2\u2014NR2.2\u2014CO\u2014NR2.2R2.3, CO\u2014NR2.2R2.3, CH2\u2014NR2.2R2.3, and NR2.2R2.3, and
R3 is a group selected from a het and a hetaryl, each optionally substituted by one or more groups selected from halogen, C1-3-fluoroalkyl, CN, OH, oxo, \u2014C1-6-alkyl, \u2014O\u2014R2.1, \u2014COOR2.1, SO\u2014R2.1, SO2\u2014R2.1, C6-10-aryl, C1-3-alkylene-C6-10-aryl, \u2014C1-3-alkylene-NR2.2R2.3, \u2014NR2.2R2.3, a C3-10-cycloalkyl, a C1-3-alkylene-C3-10-cycloalkyl, a het, a hetaryl, C1-3-alkylene-hetaryl, and C1-3-alkylene-het, each optionally substituted by one or more groups selected from OH, halogen, \u2014C1-3-fluoroalkyl, C1-6-alkyl, C6-10-aryl, \u2014COO(C1-3-alkyl), and O\u2014(C1-3-alkyl).
2. The medicament according to claim 1, wherein the EP4-receptor antagonist is an EP4-specific antagonist.
3. The medicament according to claim 1, the EP4-receptor antagonist is:
N-{4-(5,9-diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo3,4-gquinolin-7-yl)-3-methylbenzylsulphonyl}-2-(2-methoxyphenyl)acetamide (2.1);
5-butyl-2,4-dihydro-4-2\u2032-N-(3-methyl-2-thiophene-carbonyl)sulphamoylbiphenyl-4-ylmethyl-2-(2-trifluoromethyl)phenyl-1,2,4-triazol-3-one (2.2);
(4-{(1S)-1-({5-chloro-2-(4-fluorophenyl)oxyphenyl}carbonyl)aminoethyl}benzoic acid (2.3);
N-({2-4-(2-ethyl-4,6-dimethyl-1H-imidazo4,5-cpyridin-1-yl)phenylethyl}-amino)carbonyl-4-methylbenzene sulphonamide (2.4);
4-4-(5-methoxy-2-pyridinyl)phenoxymethyl-5-methyl-N-(2-methylphenyl)sulphonyl-2-furancarboxamide (2.5);
methyl-11\u03b1,15\u03b1-dihydroxy-16-(3-methoxymethylphenyl)-9-oxo-17,18,19,20-tetranor-5-thia-13(E) prostanoate (2.6);
4-cyano-2-2-(4-fluoro-1-naphthalenyl)-1-oxopropylamino-benzenebutanoic acid (2.7); or
N-{2-4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzofisoindol-2-yl)phenylacetyl}-benzene sulphonamide (2.8).
4. The medicament according to claim 1, wherein:
X is SO;
R1 is H;
R2 is H or C1-6-alkyl optionally be substituted by one or more groups selected from F, CF3, CHF2, or CH2F or optionally substituted by one or more groups selected from OR2.1, COOR2.1, CONR2.2R2.3, SR2.1, SO\u2014R2.1, SO2\u2014R2.1, phenyl, a het, a hetaryl, a monocyclic C3-7-cycloalkyl, CH2\u2014NR2.2R2.3, and NR2.2R2.3, each optionally be substituted by one or more groups selected from OH, F, Cl, Br, CF3, CHF2, CH2F, OR2.1, oxo, methyl, ethyl, propyl, isopropyl, C1-2-alkanol, phenyl, COOR2.1, CH2\u2014NR2.2R2.3, and NR2.2R2.3,
wherein R2.1 is H or a group selected from methyl, ethyl, propyl, isopropyl, monocyclic C3-7 cycloalkyl, phenyl-C1-2-alkylene, hetaryl-C1-2-alkylene, het-C1-2-alkylene, C3-7-cycloalkyl-C1-2-alkylene, phenyl, a hetaryl, and a het, each optionally substituted by one or more groups selected from OH, halogen, methyl, ethyl, propyl, isopropyl, O-methyl, O-ethyl, O-propyl, O-isopropyl, and phenyl,
wherein R2.2 and R2.3 are each independently H or a group selected from methyl, ethyl, propyl, isopropyl, monocyclic C3-7-cycloalkyl, phenyl-C1-3-alkylene, hetaryl-C1-3-alkylene, phenyl, het, hetaryl, CO\u2014NH2, CO\u2014NHCH3, CON(CH3)2, SO2\u2014(C1-C2-alkyl), CO\u2014R2.1, and COOR2.1, each optionally substituted by one or more groups selected from OH, F, Cl, Br, methyl, ethyl, propyl, isopropyl, phenyl, and COOR2.1,

