Patent Application: US-98054001-A

Abstract:
the present invention relates to triazoloquinazoline - 5 - ones and 5 - thiones of formula i and formula ii , whereby i and ii are position isomers of group r on nitrogen 3 or 4 . optionally , the invention also relates to the racemic forms , isomers and pharmaceutically acceptable salts thereof . the invention further relates to a method for the production thereof and to compositions containing said derivatives . the compounds act as inhibitors of phosphodiesterase iv and , as such , have utility in treating asthma , chronic bronchitis , acutte pulmonary attack , atopic dermatitis , pulmonary hypertension , pulmonary insufficiency , cardiac insufficiency , psoriasis , inflammatory conditions of the digestive system such as haemorrhagic rectocolitis and crohn &# 39 ; s disease , acute respiratory distress syndrome , acute pancreatitis , benign hypertrophy of the prostate , rheumatoid arthritis , multiple sclerosis , depression , ischaemia - induced neuronal damage , partial cerebral ischaemia , and cancer such as malignant tumor and chronic lymphoid leukemia .

Description:
the current invention relates also to general formula i or ii compounds : in which x 1 , x 2 , a 1 , r , r 4 and r 5 are such as previously defined . the invention relates particularly to general formula i or ii compounds in which : x 1 represents a hydrogen and x 2 is a halogen , amino , lower alkyl , hydroxy or — nhr 1 group , a lower alkyl , lower alcenyl , aryl alkynyl , 2 -, 3 - or 4 - pyridylalkyl group possibly substituted on the pyridine ring by a lower alkyl , halogen or hydroxy ; y1 , y2 and y3 represent each a hydrogen atom or a lower alkoxy group , more particularly methoxy , y1 and y2 represent each a hydrogen atom and y3 represents a lower alkoxy group , amino , nitro , hydroxy group , —( ch 2 ) s co — q 1 — q 2 — q 3 group , ( ch 2 ) s — cn group in which , q 1 , q 2 , q 3 are such as previously defined , or a lower alkyl possibly substituted by one or several halogen atoms , the particularly preferred of the substituent y3 being the position 4 , or , y1 represents a hydrogen atom and y2 and y3 , similar or different , represent a hydroxy , halogen or lower alkoxy group , or y1 and y2 represent each a hydrogen atom and y3 is lower alkoxy or halogen ; lower alkyl when r4 and r5 are similar , aralkyl , cycloalkyl or cycloalkyl alkyl , when r 4 and r 5 are different , lower alkyl , r 4 and r 5 being able to be linked to form a saturated cycle or including one or several double - bonds with one or several heteroatoms chosen among o , s or n and possibly substituted by a lower alkyl , a hydroxy or a lower alkoxy or bridged by a lower alkyl , dialkylated gem or substituted by one or several groups chosen among hydroxy , keto , lower alkyl , lower alkoxy , phenyl alkyl or co — q 1 — q 2 — q 3 , two atoms of the cycle then formed may also be part of another cycle chosen among phenyl or heteroaryl comprising from 4 to 8 atoms including 1 to 4 heteroatoms ; the invention relates more particularly to general formula i compounds in which : x 2 represents a halogen atom , amino , lower alkyl , hydroxy or — nhr 1 ; y1 , y2 and y3 represent each a hydrogen atom or a lower alkoxy group , more particularly methoxy and in particular 3 , 4 , 5 - trimethoxy , y1 and y2 represent each a hydrogen atom and y3 represents a lower alkoxy group , amino , nitro , or hydroxy , a lower alkyl group possibly substituted by one or several halogen atoms , a —( ch 2 ) s co — q 1 — q 2 — q 3 group in which s is 0 or 1 , q 1 is o , — nh — or a valence bond , q 2 is —( ch 2 ) q —, q being equal to 0 , 1 , 2 , 3 or 4 and q 3 is h , oh or — nx 3 x 4 in which x 3 and x 4 are such as previously defined , a ( ch 2 ) s — cn group in which s is 0 or 1 , the position particularly preferred of the substituent y3 being the position 4 , or y1 represents a hydrogen atom and y2 and y3 , similar or different , represent a hydroxy , halogen or lower alkoxy group ; or ar 1 is an aromatic cycle including 6 atoms , one may be a nitrogen atom in position 2 , 3 or 4 and preferably in position 3 ; y1 and y2 represent each a hydrogen atom and y3 is a lower alkoxy group or a halogen group when ar 1 does not include a nitrogen atom ; and lower alkyl when r 4 and r 5 are similar , aralkyl , cycloalkyl or cycloalkyl alkyl , when r 4 and r 5 are different , lower alkyl , r 4 and r 5 being able to be linked to form a saturated cycle or including one or several double - bonds with one or several heteroatoms chosen among o , s or n and possibly substituted by a lower alkyl , a hydroxy or a lower alkoxy or bridged by a lower alkyl , dialkylated gem or substituted by one or several groups chosen among hydroxy , keto , lower alkyl , lower alkoxy , phenyl alkyl or co — q 1 — q 2 — q 3 , two atoms from the cycle then formed may also be part of another cycle chosen among phenyl or heteroaryl comprising from 4 to 8 atoms with 1 to 4 heteroatoms ; the invention relates also to general formula i or ii compounds in which : x 1 , x 2 , a 1 , r 4 and r 5 are such as previously defined in the summary of the invention ; and lower alkynyl , aryl alkynyl , 2 -, 3 - or 4 - pyridylalkyl possibly substituted by a lower alkyl , a lower alkoxy , a hydroxy or a halogen group , n is an integer from 1 to 5 and m is an integer from 3 to 5 ; ar is an aromatic cycle including 5 or 6 atoms with 0 to 3 heteroatoms chosen among o , s or n ; hydroxy , mercapto , amino , nitro , halogen , —( ch 2 ) s co — q 1 — q 2 — q 3 , ( ch 2 ) s — cn , in which s is an integer from 0 to 6 , lower alkyl , lower alkoxy or lower thioalkyl , possibly substituted by one or several halogen atoms . in another of its embodiments , the current invention relates to general formula i or ii compounds in which : x 1 , x 2 , r 4 and r 5 are such as previously defined in the summary of the invention ; and ar is an aromatic cycle including 5 or 6 atoms with 0 to 3 heteroatoms chosen among o , s or n ( aromatic cycles including 6 atoms , one atom could be a nitrogen in position 2 , 3 or 4 , preferably in position 3 ); hydrogen , hydroxy , mercapto , amino , nitro , halogen , cyano , —( ch 2 ) s co — q 1 — q 2 — q 3 in which s is an integer from 0 to 6 , lower alkyl , lower alkoxy or lower thioalkyl , possibly substituted by one or several halogen atoms . y1 and y2 represent each a hydrogen atom and y3 is a lower alkoxy or halogen . in another of its embodiments , the current invention relates to general formula i or ii compounds in which : x 1 , x 2 , a 1 , r 4 and r 5 are such as previously defined above in the summary of the invention ; and hydroxy , mercapto , amino , nitro , halogen , —( ch 2 ) s co — q 1 — q 2 — q 3 , ( ch 2 ) s — cn in which s is an integer from 0 to 6 , lower alkyl , lower alkoxy or lower thioalkyl , possibly substituted by one or several halogen atoms . y1 , y2 and y3 represent each a lower alkoxy group , more particularly methoxy and in particular 3 , 4 , 5 - triméthoxy , y1 and y2 represent each a hydrogen atom and y3 represents a lower alkoxy group , cyano , amino , nitro or hydroxy , a lower alkyl group possibly substituted by one or several halogen atoms or a —( ch 2 ) s co — q 1 — q 2 — q 3 group in which s is 0 or 1 , q 1 is o , — nh — or a valence bond , q 2 is —( ch 2 ) q —, q being equal to 0 , 1 , 2 , 3 or 4 and q 3 is h , oh or — nx 3 x 4 in which x 3 and x 4 are such as previously defined , the position particularly preferred of substituent y3 being position 4 , or y1 represents a hydrogen atom and y2 and y3 , similar or different , represent a hydroxy , halogen or lower alkoxy group . in another of its embodiments , the current invention relates to general formula i or ii compounds in which x 1 , x 2 , a 1 , r 4 and r 5 are such as previously defined in the summary of the invention ; and hydrogen , hydroxy , mercapto , amino , nitro , halogen , —( ch 2 ) s co — q 1 — q 2 — q 3 , ( ch 2 ) s — cn , in which s is an integer from 0 to 6 , lower alkyl , lower alkoxy or lower thioalkyl , possibly substituted by one or several halogen atoms . y1 and y2 represent each a hydrogen atom and y3is lower alkoxy or halogen . in another of its embodiments , the current invention relates to general formula i or ii compounds in which x 1 , x 2 , a 1 , r , r 4 and r 5 are such as previously defined in the summary of the invention ; and when x 1 and x 2 represent hydrogen , r is not alkyl , phenyl , benzyl or allyl , when x 1 represents hydrogen and x 2 represents 7 - cl or ch 3 , r is not alkyl ; and the invention relates also to a group of a formula i or ii compounds particularly active as tnfα inhibitors and in which : lower alkyl , lower alkoxy or — s ( o ) m r 8 in which m is 0 , 1 or 2 and r 8 is lower alkyl , possibly substituted by one or several halogen atoms . in a preferred manner , x 1 is h and x 2 is halogen , notably 7 - br , or lower alkyl , notably 7 - ch 3 . ar is an aromatic cycle including 5 or 6 atoms with 0 to 3 heteroatoms chosen among o , s or n , hydrogen , hydroxy , mercapto , amino , nitro , halogen , —( ch 2 ) s co — q 1 — q 2 — q 3 , ( ch 2 ) s — cn in which s is an integer from 0 to 6 ; lower alkyl , lower alkoxy or — s ( o ) m r 8 in which m is 0 , 1 or 2 and r 8 is a lower alkyl , possibly substituted by one or several halogen atoms . the substituents particularly preferred forming the group r include cinnamyl , 3 - pyridyl allyl , paracyano benzyl , dimethoxy benzyl and 3 - pyridyl méthyl . lower alkyl , r 4 and r 5 being able to be linked to form a saturated cycle or including one or several double - bonds with one or several heteroatoms chosen among o , s or n and possibly bridged by a lower alkyl , dialkylated gem or substituted by one or several groups chosen among hydroxy , keto , lower alkyl , lower alkoxy , phenyl alkyl or co — q 1 — q 2 — q 3 . substituants particularly preferred forming the group nr 4 r 5 include dimethylamino , pyrrolidine and azepanyl . in a general manner for groups x 1 , x 2 , x 3 , x 4 , r , r 1 , r 2 , r 3 , r 4 , r 5 : lower alkyl : linear or branched including 1 to 6 , preferably 1 to 3 carbon atoms , lower alkoxy : linear or branched comprising from 1 to 5 , preferably 1 to 3 carbon atoms , lower alkylthio : linear or branched comprising from 1 to 5 , preferably 1 to 3 carbon atoms , lower alcenyl : comprising from 3 to 6 , preferably 3 to 4 carbon atoms , more particularly allyl , lower alkynyl : comprising from 3 to 9 carbon atoms , more particularly propargyl and phényl - propargyl , 2 -, 3 - or 4 - pyridylalkyl in which