AU2013234404B2

AU2013234404B2 - Pyrazolone Derivatives as PDE4 Inhibitors

Info

Publication number: AU2013234404B2
Application number: AU2013234404A
Authority: AU
Inventors: Johannes A. M. Christiaans; Martin P. Feth; Armin Hatzelmann; Anke Heuser; Rolf-Peter Hummel; Hans-Peter Kley; Degenhard Marx; Wiro M P. B. Menge; Deborah Ockert; Christian Scheufler; Beate Schmidt; Geert Jan Sterk; Juergen Volz; Andrea Wohlsen; Christof Zitt
Original assignee: Takeda GmbH
Current assignee: Takeda GmbH
Priority date: 2007-05-16
Filing date: 2013-09-27
Publication date: 2016-04-28
Anticipated expiration: 2028-05-14
Also published as: AU2013234404A1

Abstract

- 67 Abstract The compounds of a certain formula 1, in which R1, R7, R8, R9 and n have the meanings as given in 5 the description, are novel effective inhibitors of the type 4 phosphodiesterase. (C2 R9 N-N (1) R1 -- O

Description

Description Pyrazolone Derivatives as PDE4 Inhibitors 5 Field of application of the invention The invention relates to novel pyrazolone-derivatives, which are used in the pharmaceutical industry for the manufacture of pharmaceutical compositions. 10 Known technical background In the International patent application W098/31674 phthalazinone derivatives are described as PDE4 inhibitors. In the International patent applications W002/064584, W002/085906, W02004/017974, W02004/018449, W02004/018451, W02004/018457, W02005/075456 and W02005/075457 phthal 15 azinone- or pyridazinone-derivatives with a piperidinyl substituent are described as PDE4 inhibitors. In the European patent application EP0126651 2,4-dihydro-5-[(substituted) phenyl]-4,4-disubstituted-3H pyrazol-3-ones and 2,4-dihydro-5-[(substituted) phenyl]-4,4-disubstituted-3H-pyrazol-3-thiones are dis closed for use as cardiotonic and antihypertensive agents. In USP2903460 pyrazolone derivatives with a piperidinyl substituent are described as analgetic and antipyretic compounds. 20 Summary of Invention In one embodiment, the present invention provides a fixed combination, non-fixed combination or kit of parts comprising 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 25 yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione, at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, p 2 -adrenoceptor agonists, H1 receptor antagonists, leu kotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA reductase inhibitors, lung surfactants, antibiotics and anti-diabetic agents, and at least one pharmaceutically acceptable auxiliary. 30 Description of the invention It has now been found that the pyrazolone-derivatives, which are described in greater details below, have surprising and particularly advantageous properties. 35 There is disclosed a compound of formula 1 0

(CH

2 ) R9 N-N (1) RI O -2 wherein R1 represents a phenyl derivative of formulae (a) or (b) R2 P R4 R3 (a) O (b) R5 R6 wherein 5 R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R3 is selected from the group consisting of 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmeth oxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or 10 predominantly substituted by fluorine; R5 is 1-2C-alkyl and R6 is selected from the group consisting of hydrogen and 1-2C-alkyl; or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; 15 R7 is 1-3C-alkyl and R8 is 1-3C-alkyl or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 3-, 4-, 5- or 6-membered hydrocarbon ring, R9 is -N(R11)R12, 20 wherein R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3 dione-2-yl-, 2-oxo-2,3-dihydro-1 H-indol-1 -yl-, pyrrolidin-2-one-1 -yl-, piperidin-2,6-dione-1 -yl-, mor pholin-3,5-dione-4-yl-, thiomorpholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and a 25 thiomorpholine-1,1-dioxide-3,5-dione-4-yl-ring; and n is 1 or 2; or a stereoisomer of the compound. 1-3-Alkyl is a straight-chain alkyl radical having 1 to 3 carbon atoms. Examples are the propyl, ethyl and 30 methyl radicals. 1-2C-Alkyl is a straight-chain alkyl radical having 1 to 2 carbon atoms. Examples are the ethyl and me thyl radicals.

-3 1-2C-Alkoxy is a radical, which in addition to the oxygen atom, contains a straight-chain alkyl radical having 1 to 2 carbon atoms. Examples are the ethoxy and the methoxy radicals. 5 1-2C-Alkoxy which is completely or predominantly substituted by fluorine is, for example, the perfluoro ethoxy, the 1,2,2-trifluoroethoxy, the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoro methoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred. "Predomi nantly" in this connection means that more than half of the hydrogen atoms of the 1-2C-alkoxy group are replaced by fluorine atoms. 10 3-5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy or cyclopentyloxy. 3-5C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy. 15 As spiro-linked 5- or 6-membered hydrocarbon rings may be mentioned the cyclopentane and the cy clohexane ring. As spiro-linked 3-, 4-, 5- or 6-membered hydrocarbon rings may be mentioned the cyclopropane, the cyclobutane, the cyclopentane and the cyclohexane ring. 20 In a preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents a phenyl derivative of formulae (a) or (b) R2 R4 R3 (a) O (b) R5 R6 wherein 25 R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R3 is selected from the group consisting of 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmeth oxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or 30 predominantly substituted by fluorine; R5 is 1-2C-alkyl and R6 is selected from the group consisting of hydrogen and 1-2C-alkyl; -4 or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and R8 is 1-3C-alkyl 5 or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 3-, 4-, 5- or 6-membered hydrocarbon ring, R9 is -N(R11)R12, wherein R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a 10 heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3 dione-2-yl-, pyrrolidin-2-one-1-yl-, piperidin-2,6-dione-1-yl-, morpholin-3,5-dione-4-yl-, thiomor pholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5 dione-4-yl-ring; and n is 1 or 2; 15 or a stereoisomer of the compound. In a further preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents a phenyl derivative of formulae (a) or (b) R2 R4 R3 (a) O (b) R5 R6 20 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R3 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; 25 R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R5 is 1-2C-alkyl and R6 is selected from the group consisting of hydrogen and 1-2C-alkyl, or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, 30 form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and R8 is 1-3C-alkyl -5 or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R9 is -N(R11)R12, wherein 5 R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3 dione-2-yl-, 2-oxo-2,3-dihydro-1 H-indol-1 -yl-, pyrrolidin-2-one-1 -yl-, piperidin-2,6-dione-1 -yl-, mor pholin-3,5-dione-4-yl-, thiomorpholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5-dione-4-yl-ring; and 10 n is 1 or 2; or a stereoisomer of the compound. In a further preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents a phenyl derivative of formulae (a) or (b) 15 R2 P R4 R3 (a) O (b) R5 R6 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R3 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or 20 predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R5 is 1-2C-alkyl and R6 is selected from the group consisting of hydrogen and 1-2C-alkyl, 25 or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and R8 is 1-3C-alkyl or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 5- or 30 6-membered hydrocarbon ring; R9 is -N(R11)R12, wherein -6 R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3 dione-2-yl-, pyrrolidin-2-one-1-yl-, piperidin-2,6-dione-1-yl-, morpholin-3,5-dione-4-yl-, thiomor pholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5 5 dione-4-yl-ring; and n is 1 or 2; or a stereoisomer of the compound. 10 In a further preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents a phenyl derivative of formulae (a) or (b) R2 P R4 R3 (a) O (b) R5 R6 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or 15 predominantly substituted by fluorine; R3 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; 20 R5 is methyl and R6 is hydrogen, or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and 25 R8 is 1-3C-alkyl; R9 is -N(R11)R12, wherein R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, morpholin-3,5 30 dione-4-yl-, thiomorpholin-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5-dione-4-yl-ring; and n is 1 or 2; or a stereoisomer of the compound.

-7 In a further preferred embodiment, there is disclosed compounds of formula 1, wherein R1 represents a phenyl derivative of formulae (a) or (b) R2 P R4 R3 (a) O (b) R5 R6 wherein 5 R2 is methoxy; R3 is methoxy; R4 is methoxy; R5 is methyl; R6 is hydrogen, 10 or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is methyl; R8 is methyl; R9 is -N(R11)R12, 15 wherein R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, morpholin-3,5 dione-4-yl- and a thiomorpholin-3,5-dione-4-yl-ring; and n is 1. 20 In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (a) and R2, R3, R7, R8, R9 and n are as defined above. 25 In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (a), R2 is methoxy, R3 is methoxy and R7, R8, R9 and n are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents 30 a phenyl derivative of formula (a), R7 is methyl, R8 is methyl and R2, R3, R9 and n are as defined above.

-8 In a further preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents a phenyl derivative of formula (a), R2 is methoxy, R3 is methoxy, R7 is methyl, R8 is methyl, and R9 and n are as defined above. 5 In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (a), n is 1 and R2, R3, R7, R8 and R9 are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents 10 a phenyl derivative of formula (a), R2 is methoxy, R3 is methoxy, n is 1 and R7, R8 and R9 are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents a phenyl derivative of formula (a), R2 is methoxy, R3 is methoxy, R7 is methyl, R8 is methyl, n is 1 and 15 R9 is as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (a), R9 is morpholin-3,5-dione-4-yl and R2, R3, R7, R8 and n are as defined above. 20 In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (a), R9 is morpholin-3,5-dione-4-yl, n is 1 and R2, R3, R7 and R8 are as defined above. 25 In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (a), R9 is pyrrolidin-2,5-dione-1-yl and R2, R3, R7, R8 and n are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer 30 thereof, wherein R1 represents a phenyl derivative of formula (a), R9 is pyrrolidin-2,5-dione-1-yl, n is 1 and R2, R3, R7 and R8 are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (b) and R4, R5; R6, R7, R8, R9 and n are 35 as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (b), R4 is methoxy, R5 is methyl, R6 is hydrogen and R7, R8 and R9 are as defined above. 40 -9 In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (b), R4 is methoxy, R5 and R6 together and with inclusion of the two carbon atoms to which they are bonded form a spiro-linked cyclopentane ring and R7, R8 and R9 are as defined above. 5 In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (b), R7 is methyl, R8 is methyl, and R4, R5, R6, R9 and n are as defined above. 10 In a further preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents a phenyl derivative of formula (b), R4 is methoxy, R5 is methyl, R6 is hydrogen, R7 is methyl, R8 is methyl and R9 and n are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents 15 a phenyl derivative of formula (b), R4 is methoxy, R5 and R6 together and with inclusion of the two carbon atoms to which they are bonded form a spiro-linked cyclopentane ring, R7 is methyl, R8 is methyl and R9 and n are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer 20 thereof, wherein R1 represents a phenyl derivative of formula (b), n is 1 and R4, R5, R6, R7, R8 and R9 are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (b), R4 is methoxy, R5 is methyl, R6 is 25 hydrogen, n is 1 and R7, R8 and R9 are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (b), R4 is methoxy, R5 and R6 together and with inclusion of the two carbon atoms to which they are bonded form a spiro-linked cyclopentane 30 ring, n is 1 and R7, R8 and R9 are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents a phenyl derivative of formula (b), R4 is methoxy, R5 is methyl, R6 is hydrogen, R7 is methyl, R8 is methyl, n is 1 and R9 is as defined above. 35 In a further preferred embodiment, there is disclosed a compound of formula 1, wherein R1 represents a phenyl derivative of formula (b), R4 is methoxy, R5 and R6 together and with inclusion of the two carbon atoms to which they are bonded form a spiro-linked cyclopentane ring, R7 is methyl, R8 is methyl, n is 1 and R9 is as defined above. 40 - 10 In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (b), R9 is morpholin-3,5-dione-4-yl, and R4, R5, R6, R7, R8 and n are as defined above 5 In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (b), R9 is morpholin-3,5-dione-4-yl, n is 1 and R4, R5, R6, R7 and R8 are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer 10 thereof, wherein R1 represents a phenyl derivative of formula (b), R9 is pyrrolidin-2,5-dione-1-yl, and R4, R5, R6, R7, R8 and n are as defined above. In a further preferred embodiment, there is disclosed a compound of formula 1 or a stereoisomer thereof, wherein R1 represents a phenyl derivative of formula (b), R9 is pyrrolidin-2,5-dione-1-yl, n is 1 15 and R4, R5, R6, R7 and R8 are as defined above. It is to be understood that the invention covers all combinations of substituent groups referred to here inabove. In particular, the invention covers all combinations of preferred groups described herein. 20 The compounds may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are, therefore, all solvates of the compounds of formula 1 and the stereoisomers thereof. Hydrates are a preferred example of said solvates. The compounds of formula 1 include stereoisomers. In case R7 and R8 represent different groups 25 and/or R5 and -CH 2 R6 represent different groups, the compounds according to the invention have one or two stereogenic centers. Each of said stereogenic centers may have the absolute configuration R or the absolute configuration S (according to Cahn, Ingold and Prelog). Accordingly, the stereoisomers (4R) and (4S) in case of a compound of formula 1 a* and the stereo 30 isomers (2R, 4R), (2R, 4S), (2S, 4R) and (2S, 4R) in case of a compound of formula 1b* -11 R2 2 0 _Ni R3 R7 N N (CH 2 ),R9 R7 4_ 5 R8 0 (la*) 6 R4 2 0 01 3 R3 N N ( R9 R75

(CH

2 ) R5 2 4 R8 0 (lb*) R6 are part of the invention (the numbers refer to the atoms indicated in formulae 1 a* and 1 b*). 5 The invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates. Some of the compounds of formula 1 or stereoisomers thereof may exist in different crystalline forms (polymorphs), which are within the scope of the invention. 10 There is disclosed compounds of formula 4, which are key intermediates in the process of producing the compounds of formula 1 as described hereinafter. Therefore there is also disclosed a compound of formula 4, 15 H N N-N R1 0 (4) R7 R8 wherein R1 represents a phenyl derivative of formulae (a) or (b) -12 R2 P R4 R3 (a) O (b) R5 R6 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; 5 R3 is selected from the group consisting of 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmeth oxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R5 is 1-2C-alkyl and 10 R6 is selected from the group consisting of hydrogen and 1-2C-alkyl, or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and R8 is 1-3C-alkyl 15 or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 3-, 4-, 5- or 6-membered hydrocarbon ring; a salt thereof, a stereoisomer thereof or a salt of the stereoisomer thereof. Salts of the compounds of formula 4 or the salts of the stereoisomers thereof include all inorganic and 20 organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, particularly all pharmaceutically acceptable inor ganic and organic acid addition salts and salts with bases customarily used in pharmacy. Examples of acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phos 25 phates, nitrates, sulfates, acetates, trifluoroacetates, citrates, D-gluconates, benzoates, 2-(4-hydroxy benzoyl)benzoates, butyrates, sulfosalicylates, maleates, laurates, malates, lactates, fumarates, succinates, oxalates, tartrates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), methanesulfonates (mesilates) and 3-hydroxy-2-naphthoates. Of these, hydrochlorides are preferred. 30 Examples of salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine and guanidinium salts. The salts include water-insoluble and, particularly, water-soluble salts.

