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Phthalazine Derivatives Useful As Europäisches Patentamt *EP001042300B1* (19) European Patent Office Office européen des brevets (11) EP 1 042 300 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C07D 237/30, C07D 237/34 of the grant of the patent: 11.02.2004 Bulletin 2004/07 (86) International application number: PCT/EP1998/008291 (21) Application number: 98966900.7 (87) International publication number: (22) Date of filing: 17.12.1998 WO 1999/032456 (01.07.1999 Gazette 1999/26) (54) PHTHALAZINE DERIVATIVES USEFUL AS PHOSPHODIESTERASE 4 INHIBITORS PHTALAZIN DERIVATE WIRKSAM ALS PHOSPHODIESTERASE 4 INHIBITOREN DERIVES DE PHTALAZINE COMME INHIBITEURS DE PHOSPHODIESTERASE 4 (84) Designated Contracting States: • MORAZZONI, Gabriele AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL I-20020 Lainate (IT) PT SE • SANTANGELO, Francesco I-20148 Milano (IT) (30) Priority: 19.12.1997 IT MI972806 • SIRO HERRERO, Jorge G. E-28893 Cala’ d’Henares (ES) (43) Date of publication of application: • GARCIA NAVIO, José Luis 11.10.2000 Bulletin 2000/41 E-28002 Madrid (ES) • ALVAREZ-BUILLA, Julio G. (73) Proprietor: ZAMBON GROUP S.p.A. E-28033 Madrid (ES) 36100 Vicenza (IT) (74) Representative: Panossian, Stefano et al (72) Inventors: Zambon Group S.p.A • NAPOLETANO, Mauro Industrial Property & Intelligence Director I-20127 Milano (IT) Via Lillo del Duca, 10 • NORCINI, Gabriele 20091 Bresso (Milano) (IT) I-21010 Vizzola Ticino (IT) • BOTTA, Daniela (56) References cited: I-22100 Como (IT) FR-A- 2 468 593 • GRANCINI, Giancarlo I-20054 Nova Milanese (IT) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 042 300 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 042 300 B1 Description [0001] The present invention relates to phthalazine derivatives, to pharmaceutical compositions comprising them and to their use as phosphodiesterase 4 inhibitors. 5 [0002] Phosphodiesterases are a family of isoenzymes which constitutes the basis of the main mechanism of cAMP (cyclic adenosine-3',5'-monophosphate) hydrolytic inactivation. cAMP has been shown to be the second messenger mediating the biologic response to many of hormones, neurotransmitters and drugs [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the suitable agonist binds the cell surface, the adenylated cyclase activates and turns Mg2+-ATP into cAMP. cAMP modulates the activity of the majority, if not of all 10 the cells contributing to the pathophysiology of various respiratory diseases both of allergic origin and not. It follows that an increase of cAMP concentration yields beneficial effects such as airway smooth muscle relaxation, inhibition of the mast cell mediator release (basophil granulose cells), suppression of the neutrophil and basophil degranulation, inhibition of the monocyte and macrophage activation. Thus, compounds able of activating adenylate cyclase or of inhibiting phosphodiesterases could suppress the undesired activation of the airway smooth muscle and of a great 15 number of inflammatory cells. [0003] In the phosphodiesterase family there is a distinct group of isoenzymes, phosphodiesterases 4 (hereinafter PDE 4) specific for the hydrolysis of the airway smooth muscle and inflammatory cells cAMP (Torphy, "Phosphodieste- rase Isoenzymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Tech- nical Services Ltd, 1989). Studies carried out on this enzyme show that its inhibition yields not only the airway smooth 20 muscle relaxation, but also the mastocyte suppression, basophil and neutrophil degranulation, so as the monocyte inhibition and neutrophil activation. Furthermore the PDE 4 inhibitors activity is markedly improved when the adenylated cyclase activity of the target cells is enhanced by endogenous hormones, as the case in vivo. Thus PDE 4 inhibitors should be effective in the therapy of asthma. Such compounds would offer a unique approach to the therapy of various respiratory diseases both of allergic origin and not, and possess significant therapeutic advantages over the current 25 therapy. [0004] The excessive or irregular production of the tumor necrosis factor (hereinafter TNFα), a cytokine with pro- inflammatory activity produced by various kind of cells, affects the mediation or the exacerbation of many pathologies such as, for example, the adult respiratory disease syndrome (ARDS) and the chronic pulmonary inflammatory disease. Therefore compounds able to control the negative effects of TNFα, i.e. the inhibitors of this cytokine, are to be consid- 30 ered as useful against many pathologies. [0005] The patent application EP-0 722 936 (in the name of Eisai) claims, inter alia, compounds of formula 35 40 wherein n=0-4; R1 is optionally substituted lower alkoxy or cycloalkyl, or a -OR9 group wherein R9 is an optionally substituted arylalkyl group; Y is -CB= wherein B is an optionally substituted heteroarylalkyl group or -NR7R8 wherein one of R7 and R8 may be H and the