WO2004098633A1

WO2004098633A1 - Composition comprising a pde-4 inhibitor and a tnf alpha antagonist

Info

Publication number: WO2004098633A1
Application number: PCT/EP2004/050748
Authority: WO
Inventors: Johannes Barsig; Christian Weimar
Original assignee: Altana Pharma Ag
Priority date: 2003-05-12
Filing date: 2004-05-10
Publication date: 2004-11-18

Abstract

The invention relates to the combined administration of a PDE4 inhibitor and a TNFα antagonist selected from the group consisting of etanercept, onercept and pegsunercept for the treatment of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental.

Description

COMPOSITION COMPRISING A PDE-4 NHIBITOR AND A NF-ALPHA NTAGONIST

Field of application of the invention

The invention relates to the combination of certain known active compounds for therapeutic purposes. The substances used in the combination according to the invention are known active compounds from the phosphodiesterase 4 (PDE4) inhibitor class and known active compounds from the tumor necrosis factor alpha (TNFα) antagonist class. Their combined use in the sense according to the invention for therapeutic purposes has not yet been described in the prior art.

Prior art

In the international patent application WO02/064584 phthalazinone-piperidino derivatives are described as selective PDE4 inhibitors. In Emerging Drugs Vol. 5, 2000 pp. 309-319 the use of PDE4 inhibitors In the treatment of chronic obstructive pulmonary disease is reviewed. In the international patent application WO01/58441 the combination of PDE4 inhibitors with NSAIDs is disclosed for the treatment of an inflammatory disease. In the European Patent Application EP0433900 the recombi- nant human tumor necrosis factor binding protein-1 (r-hTBP-1 ; INN: ONERCEPT) is disclosed. In the international patent application WO98/01555 a pegylated soluble tumor necrosis factor receptor type 1 (PEG sTNFFH ; INN: PEGSUNERCEPT) is disclosed. US patent No. 5,605,690 describes a method for treating TNF-dependent inflammatory diseases in a mammal by administering a tumor necrosis factor antagonist, and particularly pointing to a TNF-receptor. WO document WO91/03553 describes treating TNF-dependent inflammatory diseases, such as arthritis, by administering tumor necrosis factor receptor protein with an interleukin-1 receptor and/or an interleukin-2 receptor. In Clinical and Experimental Rheumatology Vol 17, 1999, pp S115-S120 several combination therapies with D ARDs and biological agents in collagen -induced arthritis are disclosed.

Summary ot the invention

The invention relates to pharmaceutical compositions and methods for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental. In particular it relates to compositions and methods for treating a disease mediated by phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity by administering a PDE4 inhibitor in combination with a TNFα antagonist.

In this connection, it is the object of the present invention to make available a certain especially anti- inflammatory therapeutic, which fulfills the following conditions:

Pronounced antiinflammatory action

Minor side effects

Good suitability for long-term therapy

It has now been found that the combined use of a PDE4 inhibitor and a TNFα antagonist selected from the group consisting of etanercept, onercept and pegsunercept outstandingly fulfills the above- mentioned conditions.

Accordingly, the invention relates in a first aspect to a method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental by administering to a patient in need thereof simultaneously an effective amount of (1) a PDE4 inhibitor and (2) a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept.

In a second aspect the invention relates to a method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental by administering to a patient in need thereof in succession, close in time or remote in time, in any order whatever an effective amount of (1) a PDE4 inhibitor and (2) a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept.

The invention also relates to a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, comprising as a fixed combination an effective amount of

(a) a PDE4 inhibitor and (b) a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept and optionally

(c) a pharmaceutically acceptable carrier.

The invention further relates to a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, comprising as a free combination an effective amount of

(a) a PDE4 inhibitor and optionally a pharmaceutically acceptable carrier and

(b) a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept and optionally a pharmaceutically acceptable carrier.

The invention additionally relates to a method for preparing a pharmaceutical composition which is effective for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, or treating or leduciπg the severity of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, which method comprises mixing an effective amount of a PDE4 inhibitor and a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept with a pharmaceutically acceptable carrier.

The invention furthermore relates to the use of a combination of a PDE4 inhibitor and a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept for the preparation of a pharmaceutical composition for reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental.

Detailed description of the invention

The combination therapy, which is the subject matter of this invention comprises administering a PDE4 inhibitor with a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept to prevent onset of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental or to treat such an existing condition. The invention thus relates to the combined use of a PDE4 inhibitor and a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept in pteventing the symptoms of, or treating a a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental.