- 13 The compounds of formula 4, the salts, the stereoisomers and the salts of the stereoisomers thereof may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are, therefore, all solvates of the compounds of formula 4, as well as the sol 5 vates of the salts, the stereoisomers and the salts of the stereoisomers of the compounds of formula 4. In a preferred embodiment there is disclosed a compound of formula 4, wherein R1 represents a phenyl derivative of formulae (a) or (b) R2 R4 R3 (a) O (b) R5 R6 10 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R3 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; 15 R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R5 is 1-2C-alkyl and R6 is selected from the group consisting of hydrogen and 1-2C-alkyl, or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, 20 form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and R8 is 1-3C-alkyl or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; 25 a salt thereof, a stereoisomer thereof or a salt of the stereoisomer thereof. In another preferred embodiment, there is disclosed a compound of formula 4, wherein R1 represents a phenyl derivative of formulae (a) or (b) -14 R2 P R4 R3 (a) O (b) R5 R6 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; 5 R3 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R5 is methyl and 10 R6 is hydrogen, or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and R8 is 1-3C-alkyl; 15 a salt thereof, a stereoisomer thereof or a salt of the stereoisomer thereof. In a further preferred embodiment there is disclosed compounds of formula 4, wherein R1 represents a phenyl derivative of formulae (a) or (b) 20 R2 P R4 R3 (a) O (b) R5 R6 wherein R2 is methoxy; R3 is methoxy; R4 is methoxy; 25 R5 is methyl; R6 is hydrogen, - 15 or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is methyl; R8 is methyl; 5 or a salt thereof. In a further preferred embodiment, there is disclosed a compound of formula 4, wherein R1 represents a phenyl derivative of formula (a), R2 is methoxy, R3 is methoxy, R7 is methyl and R8 is methyl, or a salt thereof. 10 In a further preferred embodiment, there is disclosed a compound of formula 4, wherein R1 represents a phenyl derivative of formula (b), R4 is methoxy, R5 is methyl, R6 is hydrogen, R7 is methyl and R8 is methyl, or a salt thereof. 15 In a further preferred embodiment, there is disclosed a compound of formula 4, wherein R1 represents a phenyl derivative of formula (b), R4 is methoxy, R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane-ring, R7 is methyl and R8 is methyl, or a salt thereof. 20 The compounds of formula 4 include stereoisomers. In case R7 and R8 represent different groups and/or R5 and -CH 2 R6 represent different groups, the compounds of formula 4 have one or two stereogenic centers. Each of said stereogenic centers may have the absolute configuration R or the absolute configuration S (according to Cahn, Ingold and Prelog). 25 Accordingly, the stereoisomers (4R) and (4S) in case of a compound of formula 4a* and the stereoiso mers (2R, 4R), (2R, 4S), (2S, 4R) and (2S, 4R) in case of a compound of formula 4b* R2 2 Ni1 R3 3 -- N NH R7 4 5 R8 O (4a*) 6 R4 7 4 2 N1 01 3 N NH R7 4 5 R5 2 R8 0 (4b*) R6 - 16 are also disclosed (the numbers refer to the atoms indicated in formulae 4a* and 4b*). The invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates. 5 The compounds of formula 1 and the compounds of formula 4 can be prepared as follows. As shown in reaction scheme 1 the compounds of formula 1, wherein R1, R7, R8 and R9 have the above-mentioned meanings and n is 1 can be obtained by reacting a corresponding compound of 10 formula 2 with a compound of formula R9-H, wherein R9 has the above-mentioned meanings in an appropriate solvent, such as, for example N,N-dimethylformamide, 1-methyl-pyrrolidin-2-one, ethanol, 2-propanol, 1-propanol, butanol, acetonitril or tetrahydrofurane, preferably in the presence of a base, such as, for example potassium carbonate, sodium carbonate or diisopropylethylamine and preferably at raised temperature up to the boiling point of the solvent being used. 15 The compounds of formula 2, wherein R1, R7 and R8 have the above-mentioned meanings can be obtained by reacting a corresponding compound of formula 4 with chloroacetylchloride or chloroacetic anhydride in an inert solvent, such as, for example dichloromethane, chloroform, toluene, tetrahydro furane or acetonitril, preferably in the presence of a base, such as, for example triethylamine or diiso 20 propylethylamine, preferably at a temperature between 00C and ambient temperature. The compounds of formula 1, wherein R1, R7, R8 and R9 have the above-mentioned meanings and n is 2 can be obtained by reacting a corresponding compound of formula 3 with a compound of formula R9-H, wherein R9 has the above-mentioned meanings in an appropriate solvent, such as, for example 25 N,N-dimethylformamide, 1-methyl-pyrrolidin-2-one, methanol, ethanol, tetrahydrofurane, dichlorome thane or toluene, preferably in the presence of an base, such as, for example potassium carbonate, sodium carbonate, diisopropylethylamine or triethylamine, and preferably at raised temperature up to the boiling point of the solvent being used. 30 The compounds of formula 3, wherein R1, R7 and R8 have the above-mentioned meanings can be prepared by reacting a corresponding compound of formula 4 with prop-2-enoyl chloride in an inert solvent, such as, for example dichloromethane, chloroform, acetonitril or tetrahydrofurane, preferably in the presence of a base, such as, for example triethylamine or diisopropylethylamine. The reaction is preferably carried out at ambient temperature. 35 The compounds of formula 4, wherein R1, R7 and R8 have the above-mentioned meanings can be prepared by reacting a corresponding compound of formula 5 with an in 4-position activated and in 1-position protected piperdine-derivative, such as, for example tert-butyl 4-(toluene-4-sulfonyloxy) piperidine-1-carboxylate or tert-butyl 4-(methanesulfonyloxy)-piperidine-1-carboxylate in an inert 40 solvent, such as, for example N,N-dimethylformamide, 1-methyl-pyrrolidin-2-one or dioxane, in the - 17 presence of a strong base, such as, for example sodium ethoxide, potassium tert-butoxide, sodium hydride, and preferably at raised temperature, such as, for example 80 to 1500C. Alternatively, the compounds of formula 4, wherein R1, R7 and R8 have the above-mentioned 5 meanings can be prepared by reacting a corresponding compound of formula 6 with piperidin-4 ylhydrazine dihydrochloride in a methanol/water solvent system, preferably at raised temperatures, especially at the boiling point of the solvent system being used. The compounds of formula 5, wherein R1, R7 and R8 have the above-mentioned meanings can be 10 obtained by reacting an appropriately substituted a,a-disubstituted-p-oxobenzene propionic acid ester of formula 6 with hydrazine hydrate in an appropriate solvent, such as, for example an alcohol like ethanol or methanol, preferably at raised temperature, especially at the boiling point of the solvent being used. The ester of the a,a-disubstituted-p-oxobenzene propionic acid ester may be a 1-4C-alkyl ester; particularly preferred is - as shown in reaction scheme 1 - the methyl ester. 15 The compounds of formula 6, wherein R1, R7 and R8 have the above-mentioned meanings can be prepared by reacting an activated benzoic acid derivative of formula 8, wherein R1 has the above mentioned meanings with an ester of formula 7, wherein R7 and R8 have the above-mentioned mea nings, in an inert solvent, such as, for example tetrahydrofurane, diethyl ether, toluene, N,N-dimethyl 20 formamide or 1 -methyl-pyrrolidin-2-one, in the presence of a strong base, such as for example lithium diisopropylamine, butyl lithium or sodium hydride, at low temperatures, preferably below -40'C. Suitable esters of formula 7 are for example methyl 2-methylproponate, methyl-2-methylbutanoate, methyl-2-ethylbutanoate, methyl 2-methylpentanoate and methyl cyclopentancarboxylate. 25 The esters of formula 7 are commercially available or can be prepared according to procedures known in the art. The activated benzoic acid derivatives of formula 8 can be obtained, for example, according to the 30 procedures described in the international patent applications W092/12961, W094/02465, W095/01338 and W096/03399. An alternative synthesis route to compounds of formula 5 is described in the European patent appli cation EP0126651. 35 - 18 Reaction scheme 1: R7 0 R8 -(7) O O (8) 0o- RI C HCI (6) HCI NH R7 R8 H2

I

2 NH 2

N-NH

2 /ethanol SN-N (5) N-N (4) R1 0 RI 0 R7 R8 R7 R8 0 or Nci cN N-N (2) N-N (3) RI 0 R1 0 R7 R8 R7 R8 R9-H R9-H R9 N R9 N-N (1, n=1) N-N (1, n=2) RI 0 RI 0 R7 R8 R7 R8 - 19 Compounds of formula 1 can be converted into further compounds of formula 1 by methods known in the art. For example 5 * a compound of formula 1, wherein R9 is a thiomorpholine-1-oxide-3,5-dione-4-yl- or a thio morpholine-1,1-dioxide-3,5-dione-4-yl-ring can be prepared from a compound of formula 1, wherein R9 is a thiomorpholine-3,5-dione-4-yl-ring by an oxidation reaction, for example by using 3-chloroperbenzoic acid in dichloromethane as an oxidant. 10 A further possibility to prepare compounds of formula 1 is to use a temporarily protective group in order to introduce a specific substituent at the end of a reaction sequence. This method can be advanta geously used, for example, to introduce different alkoxy groups in the position of the R3 substituent. Examples 5, 6 and 7 have been prepared using such a method; here, the benzyl group served as a temporarily protective group for a hydroxyl group in R3 position. 15 It is known to the person skilled in the art that, if there are a number of reactive centers on a starting or intermediate compound, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. A detailed description for the use of a large number of proven protective groups is found, for example, in 20 T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, 3rd Ed., or in P. Kocienski, Protecting Groups, Thieme Medical Publishers, 2000. The compounds are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the 25 customary purification methods, such as column chromatography on a suitable support material. Salts of the compounds of formula 4 and the stereoisomers thereof can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofurane or dioxane, a chlorinated 30 hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol, a low molecular weight aliphatic ester such as ethyl acetate or isopropyl acetate, or water) which contains the desired acid or base, or to which the desired acid or base is then added. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar 35 quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipi tating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the 40 person skilled in the art.

- 20 Pure diastereomers and pure enantiomers of the compounds can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis. Preferably, the pure diastereomeric and pure enantio 5 meric compounds of the invention are obtained by using chiral starting compounds in synthesis. Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastere omers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separa ted by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures 10 can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereo mers obtained and removing the chiral auxiliary agent. As chiral auxiliary agents, for example, chiral acids can be used to separate enantiomeric bases and chiral bases can be used to separate enantio meric acids via formation of diastereomeric salts. Furthermore, diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures 15 of acids, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxiliary agents. Additionally, diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures. Alternatively, enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation. 20 As will be appreciated by persons skilled in the art, the invention is not limited to the particular embodi ments described herein, but covers all modifications that are within the spirit and scope of the invention as defined by the appended claims. 25 All patents, patent applications, publications, test methods and other materials cited herein are incorpo rated by reference in their entireties. The following examples illustrate the invention in greater detail, without restricting it. Further com pounds according to the invention, of which the preparation is not explicitly described, can be prepared 30 in an analogous way. The compounds, which are mentioned in the examples and the stereoisomers thereof represent pre ferred embodiments of the invention. 35 Examples The following abbreviations are used: min: minutes, h: hour(s), DCM: dichloromethane, THF: tetrahy drofurane, EA: ethyl acetate, DMF: N,N-dimethylformamide, M. p.: melting point, RT: room temperature (20 to 250C), MS: mass spectrometry and calc: calculated. 40 - 21 Final products 1. 4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl} 2-oxoethyl)morpholine-3,5-dione 5 1.0 g 2-[1 -(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazo-3 one (compound Al), 0.5 g morpholine-3,5-dione and 1.0 g K 2

CO

3 in 20 ml of DMF is heated for 17 h at 80-1 00C. The DMF is removed in vacuo and the residue dissolved in 70 ml of DCM, washed four times with 30 ml of water and 20 ml of 0.5 M H 2

