USE OF ANTI-CLOTTING COMPOUNDS AS RODENTICIDES

Abstract

The present invention proposes a composition for controlling pest rodents, the composition comprising: a) at least one direct coagulation factor inhibitor and b) at least one P-glycoprotein inhibitor (p-GP inhibitor). Through the composition, it is possible to achieve that existing resistances in pest rodents can be circumvented and at the same time a good effect can be achieved with a lower dosage, which can result in a comparatively more environmentally friendly application.

Claims

1. A composition for controlling pest rodents, characterized in that the composition has: a) at least one direct clotting factor inhibitor, and b) at least one P-glycoprotein inhibitor (Pgp inhibitor), characterized in that the P-glycoprotein inhibitor (Pgp inhibitor) is at least one compound selected from the group consisting of amiodarone, dronedarone, diltiazem, verapamil, atorvastatin, rosuvastatin, lovastatin, simvastatin, clarithromycin, roxithromycin, erythromycin, moxifloxacin, ofloxacin, fluconazole, voriconazole, itraconazole, mefloquine, quinidine, ritonavir, nefinavir, saquinavir, elacridar, tamoxifen, cyclosporin, tacrolimus, ciclosporin, lansoprazole, omeprazole and ondansetron.

2. The composition for controlling pest rodents as claimed in claim 1, characterized in that the Pgp inhibitor in the composition is at least one compound selected from the group consisting of voriconazole, ritonavir, elacridar and fluconazole.

3. The composition as claimed in claim 1, characterized in that the clotting factor inhibitor is selected from the group consisting of factor Xa inhibitors and factor IIa inhibitors.

4. The composition as claimed in claim 1, characterized in that the composition has at least one factor Xa inhibitor as clotting factor inhibitor, wherein the at least one factor Xa inhibitor is preferably selected from the group consisting of: i) a compound of the following formula: ##STR00056## wherein R.sup.27 is halogen, cyano, nitro, amino, aminomethyl, C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, imidazolinyl, C(?NH)NH.sub.2, carbamoyl or mono- and di-(C.sub.1-4)-alkylaminocarbonyl, and R.sup.28, R.sup.29, R.sup.30, R.sup.31, R.sup.32, R.sup.33 and R.sup.34 are, independently of one another, H or C.sub.1-6 alkyl; ii) a compound of the following formula: ##STR00057## wherein A is a C.sub.3-C.sub.10 carbocycle or a 5-12-membered heterocycle composed of carbon atoms and 1-4 heteroatoms N, O or S, P is a 5-7-membered carbocycle or a 5-7-membered heterocycle composed of carbon atoms and 1-3 heteroatoms N, O or S, and contains 0-3 double bonds in the ring, M is a 3-10-membered carbocycle or a 4-10-membered heterocycle composed of carbon atoms and 1-3 heteroatoms N, O or S, G.sup.1 is phenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazonyl, G.sup.2 is a 4-8-membered monocyclic or bicyclic hydrocarbon ring having 0 to 2 C?C double bonds, and R.sup.37 and R.sup.137 are, independently of one another, H, OH, F, Cl, Br, I, CN, C.sub.1-C.sub.4 alkyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, O(CH.sub.3).sub.2, OCF.sub.3 or amino; iii) a compound of the following formula: ##STR00058## wherein Q.sup.1 is a saturated or unsaturated 5- or 6-membered hydrocarbon ring, a saturated or unsaturated 5-7-membered heterocyclic group, a saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group, B.sup.10 is N or CH.sub.2, X.sup.2 is O or S, R.sup.38 is H, OH, alkoxy, alkyl, alkenyl, alkynyl, halogen, CN, amino, aminoalkyl, acyl, acylamino, carbamoyl, aryl or aralkyl, R.sup.39 and R.sup.40 are, independently of one another, H, OH, an alkyl group or an alkoxy group, Q.sup.4 is an aryl group, an arylalkenyl group, an arylalkynyl group, a heteroaryl group, a heteroarylalkenyl group, a saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group, and T.sup.1 is a carbonyl group, a sulfonyl group, C(?O)C(?O)-, C(?O)C(?O)NH, C(?O)C(?O)N(alkyl)-, C(?O)(C.sub.1-5alkylene)-N(alkyl), C(?O)(C.sub.1-5 alkylene)NH, C(?O)(C.sub.1-5 alkylene)-C(?O) or C(?O)N?N; iv) a compound of the following formula: ##STR00059## wherein Q.sup.3 is: ##STR00060## R.sup.59 is H, F, Cl or Br, R.sup.60, R.sup.61, R.sup.62 and R.sup.63 are, independently of one another, H, F, Cl, Br, Me, NO.sub.2, OH, OMe, NH.sub.2, NHAc, NHSO.sub.2Me, CH.sub.2OH or CH.sub.2NH.sub.2, and R.sup.64 is F, Cl, Br, Me, OH or OMe; v) a compound of the following formula: ##STR00061## wherein E is a benzene ring or a 5- or 6-membered heterocycle having 1 to 4 heteroatoms N, S or O, G is a piperidine ring or a benzene ring substituted with ##STR00062## wherein R.sup.69 is H, C.sub.1-6 alkyl, SO.sub.2(C.sub.1-6 alkyl) or a 5- or 6-membered heterocycle having 1 to 4 heteroatoms N, S or O, X.sup.3 and X.sup.4 are, independently of one another, C(?O)NH, C(?O)N(C.sub.1 to C.sub.6 alkyl), NHC(?O), N(C.sub.1 to C.sub.6 alkyl)-C(?O), CH.sub.2NH, CH.sub.2-N(C.sub.1 to C.sub.6 alkyl)-, NHCH.sub.2 or N(C.sub.1-C.sub.6 alkyl)-CH.sub.2, R.sup.65 is halogen, C.sub.1 to C.sub.6 alkyl or C.sub.1 to C.sub.6 alkoxy, R.sup.66 and R.sup.67 are, independently of one another, H, halogen, CN, NHSO.sub.2(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), CO(C.sub.1-6 alkyl), CO(C.sub.1-6 alkoxy), C(O)NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or S(C.sub.1-6 alkyl), and R.sup.68 is H, SO.sub.3H or a sugar residue; vi) a compound of the following formula: ##STR00063## wherein R.sup.70 and R.sup.71 are, independently of one another, H or ?NR.sup.82, wherein R.sup.82 is one of the groups R.sup.82aO.sub.2C, R.sup.82aO, HO, amino, CN, R.sup.82aCO, HCO, C.sub.1-6 alkyl, NO.sub.2, aralkyl or heteroaralkyl, wherein R.sup.82a is alkyl, or aralkyl including heteroalkyl, R.sup.72 is CO.sub.2H, CO.sub.2(C.sub.1-6 alkyl), CHO, CH.sub.2OH, CH.sub.2SH, C(O)(C.sub.1-6 alkyl), CONH.sub.2, CON(C.sub.1-6 alkyl).sub.2, CH.sub.2O(C.sub.1-6 alkyl), CH.sub.2O-aryl, CH.sub.2S(C.sub.1-6 alkyl) or CH.sub.2S-aryl, R.sup.73 is H, alkyl, cycloalkyl, or CH.sub.2 aryl, R.sup.74 is H or C.sub.1-6 alkyl, and R.sup.75 is alkyl, alkenyl or aryl; vii) a compound of the following formula: ##STR00064## wherein X.sup.5 is one or more of (i) CF.sub.3, F, COOH, C.sub.1-6 alkyl, CONH.sub.2, CONH(C.sub.1-3 alkyl), CON(C.sub.1-3 alkyl).sub.2, C(O)-phenyl, a 5- to 6-membered cycloalkyl radical, a 5- to 6-membered heterocycle having at least one heteroatom O, N or S, or (ii) a second phenyl ring, a 5- to 6-membered cycloalkyl radical or a 5- to 6-membered aromatic heterocycle having at least one heteroatom O, N or S, wherein the second ring is fused to the heterocyclic ring of the above formula, B.sup.3 is one of the following groups: ##STR00065## wherein alk is C.sub.2-3 alkylene or C.sub.2-3 alkenylene, T is S, O or N, W is C.sub.1-3 alkyl, and Z is H, OH or halogen, R.sup.76 is H, C.sub.1-6 alkyl, C.sub.3-6 alkenyl, phenyl or a 5- to 6-membered aromatic heterocyclic group, and R.sup.77 and R.sup.78 are, independently of one another, H, C.sub.1-3 alkyl or CF.sub.3; viii) a compound of the following formula: ##STR00066## wherein B.sup.4 is one of the following groups: ##STR00067## wherein R.sup.83 and R.sup.84 are, independently of one another, a C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl group or, together with the N atom to which they are bonded, define a 3- to 7-membered heterocycloalkyl group having 1 or 2 heteroatoms N, O or S, R.sup.85 is H, halogen, CN, C.sub.1-6 alkyl or C.sub.1-6 alkoxy, R.sup.79 is H, a C.sub.1-6 alkyl group or a C.sub.3-7 cycloalkyl group, R.sup.80 is H or a C.sub.1-6 alkyl group, and R.sup.81 is OH, halogen, CN, a C.sub.1-6 alkyl group or a C.sub.1-6 alkoxy group, or ix) a compound of the following formula: ##STR00068## wherein R.sup.86 is hydrogen or fluorine.