The PDE4 inhibitors useful in this invention may be any compound that is known to inhibit the PDE4 enzyme ot which is discovered to act as a PDE4 inhibitor, and which is only or essentially only a PDE4 inhibitor, not compounds which inhibit to a degree of exhibiting a therapeutic effect other members of the PDE family as well as PDE4

One group of PDE4 inhibitors that may be usefully employed in the present invention [hereinafter referred to as "SELECTED PDE4 INHIBITORS"] include a compound of formula (1 )

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 1-4G-alkoxy which is completely or predominantly substituted by fluorine,

R6 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5G-cycloalkylmethoxy, or 1-4G-alkoxy which is completely or predominantly substituted by fluorine, R7 is 1-4C-alkyl and R8 is hydrogen or 1 -4G-alkyl, or wherein

R7 and R8 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sulphur atom,

R9 is 1-4C-Alkyl, -S(O)₂-R10, -S(0)₂-(CH₂)_n-R11 , -(CH₂)_m-S(0)₂-R12, -G(0)R13, -C(0)-(CH₂)_n-R14, -(CH₂)_m-C(0)-R15, Hetaryl, AryM or Aryl2-(1 -4C)-alkyl,

R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1 -yl, -N(R16)R17, phenyl or phenyl substituted by R18 and/or R19,

R11 is -N(R16)R17,

R12 is -N(R16)R17,

R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazin-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, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl- methyl, 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-, 1-pyr- rolidinyl-, 1 -piperidinyl-, 1 -hexahydroazepino- or a 1-piperazinyl-ring of formula (c)

wherein

R21 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyl-diιnethylamino, dimethylaminocarbonylmethyl,

N-methyl-piperidin-4-yl, 4-morpholino -ethyl or tetrahydrofuran-2-ylmethyl, R18 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino, mono-or di-1 -4G-alkylamiπo, aminocarbonyl, 1-4C-alkylcarbonylamino or mono-or di-

1 -4C"alkylaminocarboπyl, 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-1 H-pyrazolo-[3 d]pyrimidin-4-yl, thia- zolyl, imidazolyl or furanyl, 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-chromeπ-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, or a pharmaceutically acceptable salt or a N-oxide thereof or a pharmaceutically acceptable salt of the latter.

1 -4C-Alkyl is a straight -chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

1 -4G-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 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, isopropoxy, ethoxy and methoxy radicals.

1 -8C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight -chain or branched 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, isohexyloxy (4-methylpentyloxy), neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy (3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.

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 means that more than half of the hydrogen atoms of the 1-4C-alkoxy group are replaced by fluorine atoms.

3-7G-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cyclo- heptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy, cyclopentyl methoxy, cy- clohexylmethoxy or cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclo- pentylmethoxy are preferred.

3-5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy. 3-5G-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmβthoxy.

Halogen within the meaning of the present invention is bromine, chlorine or fluorine.

As spiro-linked 5-, 6- or 7-membβred hydrocarbon rings, optionally interrupted by an oxygen or sulphur atom, may be mentioned the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahy- dropyran and the tetrahydrothiophen ring.

1 -4G-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned 1-4G-alkoxy radicals is bonded. Examples are the methoxycarbonyl [CH₃0-C(0)-] and the ethoxycarbonyl [CH₃CH₂0-C(0)-] radical.

An 1-4G-Alkylcarbonylamino radical is, for example, the propionylamino [C₃H₇C(0)NH-] and the ace- tylamino radical [CH₃C(0)NH-].

Mono- or Di-1-4C-alky)amino radicals contain in addition to the nitrogen atom, one or two of the abovementioned 1-4C-alkyl radicals. Preferred are the di-1 -4C-alkylamino radicals, especially the dimethylamino, the diethylamino and the diisopropylamino radical.

Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to the carbonyl group one of the abovementioned mono- or di-1-4C-alkylamino radicals. Examples which may be mentioned are the N-methyl- the N,N-dirnethyl-, the N-ethyl-, the N-propyl-, the N,N-diethyl- and the N-isopropylamino- carbonyl radical.

Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds which are generally prepared by reacting a free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Particular mention may be made of the pharmaceutically acceptable inorganic and organic acids customarily used in pharmacy. Those suitable are in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-glucoπic acid, benzole acid, 2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom. As examples of salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, mβglumine or guanidmium salts, here, too, the bases being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom

It is understood that the active compounds and their pharmaceutically acceptable salts mentioned can also be present, for example, in the form of their pharmaceutically acceptable solvates, in particular in the form of their hydrates

SELECTED PDE4 INHIBITORS, which are to be emphasized include a compound of formula (1 ), in which

R1 and R2 together form an additional bond,

R3 represents a benzene derivative of formula (a) or (b)

wherein

R4 is 1-4G-alkoxy,

R5 is 1-4C-alkoxy,

R6 is 1-2C-alkoxy,

R7 is methyl and

R8 is hydrogen, R9 is 1-4C-alkyl, -S(O)₂-R10, -C(0)R13, -C(0)-(CH₂)_n-R14, -(CH₂)_m-C(0)-R15, Hetaryl, Aryll or

Aryl2-(1-2C-)alkyl, R10 is 1-4C-alkyl, 5 dιmethyiamιnonaphthalιn-1 -yl, phenyl or phenyl substituted by R18, R13 is 1-4G-alkyl, hydroxycarbonyl-1-4C-alkyl, pyridyl, 4-ethyl-pιperazιn-2,3-dιon-1-yl oi

-N(R16)R17, R14 ls -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 R16 and R17 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholιnyl ring or a 1-pιperazιnyl ring of formula (c)

wherein

R21 is dimethylamino-1 -4C-alkyl, R18 is halogen, nitro, 1-4G-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-1 H-pyrazolo-[3,4-d]pyrimidin-4-yl, Aryh 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, or a pharmaceutically acceptable salt or a N-oxide thereof or a pharmaceutically acceptable salt of the latter.

SELECTED PDE4 INHIBITORS, which are preferred include a compound selected from

(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H- phthalazin-1 -one,

(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1 -methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H- phthalazin-1-one,

(4aS,8aR)-2-(1 -Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1 - one,

5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1 -oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1 - yl}-5-oxo-pentanoic acid,

(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-

2H-phthalazin-1 -one,

4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalazin-2-yl]-piperidine-1- carboxylic acid tert-butylamide,

4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalazin-2-yl]-piperidine-1- carboxylic acid phenylamide,

4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalaziπ-2-yl]-piperidine-1- carboxylic acid tert-butylamide,

(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1 -oxo-4a,5,8,8a-tetrahydro-1 H- phthalazin-2-yl]-piperidine-1-carboxylic acid tert-butylamide,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1 -sulfonyl)-piperidin-4-yl]-

4a,5,8,8a-tetrahydro-2H-phthalazin-1-one, (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H- phthalazin-1 -one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1 -pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H- phthalazin-1-one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-

2H-phthalazin-1 -one,

(4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-

4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

4-(3,4-Dimethoxyphenyl)-2-[1 -(1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-te- trahydro-2H-naphthalen-1-one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1 -thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahy- dro-2H-phthalazin-1-one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1 -pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phtha- lazin-1 -one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-te- trahydro-2H-phthalazin-1-one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetra- hydro-2H-phthalazin-1-one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1 -phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-

1-one,

(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-

2H-phthalazin-1 -one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1 -pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H- phthalazin-1 -one,

(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H- phthalazin- 1 -one,

(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahy- d ro -2 H- phthalazin- 1-one,

(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1 -{2-[4-(2-dimethylamino-ethyl)-piperazin-1 -yl]-ethanoyl}-piperi- din-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1 -one,

2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalazin-2-yl]-piperidin-1- yl}-N-isopropyl-acetamide,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1 ,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetra- hydro-2H-phthalazin -1-one,

1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1 -oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-

1 -yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,

4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalazin-2-yl]-piperidin-

1 -yl}-ethanoylamino)-benzoic acid ethyl ester, 2-{4-t(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalazin-2-yl]-piperidin-1- yl}-acetamide, or a pharmaceutically acceptable salt or a N-oxide thereof or a pharmaceutically acceptable salt of the latter.

SELECTED PDE4 INHIBITORS, which are particularly preferred include a compound selected from

(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H- phthalazin-1-one,

2-{4-[(4aS, 8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalazin-2-yl]-piperidin-1 - yl}-acetamide, or a pharmaceutically acceptable salt or a N-oxide thereof or a pharmaceutically acceptable salt of the latter.

