Combinations of medicaments, containing pde4-inhibitors and ep4-receptor- antagonists

A method of treating a disease selected from respiratory complaints, pulmonary diseases, gastrointestinal diseases, inflammatory diseases of the skin or eyes, and diseases of the peripheral or central nervous system in a patient in need thereof, comprising administering to the patient N-{[4-(5,9-diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-d]quinolin-7-yl)-3-methylbenzyl]sulphonyl}-2-(2-methoxyphenyl)acetamide and a PDE4 inhibitor of formula 1

• wherein:
• X is SO or SO2,
• R1 is H or 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 which is optionally substituted by one or more groups selected from OR2.1, COOR2.1, CONR2.2R2.3, SR2.1, SO—R2.1, SO2—R2.1, C6-10-aryl, het, hetaryl, a mono- or bicyclic C3-10-cycloalkyl, CH2—NR2.2R2.3, and NR2.2R2.3, each optionally 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—NR2.2R2.3, and NR2.2R2.3,
• 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 ten-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,
• 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, hetaryl-C1-6-alkylene, het-C1-6-alkylene, C3-10-cycloalkyl-C1-6-alkylene, a mono- or bicyclic C6-10-aryl, heteroaryl, and a -het, each optionally substituted by one or more groups selected from OH, O—(C1-3-alkyl), halogen, C1-6-alkyl, and C6-10-aryl,
• wherein R2.2 and R2.3 are each 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—NH2, CO—NHCH3, —CO—N(CH3)2, SO2—(C1-C2-alkyl), CO—R2.1, and COOR2.1, each optionally substituted by one or more groups selected from OH, halogen, C1-6-alkyl, C6-10-aryl, and COOR2.1, or
• R2 is a mono- or polycyclic C3-10 cycloalkyl optionally singly or multiply bridged by C1-3-alkyl groups and 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—NR2.2R2.3, het, —NH—CO—O—(C1-6-alkyl), —NH—CO—(C1-6-alkyl), —NH—CO—O—(C6-10-aryl), —NH—CO—(C6-10-aryl), —NH—CO—O-hetaryl, —NH—CO-hetaryl, —NH—CO—O—(C1-3-alkylene)-(C6-10-aryl), —NH—CO—(C1-3-alkylene)-(C6-10-aryl), —N(C1-3-alkyl)-CO—(C1-6-alkyl), —N(C1-3-alkyl)-CO—O—(C6-10-aryl), —N(C1-3-alkyl)-CO—(C6-10-aryl), —N(C1-3-alkyl)-CO—O-hetaryl, —N(C1-3-alkyl)-CO-hetaryl, —N(C1-3-alkyl)-CO—O—(C1-3alkylene)-(C6-10-aryl), —N(C1-3-alkyl)-CO—(C1-3-alkylene)-(C6-10-aryl), C6-10-aryl, C1-6-alkyl, C6-10-aryl-C1-6-alkylene, hetaryl-C1-6-alkylene, mono- or bicyclic C3-10cycloalkyl 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, COOR2NR2.2R2.3, CH2—NR2.2R2.3, C3-10-cycloalkyl, het, C1-6-alkyl, C1-3-fluoroalkyl, CF3, CHF2, CH2F, C6-10-aryl-C1-6-alkylene, het-C1-6-alkylene, hetaryl-C1-6-alkylene, C6-10-aryl, SO2—CH3, SO2—CH2CH3 and SO2—NR2.2R2.3, each optionally substituted by one or more or several groups 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—R2.1, SO2R2.1, COOR2.1, COR2.1, C1-6-alkanol, mono- or bicyclic 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
• NR1R2 together are a heterocyclic C4-7 ring that is optionally bridged, which contains 1, 2, or 3 heteroatoms selected from N, O, and S, and 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—NR2.2—COO—R2.1, CH2—NR2.2—CO—R2.1, CH2—NR2.2—CO—CH2—NR2.2R2.3, CH2—NR2.2—SO2—C1-3-alkyl, CH2—NR2.2—SO2—NR2.2R2.3, CH2—NR2.2—CO—NR2.2R2.3, CO—NR2.2R2.3, CH2—NR2.2R2.3, and NR2.2R2.3, and
• R3 is a C6-10-aryl optionally substituted in the ortho, para, or meta position with one, two, or three groups independently selected from fluorine, chlorine, bromine, hydroxy, CN, C1-6-alkyl, C1-3-fluoroalkyl, —C1-3-alkylene-OR2.1—C1-3-alkylene-NR2.2R2.3, —NR2.2R2.3, O—R2.1;