alkyl includes from 1 to 5 , preferably 1 to 3 carbon atoms , aralkyl in which alkyl includes from 1 to 6 , preferably 1 to 4 carbon atoms , cycloalkyl alkyl in which alkyl includes from 1 to 6 , preferably 1 to 3 atoms de carbone and cycloalkyl include from 3 to 8 , de preferably 3 to 6 carbon atoms , lower alkyl , lower alkoxy or lower alkylthio possibly substituted by one or several halogen atoms : we will prefer trisubstituted groups of type —( ch 2 ) p — cf 3 , — o —( ch 2 ) p — cf 3 or — s —( ch 2 ) p — cf 3 , in which p is an integer from 0 to 3 . in particular manner for the groups x 1 and x 2 : — nh — r 1 , or — nr 2 r 3 : when lower alkyl is substituted by one or several groups chosen among halogen , hydroxy , cyano , lower alkoxy or co — q 1 — q 2 — q 3 , the substituents number varies between 1 and 4 , preferably between 1 and 2 , — nr 2 r 3 : when r 2 and r 3 are bound to form a cycle , this cycle is characterized as including preferably : between 1 and 4 , more particularly between 1 and 2 heteroatoms chosen among o , s or n , the cyclic substituents of this type being , in a preferred manner , saturated cycles of type c m n in which m is an integer from 2 to 7 , preferably 4 to 6 , particularly preferred cycles being chosen among group including pyrrolidine , piperidine , homopiperidine or cyclooctylamine and between 0 and 4 , in a preferred manner between 0 and 2 , more particularly between 1 and 2 substituents chosen among hydroxy , keto , lower alkyl , lower alkoxy or — co — q 1 — q 2 — q 3 , groups x 1 and x 2 are particularly localized in position 7 and 8 of aromatic cycle , for formula i and ii compounds to which they are bound . the substituents y1 , y2 and y3 are particularly localized in position 3 and / or 4 of the aromatic cycle to which they are bound . in particular manner for the groups r 4 and r 5 : when r 4 and r 5 are bound to form a cycle , this cycle is characterized as preferably including : between 1 and 4 heteroatoms chosen among o , s or n , cyclic substituents of this type being , in a preferred manner , saturated cycles of type c m n , m being an integer between 2 and 7 , cycles particularly preferred being chosen among group including pyrrolidine , piperidine , homopiperidine or cyclooctylamine , and between 0 and 4 , in a preferred manner between 0 and 2 substituents chosen among hydroxy , keto , lower alkyl , lower alkoxy or — co — q 1 — q 2 — q 3 . among the preferred compounds of the current invention , we find the following compounds : the invention relates also to salts acceptable in pharmacy of a formula i or ii compounds . we will find a review of pharmacologically acceptable salts in j . pharm . sci ., 1977 , 66 , 1 - 19 . however , by a pharmacologically acceptable salt of a formula i or ii compound presenting a basic function , we mean the addition salt of a formula i or ii compounds from non toxic inorganic or organic acids as for example salts of hydrobromic , hydrochloric , sulfuric , phosphoric , nitric , acetic , succinic , tartric , citric , maleic , hydroxymaleic , benzoic , fumaric , toluene - sulfonic , isethionic acids and others . various salts of quaternary ammonium of i or ii formula are also included in category compounds of this invention . and by pharmacologically acceptable salts of a formula i or ii compound presenting an acid function , we mean usual salts of a formula i or ii compounds made from non - toxic mineral or organic bases as for example hydroxides of alkaline and alkaline earth metals ( sodium , potassium , magnesium and calcium ), amines ( dibenzylethylenediamine , trimethylamine , piperidine , pyrrolidine , benzylamine and others ) or also quaternary ammonium hydroxides like tetramethylammonium hydroxide . as previously mentioned , formula i and ii compounds of the current invention are inhibitors of phosphodiesterase enzyme and particularly of phosphodiesterase 4 ( pde4 ) enzyme . consequently , their use is recommended for treatment of diseases or affections relying on therapy by pde4 inhibition . as an example , compounds of the current invention can be recommended for treatment of septicemia , polyvisceral deficiency , asthma , chronic bronchitis , emphysema , chronic obstructive pneumopathy ( or copd ), allergic rhinitis , atopic dermatitis , pulmonary high blood pressure , cardiac or pulmonary insufficiency , congestive cardiac insufficiency , psoriasis , inflammatory diseases of the digestive system such as hemorrhagic rectocolitis and crohn &# 39 ; s disease , diseases linked to elevated tnf - α levels such as acute respiratory distress syndrome in the adult and acute pancreatitis , rhumatoid arthritis , osteoporosis , multiple sclerosis and depression . pde4 inhibitors of the current invention may also be used for treatment of acute pulmonary attack , neuronal attack caused by ischemia ( ischemia - induced neuronal damage ), diabetes , chronic lymphoid leukemia , and to attenuate development of tolerance or dependence phenomena to morphine . compounds of the invention may also contribute to decreasing memory loss of behavior ( behavioral memory ) such as observed for example in patients suffering from alzheimer &# 39 ; s disease . we may also consider use of the compounds of the current invention in the fields of urology , more particularly in treatment of prostate disease such as benign hypertrophy of the prostate or for prevention of premature child birth , for example by inhibition of contraction triggering before term , preferably by pde4 inhibitor action on myometrium . the inventors , wishing not to be bound in a formal manner to a definitive theory , agree that structural parameters mentioned below may be considered in order to guide the person skilled in the art in the choice of substituents combination which , beyond preferred compounds disclosed in the current application , may allow not only an optimization of the pdb4 inhibitor activity , but also a better optimization of important additional parameters such as solubility , biodisposability and toxicity of considered compounds . first , the inventors consider that the catalytic site of the enzyme pde4 is of a sufficiently large size to globally accommodate a fairly wide range of structural changes in substituents of the compounds of the invention which can bind to this site . in this respect , the inventors consider that compounds of the current invention have probably the capacity to interact at least on three distinct points of the catalytic site of the isoenzyme pde4 . one first interaction point may be localized on the aromatic ring including the substituents x 1 and x 2 . a second interaction point is probably localized on substituent r while a third interaction point is probably localized on group nr 4 r 5 . potential functionality of each binding point is suggested below . however , it is important to precise here that interaction points mentioned above are not necessarily classified by increasing or decreasing importance order relating to their incidence on inhibitory activity of invention compounds . in fact , it seems possible that each interaction point participates in a different manner in global pharmacological properties of these compounds . the first interaction point mentioned previously may be localized then on the aromatic ring including substituents x 1 and x 2 . this aromatic ring may participate to the invention compound binding to enzyme pde4 catalytic site , it seems possible to modulate this binding by substituents x 1 and x 2 choice . experiments performed up - to - date by the inventors tend to demonstrate that substituents x 1 and x 2 currently preferred are those for which x 1 is hydrogen and x 2 is chosen among halogen , more particularly br and cl , methyl , hydroxy , amino and alkylamino . we establish then that among preferred substituents x 2 , we simultaneously find some donors ( e . g . methyl ) and some attractors ( e . g . br , cl ) of electrons . it seems then unlikely that x 2 could be chosen solely according to electronic properties of the recommended substituent . the inventors agree that important selection criteria are placed initially on substituent position in the aromatic ring and therefore on the level of some parameters such as substituent steric congestion or presence of donor atom or proton acceptor . however , it seems established that substituents x 1 and x 2 position on the aromatic ring could have an influence on final activity of invention compounds . as an example , compounds including a substituent other than hydrogen in position 7 are generally more active that the same compounds including this substituent in position 8 . thus it seems probable than choice and position of substituents x 1 and x 2 allow to move the aromatic ring inside the cavity of the pde4 catalytic site and consequently to modulate inhibitory activity of invention compounds . moreover , it seems that compounds including a substituent in position 7 are more selective of sub - type pde4 compared to the other isoenzymes pde5 , pde3 and pde1 than compounds including a substituent in position 8 . these latter have a pde4 inhibitory activity ( although less ) but they seem less selective compared to the other isoenzymes . however , it seems clearly also that although x 1 and x 2 could be chosen among an outstanding number of substituents , we will obtain a better tolerance for this choice if substituent r is well targeted . the second interaction point of compounds of the current invention with the enzyme pde4 will be localized on the substituent r . the inventors reckon that it concerns presumably of the most important anchorage point of the molecule to the enzyme . it seems indeed probable that this second interaction is localized in a large cavity inside the pde4 catalytic site . it is then essential that the substituent r can be anchored to the catalytic site . however , the choice of groups included in the definition of r given above , seems to demonstrate some flexibility on r anchorage to this second binding site . therefore , it could be possible to obtain a pde4 inhibitory activity with compounds having rather different substituents r from a structural point of view . as an example , we will prefer the use of a substituent including an aromatic ring , preferably substituted itself , and separated from the principal heterocycle by a chain including between 1 and 4 atoms , particularly some carbon atoms , the said substituent presenting a relatively variable spatial orientation . this observation seems to open the way to the