Title of Invention

PHTHALAZINONE-PIPERIDINO-DERIVATIVES AS PDE4 INHIBITORS

Abstract

Compounds of formula I, for preparing medicaments for the treatment of airway disorders, Formula I in which Rl and R2 together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) wherein R4 is methoxy or ethoxy, R5 is methoxy or ethoxy, R6 is methoxy or ethoxy, R7 is methyl and R8 is hydrogen, R9 is toluene-4-sulfonyl, methanesulfonyl, acetyl, 5-oxo-pentanoic acid, pyridin-4-yl- carbonyl, tert butylaminocarbonyl, phenylaminocarbonyl, 5-dimethylamino- naphthalene-1-sulfonyl, 4-nitrophenyl, pyridin-4-ylmethyl, morpholine-4-carbonyl, 2- (4-amino-3, 5-dichlorophenyl)-2-oxo- ethyl, 1-methyl-l H-pyrazolo [3,4- d]pyrimidin-4-yl, thieno [2,3-d] pyrimidin-4-yl,pyrimidin-2-yl, 2-oxo-2H-chromen-7-ylmethyl, isopropyl, morpholin-4-yl-2-oxo-ethyl, phenethyl, pyridin-3 ylmethyl, pyridin-2-ylmethyl, pyridin-4-ylmethyl, 2-morpholin-4-ylethanoyl, 2- [4- (2-dimethylamino- ethyl)-piperazin-l-yl]-ethanoyl, isopropylaminocarbonylmethyl, 4-ethyl-piperazine-2, 3-dione-l- carbonyl,4- (1, 2,3-thiadiazol-4-yl-) benzyl, 4-ethoxycarbonylphenylamino-2-oxo-ethyl or amino carbonylmethyl, and the salts, hydrates, solvates of these compounds.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See Section 10) PHTHALAZINONE-PIPERIDINO-DERIVATIVES AS PDE4 INHIBITORS; ALTANA PHARMA AG of BYK-GULDEN-STRASSE 2, D-78467 KONSTANZ, DEUTSCHLAND, GERMANY, GERMAN Company The following specification particularly describes the nature of the invention and the manner in which it is to be performed : - PHTHALAZINONE-PIPERIDIJIO-DERIVATIVES AS PDE4 INHIBlTOkii Field of application of the Invention The invention relates to novel piperidino-derivgtives, which are used in the pharmaceutical industry for the production of medicaments. Known technical background International Patent Applications W098/31674 (= USP 6,103,718), WO99/31071, WO99/31090 and WQQW475(J5 (= USP 6,255,303) effscfose phtriafazinone derivatives having selective POE4 inhibitory properties. In the International Patent Application W094/124S1 and in the European Patent Application EP 0 763 534 3-aryl-pyridazin-6-one and aryialKyl-dlazinono derivatives arc described as selective PDE4 Inhibitors. International Patent Application WO93/07146 (= USP 5,716,954) discloses b^nzo and pyrido pyridazinone and pyridazinthione compounds with PDE1V inhibiting activity. Description of the invention It has now been found that the piperidino-denvatives, which are described in greater details below, have surprising and particularly advantageous properties. The invention thus relates to compounds of formula I R2 R1 in which R1 and R2 are both hydrogen or together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) wherein R4 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine, R5 is 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which is com¬pletely or predominantly substituted by fluorine, R6 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is com¬pletely or predominantly substituted by fluorine, R7 is 1-4C-alkyl and R8 is hydrogen or 1-4C-a!kyl, or wherein R7 and R8 together and with inclusion of the two carbon atoms, to which they are bonded, fotm a spiro-iinked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sul¬phur atom, R9 is 1-4C-alkyl, -S(O)2-R10, -S(0)r(CH2)n-R11, -(CH2)(11-S(0)2-R12, -C(0)R13, -C(O)-(CH2)0-R14, -(CH2)m-C(0)-R15, Hetaryl, Aryll or 1-4C-alkyl-Aryl2, R10 is 1-4C-alkyl, 5-dimetnylaminonaphtbalin-1-yl, -N(R16)R17, phenyl or phenyl substituted by R10 and/or R19, R11 ls-N(R16)R17, R12 is-N(R16)R17, R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazin-2,3-clion-1-yl or -N(R16)R17, R14 is-N(R16)R17, R15 is -N(R16)R17, phenyl, phenyl substituted by R18 and/or R19 and/or R20, R16 and R17 are independent from each other hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, phenyl or phenyl substituted by R18 and/or R19 and/or R20, or R1I3 and R17 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morphollnyl-, 1-pyrrolidinyl-, 1-plperidinyl-, l-hexahydroci.'.epino- or a l-piporfiaiiyl-rinrj of for¬mula (c) wherein R21 is pyrid-4-yl, pyricl-4-ylmelhyl, 1-4C-alkyl-dimolhylamino, dimothyltiniinocarbonylmothyl, N-methyl-piperidin-4-yl, 4-morpholino-ethyl or tetrahydrofuran-2-ylmelhyl, R18 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino, mono-or di-1-4C-alkylamino, aminocarbonyl 1-4C-alkylcarbonylamino or mono-or di- 1 -4C-alkylaminocarbonyl, R19 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy, R20 is halogen, Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl, 1-methyl-1H-pyrazolo-[3,4-dJpyrimidin-4-yl, thl- azolyl, imidazolyl orfuranyl, Aryll is pyridyl, phenyl or phenyl substituted by R18 and/or R19, Aryl2 is pyridyl, phenyl, phenyl substituted by R18 and/or R19, 2~oxo-2H-chromen-7-yl or 4-(1,2,3- thiadiazol-4-yl)phenyl, n is an integer from 1 to 4, m is an integer from 1 to 4, and the salts of these compounds. 1-4C-A)kyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are (lie butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals. 1-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 io 4 carbon atoms. Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, iso-propoxy, ethoxy and methoxy radicals. l-OC-Alkoxy Is a mdlciil which, lit rulillllun to IIio oxyyuii uluin, coiiltilny u ulmlijlil-uhulii oi biuiiuliud alkyl radical having 1 to 8 carbon atoms, Alkoxy radicals having 1 to 8 carbon atoms which may be mentioned in this context are, for example, the octyloxy, heptyloxy, isoheptyloxy (5-methylhexyloxy), hexyloxy, isohexvloxy (4-methylpentyloxy), neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy (3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, pro¬poxy, isopropoxy, ethoxy and methoxy radicals. Halogen within the meaning of the present invention is bromine, chlorine or fluorine. 3-7C-Cycloalkoxy stands for cyclopropyloxy, cyciobutyloxy, cyclopentyloxy, cyclohexyloxy or cyclo-heptyloxy, of which cyclopropyloxy, cyciobutyloxy and cyclopentyloxy are preferred. 3-7C-Cyr;lo.'ill'.ylmolhoxy slnnfls for oycloptopylmolhoxy, cyclobnlylmethoxy, oyclnpoulylmollinxy, r;y-clohexylmethoxy or cycloheptylmethoxy, of which cyclopropylmcthoxy, cyclobutylinolhoxy and cyclo-penlylmethoxy are preferred. 3-5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy. 3-5C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy. 1-4C-Alkoxy which is completely or predominantly substituted by fluorine is, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred. "Predominantly" in this connection moans that more than half of the hydrogen atoms of the 1-4C-alkoxy group are replaced by fluorine atoms, As spiro-linked 5-, 6- or 7-membered hydrocarbon rings, optionally interrupted by an oxygon or sulphur atom, may be mentioned the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydropy-ran and the tetrahydrothiophen ring. 1-4C-Alkylcarbonyl is a carbonyl group to which one of the abovementioned 1-4C~alkyl radicals is bon¬ded. An example Is the acetyl radical (CH3C(0)-], An 1-4C-Alkylcarbonylamino radical is, for example, the propionylamino [C3H7C(0)NH-] and the acety-lamino radical [CH3C(0)NH-]. Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogen atom, one or two of the abo¬vementioned 1-4C-alkyl radicals. Preferred are the di-1-4C-alkylamino radicals, especially the dimeth-ylamino, the diethylamino and the diisopropylamino radical. Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to the carbonyl group one of the abo¬vementioned mono- or di-1-4C-alkylarnino radicals. Examples which may be mentioned are the N-methyl- the N.N-dimethyl-, the N-othyl-, the N-propyl-, the N.N-dicthyl- and the N-isopropylaminocarbonyl radical. Suitable salts for compounds of the formula I are all acid addition salts. Particular mention may be made of the pharmacologically tolerable inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for exam¬ple, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric-acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosaiicylic acid, maloic acid, lauric acid, malic acid, fumaric acid, succinic ncid, oxalic acid, tartaric acid, cmbonic acid, stearic ac'ici, toluenesulphonic acid, mothnnesiilphonic ncid tir 3-hy Pharmacologically intolerable salts, which can be obtained, for example, as process products during the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art. According to expert's knowledge the compounds of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the inven¬tion are therefore all solvates and in particular all hydrates of the compounds of formula I as well as till solvates and in particular all hydrates of the salts of the compounds of formula I. Compound of formula I to be emphasized are those in which R1 and R2 are both hydrogen or together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) ' wherein R4 is 1-4C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine, R5 is 1.-4C-alkoxy, R6 is 1-2C-alkoxy or 1-2C-alk.oxy which is comptetety or predominantly substituted by fluorine, R7 is methyl and R8 is hydrogen, or wherein R7 and R8 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofurane or tetrahydropyran ring, R9 is 1-4C-alkyl, -S(O)2-R10, -S(0)2-(CH2)n-R11, -C(0)R13, -C(0)-(CH2)n-R14, -(CHa)n,-C(0)-R15, Hetaryl, Aryll or 1-2C-alkyl-Aryl2, R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, -N(R16)R17, phenyl or phenyl substituted by RI8, R11 is-N(R16)R17, R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyriclyl, 4-ethyl-pipera/in-2,3-dion-1-yl or -N(R16)R17, R14 is-N(R16)R17, R15 is -N(R16)R17( phenyl, phenyl substituted by R18 and/or R19 and/or R20, R16 and R17 are independent from each other hydrogen, 1-4C-alkyl, phenyl or phenyl substituted by R18 and/or R19 and/or R20, or R16 and R17 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl ring, a 1-piperidinyl ring or a 1-piperazinyl ring of formula (c) (c) wherein R21 is pyrid-4-yl, pyrid-4-yimethyl, dimethylamino-1-4C-alkyl, dimethylaminocarbonylmethyl, N-methyl-piperidin-4-yl, 4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl, R18 is halogen, nitro, 1-40alkyl, trifluoromethyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl, R19 is halogen, amino, nitro, 1-4C-atkyl or 1-4C-alkoxy, R20 is halogen, Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimldin-4-yl or 1-methyl-1H-pyraz;olo-[3,4-djpyiiniidin-4-y(, AryM is pyriclyl, phenyl or phenyl substituted by R18, Aryl2 is pyridyl, phenyl, phenyl substituted by R18, 2-oxo-2H-chromen-7-yl or 4-(1,2,3-thiadiazol-4- yl)phenyl, n is 1 or 2, m is 1 or 2, and the salts of these compounds. Preferred compounds of formula I are those, in which R1 and R2 together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) wherein R4 is 1-4C-alkoxy, R5is 1-4C-alkoxy, R6is 1-2C-alkoxy, R7 is methyl and R8 is hydrogen, R9 is 1-4C-alkyl, -S(O)z-R10, -C(0)R13, -C(0)-(CH2)n-R14, -(CH2)m-C(0)-R15, Hetaryl, Aryil or 