The preparation of the SELECTED PDE4 INHIBITORS as well as their use as phosphodiesterase (PDE) 4 inhibitors is described in WO02/064584.

Another group of PDE4 inhibitors that may be usefully employed in the present invention include a compound selected from

• N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN: PICLAMILAST] and its salts; the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the international patent application W092/12961

• 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research Code: V-11294A]; the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the international patent application WO95/00516

• N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1 ,4]benzo-diazepin-3(R)-yl]pyridine- 4-carboxamide [Research Code: GI-1018]; the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the international patent application W096/11690.

• 3,7-dihydro-3-(4-chlorophenyl)-1 -propyl-1 H-purine-2,6-dione [INN AROFYLLINE]; the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the European patent application EP0435811.

• N-(3,5-dichloro-4-pyridinyl)-2-[1 -(4-fluorobenzyl)-5-hydroxy-1 H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-281]; the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the international patent application WO98/09946

• N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1 H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-343]; the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the international patent application WO98/09946.

• Tetrahydro-5-[4-methoxy-3-[(1 S,2S,4R)-2-norbomyloxy]phenyl]-2(1 H)-pyrimidone [INN: ATIZO- RAM]; the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the European patent application EP0389282.

• β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1 ,3-dihydro-1 ,3-dioxo-2H-isoindole-2-propanamide [Research Code: CDC-801]; the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the international patent application W097/23457.

• Methanesulfonic acid 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN: LI RIM I- LAST]; the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the European patent application EP0731099.

• 3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide [Research Code: SCH-351591]; the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the international patent application WO00/26208;

• cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1 -carboxylic acid [INN: Cilomilast], the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the international patent application W093/19749

• the compounds with the research codes CDG-998, IC-485, CG-1088 and KW4490 and the pharmaceutically acceptable salts of the above listed compounds. In this second group of PDE4 inhibitors, Cilomilast and AWD-12-281 are particularly preferred.

In the sense of the invention, the term "etanercept" is understood to include the recombinant version of the soluble p75 Tumor Necrosis Factor Receptor (TNFR) linked to the Fc portion of the human lgG1 known under the INN ETANERCEPT, or its biologically active equivalents. Etanercept inhibits tumor necrosis factor biological activity by acting as a competitive inhibitor to the binding of tumor necrosis factor to its cell receptors. ETANERCEPT is described in U.S. Patent No. 5,605,690.

The term "onercept" is understood to include the recombinant soluble monomeric human Tumor Necrosis Factor-1 Receptor Type 1 (r-hTBP-1) known under the INN ONERCEPT, or its biologically active equivalents. ONERCEPT is described in the EP patent application EP0433900.

The term "pegsunercept" is understood to include the recombinant pegylated soluble tumor necrosis factor receptor type 1 (PEG sTNFRI ) known under the INN PEGSUNERCEPT, or its biologically active equivalents. PEGSUNERCEPT is described in the international patent application WO98/01555.

"Biologically active", as used throughout the specification as a characteristic of tumor necrosis factor antagonists, means, for example, that a particular molecule shares sufficient amino acid sequence similarity with the embodiments of the present invention disclosed herein to be capable of binding detectable quantities of tumor necrosis factor receptor, transmitting a tumor necrosis factor stimulus to a cell, for example, as a component of a hybrid receptor construct, or cross-reacting with anti-tumor necrosis factor receptor antibodies raised against tumor necrosis factor receptor from natural (i.e., nonrecombinant) sources. In one embodiment of the present invention, the biologically active tumor necrosis f ctor antagonists within the scope of the present invention are capable of binding greater than O.l nmoles tumor necrosis factor per nmole receptor, and in another embodiment, are capable of binding greater than 0.5 nmole tumor necrosis factor per nmole receptor in standard binding assays (see U.S. Patent No. 5,605,690).