SO

4 . The DCM layer is dried over MgSO 4 and concen 10 trated in vacuo. The title product is crystallized from diethyl ether. M. p. 156-1570C. 2. 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl} 2-oxoethyl)pyrrolidine-2,5-dione 15 7.4 g 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazo-3 one (compound Al) and 3.6 g succinimide are suspended in 50 ml of 2-propanol and heated to 500C. 5.1 g potassium carbonate are added in portions during 1 h. After adding potassium carbonate the re action mixture is stirred for 30 min at 500C, then 3-4 h at 750C until the reaction is complete. After stir 20 ring for 3-4 h at 750C, the heating is turned off and the mixture is allowed to cool down slowly to RT. 100 ml of water is added, the mixture is stirred for 0.5 h at RT and the crystallized product is filtered. The product is dried at 500C in a vacuum dryer. M. p. 218-220'C 25 3. 1-(2-{4-[3-(3,4-diethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2 oxoethyl)pyrrolidine-2,5-dione Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dieth oxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A2) and succinimide as starting 30 compounds. M. p. 211-2130C 4. 1 -[2-(4-{3-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-5-oxo-4,5-dihydro 1 H-pyrazol-1 -yl}piperidin-1 -yl)-2-oxoethyl]pyrrolidine-2,5-dione 35 Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-[3-(cyclo propylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A3) and succinimide as starting compounds. M. p. 104-1090C - 22 5. 1 -[2-(4-{3-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1 H pyrazol-1 -yl}piperidin-1 -yl)-2-oxoethyl]pyrrolidine-2,5-dione 5 A mixture of 1 g 1-(2-{4-[3-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione (compound A4), 0.7 g of bromomethylcyclopropane and 1 g of potassium carbonate in 100 ml of acetonitril is refluxed for 8 h after which the solvent is evaporated. The residue is partitioned between water and ethyl acetate, the organic layer is dried over magnesium sulfate and the EA evaporated. The residue is crystallized from ethyl acetate. 10 M. p. 129-131'C 6. 1-[2-(4-{3-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1 H pyrazol-1 -yl}piperidin-1 -yl)-2-oxoethyl]pyrrolidine-2,5-dione 15 Prepared analogously as described for example 5 using 1-(2-{4-[3-(3-hydroxy-4-methoxyphenyl)-4,4 dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione (compound A4) and 1,1,1-trifluoro-2-iodoethane as starting compounds. M. p. 101-106'C 20 7. 1-(2-{4-[3-(3-ethoxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperi din-1 -yl}-2-oxoethyl)pyrrolidine-2,5-dione Prepared analogously as described for example 5 using 1-(2-{4-[3-(3-hydroxy-4-methoxyphenyl)-4,4 dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione (compound 25 A4) and iodoethane as starting compounds. M. p. 186-1870C 8. 1-(2-{4-[3-(7-methoxy-2,2-dimethyl-2,3-dihydro-1 -benzofuran-4-yl)-4,4-dimethy-5-oxo-4,5 dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine-2,5-dione 30 Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(7-methoxy 2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A5) and succinimide as starting compounds. M. p. 214-2150C 35 9. 1-(2-{4-[3-(7-methoxy-3H-spiro[1 -benzofuran-2, 1'-cyclopentan]-4-yl)-4,4-dimethyl-5-oxo-4,5 dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl) pyrrolidine-2,5-dione - 23 Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(7-methoxy 3H-spiro[1-benzofuran-2,1'-cyclopentan]-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A6) and succinimide as starting compounds. M. p. 220-222'C 5 10. 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-diethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2 oxoethyl)pyrrolidine-2,5-dione The title compound may be prepared analogously as described for example 1 using 2-[1-(chloroacetyl) 10 piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-diethyl-2,4-dihydro-3H-pyrazol-3-one (compound A7) and succinimide as starting compounds. 11. 1 -(2-{4-[3-(3,4-dimethoxyphenyl)-4-methyl-5-oxo-4-propyl-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin 1 -yl}-2-oxoethyl)pyrrolidine-2,5-dione 15 Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimeth oxyphenyl)-4-methyl-4-propyl-2,4-dihydro-3H-pyrazol-3-one (compound A8) and succinimide as starting compounds. M. p. 167-169'C 20 12. 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin 1 -yl}-2-oxoethyl)pyrrolidine-2,5-dione Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimeth 25 oxyphenyl)-4-ethyl-4-methyl-2,4-dihydro-3H-pyrazol-3-one (compound A9) and succinimide as starting compounds. M. p. 121-124'C 13. 1-(2-{4-[4-(3,4-dimethoxyphenyl)-1 -oxo-2,3-diazaspiro[4.4]non-3-en-2-yl]piperidin-1 -yl}-2-oxo 30 ethyl)pyrrolidine-2,5-dione Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-4-(3,4-dimeth oxyphenyl)-2,3-diazaspiro[4.4]non-3-en-1-one (compound Al0) and succinimide as starting com pounds. 35 M. p. 186-1890C 14. 2-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl} 2-oxoethyl)-1 H-isoindole-1,3(2H)-dione - 24 Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimeth oxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound Al) and phthalimide as starting compounds. M. p. 209-211C 5 15. 1-(2-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1 -yl]-piperidin-1 -yl}-2 oxo-ethyl)-piperidine-2,6-dione Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimeth 10 oxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound Al) and 2,6-dioxopiperidine as start ing compounds. M. p. 146-149'C 16. 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-{1 -[(2-oxopyrrolidin-1 -yl)acetyl]piperidin-4-yl}-2,4 15 dihydro-3H-pyrazol-3-one A mixture of 0.5 g of 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazo-3 one hydrochloride (compound B1), 0.24 g of (2-oxo-pyrrolidin-1-yl)acetyl chloride and 0.5 ml of triethyl amine in 50 ml of dichloromethane is stirred for 30 min and washed subsequently with aqueous sodium 20 carbonate. After drying over magnesium sulphate the solvent is evaporated and the residue purified by column chromatography [silica, ethyl acetate / methanol: 6:1 (Vol/Vol)]. Crystallized from diethyl ether. M. p. 125-131 C 17. 4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl} 25 2-oxoethyl)thiomorpholine-3,5-dione A mixture of 1 g 5-(3,4-dimethoxyphenyl)-2-(1-glycylpiperidin-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol 3-one hydrochloride (compound Fl), 0.3 g triethylamine, 0.34 g 2,6-dioxothiomorpholine and 0.83 g 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride in 5 ml of dichloromethane is heated in a 30 sealed cap for 10 min at 1500C in a microwave. After cooling to RT, 100 ml of DCM is added and the resulting mixture is washed with water. After drying over magnesium sulphate and evaporating the sol vent, the title compound is purified by column chromatography [silica, ethyl acetate]. The title compound is crystallised from diethyl ether. M. p. 121-124'C 35 18. 4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl} 2-oxoethyl)thiomorpholine-3,5-dione 1,1-dioxide A solution of 0.5 g of 4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl] 40 piperidin-1-yl}-2-oxoethyl)thiomorpholine-3,5-dione (compound 17) in 20 ml of DCM is cooled to OC; - 25 then 0.57 g 3-chloroperbenzoic acid is added. The resulting mixture is stirred for another 20 min and subsequently washed with aqueous sodium carbonate. The organic phase is dried over magnesium sulphate and the solvent evaporated. The title compound is crystallized from ethyl acetate. M. p. 146-148'C 5 19. 1-(3-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1 -yl]-piperidin-1 -yl}-3 oxo-propyl)-pyrrolidine-2,5-dione A mixture of 1 g 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one 10 hydrochloride (compound B1), 0.5 g prop-2-enoyl chloride and 1 ml of triethylamine in 100 ml of DCM is stirred for 30 min and subsequently washed with aqueous sodium carbonate. After drying over magne sium sulphate, the solvate is evaporated; the residue is dissolved in DMF, 1 g potassium carbonate and 0.3 g succinimide is added and the resulting mixture is heated for 4 h at 70 0C. The solvent is removed by evaporation; the residue is dissolved in EA and washed with water. After drying over magnesium 15 sulphate and evaporating the solvent, the title compound is crystallized from diethyl ether. M. p. 207-209'C 20. 1-(2-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1 -yl]-piperidin-1 -yl}-2 oxo-ethyl)-1,3-dihydro-2H-indol-2-one 20 0.5 g 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazo-3 one (compound Al), 0.16 g 1,3-dihydro-2H-indol-2-one and 0.7 g K 2

CO

3 in 20 ml of acetonitrile is heat ed to reflux for 10 h. The acetonitrile is removed in vacuo and the residue dissolved in 70 ml of ethyl acetate and washed four times with 30 ml of water. The organic layer is dried over MgSO 4 and concen 25 trated in vacuo. The title product is isolated by column chromatography (silica gel, eluent: ethyl acetate to ethyl acetate/methanol 4:1). M. p. 1780C Starting Compounds 30 Al. 2-[1 -(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazo-3 one 157.1 g 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydro 35 chloride (compound B1) is dissolved in 1000 ml of DCM and 130 ml triethylamine and cooled in an icebath. A solution of 75 g chloroacetic anhydride in 200 ml of DCM is added, the icebath removed and the mixture is stirred at RT until the starting material is consumed (60 min). The reaction mixture is washed with 400 ml of water, 200 ml of 1 M Na 2

CO

3 (twice), dried over MgSO 4 and concentrated in vacuo. The title compound is purified by filtering over silica in EA and crystallized from diethyl ether. 40 M. p. 146-148'C - 26 Alternative: 430 g 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound 5 B1; synthesis alternative 2) and 215 g potassium carbonate are suspended in 6.5 I of DCM. The mix ture is heated to reflux and 162 g chloroacetylchlorid is added drop wise during 1 h. The mixture is stirred at reflux temperature for 5 h, then 30g of potassium carbonate and further 36 g of chloroacetyl chlorid are added. After 1 h additional reaction time at reflux the reaction is complete. 116 g of acetic acid is added to the mixture during 10 min, then the mixture is cooled to 200C and during cooling 3 I of 10 water is added. The organic layer is separated from the aqueous layer; the organic layer is washed twice with 1.5 I of water. The combined aqueous layers are extracted twice with 0.5 I of DCM. The or ganic layers are combined and 6 I is distilled off in vacuum. Then 2.5 I of tert. butylmethylether is added and the solution is concentrated in vacuum until crystallization starts (about 0.8 litre is distilled off). The suspension is cooled down and stirred overnight. The suspension is filtered, the solid dried in vacuum 15 by 50'C. M. p. 146.5-148.5'C A2. 2-[1 -(chloroacetyl)piperidin-4-yl]-5-(3,4-diethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazo-3 one 20 Prepared analogously as described for example Al using 5-(3,4-diethoxyphenyl)-4,4-dimethyl-2 piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B2) and chloroacetic anhydride as starting compounds. MS [M+H] calc: 436 found: 436 25 A3. 2-[1-(chloroacetyl)piperidin-4-yl]-5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4 dimethyl-2,4-dihydro-3H-pyrazol-3-one Prepared analogously as described for example Al using 5-[3-(cyclopropylmethoxy)-4-(difluorometh 30 oxy)phenyl]-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B3) and chloroacetic anhydride as starting compounds. MS [M+H]: calc: 484 found: 484 A4. 1-(2-{4-[3-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin 35 1 -yl}-2-oxoethyl)pyrrolidine-2,5-dione Step 3: A mixture of 5.5 g of 1-[2-(4-{3-[3-(benzyloxy)-4-methoxyphenyl]-4,4-dimethyl-5-oxo-4,5-di hydro-1 H-pyrazol-1 -yl}piperidin-1 -yl)-2-oxoethyl]pyrrolidine-2,5-dione (see below), 0.2 g of 10% Pd/C and 3 g of ammonium formiate in 150 ml methanol is refluxed for 10 min. After cooling to RT, the mix 40 ture is filtered over Hyflo and the solution evaporated. The residue is washed with EA and dried.

- 27 M. p. 136-1390C Step 2: 1-[2-(4-{3-[3-(benzyloxy)-4-methoxyphenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl} piperidin-1 -yl)-2-oxoethyl]pyrrolidine-2,5-dione 5 Prepared analogously as described for example 1 using 5-[3-(benzyloxy)-4-methoxyphenyl]-2-[1-(chlo roacetyl)piperidin-4-yl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (see below) and succinimide as start ing compounds. M. p. 212-214'C 10 Step 1: 5-[3-(benzyloxy)-4-methoxyphenyl]-2-[1 -(chloroacetyl)piperidin-4-yl]-4,4-dimethyl-2,4-dihydro 3H-pyrazol-3-one Prepared analogously as described for example Al using 5-[3-(benzyloxy)-4-methoxyphenyl]-4,4-di 15 methyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B4) and chloroacetic anhydride as starting compounds. M. p. 93-970C A5. 2-[1 -(chloroacetyl)piperidin-4-yl]-5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1 -benzofuran-4-yl)-4,4 20 dimethyl-2,4-dihydro-3H-pyrazol-3-one Prepared analogously as described for example Al using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1 benzofuran-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5) and chloroacetic anhydride as starting compounds. 25 M. p. 205-207'C A6. 2-[1 -(chloroacetyl)piperidin-4-yl]-5-(7-methoxy-3H-spiro[1 -benzofuran-2, 1'-cyclopentan]-4-yl)-4,4 dimethyl-2,4-dihydro-3H-pyrazol-3-one 30 Prepared analogously as described for example Al using 5-(7-methoxy-3H-spiro[l-benzofuran-2,1'-cy clopentan]-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B6) and chloroacetic anhydride as starting compounds. M. p. 208-213'C 35 A7. 2-[1 -(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-diethyl-2,4-dihydro-3H-pyrazo-3 one Title compound may be prepared analogously as described for example Al using 5-(3,4-dimethoxy phenyl)-4,4-diethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B7) and 40 chloroacetic anhydride as starting compounds.