possibility to modulate in a more subtle manner the global properties of invention compounds . the inventors agree indeed that although substituent r remains most probably a determinant element on pde4 inhibitory activity of invention compounds , it is probably possible to make it vary and then act on the important extra pharmacological parameters without altering this inhibitory activity in a substantial manner . as an example , some compounds including in substituent r a group — ch 2 ch ═ ch — c 6 h 5 or a substituted benzyl group , preferably in position 4 ( other substituents being identical for the two compounds ), have pde4 inhibitory activity of same magnitude order . the third interaction site of the compounds of the invention on pde4 is localized presumably on group — nr 4 r 5 . the inventors agree that it concerns probably a binding site much more specific that the two sites disclosed above although substituent r moving in the enzymatic cavity may however influence on specificity of this third site . compounds of the invention having the best inhibitory activities are those for which r 4 and r 5 , which represent each a lower alkyl , are bound to form a cycle , preferably including between 5 and 8 carbon atoms , more particularly a cycle with 5 or 7 carbon atoms . the skilled person &# 39 ; s scope for manoeuvre on this group &# 39 ; s variation seems then more limited . in summary , experimentation performed by the inventors with compounds of the current invention seem to demonstrate that the size of pde4 catalytic site is large enough to accommodate several structural changes on the three binding sites disclosed previously . however , the most important handling margin seems anyway to be localized on the substituent r variation . the compounds of the invention are administrated as an appropriate composition accordingly to the nature and the scale of the disease to treat . the daily posology in humans is usually between 2 mg and 1 g of product that can be absorbed in one or several intakes . the compositions are prepared by usual methods for the skilled man and contain in a general manner 0 . 5 to 60 % by weight of active principle ( formula i compounds ) and 40 to 99 . 5 % by weight of appropriate pharmaceutical carrier . the compositions of the current invention are then prepared under forms compatible with the desired administering route . as an example , the following pharmaceutical forms may be considered , although the listing provided below is not limiting : drinkable solutions , suspensions , powder sachets for drinkable solution , capsules , gastro - resistant capsules , prolonged - release forms , emulsions , hpmr capsules , lyophilisates to melt beneath the tongue . aqueous solutions , solutions water / co - solvent , solutions using one or several solubilizing agents , colloidal suspensions , emulsions , nano - particle suspensions usable for injection of long - lasting release forms , diffuse forms and liposomes . in addition , forms usable as intravenous route which are also usable for subcutaneous and intra - muscular routes , other form types such as suspensions , diffused forms , long - lasting release colloids as well as long - lasting release implants can also be used . among the most used topic forms , we distinguish creams , colloids ( aqueous phases jellified by polymers ), patches , which are dressings to stick directly on skin and which can be used to treat dermatitis without percutaneous penetration of the active substance , sprays , emulsions and solutions . in this category we distinguish forms of solutions for aerosols , powders for inhaling apparatus , and other appropriate forms . we can also consider the use of forms allowing ophthalmic solution administering or allowing administering of active principle by vaginal route . another important category of pharmaceutical form , which can be used in the context of the current invention , relates to forms allowing improvement in solubility of the active principle . as an example , we can consider the use of aqueous solutions of cyclodextrin , and more particularly forms including hydroxypropyl beta cyclodextrin . a detailed review of this type of pharmaceutical form is presented in an article issued in the journal of pharmaceutical sciences , 1142 - 1169 , 85 ( 11 ), 1996 , and incorporated herein by . different pharmaceutical forms recommended above are disclosed in a detailed manner in the to book (( pharmacie galénique )) by a . lehir ( ed . masson , 1992 ( 6 th edition ) incorporated reference . the current invention relates also to general formula iii intermediaries compounds : in which x 1 , x 2 , a 1 , r 6 and r 7 are such as previously defined . the invention relates particularly to general formula iii intermediaries compounds in which : x 1 and x 2 are such as previously defined , and r 7 is bound to nitrogen in r 6 to form a triazol , substituted in position 1 by a br , cl , mercapto or lower thioalkyl group preferably ch 3 — s —. in a general manner for the groups x 1 , x 2 , r 6 and r 7 : lower alkyl : linear or branched comprising from 1 to 6 , preferably from 1 to 3 carbon atoms , lower alkoxy : linear or branched comprising from 1 to 5 , preferably 1 to 3 carbon atoms , lower thioalkyl : linear or branched comprising from 1 to 5 , preferably 1 to 3 carbon atoms . in particular manner for the groups x 1 and x 2 : x 1 and x 2 are particularly localized in position 6 and 7 of the main quinazolinone cycle . in particular manner for the groups r 6 and r 7 : when r 7 is bound to the nitrogen in r 6 to form a cycle , the formed cycle is preferably a triazole , substituted in position 1 by a group br , cl , mercapto or lower thioalkyl , preferably ch 3 — s —. a second series of intermediaries includes the following general formula iv compounds : in which x 1 , x 2 , a 1 , r 4 and r 5 are such as previously defined . in a general manner for the groups x 1 , x 2 , r 4 and r 5 : lower alkyl : linear or branched comprising from 1 to 6 , preferably 1 to 3 carbon atoms , lower alkyl : linear or branched comprising from 1 to 5 , preferably 1 to 3 carbon atoms , lower alkyl , r 4 and r 5 being able to be linked to form a saturated cycle or including one or several double - bonds including one or several heteroatoms chosen among o , s or n and possibly bridged by a lower alkyl , dialkylated gem or substituted by one or several groups chosen among hydroxy , keto , lower alkyl , lower alkoxy , phenyl alkyl or co — q 1 — q 2 — q 3 , two atoms of the cycle then formed could also be part of another cycle chosen among phenyl or heteroaryl comprising from 4 to 8 atoms with 1 to 4 heteroatoms . in particular manner for the groups x 1 and x 2 : x 1 and x 2 are particularly localized in position 6 and 7 of the main quinazolinone cycle . in particular manner for the groups r 4 and r 5 : r 4 and r 5 are lower alkyl , r 4 and r 5 being able to be linked to form a saturated cycle or including one or several double - bonds with one or several heteroatoms chosen among o , s or n , substituted by one or several groups chosen among hydroxy , keto , lower alkyl or lower alkoxy . the particularly preferred substituents forming the group nr 4 r 5 includes pyrrolidine , 3 - hydroxy pyrrolidine , thiamorpholine , dimethyl amino , azepanyl and piperidinyl . a third series of intermediaries includes the following general formula v compounds : in which x 1 , x 2 , x 5 , a 1 and r are such as previously defined . in a general manner for the groups x 1 , x 2 and x 5 : lower alkyl : linear or branched comprising from 1 to 6 , preferably 1 to 3 carbon atoms , lower alkoxy : linear or branched comprising from 1 to 5 , preferably 1 to 3 carbon atoms : in particular manner for the groups x 1 and x 2 : x 1 and x 2 are particularly localized in position 6 and 7 of the main quinazolinone cycle . in particular manner for the group x 5 : x 5 is f , br or cl . a fourth series of intermediaries includes the following general formula vi compounds : in which x 2 , x 5 , a 1 and r are such as previously defined . in a general manner for the groups x 2 and x 5 : lower alkyl : linear or branched comprising from 1 to 6 , preferably 1 to 3 carbon atoms , lower alkoxy : linear or branched comprising from 1 to 5 , preferably 1 to 3 carbon atoms . x 2 is particularly localized in position 7 of the main quinazolinone cycle . in particular mariner for the group x 5 : x 5 is f , br or cl . a fifth series of intermediaries includes the following general formula vii compounds : in which x 2 , x 5 a 1 , r 2 r 3 are such as previously defined . in a general manner for the groups x 2 , x 5 , r 2 and r 3 : lower alkyl : linear or branched comprising from 1 to 6 , preferably 1 to 3 carbon atoms , lower alkoxy : linear or branched comprising from 1 to 5 , preferably 1 to 3 carbon atoms , hydrogen , lower alkyl , possibly substituted by one or several groups hydroxy , halogen , cyano , lower alkoxy or — co — q 1 — q 2 — q 3 , r 2 and r 3 being able to be linked to form a cycle , including one or several heteroatoms chosen among o , s or n and possibly bridged by a lower alkyl , dialkylated gem or substituted by one or several groups chosen among hydroxy , keto , lower alkyl , lower alkoxy or — co — q 1 — q 2 — q 3 . x 2 is particularly localized in position 7 of the main quinazolinone cycle . in particular manner for the group x 5 : x 5 is f , br or cl . in particular manner for the groups r 2 and r 3 : r 2 and r 3 , similar or different , are hydrogen , lower alkyl r 2 and r 3 being able to be linked to form a cycle , including one or several heteroatoms chosen among o , s or n and possibly substituted by one or several groups chosen among hydroxy , keto , lower alkyl , lower alkoxy or co — q 1 — q 2 — q 3 . among the particular preferred embodiments of the substituent nr 2 r 3 , we find the groups azepanyl , pyrrolidine , nh 2 and nhch 3 . a ) the compounds of the current invention can be obtained by bringing several synthesis processes into operation . some of these synthesis processes are disclosed below . the compounds of the current invention can be initially obtained in a convergent manner by the method represented in scheme 1 . in which x 1 , x 2 , a 1 , r , r 4 and r 5 are such as previously defined , and r 8 represents cl , br , oso 2 ch 3 , oso 2 cf 3 or oso 2 ar . the 4 - benzyl 1 - amino triazolo [ 4 , 3 - a ] quinazoline - 5 - one and / ou − 5 - thione ( iva ) is treated by aluminium trichloride in aromatic solvent such as benzene or toluene to make the corresponding compound