"Diseases in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental" which may be mentioned are in particular acute and chronic (in particular inflammatory and allergen-induced) airway disorders of varying origin (bronchitis, allergic bronchitis, chronic bronchitis, bronchial asthma, severe chronic asthma, emphysema, COPD, pulmonary sarcoidosis, pulmonary fibro- sis, siliciosis); dermatoses (especially of proliferative, inflammatory and allergic type) such as psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in the anogenital 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 excessive release of TNF and leukotrienes, for example disorders of the arthritis type (rheumatoid arthritis, psoriatric arthritis, juvenile rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions), spondylarthropathies (ankylosing spondylitis), Wegener's granulomatosis, adult Still's disease, Behcet's disease, polymyositis,myelodysplastic syndrome, scleroderma, dermatomyositis, Sjogren's syndrome, disorders of the immune system (AIDS), autoimmune diseases (e.g., Multiple Sclerosis, allergy, autoimmune uveitis and nephritic syndrome), transplant rejection, including rejections of allografts and xenografts, graft versus host disease, 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 (Inflammatory bowel disease, Crohn's disease and ulcerative colitis); disorders which are based on allergic and/or chronic, immunological false reactions in the region of the upper airways (pharynx, 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 and/or TNFα inhibitors, such as cardiac insufficiency, ischemia of the heart and congestive heart failure, or disorders which can be treated on account of the tissue-relaxant action of the PDE inhibitors, such as colics of the kidneys and of the ureters in connection with kidney stones. The pharmaceutical compositions according to the invention can furthermore be used in the treatment of conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease or multiinfarct dementia; in the treatment of malignancies to inhibit tumor growth, or metastasis, and/or to alleviate cachexia secondary to malignancy; in the treatment of infectious diseases like bacterial meningitis, cachexia or cerebral malaria; and in the treatment of diseases like sciatica, inflammatory bone disease, bone resorption disease, hepatitis, viral hepatitis, reperfusion injury, scar tissue formation, pyrexia, perio- dontal disease and radiation toxicity. The pharmaceutical compositions according to the invention can as well be used in the treatment of chronic fever syndromes, metabolic syndrome and sequalae, e.g. type 2 diabetes.

The phrase "combined use" (or "combination") embraces the administration of a PDE4 inhibitor and a TNFα antagonist selected from the group etanercept, onercept and pegsunercept as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually, minutes, hours, days or weeks depending upon the combination selected). "Combined use" generally is not intended to encompass the administration of two of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.

"Combined use" or "combination" within the meaning of the present invention is to be understood as meaning that the individual components can be administered simultaneously (in the form of a combination medicament - fixed combination) or more or less simultaneously, respectively in succession (from separate pack units - free combination; directly in succession or else alternatively at a relatively large time interval). As an example, one therapeutic agent could be taken in the morning and one later in the day. Or in another scenario, one therapeutic agent could be taken once daily and the other twice weekly.

Simultaneous administration preferably is accomplished, for example, by administering to the subject in need thereof a subcutaneous injection having a fixed ratio of each therapeutic agent. More or less simultaneous administration or administration in succession of each therapeutic agent can be effected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous or subcutaneous injection while the other therapeutic agent of the combination may be administered orally. The sequence in which the therapeutic agents are administered is not narrowly critical.

The TNFα antagonist compositions according to the invention are preferably administered via par- enteral administration, for example, intravenous injection, subcutaneous injection, intramuscular injection, or intramedullary injection. Other routes of administration for the TNFα antagonists include, for example, intra-articular, intraperitoneal or subcutaneous routes by bolus injection, continuous infusion, sustained release from implants, or other suitable techniques. Typically, the TN Fα antagonists according to the invention will be administered in the form of a composition comprising purified protein in conjunction with physiologically acceptable carriers, excipients or diluents. Such carriers will be non- toxic to recipients at the dosages and concentrations employed. Ordinarily, the preparation of such compositions entails combining the TNFα antagonists with buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, sucrose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients. Neutral buffered saline or saline mixed with conspecific serum albumin are exemplary appropriate diluents. Preferably, product is formulated as a lyophilizate using appropriate excipi- ent solutions (e.g. sucrose) as diluents. Appropriate dosages can be determined in trials. In accordance with appropriate industry standards, preservatives may also be added, such as benzyl alcohol. The amount and frequency of administration will depend, of course, on such factors as the nature and severity of the indication being treated, the desired response, the condition of the patient, and so forth.

The most preferred mode of administration of a PDE4 inhibitor is oral. In another preferred embodiment the PDE4 inhibitor administered by intravenous infusion or injection. In a further embodiment the PDE4 inhibitor is administered by intramuscular or subcutaneous injection. Other routes of administration are also contemplated, including intranasal and transdermal routes, and by inhalation.