- 28 A8. 2-[1 -(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4-methyl-4-propyl-2,4-dihydro-3H pyrazol-3-one 5 Prepared analogously as described for Al using 5-(3,4-dimethoxyphenyl)-4-methyl-2-piperidin-4-yl-4 propyl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B8) and chloroacetic anhydride as start ing compounds. MS [M+H] calc: 436 found: 436 10 A9. 2-[1 -(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2,4-dihydro-3H pyrazol-3-one Prepared analogously as described for Al using 5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2-piperidin 4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B9) and chloroacetic anhydride as starting 15 compounds. MS [M+H] calc: 422 found: 422 Al 0. 2-[1 -(chloroacetyl)piperidin-4-yl]-4-(3,4-dimethoxyphenyl)-2,3-diazaspiro[4.4]non-3-en-1 -one 20 Prepared analogously as described for Al using 4-(3,4-dimethoxyphenyl)-2-piperidin-4-yl-2,3-diaza spiro[4.4]non-3-en-1 -one hydrochloride (compound B10) and chloroacetic anhydride as starting com pounds. MS [M+H] calc: 434 found: 434 25 B1. 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazo-3-one hydrochlo ride Alternativel: Preparation of the title compound starting from compound Cl: 30 20 g NaH (60% in mineral oil) is suspended in 500 ml of dry DMF under a blanket of dry nitrogen. 124 g 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound Cl) is added in por tions and stirred for an additional 30 min at RT. The solution becomes slightly yellow. 168 g tert-butyl 4-(Toluene-4-sulfonyloxy)-piperidine-l-carboxylate (compound El) in 150 ml of DMF is added in one portion and the mixture is placed in a preheated oil bath (1400C) and heated for 1.0 hr. The mixture is 35 cooled to 500C (part of the sodium toluenesulfonate crystallizes) 1000 ml of water is added and the mixture is extracted with 200 ml of ethyl acetate (five times). The combined organic layers are washed with 100 ml of water (five times), 50 ml of brine, dried over MgSO 4 and concentrated in vacuo. The oil obtained is dissolved in 300 ml of ethanol and 300 ml of 1 M H 2

SO

4 is added and heated at reflux for 60 min. The ethanol is removed in vacuo, 200 ml of water is added and washed with 100 ml DCM (five 40 times). The aqueous layer is basified with 40 g NaOH in 250 ml water and extracted with 200 ml of - 29 dichloromethane (three times), dried over MgSO 4 and concentrated in vacuo. The oil is suspended in 300 ml of ethanol with 30 ml of concentrated hydrochloric acid and heated until it dissolves. Cooling in ice causes precipitation. M. p. 217-220'C 5 Alternative 2: Preparation of 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H pyrazol-3-one starting from compound D1: 1000 g of methyl 3-(3,4-dimethoxyphenyl)-2,2-dimethyl-3-oxopropanoate (compound D1) are dissolved 10 in 10.5 1 of methanol. 2500 g piperidin-4-yl-hydrazine-dihydrochloride, solved in 4 1 of water are added rapidly. The mixture is heated to reflux and kept at reflux temperature for 4 days. The reaction mixture is cooled to 200C, 10 1 of water are added and then methanol is removed by distillation in vacuum. The aqueous solution is allowed to stand overnight at RT. The solution is cooled and aqueous sodium hy droxide (c=1 0 mol/I) (about 2 I) is added during 4 to 5 h by keeping the temperature below 200C and the 15 pH should be higher than 13. The product crystallizes during adding of sodium hydroxide. The mixture is stirred 1 h at 10 C, filtered over a filter press and washed with 0.5 I of water. The product is dried at 500C in a circulating air dryer. M. p. 119-122'C 20 B2. 5-(3,4-diethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazo-3-one hydrochloride Prepared analogously as described for example B1 (Alternative 1) using 5-(3,4-diethoxyphenyl)-4,4-di methyl-2,4-dihydro-3H-pyrazol-3-one (compound C2) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperi dine-1-carboxylate (compound El) as starting compounds. 25 M. p. 221-224'C B3. 5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethy-2-piperidin-4-yl-2,4-dihydro 3H-pyrazol-3-one hydrochloride 30 Prepared analogously as described for example B1 (Alternative 1) using 5-[3-(cyclopropylmethoxy)-4 (difluoromethoxy)phenyl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C3) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperidine-l-carboxylate (compound El) as starting compounds. M. p. 236-237'C 35 B4. 5-[3-(benzyloxy)-4-methoxyphenyl]-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride Prepared analogously as described for example B1 (Alternative 1) using 5-[3-(benzyloxy)-4-methoxy phenyl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C4) and tert-butyl 4-(Toluene-4-sulfon- - 30 yloxy)-piperidine-1-carboxylate (compound El) as starting compounds. M. p. 2430C (with decomposition) B5. 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1 -benzofu ran-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4 5 dihydro-3H-pyrazol-3-one hydrochloride Prepared analogously as described for example B1 (Alternative 1) using 5-(7-methoxy-2,2-dimethyl-2,3 dihydro-l-benzofuran-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C5) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperidine-l-carboxylate (compound El) as starting compounds. 10 M. p. >2600C B6. 5-(7-methoxy-3H-spiro[1 -benzofuran-2, 1'-cyclopentan]-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4 dihydro-3H-pyrazol-3-one hydrochloride 15 Prepared analogously as described for example B1 (Alternative 1) using 5-(7-methoxy-3H-spiro[1-ben zofuran-2,1'-cyclopentan]-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C6) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperidine-l-carboxylate (compound El) as starting compounds. M. p. 2120C (with decomposition) 20 B7. 5-(3,4-dimethoxyphenyl)-4,4-diethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazo-3-one hydrochloride The title compound may be prepared analogously as described for B1 (Alternative 1) using 5-(3,4-di methoxyphenyl)-4,4-diethyl-2,4-dihydro-3H-pyrazol-3-one (compound C7) and tert-butyl 4-(Toluene-4 sulfonyloxy)-piperidine-l-carboxylate (compound El) as starting compounds. 25 B8. 5-(3,4-dimethoxyphenyl)-4-methyl-2-piperidin-4-yl-4-propyl-2,4-dihydro-3H-pyrazo-3-one hy drochloride Prepared analogously as described for example B1 (Alternative 1) using 5-(3,4-dimethoxyphenyl)-4 30 methyl-4-propyl-2,4-dihydro-3H-pyrazol-3-one (compound C8) and tert-butyl 4-(Toluene-4-sulfonyloxy) piperidine-1-carboxylate (compound El) as starting compounds. M. p. 147-1520C B9. 5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazo-3-one hydro 35 chloride Prepared analogous as described for example B1 (Alternative 1) using 5-(3,4-dimethoxyphenyl)-4-ethyl 4-methyl-2,4-dihydro-3H-pyrazol-3-one (compound C9) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperi dine-l-carboxylate (compound El) as starting compounds.

- 31 M. p. 214-216'C B10. 4-(3,4-dimethoxyphenyl)-2-piperidin-4-yl-2,3-diazaspiro[4.4]non-3-en-1 -one hydrochloride 5 Prepared analogous as described for example B1 (Alternative 1) using 4-(3,4-dimethoxyphenyl)-2,3 diazaspiro[4.4]non-3-en-1-one (compound C10) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperidine-1 carboxylate (compound El) as starting compounds. M. p. 2350C (with decomposition) 10 C1. 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one 192 g of methyl 3-(3,4-dimethoxyphenyl)-2,2-dimethyl-3-oxopropanoate (compound D1) is dissolved in 600 ml of ethanol 145 ml hydrazine hydrate is added and the mixture is heated under reflux for 17 h. The mixture is concentrated in vacuo, resuspended in 400 ml of ethanol and concentrated again. The 15 solids are refluxed for 60 min in 400 ml of ethanol, cooled to RT and filtered. The product is washed with 50 ml of ethanol followed by 100 ml of diethyl ether and dried in vacuo at 500C. M. p. 193-1940C C2. 5-(3,4-diethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one 20 Prepared analogously as described for example C1 using methyl 3-(3,4-diethoxyphenyl)-2,2-dimethyl-3 oxopropanoate (compound D2) and hydrazine hydrate as starting compounds. M. p. 121-122'C 25 C3. 5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-2,4-dihydro-3H-pyrazo-3 one Prepared analogously as described for example C1 using methyl 3-[3-(cyclopropylmethoxy)-4-(difluo romethoxy)phenyl]-2,2-dimethyl-3-oxopropanoate (compound D3) and hydrazine hydrate as starting 30 compounds. M. p. 83-85'C C4. 5-[3-(benzyloxy)-4-methoxyphenyl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one 35 Prepared analogously as described for example C1 using methyl 3-[3-(benzyloxy)-4-methoxyphenyl] 2,2-dimethyl-3-oxopropanoate (compound D4) and hydrazine hydrate as starting compounds. M. p. 201-206'C C5. 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-l-benzofuran-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol 40 3-one - 32 1.1 g of diisopropylamine is dissolved in 50 ml of THF under a blanket of dry nitrogen and cooled to OC and 7.5 ml n-BuLi (1.6M in hexane) is added dropwise. Next, the mixture is cooled to minus 400C, using an acetone/N2 bath, and 1.2 g of methyl 2-methylproponate is added. The resulting mixture is stirred for 5 an additional 15 min at minus 400C, afterwhich 2.6 g of 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofu ran-4-carbonyl chloride dissolved in 50 ml of THF is added dropwise in 60 min during which the tempe rature is kept below -40'C. The cooling bath is removed and stirring is continued for 60 min at RT. 10 ml of 4M hydrochloric acid is added, the THF is removed in vacuo and the aqueous layer is extracted with ethyl acetate. The ethyl acetate solution is washed subsequently with 50 ml of water, 50 ml 1 M 10 sodium carbonate and 50 ml of brine, dried over MgSO 4 and concentrated in vacuo. The residue is dissolved in ethanol, 2.4 g of hydrazine hydrate is added and the resulting mixture refluxed for 18 h. After cooling to room temperature, the precipitate is filtered off and dried. M. p. 202-205'C 15 C6. 5-(7-methoxy-3H-spiro[1 -benzofuran-2,1'-cyclopentan]-4-yl)-4,4-dimethyl-2,4-dihydro-3H pyrazol-3-one Prepared analogous as described for example C5 using 7-methoxy-2,2-spirocyclopentyl-2,3-dihydro benzofuran-4-carbonyl chloride, methyl 2-methylproponate and hydrazine hydrate as starting com 20 pounds. M. p. 214-215'C C7. 5-(3,4-dimethoxyphenyl)-4,4-diethyl-2,4-dihydro-3H-pyrazol-3-one 25 The title compound may be prepared analogously as described for example C5 using 3,4-dimethoxy benzoyl chloride, methyl 2-ethylbutanoate and hydrazine hydrate as starting compounds. C8. 5-(3,4-dimethoxyphenyl)-4-methyl-4-propyl-2,4-dihydro-3H-pyrazol-3-one 30 Prepared analogously as described for example C5 using 3,4-dimethoxybenzoyl chloride, methyl 2-methylpentanoate and hydrazine hydrate as starting compounds. M. p. 119-120'C C9. 5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2,4-dihydro-3H-pyrazol-3-one 35 Prepared analogously as described for example C5 using 3,4-dimethoxybenzoyl chloride, methyl 2-methylbutanoate and hydrazine hydrate as starting compounds. M. p. 145-146'C 40 C10. 4-(3,4-dimethoxyphenyl)-2,3-diazaspiro[4.4]non-3-en-1 -one - 33 Prepared analogously as described for example C5 using 3,4-dimethoxybenzoyl chloride, methyl cyclo pentancarboxylate and hydrazine hydrate as starting compounds. M. p. 200-202'C 5 D1. Methyl 3-(3,4-dimethoxyphenyl)-2,2-dimethyl-3-oxopropanoate 124 ml of diisopropylamine is dissolved in 500 ml of THF under a blanket of dry nitrogen and cooled to O0C and 550 ml n-BuLi (1.6M in hexane) is added dropwise. Next, the mixture is cooled to minus 400C, 10 using an acetone/N2 bath, and 100 ml methyl 2-methylproponate is added. The resulting mixture is stirred for an additional 15 min at minus 400C, after which 160.5 g of 3,4-dimethoxybenzoyl chloride dissolved in 750 ml of THF is added dropwise in 60 min during which the temperature is kept below 400C. The cooling bath is removed and stirring is continued for 60 min at RT. 150 ml of 4M hydrochloric acid is added and the THF layer is separated and washed with 100 ml of water, 200 ml 1M of sodium 15 carbonate and 100 ml of brine, dried over MgSO 4 and concentrated in vacuo. NMR (CDC13): 5 = 1.56 (s,6H), 3.65 (s,3H), 3.89 (s,3H), 3.91 (s,3H), 6.82 (d, J=8.4Hz,1H), 7.41 (dd,1H,J=1.4, 8.4Hz) 7.99 (d,1H,J=1.4Hz). 20 D2. Methyl 3-(3,4-diethoxyphenyl)-2,2-dimethyl-3-oxopropanoate Prepared analogously as described for example D1 using methyl 2-methylproponate and 3,4-dieth oxybenzoyl chloride as starting compounds. 25 NMR (CDC13): 5 = 1.31-154 (dt,6H,J=5.6Hz), 1.56 (s,6H), 3.65 (s,3H), 4.07(m,6H), 6.82 (d, J=8.4Hz,1H), 7.41 (dd,1H,J=1.4, 8.4Hz) 7.99 (d,1H,J=1.4Hz). D3. Methyl 3-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2,2-dimethyl-3-oxopropanoate 30 Prepared analogously as described for example D1 using methyl 2-methylproponate and 3-cyclopropyl methoxy-4-difluoromethoxybenzoy chloride as starting compounds. NMR (CDC13): 5 = 1.20-1.33 (m,2H), 1.50-1.63 (m,6H), 1.46 (s,6H), 3.65 (s,3H), 3.57 (s,3H), 3.82 (d,J=5.7Hz,2H), 6.30 (s,0.4H), 6.68 (s,0.6H), 7.07 (d, J=8.4Hz,1H), 7.27 (dd,1H,J=1.4, 8.4Hz), 7.49 35 (d,1H,J=1.4Hz). D4. Methyl 3-[3-(benzyloxy)-4-methoxyphenyl]-2,2-dimethyl-3-oxopropanoate Prepared analogously as described for example D1 using methyl 2-methylproponate and 3-benzyloxy 40 4-methoxybenzoyl chloride as starting compounds.