n - debenzylated ( iv ). this one is therefore treated in basic conditions by a halide or a sulfonate chosen according to desired substituent r ; for example sodium hydride in a solvent such as 1 , 2 - dimethoxyethane ( dme ) or cesium in dimethylformamide , to lead to 1 - amino triazolo [ 4 , 3 - a ] quinazoline - 5 - ones of formula ( i ) and ( ii ). in fact , relying of the basic conditions used , the alkylation is a little regioselective in some cases . then we obtain a mixture of n 4 and n 3 , regioisomers , ( i ) and ( ii ) respectively . the two compounds are usually separated by conventional chromatographic methods . b ) another example of synthesis method used to construct correctly substituted formula ( i ) triazolo [ 4 , 3 - a ] quinazoline - 5 - one and / or − 5 - thione motif is illustrated by scheme 2 : in which x 1 , x 2 , a 1 , r , r 4 and r 5 are such as previously defined and , r ′ represents a linear or branched lower alkyl group comprising from 1 to 6 , preferably 1 to 3 carbon atoms . an acid or anthranilic ester which is correctly substituted on the aromatic cycle ( va ) is initially transformed into corresponding 2 - thio quinazoline - 4 - one and / or - 4 - thione ( vb ) by cyclization using isothiocyanate of alkyl , aryl or aralkyl , in a solvent such as acetic acid or pyridine . the thio quinazoline - 4 - one and / or - 4 - thione ( vb ) is treated by hydrazine hydrate to give 2 - hydrazino quinazoline4 - one and / or - 4 - thione ( vc ) which is also cyclized into 1 - mercapto triazolo [ 4 , 3 - a ] quinazoline - 5one and / or - 5 - thione ( vd ) by action of potassium xanthogenate or other reagents such as cs 2 . by action of an alkylating agent such as dimethyl sulfate , the thiol ( vi ) is transformed into derivative 1 - methylthio ( ve ) which is then converted using chlorine , into 1 - chloro triazolo [ 4 , 3 - a ] quinazoline - 5 - one and / ou - 5 - thione ( v ). this latter is treated by a primary our secondary amine to lead finally to 1 - amino triazolo [ 4 , 3 - a ] quinazoline - 5 - one of formula ( i ). c ) another advantageous method in some cases is represented in scheme 3 . in which x 1 , x 2 , a 1 , r , r 4 and r 5 are such as previously defined and , r ″ represents a linear or branched lower alkyl group comprising from 1 to 6 , preferably 1 to 3 carbon atoms such as ch 3 or c 2 h 5 . la 2 - hydrazino quinazoline - 4 - one and / or - 4 - thione ( vc ), obtained from an anthranilate in 2 steps ( as illustrated in scheme 2 ), is cyclized using alkyl orthoformiate , in acid medium , into triazolo [ 4 , 3 - a ] quinazoline - 5 - one and / or - 5 - thione ( vf ). this is then brominated by bromine or n - bromosuccinimide ( nbs ) to give 1 - bromotriazolo [( 4 , 3 - a ] quinazoline - 5 - one and / or - 5 - thione ( v ). this brominated derivative is finally treated by ethanolic solution of primary or secondary amine to lead to formula ( i ) 1 - amino triazolo [ 4 , 3 - a ] quinazoline - 5 - one and / or - 5 - thione . d ) when x 1 represents h and x 2 represent a reactive phenolic function oh , this group must generally be protected during the last steps of compound ( i ) synthesis . as an example , scheme 4 shows synthesis of such as hydroxyled in position 7 compound . the 4 - benzyl - 7 - hydroxy - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one and / or - 5 - thione ( vg ), obtained by a method represented in scheme 3 , is treated by a compound allowing insertion of oxygen protector group ( p ) on the function oh . the person skilled in the art will be able to choose without any problem the appropriate protector group . the protector group can be chosen also among silyl trimethyl , methoxymethyl , tolylsulfonyl , methylsulfonyl ( mesyl ) or also methoxyethylmethoxy ( mem ). as an example , the compound ( vg ) is treated by tosyl chloride , in a solvent such as methylene chloride , in the presence of a base or an amine such as triethylamine , to give the corresponding o - tosyled phenol ( vf ). this is treated by bromine to lead to 4 - benzyl - 1 - bromo - 7 -( 4 - tolylsulfonyl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one and / or - 5 - thione ( v 3 ), which reacts with an amine hnr4r5 by reflux , preferably in the presence of a base like sodium bicarbonate , in a solvent such as dimethylformamide , to give the 1 - amino - 4 - benzyl - 7 -( 4 - tolylsulfonyl )- 4 - h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one and / or - 5 - thione ( iva 1 ). we can then replace the benzyl group in position 4 by another group r , for example by debenzylating the compound ( iva 1 ) obtained previously using aluminium chloride in a solvent like benzene , then by alkylating the obtained intermediate ( iv 1 ) by treatment with a halide or a sulfonate r — x 5 , in basic conditions , to obtain the 1 - amino - 7 -( 4 - tolylsulfonyl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one and / or - 5 - thione ( ia ) diversely substituted in position 4 . these ones are preferably detosyled into 7 - hydroxy derivative ( i ) for example by heating for several hours in pyrrolidine . in which a 1 , r 4 and r 5 are such as previously defined . e ) when x 1 represents h and x 2 represents a reactive anilino function nh2 , nhr2 or nr 2 r x ( r 2 such as previously defined and r x represents r 2 or such as previously defined ), the amino group nh 2 must generally be protected during the last steps of the compound ( i ) synthesis . as an example , scheme 5 shows synthesis of such as aminated compound in position 7 . the 7 - acetamido - 4 - benzyl - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one and / or - 5 - thione ( vf 1 ), obtained by a method represented in scheme 3 , is treated by bromine to lead to the 7 - acétamido - 4 - benzyl - 1 - bromo - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one and / or - 5 - thione ( v 4 ). this one is used in the reaction with an amine hnr 4 r 5 by reflux , preferably in the presence of a base as sodium bicarbonate , in a solvent such as dimethylformamide , to give the 7 - acétamido - 1 - amino - 4 - benzyl - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one and / or - 5 - thione ( iva 2 ). in the example disclosed above , the protector group ( p 1 ) of the function nh is an acetyl group . however the man of art may choose another protector group , for example methylsulfonyl , tolylsulfonyl or phtalimido . we can also replace the benzyl group in position 4 by another group r , for example by debenzylating the compound ( iva 2 ) obtained previously , using ammonium formiate and palladium on charcoal , in a solvent such as tetrahydrofuran , then by alkylating the obtained intermediate ( iv 2 ) by treatment with a halide or a sulfonate r — x 5 , in basic conditions , to obtain the 7 - acetamido - 1 - amino - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one and / or - 5 - thione ( i ) diversely substituted in position 4 . these ones can be n - deacetylated into final compounds ( ib ) bearing a function nh2 in position 7 , by classic methods like for example by reflux heating in an aqueous solution of hydrochloric acid . the compounds can be treated in at their turn , relying on the case , by a reagent r 2 — x 5 ( r 2 and x 5 having the meaning given previously ) to lead to a final n - monosubstituted compound ( ic ), which then can be treated by a reagent r x x 5 to lead to a final n , n - disubstituted compound ( 1d ). also it is possible to treat 7 - acetamido - 1 - amino - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one and / or - 5 - thione ( i ) diversely substituted in position 4 initially by a reagent r 2 x 5 to obtain ( 1b 2 ) which is then n - deacetylated to obtain the compound ( ic ). f ) when the substituent r in position 4 of compounds ( i ) represents a group 4 -( carboxymethyl )- benzyl , it can be advantageous to transform the carboxylic acid function into ester , amide , nitrile or hydroxamic acid derived . for that , methods represented in scheme 6 can be applied to a general formula acid ( id ). this is transformed into chloride of acid ( ie ), which is directly condensed either with ammonia to give a primary amide ( if ), either with a primary or secondary amine to give a secondary ( ih ) or tertiary ( ii ) amide respectively . ( in these structures , r 11 has the same meaning as r 2 and r 12 have the same meaning as r 4 , r 5 respectively ). the hydroxamic acid ( ij ) can be obtained by reaction of chloride of acid ( ie ) with hydroxylamine . the primary amide ( if ) can be dehydrated by classic and current methods , for example using phosphorus pentoxide to lead to corresponding nitrile ( ig ). in which x 1 , x 2 , a 1 , r 4 and r 5 are such as previously defined . g ) the compounds of structure ( i ) in which x 1 or x 2 represents an amino nr 2 r 3 group in position 8 identical to the nr 4 r 5 group , can also be obtained by heating of corresponding 1 - bromo ( vi ; x 5 = hal ) intermediates in the presence of an excess of hnr 4 r 5 amine , without solvent or in a solvent such as dimethylformamide as illustrated in scheme 7 . in x 2 , x 5 , a 1 , r , r 4 and r 5 are such as previously defined . however it is preferable to avoid for this reaction type substituents r including a halogen group able to react in a competitive manner with the reagent hnr 4 r 5 . h ) in the case where two nr 2 r 3 and nr 4 r 5 amino groups are different , a slightly modified synthesis path is indicated in scheme 8 . in which x 2 , a 1 , r , r 2 , r 3 , r 4 and r 5 are such as previously defined . the substituent amino nr 2 r 3 is localized in position 8 . 1 - bromo 8 - chlorotriazolo [ 4 , 3 - a ] quinazoline - 5 - one and / or - 5 - thione ( via ) correctly substituted in position 4 , and prepared as previously by bromination of non - substituted in position 1 derivative , is treated by slight excess of amine hnr 2 r 3 , in a solvent such as dimethylformamide to lead to intermediate ( vii ). this intermediate is also heated in an excess of amine hnr 4 r 5 , in a solvent such as dimethylformamide to lead to compound ( i ). surprisingly , the inventors have noticed that reactivity of the halogen atom in position 8 is much more important than reactivity of the other halogen atom of the intermediate . this allows then a first selective reaction on the level of this halogen in position 8 than can be followed by reaction on the level of the second halogen . the example as above illustrates use of chlorine in position 8 . however it is possible to use other halogens such as bromine and fluorine , the latter proving to be particularly reactive . in a reactor protected from humidity , we place 2 . 