ZA200006575B - Phthalazine derivatives phosphodiesterase 4 inhibitors. - Google Patents

Description

"PHTHALAZINE DERIVATIVES PHOSPHODIESTERASE 4 INHIBITORS" eo ke oe se ok se a ob oe oe oe of ole of ok of of ole of ok ok ok ok ok ok oF ok ok oo

The present invention relates to phthalazine derivatives, to the pharmaceutical compositions containing them and to their use as phosphodiesterase 4 inhibitors.

Phosphodiesterases are a family of isoenzymes which constitute the basis of the main mechanism of cAMP (cyclic adenosine-3’,5°-monophosphate) hydrolytic inactivation. cAMP has been shown to be the second messenger mediating the biologic response to many hormones, neurotransmitters and drugs [Krebs Endocrinology Proceedings of the 4th

International Congress Excerpta Medica, 17-29, 1973]. When the suitable agonist binds to the cell surface, the adenylate cyclase activates and turns Mg?*-ATP into cAMP. cAMP modulates the activity of the majority, if not of all the cells contributing to the pathophysiology of various respiratory diseases, both of allergic origin and not. It follows that an increase of the cAMP concentration yields beneficial effects such as airway smooth muscle relaxation, inhibition of the mast cell mediator release (basophil granulose cells), suppression of the neutrophil and basophil degranulation, inhibition of the monocyte and macrophage activation. Thus, compounds able of activating adenylate cyclase or of inhibiting phosphodiesterases could suppress the undesired activation of the airway smooth muscle and of a great number of inflammatory cells.

In the phosphodiesterase family there is a distinct group of isoenzymes, 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 the airway smooth muscle relaxation, but also the suppression of mastocyte, basophil and neutrophil degranulation, so as the inhibition of the monocyte and neutrophil activation. Thus PDE 4 inhibitors are effective in the therapy of asthma. Such compounds offer a unique approach to the therapy of various respiratory diseases both of allergic origin and not, and possess significant therapeutic advantages over the current therapy.

The excessive or irregular production of turnour necrosis factor (hereinafter TNF,), a cytokine with pro-inflammatory activity produced by various kind of cells, affects the

<2. mediation or the exacerbation of many pathologies such as, for example, the adult respiratory distress syndrome (ARDS) and the chronic pulmonary inflammatory disease.

Therefore, compounds able to control the negative effects of TNF, i.e. the inhibitors of this cytokine, are to be considered as useful against many pathologies.

The patent application EP 722 936 (Eisai) claims, inter alia, compounds of formula i = Toy ®, Lh

A wherein n=0-4; R, is optionally substituted lower alkoxy, optionally substituted cycloalkyl, or a -ORy group wherein Ry represents an optionally substituted arylalkyl group; X is -N= or -NR¢- wherein Rs is hydrogen, a lower alkyl group, or optionally substituted arylalkyl! or heteroarylalkyl groups; Y is ~CO or -CB= wherein B is -NRsRs wherein one of Ry and Rs may be H and the other an optionally substituted heteroarylalky! group, or B is hydrogen or an optionally substituted aryl, heteroary}, arylalkyl or heteroarylalkyl group; A is a hydrogen or halogen atom, or an optionally mono- or disubstituted amino group, an optionally substituted aryl, heteroaryl or heteroarylalkyl group. Among the groups optionally substituting the above mentioned residues, halogen atoms are cited. These compounds are said to be active as inhibitors of ¢GMP-PDE, i.e. PDE 5, a phosphodiesterase just acting through a cGMP-dependent mechanism and whose field of application is markedly cardiovascular (Schudt C. et al., Phosphodiesterase Inhibitors, Academic Press).

The patent application EP 634 404 (Rhone Poulenc Agriculture) describes, inter alia, phthalazinones of formula 0 -R (Ry 36. aA

R wherein R is an arylalkyl group, in particular pyridyl optionally substituted by halogen

¢ L) CC CT ee atoms; R; represents an alkyl chain up to 6 carbon atoms or an arylalkyl group, in particular phenyl; R, represents a phenoxy or benzyloxy group; and m=0-4. These compounds are useful as pesticides.

The patent US 3,274,185 (Messengill) describes, inter alia, phthalazines of formula

Y, R

NNN oL

Y z wherein Y and Y are independently hydrogen or lower alkoxy; Z is phenyl optionally substituted by halogen or benzyl optionally substituted by lower alkyl or alkoxy; and R is hydrogen. These phthalazines are endowed with sedative and hypotensive activity, without mentioning the mechanism of action.

