WO2005013995A1 - 4-substituted 7-alkoxy-2-aminosulfonyl-1,2-dihydro-phtalazin derivatives as phosphodiesterase 4 inhibitors for the treatment of allergies and inflammations - Google Patents

4-substituted 7-alkoxy-2-aminosulfonyl-1,2-dihydro-phtalazin derivatives as phosphodiesterase 4 inhibitors for the treatment of allergies and inflammations Download PDF

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WO2005013995A1
WO2005013995A1 PCT/EP2004/007714 EP2004007714W WO2005013995A1 WO 2005013995 A1 WO2005013995 A1 WO 2005013995A1 EP 2004007714 W EP2004007714 W EP 2004007714W WO 2005013995 A1 WO2005013995 A1 WO 2005013995A1
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group
alkyl
methyl
alkyl group
compound
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PCT/EP2004/007714
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French (fr)
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Mauro Napoletano
Thomas Haack
Silvia Macecchini
Lara Pippo
Jean-Dominique Moriggi
Gabriele Morazzoni
Leopoldo Allievi
Ermanno Moriggi
Franco Pellacini
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Zambon Group S.P.A.
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Publication of WO2005013995A1 publication Critical patent/WO2005013995A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to dihydro-phthalazine derivatives, pharmaceutical compositions comprising them and the use thereof as phosphodiesterase 4 inhibitors.
  • 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 demonstrated to be the second messenger mediating the biologic response to many among hormones, neurotransmitters and drugs [Krebs Endocrinology Proceedings of the 4 th International Congress Excerpta Medica, 17-29, 1973].
  • cAMP modulates the activity of the majority, if not of all, of the cells contributing to the pathophysiology of various respiratory diseases of allergic origin and not. It follows that a huge increase in cAMP levels 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 granulation, inhibition of the monocyte and macrophage activation.
  • PDE 4 phosphodiesterases 4
  • PDE 4 phosphodiesterases 4
  • Torphy "Phosphodiesterase Isoenzymes: Potential Targets for Novel Anti-asthmatic Agents” in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd, 1989).
  • PDE 4 inhibitors are effective in the therapy of asthma.
  • the PDE 4 selective inhibition weakens the functionality of inflammatory cells, such as, for example, neutrophils, alveolar macrophages and T cells having, as it is known, a key role in the COPD (chronic obstructive pulmonary disease) and such activity emphasizes how this class of compounds can provide an effective therapy for this kind of pathology (Douglas WP Hay, Curr. Opin. Chem. Biol., 2000, 4, page 412-419).
  • TNF ⁇ tumor necrosis factor
  • ARDS adult respiratory disease syndrome
  • R 3 is a ( -C ⁇ -alkylsulfonyl group; these compounds are active as PDE 4 and TNF ⁇ release inhibitors.
  • the additional polarity introduced in the molecules by the sulfonamide group has allowed obtaining both compounds with chemical physical features, such as hydrosolubility, which can be managed in a much easier way from the formulative point of view, and checking in pharmaceutically acceptable carriers the bioavailability of the compounds object of the present invention.
  • object of the present invention are the compounds of formula
  • Z is a methylene, mono or di-fluoro-methylene group or a -NH- group.
  • sustituent(s) selected among alkyl, alkoxy, a carboxyl group, an alkoxy- carbonyl group, an acyl group, alkyltio, alkyl-sulfon
  • R is a (C ⁇ -C )-alkyl group or a mono or poly-fluoro-(C ⁇ -C )-alkyl group;
  • Ri is a hydrogen atom, an optionally branched (C ⁇ -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )- alkynyl group, a cycloalkyl group, an optionally substituted aryl or heterocycle, an optionally substituted aryl-(C ⁇ -C 4 )-alkyl or heterocyclil-(C ⁇ -C )-alkyl group, a cyano-(C ⁇ -C 6 )-alkyl group, a formyl-(C ⁇ -C 6 )-alkyl or formyl-(C ⁇ -C 6 )-alkenyl group, a carboxy-(C ⁇ -C 6 )-alkyl group or a carboxy-(C 1 -C 6 )-alkenyl group, an alkoxy-carbonyl-(C ⁇ -C 6 )-alkyl group or an alkoxy-carbonyl-(C ⁇ -
  • R 2 has the same meanings of Ri and moreover it is a-CO-O-R t group wherein i is an optionally branched (C ⁇ -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl group, a cycloalkyl group, an optionally substituted aryl or heterocycle, an optionally substituted aryl-(C ⁇ -C 4 )- alkyl or heterocyclil-(C ⁇ -C 4 )-alkyl group;
  • R 3 is a hydrogen atom or a -O-R group wherein R has the meanings defined above; the N-oxidized derivatives of the compounds of formula I and pharmaceutically acceptable salts thereof.
  • the compounds of formula I are active as PDE 4 inhibitors and therefore they are utilized as therapeutic agents in allergic and inflammatory pathologies, such as, for example, ARDS, COPD, asthma and allergic rhinitis.
  • alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t- butyl, n-pentyl, 1 -methyl-butyl, 2-etyl-propyl, 3-methyl-butyl, 3-methyl-2-butyl, n-hexyl, heptyl, octyl and the likes.
  • cycloalkyl group cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl are meant.
  • halogen a fluorine, chlorine, bromine or iodine atom is meant.
  • aryl and aryl-(C ⁇ -C )-alkyl designate a monocyclic or multicyclic aromatic system constituted by 6-10 carbon atoms such as, for example, phenyl, benzyl, phenethyl, phenyl-pentyl, naphtyl, naphtyl-methyl, indanyl, indanyl-pentyl and the likes.
  • aromatic heterocycle containing from one to three heretoatoms selected among nitrogen, oxygen and sulphur, aromatic heterocycles such a s pyrrole, thiophene, fiiran, imidazole, pyrazole, thiazole, isothiazole, isoxazole, oxazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole and thiadiazole are meant.
  • heterocycle existing in the meanings of Ri and R 2 in particular pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyperazine, triazine, morpholine, pyrrolidine, pyrroline, imidazoline, pyrazoline, pyrazolidine, imidazolidine, piperidine, furan, pyran, dioxane, thiophene, thiazole, isothiazole, isoxazole, oxazole, triazole and thiadiazole and the likes are meant.
  • the substituents optionally present on the aryl or heterocycle groups in the meanings of Ri and R 2 are a cyl, alkyl, alkoxy, alkoxy-carbonyl, alkyltio, alkyl-sulfonyl, amino, carboxyl, cyano, mercapto, nitro, oxy ⁇ ryle, oxo and halogen under which term a fluorine, chlorine, bromine or iodine atom is meant.
  • acyloxy in the acyloxy-(C C 4 )-alkyl substituents, a H-CO-O- or alkyl-CO- O- group is meant, wherein the alkyl group preferably contains from one to four carbon atoms such as, for example, a formyl, acetyl propanoyl, 2-methyl-propanoyl, butanoyl and palmitoyl group.
  • the N-oxidized form if present, may regard both the nitrogen atoms existing on the phtalazine ring and the ones present on the hererocyclic rings, in particular the nitrogen atom present on the pyridine ring.
  • the compounds of formula I may have one or more asymmetric centres and therefore they may be in the form of stereoisomers.
  • the object of the present invention are the compounds of formula I in the form of stereoisomeric mixtures as well as single stereoisomers.
  • Examples of pharmaceutically acceptable salts of the compounds of formula I are salts with organic or inorganic acids such as, for example, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, tartaric, citric, benzoic, maleic, fumaric, succinic and glutaric acid or they are the salts with the alkaline, alkaline-earthy metals, the zinc salts and the salts with the pharmaceutically acceptable organic bases such as, for example, trometamol (2-amino-2-hydroxymethyl-propan- 1,3 -diol), N-methyl glucamine.
  • organic or inorganic acids such as, for example, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, tartaric, citric, benzoic, maleic, fumaric, succinic and glutaric acid or they are the salts with the alkaline, alkaline-earthy metals,
  • R, Ri, R 2 , R 3 and A have the meanings defined in formula I and Z is a methylene group or mono or di-fluoro-methylene.
  • Z is a methylene group or mono or di-fluoro-methylene.
  • R 3 is a hydrogen atom
  • i is a hydrogen atom
  • an optionally branched (C C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 4 )- alkynyl group a cycloalkyl group, an aryl or a heterocycle, an optionally substituted aryl- (C C 4 )-alkyl or heterocyclil-(C C )-alkyl group, a cyano-(C C 4 )-alkyl group, a formyl-(C ⁇ - C 4 )-alkyl or formyl-(C ⁇ -C )-alkenyl group, a carboxy-(C ⁇ -C 4
  • Z is a methylene group
  • R ! is a hydrogen atom, an optionally branched (C ⁇ -C 5 )-alkyl, (C 2 -C 5 )- alkenyl or (C 2 -C 4 )-alkynyl group, an aryl selected between phenyl or indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole, an optionally substituted aryl-(C ⁇ -C 3 )-alkyl or heterocyclil-(C ⁇ -C 3 )-alkyl group, a cyano-(C ⁇ -C 3 )-alkyl group, a formyl-(C ⁇ -C 3 )-alkyl or formyl-(C ⁇ -C 3 )-alkenyl group
  • Ri is a hydrogen atom, an optionally branched (C ⁇ -C 5 )-alkyl, (C 2 -C 5 )-alkenyl or (C 2 -C )-alkynyl group, an indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, pyridine, pyrimidine and triazole, a benzyl or an optionally substituted furanyl-methyl, imidazolyl-methyl, pyridinyl-methyl, pyrimidinyl-methyl, dioxaneyl-ethyl, morpholinyl- propyl group, a cyano-(CrC 3 )-alkyl group, a formyl-(C ⁇ -C 3 )-alkyl group, a carboxy-(C C 3 )- alkyl group, an alkoxy-carbonyl-(C ⁇ -
  • R 3 is a hydrogen atom and A is a 5- or 6-membered aromatic heterocycle containing from one to three heteroatoms selected among nitrogen, oxygen and sulphur optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, a carboxyl group, an alkoxy- carbonyl group, an acyl group, alkyl-tio, alkyl-sulfonyl, amino, cyano, mercapto, nitro, hydroxy or halogen.
  • Z is a methylene group and A is an aromatic heterocycle selected among pyrrole, thiophene, furan, imidazole, thiazole, pyridine, pyrimidine and triazole optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, alkyl-tio, amino, cyano, nitro, hydroxy or halogen.
  • R is a ( - C )-alkyl group and A is a pyridine optionally substituted by one or more substituents selected among alkyl, alkoxy, alkyltio, amino, cyano, nitro, hydroxy or halogen.
  • R is a methyl group and A is a 3,5-Dichloro-pyridine.
  • R, R 3 and Z have the meanings defined in formula I
  • A is a 5 - or 6-membered aromatic heterocycle containing from one to three heteroatoms selected among nitrogen, oxygen and sulphur optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, a carboxyl group, an alkoxy-carbonyl group, an acyl group, alkyl-tio, alkyl-sulfonyl, amino, cyano, mercapto, nitro, hydroxy or halogen
  • Ri is a hydrogen atom, an optionally branched (C ⁇ -C 6 )-alkyl, (C 2 - C 6 )-alkenyl or (C 2 -C 4 )-alkynyl group, a cycloalkyl group, an aryl selected between phenyl or indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole
  • R, R 3 and Z have the meanings defined in formula I
  • A is an aromatic heterocycle selected among pyrrole, thiophene, furan, imidazole, thiazole, pyridine, pyrimidine and triazole optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, alkyltio, amino, cyano, nitro, hydroxy or halogen
  • Ri is a hydrogen atom, an optionally branched (C 1 -C 5 )- alkyl, (C 2 -C 5 )-alkenyl or (C 2 -C )-alkynyl group, an aryl selected between phenyl or indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, pyridine, pyrimidine and triazole, a benzyl group or an optionally substituted furanyl-methyl, imi
  • R is a ( - C 4 )-alkyl group and Z is a methylene group.
  • R is a ( - C 4 )-alkyl group and Z is a methylene group.
  • A is a pyridine optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, alkyltio, amino, cyano, nitro, hydroxy or halogen, R !
  • a hydrogen atom is a hydrogen atom, an optionally branched (C C 5 )-alkyl, (C 2 -C 5 )-alkenyl or (C 2 -C )-alkynyl group, an indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, pyridine, a benzyl group or a furanyl-methyl, pyridinyl-methyl dioxaneyl-ethyl, morpholinyl-propyl group optionally substituted by a cyano group, methoxy-carbonyl or methyl-tio, a cyano-(C ⁇ -C 3 )-alkyl group, a formyl-(C ⁇ -C 3 )-alkyl group, a carboxy-(C]-C 3 )-alkyl group, an alkoxy-carbonyl-(C ⁇ -C 3 )- alkyl group or an alkoxy
  • R, R 3 , Z and A have the meanings defined for the compounds of formula I; with reagents suitable to introduce a sulfonyl-amino group in the nitrogen (sp 3 ) atom of the dihydro-phthalazine nucleus.
  • dihydro-phtalazine derivatives of formula II wherein R 3 is different from a hydrogen atom are synthetized according to the synthetic scheme described in the International patent application WO 00/05219 in the name of Zambon Group S.p.A.
  • the preparation of the compounds of formula I proceeds by utilizing arts known to the person skilled in the art and it may follow alternative synthetic ways.
  • the functionalization of the dihydro-phthalazine nucleus is carried out by reacting the compounds of formula II in presence of a base such as, for example, triethylamine and an organic solvent, such as, for example methylene chloride, with the compound of formula
  • R t has the meanings defined for the compounds of formula I; obtained by treating chloro-sulfonyl-isocyanate with specific alcohols in presence of an organic solvent such as, for example, methylene chloride to give the compounds of formula
  • R, R 3 , R t , Z and A have the meanings defined previously for the compounds of formula I.
  • the compounds of formula III are prepared in situ.
  • the compounds of formula la are utilized as substrates to obtain the additional functionalization of the sulfonamide nitrogen atom in particular the alkylation which is carried out according to conventional methods, for example, by reaction with a halogen- derivative in presence of TBD-methyl (7-methyl-l,5,7-triaza-bicycle-[4,4,0]-dec-5-ene) polystyrene in dichloromethane/DMF to give the compounds of formula
  • R, Ri, R 3 , R t , Z and A have the meanings defined previously for the compounds of formula
  • the compounds of formula lb wherein Ri is a carboxy-alkyl or carboxy-alkenyl group are obtained from the corresponding alkoxy-carbonyl-alkyl or alkenyl derivatives, by a selective hydrolysis reaction of the ester bond belonging to the substituent itself.
  • t he alkylation o f t he s ulfonamide n itrogen o f t he c ompounds o f formula I a wherein R t is a t-butyl group is performed by the Mitsunobu reaction, carried out by mixing the compounds mentioned above, diisopropylazadicarboxylate, triphenylphosphine supported on polystyrene and specific alcohols in presence of an organic solvent such as, for example, methylene chloride.
  • the compounds of formula lb wherein R ! is an optionally branched (C C 6 )-alkyl group, an aryl, an optionally substituted aryl-(C ⁇ -C )-alkyl or heterocyclil-(C ⁇ -C 4 )-alkyl group are prepared.
  • R, R R 3 , Z and A have the meanings defined previously for the the compounds of formula I are obtained.
  • the urethanee group of the compounds of formula lb wherein the substituent R t is a t-butyl group is hydrolized, for example, by treatment with Dichloromethane /TFA at room temperature for few hours.
  • the compounds of formula Ic wherein Rj is a carboxy-alkyl or carboxy-alkenyl group are obtained from the corresponding alkoxy-carbonyl-alkyl or alkenyl derivatives, through a hydrolysis reaction carried out according to conventional methods, for example, by treatment at room temperature for few hours of the phtalazine derivatives dissolved in dioxane with LiOH dissolved in water.
  • the compounds of formula Ic can be further functionalized to the sulfonamide nitrogen in particular alkylated according to conventional methods, for example by reaction with a halogen-derivative in presence of TBD-methyl polystyrene as previously described to give the corresponding compounds of formula I.
  • the compounds of formula I wherein Ri and R 2 are alkyl groups are prepared according to conventional methods as well as, for example, the introduction of the dimethylamino sulfonyl group is carried out through the reaction of the compounds of formula II in presence of a base such as, for example, triethylamine with the dimethyl- amino-sulfonyl chloride reagent in presence of an organic solvent, such as for example DMF.
  • the synthesis of the N-oxidized compounds of formula I takes place by treatment with peracids such as, for example, m-chloroperbenzoic acid.
  • peracids such as, for example, m-chloroperbenzoic acid.
  • the preparation of the salts of the compounds of formula I is carried out according to conventional methods.
  • the compounds of formula I are PDE 4-inhibitors as it results from the enzymatic inhibition tests (Example 83) and moreover some thereof are able to inhibit the TNF ⁇ release (Example 84). Furthermore, the inhibition activity of the compounds of the present invention is highly selective with regard to this particular group of isoenzymes group, PDE 4, belonging to the phosphodiesterase family.