wherein
het is a three- to seven-membered, monocyclic, saturated or partly saturated heterocyclic group which contains 1, 2, or 3 heteroatoms independently selected from N, S, or O, and wherein
hetaryl is a five- to six-membered, monocyclic, aromatic heteroaryl, which contains 1, 2, or 3 heteroatoms independently selected from N, S, or O, and
cycloalkyl is saturated or partly saturated, or

R2 is a monocyclic C3-7 cycloalkyl optionally substituted by a group selected from branched or unbranched C1-2-alkanol, C1-3-fluoroalkyl, C1-3-alkylene-OR2.1, OR2.1, COOR2.1, SO2\u2014NR2.2R2.3, het, methyl, ethyl, propyl, isopropyl, phenyl, phenyl-C1-2-alkylene, hetaryl-C1-2-alkylene, monocyclic C3-7 cycloalkyl, and NR2.2R2.3, each optionally substituted by one or more groups selected from OH, OR2.1, oxo, halogen, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, phenyl, and NR2.2R2.3, or
R2 is a phenyl optionally substituted by OH, SH, F, Cl, or Br or by one or more groups selected from OR2.1, COOR2.1, NR2.2R2.3, CH2\u2014NR2.2R2.3, C3-7-cycloalkyl, het, methyl, ethyl, propyl, isopropyl, CF3, CHF2, CH2F, phenyl-C1-2-alkylene, het-C1-2-alkylene, hetaryl-C1-2-alkylene, phenyl, SO2\u2014CH3, SO2\u2014CH2CH3, and SO2\u2014NR2.2R2.3, each optionally substituted by one or more or several groups selected from OH, OR2.1, oxo, F, Cl, Br, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, phenyl, and NR2.2R2.3, or
R2 is a group selected from a het and a hetaryl, each optionally substituted by one or more groups selected from F, Cl, Br, OH, oxo, CF3, CHF2, CH2F and SH or by one or more groups selected from OR2.1, C1-3-alkylene-OR2.1, SR2.1, SO\u2014R2.1, SO2\u2014R2.1, COOR2.1, COR2.1, C1-2-alkanol, C3-10-cycloalkyl, phenyl, methyl, ethyl, propyl, isopropyl, phenyl-C1-2-alkylene, hetaryl-C1-2-alkylene, het, hetaryl, C1-2-alkanol, and NR2.2R2.3, each optionally substituted by one or more groups selected from OH, OR2.1, oxo, F, Cl, Br, CF3, CHF2, CH2F, C1-6-alkyl, phenyl, and NR2.2R2.3, and
R3 is a group selected from a saturated or partly saturated, monocyclic three- to seven-membered heterocyclic group, a saturated or partly saturated, bicyclic five- to eleven-membered heterocyclic group, a monocyclic, five- to six-membered heteroaryl, and a bicyclic, seven- to eleven-membered heteroaryl, which contains in each case 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, each optionally substituted in each case by one or more groups selected from halogen, C1-3-fluoroalkyl, CN, OH, oxo, C1-6 alkyl, \u2014O\u2014R2.1, \u2014COOR2.1, SO\u2014R2.1, SO2\u2014R2.1, C6-10-aryl, C1-3-alkylene-C6-10-aryl, \u2014C1-3-alkylene-NR2.2R2.3, \u2014NR2.2R2.3, a C3-10-cycloalkyl, a C1-3-alkylene-C3-10-cycloalkyl, het, a hetaryl, C1-3-alkylene-hetaryl, and C1-3-alkylene-het, each optionally substituted by one or more groups selected from OH, halogen, \u2014C1-3-fluoroalkyl, C1-6-alkyl, C6-10-aryl, \u2014COO(C1-3-alkyl), and O\u2014(C1-3-alkyl).