5. The composition as claimed in claim 1, characterized in that the composition has at least one factor IIa inhibitor as clotting factor inhibitor, wherein the at least one factor IIa inhibitor is preferably a thrombin inhibitor, particularly preferably selected from the group consisting of: i) a compound of the following formula: ##STR00069## wherein R.sup.1 is H, C.sub.1-4 alkyl, C.sub.1-4 alkylphenyl, A.sup.1C(O)N(R.sup.4)R.sup.5 or A.sup.1C(O)OR.sup.4, wherein A.sup.1 is a C.sub.1-5 alkylene, R.sup.4 and R.sup.5 are, independently of one another, H, C.sub.1-6 alkyl, phenyl, 2-naphthyl or, if R.sup.1 is A.sup.1C(O)N(R.sup.4)R.sup.5, they are, together with the nitrogen atom to which they are bonded, pyrrolidinyl or piperidinyl, R.sup.2 is OH, OC(O)R.sup.6 or C(O)OR.sup.7, wherein R.sup.6 is a C.sub.1-17 alkyl, phenyl or 2-naphthyl, R.sup.7 is a C.sub.1-3 alkylphenyl, phenyl, 2-naphthyl, or C.sub.1-12 alkyl, and R.sup.3 is H or C.sub.1-4 alkyl; ii) a compound of the following formula: ##STR00070## wherein R.sup.24 is C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl, Ar.sup.3 is a phenylene, naphthylene, thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group, Ar.sup.4 is a phenyl group or a 2-pyridinyl group, R.sup.25 is (a) a C.sub.1-3 alkyl group, or (b) a C.sub.2-3 alkyl group substituted with a hydroxyl-, benzyloxy-, carboxy-C.sub.1-3 alkylamino-, C.sub.1-3 alkoxycarbonyl-C.sub.1-3 alkylamino-, N(C.sub.1-3 alkyl) -carboxy-C.sub.1-3 alkylamino- or N(C.sub.1-3 alkyl)-C.sub.1-3 alkoxycarbonyl-C.sub.1-3 alkylamino group, E is a cyano or R.sup.26NHC(?NH) group, in which R.sup.26 is a hydrogen atom, a hydroxyl group, a C.sub.1-3 alkyl group or a residue that is cleavable in vivo; iii) a compound of the following formula: ##STR00071## wherein Ar is phenyl, quinolinyl, tetrahydroquinolinyl, naphthyl, naphthoquinone or indane, R.sup.8 is ##STR00072## wherein R.sup.9 is H, a C.sub.1-10 alkyl, a C.sub.6-10 aryl, a C.sub.7-12 aralkyl or 5-indanyl, and R.sup.10 is a C.sub.1-5 alkyl or alkoxy; iv) a compound of the following formula: ##STR00073## wherein Q is C or Si, R.sup.41 is H or, together with R.sup.42, defines a C.sub.3-8 carbocycle, R.sup.42 is halogen, CF.sub.3, or C.sub.1-6 alkyl or, together with R.sup.43, defines a C.sub.3-8 carbocycle or, together with R.sup.41, defines a C.sub.3-8 carbocycle, R.sup.43 is H, halogen, OH, C.sub.1-6 alkyl or, together with R.sup.42, defines a C.sub.3-8 carbocycle, R.sup.44 is a heterocycle, (CR.sup.45R.sup.46).sub.2NH.sub.2 or (CR.sup.45R.sup.46)NH.sub.2, wherein R.sup.45 and R.sup.46 are, independently of one another, H, C.sub.1-6 alkyl, CH.sub.2F, CHF.sub.2, CF.sub.3 or CH.sub.2OH; v) a compound of the following formula: ##STR00074## wherein m is 0 or 1, R.sup.43 is H, halogen, OH, C.sub.1-6 alkyl or, together with R.sup.47, defines a C.sub.3-8 carbocycle, R.sup.44 is a heterocycle, (CR.sup.45R.sup.46).sub.2NH.sub.2 or (CR.sup.45R.sup.46)NH.sub.2, wherein R.sup.45 and R.sup.46 are, independently of one another, H, C.sub.1-6 alkyl, CH.sub.2F, CHF.sub.2, CF.sub.3 or CH.sub.2OH, R.sup.47 is H, halogen, CF.sub.3, C.sub.1-6 alkyl or, together with R.sup.43, defines a C.sub.3-8 carbocycle, and R.sup.48 is C.sub.1-6 alkyl; or vi) a compound of the following formula: ##STR00075## or wherein the at least one factor IIa inhibitor is preferably a thrombin receptor antagonist, particularly preferably selected from the group consisting of: i) a compound of the following formula: ##STR00076## wherein Ar.sup.2 is a phenyl or morpholino group, X.sup.1 is H or halogen, and R.sup.11 and R.sup.12 are, independently of one another, H, methoxy or ethoxy; ii) a compound of the following formula: ##STR00077## wherein Het.sup.1 is a mono- or bicyclic heteroaromatic group of 5 to 10 atoms, containing 1 to 9 carbon atoms and 1 to 4 of the heteroatoms N, O or S, and B.sup.1 is (CH.sub.2).sub.n1, cis- or trans-(CH.sub.2)n.sub.2CR.sup.14?CR.sup.15(CH.sub.2).sub.n3 or (CH.sub.2).sub.n2C?C(CH.sub.2).sub.n3, wherein n.sub.1 is 0 to 5 and n.sub.2 and n.sub.3 are, independently of one another, 0 to 2, R.sup.14 and R.sup.15 are, independently of one another, H, C.sub.1-6 alkyl or halogen, and R.sup.20 is H, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, NHC(O)OR.sup.21, or NHC(O)R.sup.21, wherein R.sup.21 is H, C.sub.1-6 alkyl, C.sub.1-6 alkyl-OH, or C.sub.1-6alkoxy; iii) a compound of the following formula: ##STR00078## wherein Het.sup.2 is a mono- or bicyclic heteroaromatic group of 5 to 14 atoms, containing 1 to 13 carbon atoms and 1 to 4 heteroatoms N, O or S, B.sup.2 is (CH.sub.2).sub.n1, CH.sub.2O, CH.sub.2S, CH.sub.2NR.sup.13, C(O)NR.sup.13, NR.sup.13C(O), ##STR00079## cis- or trans-(CH.sub.2).sub.n2CR.sup.14?CR.sup.15(CH.sub.2).sub.n3 or (CH.sub.2).sub.n2C?C(CH.sub.2).sub.n3, wherein n.sub.1 is 0 to 5 and n.sub.2 and n.sub.3 are, independently of one another, 0 to 2, wherein R.sup.13 is H, C.sub.1-6 alkyl, phenyl, C.sub.3-7 cycloalkyl, (C.sub.3-7 cycloalkyl)-(C.sub.1-6 alkyl), (C.sub.1-6 alkoxy)-(C.sub.1-6 alkyl), (C.sub.1-6 alkyl)-OH or (C.sub.1-6 alkyl)amino, and R.sup.14 and R.sup.15 are, independently of one another, H, C.sub.1-6 alkyl or halogen, R.sup.22 and R.sup.23 are, independently of one another, H, R.sup.16(C.sub.1-10 alkyl), R.sup.16(C.sub.2-10 alkenyl), R.sup.16(C.sub.2-10 alkynyl), R.sup.16(C.sub.1-10 alkyl), heterocycloalkyl, R.sup.17-aryl, R.sup.17-aryl)-(C.sub.1-C.sub.8 alkyl), OH, OC(O)R.sup.18, CO(O)R.sup.19, C(O)R.sup.18, C(O)NR.sup.18R.sup.19 or NR.sup.18R.sup.19, wherein R.sup.16 and R.sup.17 are, independently of one another, H, a halogen or OH, and R.sup.18 and R.sup.19 are, independently of one another, H or C.sub.1-10 alkyl; or iv) a compound of the following formula: ##STR00080## wherein B is a monocyclic aromatic ring, R.sup.49 is NHCOR.sup.53, NHSO.sub.2R.sup.54, NHCON(R.sup.55)(R.sup.56), NHCOOR.sup.57 or CONHR.sup.58, wherein R.sup.53 to R.sup.58 are, independently of one another, H, a hydrocarbon group, a heterocyclic group or an alkoxy group, and R.sup.50 and R.sup.52 are, independently of one another, H, a hydrocarbon group, a heterocyclic group or an alkoxy group.

6. The composition as claimed in claim 1, characterized in that the composition has at least one factor Xa inhibitor and at least one factor IIa inhibitor as clotting factor inhibitor.

7. The composition as claimed in claim 1, characterized in that the composition additionally has: c) at least one platelet aggregation inhibitor.

8. The composition as claimed in claim 7, characterized in that the at least one platelet aggregation inhibitor is selected from the group consisting of cyclooxygenase inhibitors, P2Y12 receptor antagonists, phosphodiesterase inhibitors and glycoprotein GPIIb/IIIa receptor antagonists.

9. The composition as claimed in claim 7, characterized in that the at least one platelet aggregation inhibitor is a cyclooxygenase inhibitor selected from the group consisting of: i) a compound of the following formula: ##STR00081## or the at least one platelet aggregation inhibitor is a P2Y12 receptor antagonist selected from the group consisting of: i) a compound of the following formula: ##STR00082## wherein R.sup.94 is H, halogen, hydroxyl or C.sub.1-6 alkyl, R.sup.95 is H, halogen, hydroxyl, nitro, C.sub.1-6 alkyl or C.sub.1-4 alkoxy, and R.sup.96 is H or halogen; ii) a compound of the following formula: ##STR00083## wherein Y.sup.1 is OR.sup.98 or N(R.sup.99)R.sup.100, wherein R.sup.99 and R.sup.100 are, independently of one another, H, halogen or a C.sub.1-4 alkyl group, and R.sup.98 is H or C.sub.1-4 alkyl, and R.sup.97 is H, halogen, or a C.sub.1-4 alkyl group; iii) a compound of the following formula: ##STR00084## wherein R.sup.101 is H, OH, amino, C.sub.1 to C.sub.4 alkoxy, ArC.sub.1-4 alkyloxy, C.sub.1-18 alkanoyloxy, C.sub.3-6 alkenoyloxy or arylcarbonyloxy, R.sup.102 is C.sub.1-10 alkanoyl, C.sub.3-6 alkenoyl, C.sub.4-8 cycloalkylcarbonyl having 3 to 7 ring atoms, substituted benzoyl and 5,6-dihydro-1,4,2-dioxazin-3-yl, Y.sup.2 is NH, O or S, and R.sup.103 is H, halogen, OH, amino, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio or a carboxy group; iv) a compound of the following formula: ##STR00085## wherein R.sup.104 is H, halogen, hydroxy-C.sub.1-8 alkyl, C.sub.1-8 alkoxy-C.sub.1-8 alkyl or carboxy-C.sub.1-8 alkyl, R.sup.105 is C.sub.1-8 alkyl, C.sub.1-8 alkoxy-C.sub.1-8 alkylthio-C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl-C.sub.1-8 alkyl, phenyl-C.sub.1-8 alkyl, heterocyclyl, heterocyclyl-C.sub.1-8 alkyl, heteroaryl-C.sub.1-8 alkyl or halo-C.sub.1-8 alkyl, R.sup.106 and R.sup.107 are, independently of one another, H, or, together with the carbon atom to which they are bonded, define a 5- or 6-membered heterocycle, and X.sup.8 and X.sup.9 are, independently of one another, CH, CH.sub.2 or CH(OH), and is a single bond or a double bond; v) a compound of the following formula: ##STR00086## wherein R.sup.108 is heterocyclyl, heterocyclyl-C.sub.1-8 alkyl, heteroaryl, heteroaryl-C.sub.1-8 alkyl or halo-C.sub.1-8 alkyl, and R.sup.109 is C.sub.1-8 alkyl, C.sub.1-8 alkoxy-C.sub.1-8 alkylthio-C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-8 alkyl, phenyl-C.sub.1-8 alkyl, heterocyclyl-C.sub.1-8 alkyl, heteroaryl-C.sub.1-8 alkyl or halo-C.sub.1-8 alkyl; vi) a compound of the following formula: ##STR00087## wherein R.sup.110 is OH, CH.sub.2OH or OCH.sub.2CH.sub.2OH, R.sup.111 is C.sub.3-5 alkyl, R.sup.112 is phenyl, including phenyl substituted with one or more F; vii) a compound of the following formula: ##STR00088## wherein R.sup.113 is H or C.sub.1-4 alkyl, R.sup.114 to R.sup.118 are, independently of one another, H, C.sub.1-6 alkyl, C.sub.1-3 fluoroalkyl, halogen, CN or phenyl, X.sup.10 is C.sub.3-8 alkylenyl, C.sub.1-3 cycloalkylenyl or C.sub.3-15 heterocyclyl, Z.sup.2 is alkylenyl, alkenyl or alkynyl, A.sup.1 is a 3- to 10-membered heterocyclic monocyclic, bicyclic or spiroheterocyclic ring containing 0, 1, 2 or 3 additional heteroatoms from N, S or O, Q.sup.5 is a mono- or bicyclic 3- to 15-membered heterocycle, and B.sup.6 and B.sup.7 are, independently of one another, H, C.sub.1-4 alkyl, C.sub.3-8 cycloalkyl, C.sub.6-14 aryl, a 3- to 7-membered heterocycle, C(O)OH, CNH.sub.2, C(O)NH(C.sub.1-6 alkyl), C(O)O(C.sub.1-6 alkyl) or C(O)N(R)R; viii) a compound of the following formula: ##STR00089## wherein A.sup.2 is O or NOH, B.sup.8 is a covalent bond, C(O) or methylenyl, B.sup.9 is N or CH, E is a covalent bond, OC(O) or NHC(O), R.sup.119 is H, C.sub.1-8 alkyl-, C.sub.0-4 alkylene-(C.sub.3-8 cycloalkyl), C.sub.0-4 alkylene-(C.sub.6-4 aryl) or C.sub.0-4 alkylene-heterocyclyl, R.sup.120 is H, NHC(O) or OC(O), R.sup.121 is C.sub.1-8 alkyl-, CF.sub.3, or (C.sub.1-8 alkylene)C(O)OR.sup.132 and R.sup.122 is H, halogen, C.sub.1 to C.sub.8 alkyl-, (C.sub.1-8 alkylene)C(O)OR.sup.132, (C.sub.2-6 alkenylene)-C(O)OR.sup.132 or C.sub.3-7 cycloalkyl)-C(O)OR.sup.132, wherein R.sup.132 is H, C.sub.1 to C.sub.8 alkyl- or C.sub.0-4 alkylene-(C.sub.3-8-cycloalkyl), R.sup.123 to R.sup.127 are, independently of one another, H, halogen, CN, NO.sub.2, C.sub.1-8 alkyl-, C.sub.0-4 alkylene-OR.sup.132, (C.sub.0-4 alkylene)C(O)OR.sup.132, (C.sub.0-4 alkylene)-C(O)R.sup.132, (C.sub.0-4 alkylene)-C(O)NR.sup.132R 133 or (C.sub.0-4 alkylene)-CNR.sup.132R.sup.133, wherein R.sup.133 is H or C.sub.1 to C.sub.8 alkyl-, and R.sup.128 to R.sup.131 are, independently of one another, H, ?O, OH or C.sub.1 to C.sub.8 alkyl -; or ix) a compound of the following formula: ##STR00090## wherein Z.sup.3 is a substituted -2-thiazole ring or -4-thiazole ring, wherein a 2-thiazole ring is substituted at position 4 with H, an aryl group and/or at position 5 with H, halogen, C.sub.1 to C.sub.4 alkyl-, C.sub.2 to C.sub.4 alkenyl-, phenyl or di-C.sub.1-6 alkylamino, and a 4-thiazole ring is substituted at position 2 with H or an aryl group and/or at position 5 with H, halogen, COOH, C.sub.1 to C.sub.4 alkyl-, COO(C.sub.1-4 alkyl-), C.sub.2-4 alkenyl-, phenyl, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, heterocyclyl or 2-methoxymethylcycloprop-1-yl, Y.sup.3Z.sup.4 either represent a bond and H, or Y.sup.3 is C.sub.1 to C.sub.3 alkanediyl and Z.sup.4 is H, OH, phenyl, COOH, COO(C.sub.1-4 alkyl), P(O)(OH).sub.2, P(O)(O[C.sub.1-4 alkyl]).sub.2, P(O)(O[C.sub.1-4 alkoxy]C(O)OCH.sub.2).sub.2 or P(O)(NH[C.sub.1-4 alkoxy]-C(O)[C.sub.1-4 alkyl]).sub.2, and R.sup.134 is C.sub.1 to C.sub.6 alkoxy; or the at least one platelet aggregation inhibitor is a glycoprotein GPIIb/IIIa receptor antagonist selected from the group consisting of: i) a compound of the following formula: ##STR00091## wherein Y.sup.4 and Y.sup.5 are, independently of one another, a non-interfering substituent or are absent, K* is a substituted or unsubstituted lysyl residue of formula R.sup.135R.sup.136.sub.2N(CH.sub.2).sub.4CHNHCO, wherein R.sup.135 and R.sup.136 are, independently of one another, H or C.sub.1 to C.sub.6 alkyl, X.sup.11 and X.sup.12 are, independently of one another, any desired residue which enables the ring formation shown between X.sup.11 and X.sup.12, (AA.sup.1) is a small neutral amino acid and n.sub.4 is a number from 0 to 3, (AA.sup.2) is a large nonpolar amino acid and n.sub.5 is a number from 0 to 3, (AA.sup.3) is a proline residue or a modified proline residue and n.sub.6 is 0 or 1, and (AA.sup.4) is a small neutral amino acid or an N-alkylated form thereof and n.sub.7 is a number from 0 to 3; ii) a compound of the following formula: ##STR00092## wherein Y.sup.6 is ##STR00093## q is 2 or 3, q is an integer from 0 to 4, R.sup.138 is H, C.sub.1 to C.sub.6 alkyl-, C.sub.1 to C.sub.8 alkoxy-, C.sub.1 to C.sub.8 alkoxycarbonyl-, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkyl, cycloalkyl or aryl, R.sup.139 is C.sub.1 to C.sub.6 alkyl-, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, alkoxycarbonyloxyalkyl and C.sub.3 to C.sub.6 cycloalkyl or aryl; iii) a compound of the following formula: ##STR00094## wherein Z.sup.5 is a covalent single bond, C.sub.1 to C.sub.7 alkyl-, C.sub.2 to .sub.7 alkenyl or C.sub.2 to C.sub.7 alkynyl, R.sup.139 is C.sub.1 to C.sub.6 alkyl-, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, alkoxycarbonyloxyalkyl, C.sub.3 to C.sub.6 cycloalkyl or aryl, R.sup.140 is hydroxyl, C.sub.1 to C.sub.10 alkoxy-, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy- or C.sub.7 to C.sub.11 aralkyloxy-, and is a single bond or a double bond; iv) a compound of the following formula: ##STR00095## wherein one of Z.sup.6 and Z.sup.7 is CH and the other is CH, C.sub.1 to C.sub.8 alkyl-, C.sub.1 to C.sub.8 alkoxy or N, Z.sup.8 is NH, C.sub.1 to C.sub.8 alkyl-N or C.sub.1 to C.sub.8 alkoxy-(C.sub.1 to C.sub.8 alkyl-)N, Z.sup.9 is H or C.sub.1 to C.sub.8 alkyl optionally substituted with OH, SH, CONH.sub.2, CONH C.sub.1 to C.sub.8 alkyl, C.sub.1 to C.sub.8 alkylthio, aryl, NH.sub.2, NH(C.sub.1 to C.sub.8 alkyl-), N(C.sub.1 to C.sub.8 alkyl-)(C.sub.1 to C.sub.8 alkyl-) or O-(C.sub.1 to C.sub.8 alkyl-), Z.sup.10 is O, CH.sub.2, NH, acyl-N or C.sub.1 to C.sub.8 alkyl-OC(O)N, Z.sup.11 and Z.sup.12 are H, C.sub.1 to C.sub.8 alkyl, OH, C.sub.1 to C.sub.8 alkoxy, C.sub.1 to C.sub.8 alkoxy- C.sub.1 to C.sub.8 alkyl, carboxy- C.sub.1 to C.sub.8 alkyl, P(O)(OC.sub.1 to C.sub.8 alkyl).sub.2, C(O)OC.sub.1 to C.sub.8 alkyl, OC(O)C.sub.1 to C.sub.8 alkyl, OC(O)OC.sub.1 to C.sub.8 alkyl or C(O)SC.sub.1 to C.sub.8 alkyl, wherein at least one of Z.sup.11 and Z.sup.12 is H, or Z.sup.11 and Z.sup.12, together with the N atoms to which they are bonded, are a (5,5-dimethyl- or 5-oxo)-4,5-dihydro-1,2,4-oxadiazol-3-yl group, Z.sup.16 is a 1,4-piperidinylene bonded to the keto group via the N atom, or is 1,4-phenylene optionally substituted with C.sub.1 to C.sub.8 alkyl, C.sub.1 to C.sub.8 alkoxy, OCH.sub.2COOH or OCH.sub.2COO(C.sub.1 to C.sub.8alkyl), and R.sup.141 is NH.sub.2, NH(C.sub.1 to C.sub.8 alkyl), NH(C.sub.1 to C.sub.8 alkyl-)COOH, NH(C.sub.1 to C.sub.8 alkyl)-COO(C.sub.1 to C.sub.8 alkyl), C.sub.1 to C.sub.8 alkyloxy or C.sub.1 to C.sub.8 alkenyloxy; v) a compound of the following formula: ##STR00096## wherein Q.sup.6 is a four- to eight-membered heterocyclic ring having 1, 2, 3 or 4 heteroatoms which are N, O or S, m is an integer from 0 to 8, m and m are, independently of one another, an integer from 0 to 2, Z.sup.13 and Z.sup.14 are, independently of one another, phenyl, O, SO.sub.2, ##STR00097## or a 5- or 6-membered ring containing 0 or 1 heteroatoms from N or O, Z.sup.15 is an optionally present group which is O, NHCO, CONH or C.sub.1 to C.sub.5 alkyl-OC(O)N, R.sup.142 is H or C.sub.1 to C.sub.8 alkyl, R.sup.143 and R.sup.144 are, independently of one another, H, C.sub.1 to C.sub.4 alkyl or C.sub.4 to C.sub.6 aralkyl, and R.sup.145 is aryl, C.sub.1 to C.sub.10 alkyl or cycloalkyl or C.sub.4 to C.sub.10 aralkyl; or vi) a compound of the following formula: ##STR00098## wherein Q.sup.6 is a six-membered heterocyclic ring having 1 or 2 heteroatoms which are N, m is an integer from 2 to 6, Z.sup.15 is ##STR00099## and R.sup.146 is aryl, C.sub.1 to C.sub.10 alkyl or C.sub.4 to C.sub.10 aralkyl.