  • the therapeutical dosage is generally comprised between about 0.1 and 1,000 mg a day and between about 1 and 200 mg by oral route for a single administration.
  • the therapeutically effective quantities will depend upon age and general physiological conditions of the patient, upon the administration route and upon the utilized pharmaceutical composition.
  • an additional object of the present invention is the pharmaceutical compositions comprising a therapeutically effective amount of compound of formula I or of a salt thereof in admixture with a pharmaceutically acceptable carrier.
  • compositions object of the present invention could be liquid, suitable for oral and/or parenteral administration such as, for example, drops, syrups, solutions, injectable solutions ready for use or prepared by diluting a lyophilized and solid or half-solid such as tablets, capsules, granulates, powders, pellets, ovules, suppositories, creams, pomades, gels, ointments; or still solutions, suspensions, emulsions or other forms suitable for oral administration by inhalatory and transdermic route.
  • a lyophilized and solid or half-solid such as tablets, capsules, granulates, powders, pellets, ovules, suppositories, creams, pomades, gels, ointments; or still solutions, suspensions, emulsions or other forms suitable for oral administration by inhalatory and transdermic route.
  • compositions apart from a therapeutically effective amount of one (or more) compounds of formula I, they will comprise solid or liquid or diluent excipients for p harmaceutical u se a nd i n c ase o ther a dditives, usually u tilized for the preparation o f pharmaceutical compositions, such as addensants, aggregants, lubricants, disgregants, aromatized and dyeing agents.
  • compositions object of the invention can be produced according to usual techniques.
  • the compound 2 is synthetized, acting analogously to what described for the compound 1, by using benzyl alcohol (228 ⁇ l).
  • the crude is recrystallized from ethanol.
  • a white solid is obtained (900 mg, yield: 93%).
  • the compound 4 is synthetized, acting analogously to what described for the compound 1, by using t-butyl alcohol (206 ⁇ l).
  • the crude is recrystallized from ethanol.
  • a white solid is obtained (680 mg, yield: 80%).
  • the compound 5 is synthetized, acting analogously to what described for the compound 1, by using cyclohexyl alcohol (220 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (190 mg, yield: 20%).
  • the compound 6 is synthetized, acting analogously to what described for the compound 1, by using isopropyl alcohol (132 mg).
  • the crude is recrystallized from ethanol.
  • a white solid is obtained (860 mg, yield: 95%).
  • the compound 10 is synthetized, acting analogously to what described for the compound 9, by u sing p entan- 1 -olo ( 17 ⁇ 1). T he c rude i s p urified t hrough H PLC p reparation. A w hite solid is obtained (7.4 mg, yield: 16%).
  • the compound 11 is synthetized, acting analogously to what described for the compound 9, by using isopropanol (12 ⁇ l).
  • the crude is purified through HPLC preparation. A white solid is obtained (3.5 mg, yield: 8%).
  • the compound 12 is synthetized, acting analogously to what described for the compound 9, by using pyridin-3-il-methanol (15 ⁇ l).
  • the crude is purified through HPLC preparation. A white solid is obtained (2.6 mg, yield: 5 %).
  • the compound 13 is synthetized, acting analogously to what described for the compound 9, by using indan-2-ol (20 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (8.7 mg, yield: 17%).
  • the compound 14 is synthetized, acting analogously to what described for the compound 9, by using (4-methyltio-phenyl)-methanol (23 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (10.4 mg, yield: 20%).
  • the compound 15 is synthetized, acting analogously to what described for the compound 9, by using 4-hydroxymethyl-methyl benzoate (25 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (12 mg, yield: 22%).
  • the compound 16 is synthetized, acting analogously to what described for the compound 9, by using furan-3-il-methanol (13 ⁇ l).
  • the crude is purified through HPLC preparation. A white solid is obtained (6.6 mg, yield: 13%).
  • the compound 19 is synthetized, acting analogously to what described for the compound 17, by using the compound 1 (49 mg) and iodomethane (17 mg). The crude is purified through
  • the compound 20 is synthetized, acting analogously to what described for the compound 17, by using the compound 1 (49 mg) and 4-bromo-butyronitrile (18 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (9.5 mg, yield: 18%). Rt: 8.59 min.
  • Example 23 Synthesis of 4-(3 ,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(isopropoxycarbonyl- cvanomethyl-amino-sulfonyl)-L2-dihvdro-phthalazine (compound 23).
  • the compound 23 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) andbromo-acetonitrile (15 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (5 mg, yield: 9%). Rt: 9.14 min.
  • the compound 26 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and bromomethyl cyclopropane (17 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (3.5 mg, yield: 7%). Rt: 9.78 min.
  • the compound 28 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and l-bromo-but-2-ino (16 mg). The crude is purified through HPLC preparation. A white solid is obtained (8 mg, 15% yield).
  • the compound 32 is synthetized, acting analogously to what described for the compound 17, by using the compound 1 (49 mg) and 2-(2-bromo-ethyl)-[l,3]dioxane (23.4 mg). The crude is purified through HPLC preparation. A white solid is obtained (6 mg, yield: 10%). Rt: 9.89 min. [M+H] + 587 Example 33
  • the compound 34 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and iodomethane (17 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (11 mg, yield: 22%).
  • the compound 35 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and 4-bromomethyl-benzonitrile (23.5 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (4.5 mg, yield: 7%).
  • the compound 36 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and 2-(2-bromo-ethyl)-[l,3]dioxane (23.4 mg). The crude is purified through HPLC preparation. A white solid is obtained (5.5 mg, yield: 9%). Rt: 9.06 min. [M+H] + 602
  • Example 37
  • the compound 38 is synthetized, acting analogously to what described for the compound 17, by using the compound 2 (54 mg) and iodomethane (17 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (6 mg, yield: 10%). Rt: 9.36 min. [M+H] + 549
  • Example 39 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-P3enzyloxycarbonyl-(3- methoxycarbonyl-allyl)-amino-sulfonyl]-l ,2-dihydro-phthalazine (compound 39).
  • the compound 39 is synthetized, acting analogously to what described for the compound 17, by using the compound 2 (54 mg) and 4-bromo-but-2-methyl enoate (22 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (14 mg, yield: 22%). Rt: 9.53 min. [M+H] + 634
  • the compound 40 is synthetized, acting analogously to what described for the compound 17, by using the compound 2 (54 mg) and 2-bromo-ethyl ester of acetic acid (20 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (4 mg, yield: 6%).
  • the compound 41 is synthetized, acting analogously to what described for the compound 17, by using the compound 2 (54 mg) and l-bromo-but-2-ino (16 mg).
  • the crude is purified through HPLC preparation. A white solid is obtained (16 mg, yield: 27%).
  • the compound 47 is synthetized, acting analogously to what described for the compound 43, by using the compound 2 (534 mg) and 4-bromo-ter-butyl butyrate (268 mg).
  • Example 48 Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-P-ienzyloxycarbonyl-(3- carboxy-propylVaimno-sulfonyll-l ,2-dihvdro-phthalazine (compound 48 .
  • Example 49 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[methoxycarbonyl-(3-tert- butoxycarboxy-propyl)-armno-sulfonyri-l ,2-dihydro-phthalazine (compound 49).
  • the compound 49 is synthetized, acting analogously to what described for the compound 43, by using the compound 3 (458 mg) and 4-bromo-ter-butyl butyrate (268 mg).
  • the purification on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (349 mg, yield: 58%). Rt: 6.48 min.
  • the compound 54 is synthetized, acting analogously to what described for the compound 43, by using the compound 4 (500 mg) and bromo-ethyl acetate (183 mg). The purification on
  • the compound 54 (573 mg) is dissolved in DCM/TFA 7% (10 ml) is stirred at room temperature for 15 hours. The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5. The compound 55 as white solid is obtained (380 mg, yield: 78%).
  • the compound 53 (614 mg) is dissolved in DCM/TFA 7% (10 ml) is stirred at room temperature for 15 hours. The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 56 as white solid is obtained (367 mg, yield: 80%).
  • the compound 57 is synthetized, analogously to what described for the compound 43, by using the compound 6 (486 mg) and bromo-tert-butyl butyrate (268 mg). The purification on
  • the compound 59 is synthetized, acting analogously to what described for the compound 43, by using the compound 4 (500 mg) and 2-(2-bromo-ethyl)-[l,3]dioxane (234 mg).
  • the compound 68 is synthetized, acting analogously to what described for the compound 43, by using the compound 45 (501 mg) and bromo-3 -methyl-butane (181 mg).
  • Dimethylamino sulfonyl chloride (45 mg, 1.1 eq) dissolved in DMF (1 ml) is dropped into a solution of the compound 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-l,2-dydro- phthalazine (100 mg), prepared according to what described in the International patent application WO 00/05218 Example 22 on page 26, and triethylamine (89 ⁇ l, 2 eq) in DMF (3 ml) at 0°C. The reaction is stirred at room temperature for the night. Water (2 ml) is added.
  • Pd/C 500 mg is added to a solution of the compound 4-chloro-l-(3,5-Dichloro- pyridin-4-il-methyl)-6-methoxy-phthalazine (4.2 g, 0.012 mol), prepared according to what described in the International patent application WO 00/05218 Example 45 on page 35, and ammonium formate (7.4 g, 10 eq) in MeOH (100 ml). The mixture is stirred at 70°C for 8 hours. The catalyst is then filtered. Water (30 ml) is added to the residue and the product is extracted with DCM (3 x 20 ml).
  • Benzyl alcohol (130 mg, 2.2 mmoles, 1.2 eq) is added under nitrogen to a solution of chlorosulfonyl isocyanate (192 ⁇ l, 2.2 mmoles, 1.2 eq) in methylene chloride (5 ml).
  • the solution is left under stirring at room temperature for 40 minutes then it is slowly added at 0°C to a suspension of intermediate 1 (251 mg, 1 mmoles) and triethylamine (2.4 ml, 2.4 mmoles, 1.3 eq) in methylene chloride (7 ml). After 2 hours at room temperature water (4 ml) is added and it is extracted with methylene chloride (2 x 10 ml).
  • the compound 74 is synthetized, acting analogously to what described for the compound 73, by using ethyl alcohol (60 ⁇ l).
  • the crude is recrystallized from ethanol.
  • a yellow solid is obtained (178 mg, yield: 44%).
  • Example 76 Synthesis of 7-Methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l ,2- dihvdro-phthalazine (compound75).
  • the compound 75 is synthetized, acting analogously to what described for the compound 73, by using isopropyl alcohol (80 ⁇ l).
  • the crude is purified on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5.
  • a pale yellow solid is obtained (83 mg, yield:
  • the compound 80 is synthetized, acting analogously to what described for the compound 17, by using the compound 75 (42 mg) and 2-bromo-ethyl ester of the acetic acid (21 mg).
  • the crude is purified through HPLC preparation. A yellow solid is obtained (2.4 mg, yield: 5%).
  • the compound 81 is synthetized, acting analogously to what described for the compound 17, by using the compound 75 (42 mg) and bromo-acetonitrile (15 mg). The crude is purified through HPLC preparation. A yellow solid is obtained (1.8 mg, yield: 4%).
  • PDE 4 enzyme was isolated from the U-937 cell line by using the Nielson method and others (J. Allergy Clin. Immunol. 1990, 86, page 801-807) partially modified for the FPLC (Fast
  • the U-937 cell line (Istituto Zooprofilatticosperimentale, Brescia, Italia) was kept in RPMI incubation medium, with a 10% bovine fetal serum and 2 mM glutamine, at a cell density comprised between lxlO 6 and 8xl0 6 cells per ml in an incubator at 37°C with 5% CO 2 .
  • the U-937 suspension was homogenized in a buffer containing 10 mM TRIS, 5 mM MgCl 2 ,
  • the homogenate was centrifugated and the surnatant was used for the PDE 4 enzyme purification; it was seeded on a columnn connected to a low pressure liquid chromatography system (FPLC, BIO RAD).
  • FPLC low pressure liquid chromatography system
  • the PDE 4 enzyme was eluted with a linear gradient, from 0.05 M to 1 M sodium acetate, and the eluted fractions were tested to check the PDE 4 enzyme activity.
  • fractions containing the PDE 4 enzyme activity were collected and, after one whole- night long dialysis against water to remove the sodium acetate, they were concentrated at a
  • PDE 4 enzyme (lOx solution: 500 mM TRIS/HC1 pH 7.5, 83 mM MgCl 2 and 17mM EGTA) and a suspension of SPA beads containing 18 mM zinc sulfate.
  • the radioactivity linked to the particles was measured by using a ⁇ -counter (Packard model MINAXI) ⁇ TRI-CARB 4000 SERIES).
  • the blood samples obtained from healthy volunteers were collected in heparinized test tubes and they were diluted 1 :5 with RPMI 1640 without adding serum.
  • test was carried out in 96-well plates and containing the samples 150 ⁇ l of diluted blood and 120 ⁇ l of RPMI 1640 with control carrier or with different concentrations of the products of the present invention were incubated at 37°C in an atmosphere humidified by 5% with CO 2 for 30 minutes.
  • the final dilution of the whole blood in the assay is 1 : 10 (v/v).
  • the samples were stimulated with LPS (E. coli lipopolysaccharide: serotype B
  • test subjects were dissolved in DMSO 10 "2 M and further diluted in RPMI 1640 incubation medium.
  • the DMSO final concentration does not exceed 0.1% and does not affect the TNF ⁇ release.
  • the inhibition percentage of the TNF ⁇ production was calculated at each concentration and
  • IC 50 was calculated by a four-parameter logistic equation (ORIGIN calculation programme, MICROCAL SOFTWARE INC.).
  • the compounds of formula I of the present invention resulted to inhibit the TNF ⁇ release.

Abstract

Compounds of formula (I) wherein Z, A, R, R1, R2, R3 have the meanings defined in the specification, the N-oxidized derivatives of the compounds of formula (I), the pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising them and the use thereof as phosphodiesterase 4 inhibitors for the treatment of allergic and inflammatory pathologies, such as, for example, ARDS, COPD, asthma and allergic rhinitis are described.

Description

4-SUBSTITUTED 7-ALK0XY-2-AMIN0SULF0NYL-1, 2-DIHYDRO-PHTALAZIN DERIVATIVES AS PHOSPHODIESTERASE 4 INHIBITORS FOR THE TREATMENT OF ALLERGIES AND INFLAMMATIONS
********************************* The present invention relates to dihydro-phthalazine derivatives, pharmaceutical compositions comprising them and the use thereof as phosphodiesterase 4 inhibitors. 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 demonstrated to be the second messenger mediating the biologic response to many among 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 which turns Mg2+-ATP into cAMP. cAMP modulates the activity of the majority, if not of all, of the cells contributing to the pathophysiology of various respiratory diseases of allergic origin and not. It follows that a huge increase in cAMP levels 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 granulation, inhibition of the monocyte and macrophage activation. Thus, compounds capable of activating adenylate cyclase or of inhibiting phosphodiesterases could be able to suppress the imdesired activation of the airway smooth muscle and of a great number of inflammatory cells. In the phosphodiesterase family there is a particular group of isoen-zymes, phosphodiesterases 4 (hereinafter PDE 4), specific for the hydrolysis of cAMP in the airway smooth muscle and inflammatory cells (Torphy, "Phosphodiesterase Isoenzymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd, 1989). Studies carried out on this enzyme show that its inhibition yields not only airway smooth muscle relaxation, but also suppression of mastocyte, basophil and neutrophil granulation, as well as inhibition of the monocyte and neutrophil activation. Therefore, PDE 4 inhibitors are effective in the therapy of asthma. The PDE 4 selective inhibition weakens the functionality of inflammatory cells, such as, for example, neutrophils, alveolar macrophages and T cells having, as it is known, a key role in the COPD (chronic obstructive pulmonary disease) and such activity emphasizes how this class of compounds can provide an effective therapy for this kind of pathology (Douglas WP Hay, Curr. Opin. Chem. Biol., 2000, 4, page 412-419).
Thus, such compounds offer a unique approach to the therapy of various respiratory diseases, both of allergic origin and not, and have potential significant therapeutic advantages with respect to the current therapy.
The excessive or irregular production of the tumor necrosis factor (hereinafter TNFα), a cytokine with pro-inflammatory activity produced by various kinds 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 disease.
Therefore, compounds able to control the negative effects of TNFα, that is the inhibitors of this cytokine, are to be considered useful in many pathologies.
The Menational patent application WO 00/05218 (in the name of Zambon Group S.p.A.) claims, among other things, the compounds of formula
Figure imgf000003_0001
wherein the bond between the carbon atom thereto the R2 substituent is bound and the adjacent nitrogen atom is single and Ri is a (Cι-C4)-alkylsulfonyl group; these compounds are active as PDE 4 and TNFα release inhibitors.
The International patent application WO 00/05219 (in the name of Zambon Group S.p.A.) claims, among other things, the compounds of formula
Figure imgf000003_0002
where the bond between the carbon atom thereto the R substituent is bound and the adjacent nitrogen atom is single and R3 is a ( -C^-alkylsulfonyl group; these compounds are active as PDE 4 and TNFα release inhibitors.