1-2C-alkyl-Aryl2, R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, phenyl or phenyl substituted by R18, R13 Is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl or -N(R16)R17, R14 is-N(R16)R17, R15 is -N(R16)R17, phenyl or phenyl substituted by R18 and/or R19 and/or R20, R16 and R17 are independent from each other hydrogen, 1-4C-alkyl, phenyl or phenyl substituted by R18 and/or R19 and/or R20, or RIG and R17 together and with inclusion of the nitiuyen atom to which they are bonded, form a 4-morpholinyl ring or a 1-piperazinyl ring of formula (c) wherein R21 is dimethylamino-1-4C-alkyl, R18 is halogen, nitro, 1-4C-alkyl or 1-4C-alkoxycarbonyl, R19 is amino, R20 is halogen, Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl or 1-methyl-1H-pyrazolo-[3,4-d]pyrimidln-4-yl, Aryll is phenyl or phenyl substituted by R18, Aryl2 is pyridyl, phenyl, 2-oxo-2H-chromen-7-yl or 4-(1,2,3-thiadiazol-4-yl)phenyl, n is 1 or 2, m is 1 or 2, and the salts of these compounds. Particularly preferred compounds of formula I are those in which R1 and R2 together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) wherein R4 is methoxy or ethoxy, R5 is methoxy or ethoxy, R6 is methoxy or ethoxy, R7 is methyl and R8 is hydrogen, R9 is toluene-4-sulfonyl, melhanesulfonyl, acetyl, 5-oxo-pentanoic acid, pytidin-4-yl curbunyl, tort butylaminocarbonyl, phenyiaminocarbonyl, 5-dimethylamino-naphthalene-1-sulfonyl, 4-nitrophenyl, pyridin-4-ylmethyl, morpholine-4-carbonyl, 2-(4-amino-3,5-dichlorophenyl)-2-oxo-ethyl, 1-methyl-1H-pyrazo!o[3,4-d]pyrirnidin-4-yl, thieno[2,3-d]pyrimidin-4-yl, pyrimidin-2-yl, 2-oxo-2H-chromen-7-ylrnetbyl, isopropyl, morpholin-4-yl-2-oxo-ethyl, phenethyl, pyridin-3 ylmethyl, pyridin-2-ylmethyl, pyridin-4-ylmethyl, 2-morpholin-4-ylethanoyl, 2-[4-(2-diiTiethylamino-ethyl)-piperazin-1-yfj-ethanoyl, isopropylaminocarbonylmethyl, 4-ethyl-piperazine-2,3-dione-1-carbonyl, 4-(1,2,3-thiadiazol-4-yl-)benzyl, 4-ethoxycarbonylphenylamino-2-oxo-ethyl or amino-carbonylmethyl, and the salts of these compounds. The compounds of formula I are chiral compounds. Chiral centers exist in the compounds of formula I n the positions 4a and 8a. In case R3 represents a benzene derivative of formula (b) there is one fur¬ther chiral center in the dihydrofuran-ring, if the substituents -R7 and -CH2R8 are not identical. How¬ever, preferred are in this connection those compounds, in which the substituents -R7 and -CH2R8 are identical or together and with inclusion of the two carbon atoms to which they are bonded form a spiro-connected 5-, 6- or 7-membered hydrocarbon ring. Numbering: R2 R1 Therefore the invention includes all conceivable pure diastereomers and pure enantiomers of the com¬pounds of formula I, as well as all mixtures thereof independent from the ratio, including the racemates. Preferred are those compounds of formula I, in which the hydrogen atoms in the positions 4a and 8a are cis-configuralod. Especially preferred in this connection are those compounds, in which Iho .'jbt;o-lute configuration (according to the rules of Cahn, Ingold and Prelog) is S in the position 4a and R in the position 8a. Racemates can be split up into the corresponding enantiomers by methods known by a person skilled in the art. Preferably the racemic mixtures are separated into two diastereomers during the preparation with the help of an optical active separation agent on the stage of the cyclohexane-carboxylic acids or the 1,2,3,6-tetrahydrobenzoic acids (for example, starting compounds A1, A2 and A3). As separation agents may be mentioned, for example, optical active amines such as the (+)- and (-)-forms of 1-phenylethylamine [(R)-(+)-1-phenylethylamine = (R)-(+)-a-methylben2ylamine or (S)-(-)-1-phenylethylamine = (S)-(-)-a-methylbenzylamine) and ephedrine, the optical active alkaloids quinine, cinchonine, cinchonidine and brucine. The compounds according to the invention can be prepared, for example, as described in Reaction scheme 1. Reaction scheme 1 shows that the compounds of formula I can be, for example, prepared starting from 4-oxo-piperidine-1-carboxylic acid tert-buty! ester which is reacted in a first reaction step with tert- |ju(ylci.u.l)ii/;.i(u lo uiv<. iciiihuxyln: mi lull butyl nf.ltsi compound a7 is reduced with for example the boran tetrahydrofurane complex u> ■fjivo 4-(N'-tort-Bnloxycarbony1-liyrlrazino)-piporklino-1 -ctiiboxylic acid lerl-biityl fjstor (stin¬ting compound A6). Treatment of compound A6 with concentrated hydrochloric acid results in the for¬mation of piperidin-4-yl-hydrazine dihydrochloride (starting compound A5). The reaction of piperidin-4-yl-hydrazine dihydrochloride with cyclohexanecarboxylic acids or 1,2,3,6-tetrahydrobenzoic acids of formulae ilia or lllb leads to the piperidino derivatives of formula II. These are reacted in the final reaction step with compounds of formula R9-X, wherein X represents a suitable leaving group, preferably a chlorine atom, to give the compounds of formula I, For some compounds of formula I, it can be advantageous, to introduce the substituent R9 in two reac¬tion steps. As example may be mentioned those compounds of formula I, wherein R9 represents mor-pholin-4~ylethanoyl. Here, the corresponding compounds of formula II are reacted in a lirst step with chloroacetylchloride and then in a second step with morpholine. Suitably, the conversions are carried out analogous to methods which are familiar per so to the person skilled in the art, for example, in