10. The composition as claimed in claim 7, characterized in that the composition has at least two platelet aggregation inhibitors, wherein preferably at least one platelet aggregation inhibitor is a cyclooxygenase inhibitor and at least one platelet aggregation inhibitor is a P2Y12 receptor antagonist or a glycoprotein GPIIb/IIIa receptor antagonist.

11. The composition as claimed in claim 1, characterized in that the at least one Pgp inhibitor is selected from the group consisting of: i) a compound of the following formula: ##STR00100## ii) a compound of the following formula: ##STR00101## iii) a compound of the following formulae: ##STR00102## or a mixture thereof, in particular a racemate thereof; iv) a compound of the following formula: ##STR00103## v) a compound of the following formula: ##STR00104## vi) a compound of the following formula: ##STR00105## vii) a compound of the following formulae: ##STR00106## or a mixture thereof, in particular a racemate thereof; or viii) a compound of the following formula: ##STR00107## or ix) a compound of the following formulae: ##STR00108## or x) a compound of the following formula: ##STR00109## or xi) a compound of the following formula: ##STR00110##

12. The use of a composition as claimed in claim 1 as rodenticide.

13. A pest rodent bait containing a composition as claimed in claim 1.

14. The pest rodent bait as claimed in claim 13, characterized in that each of the individual components of the composition are present at a concentration in a range from greater than 0 ppm to less than or equal to 10 000 ppm, preferably greater than 10 ppm to less than or equal to 6000 ppm, in particular greater than 50 ppm to less than or equal to 5000 ppm, relative to the total weight of the pest rodent bait.

15. The pest rodent bait as claimed in claim 12, characterized in that said bait contains a Pgp inhibitor at a concentration in a range from greater than 0 ppm to less than 6000 ppm relative to the total weight of the pest rodent bait, preferably greater than 250 ppm to less than or equal to 5500 ppm, in particular greater than 750 ppm to less than or equal to 5000.

16. The pest rodent bait as claimed in claim 12, characterized in that said bait contains a factor Xa antagonist at a concentration in a range from greater than 0 ppm to less than or equal to 8000 ppm, preferably greater than 50 ppm to less than or equal to 5000 ppm, in particular greater than 100 ppm to less than or equal to 4000 ppm.

17. The pest rodent bait as claimed in claim 12, characterized in that said bait contains a factor IIa antagonist at a concentration in a range from greater than 0 ppm to less than or equal to 8000 ppm, preferably greater than 50 ppm to less than or equal to 5000 ppm, in particular greater than 100 ppm to less than or equal to 4000 ppm.

18. A method for controlling pest rodents, wherein a pest rodent bait as claimed in claim 13 is laid.

Description

DESCRIPTION OF THE INVENTION

[0031] The invention proposes a composition for controlling pest rodents, having: [0032] a) at least one direct clotting factor inhibitor, and [0033] b) at least one P-glycoprotein inhibitor (Pgp inhibitor), wherein the P-glycoprotein inhibitor (Pgp inhibitor) is at least one compound selected from the group consisting of amiodarone, dronedarone, diltiazem, verapamil, atorvastatin, rosuvastatin, lovastatin, simvastatin, clarithromycin, roxithromycin, erythromycin, moxifloxacin, ofloxacin, fluconazole, voriconazole, itraconazole, mefloquine, quinidine, ritonavir, nefinavir, saquinavir, elacridar, tamoxifen, cyclosporin, tacrolimus, ciclosporin, lansoprazole, omeprazole and ondansetron.

[0034] In the context of the present invention, a clotting factor inhibitor means a substance that can inhibit blood clotting factors. In the context of the present invention, blood clotting factors are substances involved in functioning blood clotting. In the context of the present invention, inhibition means restricting the function of the corresponding substance, the term being used independently of the mechanism of action of the inhibitor. In the context of the present invention, an inhibitor can therefore for example be a true inhibitor or also an antagonist. In the context of the present invention, direct clotting factor inhibitors are clotting factor inhibitors which directly inhibit the clotting factors and which, in comparison to indirect clotting factor inhibitors such as vitamin K antagonists, do not require cofactors or for example only inhibit the synthesis of the clotting factors.

[0035] In the context of the present invention, a P-glycoprotein inhibitor means a substance that restricts the function of P-glycoprotein. The term P-glycoprotein means, in a known way, a specific membrane protein which is a primary efflux pump which can transport its substrate out of the cell membrane and into the extracellular space. P-glycoprotein inhibitors are also referred to as multidrug resistance protein (MDRP) or MDR1, breast cancer resistance protein (BCRP), or ATP-binding cassette (ABC) superfamily.

[0036] It was possible to demonstrate that pest rodents could be killed by the above-described composition. In particular, it was possible to demonstrate that, by combining at least one clotting factor inhibitor, at a dosage which causes absolutely no bleeding in rats when administered acutely or chronically, with at least one P-glycoprotein inhibitor which on its own has no hemorrhagic effect whatsoever, it is possible to increase the effect of the abovementioned clotting factor inhibitor such that, even at a comparatively low consumption of the composition by a pest rodent, a clotting cascade can be inhibited in such a way as to induce, after a latency period, the death of the pest rodent by spontaneous bleeding.

[0037] Advantageously, it was possible to demonstrate that the efficacy of the composition according to the invention is effective even in rat strains which potentially have resistance to vitamin K antagonists.