Surprisingly, we have now found a new class of dihydro-phtalazine derivatives able to inhibit selectively the PDE 4 enzyme.
The additional polarity introduced in the molecules by the sulfonamide group has allowed obtaining both compounds with chemical physical features, such as hydrosolubility, which can be managed in a much easier way from the formulative point of view, and checking in pharmaceutically acceptable carriers the bioavailability of the compounds object of the present invention.
Furthermore, these new dihydro-phtalazine derivatives are stable to enzymatic chemical hydrolysis and, consequently, they are not quickly inactivated metabolically.
Therefore, object of the present invention are the compounds of formula
Figure imgf000004_0001
wherein
Z is a methylene, mono or di-fluoro-methylene group or a -NH- group.
A i s a p henyl g roup or a 5 - o r 6 -membered a romatic h eterocycle c ontaining from o ne t o three heteroatoms selected among nitrogen, oxygen and sulphur optionally substituted by one or more sustituent(s) selected among alkyl, alkoxy, a carboxyl group, an alkoxy- carbonyl group, an acyl group, alkyltio, alkyl-sulfonyl, amino, a N-acetylamino group, a N- methansulfonyl-amino group, cyano, mercapto, nitro, oxydryl or halogen.
R is a (Cι-C )-alkyl group or a mono or poly-fluoro-(Cι-C )-alkyl group;
Ri is a hydrogen atom, an optionally branched (Cι-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)- alkynyl group, a cycloalkyl group, an optionally substituted aryl or heterocycle, an optionally substituted aryl-(Cι-C4)-alkyl or heterocyclil-(Cι-C )-alkyl group, a cyano-(Cι-C6)-alkyl group, a formyl-(Cι-C6)-alkyl or formyl-(Cι-C6)-alkenyl group, a carboxy-(Cι-C6)-alkyl group or a carboxy-(C1-C6)-alkenyl group, an alkoxy-carbonyl-(Cι-C6)-alkyl group or an alkoxy-carbonyl-(Cι-C6)-alkenyl group, a cycloalkyl-^t-C^-alkyl group or an acyloxy-(C C )-alkyl group;
R2 has the same meanings of Ri and moreover it is a-CO-O-Rt group wherein i is an optionally branched (Cι-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group, a cycloalkyl group, an optionally substituted aryl or heterocycle, an optionally substituted aryl-(Cι-C4)- alkyl or heterocyclil-(Cι-C4)-alkyl group;
R3 is a hydrogen atom or a -O-R group wherein R has the meanings defined above; the N-oxidized derivatives of the compounds of formula I and pharmaceutically acceptable salts thereof.
The compounds of formula I are active as PDE 4 inhibitors and therefore they are utilized as therapeutic agents in allergic and inflammatory pathologies, such as, for example, ARDS, COPD, asthma and allergic rhinitis. Specific examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t- butyl, n-pentyl, 1 -methyl-butyl, 2-etyl-propyl, 3-methyl-butyl, 3-methyl-2-butyl, n-hexyl, heptyl, octyl and the likes. Under cycloalkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl are meant. Under halogen, a fluorine, chlorine, bromine or iodine atom is meant. Whereas aryl and aryl-(Cι-C )-alkyl designate a monocyclic or multicyclic aromatic system constituted by 6-10 carbon atoms such as, for example, phenyl, benzyl, phenethyl, phenyl-pentyl, naphtyl, naphtyl-methyl, indanyl, indanyl-pentyl and the likes.
Under the term 5- or 6-membered aromatic heterocycle containing from one to three heretoatoms selected among nitrogen, oxygen and sulphur, aromatic heterocycles such a s pyrrole, thiophene, fiiran, imidazole, pyrazole, thiazole, isothiazole, isoxazole, oxazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole and thiadiazole are meant.
Under the term heterocycle existing in the meanings of Ri and R2, in particular pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyperazine, triazine, morpholine, pyrrolidine, pyrroline, imidazoline, pyrazoline, pyrazolidine, imidazolidine, piperidine, furan, pyran, dioxane, thiophene, thiazole, isothiazole, isoxazole, oxazole, triazole and thiadiazole and the likes are meant. The substituents optionally present on the aryl or heterocycle groups in the meanings of Ri and R2 are a cyl, alkyl, alkoxy, alkoxy-carbonyl, alkyltio, alkyl-sulfonyl, amino, carboxyl, cyano, mercapto, nitro, oxyάryle, oxo and halogen under which term a fluorine, chlorine, bromine or iodine atom is meant.
Under the term acyloxy, in the acyloxy-(C C4)-alkyl substituents, a H-CO-O- or alkyl-CO- O- group is meant, wherein the alkyl group preferably contains from one to four carbon atoms such as, for example, a formyl, acetyl propanoyl, 2-methyl-propanoyl, butanoyl and palmitoyl group. The N-oxidized form, if present, may regard both the nitrogen atoms existing on the phtalazine ring and the ones present on the hererocyclic rings, in particular the nitrogen atom present on the pyridine ring.
The compounds of formula I may have one or more asymmetric centres and therefore they may be in the form of stereoisomers. The object of the present invention are the compounds of formula I in the form of stereoisomeric mixtures as well as single stereoisomers.
Examples of pharmaceutically acceptable salts of the compounds of formula I are salts with organic or inorganic acids such as, for example, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, tartaric, citric, benzoic, maleic, fumaric, succinic and glutaric acid or they are the salts with the alkaline, alkaline-earthy metals, the zinc salts and the salts with the pharmaceutically acceptable organic bases such as, for example, trometamol (2-amino-2-hydroxymethyl-propan- 1,3 -diol), N-methyl glucamine. The preferred compounds of formula I are the ones wherein R, Ri, R2, R3 and A have the meanings defined in formula I and Z is a methylene group or mono or di-fluoro-methylene. Within this group the compounds are much more preferred wherein R3 is a hydrogen atom, i is a hydrogen atom, an optionally branched (C C6)-alkyl, (C2-C6)-alkenyl or (C2-C4)- alkynyl group, a cycloalkyl group, an aryl or a heterocycle, an optionally substituted aryl- (C C4)-alkyl or heterocyclil-(C C )-alkyl group, a cyano-(C C4)-alkyl group, a formyl-(Cι- C4)-alkyl or formyl-(Cι-C )-alkenyl group, a carboxy-(Cι-C4)-alkyl group or a carboxy-(Cι- C4)-alkenyl group, an alkoxy-carbonyl-(Cι-C )-alkyl group or an alkoxy-carbonyl-(Cι-C4)- alkenyl group, a cycloalkyl-(Cι-C4)-alkyl group or an acyloxy-(C C )-alkyl group and R2 has the same meanings of Ri and furthermore it is a -CO-O-R-t group wherein Rt is an optionally branched (C C6)-alkyl, (C2-C )-alkenyl or (C2-C )-alkynyl group, a cycloalkyl group, an aryl or a heterocycle, an optionally substituted aryl-(Cι-C4)-alkyl or heterocyclil- (Cι-C4)-alkyl group;
Belonging to this group, and much more preferred, are the compounds wherein Z is a methylene group, R! is a hydrogen atom, an optionally branched (Cι-C5)-alkyl, (C2-C5)- alkenyl or (C2-C4)-alkynyl group, an aryl selected between phenyl or indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole, an optionally substituted aryl-(Cι-C3)-alkyl or heterocyclil-(Cι-C3)-alkyl group, a cyano-(Cι-C3)-alkyl group, a formyl-(Cι-C3)-alkyl or formyl-(Cι-C3)-alkenyl group, a carboxy-(Cι-C3)-alkyl group or a carboxy-(Cι-C3)-alkenyl group, an alkoxy-carbonyl-(Cι-C3)-alkyl group or an alkoxy-carbonyl-(Cι-C3)-alkenyl group, a cycloalkyl-(Cι-C3)-alkyl group or an acyloxy-(Cι-C3)-alkyl group and R2 has the same meanings of Rj and furthermore it is a -CO-O-R/t group wherein R is an optionally branched (Cι-C )-alkyl group, a cycloalkyl group, an aryl-(Cι-C )-alkyl group or a heterocyclil-(Cι-C4)-alkyl group;
Belonging to this group, and much more preferred, are the compounds wherein Ri is a hydrogen atom, an optionally branched (Cι-C5)-alkyl, (C2-C5)-alkenyl or (C2-C )-alkynyl group, an indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, pyridine, pyrimidine and triazole, a benzyl or an optionally substituted furanyl-methyl, imidazolyl-methyl, pyridinyl-methyl, pyrimidinyl-methyl, dioxaneyl-ethyl, morpholinyl- propyl group, a cyano-(CrC3)-alkyl group, a formyl-(Cι-C3)-alkyl group, a carboxy-(C C3)- alkyl group, an alkoxy-carbonyl-(Cι-C3)-alkyl group or an alkoxy-carbonyl-(Cι-C3)-alkenyl group, a cyclopropyl-(Cι-C3)-alkyl group, a formyloxy-(C C3)-alkyl group or acetyloxy-(Cι- C3)-alkyl group and R2 has the same meanings of Ri and furthermore it is a -CO-O-Rt group wherein R* is an optionally branched (Cι-C )-alkyl group, a cycloalkyl group, a benzyl group or a pyridinyl-methyl group; Belonging to this group, and much more preferred, are the compounds wherein R is a (C C )-alkyl group, Ri is a hydrogen atom, an optionally branched (C C5)-alkyl, (C2-C5)- alkenyl or (C2-C )-alkynyl group, an indanyl or a furan, a benzyl group or a furanyl-methyl, dioxaneyl-ethyl, morpholinyl-propyl group optionally substituted by a cyano group, metoxy- carbonyl or methyl-tio, a cyano-(C C3)-alkyl group, a formyl-(Cι-C3)-alkyl group, a carboxy-(Cι-C3)-alkyl group, an alkoxy-carbonyl-(C C3)-alkyl group or an alkoxy-carbonyl- (Cι-C3)-alkenyl group, a cyclopropyl-methyl group or an acetyloxy-(C!-C3)-alkyl group and R2 has the same meanings of Ri and furthermore it is a -CO-O-R4 group wherein j is an optionally branched (Cι-C4)-alkyl group, a cyclohexyl group, a benzyl group or a pyridinyl- methyl group; Belonging to this group, and much more preferred, are the compounds wherein R is a methyl, Ri is a hydrogen atom or a carboxy-(Cι-C3)-alkyl group and R2 has the same meanings of Ri and furthermore it is a -CO-O-Rt group wherein t is a benzyl group. Belonging to the class of the compounds of formula I wherein Z is a methylene or mono or di-fluoro-methylene group are furthermore preferred the compounds wherein R3 is a hydrogen atom and A is a 5- or 6-membered aromatic heterocycle containing from one to three heteroatoms selected among nitrogen, oxygen and sulphur optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, a carboxyl group, an alkoxy- carbonyl group, an acyl group, alkyl-tio, alkyl-sulfonyl, amino, cyano, mercapto, nitro, hydroxy or halogen. Belonging to this group, and much more preferred, are the compounds wherein Z is a methylene group and A is an aromatic heterocycle selected among pyrrole, thiophene, furan, imidazole, thiazole, pyridine, pyrimidine and triazole optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, alkyl-tio, amino, cyano, nitro, hydroxy or halogen. Belonging to this group, and much more preferred, are the compounds wherein R is a ( - C )-alkyl group and A is a pyridine optionally substituted by one or more substituents selected among alkyl, alkoxy, alkyltio, amino, cyano, nitro, hydroxy or halogen. Belonging to this group, and much more preferred, are the compounds wherein R is a methyl group and A is a 3,5-Dichloro-pyridine. An additional class of preferred compounds is the one wherein R, R3 and Z have the meanings defined in formula I, A is a 5 - or 6-membered aromatic heterocycle containing from one to three heteroatoms selected among nitrogen, oxygen and sulphur optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, a carboxyl group, an alkoxy-carbonyl group, an acyl group, alkyl-tio, alkyl-sulfonyl, amino, cyano, mercapto, nitro, hydroxy or halogen, Ri is a hydrogen atom, an optionally branched (Cι-C6)-alkyl, (C2- C6)-alkenyl or (C2-C4)-alkynyl group, a cycloalkyl group, an aryl selected between phenyl or indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole, an optionally substituted aryl-(Cι- C )-alkyl or heterocyclil-(C C4)-alkyl group, a cyano-(CrC4)-alkyl group, a formyl-(C C4)- alkyl or formyl-(Cι-C4)-alkenyl group, a carboxy-(Cι-C4)-alkyl group or a carboxy-(Cι-C4)- alkenyl group, an alkoxy-carbonyl-(Cι-C4)-alkyl group or an alkoxy-carbonyH - )- alkenyl group, a cycloalkyl-(CrC )-alkyl group or an acyloxy-(Cι-C4)-alkyl group and R2 has the same meanings of Ri and furthermore it is a -CO-O-Rt group wherein R, is an optionally branched (Cι-C )-alkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl group, a cycloalkyl group, an aryl or a heterocycle, an optionally substituted aryl-(Cι-C )-alkyl or heterocyclil- (C C )-alkyl group;
Belonging to this group, and much more preferred, are the compounds wherein R, R3 and Z have the meanings defined in formula I, A is an aromatic heterocycle selected among pyrrole, thiophene, furan, imidazole, thiazole, pyridine, pyrimidine and triazole optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, alkyltio, amino, cyano, nitro, hydroxy or halogen, Ri is a hydrogen atom, an optionally branched (C1-C5)- alkyl, (C2-C5)-alkenyl or (C2-C )-alkynyl group, an aryl selected between phenyl or indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, pyridine, pyrimidine and triazole, a benzyl group or an optionally substituted furanyl-methyl, imidazolyl-methyl, pyridinyl-methyl, pyrimidinyl-methyl, dioxaneyl-ethyl, morpholinyl-propyl group, a cyano- (Cι-C3)-alkyl group, a formyl-(Cι-C3)-alkyl group, a carboxy-(Cι-C3)-alkyl group, an alkoxy-carbonyl-(Cι-C3)-alkyl group or an alkoxy-carbonyl-(Cι-C3)-alkenyl group, a cyclopropyl-(C C3)-alkyl group or an acetyloxy-(Cι-C3)-alkyl group and R2 has the same meanings of Ri and furthermore it is a -CO-O-Rt group wherein t is an optionally branched (Cι-C4)-alkyl group, a cycloalkyl group, an aryl-(Cι-C4)-alkyl group or a heterocyclil-(Cι-C4)-alkyl group;
Belonging to this group, and much more preferred, are the compounds wherein Z is methylene or mono or di-fluoro-methylene group.
Belonging to this group, and much more preferred, are the compounds wherein R3 is a hydrogen atom.
Belonging to this group, and much more preferred, are the compounds wherein R is a ( - C4)-alkyl group and Z is a methylene group. Belonging to this group, and much more preferred, are the compounds wherein A is a pyridine optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, alkyltio, amino, cyano, nitro, hydroxy or halogen, R! is a hydrogen atom, an optionally branched (C C5)-alkyl, (C2-C5)-alkenyl or (C2-C )-alkynyl group, an indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, pyridine, a benzyl group or a furanyl-methyl, pyridinyl-methyl dioxaneyl-ethyl, morpholinyl-propyl group optionally substituted by a cyano group, methoxy-carbonyl or methyl-tio, a cyano-(Cι-C3)-alkyl group, a formyl-(Cι-C3)-alkyl group, a carboxy-(C]-C3)-alkyl group, an alkoxy-carbonyl-(Cι-C3)- alkyl group or an alkoxy-carbonyl-(Cι-C3)-alkenyl group, a cyclopropyl-methyl group or an acetyloxy-(Cι-C3)-alkyl group and R2 has the same meanings of Ri and furthermore it is a — CO-O-Rt group wherein Rt is an optionally branched (C C4)-alkyl group, a cyclohexyl group, a benzyl group or a pyridinyl-methyl group;
Belonging to this group, and much more preferred, are the compounds wherein A is a 3,5- Dichloro-pyridine R! is a hydrogen atom or a carboxy-(Cι-C3)-alkyl group and R2 has the same meanings of Ri and furthermore it is a -CO-O-Rt group wherein Rt is a benzyl group. Belonging to this group, and much more preferred, are the compounds wherein R is a methyl.
