Specific pde4b-inhibitors for the treatment of diabetes mellitus

A method of treating diabetes mellitus or a microvascular or macrovascular complication of diabetes mellitus in a patient in need thereof, the method comprising administering to the patient a compound of formula 1

• wherein:
• R1 is H or C1-6-alkyl,
• R2 is H or C1-10-alkyl or C2-6-alkenyl, each optionally substituted by one or more groups selected from halogen and C1-3-fluoroalkyl or optionally substituted by one or more groups selected from OR2.1, COOR2.1, CONR2.2R2.3, SR2.1, SO—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, which in turn are 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,
• R2 is a mono- or polycyclic C3-10 cycloalkyl optionally bridged one or more times via 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—(C1-3-alkylene)-(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 C3-10 cycloalkyl, and NR2.2R2.3, each optionally substituted by one or more groups selected from OH, OR2.1, oxo, halogen, CF3, CHF2, CH2F, C1-6-alkyl, C6-10-aryl, and NR2.2R2.3,
• R2 is a mono- or polycyclic C6-10-aryl optionally substituted by OH, SH, or halogen or by one or more groups selected from OR2.1, COOR2.1, NR2.2R2.3, CH2—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 groups selected from OH, OR2.1, CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C1-6-alkyl, C6-10-aryl, and NR2.2R2.3,
• R2 is het or 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, SO2—R2.1, 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 an optionally bridged heterocyclic C4-7 ring, 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,
• R3 is a C6-10-aryl 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, —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,
• R3 is 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),
• R3 is —O—R3.1, wherein R3.1 is a group selected from —C1-6-alkyl, —C6-10-aryl, —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, COO—(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), or —(C1-2-alkylene)-N(C1-3-alkyl)-CO—(C1-2-alkylene)-O—(C1-3-alkyl), wherein the aryl thereof is 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 partially saturated heterocycle, which contains 1, 2 or 3 heteroatoms selected from N, O, and S, and is 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,
• wherein:
• R2.1 is H or is 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 het, each optionally substituted by one or more groups selected from OH, O—(C1-3-alkyl), halogen, C1-6-alkyl, and C6-10-aryl,
• R2.2 and R2.3 are independently H or a group selected from C1-6-alkyl, mono- or bicyclic C3-10 cycloalkyl, C6-10-aryl-C1-6-alkylene, hetaryl-C1-6-alkylene, mono- or bicyclic C6-10-aryl, het, hetaryl, CO—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 among OH, halogen, C1-6-alkyl, C6-10-aryl, and COOR2.1,
• het is a three- to eleven-membered, mono- or bicyclic, saturated or partially saturated, optionally anellated or optionally bridged heterocycle 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 anellated heteroaryl, which contains 1, 2, 3, or 4 heteroatoms selected independently from N, S, or O, and
• cycloalkyl is saturated or partially saturated,
• or a pharmacologically acceptable salt thereof.