5 g ( 7 . 87 mmol ) of 1 - azepan - yl - 7 - chloro - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one , in suspension in 35 ml of 1 , 2 - dimethoxyethane then we shake . under inert atmosphere , we then add 240 mg of sodium hydride suspension at 75 % ( representing 7 . 90 mmol nah ). the mixture is heated to 60 ° c . under shaking for 6 hours . then we add 1 . 56 g ( 7 . 90 mmol ) of cinnamyl bromide by fraction . the obtained mixture is heated then to 60 ° c . for 20 hours , under shaking . after cooling down , the suspension is poured into 200 ml of iced water . we extract three times with ethyl acetate ; the joined organic phases are washed with aqueous solution saturated with sodium chloride , dried on sodium sulfate ; then the solvent is evaporated under vacuum . we obtain 3 . 5 g of crude mixture of the two regioisomers ( theory : 3 . 4 g ). the 2 isomers are separated by flash chromatography on silica column with elution using methylene chloride 99 / methanol 1 mixture . rmn 1 h δ ( ppm ) cdcl 3 : 1 . 7 - 2 . 0 ( m , 8h ); 3 . 3 - 3 . 5 ( m , 4h ); 5 . 05 ( d , 2h ); 6 . 45 ( dt , 1h ); 6 . 9 ( d , 1h ); 7 . 15 - 7 . 3 ( m , 3h ); 7 . 35 ( d , 2h ); 7 . 75 ( d , 1h ); 8 : 35 ( s , 1h ); 8 . 4 ( d , 1h ). rmn 1 h δ ( ppm ) cdcl 3 : 1 . 7 - 2 . 0 ( m , 8h ); 3 . 4 ( m , 4h ); 4 . 9 ( d , 2h ); 6 . 35 ( d , 1h ); 6 . 75 ( d , 1h ); 7 . 2 - 7 . 45 ( m , 5h ); 7 . 65 ( d , 1h ); 8 . 2 ( d , 1h ); 8 . 45 ( s , 1h ) in a reactor equipped with magnetic shaker and refrigeration , we resuspend 7 . 4 g ( 0 . 024 mol ) of 7 - bromo - 1 -( n , n - dimethylamino )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one in 200 ml de 1 , 2 - dimethoxyethane then we shake . we add 17 . 0 g ( 0 . 052 mol ) of cesium carbonate then shake at ambient temperature for 15 minutes . 4 . 5 g ( 0 . 024 mol ) of 3 -( 3 - pyridyl )- allyl chloride hydrochloride are then added by fraction , then the mixture is heated to 70 ° c ., under shaking , for 3 hours . the solvent is evaporated under vacuum then the residue is then put in suspension in 300 ml of iced water . after repeated extractions with ethyl acetate , the joined organic phases are washed with aqueous solution saturated with sodium chloride , dried on sodium sulfate then the solvent is evaporated under vacuum . the residue is chromatographied on silica column by elution using ch 2 cl 2 98 / ch 3 oh 2 / nh 4 oh 0 , 2 mixture . we recover 6 . 3 g of isomer ( i ) pure in ccm . this one is recrystallized in 20 ml of isopropanol to give 5 . 3 g of example 3 compound : rmn 1 h δ ( ppm ) cdcl 3 : 2 . 95 ( s , 6h ); 5 . 1 ( d , 2h ); 6 . 45 ( dt , 1h ); 6 . 8 ( d , 1h ); 7 . 15 ( m , 1h ); 7 . 65 ( d , 1h ); 7 . 9 ( d , 1h ); 8 . 25 ( d , 1h ); 8 . 4 - 8 . 6 ( m , 3h ). in a reactor protected from humidity , equipped with magnetic shaking and refrigeration , we add 2 . 0 g ( 0 . 006 mol ) of 1 -( pyrrolidin - 1 - yl )- 7 - bromo - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one into 125 ml of dimethylsulfoxyde ( dmso ) solution then we add 1 . 0 g ( 0 . 018 mol ) of finely crushed potash . the mixture is shaken at ambient temperature for 1 . 5 h , until obtaining of slightly cloudy solution . then we add once 0 . 82 g ( 0 . 005 mol ) of 3 - picolyl chloride hydrochloride then keep shaking at ambient temperature for 4 hours . the obtained mixture is poured into iced water and the resulting suspension is extracted 3 times with ethyl acetate . the joined organic extracts are washed in nacl saturated solution , dried on na 2 so 4 then concentrated under vacuum . we obtain 2 . 0 g of crude mixture of the 2 regioisomers which are separated by chromatography on silica column by elution using ch 2 cl 2 98 - ch 3 oh 2 - nh 4 oh 0 . 4 mixture . 1 ) 1 . 2 g of majority product which is recrystallized in methanol to give after drying under vacuum 1 , 1 g of example 4 compound . rmn 1 h δ ( ppm ) cdcl 3 : 1 . 95 - 2 . 1 ( m , 4h ); 3 . 35 - 3 . 45 ( m , 4h ); 5 . 45 ( s , 2h ); 7 . 2 - 7 . 3 ( dd , 1h ); 7 . 85 ( d , 1h ); 8 . 0 ( d , 1h ); 8 . 2 ( d , 1h ); 8 . 45 - 8 . 55 ( m , 2h ); 8 . 9 ( s , 1h ). 2 ) 0 . 25 g of minority product which is recrystallized in methanol to give after drying under vacuum 0 . 17 g of example 5 compound . rmn 1 h δ ( ppm ) cdcl 3 : 1 . 9 - 2 . 05 ( m , 4h ); 3 . 2 - 3 . 4 ( m , 4h ); 5 . 25 ( s , 2h ); 7 . 1 - 7 . 2 ( m , 1h ); 7 . 7 ( d , 1h ); 7 . 8 ( d , 1h ); 7 . 9 ( d , 1h ); 8 . 45 - 8 . 60 ( m , 2h ); 8 . 65 ( s , 1h ). compounds ( i ) of examples 6 to 108 and compounds ( ii ) of examples 109 to 162 , in which x 2 = h 1 are prepared according to process of example 1 : after cooling down , the obtained solution is concentrated under vacuum to give 4 . 8 g of residue which is purified by flash chromatography on silica column , by elution with the mixture ch 2 cl 2 99 . 6 / ch 3 oh 0 . 4 . the fractions pure in ccm are joined , evaporated until dry and the obtained product ( 4 . 0 g ) is recrystallized in ethanol . we obtain 3 . 2 g of compound from example 163 as crystals . nmr 1 h δ ( ppm ) cdcl3 : 1 . 7 - 1 . 85 ( m . 8h ); 3 . 3 ( m . 4h ); 5 . 3 ( s . 2h ); 7 . 2 - 7 . 35 ( m . 3h ); 7 . 45 - d . 2h ); 8 . 0 ( d . 1h ); 8 . 15 ( s . 1h ); 8 . 4 ( d . 1h ) in a reactor protected from humidity , we resuspend 37 . 0 g ( 85 mmol ) of 4 - benzyl - 1 , 7 - dibromo - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one in 750 ml of dimethylformamide ( dmf ) and add 14 . 3 g ( 340 mmol ) of sodium bicarbonate then 12 . 1 g ( 340 mmol ) of pyrrolidine . the mixture is then heated by reflux , under shaking , for 6 hours . after cooling down , the solvent is evaporated under vacuum , the obtained residue is resuspended in a mixture water / ethyl acetate and the insoluble fraction is triturated then filtered and dried : we obtain then from a first round 18 . 3 g of compound from example 164 , this compound being pure by ccm . the aqueous and organic phases are separated , the ethyl acetate phase is washed in water and dried on na 2 so 4 . after solvent concentration under vacuum , we obtain from a second round 14 . 2 g of compound from example 164 , also pure by ccm . yield ( as crude product )= 90 %; the product will be used like this in the next step . a 0 . 35 g sample is recrystallized in methanol to give 0 . 32 g of pure compound as crystal . n . m . r . 1 h δ ( ppm ): 2 . 1 ( m . 4h ); 3 . 4 ( m . 4h ); 5 . 45 ( s . 2h ); 7 . 3 ( m . 3h ); 7 . 65 ( d . 2h ); 7 . 85 ( d . 1h ); 8 . 15 ( d . 1h ); 8 . 45 ( s . 1h ) in a pressure reactor , we resuspend 2 . 5 g ( 5 . 75 mmol ) of 4 - benzyl - 1 , 7 - dibromo - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one in 30 ml of ethanol . we add 5 . 0 g of n - butyl - methylamine ( 57 . 5 mmol ), we hermetically seal the reactor then we heat in an oil bath at 160 ° c . for 8 hours . after cooling down and leaving aside for 2 days , the residual oil ( 2 . 8 g ) is chromatographied on silica column by elution with the mixture ch 2 cl 2 99 . 5 - ch 3 oh 0 . 5 . we obtain 1 . 8 g of compound from example 165 . n . m . r . 1 h δ ( ppm ): 0 . 9 ( t . 3h ); 1 . 25 - 1 . 4 ( m . 2h ); 1 . 55 - 1 . 7 ( m . 2h ); 2 . 85 ( s . 3h ); 2 . 9 - 3 . 5 ( m . 2h ); 5 . 5 ( s . 2h ); 7 . 2 - 7 . 35 ( m . 3h ); 7 . 7 ( d . 2h ); 7 . 9 ( d . 1h ); 8 . 25 ( s . 1h ) the compounds ( i ) from examples 166 to 198 ( table 3 ) are prepared according to one of the methods a , b or c described in examples 163 to 165 . in a 50 ml balloon flask , equipped with a shaker and refrigeration , we resuspend 0 . 44 g ( 1 , 27 mmol ) of 4 - benzyl - 1 , 7 - dichloro - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( example 254 ) in 2 . 5 ml of hexamethylene imine . under shaking , the mixture is heated by reflux for 16 hours . the obtained brown solution is then left aside to ambient temperature until complete cooling down ; then we pour in a mixture of water and methylene chloride , shake and separate the 2 phases by decantation . the organic phase is washed twice in water , dried on na 2 so 4 then evaporated under vacuum to give 0 . 59 g of brown solid residue . this is chromatographied on silica column by elution with the mixture ch 2 cl 2 99 . 5 / ch 3 oh 0 . 5 . we obtain after joining and evaporation of pure by ccm fractions , 0 . 46 g of compound from example 199 . this is recrystallized in ethanol to give 0 . 4 g of colorless crystal . n . m . r . 1 h δ ( ppm ): 1 . 7 - 1 . 85 ( m . 8h ); 3 . 3 ( s . 4h ); 5 . 3 ( s . 2h ); 7 . 25 - 7 . 5 ( m . 5h ); 8 . 0 ( m . 1h ); 8 . 15 ( d . 1h ); 8 . 4 ( d . 1h ) the compounds ( i ) from examples 200 to 214 ( table 4 ) are prepared according to the process from example 199 . 0 . 3 g ( 0 . 8 mmol ) of 4 - benzyl - 7 - bromo - 1 -( n - methylamino )- 4h -[ 1 , 2 , 4 ] triazolo -[ 4 , 3 - a ] quinazolin - 5 - one ( compound from example 188 ) is dissolved in 5 ml of dmf . we add 0 . 135 g ( 0 . 85 mmol ) of methyl iodide and 0 . 13 g ( 0 . 93 mmol ) of potassium carbonate . the obtained mixture is shaken at ambient temperature for a night then heated at 100 ° c . for 6 hours . after cooling down , the solvent is evaporated under vacuum , the residue is resuspended in water and ethyl acetate . the organic phase is separated by decantation , washed with a saturated solution of sodium chloride , dried on na 2 so 4 and evaporated under vacuum . we obtain 0 . 3 g of crude product which is purified by chromatography on silica column by elution with the mixture ch 2 cl 2 99 / ch 3 oh 1 . the fractions containing the desired product are joined , concentrated under vacuum then the residue is recrystallized in methanol to give 0 . 05 g of pure compound from example 215 . n . m . r . 1h δ ( ppm ): 1 . 25 ( t . 3h ); 2 . 9 ( s . 3h ); 3 . 2 - 3 . 4 ( m . 2h ); 5 . 45 ( s . 2h ); 7 . 2 - 7 . 35 ( m . 3h ); 7 . 7 ( d . 2h ); 7 . 9 ( d . 1h ); 8 . 3 ( d . 1h ); 8 . 5 ( s . 1h ) 2 . 3 g ( 5 . 87 mmol ) of 4 - benzyl - 7 - methyl - 1 -( thiamorpholin - 4 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( compound from example 193 ) are resuspended in 250 ml of ethanol . we add a catalytic amount of raney &# 39 ; s nickel and we heat by reflux , under shaking , for 24 hours . the catalyzer is eliminated by filtration on celite and the alcoholic solution is concentrated under vacuum : we obtain 1 . 6 g of crude product which is purified by chromatography on silica column by elution using ch 2 cl 2 and methanol gradient from 99 . 5 / 0 . 5 to give 0 . 9 g of pure by ccm product . a sample is recrystallized in ethanol to determinate physical parameters . n . m . r . 