Specific examples of compounds object of the invention are:
4-(3 ,5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(ethoxycarbonyl-amino-sulfonyl)- 1 ,2- dihydro-phthalazine; 4-(3 ,5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(benzyloxycarbonyl-amino-sulfonyl)- 1,2- dihydro-phthalazine;
4-(3,5-Dichloro-pvridin-4-il-methyl)-7-methoxy-2-(memoxycarbonyl-amino-sulfonyl)-l,2- dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(tert-butyloxycarbonyl-amino-sulfonyl)-
1 ,2-dihydro-phthalazine;
4- ,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(cyclohexyloxycarbonyl-amino-sulfonyl)-
1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)- 1,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(pyridin-3-il-methoxycarbonyl)-amino- sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl amide;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl butylamide; 4-(3,5-Dichloro-pvridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl pentylamide;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl isopropylamide;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl (pyridin-2-il- methyl)-amide;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl indan-2-il- amide;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl (4-tiomethyl)- benzylamide;
4-{[4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonylamino]- methyl} -methyl benzoate; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl (fiιran-3-il- methyl)-amide;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(ethoxycarbonyl-cyanomethyl-amino- sulfonyl)- 1 ,2-dihydro-phthalazine;
4-(3 ,5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(ethoxycarbonyl-furan-3 -il-amino- sulfonyl)- 1 ,2-dihydro-phthalazine; 4-(3,5-Dichloro-pvridin-4-il-methyl)-7-methoxy-2-(ethoxycarbonyl-methyl-amino-sulfonyl)-
1 ,2-dihydro-phthalazine;
4-(3 ,5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[ethoxycarbonyl-(3 -cyano-propyl)amino- sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[ethoxycarbonyl-(3-methoxycarbonyl- allyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[ethoxycarbonyl-(3-methyl-but-2-enyl)- amino-sulfonyl] - 1 ,2-dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(isopropoxycarbonyl-cyanomethyl- amino-sulfonyl)- 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[isopropoxycarbonyl-(3-cyano-propyl)- amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[isopropoxycarbonyl-(3- methoxycarbonyl-allyl)-amino-sulfonyl]-l,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(isopropoxycarbonyl-cyclopropylmethyl- amino-sulfonyl)- 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[isopropoxycarbonyl-(2-acetoxy-ethyl)- amino-sulfonyl] - 1 ,2-dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[isopropoxycarbonyl-(but-2-inyl)-amino- sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[isopropoxycarbonyl-(3-methyl-but-2- enyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(ethoxycarbonyl-cyclopropylmethyl- amino-sulfonyl)- 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[ethoxycarbonyl-(4-cyano-benzyl)- amino-sulfonyl]-l,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[ethoxycarbonyl-(2-[l,3]dioxane-2-il- ethyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[ethoxycarbonyl-(but-2-inyl)-amino- sulfonyl- 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pvridin-4-il-methyl)-7-methoxy-2-(isopropoxycarbonyl-methyl-amino- sulfonyl)- 1 ,2-dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[isopropoxycarbonyl-(4-cyano-benzyl)- amino-sulfonyl]-l,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[isopropoxycarbonyl-(2-[l,3]dioxane-2- il-ethyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(isopropoxycarbonyl-cyanomethyl- amino-sulfonyl)- 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(ben..^loxycarbonyl-methyl-amino- sulfonyl)- 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[benzyloxycarbonyl-(3-methoxycarbonyl- allyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[benzyloxycarbonyl-(2-acetoxy-ethyl)- amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-P3enzyloxycarbonyl-(but-2-inyl)-amino- sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[benzyloxycarbonyl-(3-methyl-but-2- enyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[tert-butoxycarbonyl-(3-tert- butoxycarbonyl-propyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3 ,5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[tert-butoxycarbonyl-(3 - methoxycarbonyl-propyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-methoxycarbonyl-propyl)-amino- sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3 ,5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3 -carboxy-propyl)-amino-sulfonyl] - 1 ,2- dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[benzyloxycarbonyl-(3-tert- butoxycarboxy-propyl)-amino-sulfonyl]-l,2-dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[benzyloxycarbonyl-(3-carboxy-propyl)- amino-sulfonyl]-l,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[methoxycarbonyl-(3-tert-butoxycarboxy- propyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[methoxycarbonyl-(3-carboxy-propyl)- amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[benzyloxycarbonyl-(3-tert- butoxycarbonyl-methyl)-amino-sulfonyl]-l,2-dihydro-phthalazine; 4-(3 ,5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[benzyloxycarbonyl-(3 -carboxymethyl)- amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[tert-butoxycarbonyl-(3-tert- butoxycarbonyl-methyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[tert-butoxycarbonyl-(3- methoxycarbonyl-methyl)-arnino-sulfonyl]-l,2-dihydro-phthalazine;
4-(3 ,5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3 -methoxycarbonyl-methyl)-amino- sulfonyl]-l,2-dihydro-phthalazine;
4-(3 ,5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3 -carboxy-propyl)-amino-sulfonyl]- 1 ,2- dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[isopropoxycarbonyl-(3-tert- butoxycarboxy-propyl)-amino-sulfonyl]-l,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[isopropoxycarbonyl-(3-carboxy-propyl)- amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[tert-butoxycarbonyl-(2-[l,3]Dioxane-2- il-ethyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-propyloxy)-amino-sulfonyl]-l,2- dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-morpholine-4-il-propyl)-amino- sulfonyl]- 1 ,2-dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(carboxymethyl-methyl-amino-sulfonyl)- 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(methoxycarbonylmethyl-methyl-amino- sulfonyl)- 1 ,2-dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-methoxycarbonyl-propyl)-methyl- amino-sulfonyl]-l,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-carboxy-propyl)-methyl-amino- sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[methoxycarbonylmethyl-(3-methyl- butyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[carboxymethyl-(3-methyl-butil)-amino- sulfonyl]-l,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-methoxycarbonyl-propyl)-(3-methyl- butyl)-amino-sulfonyl] - 1 ,2-dihydro-phthalazine; 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-carboxy-propyl)-(3-methyl-butyl)- amino-sulfonyl]-l,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-methoxycarbonyl-propyl)-ethyl- amino-sulfonyl]-l,2-dihydro-phthalazine;
4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-carboxy-propyl)-ethyl-amino- sulfonyl] - 1 ,2-dihydro-phthalazine;
4-(3 J5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(di-methyl-amino-sulfonyl)- 1 ,2-dihydro- phthalazine;
7-methoxy-2-(benzyloxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l,2-dihydro- phthalazine; 7-methoxy-2-(ethoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl- 1 ,2-dihydro- phthalazine;
7-methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l,2-dihydro- phthalazine;
7-methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l,2-dihydro- phthalazine; 7-methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l,2-dihydro- phthalazine;
7-methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l,2-dihydro- phthalazine;
7-methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l,2-dihydro- phthalazine;
7-methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l,2-dihydro- phthalazine; 7-methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl- 1 ,2-dihydro- phthalazine;
The compounds of formula I, object of the present invention, are prepared by treatment of compounds of formula
Figure imgf000016_0001
wherein R, R3, Z and A have the meanings defined for the compounds of formula I; with reagents suitable to introduce a sulfonyl-amino group in the nitrogen (sp3) atom of the dihydro-phthalazine nucleus.
The dihydro-phtalazine derivatives of formula II wherein R3 is a hydrogen atom are synthetized according to the synthetic scheme described in the International patent application WO 00/05218 in the name of Zambon Group S.p.A.
The dihydro-phtalazine derivatives of formula II wherein R3 is different from a hydrogen atom are synthetized according to the synthetic scheme described in the International patent application WO 00/05219 in the name of Zambon Group S.p.A.
The preparation of the compounds of formula I proceeds by utilizing arts known to the person skilled in the art and it may follow alternative synthetic ways. Generally, the functionalization of the dihydro-phthalazine nucleus is carried out by reacting the compounds of formula II in presence of a base such as, for example, triethylamine and an organic solvent, such as, for example methylene chloride, with the compound of formula
Figure imgf000017_0001
wherein
Rt has the meanings defined for the compounds of formula I; obtained by treating chloro-sulfonyl-isocyanate with specific alcohols in presence of an organic solvent such as, for example, methylene chloride to give the compounds of formula
Figure imgf000017_0002
wherein R, R3, Rt, Z and A have the meanings defined previously for the compounds of formula I. Preferably, the compounds of formula III are prepared in situ.
From the compounds of formula la, preferably from the ones wherein R( is a t-butyl group, by a hydrolysis reaction performed according to conventional methods the compounds of formula I wherein Ri = R2 = H, object of the present invention, are obtained. Alternatively, the compounds of formula I wherein Ri = R2 = H are obtained, according to known arts, by direct reaction of the compounds of formula II with the chloride of the sulfonamide acid.
The compounds of formula la are utilized as substrates to obtain the additional functionalization of the sulfonamide nitrogen atom in particular the alkylation which is carried out according to conventional methods, for example, by reaction with a halogen- derivative in presence of TBD-methyl (7-methyl-l,5,7-triaza-bicycle-[4,4,0]-dec-5-ene) polystyrene in dichloromethane/DMF to give the compounds of formula
Figure imgf000018_0001
wherein
R, Ri, R3, Rt, Z and A have the meanings defined previously for the compounds of formula
I.
The compounds of formula lb wherein Ri is a carboxy-alkyl or carboxy-alkenyl group are obtained from the corresponding alkoxy-carbonyl-alkyl or alkenyl derivatives, by a selective hydrolysis reaction of the ester bond belonging to the substituent itself.
Generally derivatives of formula lb wherein R! is a t-butoxy-carbonyl-alkyl or alkenyl group are utilized and one proceeds, for example, in treating the same with dichloromethane/TFA at room temperature for few hours.
Alternatively, t he alkylation o f t he s ulfonamide n itrogen o f t he c ompounds o f formula I a wherein Rt is a t-butyl group is performed by the Mitsunobu reaction, carried out by mixing the compounds mentioned above, diisopropylazadicarboxylate, triphenylphosphine supported on polystyrene and specific alcohols in presence of an organic solvent such as, for example, methylene chloride.
Preferably, by the Mitsunobu reaction the compounds of formula lb wherein R! is an optionally branched (C C6)-alkyl group, an aryl, an optionally substituted aryl-(Cι-C )-alkyl or heterocyclil-(Cι-C4)-alkyl group are prepared.
From the compounds of formula lb by hydrolysis of the urethane group thereto the substituent Rt is linked, carried out according to conventional methods, the compounds of formula
Figure imgf000019_0001
wherein
R, R R3, Z and A have the meanings defined previously for the the compounds of formula I are obtained. In particular, the urethanee group of the compounds of formula lb wherein the substituent Rt is a t-butyl group is hydrolized, for example, by treatment with Dichloromethane /TFA at room temperature for few hours.
The compounds of formula Ic wherein Rj is a carboxy-alkyl or carboxy-alkenyl group are obtained from the corresponding alkoxy-carbonyl-alkyl or alkenyl derivatives, through a hydrolysis reaction carried out according to conventional methods, for example, by treatment at room temperature for few hours of the phtalazine derivatives dissolved in dioxane with LiOH dissolved in water.
Alternatively, one proceeds in the treatment of the compounds of formula lb wherein the substituent t is a t-butyl group and Ri is a t-butoxy-carbonyl-alkyl or alkenyl group with Dichloromethane/TFA at room temperature for few hours .
The compounds of formula Ic, in turn, can be further functionalized to the sulfonamide nitrogen in particular alkylated according to conventional methods, for example by reaction with a halogen-derivative in presence of TBD-methyl polystyrene as previously described to give the corresponding compounds of formula I. Alternatively, the compounds of formula I wherein Ri and R2 are alkyl groups are prepared according to conventional methods as well as, for example, the introduction of the dimethylamino sulfonyl group is carried out through the reaction of the compounds of formula II in presence of a base such as, for example, triethylamine with the dimethyl- amino-sulfonyl chloride reagent in presence of an organic solvent, such as for example DMF.
The synthesis of the N-oxidized compounds of formula I takes place by treatment with peracids such as, for example, m-chloroperbenzoic acid. The preparation of the salts of the compounds of formula I is carried out according to conventional methods.
The compounds of formula I are PDE 4-inhibitors as it results from the enzymatic inhibition tests (Example 83) and moreover some thereof are able to inhibit the TNFα release (Example 84). Furthermore, the inhibition activity of the compounds of the present invention is highly selective with regard to this particular group of isoenzymes group, PDE 4, belonging to the phosphodiesterase family.
It is apparent how these selectivity and enzymatic specificity features joined with the lack of activity on the cardiovascular system make the compounds of formula I particularly suitable for the treatment of pathologies involving PDE 4 and TNFα such as asthma, COPD, ARDS, allergic rhinoconjunctivitis, psoriasis, atopic dermatitis, rheumatoid arthritis, septic shock, ulcer colitis, even if in the present context the interest is particularly focalized on the respiration pathologies. In particular the compounds of the invention are useful for the treatment of allergic and inflammatory disorders and above all in the therapy of ARDS, COPD, asthma and allergic rhinitis.
The therapeutical dosage is generally comprised between about 0.1 and 1,000 mg a day and between about 1 and 200 mg by oral route for a single administration. The therapeutically effective quantities will depend upon age and general physiological conditions of the patient, upon the administration route and upon the utilized pharmaceutical composition.
The compounds of the present invention to be used in the therapy and/or prophylaxis of the pathologies mentioned above will be preferably utilized in a pharmaceutical form suitable for oral, rectal, sublingual, parental, topic, transdermic and inhalatory administration. Therefore, an additional object of the present invention is the pharmaceutical compositions comprising a therapeutically effective amount of compound of formula I or of a salt thereof in admixture with a pharmaceutically acceptable carrier.
The pharmaceutical compositions object of the present invention could be liquid, suitable for oral and/or parenteral administration such as, for example, drops, syrups, solutions, injectable solutions ready for use or prepared by diluting a lyophilized and solid or half-solid such as tablets, capsules, granulates, powders, pellets, ovules, suppositories, creams, pomades, gels, ointments; or still solutions, suspensions, emulsions or other forms suitable for oral administration by inhalatory and transdermic route.
According to the type of composition, apart from a therapeutically effective amount of one (or more) compounds of formula I, they will comprise solid or liquid or diluent excipients for p harmaceutical u se a nd i n c ase o ther a dditives, usually u tilized for the preparation o f pharmaceutical compositions, such as addensants, aggregants, lubricants, disgregants, aromatized and dyeing agents.
The pharmaceutical compositions object of the invention can be produced according to usual techniques.
In order to better illustrate the invention, the following examples are now provided.
The 'H-NMR spectra have been stored in solution of CDC13 or d6-DMSO with a Varian
Gemini 200 MHz spectrometer. The chemical shifts are defined as δ with CDC13 or d6-
DMSO as inner standard. The HPLC/MS analyses are stored with a Gilson instrument by utilizing a C18 Zorbax
SBC 18 column (3.5 μm, 2.1 x 50 mm) coupled to a UN detector (220 nm) and a Finnigan
Aqa mass spectrometer (electron spray, positive ionization). Conditions utilized for the analyses: flow: lmL/min; column temperature: 40°C; A/B eluition gradient (eluent A: 0.5% formic acid in water; eluent B: 0.5% formic acid in acetonitrile): t = 0 min., A/B = 95:5, t = 8 min., A/B = 5:95. Example 1
Synthesis of 4-(3 ,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(ethoxycarbonyl-amino- sulfonyl)-1.2-dihvdro-phthalazine (compound 1)
Ethyl alcohol (100 μl, 2.2 mmoles, 1.2 eq) is added under nitrogen to a solution of chlorosulfonyl isocyanate (192 μl, 2.2 mmoles, 1.2 eq) in methylene chloride (5 ml). The solution is left under stirring at room temperature for 40 minutes, then is slowly added at 0°C to a suspension of the 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-l,2-dihydro- phthalazine (600 mg, 1.86 mmoles) compound, prepared according to what described in the International p atent application WO 00/05218 E xample 22 o n p age 26, a nd t riethylamine
(2.4 ml, 2.4 mmoles, 1.3 eq) in methylene chloride (7 ml). After 2 hours at room temperature water (4 m 1) i s a dded a nd e xtracted w ith m ethylene c hloride ( 2 x 10 m 1) . T he s olvent is brought to dryness and the crude is recrystallized from ethanol. The compound 1 is obtained as a white solid (825 mg, yield: 94%). Rt: 5.77 min.
[M+H]+ 472
NMR DMSO_d6: 11.64 (s-broad, 1H, NH); 8.58 (s, 2H, Py); 7.68 (d, 1H, JHH=8.5 Hz,
*CH=CH-C-OMe); 7.07 (d, 1H, JHH=2.4 Hz, C=*CH-C); 7.00 (dd, 1H, CH=*CH-C-OMe);
4.71 (s, 2H, CHN); 4.33 (s, 2H, *CH2-Py); 4.05 (q, JHH=7.3 Hz, 2H, *CH2-CH3); 3.82 (s, 3H, OMe); 1.17 (t, 3H, *CH3-CH2). Example 2
Synthesis of 4-(3J-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(benzyloxycarbonyl-amino- sulfonyl)-! ,2-dihydro-phthalazine (compound 2)
The compound 2 is synthetized, acting analogously to what described for the compound 1, by using benzyl alcohol (228 μl). The crude is recrystallized from ethanol. A white solid is obtained (900 mg, yield: 93%).
Rt: 6.98 min.
[M+H]+ 535
NMR DMSO_d6: 11.81 (s-broad, 1H, NH); 8.54 (s, 2H, Py); 7.69 (d, 1H, JHH=8.4 Hz, *CH=CH-C-OMe); 7.42-7.29 (m, 5H, Ph); 7.05 (d, 1H, JHH=2.3 Hz, C=*CH-C); 7.00 (dd,
1H, CH=*CH-C-OMe); 5.08 (s, 2H, O-*CH2-Ph); 4.71 (s, 2H, CHN); 4.33 (s, 2H, *CH2-
Py); 3.83 (s, 3H, OMe). Example 3
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methylV7-methoxy-2-(methoxycarbonyl-amino- sulfonyl)- 1,2-dihvdro-phthalazine (compound 3) The compound 3 is synthetized, acting analogously to what described for the compound 1, by using methyl alcohol (90 μl). The crude is recrystallized from methanol. A white solid is obtained (680 mg, yield: 80%). Rt: 5.51 min.