- 34 NMR (CDC13): 1.46 (s,6H), 3.60 (s,3H), 3.92 (s,3H), 5.12 (2,2H), 6.83 (d, J=8.4Hz,1H), 7.20-7.55 (m,7H) 5 El. tert-Butyl 4-(toluene-4-sulfonyloxy)-piperidide-l-carboxylate 201 g tert Butyl 4-hydroxy-piperidine-l-carboxylate, 160 ml triethylamine and 6.0 g 4-dimethylamino pyridine are dissolved in 750 ml DCM. 191 g 4-toluenesulfonylchloride is added and the mixture is re fluxed for 7 h. The mixture is cooled in ice and acidified with 100 ml of 1 M H 2 SO4; the organic layer is 10 washed with 300 ml of water (twice), 250 ml of 1 M Na 2

CO

3 solution (twice), dried over MgSO 4 , filtered and concentrated in vacuo. M. p. 98-101 'C Fl. 5-(3,4-dimethoxyphenyl)-2-(1 -glycylpiperidin-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one 15 hydrochloride Step 2: A solution of 4 g tert-Butyl (2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)carbamate (see below) and 7 ml of trifluoroacetic acid in 50 ml of dichloromethane is stirred at RT for 16 h after which the mixture is washed with aqueous sodium car 20 bonate. After drying over magnesium sulphate, a solution of hydrochloric acid in ether is added. The precipitate is filtered off and dried. M. p. 70-74'C Step 1: tert-Butyl (2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]pi 25 peridin-1-yl}-2-oxoethyl)carbamate: A mixture of 5 g of 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-pipe ridin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1), 1.9 ml of triethylamine and 2.5 g of N-BOC-glycine in 25 ml of DCM is stirred until complete dissolution (about 15 min). 3.9 g of 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added and the resulting mixture is stirred at RT for 3 h. After washing with 1 M sodium carbonate, the organic layer is dried over magnesium sul 30 phate and evaporated. The residue is purified by column chromatography [silica, ethyl acetate]. The title compound is crystallized from diethyl ether. M. p. 146-148'C Commercial utility 35 The compounds of formula 1 and the stereoisomers of the compounds of formula 1 are hereinafter referred to as the compounds. In particular, the compounds are pharmaceutically acceptable. The compounds have valuable pharmaceutical properties, which make them commercially utilizable. In 40 particular, as type 4 phosphodiesterase (PDE4) inhibitors, they are suitable on the one hand as bron- - 35 chial therapeutics (for the treatment of airway obstructions on account of their dilating action but also on account of their respiratory rate- or respiratory drive-increasing action) and for the removal of erectile dysfunction on account of their vascular dilating action, but on the other hand especially for the treat ment of disorders, in particular of an inflammatory nature, e.g. of the airways, of the skin, of the intes 5 tine, of the eyes, of the CNS and of the joints, which are mediated by mediators such as histamine, PAF (platelet-activating factor), arachidonic acid derivatives such as leukotrienes and prostaglandins, cyto kines, interleukins, chemokines, alpha-, beta- and gamma-interferon, tumor necrosis factor (TNF) or oxygen free radicals and proteases. In this context, the compounds are distinguished by valuable and desirable properties, such as, for example, high efficacy, high selectivity, low toxicity, superior bioavail 10 ability in general (e.g. good enteral absorption), superior therapeutic window, superior pharmacokinetics (e.g. half life), absence of significant side effects, and further beneficial effects related to their therapeu tic and pharmaceutical suitability. Accordingly, the invention further relates to the compounds for use in the treatment or prophylaxis of 15 diseases, especially diseases alleviated by inhibition of type 4 phosphodiesterase. In particular, the invention relates to the compounds for use in the treatment or prophylaxis of the fol lowing diseases: 20 acute and chronic airway diseases, such as, but not limited to, bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD (chronic obstructive pulmonary disease), pulmonary hypertension and lung fibrosis; diseases which are based on allergic and/or chronic, immunological false reactions in the region of the 25 upper airways (pharynx, nose) and the adjacent regions (paranasal sinuses, eyes), such as, but not limited to, allergic rhinitis/sinusitis, chronic rhinitis/sinusitis, allergic conjunctivitis and also nasal polyps; dermatological diseases especially of proliferative, inflammatory and allergic type, such as, but not lim ited to psoriasis (vulgaris), toxic and allergic contact eczema, atopic dermatitis (eczema), seborrhoeic eczema, Lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, 30 discoid lupus erythematosus, follicular and widespread pyodermias, endogenous and exogenous acne, acne rosacea and other proliferative, inflammatory and allergic skin disorders; diseases which are based on an excessive release of TNF and leukotrienes, such as, for example, diseases of the arthritis type like rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions; 35 fibrotic diseases, such as, but not limited to, cystic fibrosis, pulmonary fibrosis, hepatic fibrosis and re nal fibrosis; viral, alcoholic or drug-induced acute and fulminant hepatitis, hepatic steatosis (alcoholic and non alcoholic steatio-hepatitis); diseases of the immune system, such as, but not limited to, AIDS, multiple sclerosis, graft versus host 40 reaction, allograft rejections; - 36 cachexia, cancer cachexia, AIDS cachexia; types of shock, such as, but not limited to, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome and ARDS (adult respiratory distress syndrome); diseases in the gastrointestinal region, such as Crohn's disease and ulcerative colitis; 5 diseases of the heart which can be treated by PDE inhibitors, such as cardiac insufficiency; diseases which can be treated on account of the tissue-relaxant action of the PDE inhibitors, such as, for example, erectile dysfunction, colics of the kidneys and of the ureters in connection with kidney stones or oncolytic action (to treat preterm delivery); glomerulonephritis; diabetes insipidus, diabetes mellitus (type I and in particular type II); cancer (in particular lymphoid and 10 myeloid leukaemia); osteoporosis; conditions associated with cerebral metabolic inhibition, such as, but not limited to, cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease or multiinfarct dementia; and also diseases of the central nervous system, such as, but not limited to, depressions, anxiety 15 states, spinal cord injury, schizophrenia or arteriosclerotic dementia. Preferably, there is further disclosed the compounds for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as bronchitis, allergic bronchitis, bronchial asthma, 20 emphysema, COPD, pulmonary hypertension and lung fibrosis; allergic rhinitis; rheumatoid arthritis; dermatological diseases, such as psoriasis and atopic dermatitis (eczema); inflammations in the gastrointestinal region, such as Crohn's disease and ulcerative colitis and 25 diabetes mellitus (type I and in particular type II). There is also disclosed the use of the compounds in the manufacture of a pharmaceutical composition inhibiting the type 4 phosphodiesterase, in particular a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of type 4 phosphodiesterase, preferably, a 30 pharmaceutical composition for the treatment or prophylaxis of the diseases exemplified above. In particular, there is disclosed the use of the compound in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, such as, but not limited to, bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD, pulmonary 35 hypertension or lung fibrosis. There is also disclosed the use of the compounds in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of allergic rhinitis.

- 37 Furthermore, there is disclosed the use of the compounds in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of dermatological diseases, such as, but not limited to, psoriasis or atopic dermatitis (eczema). 5 Additionally, there is disclosed the use of the compounds in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of inflammations in the gastrointestinal region, such as, but not limited to, Crohn's disease or ulcerative colitis. As well, there is disclosed the use of the compounds in the manufacture of a pharmaceutical 10 composition for the treatment or prophylaxis of diabetes mellitus (type I and in particular type II). There is further disclosed a method of treating or preventing a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds. 15 In particular, there is disclosed a method of treating or preventing one of the above mentioned diseases comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds. Especially, there is disclosed a method of treating or preventing a disease, which is alleviated by 20 inhibition of the type 4 phosphodiesterase comprising administering to a patient in need thereof a thera peutically effective amount of at least one of the compounds. Preferably, there is disclosed a method of treating or preventing an acute or chronic airway disease, for example, but not limited to, bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD, 25 pulmonary hypertension or lung fibrosis comprising administering to a patient in need thereof a thera peutically effective amount of at least one of the compounds. There is also disclosed a method of treating or preventing allergic rhinitis comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds. 30 Furthermore, preferably there is disclosed a method of treating or preventing dermatological diseases, such as, but not limited to, psoriasis or atopic dermatitis (eczema) comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds. 35 Additionally, preferably there is disclosed a method of treating or preventing diseases in the gastrointestinal region, such as, but not limited to, Crohn's disease or ulcerative colitis comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the com pounds.

- 38 As well, preferably there is disclosed a method of treating or preventing diabetes mellitus (type I and in particular type II) comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds. 5 In the above methods, the patient is preferably a mammal, more preferably a human. Furthermore, in the above methods, at least one of the compounds can be used. Preferably, one or two of the compounds are used, more preferably, one of the compounds of the invention is used. In a particularly preferred embodiment, the above methods of treating or preventing one of the above 10 mentioned diseases comprise administering to a patient in need thereof a therapeutically effective amount of one compound of the examples. There is furthermore provided a pharmaceutical composition, which comprises at least one of the compounds together with at least one pharmaceutically acceptable auxiliary. 15 Preferably, the pharmaceutical composition comprises one or two of the compounds. More preferably, the pharmaceutical composition comprises one of the compounds . In a particularly preferred embodiment, the pharmaceutical composition comprises a compound of the 20 examples together with at least one pharmaceutically acceptable auxiliary. There is furthermore provided a pharmaceutical composition inhibiting the type 4 phosphodiesterase, especially for the treatment or prophylaxis of diseases alleviated by inhibition of type 4 phosphodiesterase, in particular for the treatment or prophylaxis of the diseases exemplified above. 25 There is also encompassed pharmaceutical compositions, as defined above, for the treatment or prophylaxis of one or more of the following diseases: acute and chronic airway diseases, such as, bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD, pulmonary hypertension and lung fibrosis; allergic rhinitis; rheumatoid arthritis; dermatological diseases, such as psoriasis and atopic 30 dermatitis (eczema); and inflammations in the gastrointestinal region, such as Crohn's disease and ulcerative colitis; and diabetes mellitus (type I and in particular type II) Depending on the particular disease to be treated or prevented, additionally therapeutic agents, which are normally administered to treat or prevent that disease, may optionally be co-administered with the 35 compounds. In a preferred embodiment, at least one of the compounds is co-administered with at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, p 2 -adrenoceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 phospho- - 39 diesterase inhibitors, HMG-CoA reductase-inhibitors, lung surfactants, antibiotics and anti-diabetic agents. In this respect, the "therapeutic agent" includes the corticosteroids, anticholinergics, p 2 -adrenoceptor 5 agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 phosphodiesterase inhibi tors, HMG-CoA reductase-inhibitors, lung surfactants, antibiotics and anti-diabetics in form of the free compounds, the pharmaceutically acceptable salts thereof, the pharmaceutically acceptable derivatives thereof (e.g., but not limited to, ester derivatives, N-oxides etc.), the solvates (hydrates) thereof and the stereoisomers of the compounds, salts, derivatives and solvates. 10 Co-administration of at least one of the compounds with at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, p 2 -adrenoceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA reductase-inhibitors, lung surfactants, antibiotics and anti-diabetic agents can take place in form of a 15 fixed combination, a non-fixed combination or a kit of parts. A "fixed combination" is defined as a combination wherein at least one of the compounds and the therapeutic agent intended for co-administration are present in one dosing unit or in a single entity. One example of a fixed combination is a pharmaceutical composition wherein at least one of the compounds 20 and the therapeutic agent are present in admixture for simultaneous administration. Another example of a fixed combination is a pharmaceutical composition wherein at least one of the compounds and the therapeutic compound are present in one dosing unit without being in admixture. A "non-fixed combination" or "kit of parts" is defined as a combination wherein at least one of the 25 compounds and the therapeutic agent are present in more than one dosing unit. In a non-fixed combi nation or a kit of parts at least one of the compounds and the therapeutic compound are provided as separate formulations. They might be packaged and presented together as separate components of a combination pack for simultaneous, sequential or separate use in combination therapy. In case of sequential or separate administration of at least one of the compounds and the therapeutic agent, the 30 compound can be administered before or after administration of the therapeutic agent. The type of formulation of at least one of the compounds and the therapeutic agent of a non-fixed combination or a kit of parts can be identical, similar, i.e. both, the compound and the therapeutic agent are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration 35 forms, such as e.g. the compound is formulated as tablet or capsule and the therapeutic agent is formulated as powder, solution or suspension. Accordingly, the invention additionally relates to a fixed combination, a non-fixed combination or kit of parts comprising at least one of the compounds, at least one therapeutic agent selected from the group 40 consisting of corticosteroids, anticholinergics, p 2 -adrenoceptor agonists, H1 receptor antagonists, - 40 leukotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA reducetase-inhibitors, lung surfactants, antibiotics and anti-diabetic agents, and at least one pharmaceutically acceptable auxiliary. 5 The above-mentioned combinations of at least one of the compounds and a therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, p 2 -adrenoceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA reduc tase-inhibitors, lung surfactants and antibiotics are particularly useful for the treatment of acute and chronic airway diseases. Combinations of at least one of the compounds and a therapeutic agent se 10 lected from the group consisting of corticosteroids, H1 receptor antagonists and leukotriene receptor antagonists might as well be useful for the systemic or topical treatment of dermatogical diseases. Combinations of at least one of the compounds and an anti-diabetic agent are useful for the treatment of diabetes mellitus (type I and in particular type II). 15 In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise at least one of the compounds (in particular the compound is one of the examples), a corticosteroid and at least one pharmaceutically acceptable auxiliary. In a particularly preferred embod iment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise: at least one of the compounds and budesonide, 20 at least one of the compounds and fluticasone, at least one of the compounds and beclometasone, at least one of the compounds and mometasone, at least one of the compounds and triamcinolone acetonide, or at least one of the compounds and ciclesonide, 25 and at least one pharmaceutically acceptable auxiliary. In a preferred embodiment, the pharmaceutically acceptable salt of fluticasone is fluticasone-1 7-pro pionate. In another preferred embodiment, the pharmaceutically acceptable salt of beclometasone is beclometasone dipropionate. In a preferred embodiment, the pharmaceutically acceptable salt of mo 30 metasone is mometasone furoate. In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise at least one of the compounds (in particular the compound is one of the examples), an anticholinergic and at least one pharmaceutically acceptable auxiliary. In a particularly preferred em 35 bodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise: at least one of the compounds and glycopyrronium bromide, at least one of the compounds and aclidinium bromide, at least one of the compounds and tiotropium bromide, or at least one of the compounds and ipratropium bromide, 40 and at least one pharmaceutically acceptable auxiliary.