The patent US 3,813,384 (Asta-Werke) illustrates, inter alia, benzylphthalazinones of formula 0 ZN ~(X)p—CH

Re) > \ ’ ~~ ~~ N

IAS

XC

Ry )m wherein R; and R; are hydrogen, lower alkoxy or halogen; X is an optionally branched alkylene chain; m and n are 1-3; p is 0 or 1; and the group = is an optionally substituted (Cs-Cg) mono-, di- or tricyclic residue containing one or two nitrogen atom(s). Such compounds have hystaminolytic action and are useful, for example, in the treatment of asthma. All of the exemplified compounds show a residue fy which is a saturated heterocycle.

The patent application WO 97/40020 (Schering AG) describes compounds of formula

4 9 a

WQ 00/0521 8 PCT/EPY9/04304 ® ) i

I

Rj; ~0 : : N 5 . Ry ~ 4

R ——

J wherein Y is -NRs- or -N=, R, and R, are H, lower alkyl, nitro, halogen, amino, lower alkoxy or -CF3, Ry is H, -CO- substituted by H, lower alkyl substituted by aryl, amino, lower alkoxy, cycloalkyl or cycioalkoxy, or Rs is lower alkyl or cycloalkyl, R, is H or lower alkoxy, Rs is lower alkyl. These compounds are said to be uncompetitive antagonists of excitatory amino acids.

The patent application WO 97/48697 (Rhone Poulenc Rorer) describes bicyclic compounds with PDE 4 and TNF, inhibiting activity represented by a very broad general formula. Phthalazine compounds could be included in the general formula of this patent application, nevertheless none of the exemplified compounds is a phthalazine derivative and this kind of structure is excluded from the claims.

The patent application EP 848 000 (Tanabe Seiyaku) discloses, inter alia, phthalazine derivatives of formula

A

NY Rs =

Z

N R¢ wherein A is one of

R L_.R R 1 ® N 33 1 i Rn SN

LAN oN

R; Ry 1 wherein R, and R, are H, or optionally protected hydroxy; Rs; is lower alkyl; Rs and Rg are

H, amino or may form a heterocycle. These compounds are PDE 4 inhibitors.

It has been now surprisingly found a new class of phthalazine derivatives able to inhibit

PDE 4 and TNF,

Therefore the present invention relates to compounds of formula I

R; r~° rN NR

I Z N @

Rj J wherein TA -—---- is a single or double bond;

Z is NH, methylene, a (C,-C¢)alkylene chain optionally branched and/or unsaturated and/or interrupted by a (Cs-C;)cycloalkyl residue;

A is phenyl or heterocycle optionally substituted by one or more substituent(s) selected among oxo, nitro, carboxy groups and halogen atoms, or a COR, group wherein Ry is hydroxy, (C,-Cs)alkoxy, amino optionally substituted by one or two (C1-Ce)alkyl group(s) or by hydroxy;

R is a (C,-C¢)alkyl or polyfluoro(C,-Cg)alkyl group;

R; is absent when --—— is a double bond or, when ------ is a single bond, is a) hydrogen; b) (C:-Ce)alkyl optionally substituted by aryl, by heterocycle or by a COR; group wherein

Rs is hydroxy, (C;-C,)alkoxy or hydroxyamino; ¢) -CORs wherein Rg is hydrogen, aryl, aryl-(C;-Cs)alkyl, amino optionally alkylated or monohydroxylated, hydroxy, (C;-C4)alkoxy, carboxy, (C,-C,)alkoxycarbonyl,

HN= C ~NH,, or (C;-C,)alky! optionally substituted by heterocycle; d) (C,-Cy)alkylsulfonyl,

Ry represents two hydrogen atoms or a group =O when -—-— is a single bond, or, when m— is a double bond, R, is hydrogen, cyano, (Cy-Cy)alkoxycarbonyl, amido, optionally substituted aryl or heterocycle, (C,-Cg)alkyl, (C,-Cg)alkenyl or (Cy-Cg)alkynyl optionally branched and/or substituted by aryl or heterocycle; aryloxy, heterocyclyloxy, aryl-(C,-C,)- alkoxy, heterocyclyl-(C,-C4)alkoxy, amino substituted by one or two (Ci-Cy)alkyl groups), arylamino, heterocyclylamino, aryl-(C,-Cs)alkylamino, heterocyclyl-(C,-C,)alkylamino;

t '

R; is hydrogen, or a (Ci-Cyalkyl, (C;-Cglalkenyl or (C,-Cglalkynyl group optionaily substituted by hydroxy, oxo, aryl or heterocycle, and optionally interrupted by one or more heteroatom(s) or heterogroup(s); the NO derivatives of the compounds of formula I and the pharmaceutically acceptable salts thereof.