[M+H]+ 459
NMR DMSO_d6: 11.70 (s-broad, 1H, NH); 8.59 (s, 2H, Py); 7.68 (d, 1H, JHH=8.3 Hz,
*CH=CH-C-OMe); 7.07 (d, 1H, JHH=2.6 Hz, C=*CH-C); 7.00 (dd, 1H, CH=*CH-C-OMe);
4.71 (s, 2H, CHN); 4.33 (s, 2H, *CH2-Py); 3.82 (s, 3H, OMe); 3.60 (s, 3H, CO-OMe). Example 4
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-rtert-butyloxycarbonyl- amino-sulfonyl)-1.2-dihvdro-ρhthalazine (compound 4)
The compound 4 is synthetized, acting analogously to what described for the compound 1, by using t-butyl alcohol (206 μl). The crude is recrystallized from ethanol. A white solid is obtained (680 mg, yield: 80%).
Rt: 6.65 min.
[M+H]+ 501
NMR CDC13: 10.51 (s-broad, 1H, NH); 8.31 (s, 2H, Py); 7.49 (d, 1H, JHH=8.5 Hz,
*CH=CH-C-OMe); 6.93 (dd, 1H, CH=*CH-C-OMe); 6.77 (d, 1H, JHH=2.6 Hz, C=*CH-C); 4.89 (s, 2H, CHN); 4.34 (s, 2H, *CH2-Py); 3.89 (s, 3H, OMe).1.53 (s, 9H, OtBu). Example 5
Synthesis of 4-(3-5-Dichloro-pyridm-4-il-methyl)-7-methoxy-2-(cvclohexyloxycarbonyl- amino-sulfonyl)-l,2-dihydro-phthalazine (compound 5).
The compound 5 is synthetized, acting analogously to what described for the compound 1, by using cyclohexyl alcohol (220 mg). The crude is purified through HPLC preparation. A white solid is obtained (190 mg, yield: 20%).
Rt: 6.78 min.
[M+H]+ 527 Example 6 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(isopropoχycarbonyl-amino- sulfonyl V1.2-dihvdro-phthalazine (compound 6).
The compound 6 is synthetized, acting analogously to what described for the compound 1, by using isopropyl alcohol (132 mg). The crude is recrystallized from ethanol. A white solid is obtained (860 mg, yield: 95%).
Rt: 10.38 min.
[M+H]+ 487
NMR DMSO_d6: 11.56 (s-broad, IH, NH); 8.58 (s, 2H, Py); 7.69 (d, IH, JHH=8.6 Hz,
*CH=CH-C-OMe); 7.07 (d, IH, JHH=2.2 Hz, C=*CH-C); 7.00 (dd, IH, CH=*CH-C-OMe); 4.83-4.70 (m, 3H, CHN, *CH(CH3)2); 4.35 (s, 2H, *CH2-Py); 3.83 (s, 3H, OMe); 1.19 (d,
6H, *CH3CH*CH3). Example 7
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-|"(pyridin-3-il- methoxycarbonyl)-amino-sulfonyll-l .2-dihvdro-phthalazine (compound 7). The compound 7 is synthetized, acting analogously to what described for the compound 1, by using pyridin-3-il-methanol (240 mg). The crude is purified through HPLC preparation. A white solid is obtained (180 mg, yield: 18%)
Rt: 4.08 min.
[M+H 536 Example 8
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl amide (compound 8).
A solution of compound 4 (20 mg, 0.04 mmoles) in methanol (2 ml) is added with HC1 1M in diethyl ether (1 ml). The reaction is stirred at room temperature for 15 hours, then the solvent is evaporated. The obtained crude is washed with diethyl ether obtaining the compound 8 as pale yellow solid (10 mg, yield: 62%).
Rt: 3.21 min.
[M+H]+ 401
NMR DMSO_d6: 8.57 (s, 2H, Py); 7.61 (d, IH, JHH=8.4 Hz, *CH=CH-C-OMe); 7.05 (d, IH, JHH=2.3 Hz, C=*CH-C); 6.97 (dd, IH, CH=*CH-C-OMe); 4.32 (s, 2H, *CH2-Py); 4.29 (s, 2H, CHN); 3.81 (s, 3H, OMe). Example 9
Synthesis of 4-r3.5-Dichloro-pyridin-4-il-methylV7-methoxy-lH-phthalazine-2-sulfonyl butylamide (compound 9).
A mixture of compound 4 (50 mg, 0.1 mmoleses), diisopropylazadicarboxylate (20 μl, 0.15 mmoleses, 1.5 eq), triphenylphosphine supported on polystyrene (130 mg, 0.15 mmoles, 1.5 eq), butan-1-olo ( 14 μl, 0.15 mmoles, 1 .5 eq) and methylene chloride (5 ml) is stirred at
35°C for 15 hours. The resin is filtered and washed with DCM (5 ml). The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridge eluting by
Cyclohexane/AcOEt 1:1.
The product is then dissolved in methanol (2 ml) and it is added with HC1 1M in diethyl ether (1 ml). The reaction mixture is stirred at room temperature for 15 hours and the solvent is brought to dryness. The residue is purified in HPLC preparation. The compound 9 as white solid is obtained (5.8 mg, yield: 13%).
Rt: 5.92 min.
[M+H]+ 457 Example 10
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl pentylamide (compound 10).
The compound 10 is synthetized, acting analogously to what described for the compound 9, by u sing p entan- 1 -olo ( 17 μ 1). T he c rude i s p urified t hrough H PLC p reparation. A w hite solid is obtained (7.4 mg, yield: 16%).
Rt: 6.28 min. [M+H]+ 471 Example 11
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl isopropylamide (compound 11).
The compound 11 is synthetized, acting analogously to what described for the compound 9, by using isopropanol (12 μl). The crude is purified through HPLC preparation. A white solid is obtained (3.5 mg, yield: 8%).
Rt: 5.48 min.
[M+H]+ 443 Example 12
Synthesis of 4- 3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl
(pyridin-2-il-methyl)-amide (compound 12).
The compound 12 is synthetized, acting analogously to what described for the compound 9, by using pyridin-3-il-methanol (15 μl). The crude is purified through HPLC preparation. A white solid is obtained (2.6 mg, yield: 5 %).
Rt: 3.82 min.
[M+H]+ 492 Example 13
Synthesis of 4-(3.5 -Dichloro-pyridin-4-il-methyl)-7-methoxy- lH-phthalazine-2-sulfonyl indan-2-il-amide (compound 13).
The compound 13 is synthetized, acting analogously to what described for the compound 9, by using indan-2-ol (20 mg). The crude is purified through HPLC preparation. A white solid is obtained (8.7 mg, yield: 17%).
Rt: 6.32 min. [M+H]+ 517 Example 14
Synthesis of 4 -(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl (4- tiomethvD-benzylamide (compound 14).
The compound 14 is synthetized, acting analogously to what described for the compound 9, by using (4-methyltio-phenyl)-methanol (23 mg). The crude is purified through HPLC preparation. A white solid is obtained (10.4 mg, yield: 20%).
Rt: 6.33 min.
[M+H]+ 537 Example 15 Synthesis of 4-{|"4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2- sulfonylaminol-methy - methyl benzoate (compound 15V
The compound 15 is synthetized, acting analogously to what described for the compound 9, by using 4-hydroxymethyl-methyl benzoate (25 mg). The crude is purified through HPLC preparation. A white solid is obtained (12 mg, yield: 22%).
Rt: 5.86 min.
[M+H]+ 549 Example 16
Synthesis of 4-("3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-lH-phthalazine-2-sulfonyl (furan-3-il-methyl)-amide (compound 16).
The compound 16 is synthetized, acting analogously to what described for the compound 9, by using furan-3-il-methanol (13 μl). The crude is purified through HPLC preparation. A white solid is obtained (6.6 mg, yield: 13%).
Rt: 5.57 min. [M+H]+ 481 Example 17
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(ethoxycarbonyl- cyanomethyl-amino-sulfonyl)- 1 ,2-dihydro-phthalazine (compound 17) .
A mixture of compound 1 (49 mg, 0.1 mmoles), bromo-acetonitrile (15 mg, 0.12 mmoles) and TBD-methyl polystyrene (50 mg, 0.14 mmoles) in DCM/DMF 1:2 (2 ml) is stirred at room temperature for 15 hours.
The resin is filtered and washed with DMF (1 ml). The solvent is evaporated and the residue solid is purified in HPLC preparation. The compound 17 as white solid is obtained (4 mg, yield: 8%). Rt: 8.72 min.
[M+H]+ 512 Example 18
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(ethoxycarbonyl-furan-3-il- amino-sulfonyl)- 2-dihvdro-phthalazine (compound 18). The compound 18 is synthetized, acting analogously to what described for the compound 17, by using the compound 1 (49 mg) and 3-bromo-furan (18 mg). The crude is purified through
HPLC preparation. A white solid is obtained (2 mg, yield: 4%).
Rt: 8.83 min. [M+H]+ 539 Example 19
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(ethoxycarbonyl-methyl- amino-sulfonyl)-1.2-dihvdro-phthalazine (compound 19).
The compound 19 is synthetized, acting analogously to what described for the compound 17, by using the compound 1 (49 mg) and iodomethane (17 mg). The crude is purified through
HPLC preparation. A white solid is obtained (8 mg, yield: 16%).
Rt: 8.77 min.
[M+H]+ 487 Example 20 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-rethoxycarbonyl-(3-cyano- propyl)amino-sulfonyl]-1.2-dihvdro-phthalazine (compound 20 .
The compound 20 is synthetized, acting analogously to what described for the compound 17, by using the compound 1 (49 mg) and 4-bromo-butyronitrile (18 mg). The crude is purified through HPLC preparation. A white solid is obtained (9.5 mg, yield: 18%). Rt: 8.59 min.
[M+H]+ 540 Example 21
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl')-7-methoxy-2-[ethoxycarbonyl-(3-
methoxycarbonyl-allyl -amino-sulfonyl]-l ,2-dihydro-phthalazine (compound 21). The compound 21 is synthetized, acting analogously to what described for the compound 17, by using the compound 1 (49 mg) and 4-bromo-but-2-methyl enoate (22 mg). The crude is purified through HPLC preparation. A white solid is obtained (6 mg, yield: 10%).
Rt: 9.11 min.
[M+H]+ 571 Example 22 Synthesis of 4-("3.5-Dichloro-pyridin-4-il-methylV7-methoxy-2-[ethoxycarbonyl-(3-methyl- but-2-enyl)-amino-sulfonyl]-1.2-dihvdro-phthalazine (compound 22). The compound 22 is synthetized, acting analogously to what described for the compound 17, by using the compound 1 (49 mg) and l-bromo-3-methyl-but-2-ene (18 mg). The crude is purified through HPLC preparation. A white solid is obtained (7 mg, yield: 13%). Rt: 9.79 min.
Figure imgf000029_0001
Example 23 Synthesis of 4-(3 ,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(isopropoxycarbonyl- cvanomethyl-amino-sulfonyl)-L2-dihvdro-phthalazine (compound 23). The compound 23 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) andbromo-acetonitrile (15 mg). The crude is purified through HPLC preparation. A white solid is obtained (5 mg, yield: 9%). Rt: 9.14 min. [M+H]+ 526 Example 24 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-|"isopropoxycarbonyl-(3- cvano-propyl)-amino-sulfonyl]- 2-dihydro-phthalazine (compound 24). The compound 24 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and 4-bromo-butyronitrile (18 mg). The crude is purified through HPLC preparation. A white solid is obtained (7.5 mg, yield: 13%). Rt: 9.02 min. [M+H]+ 554 Example 25
Synthesis of 4-(3,5-Dichloro-pyridm-4-il-methyl)-7-methoxy-2- isopropoxycarbonyl-(3- methoxycarbonyl-allyl)-amino-sulfonyl]-l,2-dihydro-phthalazine (compound 25). The compound 25 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and 4-bromo-but-2-methyl enoate (22 mg). The crude is purified through HPLC preparation. A white solid is obtained (6.5 mg, yield: 10%). Rt: 9.51 min.
[M+H]+ 585 Example 26 Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(isopropoxycarbonyl- cyclopropylmethyl-amino-sulfonyl)- 1 ,2-dihydro-phthalazine (compound 26) .
The compound 26 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and bromomethyl cyclopropane (17 mg). The crude is purified through HPLC preparation. A white solid is obtained (3.5 mg, yield: 7%). Rt: 9.78 min.
[M+H]+ 541 Example 27
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[isopropoxycarbonyl-(2- acethoxy-ethvD-amino-sulfonyll-l ,2-dihydro-phthalazine (compound 27). The compound 27 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and 2-bromo-ethyl ester of acetic acid (20 mg). The crude is purified through HPLC preparation. A white solid is obtained (4 mg, yield: 7%).
Rt: 8.82 min.
[M+H]+ 573 Example 28
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[isopropoxycarbonyl-(but-2- inyl)-amino-sulfonyl]-l,2-dihydro-phthalazine (compound 28).
The compound 28 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and l-bromo-but-2-ino (16 mg). The crude is purified through HPLC preparation. A white solid is obtained (8 mg, 15% yield).
Rt: 9.50 min.
[M+H]+ 539 Example 29
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-risopropoxycarbonyl-(3- methyl-but-2-enyl)-amino-sulfonyl]-l,2-dihvdro-phthalazine (compound 29). The compound 29 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and l-bromo-3-methyl-but-2-ene (18 mg). The crude is purified through HPLC preparation. A white solid is obtained (5.5 mg, yield: 10%). Rt: 9.85 min. [M+H]+ 555 Example 30
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(ethoxycarbonyl- cyclopropylmethyl-amino-sulfonyl)-l,2-dihvdro-phthalazme (compound30). The compound 30 is synthetized, acting analogously to what described for the compound 17, by using the compound 1 (49 mg) and bromomethyl cyclopropane (17 mg). The crude is purified through HPLC preparation. A white solid is obtained (3 mg, yield: 7%). Rt: 9.72 min. [M+H]+ 527 Example 31
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-|"ethoxycarbonyl-(4-cyano- benzyl)-amino-sulfonyl]-1.2-dihvdro-phthalazine (compound 31).
The compound 31 is synthetized, acting analogously to what described for the compound 17, by using the compound 1 (49 mg) and 4-bromomethyl-benzonitrile (23.5 mg). The crude is purified through HPLC preparation. A white solid is obtained (5mg, yield: 8.5%). Rt: 9.43 min. [M+H 588 Example 32 Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-|"ethoxycarbonyl-(2- |"1.3]dioxane-2-il-ethyl -amino-sulfonyll-1.2-dihvdro-phthalazine (compound 32).
The compound 32 is synthetized, acting analogously to what described for the compound 17, by using the compound 1 (49 mg) and 2-(2-bromo-ethyl)-[l,3]dioxane (23.4 mg). The crude is purified through HPLC preparation. A white solid is obtained (6 mg, yield: 10%). Rt: 9.89 min. [M+H]+ 587 Example 33
Synthesis of 4-(3.5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-['ethoxycarbonyl-(but-2- inyl)-amino-sulfonyl-1.2-dihvdro-phthalazine (compound 33). The compound 33 is synthetized, acting analogously to what described for the compound 17, by u sing t he c ompound 1 (49 m g) a nd 1 -bromo-but-2-ine ( 16 m g) . T he c rude is p urified through HPLC preparation. A white solid is obtained (3.5 mg, yield: 7%).
Rt: 9.38 min.
[M+H]+ 525 Example 34
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(isopropoxycarbonyl- methyl-amino-sulfonyl)-l,2-dihydro-phthalazine (compound 34)
The compound 34 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and iodomethane (17 mg). The crude is purified through HPLC preparation. A white solid is obtained (11 mg, yield: 22%).
Rt: 8.87 min.
[M+H]+ 501 Example 35
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-risopropoxycarbonyl-(4- cyano-benzvD-amino-sulfonyl] - 1 ,2-dihvdro-phthalazine (compound 35) .
The compound 35 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and 4-bromomethyl-benzonitrile (23.5 mg). The crude is purified through HPLC preparation. A white solid is obtained (4.5 mg, yield: 7%).
Rt: 9.75 min. [M+H]+ 603 Example 36
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-risopropoxycarbonyl-(2-
[1 ,3]dioxane-2-il-ethyl)-amino-sulfonyl]-l ,2-dihvdro-phthalazine (compound 36).