• SO—R2.1, SO2—R2.1, COOR2.1, —CO—NH—(C1-6-alkylene)-hetaryl, —CO—NH-hetaryl, —CO—N(CH3)-het, —CO—N(CH3)—(C1-3-alkylene)-het, —CO—N(CH3)—(C1-3-alkylene)-hetaryl, —CO—N(C3-7-cycloalkyl)-het, —CO—NR2.2R2.3, —CO—NH—(C1-6-alkylene)-het, NR2.2—CO—R2.1, C6-10-aryl, C6-10-aryl-C1-2-alkylene, het-C1-2-alkylene,-het, —CO-het, CO—N(CH3)—C3-7-cycloalkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-2-alkylene, hetaryl-C1-2-alkylene, and hetaryl, each optionally substituted by one or more groups selected from OH, halogen, —C1-3-fluoroalkyl, oxo, methyl, and phenyl, or
• R3 is a group selected from het and hetaryl, each optionally substituted by one or more groups selected from halogen, C1-3-fluoroalkyl, CN, OH, oxo, —C1-6-alkyl, —C1-3-alkylene-NR2.2R2.3, —NR2.2R2.3, SO—R2.1, SO2—R2.1, —O—R2.1, —COOR2.1, SO2—(CH3), SO2—(CH2—CH3), C6-10-aryl, het, C3-7-cycloalkyl, and hetaryl, each optionally substituted by one or more groups selected from OH, halogen, —C1-3-fluoroalkyl, C1-6-alkyl, C6-10-aryl, —COO(C1-3-alkyl), and O—(C1-3-alkyl), or
• R3 is —O—R3.1, wherein R3.1 is a group selected from —C1-6-alkyl, —C6-10aryl, —C1-3-alkylene-C6-10-aryl, hetaryl, and het, each optionally substituted in the ortho, para, or meta position by one, two, or three groups independently selected from fluorine, chlorine, bromine, hydroxy, CN, C1-6-alkyl, C1-3-fluoroalkyl, CO—(C1-5-alkyl), —CO—(C1-3-fluoroalkyl), —CO—NH—(C1-6-alkylene)-hetaryl, —CO—N(C1-3-alkyl)-(C1-6-alkylene)-hetaryl, —CO—N(C1-3-alkyl)-het, —CO—N(C3-7-cycloalkyl)-het, —C1-3-alkylene-OR2.1, —C1-3-alkylene-NR2.2R2.3, —NR2.2R2.3, O—R2.1, SO—R2.1, SO2—R2.1, COOH, CCO—(C1-4-alkyl), —O—C1-3-alkylene-N(C1-3-alkyl)2, CO—NR2.2R2.3, NR2.2—CO—R2.1, C6-10-aryl, C6-10-aryl-C1-2-alkylene, het-C1-2-alkylene, —CO-het, het, —CO—C3-7-cycloalkyl, —CO—N(C1-3-alkyl)-C3-7-cycloalkyl C3-7-cycloalkyl, C3-7-cycloalkyl-C1-2-alkylene, hetaryl-C1-2-alkylene, and hetaryl, each optionally substituted by 1, 2, 3, or 4 groups independently selected from F, Cl, Br, methyl, O-methyl, ethyl, O-ethyl, OH, oxo, and CF3, and
• R4 is H, CN, OH, CF3, CHF2, CH2F, F, methyl, ethyl, —O—(C1-3-alkyl), —C1-3-alkylene-OH, —COO(C1-3-alkyl), —CO-het, —(C1-2-alkylene)-NH—SO2—(C1-2-alkyl), —(C1-2-alkylene)-N(C1-3-alkyl)-SO2—(C1-2-alkyl), —(C1-2-alkylene)-O—(C1-2-alkylene)-C6-10-aryl, —C1-3-alkylene-O—C1-3-alkyl, —(C1-2-alkylene)-N(C1-3-alkyl)-CO—(C1-2-alkyl), —NH—CO—(C1-3-alkylene)-O—(C1-3-alkyl), —C1-3-alkylene-NH—CO—(C1-3-alkyl), —C1-3-alkylene-NH—CO—(C1-3-alkylene)-N(C1-3-alkyl)2, —O—(C1-2-alkylene)-(C6-10-aryl), —C1-3-alkylene-NH—CO—(C1-3-alkylene)-O—(C1-3-alkyl), —CO—(C6-10-aryl), and —(C1-2-alkylene)-N(C1-3-alkyl)-CO—(C1-2-alkylene)-O—(C1-3-alkyl), wherein the aryl in the above groups are optionally substituted by one or more groups selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, cyclopropyl, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-cyclopropyl, —OH, and CF3, or
• R3 and R4 together form a mono- or bicyclic, unsaturated, saturated, or partly saturated heterocyclic group, which contains 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally substituted by one or more groups selected from halogen, OH, oxo, C1-3-fluoroalkyl, CN, C1-6-alkyl, —O—R2.1, —COOR2.1, SO—R2.1, SO2—R2.1, —C1-3-alkylene-NR2.2R2.3, —NR2.2R2.3, C6-10-aryl, C3-7-cycloalkyl, het, and hetaryl.