5. The medicament according to claim 4, wherein:
R2 is a group according to formula 3
R5 is OH or NH2, and
R4 is a group selected from C1-4-alkyl, hetaryl, and phenyl, each optionally substituted by one or more groups selected from OH, F, Br, OR2.1, oxo, methyl, ethyl, C1-2-alkanol, phenyl, COOR2.1, CH2\u2014NR2.2R2.3, and NR2.2R2.3.
6. The medicament according to claim 5, wherein:
R4 is methyl, ethyl, propyl, or isopropyl.
7. The medicament according to claim 4, wherein:
R2 is a monocyclic three, four, five, six, or seven-membered cycloalkyl ring optionally substituted in the spiro position by a group selected from \u2014CH2\u2014OR2.1, branched or unbranched C2-6-alkylene-OR2.1, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, \u2014CF3, CHF2, CH2F, and C2-4-fluoroalkyl, and
R2.1 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
8. The medicament according to claim 4, wherein:
R2 is a phenyl optionally substituted in one or both meta positions by one or more groups selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, F, Cl, Br, OH, OR2.1, COOR2.1, CF3, CHF2, CH2F, NH2, and N(CH3)2, wherein R2.1 is H, methyl or ethyl.
9. The medicament according to claim 4, wherein:
R2 is a monocyclic, saturated three-, four-, five-, six-, or seven-membered heterocyclic group with 1, 2, or 3 heteroatoms selected in each case from N, O, and S, each optionally substituted by one or more groups selected from fluorine, chlorine, bromine, CF3, CHF2, CH2F, OH, oxo, and SH or by one or more groups selected from OR2.1, C1-3-alkylene-OR2.1, SR2.1, SO\u2014R2.1, SO2\u2014R2.1, COOR2.1, COR2.1, C1-6-alkanol, C3-10-cycloalkyl, phenyl, C1-6-alkyl, phenyl-C1-6-alkylene, hetaryl-C1-6-alkylene, het, hetaryl, and NR2.2R2.3, each optionally substituted by one or more groups selected from OH, OR2.1, oxo, F, Cl, CF3, CHF2, CH2F, C1-6-alkyl, phenyl, and NR2.2R2.3.
10. The medicament according to claim 9, wherein:
R2 is a monocyclic, saturated, six-membered heterocyclic group with a heteroatom selected from N, O, and S, optionally substituted by one or more groups selected from F, Cl, Br, CF3, CHF2, CH2F, OH, oxo, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, and ethoxy.
11. The medicament according to claim 10, wherein:
R2 is a group selected from piperidine or tetrahydropyran, each optionally substituted by one or more groups selected from F, Cl, Br, OH, CF3, CHF2, CH2F, NH2, NHCH3, N(CH3)2, oxo, methyl, and methoxy.
12. The medicament according to claim 10, wherein:
R3 is a monocyclic five- or six-membered heteroaryl ring optionally substituted by one or more groups selected from F, Cl, Br, CF3, CHF2, CH2F, CN, OH, methyl, ethyl, propyl, isopropyl, \u2014O-methyl, O-ethyl, \u2014COOmethyl, \u2014COOethyl, SO2\u2014(CH3), SO\u2014(CH3), SO2\u2014(CH2CH3), SO\u2014(CH2CH3), phenyl, -methylene-phenyl, -ethylene-phenyl, \u2014NH2, \u2014NH(CH3), N(CH3)2, -methylene-NH2, -methylene-NH(CH3), -methylene-N(CH3)2, a C3-6-cycloalkyl, a methylene-C3-6-cycloalkyl, a saturated or partly saturated, five- to six-membered heterocyclic group, a five- or six-membered heteroaryl, -methylene-hetaryl, and -methylene-het, each optionally substituted by one or more groups selected from OH, F, Cl, Br, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, phenyl, \u2014COO(CH3), \u2014O-methyl, and \u2014O-ethyl.