the manner which is described in the following examples. The preparation of the cyclohexanecarboxylic acids and 1,3,5,6-tetrahydrobenzoic acids of the formu¬lae Ilia or lllb is described, for example, in W098/31674, WO99/31090 and WO99/47505. The substances according to the invention are isolated and purified in a manner known per so, e.g. by distilling off the solvent in vacuo and recrystallislng the residue obtained from a suitable solvent or subjecting it (o one of the customary purification methods, such as column chromatorimphy on a suit¬able support material. Salts are obtained by dissolving the free compound in a suitable solvent (for example a ketone like acetone, methylethylketone, or methylisobutylketone, an ether, like diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol, such as ethanol, isopropanol) which contains the desired acid, or to which the desired acid is then added. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basifica-tion into the free compounds which, in turn, can be converted into salts. In this manner, pharmacologi¬cally non-tolerable salts can be converted into pharmacologically tolerable salts. The following examples illustrate the invention in greater detail, without restricting it. As well, further compounds of formula I, of which the preparation is explicitly not described, can be prepared in an Exampjes Final products 1. (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1 -(toluene-4-sulfonyl)-pipcridin-4-yl]-4a, 5,8,8a- tctrahydro-2H-phthalazin-1-one A solution of 1.0 g of starting compound A2 and 1.0 g of p-toluenesulfonyi chloride in 50 ml of pyridine is stirred at RT for 18 h after which the mixture is evaporated. The residue is partitioned between aqueous sodium carbonate and dichloromethane. The dichloromethane layer is dried over magnesium sulfate and evaporated. The compound is crystallised from methanol. M. p. 99-101 °C 2. (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,3a- tetrahydro-2H-phthalazin-1-one Prepared from methanesulfonylchloride and starting compound A2 as described for compound 1. Crystallisation from methanol /water. M. p. 99-102°C 3. (4aS,8aR)-2-(1-Acetyl-pi>eridin-4-yl)-4-(3,4-diejhoxyph3nyl)-4a,5,8)8a4otrahydro-2H- phthalazin-1-one Prepared from acetic anhydride and starting compound A2 as described for compound 1. Crystallised from diethyl ether. M, p. 148-150°C 4. 5-{4-[(4aS,8aR)-4-(3,4-Pi6thoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]- piperidin-1 -yl}-5-oxo-pentanoic acid Prepared from glutaric anhydride and starting compound A2 as described for compound 1. After evaporating the pyridine, the residue is partitioned between ethyl acetate and 1N hydrochloric acid. The ethyl acetate solution is dried over magnesium sulfate and evaporated. Crystallisation from diethyl ether. M. p. 133-135°C 5. (4aS,8aR)-4-(3,4-Diothoxyplicnyl)-2:[1-[1-pyrklin-4-yl-mothanoyl)-piporidln-4-yl]-4a,5,8,8n- tetrahydro-2H-phthalazin-1-one hydrochloride- Prepared from isonicofinoyl chloride hydrochloride and starling compound A2 as described for compound 1. After evaporating the dichloromethane solution, the residue is dissolved in diethyl ether, After addition of a saturated solution of hydrochloric acid in ether, the titel compound precipitates. M. p. 66-68°C 6. 4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]- piperidine-1-carboxyllc acid tert-butylamide A mixture of 1.0 g of starting compound A2, 0.5 g of t-butylisocyanate and 2 ml of trielhylamine in 50 ml of tetrahydrofurane is stirred for 18 h at RT. After evaporating the solution, the residue is partitioned IPUIWHIIII Wil1'>! g II i ether (60-80"C). M. p. 145-148°C 7. 4-[(4aS,8aR)-4-(3,4-Diothoxyphonyl)-1-oxo'4a,5,8,8a-totrahydro-1H-phthalazin-2-yl]- piperidine-1-carboxylic acid phenylamide Prepared from starting compound A2 and phenylisocyanate as described for compound 6. Crystallisation from ether. M. p. 109-112°C 8. 4-t(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]- piperidine-1-carboxylic acid tert-butylamide Prepared from starting compound A1 and t-butylisocyanate as described for compound 6. Crystallisation from ether. M. p. 164-166°C 9- (cis)-4-[4-(7>IVlethoxy-2,2-dimethyl-2,3-dihydro-j?enzofuran-4-yj)r1-oxo-4a,5,8,8n- totrahydro-1 ll-phthal azln-2-yl]-piporldin o^bcajlj ojty M^acltj Joi-N) 11 ty I ;> m i d o Prepared from starting compound A3 and t-butylisocyanate as described for compound 6. Crystallisation from ether. M. p. 145-147°C 10. r (4aS,8aR)-4-(3,4-Dimetfioxyphenyl)-2-f1-(5-dimethylamino-naphthalene-1-sulfonyl)- piperidin-4-ylHa,5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from dansylchloride and starting compound A1 as described for compound 1. Crystallisation ■from methanol. M. p. 198-200°C 11. (4aS,8aR)-4-(3,4>Dimetrioxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a: tetrahydro-2H-phthalazin-1 -one A mixture of 1.0 g of compound A1,1.0 g of 1 -iodo-4-nitrobenzene and 1.0 g of potassium carbonate in 20 ml of dimethyiformamide is stirred for 18 h at RT after which 100 ml of water is added to the reaction mixture. The precipitate is filtered off and crystallised from methanol. M. p. 196-197°C 12. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)- 4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from starting compound A1 and 4-picolylchloride hydrochloride as described for compound 11. After the addition of 100 ml of water, 20 ml of diethyl ether is added and the resulting mixture stirred for 30 min. The precipitate is filtered off and dried. M. p. 196-197"C. 13. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morphollne-4-carbonyl)-piperidiiv 4-yl]-4a,5,8,8a-tetrahydrojj!H-phthalazin-1-one Prepared from 4-morpholinocarbor\yl chloride and compound A1 as described for compound I. Crystallisation from diethyl ether. M. p. 184-185°C 14. (4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-pheiiyl)-2-oxo-ethyl]:pjjjgricjiiv4-yl)-4-(3,4- dimethoxy-phonyl)-4a,5,8,8a-totrahydro-2H-phthalazin-1-ono hydrochlorido Prepared from (4-Amino-3,5-dichloro-phenyl)-2-bromo-ethanone and starting compound A1 as described for compound 11. After the addition of water, the mixture is extracted with diethyl ether. The ether solution is dried over magnesium sulfate. After the addition of a saturated solution of hydrochloric acid in ether, the compound precipitates. Crystallisation from tetrahydrofurane. M. p. 206°C (decomposition). 15. 4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)- piperidm-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one Prepared from 4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine and starting compound A1 as described for compound 11. Crystallisation from methanol. M. p. 193-194°C 1p- (4aS,8aR)-4-(3,4-Dimethoxyphonyl)-2-(1-thleno[2,3-d]pyrimidin-4-yl-pipcriclin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from 4-Chloro-lhieno[2,3-d]pyrimidine and starting compound A1 as described for compound 11. After the addition of water, the mixture is extracted with diethyl ether. The ether solution is dried over mnfinor.ilim sulfate. After the addition of a r.ntiimtocl solution of hydrochloric ficid In ollioi, HIM compound precipitates. M. p. 219-220°C . 17. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Prepared from 2-Chloro-pyrimidine and starting compound A1 as described for compound 11. Crystallisation from methanol. M. p. 163-166°C 18. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1'(2-oxo-2H-chromen-7-ylmethyl)-pipeiidin-4-yl]- 4a,5,8,8a-tetrahydro-2H-phthalazin-1»ono hydrochloride Prepared from 7-Chloromethyl-chromen-2-one and starting compound A1 as described for compound 11. After the addition of water, the mixture is extracted with diethyl ether. The elhor solution is dried over magnesium sulfate. After the addition of a saturated solution of hydrochloric acid in ether, the compound precipitates. M. p. 264-267°C 19. 4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H- phthalazin-1-ono hydrochlorido Prepared from 2-iodopropane and starting compound A1 as described for compound 18. M. p. 158-159°C 20- (4aS,8aR)-4-(3,4-Dimethoxyphcnyl)-2-[1-(2-morpholin-4-yl-2-oxo-othyl)-|)iporiciin-4-yl]- 4a,5,8,8a-tctrahydro-2H-phthalazin-1 -one hydrochloride Prepared from 4-(2-chloroacetyl)rnorpholine and starting compound A1 as described for compound 10. M. p. 159-162°C 3849113 21 • (^;iS,0aR)-4-(3,4;Dliiiotli(jxyplluiiyl)-2-(l-[.)lioiiotl)yl-pipo[ldiii-4-yl)-4a,^,«,8a -tetrahydro-2H-phthalazin-1 -one hydrochloride Prepared from 2-bromoethylbenzene and starting compound A1 as described for compound 18. M. p.216-217°C 22. (4aS,8aR)-4-(3,4-Dietrioxyphenyl)-2-[1-(morpholine-4-carbony))-piperidin-4-y)l-4a,5,8,8a- tetrahydro-2H-phthalazin-l-one Prepared from 4-morpholinocarbonyl chloride and starting compound A2 as described for compound 1. Crystallisation from diethyl ether. M. p. 139-14TC 23. (4aS,8aR)-4-(3,4-Dimethoxyphcnyl)-2-(1-pyridin-3-ylmethyl-piporidin-4-yl)-4a,5,8,8a- tetrahydro-2H-phthalazin-1-onedihydrochloride Prepared from starting compound A1 and 3-picolylchloride hydrochloride, as described for compound 18. M. p. 252-25d°C 24. (4aS,8aR)-4-(3,4-Pimethoxy-phenyl)-2-(1-pyndin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a- tetrahydro-2H-phthalazin-1-one dihydrochloride Prepared from compound A1 and 2-picolylchloride hydrochloride as described for compound 18. M. p. 214-21G°C 25. (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2"[1-(2-morpho)in-4-yl-ethanoyl)-piperidin-4-yl]- 4a,5,8,8a-tetrahydro-2H-phthalazin-1 -one hydrochloride Prepared from starting compound A5 and morpholine as described for compound 18. M. p. 219"C (decomposition). 26. (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-pipcrazin-1~yl]- ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahyclro-2H-phthalazin-1-one trihydrochloricle Prepared from starting compound A4 and dimethyl-(2-piperazin-1-yl-ethyl)-amine as described for compound 18. M. p. 195-197°C 27. 2-{4-[(4a5,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]- piperidin-1-yl}-2H-isopropyl-acetamide Prepared from starting compound A1 and N-(chloroacetyl)isopropylamine as described for compound 11. Crystallisation from ether. M. p. 172-173°C 28. (4aS,BaR)-4-(3,4-Dimctlioxyphoi)yl)-2-[1-(4-1,2,3-thiadiazol-4-yUbonzyl)-piporidiii-4-yl]- 4a,5,8,fla»tetrahydro-2H-pl)thalozln-1-ono dlhydrochlorido Prepared from starling compound A1 and 4-(4-Bromomelhyl-phenyl)-[1,2,3jthiadiazole as described for compound 18. M. p. 243-245°C 29. 1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthala2in-2- yl]-piperidin-1"yl}-methanoyl)-4-ethyl-piperazine-2,3-dione Prepared from 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride and starting compound A1 us described for compound 1. Crystallisation from ethyl acetate / diethyl ether. M. p. 226-228°C 30. 