Preferred compounds according to the present invention are the compounds of formula I wherein -—-—- is a double or single bond; and Z is methylene or a (C,-C¢)alkylene chain.

Still more preferred compounds according to the invention are the compounds of formula I wherein --——-- is a double or single bond; Z is methylene or a (C,-Cs)zlkylene chain; and A is a heterocycle optionally substituted by one or more substituent(s).

Still more preferred compounds according to the invention are the compounds of formula I wherein ————— is a double or single bond; Z is methylene; and A is pyridine substituted by two substituents.

Within this class a preferred subset is represented by the compounds of formula I-A

Ry rR | SE [ . % aA ai (¥-A)

N a ~FN (formula I —- Z is methylene, A is 3,5-dichloro-pyridin-4-y1).

Still more preferred compounds are the compounds of formula I-A wherein ----— is a single bond and R; represents two hydrogen atoms.

Another class of still more preferred compounds are the compounds of formula I-A wherein -——- is a double bond; and R, is cyano, (Cy-Cylalkoxycarbonyl, amido, optionaily substituted heterocycle, {(C,-Cgalkeny! or (C,-Cg)alkynyl optionally substituted by ary! or heterocycle; aryloxy, heterocyclyloxy, arylamino, heterocyclylamino.

Within this class particularly preferred compounds are the compounds of formuia I-B

CH; Ry oO N

ZN (I-B)

SN cl | ZN (formula I-A - ——- is a double bond, R; is hydrogen, R is methyl) wherein R; is a heterocycle.

Specific examples of preferred compounds according to the invention are: 1 “(3,5-dichloro-pyridin-4-ylmethy!l)-6-methoxy-4-phenyl-phthalazine ; 4-3,5-dichloro-pyridin-4-ylmethy!)-7-methoxy-1 H-phthalazin-2-carboxylic acid methyl ester; benzyl-{3-[1-(3 »>-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5 -yl]-prop-2-ynyl}- methyl-amine; 1-3 »5-dichloro-pyridin-4-yimethyl)-6-methoxy-5-(S-morpholin-4-yl-pent- lI-ynyl)- phthalazine dihydrochloride; 3-{1-G,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-y1]-prop-2-yn-1-ol; 1-3.5-dichloro-pyridin-4-ylmethyl)-6-methoxy-4-morpholin-d-yl-phthalazine 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-4-[ 1,2,4]triazol-1-yl-phthalazine.

The compounds of formula I may have one or more asymmetric centre(s) and thus be in form of stereoisomers. Object of the present invention are compounds of formula I in form of stereoisomeric mixtures so as of single stereoisomers.

The compounds of formula I are active as PDE 4 and TNF, inhibitors and thus are used as therapeutic agents in allergic and inflammatory pathologies such as, for example, COPD, asthma and allergic rhinitis.

As heterocycle pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, piperazine, triazole, morpholine, pyrrolidine, pyrroline, imidazoline, pyrazoline, pyrazolidine, imidazolidine, piperidine, furan, pyran, thiazole, isothiazole, isoxazole, thiophene and the like are particularly meant,

Halogen atom means fluorine, chiorine, bromine or iodine atom.

Specific examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, rert- butyl, n-pentyl, 1-methyl-butyl, 2-methyi-butyl, 3-methyl-butyl, 3-methy!-2-butyl, n-hexyl, heptyl, octyl and the like. As (Cs-Cr)eycloalkyl group, cyclopentyl, cyclohexyl and cycloheptyl are meant, while aryl means an aromatic ring or system of 6-10 carbon atoms and specific examples of aryl and aryl<(Cy-Cyo)alky! are phenyl, benzyl, phenethyl, phenyl- pentyl, naphthyl, indanyl, indanyl-penty! and the like.

The oxidised form N—O, if present, may involve both the nitrogen atoms present on the phthalazine ring and those present on A when it is 2 heterocyclic substituent.

Pharmaceutically acceptable salts of the compounds of formula I are those with organic and inorganic acids, such as, for example, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, benzoic, maleic, fumaric, succinic, tartaric, citric, aspartic, methanesulfonic, 3,7-di-fers-butylnaphthalen-1,5-disulfonic (dibudinic acid) or with

I5 inorganic bases such as, for example, sodium or potassium hydroxide, sodium bicarbonate.