[0038] Without being bound by a theory, it was possible to demonstrate that the direct clotting factor inhibitors are all subject to a ceiling effect, which is why even with excessive dosing when consumed orally, only limited concentrations can be reached in the blood which are insufficient to cause spontaneous bleeding. The combination with at least one Pgp inhibitor makes it possible to suppress this ceiling effect. In addition, the Pgp inhibitor makes it possible for the direct clotting factor inhibitors used to cross the blood-brain barrier and thus to also become active in the brain. This makes it possible to also cause spontaneous bleeding on the brain in a delayed manner, thereby achieving particularly rapid death of the pest rodent without any manifestations of poisoning appearing beforehand. Symptoms of poisoning or the death of a rat shortly after a rat has eaten bait can cause a rat strain to completely avoid this bait and therefore escape extermination. Furthermore, some Pgp inhibitors are also inhibitors of the various cytochrome oxidases. Cytochrome oxidases are responsible for degrading some drugs in the liver. Blocking cytochrome P450 (CYP) monooxygenase prolongs degradation and thus the half life of the dependent drugs. As a result, it is also possible to achieve more rapid accumulation of the constituents of the composition when the composition is ingested multiple times, and therefore a lethal dose can be achieved even with low repeated ingestion. When selecting a Pgp inhibitor with CYP inhibition, the degradation of the substance(s) is accordingly also inhibited, as a result of which the level increases further.

[0039] The fact that the composition has the at least one direct clotting factor inhibitor and the at least one Pgp inhibitor makes it possible to achieve a good rodenticide effect at a low dosage of the clotting factor inhibitor.

[0040] The above-described composition further makes it possible to achieve better environmental compatibility. This can advantageously be achieved because the efficacy of the composition is based on the combination of the direct clotting factor inhibitor with the at least one Pgp inhibitor. The concentration of the direct clotting factor inhibitor can therefore be kept low enough that a lethal effect can only be achieved by combination with the Pgp inhibitor. Because each of the at least two substances are metabolized very differently and also excreted differently, the composition of the active substances administered together changes by the concentration of each of the individual substances changing such that the toxic effect is rapidly lost, and even the excreta from such an animal no longer contain any toxic composition. Because the composition is so effective, the dose of the composition can also be selected such that it only begins after being ingested multiple times. Thus, the effect in animals which accidentally consume the bait in question can be reduced. Furthermore, the substances used are metabolized differently in the target animal, and therefore toxicity is rapidly lost for predators and scavengers, and also the excreta from the target animals no longer contain an active combination of the constituents of the composition. As a result, the composition may be safer to handle and have less of an environmental impact due to an overall lower dose. In particular, the poison effect for predators of the poisoned pest rodents is already weakened by metabolism by the pest rodent, because the pest rodent stays alive for a while after ingestion. Thus, carcasses of poisoned pest rodents also have a weakened poison effect for scavengers. Remaining poison can also be rapidly further degraded by the predators or scavengers, rapidly further reducing toxicity for said predators and scavengers. Furthermore, a lethal effect for predators and scavengers can only occur if they simultaneously eat several poisoned animals in succession on successive days. In particular, this reduces cross-toxicity for other animals.

[0041] As a result, therefore, the composition according to the invention makes it possible to effectively control pest rodents and at the same time ensure comparatively lower cross-toxicity for other animals and a comparatively very low impact on the environment.

[0042] Preferably, it can be provided that the clotting factor inhibitor is selected from the group consisting of factor Xa inhibitors and factor IIa inhibitors.

[0043] This makes it possible to achieve a particularly efficient composition. Without being bound to a theory, it is assumed that factor Xa inhibitors and factor IIa inhibitors are particularly efficient because their efficacy can be particularly advantageously influenced by the Pgp inhibitor and because they both inhibit each of the end sections of the intrinsic and also the extrinsic clotting cascade.

Factor Xa Inhibitors

[0044] It can preferably be provided that the composition has at least one factor Xa inhibitor as clotting factor inhibitor, wherein the at least one factor Xa inhibitor is preferably selected from the group consisting of the following listed factor Xa inhibitors i)-ix).

[0045] It was possible to demonstrate that these factor Xa inhibitors are particularly well suited to the composition because they can be particularly advantageously influenced by the Pgp inhibitor and are well suited for oral consumption.

[0046] In a preferred configuration, it can be provided that the factor Xa inhibitor is selected from [0047] i) a compound of the following formula:

##STR00001##

[0048] wherein R.sup.27 is halogen, cyano, nitro, amino, aminomethyl, C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, imidazolinyl, C(?NH)NH.sub.2, carbamoyl or mono- and di-(C.sub.1-4)-alkylaminocarbonyl, and

[0049] R.sup.28, R.sup.29, R.sup.30, R.sup.31, R.sup.32, R.sup.33 and R.sup.34 are, independently of one another, H or C.sub.1-6 alkyl.

[0050] For example, the above-described factor Xa inhibitor can preferably be rivaroxaban (Xarelto?), for example as also described in WO 01/47919.

[0051] In an alternative preferred configuration, it can be provided that the factor Xa inhibitor is selected from [0052] ii) a compound of the following formula:

##STR00002##

[0053] wherein A is a C.sub.3-C.sub.10 carbocycle or a 5-12-membered heterocycle composed of carbon atoms and 1-4 heteroatoms N, O or S,

[0054] P is a 5-7-membered carbocycle or a 5-7-membered heterocycle composed of carbon atoms and 1-3 heteroatoms N, O or S, and contains 0-3 double bonds in the ring,

[0055] M is a 3-10-membered carbocycle or a 4-10-membered heterocycle composed of carbon atoms and 1-3 heteroatoms N, O or S,

[0056] G.sup.1 is phenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazonyl,

[0057] G.sup.2 is a 4-8-membered monocyclic or bicyclic hydrocarbon ring having 0 to 2 C?C double bonds, and

[0058] R.sup.37 and R.sup.137 are, independently of one another, H, OH, F, Cl, Br, I, CN, C.sub.1-C.sub.4 alkyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, O(CH.sub.3).sub.2, OCF.sub.3 or amino.

[0059] For example, the above-described factor Xa inhibitor can preferably be apixaban (Eliquis?), for example as described in US 2003/191115.

[0060] In an alternative preferred configuration, it can be provided that the factor Xa inhibitor is selected from [0061] iii) a compound of the following formula:

##STR00003##

[0062] wherein Q.sup.1 is a saturated or unsaturated 5- or 6-membered hydrocarbon ring, a saturated or unsaturated 5-7-membered heterocyclic group, a saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group,

[0063] B.sup.10 is N or CH.sub.2,

[0064] X.sup.2 is O or S,

[0065] R.sup.38 is H, OH, alkoxy, alkyl, alkenyl, alkynyl, halogen, CN, amino, aminoalkyl, acyl, acylamino, carbamoyl, aryl or aralkyl,

[0066] R.sup.39 and R.sup.40 are, independently of one another, H, OH, an alkyl group or an alkoxy group,

[0067] Q.sup.4 is an aryl group, an arylalkenyl group, an arylalkynyl group, a heteroaryl group, a heteroarylalkenyl group, a saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group, and

[0068] T.sup.1 is a carbonyl group, a sulfonyl group, C(?O)C(?O), C(?O)C(?O)NH,

[0069] C(?O)C(?O)N(alkyl)-, C(?O)(C.sub.1-5 alkylene)-N(alkyl), C(?O)(C.sub.1-5 alkylene)-NH, C(?O)(C.sub.1-5 alkylene)-C(?O) or C(?O)N?N.

[0070] For example, the above-described factor Xa inhibitor can preferably be edoxaban (Lixiana?), as described in EP 2 343 290 or PE 2 374 456.

[0071] In an alternative preferred configuration, it can be provided that the factor Xa inhibitor is selected from [0072] iv) a compound of the following formula:

##STR00004##

[0073] wherein Q.sup.3 is:

##STR00005##

[0074] R.sup.59 is H, F, Cl or Br,

[0075] R.sup.60, R.sup.61, R.sup.62 and R.sup.63 are, independently of one another, H, F, Cl, Br, Me, NO.sub.2, OH, OMe, NH.sub.2, NHAc, NHSO.sub.2Me, CH.sub.2OH or CH.sub.2NH.sub.2, and

[0076] R.sup.64 is F, Cl, Br, Me, OH or OMe.

[0077] For example, the above-described factor Xa inhibitor can preferably be betrixaban (N-(5-chloropyridin-2-yl)-2-([4-(N,N-dimethylcarbamimidoyl)benzoyl]amino)-5-methoxybenzamide), for example as described in WO 01/64642 and WO 01/64643.

[0078] In an alternative preferred configuration, it can be provided that the factor Xa inhibitor is selected from [0079] v) a compound of the following formula:

##STR00006##

[0080] wherein E is a benzene ring or a 5- or 6-membered heterocycle having 1 to 4 heteroatoms N, S or O,

[0081] G is a piperidine ring or a benzene ring substituted with

##STR00007##

wherein R.sup.69 is H, C.sub.1-6 alkyl, SO.sub.2-(C.sub.1-6 alkyl) or a 5- or 6-membered heterocycle having 1 to 4 heteroatoms N, S or O,

[0082] X.sup.3 and X.sup.4 are, independently of one another, C(?O)NH, C(?O)N(C.sub.1 to C.sub.6 alkyl), NHC(?O), N(C.sub.1 to C.sub.6 alkyl)-C(?O), CH.sub.2NH, CH.sub.2N(C.sub.1 to C.sub.6 alkyl)-, NHCH.sub.2 or N(C.sub.1-C.sub.6 alkyl)-CH.sub.2,

[0083] R.sup.65 is halogen, C.sub.1 to C.sub.6 alkyl or C.sub.1 to C.sub.6 alkoxy,

[0084] R.sup.66 and R.sup.67 are, independently of one another, H, halogen, CN, NHSO.sub.2-(C.sub.1-6 alkyl), NHCO-(C.sub.1-6 alkyl), CO-(C.sub.1-6 alkyl), CO-(C.sub.1-6 alkoxy), C(O)NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or S-(C.sub.1-6 alkyl), and

[0085] R.sup.68 is H, SO.sub.3H or a sugar residue.

[0086] For example, the above-described factor Xa inhibitor can preferably be darexaban (N -(3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)-benzoyl]amino}phenyl)-4-methoxybenzamide), as for example described in EP 1 336 605.

[0087] In an alternative preferred configuration, it can be provided that the factor Xa inhibitor is selected from [0088] vi) a compound of the following formula:

##STR00008##

[0089] wherein R.sup.70 and R.sup.71 are, independently of one another, H or ?NR.sup.82, wherein R.sup.82 is one of the groups R.sup.82aO.sub.2C, R.sup.82aO, HO, amino, CN, R.sup.82aCO, HCO, C.sub.1-6 alkyl, NO.sub.2, aralkyl or heteroaralkyl, wherein R.sup.82a is alkyl, or aralkyl including heteroalkyl,

[0090] R.sup.72 is CO.sub.2H, CO.sub.2(C.sub.1-6 alkyl), CHO, CH.sub.2OH, CH.sub.2SH, C(O)(C.sub.1-6 alkyl), CONH.sub.2, CON(C.sub.1-6 alkyl).sub.2, CH.sub.2O(C.sub.1-6 alkyl), CH.sub.2O-aryl, CH.sub.2S(C.sub.1-6 alkyl) or CH.sub.2S-aryl,

[0091] R.sup.73 is H, alkyl, cycloalkyl, or CH.sub.2 aryl,

[0092] R.sup.74 is H or C.sub.1-6 alkyl, and

[0093] R.sup.75 is alkyl, alkenyl or aryl.

[0094] For example, the above-described factor Xa inhibitor can preferably be otamixaban (methyl(2R,3R)-2-{3-[amino(imino)methyl]benzyl}-3-{[4-(1-oxidopyridin-4-yl)benzoyl]amino}butoxide), as for example described in WO 97/24118.

[0095] In an alternative preferred configuration, it can be provided that the factor Xa inhibitor is selected from [0096] vii) a compound of the following formula:

##STR00009##

[0097] wherein X.sup.5 is one or more of (i) CF.sub.3, F, COOH, C.sub.1-6 alkyl, CONH.sub.2, CONH(C.sub.1-3 alkyl), CON(C.sub.1-3 alkyl).sub.2, C(O)-phenyl, a 5- to 6-membered cycloalkyl radical, a 5- to 6-membered heterocycle having at least one heteroatom O, N or S, or (ii) a second phenyl ring, a 5- to 6-membered cycloalkyl radical or a 5- to 6-membered aromatic heterocycle having at least one heteroatom O, N or S, wherein the second ring is fused to the heterocyclic ring of the above formula,

[0098] B.sup.3 is one of the following groups:

##STR00010##

[0099] wherein alk is C.sub.2-3 alkylene or C.sub.2-3 alkenylene, T is S, O or N, W is C.sub.1-3 alkyl, and

[0100] Z is H, OH or halogen,

[0101] R.sup.76 is H, C.sub.1-6 alkyl, C.sub.3-6 alkenyl, phenyl or a 5- to 6-membered aromatic heterocyclic group, and

[0102] R.sup.77 and R.sup.78 are, independently of one another, H, C.sub.1-3 alkyl or CF.sub.3.