13. The medicament according to claim 10, wherein:
R3 is a bicyclic 9- to 11-membered saturated, unsaturated or partly saturated heterocyclic group, each optionally substituted by one or more groups selected from F, Cl, Br, CF3, CHF2, CH2F, CN, OH, -methyl, ethyl, propyl, isopropyl, \u2014O-methyl, O-ethyl, \u2014COOmethyl, \u2014COOethyl, SO2\u2014(CH3), SO\u2014(CH3), SO2\u2014(CH2CH3), SO\u2014(CH2CH3), phenyl, -methylene-phenyl, -ethylene-phenyl, \u2014NH2, \u2014NH(CH3), N(CH3)2, -methylene-NH2, -methylene-NH(CH3), -methylene-N(CH3)2, a \u2014C3-6-cycloalkyl, a -methylene-C3-6-cycloalkyl, a saturated, partly unsaturated or unsaturated 5- to 6-membered heterocyclic group, a 5- to 6-membered heteroaryl, -methylene-hetaryl, and -methylene-het, each optionally substituted by one or more groups selected from OH, F, Cl, Br, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, phenyl, \u2014COO(CH3), \u2014O-methyl, and \u2014O-ethyl.
14. The medicament according to claim 12, wherein:
R3 is a monocyclic five- or six-membered heteroaryl ring selected from pyrrole, pyrazole, furan, thiophene, thiazole, imidazole, oxazole, pyridazine, pyrimidine, pyrazine, thiadiazole, oxadiazole, triazine, isoxazole, isothiazole, and pyridine, each optionally substituted by one or more groups selected from F, Cl, Br, CF3, CHF2, CH2F, CN, OH, -methyl, ethyl, propyl, isopropyl, \u2014O-methyl, O-ethyl, \u2014COOmethyl, \u2014COOethyl, SO2\u2014(CH3), SO2\u2014(CH2CH3), phenyl, -methylene-phenyl, -ethylene-phenyl, \u2014NH2, \u2014NH(CH3), N(CH3)2, -methylene-NH2, -methylene-NH(CH3), -methylene-N(CH3)2, a C3-6-cycloalkyl, a methylene-C3-6-cycloalkyl, a het, a hetaryl, -methylene-hetaryl, and -methylene-het, each optionally substituted by one or more groups selected from OH, F, Cl, Br, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, phenyl, \u2014COO(CH3), \u2014O-methyl, and \u2014O-ethyl.
15. The medicament according to claim 13, wherein:
R3 is a bicyclic 9- to 11-membered heterocyclic group selected from benzoxazole, benzodioxole, dihydrobenzodioxin, benzodioxin, benzisoxazole, benzothiazole, benzisothiazole, thienopyrimidine, furopyrimidine, thienopyridine, furopyridine, indole, isoindole, quinoxaline, naphthyridine, pyridopyrazine, pyridopyrimidine, quinoline, isoquinoline, benzoimidazole, 6,7,8,9-tetrahydro-5H-pyrazino2,3-dazepin, benzothiophene, benzofuran, quinazoline, indazole, isobenzofuran, and pteridine, each optionally substituted by one or more groups selected from F, Cl, Br, CF3, CHF2, CH2F, CN, OH, -methyl, ethyl, propyl, isopropyl, \u2014O-methyl, O-ethyl, \u2014COOmethyl, \u2014COOethyl, SO2\u2014(CH3), SO2\u2014(CH2CH3), phenyl, -methylene-phenyl, -ethylene-phenyl, \u2014NH2, \u2014NH(CH3), N(CH3)2, -methylene-NH2, -methylene-NH(CH3), -methylene-N(CH3)2, a C3-6-cycloalkyl, a methylene-C3-6-cycloalkyl, a het, a hetaryl, -methylene-hetaryl, and -methylene-het, each optionally substituted by one or more groups selected from OH, F, Cl, Br, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, phenyl, \u2014COO(CH3), \u2014O-methyl, and \u2014O-ethyl.