The synthesis of the compounds of formula I proceeds according to methods known to the skilled in the art. For example, it can start from a compound of formula IT

Ry,

RON 0 0

R3 | Im

Le

CH; wherein R and Rs are as defined above, and Ry, is hydrogen, optionally substituted aryl or heterocycle or (C;-Cyalkyl, {Co-Cglalkenyl or (C,-Cy)alkyny! optionally substituted by aryl or heterocycle, which can be prepared by different routes. For example, the treatment of a compound of formula INI

© WO 00/05218 PCT/EP99/04904 “TA

AF 0}

Rj A (Im)

CH;

CH; wherein R and R; are as defined above, with a strong base, for example, n-butyl lithium, gives the compound of formula ITIa 0) M

R” | x

SEO (Illa)

Rj; \

N—¢- cH,

CH; wherein R and Rj are as defined above and M is lithium or sodium, which treated with a : formyl electrophile provides a compound of formula II wherein R,, is hydrogen. Such compound can be turned into a compound of formula II wherein Rs, is other than hydrogen by treatment with a suitable organometal, for example, a Grignard reagent, to give a compound of formula IV

Roa oO ~~

R | x OH = oO

ZY, av 3

N— cH,

CH; wherein R, Ry, and R; are as defined above, which by oxidation, for example, with a pyridine-SO; complex, DMSO and triethylamine, gives the desired compound II.

The compound of formula IV can also be obtained starting from a compound of formula

Illa by reaction with an aldehyde of formula V

R;,-CHO Vv) wherein Ry, is as defined above, used in molar excess as compared to the compound IIa.

Also, a compound of formula IT wherein R,, is other than hydrogen can be synthesised

‘ . directly from a compound of formula Ila by transmetailation with a suitable salt, for example zinc chloride, and subsequent reaction with an acyl chloride in the presence of 2 transition metal catalyst, for example, palladium.

After clearing of the oxazoline group of the compound of formula I, the treatment with hydrazine, in a protic solvent, is effected to give a phthalazinone of formula

Ra

RON IN

0 NH (VD

Ry

O wherein R, R,, and R; are as defined above, which treated with a halogenating agent such as, for example, phosphorous oxychloride gives a compound of formula VII

Raa 's “YY

EY (VID)

X wherein R, Rj, and R; are as defined above, and X is a bromine or chlorine atom. This, by treatment with a compound of formula VIII

A-Z-Y (vi wherein A and Z are as defined above and Y is a metal such as, for example, Li, Na, Migora transition metal complex, gives a compound of formula I wherein R; has the meanings listed above when ----— is a double bond and R, is absent.

When a compound of formula I wherein R, is present is desired, a compound of formula I wherein --—-- is a double bond and R, is hydrogen is treated according to methods known to the skilled in the art. For example, by reduction with hydrogen in the presence of Pd/C or

PtO,, a compound of formula I wherein R, is hydrogen is obtained, which by subsequent treatment with a suitable sulfonating or acylating agent, gives a compound of formula I wherein R, is (C,-C,)alkyisulfonyl or -CO-R¢ wherein Rg is as defined above.

Alternatively, the compounds of formula I can be obtained starting from the acid of formuia f } } ’ oT TTT via

Ron = ve (VIII) wherein R and R; are as defined above, which by reaction with formaldehyde and HCI gives a compound of formula IX (0)

R” © XX 0

Sh IX)

Ry wherein R and R; are as defined above. This compound is halogenated, for example with N- bromosuccinimide in the presence of a catalyst such as benzoyl peroxide or 2,2'- azoisobutyronitrile, to give a compound of formula X 0

RON

0

SF (X)

Rj

X wherein R, R; and X are as defined above, which is treated with triphenylphosphine to give a compound of formula XI

O

RON

0

RE x G0 3 +

A\~Ph wherein R, R; and X are as defined above, which is reacted with an aldehyde of formula XII

A-Z’-CHO (XI)

‘ > wherein A is as defined above and Z' is methylene or a (C,-Cs)alkylene chain optionally branched and/or unsaturated and/or interrupted by a (Cs-Cy)cycloalkyl residue, or is absent, in the presence of an organic base such as, for example triethylamine, to give a compound of formula XIII o

RON

[So

Rj \

Z—A 16 wherein R, Rj, Z' and A are as defined above. This compound is reacted with hydrazine to give a compound of formula ¥ wherein R; is hydrogen, R, is a group =0, and Z is methylene or a (C;-Cs)alkylene chain optionally branched and/or unsaturated and/or interrupted by a (Cs-Co)eycloaikyl residue, but not on the first carbon atom. The reaction of this compound of formula I with a suitable alkyl halide or sulfonate in the presence of a base, for exampie sodium hydride, gives a compound of formula I wherein R, is a substituent other than hydrogen.