- 41 In a preferred embodiment, the stereoisomer of glycopyrronium bromide is (R,R)-glycopyrronium bro mide. In a preferred embodiment, tiotropium bromide is used in form of its monohydrate. 5 In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise at least one of the compounds (in particular the compound is one of the examples), a p 2 -adrenoceptor agonist and at least one pharmaceutically acceptable auxiliary. In a particularly pre ferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts com prise: 10 at least one of the compounds and salbutamol, at least one of the compounds and milveterol, at least one of the compounds and indacaterol, at least one of the compounds and carmoterol, at least one of the compounds and salmeterol, or 15 at least one of the compounds and formoterol, and at least one pharmaceutically acceptable auxiliary. In a preferred embodiment, the pharmaceutically acceptable salt of salbutamol is salbutamol sulfate. In a preferred embodiment, the pharmaceutically acceptable salt of milveterol is milveterol hydrochloride. 20 In a preferred embodiment, the pharmaceutically acceptable salt of carmoterol is carmoterol hydrochlo ride. In a preferred embodiment, the pharmaceutically acceptable salt of salmeterol is salmeterol xina foate. In another preferred embodiment, the pharmaceutically acceptable salt of formoterol is formoterol hemifumarate monohydrate. In another preferred embodiment, the stereoisomer of formoterol is R,R-formoterol. In another preferred embodiment, the pharmaceutically acceptable salt of R,R-formo 25 terol is R,R-formoterol L-tartrate. In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise at least one of the compounds (in particular the compound is one of the examples), a H1 receptor antagonist and at least one pharmaceutically acceptable auxiliary. In a particularly pre 30 ferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts com prise: at least one of thecompounds and azelastine, at least one of the compounds and olopatadine, at least one of the compounds and loratadine, 35 at least one of the compounds and desloratadine, or at least one of the compounds and cetirizine, and at least one pharmaceutically acceptable auxiliary. In a preferred embodiment, the pharmaceutically acceptable salt of azelastine is is azelastine hydro chloride. In a preferred embodiment, the pharmaceutically acceptable salt of olapatadine is olapatadine 40 hydrochloride. In a preferred embodiment, the pharmaceutically acceptable salt of cetirizine is cetirizine - 42 dihydrochloride. In a preferred embodiment, the stereoisomer of cetirizine is levocetirizine. In another preferred embodiment, the pharmaceutically acceptable salt of levocetirizine is levocetirizine dihydro chloride. 5 In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise at least one of the compounds (in particular the compound is one of the examples), a leukotriene receptor antagonist and at least one pharmaceutically acceptable auxiliary. In a particularly preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise: 10 at least one of the compounds and montelukast, at least one of the compounds and pranlukast, at least one of the compounds and zafirlukast, or at least one of the compounds and zileuton, and at least one pharmaceutically acceptable auxiliary. 15 In a preferred embodiment, the pharmaceutically acceptable salt of montelukast is montelukast sodium. In another preferred embodiment, pranlukast is used in form of its monohydrate. In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of 20 parts comprise at least one of the compounds (in particular the compound is one of the examples), a type 5 phosphodiesterase inhibitor and at least one pharmaceutically acceptable auxiliary. In a particu larly preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise: at least one of the compounds and sildenafil, 25 at least one of the compounds and vardenafil, at least one of the compounds and tadalafil, at least one of the compounds and udenafil, or at least one of the compounds and avanafil, and at least one pharmaceutically acceptable auxiliary. 30 In another preferred embodiment, the pharmaceutically acceptable salts of sildenafil are sildenafil hemi citrate, sildenafil citrate and sildenafil mesilate; particularly preferred is the citrate salt of sildenafil. In another preferred embodiment, the pharmaceutically acceptable salts of vardenafil are vardenafil hy drochloride or vardenafil dihyrochloride. In another preferred embodiment, the pharmaceutically ac 35 ceptable salt of avanafil is avanafil besilate. In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise at least one of the compound (in particular the compound is one of the examples), a HMG-CoA reductase inhibitor and at least one pharmaceutically acceptable auxiliary. In a particularly - 43 preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise: at least one of the compounds and lovastatin, at least one of the compounds and pravastatin, 5 at least one of the compounds and simvastatin, at least one of the compounds and atorvastatin, at least one of the compounds and fluvastatin, at least one of the compounds and rosuvastatin, at least one of the compounds and pitavastatin, 10 at least one of the compounds and bervastatin, at least one of the compounds and dalvastatin, or at least one of the compounds and glenvastatin, and at least one pharmaceutically acceptable auxiliary. 15 In a preferred embodiment the pharmaceutically acceptable salts of pravastatin are the potassium, lithium, sodium and hemi-calcium salt of pravastatin. A particularly preferred pharmaceutically accepta ble salt of pravastatin is the sodium salt of pravastatin. In a preferred embodiment the pharmaceutically acceptable salt of simvastatin is the sodium salt of simvastatin. In a preferred embodiment the pharma ceutically acceptable salts of atorvastatin are the potassium, sodium and the hemi-calcium salt of 20 atorvastatin. A particularly preferred pharmaceutically acceptable salt of atorvastatin is the hemi calcium salt of atorvastatin. As an example for a hydrate of atorvastatin may be mentioned the trihy drate and the sesqui-hydrate of the hemi-calcium salt of atorvastatin. In a preferred embodiment of the pharmaceutically acceptable salt of fluvastatin is the sodium salt of fluvastatin. In a preferred embodi ment the pharmaceutically acceptable salts of rosuvastatin are the potassium, lithium, sodium, hemi 25 magnesium and the hemi-calcium salt of rosuvastatin. A particularly preferred pharmaceutically ac ceptable salt of rosuvastatin is the hemi-calcium salt of rosuvastatin. Another particularly preferred pharmaceutically acceptable salt of rosuvastatin is the sodium salt of rosuvastatin. In a preferred em bodiment the pharmaceutically acceptable salts of pitavastatin are the potassium, sodium and the hemi-calcium salt of pitavastatin. A particularly preferred pharmaceutically acceptable salt of pitavas 30 tatin is the hemi-calcium salt of pitavastatin. In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise at least one of the compounds (in particular the compound is one of the examples), a lung surfactant and at least one pharmaceutically acceptable auxiliary. In a particularly preferred em 35 bodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise: at least one of the compounds and lusupultide, at least one of the compounds and poracant alfa, at least one of the compounds and sinapultide, at least one of the compounds and beracant, 40 at least one of the compounds and bovacant, - 44 at least one of the compounds and colfosceril palmitate, at least one of the compounds and surfactant-TA, or at least one of the compounds and calfacant, and at least one pharmaceutically acceptable auxiliary. 5 In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise at least one of the compounds (in particular the compound is one of the examples), an antibiotic and at least one pharmaceutically acceptable auxiliary. In a particularly preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise: 10 at least one of the compounds and amoxicillin, at least one of the compounds and ampicillin, at least one of the compounds and levofloxacin, at least one of the compounds and clarithromycin, at least one of the compounds and ciprofloxacin, 15 at least one of the compounds and telithromycin, or at least one of the compounds and azithromycin, and at least one pharmaceutically acceptable auxiliary. In a preferred embodiment, amoxicillin is used in form of its trihydrate. In another preferred embodi 20 ment, ampicillin is used in form of its trihydrate. In another preferred embodiment, the pharmaceutically acceptable salt of ampicillin is ampicillin natrium. In another preferred embodiment levofloxacin is used in form of its hemi hydrate. In another preferred embodiment, the pharmaceutically acceptable salt of ciprofloxacin is ciprofloxacin hydrochloride monohydrate. In another preferred embodiment, azithromy cin is used in form of its monohydrate. 25 In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise at least one of the compounds (in particular the compound is one of the examples), a corticosteroid, a p 2 -adrenoceptor agonist and at least one pharmaceutically acceptable auxiliary. In a particularly preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit 30 of parts comprise: at least one of the compounds budesonide and salbutamol, at least one of the compounds budesonide and milveterol, at least one of the compounds budesonide and indacaterol, at least one of the compounds budesonide and carmoterol, 35 at least one of the compounds budesonide and salmeterol, at least one of the compounds budesonide and formoterol, at least one of thecompounds fluticasone and salbutamol, at least one of the compounds fluticasone and milveterol, at least one of the compounds fluticasone and indacaterol, 40 at least one of the compounds fluticasone and carmoterol, - 45 at least one of the compounds fluticasone and salmeterol, at least one of the compounds fluticasone and formoterol, at least one of the compounds beclometasone and salbutamol, at least one of the compounds beclometasone and milveterol, 5 at least one of the compounds beclometasone and indacaterol, at least one of the compounds beclometasone and carmoterol, at least one of the compounds beclometasone and salmeterol, at least one of the compounds beclometasone and formoterol, at least one of the compounds mometasone and salbutamol, 10 at least one of the compounds mometasone and milveterol, at least one of the compounds mometasone and indacaterol, at least one of the compounds mometasone and carmoterol, at least one of thecompounds mometasone and salmeterol, at least one of the compounds mometasone and formoterol, 15 at least one of the compounds triamcinolone acetonide and salbutamol, at least one of the compounds triamcinolone acetonide and milveterol, at least one of the compounds triamcinolone acetonide and indacaterol, at least one of the compounds triamcinolone acetonide and carmoterol, at least one of the compounds triamcinolone acetonide and salmeterol, 20 at least one of the compounds triamcinolone acetonide and formoterol, at least one of the compounds ciclesonide and salbutamol, at least one of the compounds ciclesonide and milveterol, at least one of the compounds ciclesonide and indacaterol, at least one of the compounds ciclesonide and carmoterol, 25 at least one of the compounds ciclesonide and salmeterol, or at least one of the compounds ciclesonide and formoterol, and at least one pharmaceutically acceptable auxiliary. In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of 30 parts comprise at least one of the compounds (in particular the compound is one of the examples), a p 2 -adrenoceptor agonist, an anticholinergic and at least one pharmaceutically acceptable auxiliary. In a particularly preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise: at least one of the compounds salbutamol and glycopyrronium bromide, 35 at least one of the compounds salbutamol and aclidinium bromide, at least one of the compounds salbutamol and tiotropium bromide, at least one of the compounds salbutamol and ipratropium bromide, at least one of the compounds milveterol and glycopyrronium bromide, at least one of the compounds milveterol and aclidinium bromide, 40 at least one of the compounds milveterol and tiotropium bromide, - 46 at least one of the compounds milveterol and ipratropium bromide, at least one of the compounds salmeterol and glycopyrronium bromide, at least one of the compounds salmeterol and aclidinium bromide, at least one of the compounds salmeterol and tiotropium bromide, 5 at least one of the compounds salmeterol and ipratropium bromide, at least one of the compounds formoterol and glycopyrronium bromide, at least one of the compounds formoterol and aclidinium bromide, at least one of the compounds formoterol and tiotropium bromide, at least one of the compounds formoterol and ipratropium bromide, 10 at least one of the compounds indacaterol and glycopyrronium bromide, at least one of the compounds indacaterol and aclidinium bromide, at least one of the compounds indacaterol and tiotropium bromide, at least one of the compounds indacaterol and ipratropium bromide, at least one of the compounds carmoterol and glycopyrronium bromide, 15 at least one of the compounds carmoterol and aclidinium bromide, at least one of the compounds carmoterol and tiotropium bromide, or at least one of the compounds carmoterol and ipratropium bromide, and at least one pharmaceutically acceptable auxiliary. 20 In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise at least one of the compounds (in particular the compound is one of the examples), a corticosteroid, an anticholinergic and at least one pharmaceutically acceptable auxiliary. In a particularly preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise: 25 at least one of the compounds budesonide and glycopyrronium bromide, at least one of the compounds budesonide and aclidinium bromide, at least one of the compounds budesonide and tiotropium bromide, at least one of the compounds budesonide and ipratropium bromide, at least one of the compounds fluticasone and glycopyrronium bromide, 30 at least one of the compounds fluticasone and aclidinium bromide, at least one of the compounds fluticasone and tiotropium bromide, at least one of the compounds fluticasone and ipratropium bromide, at least one of the compounds beclometasone and glycopyrronium bromide, at least one of the compounds beclometasone and aclidinium bromide, 35 at least one of the compounds beclometasone and tiotropium bromide, at least one of the compounds beclometasone and ipratropium bromide, at least one of the compounds mometasone and glycopyrronium bromide, at least one of the compounds mometasone and aclidinium bromide, at least one of the compounds mometasone and tiotropium bromide, 40 at least one of the compounds mometasone and ipratropium bromide, - 47 at least one of the compounds triamcinolone acetonide and glycopyrronium bromide, at least one of the compounds triamcinolone acetonide and aclidinium bromide, at least one of the compounds triamcinolone acetonide and tiotropium bromide, at least one of the compounds triamcinolone acetonide and ipratropium bromide, 5 at least one of the compounds ciclesonide and glycopyrronium bromide, at least one of the compounds ciclesonide and aclidinium bromide, at least one of the compounds ciclesonide and tiotropium bromide, or at least one of the compounds ciclesonide and ipratropium bromide, and at least one pharmaceutically acceptable auxiliary. 10 In a preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise at least one of the compounds (in particular the compound is one of the examples), an anti-diabetic agent and at least one pharmaceutically acceptable auxiliary. In a particularly preferred embodiment, the above-mentioned fixed combination, non-fixed combination or kit of parts comprise: 15 at least one of the compounds and metformin, at least one of the compounds and carbutamide, at least one of the compounds and tolbutamide, at least one of the compounds and glibornuride, at least one of the compounds and glibenclamide, 20 at least one of the compounds and glimepiride, at least one of the compounds and gliquidone, at least one of the compounds and glisoxepide, at least one of the compounds and repaglinide, at least one of the compounds and rosiglitazone, 25 at least one of the compounds and pioglitazone, at least one of the compounds and rivoglitazone, at least one of the compounds and exenatide, at least one of the compounds and albiglutide, at least one of the compounds and liraglutide, 30 at least one of the compounds and sitagliptin, at least one of the compounds and saxagliptin, at least one of the compounds and vildagliptin, or at least one of the compounds and denagliptin, and at least one pharmaceutically acceptable auxiliary. 35 In a preferred embodiment the pharmaceutically acceptable salt of metformin is the hydrochloride salt of metformin. In another preferred embodiment the pharmaceutically acceptable salt of tolbutamide is the sodium salt of tolbutamide. In another preferred embodiment the pharmaceutically acceptable salt of gliquidone is the sodium salt of gliquidone. In another preferred embodiment the pharmaceutically 40 acceptable salt of rosiglitazone is the maleate salt of rosiglitazone. In another preferred embodiment the - 48 pharmaceutically acceptable salt of pioglitazone is the dihydrochloride salt of pioglitazone. In another preferred embodiment the pharmaceutically acceptable salt of rivoglitazone is the hydrochloride salt of rivoglitazone. In another preferred embodiment the pharmaceutically acceptable salt of sitagliptin is the phosphate salt of sitagliptin. 5 The pharmaceutical compositions according to the invention preferably contain the compound or compounds in a total amount of from 0.1 to 99.9wt%, more preferably 5 to 95wt%, in particular 20 to 80wt%. In case of co-administration of at least one compound with at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, p 2 -adrenoceptor agonists, H1 10 receptor antagonists, leukotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA reductase inhibitors, lung surfactants, antibiotics and anti-diabetic agents, in form of a fixed combination, non-fixed combination or kit of parts the total amount of the compound(s) and said therapeutic agent(s) in the respective pharmaceutical compositions/formulations is preferably in the range of from 0.1 to 99.9wt%, more preferably 5 to 95wt%, in particular 20 to 80wt%, under the 15 provision that the total amount of the compound(s) and the therapeutic agent(s) does not exceed 100wt%. Preferably, the at least one compound and the at least one therapeutic agent are present in the pharmaceutical compositions/formulations in a weight ratio of from 1000:1 to 1:1000. As pharmaceutically acceptable auxiliaries, any auxiliaries known to be suitable for preparing pharma 20 ceutical compositions/formulations can be used. Examples thereof include, but are not limited to, solvents, excipients, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrating agents, buffers, permeation promoters, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes. In particular, auxiliaries of a type 25 appropriate to the desired formulation and the desired mode of administration are used. The pharmaceutical compositions/formulations can be formulated, for example, into tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (e.g., but not limited to, sterile solutions), emulsions, suspensions, ointments, creams, lotions, pastes, oils, 30 gels, sprays and patches (e.g., but not limited to, transdermal therapeutic systems). Additionally, the pharmaceutical compositions can be prepared as e.g. liposome delivery systems, systems in which at least one of the compounds is coupled to monoclonal antibodies and systems in which the compound of the invention is coupled to polymers (e.g., but not limited to, soluble or biodegradable polymers). 35 The pharmaceutical compositions/formulations can be manufactured in a manner known to a person skilled in the art, e.g. by dissolving, mixing, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The selected formulation depends inter alia on the route of administering the pharmaceutical compo 40 sition. The pharmaceutical compositions/formulations of the invention can be administered by any - 49 suitable route, for example, by the oral, sublingual, buccal, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, topical, transdermal, intranasal, intraocular, intraperitoneal, intrasternal, intracoronary, transurethral, rectal or vaginal route, by inhalation or by insufflation. Oral administration of the compounds is preferred. 5 In case of non-fixed combinations or kit of parts comprising at least one of the compounds and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, p 2 adrenoceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA reductase inhibitors, lung surfactants, antibiotics and anti 10 diabetic agents, the compound of the invention and the therapeutic agent may be administered by the same route, e.g., without limitation, orally, or by different routes, e.g., without limitation, the compound of the invention can be administered orally and the therapeutic agent can be administered by inhalation or instillation. 15 Tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are e.g. suitable for oral administration. In particular, said formulations can be adapted so as to represent, for example, an enteric form, an immediate release form, a delayed release form, a repeated dose release form, a prolonged release form or a sustained release form. Said forms can be obtained, for example, by coating tablets, by dividing tablets into several compartments separated by 20 layers disintegrating under different conditions (e.g. pH conditions) or by coupling at least one of the compounds to a biodegradable polymer. Administration by inhalation or instillation is preferably made by using an aerosol. The aerosol is a liquid-gaseous dispersion, a solid-gaseous dispersion or a mixed liquid/solid-gaseous dispersion. 25 The aerosol may be generated by means of aerosol-producing devices such as dry powder inhalers (DPIs), pressurized metered dose inhalers (PMDIs) and nebulizers. Depending on the kind of the compound of the invention to be administered, the aerosol-producing device can contain the compound in form of a powder, a solution or a dispersion. The powder may contain, for example, one or more of 30 the following auxiliaries: carriers, stabilizers and fillers. The solution may contain in addition to the solvent, for example, one or more of the following auxiliaries: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavorings. The dispersion may contain in addition to the dispersant, for example, one or more of the following auxiliaries: pro pellants, surfactants, stabilizers, buffers, preservatives and flavorings. Examples of carriers include, but 35 are not limited to, saccharides, e.g. lactose and glucose. Examples of propellants include, but are not limited to, fluorohydrocarbons, e.g. 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane. The particle size of the aerosol particles (solid, liquid or solid/liquid particles) is preferably less than 100 pm, more preferably it is in the range of from 0.5 to 10 pm, in particular in the range of from 2 to 6 pm 40 (D50 value, measured by laser diffraction).