16. The medicament according to claim 1, wherein:
R1 is H,
R2 is a group selected from
R3 is a group selected from
17. The medicament according to claim 1, wherein the PDE4 inhibitor of general formula 1 is selected from:
1.1 (3-fluorophenyl)-5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl-amine;
1.2 (R)-3-methyl-2-5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino-butan-1-ol;
1.3 2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl-(3-fluorophenyl)-amine;
1.4 2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl-(tetrahydropyran-4-yl)-amine;
1.5 (R)-2-{2-4-(6-chloropyridazin-3-yl)-piperazin-1-yl-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino}-3-methylbutan-1-ol;
1.6 {2-4-(6-chloropyridazin-3-yl)-piperazin-1-yl-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl}-(3-fluorophenyl)-amine;
1.7 (R)-2-2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino-3-methylbutan-1-ol;
1.8 (1-{2-4-(5-chloropyridin-2-yl)-piperazin-1-yl-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino}-cyclopropyl)-methanol;
1.9 {2-4-(5-chloropyridin-2-yl)-piperazin-1-yl-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl}-(tetrahydropyran-4-yl)-amine;
1.10 {2-4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-cpyrimidin-4-yl}-(3-fluorophenyl)-amine;
1.11 6-chloro-4-{4-4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-2-yl-piperazin-1-yl}-pyridazin-3-ol;
1.12 2-{4-6-(2-ethoxyethoxy)-pyridazin-3-yl-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl)-(3-fluorophenyl)-amine;
1.13 (3-fluorophenyl)-5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl-amine;
1.14 (R)-2-{2-4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino}-3-methylbutan-1-ol;
1.15 (R)-2-{2-4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino2,3-dazepin-2-yl)-piperazin-1-yl-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino}-3-methylbutan-1-ol;
1.16 (R)-3-methyl-2-5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino-butan-1-ol;
1.17 4-{4-4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-2-yl-piperazin-1-yl}-pyridin-2-ol;
1.18 (R)-3-methyl-2-5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino-butan-1-ol;
1.19 (R)-2-{2-4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino}-3-methylbutan-1-ol;
1.20 6-chloro-4-{4-4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-2-yl-piperazin-1-yl}-pyridazin-3-ol;
1.21 (R)-2-(2-{4-6-(2-ethoxyethoxy)-pyridazin-3-yl-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino)-3-methylbutan-1-ol;
1.22 (R)-3-methyl-2-5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino-butan-1-ol;
1.23 {1-5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino-cyclopropyl}-methanol;
1.24 {1-5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino-cyclopropyl}-methanol;
1.25 (S)-1-methyl-5-5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino-piperidin-2-one;
1.26 {2-4-(5-fluoro-1-methyl-1H-benzoimidazol-2-yl)-piperazin-1-yl-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl}-(tetrahydropyran-4-yl)-amine;
1.27 5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl-(tetrahydropyran-4-yl)-amine;
1.28 (3-fluorophenyl)-{2-4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl}-amine;
1.29 {2-4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino2,3-dazepin-2-yl)-piperazin-1-yl-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl}-(3-fluorophenyl)-amine;
1.30 (3-fluorophenyl)-5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl-amine;
1.31 4-{4-4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-2-yl-piperazin-1-yl}-pyridin-2-ol;
1.32 (3-fluorophenyl)-5-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl-amine;
1.33 (3-fluorophenyl)-(2-{4-4-(4-fluorophenyl)-thiazol-2-yl-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl)-amine;
1.34 2-(4-benzodisoxazol-3-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-yl-(3-fluorophenyl)-amine;
1.35 (R)-2-(2-{4-4-(4-fluorophenyl)-thiazol-2-yl-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino)-3-methylbutan-1-ol; and
1.36 (R)-2-2-(4-benzodisoxazol-3-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5\u03bb4-thieno3,2-dpyrimidin-4-ylamino-3-methylbutan-1-ol.
18. The medicament according to claim 1, wherein the PDE4 inhibitor is contained in a daily dose of 0.01 mg to 50 mg.
19. The medicament according to claim 1, wherein the EP4-receptor antagonist is used in a daily dose of 0.001 to 100 mgkg body weight.