The compound of formula I wherein R, is hydrogen can provide also other compounds of formula I wherein Z is methylene or a (C,-Cs)alkylene chain optionally branched and/or unsaturated and/or interrupted by a (Cs-Cq)cycloalky! residue, but not on the first carbon atom. For example, it is reacted with a halogenating agent such as, for example POC; or

POBr;, to give an intermediate of formula XIV

X

RON

> Z N xv)

Rs Zo

A wherein A, R, Rs, Z and X are as defined above, which is then subdued to 2 coupling reaction in the presence of a catalyst, such as for example palladium, or to an aromatic nucleophilic substitution, to give a compound of formula X wherein R, has the meanings listed above when ~~~ is a double bond and Z is methylene or a (C,-Cs)alkyiene chain optionally branched and/or unsaturated and/or interrupted by a (Cs-Cy)cycloalkyl residue, but not on the first carbon atom. :

As for the substituent R; when other than hydrogen, it can be already present in the starting products of the various above synthetic routes or can be introduced and/or modified during the process according to methods known to the skilled in the art. For example, when Rj; is (Cy-Cg)alkenyl or (C-Cg)alkynyl optionally substituted by aryl or heterocycle, it can be hydrogenated to give the corresponding (C-Cylalkyl or (C,-Cs)alkenyl residue. Said hydrogenation is effected according to methods known to the skilled in the art.

Alternatively, a compound of formula XV

R, : “TX % ANN XV)

HO

0) wherein R and R,; are as defined above, is activated on the hydroxy moiety, for example with triflic anhydride, to give a compound of formula XVI

R, r~° XY” SN

An w-0 0) wherein R and R; are as defined above, and W is an activating group. This compound is then subdued to a coupling reaction in the presence of a catalyst, for example palladium, to give the desired compound of formula VI which is then worked up as above described to give the compound of formula I.

The compound of formula XV can be obtained, for example, starting from a compound of formula XVII

RON

S VD

Bz—0O wherein R is as defined above and Bz is a benzyl group, which is oxidised, for example with potassium permanganate and tetrabuiylammonium bromide, to give an acid of formula

Xvi

K Zz (XVIID

Bz—0C COOH wherein R and Bz are as defined above, which by treatment, for example, with thionyl chloride, is turned into the corresponding acyi halide of formula XIX

AA (XIX)

Bz—0 COX wherein R, Bz and X are as defined above. This is reacted with diethylamine in at least equimolar amount, to give a benzamide of formula XX zg ° N

Bz—0O “Et wherein R and Bz are as defined above, which is reacted with dimethylformamide in the presence of a strong organic base such as, for example, butyl lithium, ters-butyi lithium, sec- butyl lithium, optionally in the presence of a ligand such as, for example tetramethylethylendiamine, to give a compound of formula XXia

R,

RO | x 0

AF Et (XXla)

Bz—0O CO—N_

Et wherein R and Bz are as defined above, and R,' is hydrogen. This compound is reacted with hydrazine in acetic acid to give the compound of formula XX1I

Ry

FONTS Ny | (XXII)

Az NH

Bz—O

Oo

Claims (12)

1. Claims 1) A compound of formula Ry RON oy Ri I = N {@ R3 J wherein A ------ i$ a single or double bond;

   Z is NH, methylene, a (C;-Cs)alkylene chain optionally branched and/or unsaturated and/or interrupted by a (Cs-C;)cycloalkyl residue;

   A is phenyl or heterocycle optionally substituted by one or more substituent(s) selected among oxo, nitro, carboxy groups and halogen atoms, or a COR, group wherein R, is hydroxy, (C,-Cs)alkoxy, amino optionally substituted by one or two (Ci-Cg)alkyl group(s) or . 15 by hydroxy;

   R is a (C;-Cg)alkyl or polyfluoro(C;-Cg)alkyl group;

   R is absent when --—-—-—- is a double bond or, when --—- is a single bond, is a) hydrogen;

   b) (Ci-Colalkyl optionally substituted by aryl, by heterocycle or by a COR; group wherein