The compound 36 is synthetized, acting analogously to what described for the compound 17, by using the compound 6 (48 mg) and 2-(2-bromo-ethyl)-[l,3]dioxane (23.4 mg). The crude is purified through HPLC preparation. A white solid is obtained (5.5 mg, yield: 9%). Rt: 9.06 min. [M+H]+ 602 Example 37
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(isopropoxycarbonyl- cvanomethyl-amino-sulfonylVl,2-dihvdro-phthalazine (compound 37). The compound 37 is synthetized, acting analogously to what described for the compound 17, by u sing t he c ompound 2 (54 m g) a nd b romo-acetonitrile (15 m g). T he crude i s p urified through HPLC preparation. A white solid is obtained (8 mg, yield: 14%). Rt: 9.17 min. [M+H]+ 574 Example 38 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(benzyloxycarbonyl-methyl- amino-sulfonyl)-l,2-dihydro-phthalazine (compound 38).
The compound 38 is synthetized, acting analogously to what described for the compound 17, by using the compound 2 (54 mg) and iodomethane (17 mg). The crude is purified through HPLC preparation. A white solid is obtained (6 mg, yield: 10%). Rt: 9.36 min. [M+H]+ 549
NMR DMSO_d6: 8.57 (s, 2H, Py); 7.76 (d, IH, JHH=8.5 Hz, *CH=CH-C-OMe); 7.34 (s, 5H, Ph); 7.07-7.02 (m, 2H, C=*CH-C, CH=*CH-C-OMe); 5.20 (s, 2H, *CH2Ph); 4.67 (s, 2H, CHN); 4.35 (s, 2H, *CH2-Py); 3.84 (s, 3H, OMe); 2.62 (s, 3H, CH3N). Example 39 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-P3enzyloxycarbonyl-(3- methoxycarbonyl-allyl)-amino-sulfonyl]-l ,2-dihydro-phthalazine (compound 39). The compound 39 is synthetized, acting analogously to what described for the compound 17, by using the compound 2 (54 mg) and 4-bromo-but-2-methyl enoate (22 mg). The crude is purified through HPLC preparation. A white solid is obtained (14 mg, yield: 22%). Rt: 9.53 min. [M+H]+ 634
NMR DMSO_d6: 8.62 (s, 2H, Py); 7.77 (d, IH, JHH=8.6 Hz, *CH=CH-C-OMe); 7.33 (s,
5H, Ph); 7.08-7.02 (m, 2H, C=*CH-C, CH=*CH-C-OMe); 6.70 (dt, IH, JHH=15.5 Hz, 4.5 Hz, CH2-*CH=CH); 5.74 (d, 1 H, JHH=15.5 Hz, CH2-CH=*CH); 5.23 (s, 2H, * CH2Ph);
4.67 (s, 2H, CHN); 4.37 (s, 2H, *CH2-Py); 3.85 (s, 3H, OMe);; 3.73 (m, 2H, O*CH2); 3.67
(s, 3H, O*CH3). Example 40
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-rbenzyloxycarbonyl-(2- acethoxy-ethvD-amino-sulfonyll-l ,2-dihvdro-phthalazine (compound 40).
The compound 40 is synthetized, acting analogously to what described for the compound 17, by using the compound 2 (54 mg) and 2-bromo-ethyl ester of acetic acid (20 mg). The crude is purified through HPLC preparation. A white solid is obtained (4 mg, yield: 6%).
Rt: 10.20 min. [M+H]+ 622 Example 41
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2- benzyloxycarbonyl-(but-2- inyl)-amino-sulfonyl]-l,2-dihydro-phthalazine (compound 41).
The compound 41 is synthetized, acting analogously to what described for the compound 17, by using the compound 2 (54 mg) and l-bromo-but-2-ino (16 mg). The crude is purified through HPLC preparation. A white solid is obtained (16 mg, yield: 27%).
Rt: 9.80 min.
[M+H]+ 587 Example 42 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-p3enzyloxycarbonyl-(3- methyl-but-2-enyl)-ammo-sulfonyl]-l ,2-dihydro-phthalazine (compound 42).
The compound 42 is synthetized, acting analogously to what described for the compound 17, by using the compound 2 (54 mg) and l-bromo-3-methyl-but-2-ene (18 mg). The crude is purified through HPLC preparation. A white solid is obtained (9 mg, 15% yield). Rt: 10.56 min. [M+H]+ 604 Example 43 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[tert-butoxycarbonyl-(3-tert- butoxycarbonyl-propylVamino-sulfonyl1-l,2-dihvdro-phthalazine (compound 43).
A mixture of compound 4 (500 mg, 1 mmoles), 4-bromo-butyrate of ter-butyl (268 mg, 1.2 mmoles) and TBD-methyl polystyrene (500 mg, 1.4 mmoles) in DCM/DMF 1:3 (12 ml) is stirred at 35°C for 15 hours. The resin is filtered and washed with DCM (2 x 4 ml) and DMF (5 ml), then the solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5. The compound 43 as white solid is obtained (483 mg, yield: 75%). Rt: 4.25 min. [M+H]+ 645 Example 44 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-|"tert-butoxycarbonyl-(3- methoxycarbonyl-propyl -amino-sulfonyl]-l ,2-dihvdro-phthalazine (compound 44). The compound 44 is synthetized, acting analogously to what described for the compound 43, by using the compound 4 (500 mg) and 4-bromo-methyl butyrate (218 mg). The purification on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (494 mg, yield: 82%). Rt: 6.59 min. [M+H]+ 603 Example 45 Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-r(3-methoxycarbonyl- propyl)-amino-sulfonyl]-l,2-dihvdro-phthalazine (compound 45).
The compound 44 (602 mg, 1 mmoles) is dissolved in DCM/TFA 7% (10 ml) is stirred at room temperature for 15 hours. The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5. The compound 45 as white solid is obtained (450 mg, yield: 90%). Rt: 5.22 min. [M+H 502 Example 46 Synthesis of 4-(3.5-Dichloro-pyridm-4-il-methyl)-7-methoxy-2-r(3-carboxy-propyl)-amino- sulfonyl]-!, 2-dihydro-phthalazine (compound 46).
The compound 43 (644 mg) is dissolved in DCM/TFA 7% (10 ml) is stirred at room temperature for 15 hours. The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 46 as white solid is obtained (301 mg, yield: 62%). Alternatively, LiOH (1.2 mmoles) dissolved in water (2 ml) is added to a solution of compound 45 (501 mg) in dioxane (10 ml) and the mixture is stirred at room temperature for 15 hours. The organic solvent is evaporated, the residue is taken up with citric acid 5% aq (5 ml) and extracted with DCM (2 x 12 ml). The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 46 as white solid is obtained (321 mg, yield: 66%). Rt: 4.54 min. [M+H]+ 488
NMR DMSO_d6: 12.10 (s-broad, IH, OH); 8.61 (s, 2H, Py); 7.70 (d, IH, JHH=8.4 Hz, *CH=CH-C-OMe); 7.61 (t, IH, JHH=5.5Hz, NH); 7.08 (d, IH, JHH=2.4 Hz, C=*CH-C); 7.02 (dd, IH, CH=*CH-C-OMe); 4.34 (s, 2H, CHN); 4.30 (s, 2H, *CH2-Py); 3.84 (s, 3H, OMe); 2.55-2.44 (m, 2H, NH-*CH2-CH2-CH2); 2.10 (t, 2H, JHH=7.3Hz, NH-CH2-CH2- *CH2); 1.43 (m, 2H, CH2-*CH2-CH2). Example 47 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl -7-methoxy-2-P3enzyloxycarbonyl-(3-tert- butoxycarboxy-propyl)-amino-sulfonyl]-l ,2-dihydro-phthalazine (compound 47).
The compound 47 is synthetized, acting analogously to what described for the compound 43, by using the compound 2 (534 mg) and 4-bromo-ter-butyl butyrate (268 mg). The purification on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (406 mg, yield: 60%). Rt: 7.32 min. [M+H]+ 679 Example 48 Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-P-ienzyloxycarbonyl-(3- carboxy-propylVaimno-sulfonyll-l ,2-dihvdro-phthalazine (compound 48 .
The compound 47 (678 mg, lmmoles) is dissolved in DCM/TFA 7% (10 ml) is stirred at room temperature for 15 hours. The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 48 as white solid is obtained (423 mg, yield: 68%). Rt: 5.85 min. [M+H]+ 623
NMR CDC13: 8.44 (s, 2H, Py); 7.45 (d, IH, JHH=8.6 Hz, *CH=CH-C-OMe); 7.36 (s, 5H, Ph); 6.91 (dd, IH, CH=*CH-C-OMe); 6.64 (d, IH, JHH=2.4 Hz, C=*CH-C); 5.20 (s, 2H, *CH2Ph); 4.76 (s, 2H, CHN); 4.29 (s, 2H, *CH2-Py); 3.88 (s, 3H, OMe); 3.24 (m, 2H, NH- *CH2-CH2-CH2); 2.29 (t, 2H, JHH=7.3 Hz, NH-CH2-CH2-*CH2);1.77 (m, 2H, CH2- *CH2-CH2). Example 49 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[methoxycarbonyl-(3-tert- butoxycarboxy-propyl)-armno-sulfonyri-l ,2-dihydro-phthalazine (compound 49). The compound 49 is synthetized, acting analogously to what described for the compound 43, by using the compound 3 (458 mg) and 4-bromo-ter-butyl butyrate (268 mg). The purification on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (349 mg, yield: 58%). Rt: 6.48 min. [M+H]+ 603 Example 50 Synthesis of 4-(3,5-Dichloro-ρyridin-4-il-methyl)-7-methoxy-2-rmethoxycarbonyl-(3- carboxy-propyl)-amino-sulfonyl]-l ,2-dihydro-phthalazine (compound 50). The compound 49 (602 mg) is dissolved in DCM/TFA 7% (10 ml) is stirred at room temperature for 15 hours. The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 50 as white solid is obtained (338 mg, yield: 62%). Rt: 4.88 min. [M+H]+ 546
NMR CDC13: 8.52 (s, 2H, Py); 7.47 (d, IH, JHH=8.4 Hz, *CH=CH-C-OMe); 6.92 (dd, IH, CH=*CH-C-OMe); 6.75 (d, IH, JHH=2.5 Hz, C=*CH-C); 4.86 (s, 2H, CHN); 4.32 (s, 2H, *CH2-Py); 3.89 (s, 3H, OMe); 3.81 (s, 3H, OMe); 3.21 (m, 2H, NH-*CH2-CH2-CH2); 2.31 (t, 2H, JHH=7.3 Hz, NH-CH2-CH2-*CH2); 1.77 (m, 2H, CH2-*CH2-CH2). Example 51
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-rbenzyloxycarbonyl-(3-tert- butoxycarbonyl-methyl)-amino-sulfonyl]-l .2-dihvdro-phthalazine (compound 51). The compound 51 is synthetized, acting analogously to what described for the compound 43, by using the compound 2 (534 mg) and bromo-tert-butyl acetate (234 mg). The purification on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (406 mg, yield: 60%). Rt: 7.31 min. [M+H]+ 649 Example 52 Synthesis of 4-(3 ,5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[benzyloxycarbonyl-(3 - carboxymethvD-amino-sulfonyl]-! ,2-dihydro-phthalazine (compound 52 . The compound 51 (648 mg) is dissolved in DCM/TFA 7% (10 ml) is stirred at room temperature for 15 hours. The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 52 as white solid is obtained (302 mg, yield: 51%). Rt: 5.88 min. [M+H]+ 694
NMR DMSO_d6: 8.62 (s, 2H, Py); 7.76 (d, IH, JHH=8.8 Hz, *CH=CH-C-OMe); 7.32 (s, 5H, Ph); 7.07-7.00 (m, 2H, C=*CH-C, CH=*CH-C-OMe); 5.23 (s, 2H, *CH2Ph); 4.66 (s, 2H, CHN); 4.35 (s, 2H, *CH2-Py); 3.84 (s, 3H, OMe); 3.54 (s, 2H, N*CH2CO2H). Example 53
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[tert-butoxycarbonyl-(3-tert- butoxycarbonyl-methyl)-amino-sulfonyll-l ,2-dihvdro-phthalazine (compound 53 . The compound 53 is synthetized, acting analogously to what described for the compound 43, by using the compound 4 (500 mg) and bromo-tert-butyl acetate (234 mg). The purification on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (552 mg, yield: 90%).
Rt: 7.01 min. [M+H]+ 615 Example 54
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[tert-butoxycarbonyl-(3- methoxycarbonyl-methyl)-amino-sulfonyl]-l .2-dihydro-phthalazine (compound 54).
The compound 54 is synthetized, acting analogously to what described for the compound 43, by using the compound 4 (500 mg) and bromo-ethyl acetate (183 mg). The purification on
NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1 gave a white solid
(527 mg, yield: 92%).
Rt: 6.32 min.
[M+H]+ 574 Example 55
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-methoxycarbonyl- methyl)-amino-sulfonyl]-l,2-dihvdro-phthalazine (compound 55).
The compound 54 (573 mg) is dissolved in DCM/TFA 7% (10 ml) is stirred at room temperature for 15 hours. The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5. The compound 55 as white solid is obtained (380 mg, yield: 78%).
Rt: 4.90 min.
[M+H]+ 474 Example 56 Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methylV7-methoxy-2-r(3-carboxy-propyl)-amino- sulfonyl]-!, 2-dihydro-phthalazine (compound 56).
The compound 53 (614 mg) is dissolved in DCM/TFA 7% (10 ml) is stirred at room temperature for 15 hours. The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 56 as white solid is obtained (367 mg, yield: 80%).
Alternatively, LiOH (1.2 mmoles) dissolved in water (2 ml) is added to a solution of compound 55 (473 mg) in dioxane (10 ml) and the mixture is stirred at room temperature for
15 hours. The organic solvent is evaporated, the residue is taken up with citric acid 5% aq (5 ml) and extracted with DCM (2 x 12 ml). The solvent is evaporated and the crude is purified on NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound
56 as white solid is obtained (316 mg, yield: 69%).
Rt: 4.44 min.
[M+H]+ 460 NMR DMSO_d6: 8.60 (s, 2H, Py); 8.02 (t, IH, JHH=6.1 Hz, NH); 7.70 (d, IH, JHH=8.3
Hz, *CH=CH-C-OMe); 7.08 (d, IH, JHH=2.6 Hz, C=*CH-C); 7.01 (dd, IH, CH=*CH-C-
OMe); 4.33 (s, 2H, CHN); 4.32 (s, 2H, *CH2-Py); 3.83 (s, 3H, OMe); 3.15 (d, 2H, JHH=5.7
Hz, N*CH2C02H). Example 57 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-risopropoxycarbonyl-(3-tert- butoxycarboxy-propyl)-amino-sulfonyl]-l ,2-dihydro-phthalazine (compound 57).
The compound 57 is synthetized, analogously to what described for the compound 43, by using the compound 6 (486 mg) and bromo-tert-butyl butyrate (268 mg). The purification on
NARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (327 mg, yield: 52%).
Rt: 7.07 min.
[M+H]+ 631 Example 58
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methvπ-7-methoxy-2-|"isopropoxycarbonyl-(3- carboxy-propyl)-amino-sulfonyl]-l ,2-dihydro-phthalazine (compound 58). The compound 57 (630 mg) is dissolved in DCM/TFA 7% (10 ml) is stirred at room temperature for 15 hours. The solvent is evaporated and the crude is purified on VARIAN
BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 58 as white solid is obtained (429 mg, yield: 75%).
Rt: 5.38 min.
[M+H]+ 574
NMR CDC13: 8.52 (s, 2H, Py); 7.47 (d, IH, JHH=8.4 Hz, *CH=CH-C-OMe); 6.92 (dd, IH,
CH=*CH-C-OMe); 6.74 (d, IH, JHH=2.8 Hz,C=*CH-C); 4.98 (dq, IH, JHH=6.3 Hz, *CH(CH3)2); 4.88 (s, 2H, CHN); 4.32 (s, 2H, *CH2-Py); 3.89 (s, 3H, OMe); 3.22 (t, 2H,
JHH=7.0 Hz, NH-*CH2-CH2-CH2); 2.34 (t, 2H, JHH=6 HzNH-CH2-CH2-*CH2);1.75 (m,
2H, CH2-*CH2-CH2); 1.30 (d, 6H, *CH3-CH-*CH3). Example 59
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-rtert-butoxycarbonyl-(2- 1.31Dioxane-2-il-ethyl)-amino-sulfonyl]-l,2-dihydro-phthalazine (compound 59).
The compound 59 is synthetized, acting analogously to what described for the compound 43, by using the compound 4 (500 mg) and 2-(2-bromo-ethyl)-[l,3]dioxane (234 mg). The purification on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (338 mg, yield: 55%). Rt: 5.92 min.
[M+H]+ 616 Example 60
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-propyloxy)-amino- sulfonyl]-l,2-dihydro-phthalazine (compound 60). The compound 59 (338 mg) is dissolved in DCM/TFA 7% (10 ml) is stirred at room temperature for 15 hours. The solvent is evaporated and the crude is purified on VARIAN
BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 48 as white solid is obtained (175 mg, yield: 70%).