In case of pharmaceutical compositions, which are intended for oral administration, the therapeutic agent(s) are formulated to give medicaments according to processes known per se and familiar to the person skilled in the art. The therapeutic agents are employed as medicament, preferably in combination with suitable pharmaceutical carrier, in the form of tablets, coated tablets, capsules, caplets, emulsions, suspensions or solutions, the therapeutic agent content advantageously being between 0.1 and 95% and, by the appropriate choice of the carrier, it being possible to achieve a pharmaceutical administration form precisely tailored to the therapeutic agent(s) and/or to the desired onset of action (e.g. a sustained-release form or an enteric form).

The person skilled in the art is familiar on the basis of his/her expert knowledge with, which carriers or excipients are suitable for the desired pharmaceutical formulations. In addition to solvents, gel-forming agents, tablet excipients and other active compound carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or permeation promoters and complexing agents (e.g. cyclodextrins).

lnjectable preparations, for example, sterile injectable aqueous or oleaginous solutions/suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenteraly acceptable diluent or solvent, for example, as a solution in 1 ,3-butane- diol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including syn- thetic mono-or diglycerides. Furthermore, fatty acids, such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.

For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions can be prepared fromsterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The term parenteral as used herein includes subcutaneous, intravenous or intramuscular injections, or infusion techniques.

The therapeutic agent(s) of the present invention can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route of administration for a fixed combination of a PDE4 inhibitor and a TNFα antagonist according to the invention is subcutaneous injection.

The therapeutic agent(s) are dosed in an order of magnitude customary for the individual dose, it more likely being possible, on account of the individual actions, which are mutually positively influencing and reinforcing, to reduce the respective doses on the combined administration of the therapeutic agent(s) with the norm.

In case of oral, intravenous or subcutaneous administration of a PDE4 inhibitor, the daily dose will be in the range from 0.001 to 3 mg/kg body weight of the subject to be treated, preferably by once daily administration.

In one embodiment of the present invention the adult dose of Cilomilast is between 5 mg and 20 mg twice a day, preferably between 10 mg and 15 mg twice a day.

In another embodiment of the present invention the adult dose for oral administration of the SELEG TED PDE4 INHIBITORS (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1 -pyrimidin-2-yl-piperidin-4-yl)- 4a,5,8,8a-tetrahydro-2H-phthalazin-1-one, (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-yl- methyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one or 2-{4-[(4aS, 8aR)-4-(3,4-Dimeth- oxyphenyl)-1 -oxo-4 a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-acetamide is between 0.1 and 10 mg once a day, preferably between 0.5 and 2 mg once a day.

For treatment of arthritis or another inflammatory disease, the TNFα antagonist is administered in systemic amounts ranging from about 0.1 mg/kg/week to about 100 mg/kg/week. In preferred embodiments of the present invention, the TNFα antagonist is administered in amounts ranging from about 0.5 mg/kg/week to about 50 mg/kg/week. For local intra -articular administration, dosages preferably range from about 0.01 mg/kg to about 1.0 mg/kg per injection.

In one embodiment of the present invention the adult dose of ETANERCEPT is 25 mg twice a week, as a subcutaneous injection. In another embodiment of the present invention the adult dose of ETANERCEPT is 50 mg once a week, as a subcutaneous injection.

Claims

Patent claims

1. Combined use of a PDE4 inhibitor and a TNFα antagonist selected from the group consisting of etanercept, onercept and pegsunercept for preventing or reducing the onset of symptoms of, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, in a patient in need thereof.

2. Pharmaceutical composition suited for the combined use according to claim 1, comprising as a fixed combination an effective amount of

(a) a PDE4 inhibitor and

(b) a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept and optionally

(c) a pharmaceutically acceptable carrier.

3. Pharmaceutical composition according to claim 2, which is a fixed injectable combination.

4. Pharmaceutical composition suited for the combined use according to claim 1 , comprising as a free combination an effective amount of

(a) a PDE4 inhibitor and optionally a pharmaceutically acceptable carrier and

5. Method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental by administering to a patient in need thereof simultaneously an effective amount of (1 ) a PDE4 inhibitor and (2) a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept.

6. Method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental by administering to a patient in need thereof in succession, close in time or remote in time, in any order whatever an effective amount of (1) a PDE4 inhibitor and (2) a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept.

7. Use of a combination of a PDE4 inhibitor and a TNFα antagonist selected from the group of etanercept, onercept and pegsunercept for the preparation of a pharmaceutical composition for reducing the onset of symptoms of, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental.