4-(2:{4-[(4a5,8aR)-4-(3,4-Dimethoxy-phonyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2- yl]-piperidin-1-yl}-ethanoylamino)-benzoic acid ethyl ester hydrochloride Prepared from ethyl 4-(2-chloroacetamido)benzoate and starting compound A1 as described in ex¬ample 18. M. p. 153-156gC 31. 2-{4-j(4aS, 8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8.Sa-tetrahydro-1 H-phthalazin-2-yl]- piperidin-1 -yl}-2H-acetamide hydrochloride Prepared from 2-chloroacetamide and starting compound A1 as described for compound 16. M. p. 241-243°C Starting Compounds A1. {4aS,8aR)-4-(314-Dimethoxy-phenyl)-2-pipGridin-4-yl-4a,5,8,8a-tetrahyclro-2H-ptUhalnzin-1-one hydrochloride A solution of 50 mmol of the salt of (S)-(-)-a-methylbenzylamine and (cis)-2-(3,4-dimethoxybenzoyl)-1,2,3,G-tetr3hydrobonzolc acid (starting compound A8), 55 mmol of piporidin-4-yl-hydm7.inn dlhydrochloride and 100 mmol of triothylarnine in 150 ml of 1-propanol is retluxed for 18 h. After cooling to RT, the precipitate is filtered off and dried. M. p. 285-288°C A2. (4aS,8aR)-4-(3,4-Diethoxy-phonyi)-2-piporidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one hydrochloride Prepared from the salt of (S)-(-)-a-methylbenzylamine and (cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid (starting compound A9) in 2-propanol as described for compound A1. M. p. 248-250°C A3. (cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one hydrochloride Prepared from (cis)-2-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4 carbonyl)~1,2,3,6-tetrahydro-benzoic acid (starting compound A10) in 1-propanol as described for compound A1. After evaporating the solvent, the residue is partitioned between dichloromethane and aqueous sodium carbonate. The dichlormethane layer is dried over magnesium sulfate and evaporated. The residue is dissolved in di¬chloromethane and after the addition of a solution of hydrochloric acid in ether, the compound precipi¬tates. M. p. 288-290°C A4. (4aS,8aR)-2-[1-(2-Chloro-acetyl)-pi peridin-4-yl]-4-(3,4-diothoxy-phonyl)-4a,5,8,8a-totrahydro-2H-phthalazin-1-one A solution of 15 mmol of chloroacetylchloride in 10 ml of dichloromethane is added to a solution of 15 mmol of starting compound A2 and 8 ml of trietylamine in 50 ml of dichloromethane at 0°C. After complete addiotion, the mixture is stirred for another 45 min after which 50 ml of water is added. The dichlormethane solution is dried over magnesium sulfate and evaporated. The residue is purified by chromatography. Elution with a 2/1 mixture of ethyl acetate and petroleum ether (60-80°C). Crystcillisntion from hoxono. M. p. 135-130"C A5. Piperidin-4-yl-hydrazine dihydrochloride A mixture of 0.1 mole of 4-(N'-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxy!ic acid terl-buty! ester (starting compound A6) and 150 ml of concentrated hydrochloric acid is heated at 90°C for 60 min after which the clear solution is evaporated. The residue is washed with tetrahydrofurane, filtered off and dried under vacuum. M. p. 256-259°C A6. 4-(N'-tert-Butoxycarbonyl-hyclrazino)-piperidine-1-;carboxylic acid tort-butyl ester 150 ml of n solution of boioliyrtrkln In loilnhydiuliiiiinu (1.0 inol/l) in slowly nddod to n MIIUIIUII ol 0.1 ;■' mole of 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid tert-butyl ester (storting compound A7) in 100 ml of dry tetrahydrofurane. After complete addition, the mixture is stirred for another 30 min aftor which a 100 ml of water is added to destroy the excess of borohydride. Subsequently the tetrahydrofurane is evaporated and the resulting aqeous solution extracted with diethyl ether. After drying the solvent over magnesium sulfate, the ether is evaporated. M. p.112-115°C A7, 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid tert-butyl ester A mixture of 0.15 mole of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (commercially available) and 0.15 mole of tert-butylcarbazate in 250 ml of hexane is stirred for 18 h at RT. The precipitate is filtered off and dried under vacuum. M. p. 172-174°C A8. (cis)-2-(3,4-DiinoUioxybci)Zoyl)-1,2,3,G-totriil)ydiolJon7:olc nclcl Prepared as described in W098/31674. A9. (cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid Prepared as described in WO99/47505. A10. (cis)-2-(2,3-Dihydro-2,2-dimcthyl-7-methoxybenzofumn-4-carbonyl)-1,2,3,6-tetrahydro¬benzoic acid Prepared as described in WO99/31090. Commercial utMity The compounds according to the invention have useful pharmacological properties which make them industrially utilizable. As selective cyclic nucleotide phosphodiesterase (PDE) inhibitors (specifically of type 4), they are suitable on the one hand as bronchial therapeutics (for the treatment of airway ob¬structions 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 treatment of disorders, in particular of an inflammatory nature, e.g. of the airways (asthma prophylaxis), of the skin, of the intestine, 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, cytokines, interleukins, ohemoki-nes, alpha-, beta- and gamma-interferon, tumor necrosis factor (TNF) or oxygen free radicals and pro¬teases. In this context, the compounds according to the invention are distinguished by a low toxicity, a good enteral absorption (high bioavailability), a large therapeutic breadth and the absence of significant side effects. J n account of their PDE-inhibiting properties, the compounds according to the invention can be em¬ployed in human and veterinary medicine as therapeutics, where they can be used, for example, for (he treatment and prophylaxis of the following