1h δ ( ppm ): 1 - 1 . 3 ( m . 6h ); 2 . 4 ( s . 3h ); 2 . 9 - 3 . 45 ( m . 4h ); 5 . 4 ( s . 2h ); 7 . 1 - 7 . 3 ( m . 3h ); 7 . 45 ( d . 1h ); 7 . 6 ( d . 2h ); 8 . 15 ( s . 1h ); 8 . 3 ( d . 1h ) in a 25 ml balloon flask , we resuspend 0 . 7 g ( 1 . 8 mmol ) of 1 - amino - 4 - benzyl - 7 - bromo - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( intermediate 10 compound of example 271 ) in 5 ml of acetic acid . we add 0 . 25 g ( 1 . 9 mmol ) of 2 . 5 - dimethoxytetrahydrofuran then heat the mixture by reflux for 1 hour . after cooling down and evaporation of acetic acid under vacuum , we obtain 0 . 8 g of highly colored solid which is purified by chromatography on silica column by elution with the mixture ch 2 cl 2 / ch 3 oh ( 99 , 4 / 0 , 6 then 99 / 1 ). the solid obtained from pure fractions is recrystallized in ethanol to give 0 . 45 g of compound from example 217 . n . m . r . 1h δ ( ppm ): 5 . 55 ( s . 2h ); 5 . 8 ( d . 1h ); 6 . 5 ( s . 2h ); 6 . 9 ( s . 2h ); 7 . 25 - 7 . 4 ( m . 3h ); 7 . 7 ( d . 1h ); 7 . 75 ( d . 2h ); 8 . 55 ( s . 1h ) in a 50 ml balloon flask , we resuspend 0 . 45 g ( 0 . 96 mmol ) of 7 - bromo - 4 -( 4nitrobenzyl )- 1 -( pyrrol - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( compound from example 48 ) in 10 ml ethanol . we add 1 . 08 g ( 24 mmol ) of dehydrate stannous chloride then heat at 70 ° c ., under shaking , for 30 minutes . after cooling down , the mixture is poured into iced water . we extract several times by ethyl acetate with a little of chcl 3 , the organic phase is washed in a solution sodium chloride saturated , dried on na 2 so 4 then concentrated under vacuum . the obtained solid residue ( 0 . 35 g ) is washed in methanol ( 50 ml ) to give 0 . 25 g of pure by ccm product . n . m . r . 1h δ ( ppm ): 1 . 9 - 2 . 05 ( m . 4h ); 3 . 3 - 3 . 4 ( m . 4h ); 5 ( s . 2h ); 5 . 1 ( s . 2h ); 6 . 5 ( d . 2h ); 7 . 2 ( d . 2h ); 8 . 1 ( d . 1h ); 8 . 2 ( d . 1h ); 8 . 3 ( s . 1h ) in a reactor equipped with a shaker and refrigeration , we resuspend 1 . 46 g ( 5 mmol ) of 4 - benzyl - 7 - hydroxy - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( intermediate obtained by method from example 255 ) in 15 ml of dry methylene chloride . we add 0 . 95 g ( 5 mmol ) of tosyl chloride and then add , under shaking within 5 minutes , 1 ml ( 7 . 5 mmol ) of triethylamine , the reaction being slightly exothermic . after additional shaking at ambient temperature for 2 hours , the obtained organic solution is washed in water and dried on na 2 so 4 to give , after solvent evaporation , a colored amorphous residue which is purified by chromatography on silica column by elution with ethyl acetate . we obtain 1 . 9 g of pure product by ccm . this one will be used like this in the next step . 0 . 4 g of this compound is obtained from 0 . 45 g of 4 - benzyl - 7 -( 4 - tolylsulfonyloxy - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( example 219 - 1 ) by bromination method described in example 256 . 0 . 83 g of the brominated derived obtained in example 219 - 2 is treated by pyrrolidine in conditions of example 164 . after treatment , we obtain 1 . 0 g of crude mixture of 2 majoritary compounds which are separated by chromatography on silica column after elution with the mixture ch 2 cl 2 98 / ch 3 oh 2 . the fractions containing the first pure product are joined and concentrated to give 0 . 375 g of 4 - benzyl - 1 -( pyrrolidin - 1 - yl )- 7 -( 4 - tolylsulfonyloxy - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one . the fractions containing the second pure product are joined and evaporated under vacuum to give 0 . 12 g of 4 - benzyl - 7 - hydroxy - 1 -( pyrrolidin - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one . n . m . r . 1h δ ( ppm ): 1 . 95 ( m . 4h ); 3 . 3 ( m . 4h ); 7 . 3 ( s . 2h ); 7 . 2 - 7 . 6 ( m . 7h ); 8 . 1 ( d . 1h ): 10 . 2 ( s . 1h ) 1 . 3 g of this compound is obtained from 2 . 4 g of 4 - benzyl - 1 -( pyrrolidin - 1yl )- 7 -( 4 - tolylsulfonyloxy - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( example 219 - 3 ) by debenzylation method described in example 263 . 0 . 48 g of this compound is obtained from of 0 . 66 g of 1 -( pyrrolidin - 1yl )- 7 -( 4 - tolylsulfonyloxy - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( example 220 - 1 ) by n - alkylation method described in example 3 . 0 . 3 g ( 0 . 55 mmol ) of 4 -( 4 - cyanobenzyl )- 1 -( pyrrolidin - 1 - yl )- 7 -( 4 - tolylsulfonyloxy - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( described in example 220 - 2 ) is dissolved in 1 ml of dry dmf . we add 0 . 27 ml of pyrrolidine ( 2 . 75 mmol ) then heat at 140 ° c ., under shaking , for 6 hours . the solvent is evaporated under vacuum and the residue is resuspended by a mixture of ethyl acetate / aqueous n hydrochloric acid solution . the insoluble residue is separated by filtration , washed in water until neutral ph and dried under vacuum ; we obtain 0 . 13 g of crude product , which is crystallized in 5 ml of ethanol , filtered and dried to give 0 . 085 g of pure product . n . m . r . 1h δ ( ppm ): 2 ( m . 4h ); 3 . 3 ( m . 4h ); 5 . 35 ( s . 2h ); 7 . 35 ( d . 1h ); 7 . 6 - 7 . 7 ( m . 3h ); 7 . 8 ( d . 2h ); 8 . 1 ( d . 1h ); 10 . 2 ( s . 1h ) 0 . 45 g of this compound is obtained from 0 . 5 g of 7 - acetamido - 4 - benzyl - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one by bromination method which is described in example 256 . 8 . 7 g ( 21 mmol ) of brominated derived which is obtained in example 221 - 1 are treated by 3 . 7 ml ( 42 mmol ) of pyrrolidine and 3 . 54 g ( 42 mmol ) of sodium bicarbonate in 80 ml of dmf in conditions of example 164 . after treatment , we obtain 8 . 0 g of crude product which is purified by chromatography on silica column by elution with the mixture ch 2 cl 2 98 / ch 3 oh 2 . the fractions containing the pure product are joined and concentrated , then the residue is crystallized in ethanol to give 6 . 6 g of 7 - acetamido - 4 - benzyl - 1 -( pyrrolidin - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one . n . m . r . 1h δ ( ppm ): 2 - 2 . 1 ( m . 4h ); 2 . 25 ( s . 3 h ); 3 . 4 ( m . 4h ); 5 . 45 ( s . 2h ); 7 . 2 - 7 . 3 ( m . 3h ); 7 . 6 ( d . 2h ); 8 . 1 ( s . 1h ); 8 . 2 ( m . 2h ); 8 . 4 ( d . 1h ) from 1 . 2 g ( 3 . 0 mmol ) of 7 - acetamido - 4 - benzyl - 1 -( pyrrolidin - 1yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( described in example 221 ) debenzylated in 7 - acetamido - 1 -( pyrrolidin - 1yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one by palladium / c method described in example 257 , then directly treated with 0 . 59 g of cinnamyl bromide in the presence of 0 . 98 g cesium carbonate , in 15 ml of dmf , according to a method described in example 3 . we obtain , after purification by chromatography on silica column and recrystallization in ethanol , 0 . 4 g of pure compound from example 222 . nmr 1 h δ ( ppm ) cdcl3 : 2 . 0 - 2 . 1 ( m . 4h ); 2 . 25 ( s . 3h ); 3 . 45 ( m . 4h ); 5 ( d . 2h ); 6 . 35 - 6 . 4 ( dt . 1h ); 6 . 8 ( d . 1h ); 7 . 15 - 7 . 35 ( m . 5h ); 8 . 1 ( s . 1h ); 8 . 2 - 8 . 3 ( m . 2h ); 8 . 4 ( m . 1h ) in a 20 ml balloon flask , we resuspend 0 . 2 g ( 0 . 46 mmol ) of 7 - acetamido - 4 -[( e )- 3 - phenylallyl ]- 1 -( pyrrolidin - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( describe example 222 ) in 5 ml of 6n hydrochloric acid solution and heat by reflux , under shaking , for 15 minutes . after cooling down , the obtained solution is alkalinized by soda solution , extracted 3 times by methylene chloride . the joined organic phases are washed with a nacl - saturated solution , dried on na 2 so 4 then evaporated under vacuum . the crude product ( 0 . 12 g ) is recrystallized in ethanol to give 0 . 08 g of the pure compound from example 223 . nmr 1 h δ ( ppm ) cdcl3 : 2 . 1 ( m . 4h ); 3 . 4 ( m . 4h ); 4 . 0 ( m . 2h ); 5 . 1 ( d . 2h ); 6 . 5 - 6 . 6 ( dt . 1h ); 6 . 85 ( d . 1h ); 7 . 0 - 7 . 3 ( m . 3h ); 7 . 6 ( m . 1h ); 7 . 7 ( m . 1h ); 8 . 1 ( m . 1h ); 8 . 45 ( s . 1h ); 8 . 6 ( s . 1h ). the general formula ( i ) compounds of examples 224 to 233 in table5 are prepared by method from example 223 . in a 20 ml balloon flask , we resuspend 0 . 31 g ( 0 . 86 mmol ) of 7 - amino - 4 - benzyl - 1 - pyrrolidin - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( described in example 225 ) in 10 ml methylene chloride . we add 0 . 14 ml ( 1 . 9 mmol ) of acetone , 0 . 115 ml ( 1 . 9 mmol ) of pure acetic acid then 0 . 546 g ( 2 . 6 mmol ) of sodium detriacetoxyborohydrid . the mixture is shaken for 48 hours at ambient temperature , under nitrogen atmosphere . the solvent is evaporated under vacuum and the residue is resuspended in ethyl acetate . the organic phase is washed in a sodium bicarbonate solution , then in nacl - saturated solution . after drying on na 2 so 4 and solvent elimination under vacuum , we obtain 0 . 3 g of crude product which is purified by chromatography on silica column , after elution with mixture ch 2 cl 2 98 / ch 3 oh 2 to give 0 . 2 g of pure by ccm compound from example 234 . n . m . r . 1h δ ( ppm ): 1 . 2 ( m . 6h ); 2 . 05 ( m . 4h ); 3 . 4 ( m . 4h ); 3 . 7 - 3 . 85 ( m . 2h ); 5 . 5 ( s . 2h ); 6 . 9 ( m . 1h ); 7 . 2 - 7 . 3 ( m . 3h ); 7 . 4 ( s . 1h ); 7 . 7 ( m . 2h ); 8 . 1 ( m . 1h ) in a 20 ml balloon flask , we resuspend 0 . 55 g ( 1 . 5 mmol ) of 7 - amino - 4 - benzyl - 1 -( pyrrolidin - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( described in example 225 ) in 10 ml methylene chloride . we add 0 . 42 ml ( 3 . 0 mmol ) of triethylamine then 0 . 24 ml ( 3 . 0 mmol ) of methanesulfonyl chloride . the obtained solution is shaken for 24 hours at ambient temperature . after cooling down , the obtained solution is washed in water , dried on na 2 so 4 then evaporated under vacuum . the crude mixture of the 2 obtained compounds ( 0 . 85 g ) is chromatographied on silica column by elution with the mixture ch 2 cl 2 99 / ch 3 oh 1 / nh 4 oh 0 . 1 . the fractions containing the first product by elution order are joined and evaporated under vacuum to give 0 . 65 g of 4 - benzyl - 7 -( n , n - dimethylsulfonylamino )- 1 -( pyrrolidin - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one . n . m . r . 1h δ ( ppm ) dmso : 2 . 2 - 2 . 3 ( m . 4h ); 2 . 9 ( s . 3h ); 3 . 15 ( m . 4h ); 5 . 15 ( s . 2h ); 7 . 1 - 7 . 2 ( m . 3h ); 7 . 25 ( m . 2h ); 7 . 5 - 7 . 6 ( d . 1h ); 7 . 85 ( s . 1h ); 8 . 05 - 8 . 1 ( d . 1h ); 10 . 05 ( s . 1h ) the fractions containing the second product by elution order are treated in a similar manner to give 0 . 