[0103] Examples for factor Xa inhibitors of the above-described compound are disclosed for example in WO 02/100830.

[0104] In an alternative preferred configuration, it can be provided that the factor Xa inhibitor is selected from [0105] viii) a compound of the following formula:

##STR00011##

[0106] wherein B.sup.4 is one of the following groups:

##STR00012##

[0107] wherein R.sup.83 and R.sup.84 are, independently of one another, a C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl group or, together with the N atom to which they are bonded, define a 3- to 7-membered heterocycloalkyl group having 1 or 2 heteroatoms N, O or S,

[0108] R.sup.85 is H, halogen, CN, C.sub.1-6 alkyl or C.sub.1-6 alkoxy,

[0109] R.sup.79 is H, a C.sub.1-6 alkyl group or a C.sub.3-7 cycloalkyl group,

[0110] R.sup.80 is H or a C.sub.1-6 alkyl group, and

[0111] R.sup.81 is OH, halogen, CN, a C.sub.1-6 alkyl group or a C.sub.1-6 alkoxy group.

[0112] Examples for factor Xa inhibitors of the above-described compound are disclosed for example in WO 2013/092756.

[0113] In an alternative preferred configuration, it can be provided that the factor Xa inhibitor is selected from [0114] ix) a compound of the following formula:

##STR00013##

[0115] wherein R.sup.86 is hydrogen or fluorine.

[0116] Examples for factor Xa inhibitors of the above-described compound are disclosed for example in WO 03/084929.

Factor IIa Inhibitors

[0117] It can preferably be provided that the composition has at least one factor IIa inhibitor as clotting factor inhibitor, wherein the at least one factor IIa inhibitor is preferably a thrombin inhibitor. It can be particularly preferably provided that the thrombin inhibitor is selected from the group consisting of the following listed thrombin inhibitors i)-vi).

[0118] It was possible to demonstrate that these factor IIa inhibitors are particularly well suited to the composition because they can be particularly advantageously influenced by the Pgp inhibitor and are well suited for oral consumption.

[0119] In a preferred configuration, it can be provided that the thrombin inhibitor is selected from [0120] i) a compound of the following formula:

##STR00014##

[0121] wherein R.sup.1 is H, C.sub.1-4 alkyl, C.sub.1-4 alkylphenyl, A.sup.1C(O)N(R.sup.4)R.sup.5 or A.sup.1C(O)OR.sup.4, wherein A.sup.1 is a C.sub.1-5 alkylene, R.sup.4 and R.sup.5 are, independently of one another, H, C.sub.1-6 alkyl, phenyl, 2-naphthyl or, if R.sup.1 is A.sup.1C(O)N(R.sup.4)R.sup.5, they are, together with the nitrogen atom to which they are bonded, pyrrolidinyl or piperidinyl,

[0122] R.sup.2 is OH, OC(O)R.sup.6 or C(O)OR.sup.7, wherein R.sup.6 is a C.sub.1-17 alkyl, phenyl or 2-naphthyl, R.sup.7 is a C.sub.1-3 alkylphenyl, phenyl, 2-naphthyl, or C.sub.1-12 alkyl, and

[0123] R.sup.3 is H or C.sub.1-4 alkyl.

[0124] Examples for thrombin inhibitors of the above-described compound are disclosed in WO 1994/029336 and/or WO 1997/23499. For example, melagatran is a thrombin inhibitor according to one configuration of the present invention, which binds reversibly and with high affinity to the active center of thrombin. A prodrug form, ximelagatran (Exanta, Exarta, Exantan?) is for example also a thrombin inhibitor according to a preferred configuration.

[0125] In an alternative preferred configuration, it can be provided that the thrombin inhibitor is selected from [0126] ii) a compound of the following formula:

##STR00015##

[0127] wherein R.sup.24 is C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl,

[0128] Ar.sup.3 is a phenylene, naphthylene, thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group,

[0129] Ar.sup.4 is a phenyl group or a 2-pyridinyl group,

[0130] R.sup.25 is (a) a C.sub.1-3 alkyl group, or (b) a C.sub.2-3 alkyl group substituted with a hydroxyl-, benzyloxy-, carboxy-C.sub.1-3 alkylamino-, C.sub.1-3 alkoxycarbonyl-C.sub.1-3 alkylamino-, N(C.sub.1-3 alkyl)-carboxy-C.sub.1-3 alkylamino- or N(C.sub.1-3 alkyl)-C.sub.1-3 alkoxycarbonyl-C.sub.1-3 alkylamino group,

[0131] E is a cyano or R.sup.26NHC(?NH) group, in which R.sup.26 is a hydrogen atom, a hydroxyl group, a C.sub.1-3 alkyl group or a residue that is cleavable in vivo.

[0132] Examples for thrombin inhibitors of the above-described compound are disclosed for example in WO 1998/37075. For example, dabigatran is a thrombin inhibitor according to one configuration of the present invention, which is a competitive, reversible and direct thrombin inhibitor. A prodrug, dabigatranetexilat (Pradaxa?), which is converted in vivo into dabigatran, is described in more detail in international patent application WO 03/074056, and is also a thrombin inhibitor according to one configuration of the present invention.

[0133] In an alternative preferred configuration, it can be provided that the thrombin inhibitor is selected from [0134] iii) a compound of the following formula:

##STR00016##

[0135] wherein Ar is phenyl, quinolinyl, tetrahydroquinolinyl, naphthyl, naphthoquinone or indane,

[0136] R.sup.8 is

##STR00017##

wherein R.sup.9 is H, a C.sub.1-10 alkyl, a C.sub.6-10 aryl, a C.sub.7-12 aralkyl or 5-indanyl, and R.sup.10 is a C.sub.1-5 alkyl or alkoxy.

[0137] For example, a thrombin inhibitor of the above-described formula, argatroban (Argatra?), can be a thrombin inhibitor according to one configuration. Argatroban is an arginine derivative which, however, has to be applied parenterally. However, it can be administered in a micelle-based formulation, which is also consumed orally. Such a formulation is described in US patent application U.S. Pat. No. 5,679,690. A lipid emulsion of such a compound is also disclosed in European patent application EP 0 608 828. A solid salt of argatroban, which is obtained by precipitation and lyophilization and which should be suitable for oral consumption, is disclosed in US patent application US 2009/0221637.

[0138] In an alternative preferred configuration, it can be provided that the thrombin inhibitor is selected from [0139] iv) a compound of the following formula:

##STR00018##

[0140] wherein Q is C or Si,

[0141] R.sup.41 is H or, together with R.sup.42, defines a C.sub.3-8 carbocycle,

[0142] R.sup.42 is halogen, CF.sub.3, or C.sub.1-6 alkyl or, together with R.sup.43, defines a C.sub.3-8 carbocycle or, together with R.sup.41, defines a C.sub.3-8 carbocycle,

[0143] R.sup.43 is H, halogen, OH, C.sub.1-6 alkyl or, together with R.sup.42, defines a C.sub.3-8 carbocycle,

[0144] R.sup.44 is a heterocycle, (CR.sup.45R.sup.46).sub.2NH.sub.2 or (CR.sup.45R.sup.46)NH.sub.2, wherein R.sup.45 and R.sup.46 are, independently of one another, H, C.sub.1-6 alkyl, CH.sub.2F, CHF.sub.2, CF.sub.3 or CH.sub.2OH.

[0145] Examples for thrombin inhibitors of the above-described compound are disclosed for example in WO 2014/058538.

[0146] In an alternative preferred configuration, it can be provided that the thrombin inhibitor is selected from [0147] v) a compound of the following formula:

##STR00019##

[0148] wherein m is 0 or 1,

[0149] R.sup.43 is H, halogen, OH, C.sub.1-6 alkyl or, together with R.sup.47, defines a C.sub.3-8 carbocycle,

[0150] R.sup.44 is a heterocycle, (CR.sup.45R.sup.46).sub.2NH.sub.2 or (CR.sup.45R.sup.46)NH.sub.2, wherein R.sup.45 and R.sup.46 are, independently of one another, H, C.sub.1-6 alkyl, CH.sub.2F, CHF.sub.2, CF.sub.3 or CH.sub.2OH,

[0151] R.sup.47 is H, halogen, CF.sub.3, C.sub.1-6 alkyl or, together with R.sup.43, defines a C.sub.3-8 carbocycle, and

[0152] R.sup.48 is C.sub.1-6 alkyl.

[0153] Examples for thrombin inhibitors of the above-described compound are disclosed for example in WO 2014/028318.

[0154] In an alternative preferred configuration, it can be provided that the thrombin inhibitor is selected from [0155] vi) a compound of the following formula:

##STR00020##

[0156] The above-described thrombin inhibitor is also known under the name BMS 186282, and for example described by Malley, M. F., Tabernero, L., Chang, C. Y., Ohringer, S. L., Roberts, D. G., Das, J., Sack, J. S .: Crystallographic determination of the structures of human alpha-thrombin complexed with BMS-186282 and BMS-189090.

[0157] Alternatively, it can preferably be provided that the composition has at least one factor IIa inhibitor as clotting factor inhibitor, wherein the at least one factor IIa inhibitor is preferably a thrombin receptor antagonist. It can be particularly preferably provided that the thrombin receptor antagonist is selected from the group consisting of the following listed thrombin receptor antagonist i)-iv)

[0158] It was possible to demonstrate that these factor IIa inhibitors and preferred thrombin receptor antagonist are particularly well suited to the composition because they can be particularly advantageously influenced by the Pgp inhibitor and are well suited for oral consumption.

[0159] In a preferred configuration, it can be provided that the thrombin receptor antagonist is selected from [0160] i) a compound of the following formula:

##STR00021##

[0161] wherein Ar.sup.2 is a phenyl or morpholino group,

[0162] X.sup.1 is H or halogen, and

[0163] R.sup.11 and R.sup.12 are, independently of one another, H, methoxy or ethoxy.

[0164] Examples for thrombin receptor antagonists of the above-described formula are also described in EP 1 813 282. For example, a thrombin receptor antagonist can be the above-described compound atopaxar, also known as E5555. Atopaxar is a hydrobromide having the IUPAC name 1-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1H-isoindol-2-yl)ethanone-hydrobromide.

[0165] In an alternative preferred configuration, it can be provided that the thrombin receptor antagonist is selected from [0166] ii) a compound of the following formula:

##STR00022##

[0167] wherein Het.sup.1 is a mono- or bicyclic heteroaromatic group of 5 to 10 atoms, containing 1 to 9 carbon atoms and 1 to 4 of the heteroatoms N, O or S, and

[0168] B.sup.1 is (CH.sub.2).sub.n1, cis- or trans-(CH.sub.2).sub.n2CR.sup.14?CR.sup.15(CH.sub.2).sub.n3 or (CH.sub.2).sub.n2C?C(CH.sub.2).sub.n3, wherein n.sub.1 is 0 to 5 and n.sub.2 and n.sub.3 are, independently of one another, 0 to 2, R.sup.14 and R.sup.15 are, independently of one another, H, C.sub.1-6 alkyl or halogen, and R.sup.20 is H, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, NHC(O)OR.sup.21, or NHC(O)R.sup.21, wherein R.sup.21 is H, C.sub.1-6 alkyl, C.sub.1-6 alkyl-OH, or C.sub.1-6alkoxy.

[0169] Examples for thrombin receptor antagonists of the above-described formula are also described in US 2003/216437. For example, a thrombin receptor antagonist can be the above-described compound vorapaxar (Zontivity?), also known as SCH 530348. This is N -[(3R,3aS,4S,4aR,7R, 8aR,9aR)-4-[(E)-2-[5-(3-fluorophenyl)-2-pyridyl]vinyl]-3-methyl-1-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-3H-benzo[f]isobenzofuran-7-yl]carbamate.