illnesses: acute and chronic (in particular inflammatory and allergen-induced) airway disorders of varying origin (bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD); dermatoses (especially of proliferative, inflammatory and allergic type) such as psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrhoolc eczema, Lichen simplex, sunburn,'pruritus in the anogenilal area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and widespread pyodermias, endogenous and exogenous acne, acne rosacea and other proliferative, inflammatory and allergic skin disorders; disorders which are based on an ex¬cessive release of TNF and leukotrienes, for example disorders of the arthritis type (rheumatoid arthri¬tis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions), disorders of the immune system (AIDS, multiple sclerosis), graft versus host reaction, allograft rejections, types of shock (septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome and ARDS (adult respiratory distress syndrome)) and also generalized inflammations in the gastrointestinal region (Crohn's disease and ulcerative colitis); disorders which are based on allergic and/or chronic, immunological false reaction;', In the region ol tho upper airways (phaiynx, nose) and the adjacent regions (paranasal sinuses, eyes), such as allergic rhinitis/sinusitis, chronic rhinitis/sinusitis, allergic conjunctivitis and also nasal polyps; but also disorders of the heart which can be treated by PDE inhibitors, such as cardiac insufficiency, or disorders which can be treated on account of tho tissue-relaxant action of the PDE Inhibitors, such as, for example, erectile dysfunction or colics of the kidneys and of the ureters in connection with kidney stones. In addition, the compounds of the invention are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alz- heimor's disease), memory Impairment associated will) Pi-iikinsnn's disease or mnlliinlnrcl rlnmonlln; and also illnesses of the central nervous system, such ns depressions or fitletiosclorotic doiiiontui. The invention further relates to a method for the treatment of mammals, including humans, which are suffering from one of the above mentioned illnesses. The method is characterized in that a therapeuti¬cally active and pharmacologically effective and tolerable amount of one or more of the compounds according to the invention is administered to the ill mammal. The invention further relates to the compounds according to the invention for use in the treatment and/or prophylaxis of illnesses, especially the illnesses mentioned. The invention also relates to the use of the compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the illnesses mentioned. The invention furthermore relates to medicaments for the treatment and/or prophylaxis of the lllnesso:; mentioned, which contain one or more of the compounds according to the invention. Additionally, the invention relates to an article of manufacture, which comprises packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective for antagonizing the effects of the cyclic nucleotide phosphodiesterase of type 4 (PDE4), ameliorating the symptoms of an PDE4-mediated disorder, and wherein the packaging mate¬rial comprises a label or package insert which indicates that the pharmaceutical agent is useful for pre¬venting or treating PDE4-mediated disorders, and wherein said pharmaceutical agent comprises one or more compounds of formula I according to the invention. The packaging material, label and package insert otherwise parallel or resemble what is generally regarded as standard packaging material, labels and package inserts for pharmaceuticals having related utilities. The medicaments are prepared by processes which are known per se and familiar to the person skilled in the art. As medicaments, the compounds according to the invention (= active compounds) are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries, e.g. in the form of tablets, coated tablets, capsules, suppositories, patches, emulsions, suspensions, gels or solutions, the active compound content advantageously being between 0.1 and 95%. The person skilled in the art is familiar with auxiliaries which are suitable for the desired pharmaceutical formulations on account of his export knowledge. In addition to solvents, gel lormers, ointment bases and other active compound excipients, for example antioxidants, dispersants, emuls.fiers, preservati¬ves, solubilizers or permeation promoters, can be used. For tlio treatment of disorders of lite inr.plrnlory tincl, 11ns compounds oeeoidiiui In IIw invention oi.' preferably also administered by Initiation In the form of nn aerosol; the aerosol particles ul solid, liquid or mixed composition preferably having a diameter of 0f> lo 1fl pin, ndvnnl.'iooour.ly of:- lo li pm, Aerosol generation can be carried oui, for example, by pressure-driven jet atomizers or ultrasonic at¬omizers, but advantageously by propellant-driven metered aerosols or propellant-free administration of micronized active compounds from inhalation capsules. Depending on the inhaler system used, in addition to the active compounds the administration forms additionally contain the required excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds, For the purposes of inhalation, a large number of apparatuses are available with which aerosols of optimum particle size can be generated and administered, using nn inhalation technique which hi ON