8. Pharmaceutical composition, use or method according to any of claims 1 to 7, wherein the TNFα antagonist is etanercept.

9. Pharmaceutical composition, use or method according to any of claims 1 to 7, wherein the TNFα antagonist is onercept.

10. Pharmaceutical composition, use or method according to any of claims 1 to 7, wherein the TNFα antagonist is pegsunercept.

11. Pharmaceutical composition, use or method according to any of claims 1 to 10, wherein the PDE4 inhibitor is a SELECTED PDE4 INHIBITOR.

12. Pharmaceutical composition, use or method according to claim 11 , wherein the SELECTED PDE4 INHIBITOR is selected from

(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1 - one,

5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1 -oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1- yl}-5-oxo-pentanoic acid,

(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro- 2H-phthalazin-1 -one,

4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-l H-phthalazin-2-yl]-piperidine-1-carb- oxylic acid tert-butylamide,

4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalazin-2-yl]-piperidine-1-carb- oxylic acid phenylamide,

4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalazin-2-yl]-piperidine-1- carboxylic acid tert-butylamide,

(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2_:3-dihydro-benzofuran-4-yl)-1 -oxo-4a,5,8,8a-tetrahydro-1 H-phtha- lazin-2-yl]-piperidine-1 -carboxylic acid tert-butylamide,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1 -sulfonyl)-piperidin-4-yl]- 4a,5,8,8a-tetrahydro-2H-phthalazin-1-one, (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H- phthalazin-1 -one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1 -pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H- phthalazin-1 -one,

2H-phthalazin-1 -one,

4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

4-(3,4-Dimethoxyphenyl)-2-[1 -(1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-te- trahydro-2H-naphthalen-1 -one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1 -thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahy- dro-2H-phthalazin-1 -one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetra- hydro-2H-phthalazin -1-one,

1 -one,

2H-phthalazin-1 -one,

(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahy- dro-2H-phthalazin-1 -one,

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1 ,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-te- trahydro-2H-phthalazin-1-one,

1 -(1 -{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1 -oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-

1 -yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,

1 -yl}-ethanoylamino)-benzoic acid ethyl ester, 2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalazin-2-yl]-piperidin-1- yl}-acetamide, or a pharmaceutically acceptable salt or a N-oxide thereof or a pharmaceutically acceptable salt of the latter.

13. Pharmaceutical composition, use or method according to claim 11 , wherein the SELECTED PDE4 INHIBITOR is

(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1 -pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phtha- lazin-1 -one, or a pharmaceutically acceptable salt or a N-oxide thereof or a pharmaceutically acceptable salt of the latter.

14. Pharmaceutical composition, use or method according to claim 11 , wherein the SELECTED PDE4 INHIBITOR is

(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H- phthalazin-1 -one, or a pharmaceutically acceptable salt or a N-oxide thereof or a pharmaceutically acceptable salt of the latter.

15. Pharmaceutical composition, use or method according to claim 11 , wherein the SELECTED PDE4 INHIBITO R is

2-{4-[(4aS, 8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1 H-phthalazin-2-yl]-piperidin-1 - yl}-acetarnide, or a pharmaceutically acceptable salt or a N-oxide thereof or a pharmaceutically acceptable salt of the latter.

16. Pharmaceutical composition, use or method according to any of claims 1 to 10, wherein the PDE4 inhibitor is Cilomilast.

17. Pharmaceutical composition, use or method according to any of claims 1 to 10, wherein the PDE4 inhibitor is AWD-12-281.

18. Pharmaceutical composition, use or method according to any of claims 1 to 17, wherein the disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental is selected from rheumatoid arthritis, psoriasis, psoriatric arthritis, juvenile arthritis, inflammatory bowel disease, spondylarthropathies (ankylosing spondylitis), adult-onset Still's disease, Behcet's disease, polymyositis, sarcoidosis, Wegener granulomatosis, myelodysplastic syndrome, inflammatory myositis, Sjδgren syndrome, severe chronic asthma, septic shock, uveitis and graft versus host disease.

18. Pharmaceutical composition, use or method according to any of claims 1 to 17, wherein the disease in which phosphodiesterase 4 (PDE4) and/or tumor necrosis factor alpha (TNFα) activity is detrimental is selected from rheumatoid arthritis, psoriasis, psoriatric arthritis, juvenile arthritis, inflammatory bowel disease and spondylarthropathies (ankylosing spondylitis).