- 50 Specific aerosol-producing devices which may be used for inhaled administration include, but are not limited to, Cyclohaler@, Diskhaler@, Rotadisk@, Turbohaler@, Autohaler®, Novolizer®, Easyhaler®, Aerolizer®, Jethaler®, Diskus@, Ultrahaler® and Mystic® inhalers. The aerosol-producing devices may 5 be combined with spacers or expanders, e.g. Aerochamber@, Nebulator®, Volumatic® and Rondo®, for improving inhalation efficiency. In case of topical administration, suitable pharmaceutical formulations are, for example, ointments, creams, lotions, pastes, gels, powders, solutions, emulsions, suspensions, oils, sprays and patches 10 (e.g., but not limited to, transdermal therapeutic systems). For parenteral modes of administration such as, for example, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, intraperitoneal and intrasternal administration, preferably solutions (e.g., but not limited to, sterile solutions, isotonic solutions) are used. They are preferably administered by 15 injection or infusion techniques. In case of intranasal administration, for example, sprays and solutions to be applied in drop form are preferred formulations. 20 For intraocular administration, solutions to be applied in drop form, gels and ointments are exemplified formulations. Generally, the pharmaceutical compositions can be administered such that the dose of at least one of the compounds is in the range customary for type 4 phosphodiesterase inhibitors. In particular, a dose 25 in the range of from 0.01 to 250 mg, preferably in the range of 0.05 to 100 mg, more preferably in the range of 0.05 to 10 mg of at least one of the compounds per day is preferred for an average adult patient having a body weight of 70 kg. In this respect, it is to be noted that the dose is dependent, for example, on the specific compound used, the species treated, age, body weight, general health, sex and diet of the subject treated, mode and time of administration, rate of excretion, severity of the 30 disease to be treated and drug combination. In case of co-administration of at least one compound with at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, p 2 -adrenoceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA 35 reductase inhibitors, lung surfactants, antibiotics and anti-diabetic agents, in form of a fixed com bination, non-fixed combination or kit of parts the dose of the compound as well as the dose of the therapeutic agent will be in a range customary for the mono-therapy, it more likely being possible, on account of the individual action, which are mutually positively influencing and reinforcing, to reduce the respective doses in case of co-administration of the compound(s) and the therapeutic agent. 40 - 51 The pharmaceutical compositions can be administered in a single dose per day or in multiple subdoses, for example, 2 to 4 doses per day. A single dose unit of the pharmaceutical composition can contain e.g. from 0.01 mg to 250 mg, preferably 0.05 mg to 100 mg, more preferably 0.05 to 10 mg of at least one of the compounds. 5 In case of co-administration of at least one compound and at least one therapeutic compound selected from the group consisting of corticosteroids, anticholinergics, p 2 -adrenoceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA reductase inhibitors, lung surfactants, antibiotics and anti-diabetic agents, in form of a fixed 10 combination, a non-fixed combination or a kit of parts a single dose unit of the respective Pharma ceutical composition/formulation can contain e.g. from 0.01 mg to 250 mg, preferably 0.05 mg to 100 mg, more preferably 0.05 to 10 mg of the compound of the invention and/or e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 mg to 1000 mg, most preferably 1 mg to 500 mg, of the therapeutic agent. 15 Furthermore, the pharmaceutical composition/formulation can be adapted to weekly, monthly or even more infrequent administration, for example by using an implant, e.g. a subcutaneous or intramuscular implant, by using at least one of the compounds in form of a sparingly soluble salt or by using at least one of the compounds coupled to a polymer. Administration of the pharmaceutical composi 20 tion/formulation in a single dose per day is preferred. Biological investigations The second messenger cyclic AMP (cAMP) is well-known for inhibiting inflammatory and immunocom 25 petent cells. The PDE4 isoenzyme is broadly expressed in cells involved in the initiation and propaga tion of inflammatory diseases (H Tenor and C Schudt, in ,Phosphodiesterase Inhibitors", 21-40, ,The Handbook of Immunopharmacology", Academic Press, 1996), and its inhibition leads to an increase of the intracellular cAMP concentration and thus to the inhibition of cellular activation (JE Souness et al., Immunopharmacology 47: 127-162, 2000). 30 The antiinflammatory potential of PDE4 inhibitors in vivo in various animal models has been described (MM Teixeira, TiPS 18: 164-170, 1997). For the investigation of PDE4 inhibition on the cellular level (in vitro), a large variety of proinflammatory responses can be measured. Examples are the superoxide production of neutrophilic (C Schudt et al., Arch Pharmacol 344: 682-690, 1991) or eosinophilic (A Hat 35 zelmann et al., Brit J Pharmacol 114: 821-831, 1995) granulocytes, which can be measured as luminol enhanced chemiluminescence, or the synthesis of tumor necrosis factor-a in monocytes, macrophages or dendritic cells (Gantner et al., Brit J Pharmacol 121: 221-231, 1997, and Pulmonary Pharmacol Therap 12: 377-386, 1999). In addition, the immunomodulatory potential of PDE4 inhibitors is evident from the inhibition of T-cell responses like cytokine synthesis or proliferation (DM Essayan, Biochem 40 Pharmacol 57: 965-973, 1999). Substances which inhibit the secretion of the afore-mentioned proin- - 52 flammatory mediators are those which inhibit PDE4. PDE4 inhibition by the compounds is thus a central indicator for the suppression of inflammatory processes. Method for measuring inhibition of PDE4 activity 5 The PDE4B1 (GB no. L20966) was a gift of Prof. M. Conti (Stanford University, USA). It was amplified from the original plasmid (pCMV5) via PCR with primers Rbl 8 (5'- CAGACATCCTAAGAGGGGAT -3') and Rbl 0 (5'- AGAGGGGGATTATGTATCCAC -3') and cloned into the pCR-Bac vector (Invitrogen, Groningen, NL). 10 The recombinant baculovirus was prepared by means of homologous recombination in SF9 insect cells. The expression plasmids were cotransfected with Baculo-Gold DNA (Pharmingen, Hamburg) using a standard protocol (Pharmingen, Hamburg). Wt virus-free recombinant virus supernatants were selected using plaque assay methods. After that, high-titre virus supernatants were prepared by amplifying 3 15 times. PDE4B1 was expressed in SF21 cells by infecting 2 x 106 cells/ml with an MOI multiplicityy of infection) between 1 and 10 in the serum-free medium Insect Express Sf9-S2 (PAA, Pasching, Austria). The cells were cultured at 280C for 48 - 72 hours, after which they were pelleted for 5-10 min at 1 000xg and 40C. 20 The SF21 insect cells were resuspended, at a concentration of approx. 107 cells/ml, in ice-cold (40C) homogenization buffer (20 mM Tris, pH 8.2, containing the following additions: 140 mM NaCI, 3.8 mM KCI, 1 mM EGTA, 1 mM MgCl 2 , 10 mM p-mercaptoethanol, 2 mM benzamidine, 0.4 mM Pefablock, 10 iM leupeptin, 10 iM pepstatin A, 5 iM trypsin inhibitor) and disrupted by ultrasonication. The ho mogenate was then centrifuged for 10 min at 1 000xg and the supernatant was stored at -80'C until 25 subsequent use (see below). The protein content was determined by the Bradford method (BioRad, Munich) using BSA as the standard. PDE4B1 activity was inhibited by the compounds in a modified SPA (scintillation proximity assay) test, supplied by Amersham Biosciences (see procedural instructions "phosphodiesterase [3H]cAMP SPA 30 enzyme assay, code TRKQ 7090"), carried out in 96-well microtitre plates (MTP's). The test volume is 100 Il and contains 20 mM Tris buffer (pH 7.4), 0.1 mg /ml of BSA, 5 mM Mg 2 +, 0.5 iM cAMP (includ ing about 50,000 cpm of [3H]cAMP), 1 Il of the respective substance dilution in DMSO and sufficient recombinant PDE (1 000xg supernatant, see above) to ensure that 10-20% of the cAMP is converted under the said experimental conditions. The final concentration of DMSO in the assays (1 % v/v) does 35 not substantially affect the activity of the PDE investigated. After a preincubation of 5 min at 370C, the reaction is started by adding the substrate (cAMP) and the assays are incubated for a further 15 min; after that, they are stopped by adding SPA beads (50 i). In accordance with the manufacturer's in structions, the SPA beads had previously been resuspended in water, but were then diluted 1:3 (v/v) in water; the diluted solution also contains 3 mM IBMX to ensure a complete PDE activity stop. After the - 53 beads have been sedimented (> 30 min), the MTP's are analyzed in commercially available lumines cence detection devices. The corresponding IC50 values of the compounds for the inhibition of PDE4B1 activity are determined from the concentration-effect curves by means of non-linear regression. 5 The inhibitory values determined for the compounds follow from the following Table 1, in which the numbers of the compounds correspond to the numbers of the examples. Table I 10 Inhibition of PDE4 acitivity [measured as -logiC 50 (molI/l)] Compound PDE4 Inhibition 1 8.29 2 8.09 3 7.75 4 7.74 5 7.15 6 6.84 7 7.65 8 8.53 9 8.23 11 8.08 12 7.46 13 7.79 14 9.06 15 7.90 16 7.48 17 8.27 18 8.42 19 7.48 20 8.24 - 54 There is also disclosed various concepts of the invention as follows: 1. A compound of formula 1 0 X- (CH 2 )< R9 N N-N (1) R1 0 R7 R8 5 wherein R1 represents a phenyl derivative of formulae (a) or (b) R2 P R4 R3 (a) 0 (b) R5 R6 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or 10 predominantly substituted by fluorine; R3 is selected from the group consisting of 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmeth oxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; 15 R5 is 1-2C-alkyl and R6 is selected from the group consisting of hydrogen and 1-2C-alkyl; or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and 20 R8 is 1-3C-alkyl or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 3-, 4-, 5- or 6-membered hydrocarbon ring, R9 is -N(R11)R12, wherein - 55 R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3 dione-2-yl-, 2-oxo-2,3-dihydro-1 H-indol-1 -yl-, pyrrolidin-2-one-1 -yl-, piperidin-2,6-dione-1 -yl-, mor pholin-3,5-dione-4-yl-, thiomorpholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and a 5 thiomorpholine-1,1-dioxide-3,5-dione-4-yl-ring; and n is 1 or 2; or a stereoisomer of the compound. 2. A compound of formula 1 according to concept 1, wherein 10 R1 represents a phenyl derivative of formulae (a) or (b) R2 R4 R3 (a) O (b) R5 R6 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; 15 R3 is selected from the group consisting of 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmeth oxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R5 is 1-2C-alkyl and 20 R6 is selected from the group consisting of hydrogen and 1-2C-alkyl; or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and R8 is 1-3C-alkyl 25 or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 3-, 4-, 5- or 6-membered hydrocarbon ring; R9 is -N(R11)R12, wherein R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a 30 heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3 dione-2-yl-, pyrrolidin-2-one-1-yl-, piperidin-2,6-dione-1-yl-, morpholin-3,5-dione-4-yl-, thiomor pholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5 dione-4-yl-ring; and - 56 n is 1 or 2; or a stereoisomer of the compound. 3. A compound of formula 1 according to concept 1, wherein 5 R1 represents a phenyl derivative of formulae (a) or (b) R2 P R4 R3 (a) O (b) R5 R6 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; 10 R3 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R5 is 1-2C-alkyl and 15 R6 is selected from the group consisting of hydrogen and 1-2C-alkyl, or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and R8 is 1-3C-alkyl 20 or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R9 is -N(R11)R12, wherein R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a 25 heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3 dione-2-yl-, 2-oxo-2,3-dihydro-1 H-indol-1 -yl-, pyrrolidin-2-one-1 -yl-, piperidin-2,6-dione-1 -yl-, mor pholin-3,5-dione-4-yl-, thiomorpholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5-dione-4-yl-ring; and n is 1 or 2; 30 or a stereoisomer of the compound. 4. A compound of formula 1 according to concept 1, wherein R1 represents a phenyl derivative of formulae (a) or (b) -57 R2 P R4 R3 (a) O (b) R5 R6 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; 5 R3 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R5 is 1-2C-alkyl and 10 R6 is selected from the group consisting of hydrogen and 1-2C-alkyl, or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and R8 is 1-3C-alkyl 15 or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R9 is -N(R11)R12, wherein R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a 20 heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3 dione-2-yl-, pyrrolidin-2-one-1-yl-, piperidin-2,6-dione-1-yl-, morpholin-3,5-dione-4-yl-, thiomor pholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5 dione-4-yl-ring; and n is 1 or 2; 25 or a stereoisomer of the compound. 5. A compound of formula 1 according to concept 1, wherein R1 represents a phenyl derivative of formulae (a) or (b) 30 -58 R2 P R4 R3 (a) O (b) R5 R6 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; 5 R3 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R5 is methyl and 10 R6 is hydrogen, or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and R8 is 1-3C-alkyl 15 R9 is -N(R11)R12, wherein R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, morpholin-3,5 dione-4-yl-, thiomorpholin-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5-dione-4-yl-ring; and 20 n is 1 or 2; or a stereoisomer of the compound. 6. A compound of formula 1 according to concept 1, wherein R1 represents a phenyl derivative of formulae (a) or (b) 25 R2 : R4 R3 (a) O (b) R5 R6 wherein R2 is methoxy; - 59 R3 is methoxy; R4 is methoxy; R5 is methyl; R6 is hydrogen, 5 or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is methyl; R8 is methyl; R9 is -N(R11)R12, 10 wherein R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, morpholin-3,5 dione-4-yl- and a thiomorpholin-3,5-dione-4-yl-ring, and n is 1. 15 7. Compound according to concept 1 selected from the group consisting of 4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo ethyl)morpholine-3,5-dione; 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo 20 ethyl)pyrrolidine-2,5-dione; 1-(2-{4-[3-(3,4-diethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo ethyl)pyrrolidine-2,5-dione; 1-[2-(4-{3-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyra zol-1 -yl}piperidin-1 -yl)-2-oxoethyl]pyrrolidine-2,5-dione; 25 1 -[2-(4-{3-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl} piperidin-1 -yl)-2-oxoethyl]pyrrolidine-2,5-dione; 1-[2-(4-{3-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl} piperidin-1 -yl)-2-oxoethyl]pyrrolidine-2,5-dione; 1-(2-{4-[3-(3-ethoxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2 30 oxoethyl)pyrrolidine-2,5-dione; 1-(2-{4-[3-(7-methoxy-2,2-dimethyl-2,3-dihydro-1 -benzofuran-4-yl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine-2,5-dione; 1-(2-{4-[3-(7-methoxy-3H-spiro[1 -benzofuran-2, 1'-cyclopentan]-4-yl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine-2,5-dione; 35 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-diethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoeth yl)pyrrolidine-2,5-dione; 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4-methyl-5-oxo-4-propyl-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2 oxoethyl)pyrrolidine-2,5-dione; 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2 40 oxoethyl)pyrrolidine-2,5-dione; - 60 1-(2-{4-[4-(3,4-dimethoxyphenyl)-1 -oxo-2,3-diazaspiro[4.4]non-3-en-2-yl]piperidin-1 -yl}-2-oxoethyl) pyrrolidine-2,5-dione; 2-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo ethyl)-1 H-isoindole-1,3(2H)-dione; 5 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-{1 -[(2-oxopyrrolidin-1 -yl)acetyl]piperidin-4-yl}-2,4-dihydro-3H pyrazol-3-one; 1-(2-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1 -yl]-piperidin-1 -yl}-2-oxo ethyl)-piperidine-2,6-dione; 4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo 10 ethyl)thiomorpholine-3,5-dione; 4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo ethyl)thiomorpholine-3,5-dione 1,1-dioxide; 1-(3-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1 -yl]-piperidin-1 -yl}-3-oxo propyl)-pyrrolidine-2,5-dione; 15 or a stereoisomer of the compound. 8. Compound according to concept 1 selected from the group consisting of 4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo ethyl)morpholine-3,5-dione; 20 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo ethyl)pyrrolidine-2,5-dione; 1-(2-{4-[3-(3,4-diethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo ethyl)pyrrolidine-2,5-dione; 1-[2-(4-{3-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1 H 25 pyrazol-1 -yl}piperidin-1 -yl)-2-oxoethyl]pyrrolidine-2,5-dione; 1 -[2-(4-{3-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl} piperidin-1 -yl)-2-oxoethyl]pyrrolidine-2,5-dione; 1-[2-(4-{3-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl} piperidin-1 -yl)-2-oxoethyl]pyrrolidine-2,5-dione; 30 1-(2-{4-[3-(3-ethoxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2 oxoethyl)pyrrolidine-2,5-dione; 1-(2-{4-[3-(7-methoxy-2,2-dimethyl-2,3-dihydro-1 -benzofuran-4-yl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine-2,5-dione; 1-(2-{4-[3-(7-methoxy-3H-spiro[1 -benzofuran-2, 1'-cyclopentan]-4-yl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H 35 pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine-2,5-dione; 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-diethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoeth yl)pyrrolidine-2,5-dione; 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4-methyl-5-oxo-4-propyl-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2 oxoethyl)pyrrolidine-2,5-dione; - 61 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2 oxoethyl)pyrrolidine-2,5-dione; 1-(2-{4-[4-(3,4-dimethoxyphenyl)-1 -oxo-2,3-diazaspiro[4.4]non-3-en-2-yl]piperidin-1 -yl}-2-oxoethyl) pyrrolidine-2,5-dione; 5 2-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo ethyl)-1 H-isoindole-1,3(2H)-dione; 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-{1 -[(2-oxopyrrolidin-1 -yl)acetyl]piperidin-4-yl}-2,4-dihydro-3H pyrazol-3-one; 1-(2-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1 -yl]-piperidin-1 -yl}-2-oxo 10 ethyl)-piperidine-2,6-dione; 4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo ethyl)thiomorpholine-3,5-dione; 4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxo ethyl)thiomorpholine-3,5-dione 1,1-dioxide; 15 1-(3-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1 -yl]-piperidin-1 -yl}-3-oxo propyl)-pyrrolidine-2,5-dione and 1-(2-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1 -yl]-piperidin-1 -yl}-2-oxo ethyl)-1,3-dihydro-2H-indol-2-one or a stereoisomer thereof. 20 9. Compound or stereoisomer of the compound according to any of concepts 1 to 8 for use in the treatment or prophylaxis of diseases. 10. Pharmaceutical composition comprising at least one of the compounds or stereoisomers of the 25 compounds according to any of concepts 1 to 8 together with at least one pharmaceutically acceptable auxiliary. 11. A compound of formula 4, H N N-N R1 0 (4) 30R7 R8 wherein R1 represents a phenyl derivative of formulae (a) or (b) -62 R2 P R4 R3 (a) O (b) R5 R6 wherein R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; 5 R3 is selected from the group consisting of 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmeth oxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine; R5 is 1-2C-alkyl and 10 R6 is selected from the group consisting of hydrogen and 1-2C-alkyl, or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring; R7 is 1-3C-alkyl and R8 is 1-3C-alkyl 15 or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 3-, 4-, 5- or 6-membered hydrocarbon ring; a salt thereof, a stereoisomer thereof or a salt of the stereoisomer thereof. 12. Fixed combination, non-fixed combination or kit of parts comprising at least one of the com 20 pounds or stereoisomers of the compounds according to any of concepts 1 to 8, at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, P 2 adrenoceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA reductase inhibitors, lung surfactants and antibiotics, and at least one pharmaceutically acceptable auxiliary. 25 13. Fixed combination, non-fixed combination or kit of parts comprising at least one of the com pounds or stereoisomers of the compounds according to any of concepts 1 to 8, at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, P 2 adrenoceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 30 phosphodiesterase inhibitors, HMG-CoA reductase inhibitors, lung surfactants, antibiotics and anti diabetic agents, and at least one pharmaceutically acceptable auxiliary.