[0170] In an alternative preferred configuration, it can be provided that the thrombin receptor antagonist is selected from [0171] iii) a compound of the following formula:

##STR00023##

[0172] wherein Het.sup.2 is a mono- or bicyclic heteroaromatic group of 5 to 14 atoms, containing 1 to 13 carbon atoms and 1 to 4 heteroatoms N, O or S,

[0173] B.sup.2 is (CH.sub.2).sub.n1, CH.sub.2O, CH.sub.2S, CH.sub.2NR.sup.13, C(O)NR.sup.13, NR.sup.13C(O),

##STR00024##

cis- or trans-(CH.sub.2).sub.n2CR.sup.14?CR.sup.15(CH.sub.2).sub.n3 or (CH.sub.2).sub.n2C?C(CH.sub.2).sub.n3, wherein n.sub.1 is 0 to 5 and n.sub.2 and n.sub.3 are, independently of one another, 0 to 2, wherein R.sup.13 is H, C.sub.1-6 alkyl, phenyl, C.sub.3-7 cycloalkyl, (C.sub.3-7 cycloalkyl)-(C.sub.1-6 alkyl), (C.sub.1-6 alkoxy)-(C.sub.1-6 alkyl), (C.sub.1-6 alkyl)-OH or -(C.sub.1-6 alkyl)amino, and R.sup.14 and R.sup.15 are, independently of one another, H, C.sub.1-6 alkyl or halogen,

[0174] R.sup.22 and R.sup.23 are, independently of one another, H, R.sup.16(C.sub.1-10 alkyl), R.sup.16(C.sub.2-10 alkenyl), R.sup.16(C.sub.2-10 alkynyl), R.sup.16(C.sub.1-10 alkyl), heterocycloalkyl, R.sup.17-aryl, R.sup.17-aryl)-(C.sub.1-8 alkyl), OH, OC(O)R.sup.18, CO(O)R.sup.19, C(O)R.sup.18, C(O)NR.sup.18R.sup.19 or NR.sup.18R.sup.19, wherein R.sup.16 and R.sup.17 are, independently of one another, H, a halogen or OH, and R.sup.18 and R.sup.19 are, independently of one another, H or C.sub.1-10 alkyl.

[0175] Examples for thrombin receptor antagonists of the above-described compound are disclosed for example in WO 01/96330.

[0176] In an alternative preferred configuration, it can be provided that the thrombin receptor antagonist is selected from [0177] iv) a compound of the following formula:

##STR00025##

[0178] wherein B is a monocyclic aromatic ring,

[0179] R.sup.19 is NHCOR.sup.53, NHSO.sub.2R.sup.54, NHCON(R.sup.55)(R.sup.56), NHCOOR.sup.57 or CONHR.sup.58, wherein R.sup.53 to R.sup.58 are, independently of one another, H, a hydrocarbon group, a heterocyclic group or an alkoxy group, and

[0180] R.sup.50 and R.sup.52 are, independently of one another, H, a hydrocarbon group, a heterocyclic group or an alkoxy group.

[0181] Examples for thrombin receptor antagonists of the above-described compound are disclosed for example in EP 1 867 331.

Combination of Clotting Factor Inhibitors

[0182] It can preferably be provided that the composition has at least one factor Xa inhibitor and at least one factor IIa inhibitor as clotting factor inhibitors.

[0183] This makes it possible to achieve particularly potent clotting inhibition even at a comparatively low dose of both clotting factor inhibitors. This also makes it possible to achieve a particularly low risk of cross-contamination in predators or scavengers, since both clotting factor inhibitors are metabolized differently.

[0184] Without being bound to a theory, it is assumed that the combination of a factor Xa inhibitor and a factor IIa inhibitor is particularly efficient because two clotting factors are inhibited which are usually potentiated in functioning clotting inhibition, as a result of which efficient clotting inhibition can be achieved even at low doses.

[0185] Thus, the combination of these clotting factor inhibitors makes it possible to achieve an effect that goes beyond the effect of the individual clotting factor inhibitors.

Additional Platelet Aggregation Inhibitor

[0186] It can preferably be provided that the composition additionally has: [0187] c) at least one platelet aggregation inhibitor.

[0188] Additionally inhibiting platelet aggregation makes it possible not only for individual clotting factors, for example the clotting factors of the end sections of the intrinsic and the extrinsic blood clotting cascades, to be directly inhibited, but also the aggregation capacity of the clotting factors in the corresponding clotting factor complexes overall. This makes it possible in particular to achieve further potentiation of the clotting inhibition.

[0189] Thus, the additional platelet aggregation inhibitor makes it possible to achieve an effect that goes beyond the effect of the clotting factor inhibitors and the platelet aggregation inhibitors alone.

[0190] It can preferably be provided that the at least one platelet aggregation inhibitor is selected from the group consisting of cyclooxygenase inhibitors, P2Y12 receptor antagonists, phosphodiesterase inhibitors and glycoprotein GPIIb/IIIa receptor antagonists.

[0191] It can preferably be provided that the platelet aggregation inhibitor is a cyclooxygenase inhibitor selected from the group consisting of a compound of the following formula i).

[0192] It was possible to demonstrate that these platelet aggregation inhibitors are particularly well suited to the composition, since they particularly efficiently inhibit potentiation of clotting by the clotting factors.

[0193] In a preferred configuration, it can be provided that the cyclooxygenase inhibitor is selected from [0194] i) a compound of the following formula:

##STR00026##

[0195] It can preferably be provided that the platelet aggregation inhibitor is a P2Y12 receptor antagonist selected from the group consisting of a compound of the following formulae i)-ix).

[0196] It was possible to demonstrate that these platelet aggregation inhibitors are particularly well suited to the composition, since they particularly efficiently inhibit potentiation of clotting by the clotting factors.

[0197] In a preferred configuration, it can be provided that the P2Y12 receptor antagonist is selected from i) a compound of the following formula:

##STR00027##

[0198] wherein R.sup.94 is H, halogen, hydroxyl or C.sub.1-6 alkyl,

[0199] R.sup.95 is H, halogen, hydroxyl, nitro, C.sub.1-6 alkyl or C.sub.1-4 alkoxy, and

[0200] R.sup.96 is H or halogen.

[0201] For example, an above-described compound can be ticlopidine (Tiklyd?), as described in U.S. Pat. Nos. 4,051,141 and 4,591,592. According to one configuration, the P2Y12 receptor antagonist can also be a prodrug which can be converted in vivo into an active metabolite of the above-described compound.

[0202] In an alternative preferred configuration, it can be provided that the P2Y12 receptor antagonist is selected from [0203] ii) a compound of the following formula:

##STR00028##

[0204] wherein Y.sup.1 is OR.sup.98 or N(R.sup.99)R.sup.100, wherein R.sup.99 and R.sup.100 are, independently of one another, H, halogen or a C.sub.1-4 alkyl group, and R.sup.98 is H or C.sub.1-4 alkyl, and

[0205] R.sup.97 is H, halogen, or a C.sub.1-4 alkyl group.

[0206] For example, an above-described compound can be clopidogrel (Iscovera, Plavix?), an orally administrable platelet aggregation inhibitor according to EP 0 099 802 and U.S. Pat. No. 4,529,596. According to one configuration, the P2Y12 receptor antagonist can also be a prodrug which is only converted in vivo into an active metabolite and is described in U.S. Pat. No. 4,847,265.

[0207] In an alternative preferred configuration, it can be provided that the P2Y12 receptor antagonist is selected from [0208] iii) a compound of the following formula:

##STR00029##

[0209] wherein R.sup.101 is H, OH, amino, C.sub.1 to C.sub.4 alkoxy, ArC.sub.1-4 alkyloxy, C.sub.1-18 alkanoyloxy,

[0210] C.sub.3-6 alkenoyloxy or arylcarbonyloxy,

[0211] R.sup.102 is C.sub.1-10 alkanoyl, C.sub.3-6 l alkenoyl, C.sub.4-8 cycloalkylcarbonyl having 3 to 7 ring atoms, substituted benzoyl and 5,6-dihydro-1,4,2-dioxazin-3-yl,

[0212] Y.sup.2 is NH, O or S, and

[0213] R.sup.103 is H, halogen, OH, amino, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio or a carboxy group.

[0214] For example, the P2Y12 receptor antagonist can be prasugrel ((RS)-[5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-6,7-dihydro-4H-thieno[3,2-c]pyridin-2-yl]acetate), as described in EP 0 099 802 or U.S. Pat. No. 5,288,726, a prodrug which is converted in vivo into an active metabolite containing thiol.

[0215] In an alternative preferred configuration, it can be provided that the P2Y12 receptor antagonist is selected from [0216] iv) a compound of the following formula:

##STR00030##

[0217] wherein R.sup.104 is H, halogen, hydroxy-C.sub.1-8 alkyl, C.sub.1-8 alkoxy-C.sub.1-8 alkyl or carboxy-C.sub.1-8 alkyl,

[0218] R.sup.105 is C.sub.1-8 alkyl, C.sub.1-8 alkoxy-C.sub.1-8 alkylthio-C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl-C.sub.1-8 alkyl, phenyl-C.sub.1-8 alkyl, heterocyclyl, heterocyclyl-C.sub.1-8 alkyl, heteroaryl-C.sub.1-8 alkyl or halo-C.sub.1-8 alkyl,

[0219] R.sup.106 and R.sup.107 are, independently of one another, H, or, together with the carbon atom to which they are bonded, define a 5- or 6-membered heterocycle, and

[0220] X.sup.8 and X.sup.9 are, independently of one another, CH, CH.sub.2 or CH(OH), and is a single bond or a double bond.

[0221] Examples for P2Y12 receptor antagonists of the above-described compound are described in WO 2008/054796.

[0222] In an alternative preferred configuration, it can be provided that the P2Y12 receptor antagonist is selected from [0223] v) a compound of the following formula:

##STR00031##

[0224] wherein R.sup.108 is heterocyclyl, heterocyclyl-C.sub.1-8 alkyl, heteroaryl, heteroaryl-C.sub.1-8 alkyl or halo-C.sub.1-8 alkyl, and

[0225] R.sup.109 is C.sub.1-8 alkyl, C.sub.1-8 alkoxy-C.sub.1-8 alkylthio-C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-8 alkyl, phenyl-C.sub.1-8 alkyl, heterocyclyl-C.sub.1-8 alkyl, heteroaryl-C.sub.1-8 alkyl or halo-C.sub.1-8.

[0226] Examples for P2Y12 receptor antagonists of the above-described compound are described in WO 2008/054795.

[0227] In an alternative preferred configuration, it can be provided that the P2Y12 receptor antagonist is selected from [0228] vi) a compound of the following formula:

##STR00032##

[0229] wherein R.sup.110 is OH, CH.sub.2OH or OCH.sub.2CH.sub.2OH,

[0230] R.sup.111 is C.sub.3-5 alkyl,

[0231] R.sup.112 is phenyl, including phenyl substituted with one or more F.

[0232] For example, an above-described compound can be ticagrelor (Brilinta?, Brilique?, Possia?), as described in WO 2000/34283.

[0233] In an alternative preferred configuration, it can be provided that the P2Y12 receptor antagonist is selected from [0234] vii) a compound of the following formula:

##STR00033##

[0235] wherein R.sup.113 is H or C.sub.1-4 alkyl,

[0236] R.sup.114 to R.sup.118 are, independently of one another, H, C.sub.1-6 alkyl, C.sub.1-3 fluoroalkyl, halogen, CN or phenyl,

[0237] X.sup.10 is C.sub.3-8 alkylenyl, C.sub.1-3 cycloalkylenyl or C.sub.3-15 heterocyclyl,

[0238] Z.sup.2 is alkylenyl, alkenyl or alkynyl,

[0239] A.sup.1 is a 3- to 10-membered heterocyclic monocyclic, bicyclic or spiroheterocyclic ring containing 0, 1, 2 or 3 additional heteroatoms from N, S or O,

[0240] Q.sup.5 is a mono- or bicyclic 3- to 15-membered heterocycle, and

[0241] B.sup.6 and B.sup.7 are, independently of one another, H, C.sub.1-4 alkyl, C.sub.3-8 cycloalkyl, .sub.6-14 aryl, a 3- to 7-membered heterocycle, C(O)OH, CNH.sub.2, C(O)NH(C.sub.1-6 alkyl), C(O)O(C.sub.1-6 alkyl) or C(O)N(R)R.

[0242] Examples for P2Y12 receptor antagonists of the above-described compound are described in WO 2008/128647.