20. The medicament according to claim 1, wherein the EP4-receptor antagonist and the PDE4 inhibitor are used in a ratio by weight of 1:1 to 200:1.

The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.

1. A solid separator for separating solid particles from a mixture containing the particles and a liquid, the solid separator comprising:
a collecting vessel adapted to receive at a filling position the mixture containing the particles and the liquid, wherein the liquid does not drain out of the collecting vessel at the filling position, the collecting vessel having an impermeable bottom wall, being mounted in at least one bearing such as to be rotatable about an axis of rotation, and being rotatable from the filling position to a liquid run-off position where the liquid is able to be at least partially drained out of the collecting vessel, and wherein the collecting vessel is adapted to be moveable from at least one of the liquid run-off position and the filling position to a solid discharge position;
a device for producing a magnetic field to at least partially retain the particles in the collecting vessel at the liquid run-off position; and
a solid-holding container disposed below the collecting vessel for receiving the solid matter discharged from the collecting vessel.
2. The solid separator of claim 1, wherein the collecting vessel is rotatable from at least one of the liquid run-off position and the filling position into the solid discharge position.
3. The solid separator of claim 1, wherein separated solid matter is dischargeable from the collecting vessel at the solid discharge position by the effects of gravitational force.
4. The solid separator of claim 1, wherein the device for producing a magnetic field comprises at least one fixed magnet element.
5. The solid separator of claim 1, wherein the device for producing the magnetic field comprises at least one permanent magnet element.
6. The solid separator of claim 1, wherein the collecting vessel is formed from a non-magnetic material.
7. The solid separator of claim 1, further comprising a heating device for heating the collecting vessel.
8. The solid separator of claim 7, wherein the heating device is fixed.
9. The solid separator of claim 7, wherein the collecting vessel comprises at least one side wall which is adjacent to the heating device in each position of the collecting vessel.
10. The solid separator of claim 7, wherein the heating device comprises a heat exchanger.
11. A liquid medium processing plant, comprising:
at least one solid separator with a collecting vessel adapted to receive at a filling position a liquid medium containing solid particles and a liquid, the collecting vessel being movable from the filling position to a liquid run-off position where the liquid is able to be at least partially drained out of the collecting vessel;
a device for producing a magnetic field to at least partially retain the particles in the collecting vessel at the liquid run-off position; and
at least one vaporizing device for at least partially vaporizing the liquid that has drained out of the solid separator.
12. The liquid medium processing plant of claim 11, wherein the solid separator comprises a heat exchanger and vapour from the vaporizing device is supplied at least partially to the heat exchanger.
13. The liquid medium processing plant of claim 11 further comprising at least one magnetic separator to increase the concentration of solid particles in the liquid medium being processed.
14. A solid separator for separating solid particles from a mixture containing the particles and a liquid, the solid separator comprising:
a collecting vessel adapted to receive at a filling position the mixture containing the particles and the liquid, the collecting vessel being movable from the filling position to a liquid run-off position where the liquid is able to be at least partially drained out of the collecting vessel,
a heating device for heating the collecting vessel, wherein the heating device comprises a heat exchanger comprising a vapour flowing therethrough; and
a device for producing a magnetic field to at least partially retain the particles in the collecting vessel at the liquid run-off position.
15. A solid separator for separating solid particles from a mixture containing the particles and a liquid, the solid separator comprising:
a collecting vessel adapted to receive at a filling position the mixture containing the particles and the liquid, the collecting vessel being movable from the filling position to a liquid run-off position where the liquid is able to be at least partially drained out of the collecting vessel, the collection vessel further comprising:
a run-off wall along which the liquid drains out of the collecting vessel in the liquid run-off position; and
a wall disposed opposite the run-off wall, whereby, in the filling position of the collecting vessel, an average gradient of the run-off wall is less than an average gradient of the wall opposite the run-off wall; and

a device for producing a magnetic field to at least partially retain the particles in the collecting vessel at the liquid run-off position.
16. The solid separator of claim 15, further comprising a gutter wall aligned transversely relative to the run-off wall and arranged on an edge of the run-off wall.