right mi possible lor the patient. In addlllon lo II10 use ol adaptors (spnceis, expander:/.) mid poai shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler© or the inhaler described in European Patent Application EP 0 505 321), using which an optimal administration of active compound can be achieved. For the treatment of dermatoses, the compounds according to the invention are in particular administe¬red in the form of those medicaments which are suitable for topical application. For the production of the medicaments, the compounds according to the invention (= active compounds) are preferably mixed with suitable pharmaceutical auxiliaries and further processed to give suitable pharmaceutical formulations. Suitable pharmaceutical formulations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions. The medicaments according to the invention are prepared by processes known per se. The dosage of the active compounds is carried out in the order of magnitude customary for PDE inhibitors. Topical a ^plication forms (such as ointments) for the treatment of dermatoses thus contain the active com¬pounds in a concentration of, for example, 0.1-99%. The dose for administration by inhalation is cuslo-marly between 0.1 and 3 mg per day. The customary dose in the case of systemic therapy (p.o. or i.v.) is between 0.03 and 3 mg/kg per day. Biological investigations The second messenger cyclic AMP (cAMP) is well-known for inhibiting inflammatory and immunocom¬petent cells. The PDE4 isoenzyme is broadly expressed in cells involved in the initiation and propaga¬tion of inflammatory diseases (H Terior and C Schudt, in ..Phosphodiesterase Inhibitors", 21-40, „The Handbook of Immunopharmacology", Academic Press, 1996), and its inhibition leads !o an increase of the intracellular cAMP concentration and thus to the inhibition of cellular activation (Jl£ Soilness el al., Immunopharmacology 47: 127-162, 2000). The antiinflammatory potential of PDEE4 inhibitors in vivo in various animal models has been described \WIWI Teixe'wa, YiPS *i"b\ "ioVi"70, "iSS^V 'rvn Vrns VrwBB'iitraYiori ol "PVEU inWtoWion on Yne cardial 'levtii 'iVn 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 Hatzelmann et al., Brit J Pharmacol 114: 821-831, 1995) granulocytes, which can be measured as lu-minol-enhanced chemiluminescence, or the synthesis of tumor necrosis factor-a in monocytes, macro¬phages or dendritic cells (Gantner et alv Brit J Pharmacol 121: 221-231, 1997, and Pulmonary Phar¬macol Therap 12: 377-386, 1999). ||1 addition, the immunomodulatory potential of PDE4 inhibitors is evident from the inhibition of T-cell responses like cytokine synthesis or proliferation (DM Essayan, Biochem Pharmacol 57: 965-973, 1900). Substances which inhibit the secretion of the afore-mentioned proinflammatory mediators are those which inhibit PDE4. PDE4 inhibition by the compounds according to the invention is thus a central indicator for the suppression of inflammatory processes. Method for measuring inhibition of PDE4 activity PDE4 tiolivity was dolurmlned as described by Thompson ct nl. (Adv Cycl NucI Reis 10: 69-92, 197!)) with some modifications (Bauer and schwabe, Naunyn-Schmiedeberg's Arch Pharmacol 311: 193-198, 1980). At a final assay volume of 200 Ml (96well microtiter plates) the assay mixture contained 20 mM Tris (pH 7.4), 5 mM MgCI2, 0.5 uM cAMP, [3H]cAMP (about 30,000 cpm/assay), the test compound and an aliquot of cytosol from human neutrophils which mainly contains PDE4 activity as described by Schudt et al. (Naunyn-Schmiedeberg's Arch Pharmacol 344: 682-690, 1991); the PDE3-specific inhibi¬tor Motapizone (1 pM) was included to suppress PDE3 activity originating from contaminating platelets. Serial dilutions of the compounds were prepared in DMSO and further diluted 1:100 (v/v) In (ho jisstiys lo obtain the desired final concentrations of the Inhibitors at a DMSO concentration of 1 % (v/v) which by itself only slightly affected PDE4 activity-After preincubation for 5 min at 37°C, the reaction was started by the addition of substrate (cAMP) and the assays were incubated for further 15 min at 37°C. 50 ul of 0.2 N HCI was added to stop the reaction and the assays were left on ice for about 10 min. Following incubation with 25 pg 5'-nucleotidase (Cro-talus atrox snake venom) for 10 min at 37°C, the assays were loaded on QAE Sephadcx A-25 (1 ml bed . volume). The columns were eluted with 2 ml of 30 mM ammonium formiate (pH 6.0) and the eluate was counted for radioactivity. Results were corrected for blank values (measured in the presence of dena¬tured protein) which were below 5 % of total radioaclivity. The amount of cyclic nucleotides liydroly/ed did not exceed 30 % of the original substrate concentration. The IC50 -values for the compounds ac¬cording to the invention for the inhibition of the PDE4 activity were determined from the concentration-inhibition curves by nonlinear-regression. The inhibitory values determined for the compounds according to the invention follow from the followlncj table A, in which the numbers of the compounds correspond to the numbers of the examples. Table A Inhibition of PDE4 acitivity [measured as -loglC50 (mol/l)] compound -loglCw 7 10.28 8 10.18 9 10.65 10 9.57 11 10.34 12 10.79 13 10.03 14 10.33 15 10.27 16 10.50 17 10.51 18 10.32 20 10.40 9.69 21 22 9.37 23 10.80 24 10.63 25 10.19 27 10.37 28 10.24 29 10.87 31 9.20

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