15 g of 4 - benzyl - 7 - methylsulfonylamino - 1 -( pyrrolidin - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one . n . m . r . 1 h δ ( ppm ) dmso : 2 ( m . 4h ); 3 . 45 ( m . 4h ); 3 . 5 ( s . 3h ); 5 . 45 ( s . 2h ); 7 . 3 ( m . 3h ); 7 . 7 ( m . 3h ); 6 . 35 ( m . 2h ) in a balloon flask , we resuspend 0 . 75 g ( 2 . 05 mmol ) of 7 - amino - 4 - benzyl - 1 -( pyrrolidin - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( described in example 225 ) in 0 . 8 ml of formic acid and 0 . 8 ml of formol . under shaking , the mixture is heated at 100 ° c . for 1 hour . after cooling down , the obtained solution is poured into iced water , the suspension is extracted several times with ethyl acetate ; the joined organic phases are washed in a aqueous nacl - saturated solution , dried on na 2 so 4 then concentrated under vacuum . the obtained crude product ( 0 . 8 g ) is purified by chromatography on silica column by elution with methylene mixture chloride 98 / methanol 2 . we obtain 0 . 23 g of pure by ccm product from example 236 . n . m . r . 1h δ ( ppm ): 2 . 1 ( m . 4h ); 3 . 05 ( s . 6h ); 3 . 45 ( m . 4h ); 5 . 45 ( s . 2h ); 7 . 1 ( m . 1h ); 7 . 3 ( m . 3h ); 7 . 6 ( d . 1h ); 7 . 75 ( m . 2h ); 8 . 1 ( d . 1h ) in a 500 ml balloon flask , equipped with a shaker , refrigeration and nitrogen feeding , we add 10 . 8 g ( 27 . 1 mmol ) of 4 - benzyl - 7 - bromo - 1 -( pyrrolidin - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( example 164 ) in 100ml of n - methylpyrrolidinone ( nmp ). we add 4 . 4 g ( 49 mmol ) of cuprous cyanide then heat the mixture , under shaking and under nitrogen for 12 hours . the solvent is eliminated by evaporation under vacuum ; the residue is stirred in mixture of methylene chloride and 2n ammonia solution , the insoluble residue is eliminated by filtration , then the phases are separated by decantation . the organic phase is washed in a nacl - saturated solution , dried on na 2 so 4 and evaporated to give 24 . 0 g of crude product . this is purified by chromatography on silica column by elution using mixture of ethyl acetate 65 / cyclohexane 35 . the fractions pure in ccm are joined and evaporated under vacuum : we obtain 8 . 4 g of compound from example 237 . n . m . r . 1h δ ( ppm ): 2 . 9 ( s . 6h ); 5 . 3 ( s . 2h ); 7 . 3 ( m . 3h ); 7 . 5 ( m . 2h ); 8 . 4 ( m . 1h ); 8 . 5 ( m . 1h ); 8 . 6 ( m . 1h ) in a 250 ml balloon flask , we add 5 . 0 g ( 13 . 5 mmol ) of 4 - benzyl - 7 - cyano - 1 -( pyrrolidin - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one in 100 ml of 16 n hydrochloric acid solution then heat by reflux for 3 hours , under shaking . after cooling down , the precipitate is filtered , washed several times in water , dried and purified by chromatography on silica column , by elution with the mixture ch 2 cl 2 97 / ch 3 oh 3 , to give 2 . 3 g of pure by ccm compound from example 238 . n . m . r . 1h δ ( ppm ): 1 . 9 ( s . 4h ); 3 . 4 ( s . 4h ); 5 . 3 ( s . 2h ); 7 . 3 ( m . 3h ); 7 . 4 ( m . 2h ); 8 . 2 ( m . 1h ); 8 . 4 ( m . 1h ); 8 . 7 ( s . 1h ) 0 . 8 g ( 1 . 65 mmol ) of 7 - bromo - 4 -[( 4 - carboxymethyl ) benzyl ]- 1 -( pyrrolidin - 1 - yl )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( example 56 ) and 0 . 25 g of potassium carbonate are resuspended in 10 ml of dmf . we add 0 . 26 g ( 1 . 82 mmol ) of methyl iodide then heat at 80 ° c ., under shaking , for 2 hours . the solvent is evaporated under vacuum , the residue is resuspended in water , this latter being extracted 3 times by ethyl acetate ; the joined organic phases are washed in sodium chloride saturated solution , dried on na 2 so 4 then the solvent is evaporated under vacuum to give 0 . 7 g of crude product . this is purified by chromatography on silica column by elution with mixture ch 2 cl 2 99 / ch 3 oh 1 . we obtain 0 . 5 g of pure by ccm product . n . m . r . 1h δ ( ppm ): 2 - 2 . 1 ( m . 4h ); 3 . 35 - 3 . 45 ( m . 4h ); 3 . 6 ( s . 2h ); 3 . 7 ( s . 3h ); 5 . 45 ( s . 2h ); 7 . 2 ( d . 2h ); 7 . 65 ( d . 2h ); 7 . 85 ( d . 1h ); 8 . 15 ( d . 1h ); 8 . 5 ( s . 1h ) 0 . 85g ( 1 . 76 mmol ) of 7 - bromo - 4 -[( 4 - carboxymethyl ) benzyl ]- 1 - pyrrolidin - 1 - yl )- 4h -( 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( example xx ) is added in 85 ml of dry chloroform . under nitrogen feeding , we shake then add 0 . 42 g ( 3 . 52 mmol ) of thionyl chloride maintaining temperature below 5 ° c . after 90 minutes , the reaction is almost complete and chloride acid tends to precipitate as crystal . this solution will be used like in the next step . to the solution cooled down at 0 ° c . of 0 . 6 g ( 8 . 8 mmol ) of methylamine chlorhydrate and 1 . 06 g of triethylamine in 85 ml of acetone , we add slowly the obtained solution from example 240 - 1 , maintaining temperature below 5 ° c . shaking is then maintained at 0 ° c . for 15 minutes then the obtained solution is concentrated under vacuum . we dissolve the residue in methylene chloride , wash the organic phase twice in water , dry on na 2 so 4 , evaporate the solvent under vacuum and recover then 1 . 0 g of crude product . this is chromatographied on silica column by elution using mixture ch 2 cl 2 96 / ch 3 oh 4 to give 0 . 4 g which is recrystallized in ethanol . we obtain 0 . 27 g of pure compound after drying . n . m . r . 1h δ ( ppm ): 1 . 95 - 2 . 1 ( m . 4h ); 2 . 7 ( d . 3h ); 3 . 35 - 3 . 45 ( m . 4h ); 3 . 5 ( s . 2h ); 5 . 3 - 5 . 5 ( m . 3h ); 7 . 15 ( d . 2h ); 7 . 65 ( d . 2h ); 7 . 9 ( d . 1h ); 8 . 2 ( d . 1h ); 8 . 5 ( s . 1h ) the compounds ( i ) from examples 241 to 243 ( table6 ) are prepared according to process in example 240 . in a three - necked balloon flask equipped with shaker , refrigeration and nitrogen feeding , we add 1 . 0 g ( 4 . 1 mmol ) of 7 - methyl - 1 -( n , n - dimethylamino )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one in 70 ml of toluene and add at once 3 . 3 g ( 8 . 2 mmol ) of lawesson &# 39 ; s reagent . under shaking , the mixture is heated by reflux for 24 hours . after cooling down , we add 30 ml of 5 % hydrochloric acid solution , then we pour in 250 ml of methanol under shaking . we add 250 ml of cyclohexane and we eliminate the insoluble residue by filtration . the methanolic acid phase is separated by decantation , concentrated under vacuum and the residue is resuspended in ice and is triturated several times . the insoluble residue recovered as a resin is dissolved in 10 ml of isopropanol ; from the obtained solution , shaken for 30 minutes , the yellow crystals which have precipitated are filtered , washed in isopropanol then in ether and dried under vacuum . we obtain 0 . 98 g of product that will be used like this in the next step . from 0 . 5 g ( 1 . 93 mmol ) of 7 - methyl - 1 -( n , n - dimethylamino )- 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - thione ( example 244 - 2 ), by using method b described in example 3 , we obtain , after recrystallization in ethanol , 0 . 29 g of compound from example 244 . n . m . r . 1h δ ( ppm ): 2 . 9 ( s . 6h ); 3 . 7 ( s . 2h ); 5 . 45 ( s . 2h ); 7 . 25 ( m . 2h ); 7 . 7 ( m . 2h ); 7 . 85 ( m . 1h ); 8 . 2 ( d . 1h ); 8 . 5 ( s . 1h ) the compounds ( i ) of examples 245 to 246 ( table7 ) are prepared according to process in example 244 . particularly preferred intermediate compounds of the current invention may be prepared according to the following examples . however , the person skilled in the art may modify easily operative procedures described below depending on the desired intermediate . in a reactor equipped with shaker , refrigeration and bromide funnel , 150 g ( 694 mmol ) of 5 - bromo - 2 - amino - benzoic acid are resuspended in 1 . 5 l of acetic acid . under shaking , the mixture is heated by reflux , then 92 ml ( 103 g ; 694 mmol ) of benzyl isothiocyanate are added slowly and regularly using the bromide funnel . after addition , shaking and heating by reflux are maintained for 6 hours , solubilization is realized gradually during this period . after cooling down to ambient temperature , the solid that has precipitated is filtered and washed in acetic acid . the product obtained is dried under vacuum at 60 ° c . to give 125 . 2 g of expected pure by ccm compound ( elution solvent : ch 2 cl 2 99 . 2 / ch 3 oh 0 . 8 ; rf = 0 . 9 ) nmr 1 h and 13 c spectra are compatible with the expected structure . in a reactor equipped with shaker , refrigeration , 125 . 2 g ( 360 mmol ) of 1 , 2 , 3 , 4 - tetrahydro - 3 - benzyl - 6 - bromo - 4 - oxo - 2 - thia - quinazoline ( intermediate 1 ) are added in 3 . 5 1 of ethanol . under shaking , we add 167 . 6 g ( 3 . 348 mmol ) of hydrazine hydrate . the obtained suspension is heated by reflux for 18 hours , during which solubilization is gradually realized . after cooling down to ambient temperature , about half of solvent is evaporated under vacuum and the obtained residual solution is left aside in a ice bath for 1 hour . after filtration of the precipitate , cold ethanol wash then drying under vacuum at 60 ° c ., we obtain 89 . 7 g of expected pure by ccm compound , ( elution solvent : ch 2 cl 2 99 / ch 3 oh 1 ; nmr 1 h and 13 c spectra are compatible with the expected structure . in a reactor equipped with shaker and refrigeration , we resuspend 47 . 7 g ( 158 mmol ) of 3 , 4 - dihydro - 3 - benzyl - 6 - chloro - 2 - hydrazino - quinazolin - 4 - one ( prepared in a similar manner as intermediate 2 ) in 600 ml of pyridine . we add then 25 . 3 g ( 158 mmol ) of potassium xanthogenate by fraction , the obtained solution is heated by reflux for 7 hours , under shaking , during which the solid is gradually precipitated . after one night &# 39 ; s rest at ambient temperature , the precipitate is separated by filtration then redissolved in 1 . 5 l of water . the obtained solution is neutralized by acid acetic , then the formed precipitate is filtered , washed in water until neutral ph and dried . we obtain 54 . 0 g of crude product which will be used like this in the next step . in a reactor equipped with a shaker and bromide funnel , we resuspend 6 . 72 g of soda in 1200 ml of water then add 57 . 0 g ( 166 mmol ) of 4 - benzyl - 7 - chloro - 1 - mercapto - triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( intermediate 3 ). under shaking , we add 15 . 74 ml ( 166 mmol ) of dimethyl sulfate at ambient temperature , over a 30 minutes period . shaking is maintained for 7 hours . after leaving aside at ambient temperature for a night , the precipitate is filtered , washed in water then dried under vacuum . we obtain 51 . 