- 63 14. Use of a compound or stereoisomer of a compound according to any of concepts 1 to 8 in the manufacture of a pharmaceutical composition inhibiting type 4 phosphodiesterase. 15. Use of a compound or stereoisomer of the compound according to any of concepts 1 to 8 in the 5 manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease. 16. Use according to concept 15, wherein the acute or chronic airway disease is selected from the group consisting of bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD, pulmonary 10 hypertension and lung fibrosis. 17. Use of a compound or stereoisomer of the compound according to any of concepts 1 to 8 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of allergic rhinitis. 15 It is to be understood that, if any prior art publication is referred to herein, such reference does not con stitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country. In the claims which follow and in the preceding description of the invention, except where the context 20 requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

Claims

1. Fixed combination, non-fixed combination or kit of parts comprising 1-(2-{4-[3-(3,4 dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine 5 2,5-dione, at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, p 2 -adrenoceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA reductase inhibitors, lung surfactants, antibiotics and anti-diabetic agents, and at least one pharmaceutically acceptable auxiliary. 10

2. Fixed combination according to claim 1 comprising 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4 dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione, an anti diabetic agent, and at least one pharmaceutically acceptable auxiliary.

3. Non-fixed combination or kit of parts according to claim 1 comprising 1-(2-{4-[3-(3,4 15 dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine 2,5-dione, an anti-diabetic agent, and at least one pharmaceutically acceptable auxiliary.

4. Fixed combination according to claim 1 comprising 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4 dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione, a 20 corticosteroid, and at least one pharmaceutically acceptable auxiliary.

5. Non-fixed combination or kit of parts according to claim 1 comprising 1-(2-{4-[3-(3,4 dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine 2,5-dione, a corticosteroid, and at least one pharmaceutically acceptable auxiliary. 25

6. Fixed combination according to claim 1 comprising 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4 dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione, an anticholinergic, and at least one pharmaceutically acceptable auxiliary. 30

7. Non-fixed combination or kit of parts according to claim 1 comprising 1-(2-{4-[3-(3,4 dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine 2,5-dione, an anticholinergic, and at least one pharmaceutically acceptable auxiliary.

8. Fixed combination according to claim 1 comprising 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4 35 dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione, a P 2 adrenoceptor agonist, and at least one pharmaceutically acceptable auxiliary.

9. Non-fixed combination or kit of parts according to claim 1 comprising 1-(2-{4-[3-(3,4 dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine 40 2,5-dione, a p 2 -adrenoceptor agonist, and at least one pharmaceutically acceptable auxiliary. - 65

10. Fixed combination according to claim 1 comprising 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4 dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione, a H1 recep tor antagonist, and at least one pharmaceutically acceptable auxiliary. 5

11. Non-fixed combination or kit of parts according to claim 1 comprising 1-(2-{4-[3-(3,4 dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine 2,5-dione, a H1 receptor antagonist, and at least one pharmaceutically acceptable auxiliary. 10

12. Fixed combination according to claim 1 comprising 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4 dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione, a leukotriene receptor antagonist, and at least one pharmaceutically acceptable auxiliary.

13. Non-fixed combination or kit of parts according to claim 1 comprising 1-(2-{4-[3-(3,4 15 dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine 2,5-dione, a leukotriene receptor antagonist, and at least one pharmaceutically acceptable auxiliary.

14. Fixed combination according to claim 1 comprising 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4 dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine-2,5-dione, a type 5 20 phosphodiesterase inhibitor, and at least one pharmaceutically acceptable auxiliary.

15. Non-fixed combination or kit of parts according to claim 1 comprising 1-(2-{4-[3-(3,4 dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine 2,5-dione, a type 5 phosphodiesterase inhibitor, and at least one pharmaceutically acceptable auxiliary. 25

16. Fixed combination according to claim 1 comprising 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4 dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione, a HMG-CoA reductase inhibitor, and at least one pharmaceutically acceptable auxiliary. 30

17. Non-fixed combination or kit of parts according to claim 1 comprising 1-(2-{4-[3-(3,4 dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine 2,5-dione, a HMG-CoA reductase inhibitor, and at least one pharmaceutically acceptable auxiliary.

18. Fixed combination according to claim 1 comprising 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4 dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione, a lung sur 35 factant, and at least one pharmaceutically acceptable auxiliary.

19. Non-fixed combination or kit of parts according to claim 1 comprising 1-(2-{4-[3-(3,4 dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine 2,5-dione, a lung surfactant, and at least one pharmaceutically acceptable auxiliary. 40 - 66

20. Fixed combination according to claim 1 comprising 1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4 dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione, an antibiotic, and at least one pharmaceutically acceptable auxiliary. 5

21. Non-fixed combination or kit of parts according to claim 1 comprising 1-(2-{4-[3-(3,4 dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1 H-pyrazol-1 -yl]piperidin-1 -yl}-2-oxoethyl)pyrrolidine 2,5-dione, an antibiotic, and at least one pharmaceutically acceptable auxiliary. 10