[0243] In an alternative preferred configuration, it can be provided that the P2Y12 receptor antagonist is selected from [0244] viii) a compound of the following formula:

##STR00034##

[0245] wherein A.sup.2 is O or NOH,

[0246] B.sup.8 is a covalent bond, C(O) or methylenyl,

[0247] B.sup.9 is N or CH,

[0248] E is a covalent bond, OC(O) or NHC(O),

[0249] R.sup.119 is H, C.sub.1-8 alkyl-, C.sub.0-4 alkylene-(C.sub.3-8 cycloalkyl), C.sub.0-4 alkylene-(C.sub.6-4 aryl) or C.sub.0-4 alkylene-heterocyclyl,

[0250] R.sup.120 is H, NHC(O) or OC(O),

[0251] R.sup.121 is C.sub.1-8 alkyl-, CF.sub.3, or (C.sub.1-8 alkylene)-C(O)OR.sup.132 and R.sup.122 is H, halogen, C.sub.1 to C.sub.8 alkyl-, (C.sub.1-8 alkylene)-C(O)OR.sup.132, (C.sub.2-6 alkenylene)-C(O)OR.sup.132 or C.sub.3-7 cycloalkyl)-C(O)OR.sup.132, wherein R.sup.132 is H, C.sub.1 to C.sub.8 alkyl- or C.sub.0-4 alkylene-(C.sub.3-8-cycloalkyl),

[0252] R.sup.123 to R.sup.127 are, independently of one another, H, halogen, CN, NO.sub.2, C.sub.1-8 alkyl-, C.sub.0-4 alkylene-OR.sup.132, (C.sub.0-4 alkylene)-C(O)OR.sup.132, (C.sub.0-4 alkylene)-C(O)R.sup.132, (C.sub.0-4 alkylene)-C(O)NR.sup.132R.sup.133 or (C.sub.0-4 alkylene)-CNR.sup.132R.sup.133, wherein R.sup.133 is H or C.sub.1 to C.sub.8 alkyl-, and

[0253] R.sup.128 to R.sup.131 are, independently of one another, H, ?O, OH or C.sub.1 to C.sub.8 alkyl-.

[0254] Examples for P2Y12 receptor antagonists of the above-described compound are described in WO 2008/155022.

[0255] In an alternative preferred configuration, it can be provided that the P2Y12 receptor antagonist is selected from [0256] ix) a compound of the following formula:

##STR00035##

[0257] wherein Z.sup.3 is a substituted -2-thiazole ring or -4-thiazole ring, wherein a 2-thiazole ring is substituted at position 4 with H, an aryl group and/or at position 5 with H, halogen, C.sub.1 to C.sub.4 alkyl-, C.sub.2 to C.sub.4 alkenyl-, phenyl or di-C.sub.1-6 alkylamino, and a 4-thiazole ring is substituted at position 2 with H or an aryl group and/or at position 5 with H, halogen, COOH, C.sub.1 to C.sub.4 alkyl-, COO(C.sub.1-4 alkyl-), C.sub.2-4 alkenyl-, phenyl, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, heterocyclyl or 2-methoxymethylcycloprop-1-yl,

[0258] Y.sup.3Z.sup.4 either represent a bond and H, or Y.sup.3 is C.sub.1 to C.sub.3 alkanediyl and Z.sup.4 is H, OH, phenyl, COOH, COO(C.sub.1-4 alkyl), P(O)(OH).sub.2, P(O)(O-[C.sub.1-4 alkyl]).sub.2, P(O)(O-[C.sub.1-4 alkoxy]-C(O)OCH.sub.2).sub.2 or P(O)(NH[C.sub.1-4 alkoxy]-C(O)[C.sub.1-4 alkyl]).sub.2, and

[0259] R.sup.134 is C.sub.1 to C.sub.6 alkoxy.

[0260] Examples for P2Y 12 receptor antagonists of the above-described compound are described in WO 2010/122504.

[0261] It can preferably be provided that the platelet aggregation inhibitor is a glycoprotein GPIIb/IIIa receptor antagonist selected from the group consisting of a compound of the following formulae i)-vi).

[0262] It was possible to demonstrate that these platelet aggregation inhibitors are particularly well suited to the composition, since they particularly efficiently inhibit potentiation of clotting by the clotting factors.

[0263] In a preferred configuration, it can be provided that the glycoprotein GPIIb/IIIa receptor antagonist is selected from [0264] i) a compound of the following formula:

##STR00036##

[0265] wherein Y.sup.4 and Y.sup.5 are, independently of one another, a non-interfering substituent or are absent,

[0266] K* is a substituted or unsubstituted lysyl residue of formula R.sup.135R.sup.136.sub.2N(CH.sub.2).sub.4CHNHCO, wherein R.sup.135 and R.sup.136 are, independently of one another, H or C.sub.1 to C.sub.6 alkyl,

[0267] X.sup.11 and X.sup.12 are, independently of one another, any desired residue which enables the ring formation shown between X.sup.11 and X.sup.12,

[0268] (AA.sup.1) is a small neutral amino acid and n.sub.4 is a number from 0 to 3,

[0269] (AA.sup.2) is a large nonpolar amino acid and n.sub.5 is a number from 0 to 3,

[0270] (AA.sup.3) is a proline residue or a modified proline residue and no is 0 or 1, and

[0271] (AA.sup.4) is a small neutral amino acid or an N-alkylated form thereof and n.sub.7 is a number from 0 to 3.

[0272] For example, in one configuration, the glycoprotein GPIIb/IIIa receptor antagonist can be an arginyl-glycyl-aspartate mimetic, for example the peptide eptifibatide (Integrilin?)

[0273] In a preferred configuration, it can be provided that the glycoprotein GPIIb/IIIa receptor antagonist is selected from [0274] ii) a compound of the following formula:

##STR00037##

[0275] wherein Y.sup.6 is

##STR00038##

[0276] q is 2 or 3,

[0277] q is an integer from 0 to 4,

[0278] R.sup.138 is H, C.sub.1 to C.sub.6 alkyl-, C.sub.1 to C.sub.8 alkoxy-, C.sub.1 to C.sub.8 alkoxycarbonyl-, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkyl, cycloalkyl or aryl,

[0279] R.sup.139 is C.sub.1 to C.sub.6 alkyl-, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, alkoxycarbonyloxyalkyl and C.sub.3 to C.sub.6 cycloalkyl or aryl.

[0280] In one configuration, the glycoprotein GPIIb/IIIa receptor antagonist can for example be orbofiban (ethyl N-{[(3S)-1-(4-carbamimidoylphenyl)-2-oxo-3-pyrrolidinyl]carbamoyl}-?-alaninate), as for example described in U.S. Pat. No. 5,721,366.

[0281] In a preferred configuration, it can be provided that the glycoprotein GPIIb/IIIa receptor antagonist is selected from [0282] iii) a compound of the following formula:

##STR00039##

[0283] wherein Z.sup.5 is a covalent single bond, C.sub.1 to C.sub.7 alkyl-, C.sub.2 to C.sub.7 alkenyl or C.sub.2 to C.sub.7 alkynyl,

[0284] R.sup.139 is C.sub.1 to C.sub.6 alkyl-, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, alkoxycarbonyloxyalkyl, C.sub.3 to C.sub.6 cycloalkyl or aryl,

[0285] R.sup.140 is hydroxyl, C.sub.1 to C.sub.10 alkoxy-, C3 to C.sub.10 alkylcarbonyloxyalkyloxy- or C.sub.7 to C.sub.11 aralkyloxy-, and

[0286] is a single bond or a double bond.

[0287] In one configuration, the glycoprotein GPIIb/IIIa receptor antagonist can for example be roxifiban (DMP 754, MK 0853, XJ 754, Lumaxis?, methyl-N.sup.3-[2-{3-(4-formamidinophenyl) -isoxazolin-5-(R)-yl}-acetyl]-N.sup.2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate), as described in WO 95/14683.

[0288] In a preferred configuration, it can be provided that the glycoprotein GPIIb/IIIa receptor antagonist is selected from [0289] iv) a compound of the following formula:

##STR00040##

[0290] wherein one of Z.sup.6 and Z.sup.7 is CH and the other is CH, C.sub.1 to C.sub.8 alkyl-, C.sub.1 to C.sub.8 alkoxy or N,

[0291] Z.sup.8 is NH, C.sub.1 to C.sub.8 alkyl-N or C.sub.1 to C.sub.8 alkoxy-(C.sub.1 to C.sub.8 alkyl-)N,

[0292] Z.sup.9 is H or C.sub.1 to C.sub.8 alkyl optionally substituted with OH, SH, CONH.sub.2, CONHC.sub.1 to C.sub.8 alkyl, C.sub.1 to C.sub.8 alkylthio, aryl, NH.sub.2, NH(C.sub.1 to C.sub.8 alkyl-), N(C.sub.1 to C.sub.8 alkyl-)(C.sub.1 to C.sub.8 alkyl-) or O(C.sub.1 to C.sub.8 alkyl-),

[0293] Z.sup.10 is O, CH.sub.2, NH, acyl-N or C.sub.1 to C.sub.8 alkyl-OC(O)N.

[0294] Z.sup.11 and Z.sup.12 are H, C.sub.1 to C.sub.8 alkyl, OH, C.sub.1 to C.sub.8 alkoxy, C.sub.1 to C.sub.8 alkoxy- C.sub.1 to C.sub.8 alkyl, carboxy- C.sub.1 to C.sub.8 alkyl, P(O)(OC.sub.1 to C.sub.8 alkyl).sub.2, C(O)OC.sub.1 to C.sub.8 alkyl, OC(O)-C.sub.1 to C.sub.8 alkyl, OC(O)OC.sub.1 to C.sub.8 alkyl or C(O)SC.sub.1 to C.sub.8 alkyl, wherein at least one of Z.sup.11 and Z.sup.12 is H, or Z.sup.11 and Z.sup.12, together with the N atoms to which they are bonded, are a (5,5-dimethyl- or 5-oxo) -4,5-dihydro-1,2,4-oxadiazol-3-yl group,

[0295] Z.sup.16 is a 1,4-piperidinylene bonded to the keto group via the N atom, or is 1,4-phenylene optionally substituted with C.sub.1 to C.sub.8 alkyl, C.sub.1 to C.sub.8 alkoxy, OCH.sub.2COOH or OCH.sub.2COO(C.sub.1 to C.sub.8alkyl), and

[0296] R.sup.141 is NH.sub.2, NH(C.sub.1 to C.sub.8 alkyl), NH(C.sub.1 to C.sub.8 alkyl-)COOH, NH(C.sub.1 to C.sub.8 alkyl)-COO(C.sub.1 to C.sub.8 alkyl), C.sub.1 to C.sub.8 alkyloxy or C.sub.1 to C.sub.8 alkenyloxy.

[0297] In one configuration, the glycoprotein GPIIb/IIIa receptor antagonist can for example be sibrafiban (Ro 48-3657, Xubix?), as described in EP 0 656 348.

[0298] In a preferred configuration, it can be provided that the glycoprotein GPIIb/IIIa receptor antagonist is selected from [0299] v) a compound of the following formula:

##STR00041##

[0300] wherein Q.sup.6 is a four- to eight-membered heterocyclic ring having 1, 2, 3 or 4 heteroatoms which are N, O or S,

[0301] m is an integer from 0 to 8,

[0302] m and m are, independently of one another, an integer from 0 to 2,

[0303] Z.sup.13 and Z.sup.14 are, independently of one another, phenyl, O, SO.sub.2,

##STR00042##

or a 5- or 6-membered ring containing 0 or 1 heteroatoms from N or O,

[0304] Z.sup.15 is an optionally present group which is O, NHCO, CONH or C.sub.1 to C.sub.5 alkyl-OC(O)N,

[0305] R.sup.142 is H or C.sub.1 to C.sub.8 alkyl,

[0306] R.sup.143 and R.sup.144 are, independently of one another, H, C.sub.1 to C.sub.4 alkyl or C.sub.4 to C.sub.10 aralkyl, and

[0307] R.sup.145 is aryl, C.sub.1 to C.sub.10 alkyl or cycloalkyl or C.sub.4 to C.sub.10 aralkyl.

[0308] Examples for glycoprotein GPIIb/IIIa receptor antagonists of the above-described compound are described for example in WO 93/19046.

[0309] In a preferred configuration, it can be provided that the glycoprotein GPIIb/IIIa receptor antagonist is selected from [0310] vi) a compound of the following formula:

##STR00043##

[0311] wherein Q.sup.6 is a six-membered heterocyclic ring having 1 or 2 heteroatoms which are N, m is an integer from 2 to 6,

[0312] Z.sup.15 is

##STR00044##

and

[0313] R.sup.146 is aryl, C.sub.1 to C.sub.10 alkyl or Ca to C.sub.10 aralkyl.

[0314] In one configuration, the glycoprotein GPIIb/IIIa receptor antagonist can for example be tirofiban ((S)-2-(butylsulfonamino)-3-(4-[4-(piperidin-4-yl)butoxy]phenyl)-propanoic acid, Aggrastat?), as described in WO 93/19046.

[0315] In a preferred configuration, it can be provided that the glycoprotein GPIIb/IIIa receptor antagonist is selected from the group of fibans, consisting of fradafiban, lamifiban, lefrafiban, lotrafiban, orbofiban, roxifiban, sibrafiban and xemilofiban.