1. An adjustable knucklesteer arm assembly for adjusting a toe curve setting for a wheel of a vehicle having a suspension, comprising:
a knuckle connectable to the wheel; and
a steer arm pivotally connected to the knuckle at a pivot and connectable to a tie rod of the suspension;
wherein one of the knuckle and the steer arm has a slot formed therein and the other has a connector member which engages the slot; and
wherein the steer arm is angularly adjustable with respect to the knuckle via adjustable engagement of the connector member along the slot to enable the toe curve setting for the wheel to be adjusted.
2. The adjustable knucklesteer arm assembly of claim 1, wherein the steer arm has a proximate portion, an intermediate portion, and a distal portion; and wherein the proximate portion forms a hole, the intermediate portion forms the slot, and the distal portion is attachable to a tie rod of a vehicle suspension.
3. The adjustable knucklesteer arm assembly of claim 2, wherein the pivot is a first bolt connected with the hole and the connector member is a second bolt.
4. The adjustable knucklesteer arm assembly of claim 3, further comprising a sleeve disposed between the steer arm and the first bolt.
5. The adjustable knucklesteer arm assembly of claim 1, wherein an angular position of the steer arm with respect to the knuckle is selectively adjustable over a predetermined range of angular positions.
6. The adjustable knucklesteer arm assembly of claim 5, wherein one of the knuckle and the steer arm has a scale for determining the angular position of the steer arm with respect to the knuckle.
7. The adjustable knucklesteer arm assembly of claim 6, wherein the scale is a vernier scale.
8. A vehicle having a suspension including an adjustable knucklesteer arm assembly, comprising:
a wheel;
a tie rod of the suspension;
a knuckle connected to the wheel; and
a steer arm connected to the tie rod and pivotally connected to the knuckle at a pivot;
wherein one of the knuckle and the steer arm has a slot formed therein and the other has a connector member which engages the slot; and
wherein the steer arm is angularly adjustable with respect to the knuckle via adjustable engagement of the connector member along the slot to enable a toe curve setting for the wheel to be adjusted.
9. The vehicle of claim 8, wherein the steer arm has a proximate portion, an intermediate portion, and a distal portion; and wherein the proximate portion forms a hole, the intermediate portion forms the slot, and the distal portion is connected to the tie rod.
10. The vehicle of claim 9, wherein the pivot is a first bolt connected with the hole and the connector member is a second bolt.
11. The vehicle of claim 10, further comprising a sleeve disposed between the steer arm and the first bolt.
12. The vehicle of claim 8, wherein an angular position of the steer arm with respect to the knuckle is selectively adjustable over a predetermined range of angular positions.
13. The vehicle of claim 12, wherein one of the knuckle and the steer arm has a scale for determining the angular position of the steer arm with respect to the knuckle.
14. The vehicle of claim 13, wherein the scale is a vernier scale.

The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.

1. A method of forming a metal line, comprising:
forming a channel layer on a base substrate;
forming a metal layer on the formed channel layer;
forming a photoresist pattern in a wiring area of the metal layer;
etching the metal layer by using the photoresist pattern to form a metal line;
removing a predetermined thickness of the photoresist pattern to form a residual photoresist pattern on the metal line;
etching the channel layer by using the metal line to form an undercut under the metal line and to cause a portion of the metal line to protrude relative to the channel layer; and
removing the protruding portion of the metal line by using the residual photoresist pattern.
2. The method of claim 1, wherein the channel layer is isotropically dry etched.
3. The method of claim 1, wherein the undercut has a length of about 0.5 \u03bcm to about 1 \u03bcm.
4. The method of claim 1, wherein the protruding portion of the metal line is removed through a dry etching process.
5. The method of claim 1, wherein the residual photoresist pattern is formed on the metal line to expose an edge portion of the metal line, and a length of the undercut is longer than or equal to a length of the exposed edge portion.
6. The method of claim 5, wherein the exposed edge portion has a length of less than or equal to about 0.5 \u03bcm.
7. The method of claim 5, wherein the undercut has a length of about 0.5 \u03bcm to about 1 \u03bcm.
8. The method of claim 5, wherein the protruding portion of the metal line is removed through a dry etching process.
9. The method of claim 1, wherein the residual photoresist pattern is formed on the metal line to expose an edge portion of the metal line, and wherein the exposed edge portion has a length of less than or equal to about 0.5 \u03bcm, and the undercut has a length of about 0.5 \u03bcm to about 1 \u03bcm.