   Rs is hydroxy, (Ci-C4)alkoxy or hydroxyamino; c¢) -CORs wherein Rg is hydrogen, aryl, aryl-(C;-Cg)alkyl, amino optionally alkylated or monohydroxylated, hydroxy, (C;-Cy)alkoxy, carboxy, (Ci-Cy)alkoxycarbonyl, HN= C-NH, » or (C1-C4)alkyl optionally substituted by heterocycle; d) (C,-Cy)alkylsulfonyl;

   Rg represents two hydrogen atoms or a group =O when --——- is a single bond, or, when ---- is a double bond, R, is hydrogen, cyano, (C,-C,)alkoxycarbonyl, amido, optionally substituted aryl or heterocycle, (C,-Cy)alkyl, (C,-Cs)alkenyl or (Cy-Cs)alkynyl optionally branched and/or substituted by aryl or heterocycle; aryloxy, heterocyclyloxy, aryl-(C;-Cy)- alkoxy, heterocyclyl-(C,-C,)alkoxy, amino substituted by one or two (Cy-Cyalky! group(s),

   arylamino, heterocyclylamino, aryl-(C,-C4)alkylamino, heterocyclyl-(C,-C,)-alkylamino;

   ) © WO 80/05218 PCT/EP29/04904

   Table 3 Compound | PDE 3 PDE 5 in | % inhibition om at 10° M at 10°M

   8 [12 1 3s I VE 10 ; IS FE IO EE I I VA I A ET IF RE TE TE IR RT EE ER NR 19 | 2 [ - 1 0 27 [se 2 1 a4 ETI DE ls 2 133 a —— eee © WO 00/05218 PCT/EP99/04904

   R; is hydrogen, or a (C,-Cgalkyl, (C;-Cs)alkenyl or (C,-Cs)alkynyl group optionally substituted by hydroxy, oxo, aryl or heterocycle, and optionally interrupted by one or more heteroatom(s) or heterogroup(s); the N—O derivatives of the compounds of formula I and the pharmaceutically acceptable salts thereof.
2. 2) A compound according to claim 1 wherein --——- is a double or single bond; and Z is methylene or a (C,-Cg)alkylene chain.
3. 3) A compound according to claim 1 wherein -——-- is a double or single bond; Z is methylene or a (C,-Ce)alkylene chain; and A is a heterocycle optionally substituted by one or more substituent(s).
4. 4) A compound according to claim 1 wherein --—-—- is a double or single bond; Z is methylene; and A is pyridine substituted by two substituents.
5. 5) A compound according to claim 4 of formula R, rR | Nh 9 / aA a (I-A) R al ZN
6. 6) A compound according to claim 5 wherein --—-- is a single bond and R; represents two hydrogen atoms.
7. 7) A compound according to claim 5 wherein -—--- is a double bond; and R; is cyano, (Ci-Cy)alkoxycarbonyl, amido, optionally substituted heterocycle, (C,-Cy)alkenyl or (C,-Cp)- alkynyl optionally substituted by aryl or heterocycle; aryloxy, heterocyclyloxy, arylamino, heterocyclylamino.
8. 8) A compound according to claim 7 of formula

   . CN

   CH Ra RA ZN i (-B) : | XN ci Z wherein R; is a heterocycle.
9. 9) A compound according to claim | selected among:

   1-(3,5-dichioro-pyridin-4-yimethy!}-6-methoxy-4-phenyl-phthalazine; 4~(3,5-dichloro-pyridin-4-ylmethy!)-7-methoxy-1 H-phthalazin-2-carboxylic acid methyl ester; benzyl-{3-[1-(3 ,S-dichloro-pyridin-4-yimethyl)-6-methoxy-phthalazin-5-yl] ~-prop-2-ynyl}- methyl-amine;

   1-3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-5-{5-morpholin-4-yl-pent-1 -ynyi)- phthalazine dihydrochloride; 3-[1-(3,5-dichloro-pyridin-4-yimethyl)-6-methoxy-phthalazin-5-y1}-prop-2-yn-1-ol; 1-(3,5-dichlorc-pyridin-4-ylmethy!)-6-methoxy-4-morpholin-4-yi-phthalazine; 1+(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-4-[1,2,4]triazol- 1-yl-phthalazine.
10. 10) A pharmaceutical composition containing a therapeutically effective amount of a compound according to claim [ in admixture with a suitable carrier.
11. 11) A pharmaceutical composition according to claim 10 for the treatment of aliergic and inflammatory diseases.
12. 12) A pharmaceutical composition according to claim 10 for the treatment of respiratory diseases.