Rt: 4.03 min. [M+H]+ 457 Example 61 Synthesis of 4-(3,5-Dichloro-ρyridin-4-il-methyl)-7-methoxy-2- (3-morpholine-4-il-propyl)- amino-sulfonyl]-l,2-dihydro-phthalazine (compound 61). The morpholine (48 mg, 1.1 eq) is added to a solution of the compound 60 (20 mg) in DCM/AcOH 9:1 (1 ml) and the mixture is stirred at room temperature for 30 min, then olystirylmethyl)-trimethyl-ammonium-cyanoborohydride (12 mg, l .l eq) is added. After 30 min the resin is filtered and washed with DCM (2 x 1 ml). The solvent is evaporated and the crude is purified on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 61 as white solid is obtained (8 mg, yield: 30%). Rt: 3.51 min. [M+H]+ 528 Example 62 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(methoxycarbonylmethyl- methyl-amino-sulfonyl)-1.2-dihvdro-phthalazine (compound 62).
The compound 62 is synthetized, acting analogously to what described for the compound 43, by using the compound 55 (473 mg) and iodomethane (170 mg). The purification on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (267 mg, yield: 55%). Rt: 5.46 min. [M+H]+ 487 Example 63 Synthesis of 4-(3 ,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-(carboxymethyl-methyl- ammo-sulfonyl)-l,2-dihydro-phthalazine (compound 63). LiOH (1.2 mmoles) dissolved in water (2 ml) is added to a solution of the compound 62 (472 mg) in dioxane (10 ml) and the mixture is stirred at room temperature for 15 hours. The organic solvent is evaporated, the residue is taken up with citric acid 5% aq (5 ml) and extracted with DCM (2 x 12 ml). The solvent is evaporated and the crude is purified on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 63 as white solid is obtained (200 mg, yield: 43%). Rt: 4.84 min.
[M+H]+ 473
NMR DMSO_d6: 8.64 (s, 2H, Py); 7.74 (d, IH, JHH=8.6 Hz, *CH=CH-C-OMe); 7.08-7.01 (m, 2H, C=*CH-C, CH=*CH-C-OMe); 4.41 (s, 2H, CHN); 4.36 (s, 2H, *CH2-Py); 3.84 (s,
3H, OMe); 2.56 (s, 3H, NMe). Example 64
Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-methoxycarbonyl- propyl)-methyl-amino-sulfonyl1-l ,2-dihvdro-phthalazine (compound 64). The compound 64 is synthetized, acting analogously to what described for the compound 43, by using the compound 45 (501 mg) and iodomethane (170 mg). The purification on
VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid
(246 mg, yield: 48%).
Rt: 5.72 min. [M+H]+ 515 Example 65
Synthesis of 4-(3 ,5 -Dichloro-pyridin-4-il-methyl)-7-methoxy-2-r(3 -carboxy-propyD-methyl- amino-sulfonyl]-l,2-dihydro-phthalazine (compound 65).
LiOH (1.2 mmoles) dissolved in water (2 ml) is added to a solution of the compound 64 (514 mg) in dioxane (10 ml) and the mixture is stirred at room temperature for 15 hours. The organic solvent is evaporated, the residue is taken up with citric acid 5% aq (5 ml) and extracted with D CM (2 x 12 ml). The s olvent i s evaporated and the crude is purified on
VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 65 as white solid is obtained (235 mg, yield: 47%). Rt: 5.00 min.
[M+H]+ 501 Example 66
Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2- methoxycarbonylmethyl-(3- methyl-butyl)-amino-sulfonyl]-l ,2-dihvdro-phthalazine (compound 66). The compound 66 is synthetized, acting analogously to what described for the compound 43, by using the compound 55 (473 mg) and l-bromo-3 -methyl-butane (181 mg). The purification on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (336 mg, yield: 62%). Rt: 6.48 min. [M+H]+ 543 Example 67 Synthesis of 4-(3 ,5-Dichloro-ρyridin-4-il-methyl)-7-methoxy-2-[carboxymethyl-(3 -methyl- butyl)-amino-sulfonyl]-l,2-dihvdro-phthalazine (compound 67). LiOH (1.2 mmoles) dissolved in water (2 ml) is added to a solution of the compound 66 (542 mg) in dioxane (10 ml) and the mixture is stirred at room temperature for 15 hours. The organic solvent is evaporated, the residue is taken up with citric acid 5% aq (5 ml) and extracted with DCM (2 x 12 ml). The solvent is evaporated and the crude is purified on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 67 as white solid is obtained (211 mg, yield: 40%). Rt: 5.77 min. [M+H]+ 529 Example 68 Synthesis of 4-(3.5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2- (3-methoxycarbonyl- propyl)-(3-methyl-butyl)-amino-sulfonyl]-l ,2-dihydro-phthalazine (compound 68).
The compound 68 is synthetized, acting analogously to what described for the compound 43, by using the compound 45 (501 mg) and bromo-3 -methyl-butane (181 mg).The purification on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (3 ll mg, yield: 58%). Rt: 6.73 min. [M+H]+ 572 Example 69 Synthesis of 4-(3.5-Dichloro-pyridm-4-il-methyl)-7-methoxy-2-r(3-carboxy-propyl)-(3- methyl-butyl)-amino-sulfonyl]-l ,2-dihydro-phthalazine (compound 69). LiOH (1.2 mmoles) dissolved in water (2 ml) is added to a solution of the compound 68 (557 mg) in dioxane (10 ml) and the mixture is stirred at room temperature for 15 hours. The organic solvent is evaporated, the residue is taken up with citric acid 5% aq (5 ml) and extracted w ith D CM (2 x 12 ml). T he s olvent i s e vaporated a nd t he c rude is p urified o n VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 69 as white solid is obtained (345 mg, yield: 62%). Rt: 5.88 min. [M+H]+ 558 Example 70 Synthesis of 4-(3 ,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-|"(3 -methoxycarbonyl- propyl)-ethyl-amino-sulfonyl]-l ,2-dihydro-phthalazine (compound 70). The compound 70 is synthetized, acting analogously to what described for the compound 43, by using the compound 45 (501 mg) and bromo-3 -methyl-butane (181 mg).The purification on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave a white solid (380 mg, yield: 72%). Rt: 5.83 min. [M+H]+ 529 Example 71 Synthesis of 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-2-[(3-carboxy-ρropyl)-ethyl- atmno-sulfonyl]-l,2-dihvdro-phthalazine (compound 71).
LiOH (1.2 mmoles) dissolved in water (2 ml) is added to a solution of compound 70 (528 mg) in dioxane (10 ml) and the mixture is stirred at room temperature for 15 hours. The organic solvent is evaporated, the residue is taken up with citric acid 5% aq (5 ml) and extracted with D CM (2 x 12 ml). The s olvent i s evaporated and the crude is purified on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 9:1. The compound 71 as white solid is obtained (308 mg, yield: 60%). Rt: 5.77 min. [M+H]+ 515 Example 72 Synthesis of 4-(3,5-Dichloro-ρyridin-4-il-methyl)-7-methoxy-2-(di-methyl-amino-sulfonyl)- 1,2-dihvdro-phthalazine (compound 72).
Dimethylamino sulfonyl chloride (45 mg, 1.1 eq) dissolved in DMF (1 ml) is dropped into a solution of the compound 4-(3,5-Dichloro-pyridin-4-il-methyl)-7-methoxy-l,2-dydro- phthalazine (100 mg), prepared according to what described in the International patent application WO 00/05218 Example 22 on page 26, and triethylamine (89 μl, 2 eq) in DMF (3 ml) at 0°C. The reaction is stirred at room temperature for the night. Water (2 ml) is added. The precipitating solid is filtered and the purification on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5 gave the compound 72 as white solid (21 mg, yield: 16%). Rt: 5.51 min. [M+H]+ 429 Example 73 Synthesis of 7-methoxy-4-pyridin-4-il-methyl-l,2-dihydro-phthalazine (intermediate 1). 10%) Pd/C (500 mg) is added to a solution of the compound 4-chloro-l-(3,5-Dichloro- pyridin-4-il-methyl)-6-methoxy-phthalazine (4.2 g, 0.012 mol), prepared according to what described in the International patent application WO 00/05218 Example 45 on page 35, and ammonium formate (7.4 g, 10 eq) in MeOH (100 ml). The mixture is stirred at 70°C for 8 hours. The catalyst is then filtered. Water (30 ml) is added to the residue and the product is extracted with DCM (3 x 20 ml). The organic solvent is evaporated and the resulting solid is crumbled with EtOH/Et20 2:8 (20 ml). The intermediate 1 as white solid is obtained (2.4 g, yield: 79%). Rt: 4.12 min. [M+H]+ 252 Example 74
Synthesis of 7-Methoxy-2-(benzyloxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l ,2- dihvdro-phthalazine (compound 73).
Benzyl alcohol (130 mg, 2.2 mmoles, 1.2 eq) is added under nitrogen to a solution of chlorosulfonyl isocyanate (192 μl, 2.2 mmoles, 1.2 eq) in methylene chloride (5 ml). The solution is left under stirring at room temperature for 40 minutes then it is slowly added at 0°C to a suspension of intermediate 1 (251 mg, 1 mmoles) and triethylamine (2.4 ml, 2.4 mmoles, 1.3 eq) in methylene chloride (7 ml). After 2 hours at room temperature water (4 ml) is added and it is extracted with methylene chloride (2 x 10 ml). The solvent is brought to dryness and the crude is recrystallized from ethanol. A pale yellow solid is obtained (279 mg, yield: 60%). Rt: 3.63 min. [M+H]+467 Example 75 Synthesis of 7-Methoxy-2-(ethoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l ,2- dihvdro-phthalazine (compound 74).
The compound 74 is synthetized, acting analogously to what described for the compound 73, by using ethyl alcohol (60 μl). The crude is recrystallized from ethanol. A yellow solid is obtained (178 mg, yield: 44%). Rt: 2.77 min. [M+H]+ 404 Example 76 Synthesis of 7-Methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l ,2- dihvdro-phthalazine (compound75). The compound 75 is synthetized, acting analogously to what described for the compound 73, by using isopropyl alcohol (80 μl). The crude is purified on VARIAN BOND ELUT SI 5 g cartridges eluting with DCM/MeOH 95:5. A pale yellow solid is obtained (83 mg, yield:
Rt: 5.40 min. [M+H]+ 418 Example 77 Synthesis of 7-methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l ,2- dihydro-phthalazine (compound 76). The compound 76 is synthetized, acting analogously to what described for the compound 17, by using the compound 74 (40 mg) and l-bromo-3 -methyl-but-2-ene (18 mg). The crude is purified through HPLC preparation. A yellow solid is obtained (2.8 mg, yield: 6%). Rt: 6.42 min. [M+H]+ 473 Example 78
Synthesis of 7-methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl- 1 ,2- dihvdro-phthalazine (compound 77).
The compound 77 is synthetized, acting analogously to what described for the compound 17, by using the compound 74 (40 mg) and bromo-acetonitrile (15 mg). The crude is purified through HPLC preparation. A yellow solid is obtained (1.8 mg, yield: 4%). Rt: 5.08 min. [M+H]+ 443 Example 79 Synthesis of 7-methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l .2- dihvdro-phthalazine (compound 78).
The compound 78 is synthetized, acting analogously to what described for the compound 17, by using the compound 75 (42 mg) and 4-bromo-but-2-methyl enoate (21 mg). The crude is purified through HPLC preparation. A pale yellow solid is obtained (3.6 mg, yield: 7%). Rt: 5.89 min. [M+H]+ 517 Example 80 Synthesis of 7-Methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l ,2- dihvdro-phthalazine (compound 79). The compound 79 is synthetized, acting analogously to what described for the compound 17, by using the compound 75 (42 mg) and l-bromo-3 -methyl-but-2-ene (18 mg). The crude is purified through HPLC preparation. A pale yellow solid is obtained (2.5 mg, yield: 5%). Rt: 5.62 min. [M+H]+ 505 Example 81 Synthesis of 7-Methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l ,2- dihydro-phthalazine (compound 80).
The compound 80 is synthetized, acting analogously to what described for the compound 17, by using the compound 75 (42 mg) and 2-bromo-ethyl ester of the acetic acid (21 mg). The crude is purified through HPLC preparation. A yellow solid is obtained (2.4 mg, yield: 5%).
Rt: 6.81 min.
[M+H]+487 Example 82
Synthesis of 7-Methoxy-2-(isopropoxycarbonyl-amino-sulfonyl)-4-pyridin-4-il-methyl-l ,2- dihvdro-phthalazine (compound 81).
The compound 81 is synthetized, acting analogously to what described for the compound 17, by using the compound 75 (42 mg) and bromo-acetonitrile (15 mg). The crude is purified through HPLC preparation. A yellow solid is obtained (1.8 mg, yield: 4%).
Rt: 5.49 min. [M+H]+ 458 Example 83
Study of PDE 4 enzyme inhibition a) PDE 4 enzyme purification
PDE 4 enzyme was isolated from the U-937 cell line by using the Nielson method and others (J. Allergy Clin. Immunol. 1990, 86, page 801-807) partially modified for the FPLC (Fast
Protein Liquid Chromatography) technique.
The U-937 cell line (Istituto Zooprofilattico Sperimentale, Brescia, Italia) was kept in RPMI incubation medium, with a 10% bovine fetal serum and 2 mM glutamine, at a cell density comprised between lxlO6 and 8xl06 cells per ml in an incubator at 37°C with 5% CO2. The U-937 suspension was homogenized in a buffer containing 10 mM TRIS, 5 mM MgCl2,
4 mM EGTA, 5 mM β-mercaptoethanol, 1 μM leupeptin, 1 μM pepstatin A, 1% TRITON x-
100, and 100 μM phenylmethyl sulfonyl fluoride (PMSF) at pH 7.8.
The homogenate was centrifugated and the surnatant was used for the PDE 4 enzyme purification; it was seeded on a columnn connected to a low pressure liquid chromatography system (FPLC, BIO RAD). The PDE 4 enzyme was eluted with a linear gradient, from 0.05 M to 1 M sodium acetate, and the eluted fractions were tested to check the PDE 4 enzyme activity.
The fractions containing the PDE 4 enzyme activity were collected and, after one whole- night long dialysis against water to remove the sodium acetate, they were concentrated at a
30% volume with an Amicon filtration system (using a YM10 membrane filter).
Ethylenglycole (30% v/v) was added and the sample was kept at -20°C in a single aliquot until use. b) PDE 4 enzyme activity assessment The enzyme activity was assessed with an -Amersham kit based upon the SPA technique
(Scintillation Proximity Assay) consisting in a 3H-cAMP tracer, a buffer for analyzing the
PDE 4 enzyme (lOx solution: 500 mM TRIS/HC1 pH 7.5, 83 mM MgCl2 and 17mM EGTA) and a suspension of SPA beads containing 18 mM zinc sulfate.
The radioactivity linked to the particles was measured by using a β-counter (Packard model MINAXI) β TRI-CARB 4000 SERIES).
The compounds of formula I of the present invention resulted to inhibit selectively the PDE
4 enzyme.
Almost all exemplified compounds, representative of the whole class, were tested at a 10"7 M concentration and the results expressed as inhibition percentage of the PDE 4 enzyme are set forth in the following Table 1.
Figure imgf000051_0001
Example 84 TNFα release inhibition in whole human blood.
For the assay in diluted blood, the blood samples obtained from healthy volunteers were collected in heparinized test tubes and they were diluted 1 :5 with RPMI 1640 without adding serum.
The test was carried out in 96-well plates and containing the samples 150 μl of diluted blood and 120 μl of RPMI 1640 with control carrier or with different concentrations of the products of the present invention were incubated at 37°C in an atmosphere humidified by 5% with CO2 for 30 minutes. The final dilution of the whole blood in the assay is 1 : 10 (v/v).
For the assay in not diluted blood 200 μl of blood incubated for 30' with 10 μl RPMI containing different concentrations of the compounds or control carriers were used.
In any case, the samples were stimulated with LPS (E. coli lipopolysaccharide: serotype B
0:55, Sigma) 0.25 μg/ml and incubated for 24 hours at 37 °C in humidified atmosphere and 5% C02.
After centrifugation the surnatant was collected to determine the TNFα levels by means of an
ELISA kit available on the market (Biosource).
The test subjects were dissolved in DMSO 10"2 M and further diluted in RPMI 1640 incubation medium. The DMSO final concentration does not exceed 0.1% and does not affect the TNFα release.
Each compound was tested twice at nine concentrations and the obtained data were further confirmed by using blood deriving from a different donor.
The inhibition percentage of the TNFα production was calculated at each concentration and
IC 50 was calculated by a four-parameter logistic equation (ORIGIN calculation programme, MICROCAL SOFTWARE INC.).
The compounds of formula I of the present invention resulted to inhibit the TNFα release.
The results, expressed as IC 50 in diluted and not diluted blood, are set forth in the following
Table 2.
Figure imgf000053_0001

Claims

Claims
1) A compound of formula
Figure imgf000054_0001
wherein Z is a methylene, mono or di-fluoro-methylene group or a -NH- group.