[0316] It can preferably be provided that the composition has at least two platelet aggregation inhibitors, wherein preferably at least one platelet aggregation inhibitor is a cyclooxygenase inhibitor and at least one platelet aggregation inhibitor is a P2Y12 receptor antagonist or a glycoprotein GPIIb/IIIa receptor antagonist.

[0317] This advantageously makes it possible to achieve particularly efficient inhibition of platelet aggregation. This thus makes it possible to keep the dose particularly low, thereby reducing environmental impact and further reducing the risk of cross-contamination.

Pgp Inhibitors

[0318] Preferably, the Pgp inhibitor can be selected from the drug groups consisting of: the group of the class C antiarrhythmics, for example amiodarone and dronedarone; calcium antagonists, for example diltiazem and verapamil; HMG-CoA reductase inhibitors or statins, for example atorvastatin, rosuvastatin, lovastatin and simvastatin; macrolide antibiotics, for example clarithromycin, roxithromycin and erythromycin; gyrase inhibitors, for example moxifloxacin, ofloxacin; azolamide antimycotics, for example fluconazole, voriconazole and itraconazole; antimalarials, for example mefloquine and quinidine; HIV drugs, for example ritonavir, nefinavir, saquinavir and elacridar; cytotstatic agents, for example tamoxifen and cyclosporin; immunosuppressants and cell cycle inhibitors, for example tacrolimus and ciclosporin; proton pump inhibitors, for example lansoprazole and omeprazole; and antiemetics, for example ondansetron.

[0319] It can preferably be provided that the at least one Pgp inhibitor inhibitor is selected from the group consisting of a compound of the following formulae i)-ix).

[0320] In a not preferred configuration, certain Pgp inhibitors have proven to be less effective in the context of the invention. In particular, ketoconazole (Nizoral?) belongs to these less effective compounds. It was found that although ketoconazole does have basic efficacy in the context of the invention, this efficacy is considerably lower compared to other Pgp inhibiting substances.

[0321] In one configuration, it can be provided that the Pgp inhibitor is selected from [0322] i) a compound of the following formula:

##STR00045##

[0323] The above-described Pgp inhibitor is also known under the name quinidine (Duriles?).

[0324] In an alternative preferred configuration, it can be provided that the Pgp inhibitor is selected from [0325] ii) a compound of the following formula:

##STR00046##

[0326] The above-described Pgp inhibitor is also known under the name ritonavir (Norvir?).

[0327] In an alternative preferred configuration, it can be provided that the Pgp inhibitor is selected from [0328] iii) a compound of the following formulae:

##STR00047##

[0329] or a mixture thereof, in particular a racemate thereof.

[0330] The above-described Pgp inhibitor is also known under the name verapamil (Isoptin?).

[0331] In an alternative preferred configuration, it can be provided that the Pgp inhibitor is selected from [0332] iv) a compound of the following formula:

##STR00048##

[0333] The above-described Pgp inhibitor is also known under the name aminodarone (Cordarone?)

[0334] In an alternative preferred configuration, it can be provided that the Pgp inhibitor is selected from [0335] v) a compound of the following formula:

##STR00049##

[0336] The above-described Pgp inhibitor is also known under the name clarithromycin (Klacid?).

[0337] In an alternative preferred configuration, it can be provided that the Pgp inhibitor is selected from [0338] vi) a compound of the following formula:

##STR00050##

[0339] The above-described Pgp inhibitor is also known under the name erythromycin (Erythrocin?).

[0340] In an alternative preferred configuration, it can be provided that the Pgp inhibitor is selected from [0341] vii) a compound of the following formulae:

##STR00051##

[0342] or a mixture thereof, in particular a racemate thereof.

[0343] The above-described Pgp inhibitor is also known under the name itraconazole (Sporanox?).

[0344] In an alternative preferred configuration, it can be provided that the Pgp inhibitor is selected from [0345] viii) a compound of the following formula:

##STR00052##

[0346] The above-described Pgp inhibitor is also known under the name propafenone (Rytmonorm?).

[0347] In a particularly preferred alternative configuration, it can be provided that the Pgp inhibitor is selected from [0348] ix) a compound of the following formula:

##STR00053##

[0349] The above-described Pgp inhibitor is also known under the name voriconazole (VFend?). Surprisingly, in the context of the invention, this compound has proven to be a highly effective Pgp inhibitor and therefore forms a particularly preferred configuration of the invention.

[0350] In a further preferred alternative configuration, it can be provided that the Pgp inhibitor is selected from [0351] x) a compound of the following formula:

##STR00054##

[0352] The above-described Pgp inhibitor is also known under the name Elacridar.

[0353] In a further preferred alternative configuration, it can be provided that the Pgp inhibitor is selected from [0354] xi) a compound of the following formula:

##STR00055##

[0355] The above-described Pgp inhibitor is also known under the name fluconazole (Canifug-Fluco?, Diflucan?, Flunazul?, Fungata?).

Further Subjects

[0356] The invention further proposes the use of an above-described composition as rodenticide. This should be understood to mean that the composition is used for controlling pest rodents.

[0357] For example, the composition can be provided in a pest rodent bait which is laid such that it is consumed as food by the pest rodents to be controlled.

[0358] The invention further also proposes a pest rodent bait containing the above-described composition.

[0359] For example, it can be provided that the pest rodent bait has a carrier and the above-described composition. The carrier can in particular be a composition that is attractive to pest rodents, or a suitable food for the pest rodent.

[0360] In some embodiments, a composition disclosed herein can be combined with a composition that contains a cereal flour, a cereal bran, a gelling agent, a sugar, an oil, an emulsifier and a humectant, as for example described in international patent application WO 2014/186885.

[0361] It can preferably be provided that the pest rodent bait has the composition in an amount that induces no acute toxicity when the a normal amount of food for the pest rodent is consumed. This makes it possible on the one hand for the toxicity of the pest rodent bait to not be immediately acutely toxic if accidentally ingested by other animals or for example by humans. This further makes it possible for the effect of the pest rodent bait to only arise upon repeated consumption, so that the pest rodents do not form any avoidance behavior in respect of the pest rodent bait.

[0362] The pest rodent bait can for example contain seeds and/or cereals. The pest rodent bait can for example be provided in the form of granules (or pellets), in the form of packaged cereals or packaged pellets, or as bait blocks. In some embodiments, a composition disclosed herein can be contained in a bait block which contains a polymeric binder in the form of a polymer based on an acrylic acid ester and acrylonitrile, as for example described in international patent application WO 2014/064272.

[0363] The invention further proposes a method for controlling pest rodents, wherein an above-described pest rodent bait is laid.

[0364] For example, it can be provided that the pest rodent bait is used in conjunction with a bait station, as is for example commercially available. This for example makes it possible to prevent the pest rodent bait from being eaten by larger animals.

[0365] The different active components can be offered to the animals in various baits as pellets. paste, edible bait, etc., the basis of which can in principle be composed of the following components: 20-70 wt % carbohydrates, 5-50 wt % fat, 10-40 wt % protein, the remainder being water, table salt and sugar.

[0366] It can preferably be provided that the individual components of the above-described composition are each present at a concentration in a range from greater than 0 ppm to less than or equal to 10 000 ppm relative to the total weight of the pest rodent bait, preferably greater than 10 ppm to less than or equal to 6000 ppm, in particular greater than 50 ppm to less than or equal to 5000 ppm relative to the total weight of the pest rodent bait.

[0367] According to a preferred configuration of the invention, it may be provided that the pest rodent bait contains a Pgp inhibitor at a concentration in a range from greater than 0 ppm to less than 6000 ppm relative to the total weight of the pest rodent bait, preferably greater than 250 ppm to less than or equal to 5500 ppm, in particular greater than 750 ppm to less than or equal to 5000.

[0368] According to a further preferred configuration of the invention, it may be provided that the pest rodent bait contains a factor Xa antagonist at a concentration in a range from greater than 0 ppm to less than or equal to 8000 ppm, preferably greater than 50 ppm to less than or equal to 5000 ppm, in particular greater than 100 ppm to less than or equal to 4000 ppm.

[0369] According to a further preferred configuration of the invention, it may be provided that the pest rodent bait contains a factor IIa antagonist at a concentration in a range from greater than 0 ppm to less than or equal to 8000 ppm, preferably greater than 50 ppm to less than or equal to 5000 ppm, in particular greater than 100 ppm to less than or equal to 4000 ppm.

[0370] According to a further preferred configuration of the invention, the pest rodent bait has between greater than or equal to 40 wt % and less than or equal to 75 wt % maize, between greater than or equal to 10 wt % and less than or equal to 45 wt % oat flakes, between greater than or equal to 3 wt % and less than or equal to 10 wt % peanut butter, between greater than or equal to 0.5 wt % and less than or equal to 5 wt % sugar, and also between greater than or equal to 0.4 wt % and less than or equal to 1.2 wt % salt, the remainder being water.

[0371] According to a further configuration of the invention, the pest rodent bait can contain between greater than or equal to 100 ppm and less than or equal to 2500 ppm, preferably between greater than or equal to 250 ppm and less than or equal to 1500 ppm, in particular between greater than or equal to 500 ppm and less than or equal to 1400 ppm of acetylsalicylic acid.

[0372] According to a further configuration of the invention, the pest rodent bait has between greater than or equal to 50 ppm and less than or equal to 1000 ppm, preferably between greater than or equal to 100 ppm and less than or equal to 800 ppm, in particular between greater than or equal to 200 ppm and less than or equal to 700 ppm of prasugrel.

[0373] The following table shows example pest rodent bait compositions according to the invention and the efficacy achieved with these compositions. The basic bait composition (standard chow) used consisted of 65% maize, 25% oat flakes, % peanut butter, 3% refined finely granulated sugar, and 1% fine table salt.

TABLE-US-00001 Starting End Time to Factor Xa Factor IIa Pgp weight weight Mortality mortality antagonist antagonist antagonist (g) (g) (%) (d) 1 Apixaban I -.- Voriconazole I 319 (247-383) 284 (221-343) 50% (5/10) 9.4 (7-12) 2 Apixaban II -.- Voriconazole I 286 (223-337) 248 (202-278) 70% (7/10) 8.6 (6-11) 3 Apixaban III -.- Voriconazole II 310 (252-371) 243 (212-301) 70% (7/10) 8.3 (5-11) 4 Apixaban II Voriconazole II 291 (264-388) 266 (224-308) 60% (6/10) 7.2 (5-9) 5 Apixaban III Fluconazole 321 (285-262) 265 (251, 278) 80% (8/10) 6.9 (5-10) 6 Apixaban III Ritonavir/elacridar 304 (238-361) 306 90% (9/10) 6.4 (5-8) 7 Rivaroxaban I Voriconazole I 300 (246-325) 277 (247-306) 60% (6/10) 8.2 (7-10) 8 Rivaroxaban II Voriconazole I 309 (253-358) 299 (286-312) 70% (7/10) 7.1 (6-8) 9 Dabigatran II Voriconazole I 303 (273-358) 289 (282-300) 70% (7/10) 8.2 (7-10) 10 Dabigatran III Voriconazole I 318 (273-358) 271 (241-304) 60% (6/10) 8.8 (7-11) 11 Apixaban II Dabigatran I Voriconazole II 324 (267-351) 302 (267-336) 80% (8/10) 6.8 (7-12) 12 Apixaban II Dabigatran II Voriconazole II 303 (236-366) 317 (279-356) 70% (7/10) 6.6 (5-8) 13 Apixaban II Dabigatran III Voriconazole I 295 (241-338) -.- 100% (10/10) 5.8 (5-7) 14 Betrixaban Ketoconazole 220 (215-341) 184 (140-288) 30% (3/10) 10.3 (5-13)

[0374] The active clotting inhibitors were used at the following listed concentrations.

TABLE-US-00002 Anticoagulant: Betrixaban Apixaban I Apixaban II Apixaban III Rivaroxaban I Rivaroxaban II Dabigatran I Dabigatran II Dabigatran III 6000 mg 150 mg 300 mg 600 mg 600 mg 1200 mg 1000 mg 2000 mg 4000 mg

[0375] The Pgp inhibitors were used at the following listed concentration.

TABLE-US-00003 Pgp inhibitor Ketoconazole Voriconazole I Voriconazole II Fluconazole Ritonavir Elacridar 1300 mg 1200 mg 2400 mg 1200 mg 4000 mg 4000 mg

[0376] Surprisingly, it was found that in particular the use of voriconazole as Pgp inhibitor leads to high mortality even at comparatively low concentrations in combination with different active clotting inhibitors. In contrast, the addition of ketoconazole, even at high concentrations of active clotting inhibitor, exhibited significantly lower mortality.