other an optionally substituted heteroarylalkyl group; A is hydrogen or a halogen atom, optionally mono- or bi-substituted amino group, optionally substituted aryl, heteroaryl or heteroarylalkyl group. Among the groups optionally substituting the above mentioned residues halogen atoms are listed. Such compounds 45 are said to be active as cGMP-PDE inhibitors, i.e. PDE 5, a phosphodiesterase acting by a cGMP-dependent mech- anism and whose field of action is markedly cardiovascular (Schudt C. et al., Phosphodiesterase Inhibitors, Academic Press). [0006] The patent application EP-0 498 723 (in the name of Roussel Uclaf) discloses, inter alia, compounds of formula 50 55 2 EP 1 042 300 B1 wherein R2b and R3b are hydrogen, hydroxy, alkyl, cycloalkyl, acyloxy; at least one but no more then two of A1b, A2b, A3b and A4b are a nitrogen atom and at least one of them is a methyne radical substituted by the -R5-YB group wherein R5 is a divalent alkylene radical, and YB represents the radical -Y1B-B-Y2B wherein Y1B is a monocyclic aryl optionally containing nitrogen, B is a single bond and Y2B is hydrogen or halogen. These compounds are said to be effective for 5 the treatment of arterial hypertension, heart and renal failure and for the prevention of restenosis after angioplasty. [0007] The patent application EP-0 017 411 (in the name of Pfizer) claims phthalazines of formula 10 15 wherein R1 is lower alkyl; Y is -(CH2)m-Z wherein m is 1 or 2, and Z is carbamoyloxy, carbonylamino, sulfamoyl, ureido, amino-sulfamoyl, carboxamino substituted on the terminal portion by a (C3-7)cycloalkyl. These compounds are said to 20 be phosphodiesterase inhibitors and to have a cardiac muscle stimulating activity, thus their action does not relate to PDE 4. [0008] The patent US 3,274,185 (in the name of Messengill) describes, inter alia, phthalazines of formula 25 30 wherein Y and Y1 are lower alkoxy; Z is phenyl optionally substituted by halogen or benzyl; and R is hydrogen. These phthalazines are endowed with sedative and hypertensive activity, without an explicit mechanism of action. [0009] The patent US 3,813,384 (in the name of Asta-Werke) illustrates, inter alia, benzyl-phthalazinones of formula 35 40 45 wherein R1 and R2 are lower alkoxy or halogen; X is an optionally branched alkylene chain; m and n are 1-3; p is 0 or 1; and the 50 group is a C3-8 mono-, bi- or tricyclic residue containing one or two nitrogen atom(s). Such compounds have a hys- taminolytic action and are useful, for example, in the treatment of asthma. [0010] The patent application NL 8005411 (in the name of Mitsubishi Yuka) describes phthalazines of formula 55 3 EP 1 042 300 B1 5 10 wherein X is O or NH; R1,R2and R3 are, inter alia,(C1-5)alkyl, (C1-5)alkoxy, halogen or CF3; n, m and p are 0-3. The 15 use of these compounds is as platelet aggregation inhibitors. [0011] The patent application JP-56061365 (in the name of Showa Denko) describes phthalazinones of formula 20 25 wherein, inter alia, R is halogen and n is 1-3, as vasodilators and anti-ulcer agents. [0012] The patent application WO 97/40020 (in the name of Schering AG) illustrates, inter alia, compounds of formula 30 35 40 wherein R1 and R2 are H, nitro, halogen, amino, lower alkoxy or -CF3;R4is H or lower alkyl; R5 is lower alkyl. These compounds are uncompetitive antagonists of excitatory aminoacids. [0013] The patent application WO97/48697 (in the name of Rhone Poulenc Rorer), published on December 24, 1997, disloses, inter alia, compounds of formula 45 50 wherein A is an azaheterocycle and B an azaheteroaryl ring or an optionally halo-substituted benzene ring; Z1 is a 55 1 1 bond or an oxygen atom; R is H or lower alkyl optionally substituted by halogen atom(s); A is a bond or a C1-6 alkylene optionally substituted by aryl, cycloalkyl or heteroaryl; R2 may be H, aryl, heteroaryl; R3 may be aryl, heteroaryl, aryl- methoxy, heteroaryl-methoxy; n and m are alternatively 0 or 1. The aryl and heteroaryl moieties may be substituted by halogen atoms. These compounds are PDE 4 and TNF inhibitors. 4 EP 1 042 300 B1 [0014] Therefore the present invention relates to compounds of formula I 5 10 wherein B is methylene, ethylene, amino, CONH or a bond; Cy is phenyl or a 5- or 6-membered heterocycle containing from 1 to 3 nitrogen atom(s), being both the residues 15 optionally substituted by one or more substituent(s) selected from keto, nitro, carboxy, halogen; R is H, phenyl or a (C1-4)alkyl group optionally substituted by an aromatic or hydrogenated ring containing from 5 to 7 members; R1 is a (C1-6)alkyl or polyfluoro(C1-6)alkyl group; R2 is aryl, aryl-(C1-10)alkyl or a (C4-7)cycloalkyl group optionally containing an oxygen atom and optionally substituted 20 by a polar substituent selected from hydroxy or keto groups; and the N→O derivatives and pharmaceutically acceptable salts thereof; with the proviso that when R is H, R2 is not aryl-methyl.
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