A is a phenyl group or a 5- or 6 -membered aromatic heterocycle containing from one to three heteroatoms selected among nitrogen, oxygen and sulphur optionally substituted by one or more sustituent(s) selected among alkyl, alkoxy, a carboxyl group, an alkoxy- carbonyl group, an acyl group, alkyltio, alkyl-sulfonyl, amino, a N-acetylamino group, a N- methansulfonyl-amino group, cyano, mercapto, nitro, oxydryl or halogen. R is a (C C4)-alkyl group or a mono or poly-fluoro-(Cι-C )-alkyl group; Ri is a hydrogen atom, an optionally branched (Cι-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)- alkynyl group, a cycloalkyl group, an optionally substituted aryl or heterocycle, an optionally substituted aryl-(C C4)-alkyl or heterocyclil-(Cι-C4)-alkyl group, a cyano-(Cι-C6)-alkyl group, a formyl-(Cι-C6)-alkyl or formyl-(C C6)-alkenyl group, a carboxy-(Cι-C6)-alkyl group or a carboxy-(C1-C6)-alkenyl group, an alkoxy-carbonyl-(C]-C6)-alkyl group or an alkoxy-carbonyl-(Cι-C6)-alkenyl group, a cycloalkyl-(C C4)-alkyl group or an acyloxy-(Cr C )-alkyl group; R2 has the same meanings of Rt and furthermore it is a -CO-O-Rt group wherein t is an optionally branched (Cι-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group, a cycloalkyl group, an optionally substituted aryl or heterocycle, an optionally substituted aryl-(Cι-C4)- alkyl or heterocyclil-(Cι-C4)-alkyl group;
R3 is a hydrogen atom or a -O-R group wherein R has the meanings defined above; the N-oxidized derivatives of the compounds of formula I and pharmaceutically salts thereof. 2) The compound according to claim 1, wherein R, Ri, R2, R3 and A have the meanings defined in formula I and Z is a methylene or mono or di-fluoro-methylene group.
3) The compound according to claim 2, wherein Ri is a hydrogen atom, an optionally branched (Cι-C6)-alkyl, (C2-C6)-alkenyl or (C2-C4)-alkynyl group, a cycloalkyl group, an aryl or a heterocycle, an optionally substituted aryl-(Cι-C )-alkyl or heterocyclil-(Cι-C )- alkyl group, a cyano-(Cι-C4)-alkyl group, a formyl-(Cι-C4)-alkyl or formyl-(Cι-C )-alkenyl group, a carboxy-(Cι-C )-alkyl group or a carboxy-(C C4)-alkenyl group, a alkoxy- carbonyl-(Cι-C )-alkyl group or an alkoxy-carbonyl-(C C )-alkenyl group, a cycloalkyl-(Cι- C4)-alkyl group or an acyloxy^ -G -alkyl group and R2 has the same meanings of Ri and furthermore it is a -CO-O-Rt group wherein Rt is an optionally branched (Cι-C6)-alkyl, (C2- C4)-alkenyl or (C2-C4)-alkynyl group, a cycloalkyl group, an aryl or a heterocycle, an optionally substituted aryl-(Cι-C4)-alkyl or heterocyclil-(C C4)-alkyl group;
4) The compound according to claim 3, wherein Z is a methylene group, Ri is a hydrogen atom, an optionally branched (Cι-C5)-alkyl, (C2-Cs)-alkenyl or (C2-C4)-alkynyl group, an aryl selected between phenyl or indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole, an optionally substituted aryl-(Cι-C3)-alkyl or heterocyclil-(Cι-C3)-alkyl group, a cyano-(Cι- C3)-alkyl group, a formyl-(Cι-C3)-alkyl or formyl-(Cι-C3)-alkenyl group, a carboxy-(Cι-C3)- alkyl group or a carboxy-(Cι-C3)-alkenyl group, an alkoxy-carbonyl-(C1-C3)-alkyl group or an alkoxy-carbonyl-(Cι-C3)-alkenyl group, a cycloalkyl-(Cι-C3)-alkyl group or an acyloxy- (Cι-C3)-alkyl group and R has the same meanings of Ri and furthermore it is a -CO-O-Rt group wherein Rt is an optionally branched (C C4)-alkyl group, a cycloalkyl group, an aryl- (Cι-C4)-alkyl group or a heterocyclil-(Cι-C )-alkyl group; 5) The compound according to claim 4, wherein Ri is a hydrogen atom, an optionally branched (Cι-C5)-alkyl, (C2-Cs)-alkenyl or (C2-C4)-alkynyl group, an indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, pyridine, pyrimidine and triazole, a benzyl or an optionally substituted furanyl-methyl, imidazolyl-methyl, pyridinyl- methyl, pyrimidinyl-methyl, dioxaneyl-ethyl, morpholinyl-propyl group, a cyano-(Cι-C3)- alkyl group, a formyl-(C1-C3)-alkyl group, a carboxy-(Cι-C3)-alkyl group, an alkoxy- carbonyl-(Cι-C3)-alkyl group oran alkoxy-carbonyl-(Cι-C3)-alkenyl group, a cyclopropyl- (C!-C3)-alkyl group, a formyloxy-(Cι-C3)-alkyl group or acetyloxy-(Cι-C3)-alkyl group and R2 has the same meanings of Rt and furthermore it is a -CO-O-Rt group wherein Rt is an optionally branched (Cι-C4)-alkyl group, a cycloalkyl group, a benzyl group or a pyridinyl- methyl group;
6) The compound according to claim 5, wherein R is a (C C4)-alkyl group, R! is a hydrogen atom, an optionally branched (C1-C5)-alkyl, (C2-C5)-alkenyl or (C2-C )-alkynyl group, an indanyl or a furan, a benzyl group or a furanyl-methyl, dioxaneyl-ethyl, morpholinyl-propyl group optionally substituted by a cyano group, metoxy-carbonyl or methyl-tio, a cyano-(Cι- C3)-alkyl group, a formyl-(Cι-C3)-alkyl group, a carboxy-(Cι-C3)-alkyl group, an alkoxy- carbonyl-(Cι-C3)-alkyl group oran alkoxy-carbonyl-(Cι-C3)-alkenyl group, a cyclopropyl- methyl group or an acetyloxy-(Cι-C3)-alkyl group and R2 has the same meanings of Ri and furthermore it is a -CO-O-Rt group wherein t is an optionally branched (Cι-C4)-alkyl group, a cyclohexyl group, a benzyl group or a pyridinyl-methyl group;
7) The compound according to claim 6, wherein R is a methyl, Ri is a hydrogen atom or a carboxy-(CrC3)-alkyl group and R2 has the same meanings of Ri and furthermore it is a - CO-O-Rt group wherein Rt is a benzyl group.
8) The compound according to claim 2, wherein R3 is a hydrogen atom and A is a 5- or 6- membered aromatic heterocycle containing from one to three heteroatoms selected among nitrogen, oxygen and sulphur optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, a carboxyl group, an alkoxy-carbonyl group, an acyl group, alkyl-tio, alkyl-sulfonyl, amino, cyano, mercapto, nitro, hydroxy or halogen.
9) The compound according to claim 8, wherein Z is a methylene group and A is an aromatic heterocycle selected among pyrrole, thiophene, furan, imidazole, thiazole, pyridine, pyrimidine and triazole optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, alkyl-tio, amino, cyano, nitro, hydroxy or halogen.
10) The compound according to claim 9, wherein R is a (Cι-C )-alkyl group and A is a pyridine optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, alkyltio, amino, cyano, nitro, hydroxy or halogen. 11) The compound according to claim 10, wherein R is a methyl group and A is a 3,5- Dichloro-pyridine.
12) The compound according to claim 1, wherein R, R3 and Z have the meanings defined in formula I, A is a 5 -or 6-membered aromatic heterocycle containing from one to three heteroatoms selected among nitrogen, oxygen and sulphur optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, a carboxyl group, an alkoxy-carbonyl group, an acyl group, alkyl-tio, alkyl-sulfonyl, amino, cyano, mercapto, nitro, hydroxy or halogen, Rt is a hydrogen atom, an optionally branched (Cι-C6)-alkyl, (C2-C6)-alkenyl or (C2-C )-alkynyl group, a cycloalkyl group, an aryl selected between phenyl or indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole, an optionally substituted aryl-(Cι-C4)-alkyl or heterocyclil-(Cι-C )-alkyl group, a cyano-(C1-C4)-alkyl group, a foιmyl-(Cι-C )-alkyl or formyl-(Cι-C4)-alkenyl group, a carboxy-(C C4)-alkyl group or a carboxy-(Cι-C4)-alkenyl group, an alkoxy-carbonyl-(C C )-alkyl group or an alkoxy-carbonyl-(Cι-C4)-alkenyl group, a cycloalkyl-(Cι-C4)-alkyl group or an acyloxy-(C!-C )-alkyl group and R2 has the same meanings of Rt and furthermore it is a -CO-O-Rt group wherein Rt is an optionally branched (Cι-C4)-alkyl, (C2-C4)-alkenyl or (C2-C )-alkynyl group, a cycloalkyl group, an aryl or a heterocycle, an optionally substituted aryl-(C C4)-alkyl group or heterocyclil-(Cι- C4)-alkyl group;
13) The compound according to claim 12, wherein A is an aromatic heterocycle selected among pyrrole, thiophene, furan, imidazole, thiazole, pyridine, pyrimidine and triazole optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, alkyltio, amino, cyano, nitro, hydroxy or halogen, Ri is a hydrogen atom, an optionally branched ( - C5)-alkyl, (C2-C5)-alkenyl or (C2-C4)-alkynyl group, an aryl selected between phenyl or indanyl or a heterocycle selected between pyrrole, thiophene, furan, imidazole, pyridine, pyrimidine and triazole, a benzyl group or an optionally substituted furanyl-methyl, imidazolyl-methyl, pyridinyl-methyl, pyrimidinyl-methyl, dioxaneyl-ethyl, morpholinyl- propyl group, a cyano-(Cι-C3)-alkyl group, a formyl-(Cι-C3)-alkyl group, a carboxy-(Cι-C3)- alkyl group, an alkoxy-carbonyl-(Cι-C3)-alkyl group or an alkoxy-carbonyl-(C!-C3)-alkenyl group, a cyclopropyl-(Cι-C3)-alkyl group or an acetyloxy-(Cι-C3)-alkyl group and R2 has the same meanings of Rx and furthermore it is a -CO-O-Rt group wherein Rt is an optionally branched (Cι-C4)-alkyl group, a cycloalkyl group, an aryl-(Cι-C4)-alkyl group or a heterocyclil-(C C4)-alkyl group;
14) The compound according to claim 13, wherein Z is a methylene or mono or di-fluoro- methylene group.
15) The compound according to claim 14, wherein R3 is a hydrogen atom.
16) The compound according to claim 15, wherein R is a (Cι-C )-alkyl group and Z is a methylene group.
17) The compound according to claim 16, wherein A is a pyridine optionally substituted by one or more substituent(s) selected among alkyl, alkoxy, alkyltio, amino, cyano, nitro, hydroxy or halogen, Rt is a hydrogen atom, an optionally branched (Cι-C5)-alkyl, (C2-C5)- alkenyl or (C2-C )-alkynyl group, an indanyl or a heterocycle selected among pyrrole, thiophene, furan, imidazole, pyridine, a benzyl group or a furanyl-methyl, a pyridinyl-methyl dioxaneyl-ethyl, morpholinyl-propyl group optionally substituted by a cyano group, methoxy-carbonyl or methyl-tio, a cyano-(Cι-C3)-alkyl group, a formyl-(Cι-C3)-alkyl group, a carboxy-(Cι-C3)-alkyl group, an alkoxy-carbonyl-(Cι-C3)-alkyl group or an alkoxy- carbonyl-(Cι-C3)-alkenyl group, a ciclopropyl-methyl group or an acetyloxy-(Cι-C3)-alkyl group and R2 has the same meanings of Ri and furthermore it is a -CO-O-Rt group wherein Rt is an optionally branched (C C )-alkyl group, a cycloalkyl group, a cyclohexyl group, a benzyl group or pyridinyl-methyl group;
18) The compound according to claim 17, wherein A is a 3,5-Dichloro-pyridine, Ri is a hydrogen atom or a carboxy-(C C3)-alkyl group and R2 has the same meanings of Ri and furthermore it is a -CO-O-Rt group wherein Rt is a benzyl group.
19) The compound according to claim 18 wherein R is a methyl.
20) The compound according to claim 1 selected among the exemplified compounds.
21) A process for the preparation of a compound according to claim 1, wherein a compound of formula
Figure imgf000059_0001
wherein R, R3, Z and A have the meanings defined for the compounds of formula I; is reacted in presence of a base and in an organic solvent with a compound of formula
Figure imgf000059_0002
wherein
Rt has the meanings defined for the compounds of formula I; to give a compound of formula
Figure imgf000059_0003
wherein
R, R3, t, Z and A have the meanings defined previously for the compounds of formula I; in case, the compound of formula la is alkylated by reaction with a halogen-derivative in presence of TBD-methyl (7-methyl-l,5,7-triaza-bicycle-[4,4,0]-dec-5-ene) polystyrene in Dichloromethane/DMF to give a compound of formula
Figure imgf000060_0001
wherein
R, Ri, R3, Rt, Z ed A have the meanings defined previously for the compounds of formula I; in case, from the compound of formula lb by hydrolysis of the urethane group thereto the substituent Rt is linked, the compound di formula
Figure imgf000060_0002
wherein
R, Rl5 R3, Z and A have the meanings defined previously for the compounds of formula I is obtained.
22) The process according to claim 21, wherein the compound of formula III is prepared in situ.
23) The process according to claim 21 for preparing the compounds of formula lb wherein R! is an optionally branched (Cι-C6)-alkyl group, an aryl, an optionally substituted aryl-(d- C4)-alkyl group or a heterocyclil-(CrC4)-alkyl group, wherein the alkylation of the compound of formula la wherein Rt is a t-butyl group is performed through the Mitsunobu reaction, carried out by mixing the compound mentioned above, diisopropylazadicarboxylate, triphenylphosphine supported on polystyrene and specific alcohols in presence of an organic solvent.
24) The process according to claim 21, wherein the urethane group of the compounds of formula lb wherein the substituent Rt is a t-butyl group is hydrolized by treatment with
Dichloromethane/TFA at room temperature for few hours.
25) A pharmaceutical composition containing a therapeutically effective amount of a compound according to claim 1 in admixture with a pharmaceutically acceptable carrier.
26) The pharmaceutical composition according to claim 25 for the treatment of allergic and inflammatory pathologies.
27) The pharmaceutical composition according to claim 25 for the treatment of respiratory pathologies.
PCT/EP2004/007714 2003-07-16 2004-07-13 4-substituted 7-alkoxy-2-aminosulfonyl-1,2-dihydro-phtalazin derivatives as phosphodiesterase 4 inhibitors for the treatment of allergies and inflammations WO2005013995A1 (en)

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WO2008052734A1 (en) 2006-10-30 2008-05-08 Novartis Ag Heterocyclic compounds as antiinflammatory agents
WO2009087224A1 (en) 2008-01-11 2009-07-16 Novartis Ag Pyrimidines as kinase inhibitors
EP2286813A2 (en) 2006-01-31 2011-02-23 Novartis AG Use of naphthyridine derivatives as medicaments
JP2011093856A (en) * 2009-10-30 2011-05-12 Fujifilm Corp Composition, resist film, method for forming pattern and inkjet recording method
WO2012034091A1 (en) 2010-09-09 2012-03-15 Irm Llc Imidazo [1, 2] pyridazin compounds and compositions as trk inhibitors
WO2012034095A1 (en) 2010-09-09 2012-03-15 Irm Llc Compounds and compositions as trk inhibitors
WO2012116217A1 (en) 2011-02-25 2012-08-30 Irm Llc Compounds and compositions as trk inhibitors
CN109651580A (en) * 2018-12-05 2019-04-19 大连理工大学 A kind of solvent type polyurethane material of monomer structure high temperature resistant of the structure containing diazanaphthalene biphenyl and preparation method thereof

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2286813A2 (en) 2006-01-31 2011-02-23 Novartis AG Use of naphthyridine derivatives as medicaments
WO2008052734A1 (en) 2006-10-30 2008-05-08 Novartis Ag Heterocyclic compounds as antiinflammatory agents
WO2009087224A1 (en) 2008-01-11 2009-07-16 Novartis Ag Pyrimidines as kinase inhibitors
JP2011093856A (en) * 2009-10-30 2011-05-12 Fujifilm Corp Composition, resist film, method for forming pattern and inkjet recording method
US8808961B2 (en) 2009-10-30 2014-08-19 Fujifilm Corporation Composition, resist film, pattern forming method, and inkjet recording method
WO2012034091A1 (en) 2010-09-09 2012-03-15 Irm Llc Imidazo [1, 2] pyridazin compounds and compositions as trk inhibitors
WO2012034095A1 (en) 2010-09-09 2012-03-15 Irm Llc Compounds and compositions as trk inhibitors
WO2012116217A1 (en) 2011-02-25 2012-08-30 Irm Llc Compounds and compositions as trk inhibitors
CN109651580A (en) * 2018-12-05 2019-04-19 大连理工大学 A kind of solvent type polyurethane material of monomer structure high temperature resistant of the structure containing diazanaphthalene biphenyl and preparation method thereof

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