10. A method of manufacturing a display substrate, comprising:
forming a channel layer on a base substrate, the substrate having a gate line and a gate electrode of a switching element;
forming a source metal layer on the formed channel layer;
forming a first photoresist pattern on the source metal layer in a source line area and a first area, wherein a source electrode and a drain electrode of the switching element is formed in the first area;
forming a second photoresist pattern on the source metal layer in a second area, wherein a channel portion of the switching element is formed in the second area;
patterning the source metal layer by using the first and second photoresist patterns to form an electrode metal pattern in the first and second areas and a source line in the source line area;
forming a residual photoresist pattern on the electrode metal pattern of the first area, and removing the first and second photoresist patterns by a predetermined thickness to expose the electrode metal pattern in the second area;
etching the channel layer by using the electrode metal pattern and the source line to form undercuts under the electrode metal pattern and the source line;
etching the electrode metal pattern in the second area to form the source electrode and the drain electrode; and
forming a pixel electrode electrically connected to the drain electrode of the switching element.
11. The method of claim 10, wherein the first photoresist pattern has an inclined angle of about 60 degrees to about 90 degrees with respect to the base substrate.
12. The method of claim 11, wherein the second photoresist pattern has a thickness of about 5000 \u212b.
13. The method of claim 10, wherein the residual photoresist pattern is formed on the electrode metal pattern and the source line to expose edge portions of the electrode metal pattern and the source line, and a length of the undercuts is greater than or equal to a length of the edge portions.
14. The method of claim 10, wherein the channel layer is isotropically dry etched.
15. The method of claim 10, further comprising removing protruding portions of the electrode metal pattern and the source line by using the residual photoresist pattern, the protruding portions protruding in relation to the undercuts.
16. The method of claim 15, wherein the protruding portion of the electrode metal pattern is removed through a dry etching process.
17. The method of claim 10, wherein forming the source electrode and the drain electrode comprises selectively etching the channel layer by using the source electrode and the drain electrode to form the channel portion.
18. The method of claim 10, wherein forming the pixel electrode comprises:
forming a protective insulation layer on the base substrate having the switching element;
removing the protective insulation layer by using a third photoresist pattern to form a contact portion corresponding to the drain electrode;
forming a transparent electrode layer making contact with the drain electrode through the contact portion; and
patterning the transparent electrode layer by using a fourth photoresist pattern to form the pixel electrode.
19. The method of claim 10, further comprising forming the gate line, the gate electrode and a storage line on the base substrate.
20. The method of claim 19, wherein forming the pixel electrode comprises:
forming a protective insulation layer on the base substrate having the switching element;
forming a third photoresist pattern on areas having the switching element, the gate line and the source line;
removing a portion of the protective insulation layer corresponding to an area that has the pixel electrode and includes an end portion of the drain electrode by using the third photoresist pattern;
forming a transparent electrode layer on the base substrate having a remaining portion of the protective insulation layer; and
removing the third photoresist pattern and patterning the transparent electrode layer to form the pixel electrode to make contact with the end portion of the drain electrode.
21. The method of claim 20, wherein forming the third photoresist pattern comprises forming a fourth photoresist pattern that covers the storage line, the fourth photoresist pattern being thinner than the third photoresist pattern.
22. The method of claim 21, further comprising removing the fourth photoresist pattern prior to forming the transparent electrode layer.
23. The method of claim 20, further comprising simultaneously:
forming a cover metal pattern covering the storage line with the source line; and
removing the cover metal pattern with the protective insulation layer.
24. The method of claim 10, wherein the residual photoresist pattern is formed on the metal pattern and the source line to expose edge portions of the electrode metal pattern and the metal line, and wherein each of the exposed edge portions has a length of less than or equal to about 0.5 \u03bcm, and each of the undercuts has a length of about 0.5 \u03bcm to about 1 \u03bcm.