2 g of crude solid which is used like this in the next step . in a reactor equipped with shaker , plunging tube and refrigeration , we add 51 . 0 g ( 143 mmol ) of 4 - benzyl - 7 - chloro - 1 - methylthio - triazolo [ 4 , 3 - a ] quinazolin - 5 - one ( intermediate 4 ) in a mixture of 1 . 5 l of chloroform and 0 . 9 l of water . under shaking , we cool down to 0 ° c ., then allow a chlorine stream to flow , maintaining temperature below 10 ° c . for 2 hours . we then stop chlorine feeding , leave the mixture to return to ambient temperature then maintain shaking for 2 hours . the 2 phases are separated by decantation , the chloroformic phase is dried on na 2 so 4 and concentrated under vacuum . we obtain 50 . 9 g of crude solid residue . this is resuspended in 400 ml of ethanol and the heterogeneous mixture is shaken for 30 minutes . the insoluble residue is filtered , washed in ethanol and dried at 50 ° c . under vacuum to give 46 . 5 g of pure expected by ccm compound ( elution solvent ch 2 cl 2 99 / ch 3 oh 1 ; rf = 0 . 50 ) proton and 13 c nmr spectra are compatible with the expected structure . in a 6 liter reactor , equipped with shaker , we add 89 . 7 g ( 260 mmol ) of 3 , 4 - dihydro - 3 - benzyl - 6 - bromo - 2 - hydrazino - quinazolin - 4 - one ( intermediate 2 ) in 2 . 9 l of dry chloroform . we shake , cool the suspension down to 0 ° c . using an ice bath , then add 216 ml ( 192 . 5 g ; 1 . 299 mmol ) of triethyl orthoformiate , leading to a slight temperature increase ( up to 6 ° c .). maintaining the temperature below 5 ° c ., we add 8 . 2 ml of concentrated sulfuric acid in a single go . we shake then for 15 min at temperature below 5 ° c ., then remove the ice bath , shaking is maintained for 4 additional hours during which a solid gradually precipitates . we add 1 . 5 l of water and 0 . 7 l of chloroform , shake until complete distribution between the 2 phases then neutralize the aqueous phase to ph 7 by sodium bicarbonate . the organic phase is decanted , washed with nacl - saturated solution , dried on na 2 so 4 and evaporated under vacuum to give 91 . 3 g of expected pure by ccm compound , ( elution solvent : ch 2 cl2 97 / ch 3 oh 3 / nh4oh 0 . 3 ; rf = 0 . 5 ). nmr 1 h and 13 c spectra are compatible with the expected structure . in a 3 liter reactor equipped with shaker , refrigeration and bromide funnel , we add 35 g ( 98 . 5 mmol ) of 4 - benzyl - 7 - bromo - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazoline - 5 - one ( intermediate 6 ) in 630 ml of chloroform and 11 ml of pyridine . under shaking , 16 . 4 ml ( 320 mmol ) of bromine are then added at ambient temperature over a 30 minute period . after addition , shaking is maintained at ambient temperature for 1 hour ; the reaction medium is then distributed between 1 l of water and 1 . 5 l of chloroform and the heterogeneous mixture shaken for 15 min . the insoluble residue is dried , washed in water to a neutral ph then triturated in ethanol . after drying under vacuum at 50 ° c ., we obtain a first fraction of 8 . 2 g of pure by ccm expected compound ( elution solvent : ch 2 cl 2 99 / ch 3 oh 1 ; rf = 0 . 6 ). after separation of the chloroformic phase , washing in sodium bicarbonate solution then in water , drying on na 2 so 4 , evaporation of solvent under vacuum then triturating of residue in ethanol , filtration and drying of solid at 50 ° c ., we obtain 33 . 1 g of a second fraction of expected compound , equivalent by ccm to the precedent fraction . nmr 1 h spectrum is compatible with the expected structure . in a 150 ml balloon flask equipped with shaker and refrigeration , we dissolve 1 . 0 g ( 2 . 68 mmol ) of 1 - azepanyl - 4 - benzyl - 4h -[ 1 , 2 , 4 ] triazolo [ 4 , 3 - a ] quinazolin - 5 - one in 60 ml of tetrahydrofuran . we add 2 . 0 g of ammonium formiate then 1 . 5 g of 10 % activated palladium on charcoal . the mixture is shaken and heated by solvent reflux for 5 hours . after cooling down , the suspension is filtered , and then the solvent is evaporated under vacuum to give 0 . 55 g of residual solid . this is chromatographied on silica column by elution using mixture ch 2 cl 2 97 / ch 3 oh 3 ; the fractions pure in ccm are gathered together and concentrated under vacuum to give 0 . 42 g of residual solid . n . m . r . 1 h δ ( ppm ): 1 . 65 - 1 . 85 ( m . 8h ); 3 . 25 ( m . 4h ); 7 . 5 ( t . 1h ); 7 . 9 ( t . 1h ); 8 . 15 ( d . 1h ); 8 . 3 ( d . 1h ); 12 . 6 ( m . 1h ) the compounds ( i ; r = h ) of examples 258 to 262 ( table8 ) are prepared according to the process in example 257 . in a 500 ml reactor equipped with shaker , refrigeration equipped with a potash keeper , thermometer and nitrogen feeding , we resuspend 5 . 0 g ( 14 . 5 mmol ) of 3 , 4 - dihydro - 3 - benzyl - 6 - bromo - 2 - hydrazino - quinazolin - 4 - one ( prepared according example xx ) in 150 ml of dry methanol . we add 1 . 62 g ( 15 . 3 mmol ) of cyanogene bromide and shake the heterogeneous mixture for 1 hour at ambient temperature , then by reflux for 5 hours after cooling down , we add drop by drop , under vigorous shaking , aqueous solution of saturated sodium bicarbonate to ph 8 . the insoluble solid is filtered , washed several times in water and dried under vacuum to give 4 . 9 g of crude product . the latter is triturated in 100 ml of methanol , the insoluble fraction is separated by filtration , washed in methanol and dried under vacuum . we obtain 4 . 6 g of pure by ccm product . nmr 1 h and 13 c spectra are compatible with the expected structure . the capacity of the formula ( i ) compounds of the invention to inhibit the cyclic nucleotide phosphodiesterases is evaluated by their cl 50 measurement ( necessary concentration to inhibit 50 % of enzymatic activity ). the type 4 phosphodiesterases are obtained from a cytosolic preparation extracted from the human origin cellular line u937 according to a method adapted from t . j . torphy and al ., 1992 , j . pharm . exp . ther . 263 : 1195 - 1205 the other classes of phosphodiesterases are obtained after partial purification fplc on mono q column . ( anion exchange column ) according to a method adapted from lavan b . e ., lakey t ., houslay m . d . biochemical pharmacology , 1989 , 38 ( 22 ), 4123 - 4136 ., and from silver p . j and al ., 1988 , eur . j . pharmacol . 150 : 85 - 94 , either , from human origin cellular lines for pde 1 ( monocytar line tph1 ) and pde5 ( line mcf7 issued from an adenocarcinoma ), or from dog aorta for pde 3 , or for the human pde3a , from gene cloning in insect cells sf21 in baculovirus , according to a method adapted from luckow , v . a . and al ., 1991 in recombinant dna technology & amp ; applications ., eds . prokop , bajpai , r . k .& amp ; ho , c . s ., pp97 - 152 . the enzymatic activity measurement of the different pde classes , and in particular the pde 4 , is performed according to a method adapted from w . j . thompson and al . 1979 , advances in cyclic nucleotide research , vol . 10 : 69 - 92 , ed . g . brooker and al . raven press , ny . for the cl 50 determination , the enzymatic activity is measured in the presence of inhibitor within concentration margins of 0 . 1 to 100 μm . the following table illustrates the pde4 inhibitory activity from enzymatic preparation obtained from the line u937 . the examination of the results from the above table shows that the preferred products of the invention tested in the trial inhibit the enzyme pde4 in vitro in an efficient manner . this test aims to evaluate capacity of the compounds of the invention to inhibit tnfα ( tumor necrosis - α ) production by human leukocytes in the presence of high human serum concentration ( 75 %). indeed , it appears that a number of compounds having a capacity any longer to inhibit phosphodiesterase 4 in enzymatic or cellular tests do not present anymore this capacity when the test is performed in human blood . the test described here is based on the use of human leukocytes cultivated in 75 % of human serum . it had been previously documented that these conditions simulate the observed situation when tnfα dosage is performed in human blood . the compounds to test are dissolved into 20 mm ( sometimes 6 mm ) of dmso . 100 μl of dmso are distributed into 7 wells of a a 96 well microtiter plate ( wells b to h ). 150 μl of the compound solution are distributed into line a wells . 50 μl are then sequentially transferred 7 times . 20 μl of this serial dilutions of compounds are sequentially transferred twice in wells containing 180 μl of rpmi 1640 ( gibco ). 50 μl of these dilutions are then transferred in wells where cells will be added . each test includes a series of eight wells without lps ( 100 % of inhibition ), eight wells with lps ( 0 % of inhibition ) and a series of rolipram dilutions in order to enable comparison of the tests between each other and then to evaluate their variability . a leukocyte vial is unfrozen in bain - marie ( 37 ° c . ), its content is transferred into a 15 ml tube containing 10 ml of rpmi added with 5 % of human serum ( rpmi - 5 % hs ). the cells are sedimented ( 800 g , 6 minutes , 4 ° c . ), resuspended in 10 ml of the same medium and counted by dilution in trypan blue solution . after centrifugating ( 800 g , 6 minutes , 4 ° c . ), the cells are resuspended to 2 × 10 6 / ml in human serum . to 50 μl aliquots of different dilutions of compounds , 100 μl of cells are added . the plates are then incubated 30 minutes at 37 ° c ., then 50 μl of solution 4 μg / ml of lps prepared in human serum are added . the plates are incubated for the night at 37 ° c . after incubation for 15 - 18 hours , 90 μl of growth supernatant are taken and transferred into rounded - bottom microtiter wells . the tnfα presence is then evaluated by elisa ( pharmingen ) by using 50 μl of supernatant . the protocol described by the manufacturer is strictly applied . results obtained for some of the preferred compounds of the current invention are illustrated in the following table . the tfnα is a cytokin playing a central role in inflammation mechanisms . its production may be induced by injection of lipopolysaccharid ( lps ). it has been shown that the intracellular ampc increase , produced in particular by pde4 inhibitors , decreases the tnfα production in in vitro and in vivo models . therefore it matters here to quantify in vivo anti - inflammatory potential of the compounds of the invention , administrated by oral route ( p . o .) by measuring inhibition of tnfα production in plasma in rat , the latter having received a intraperitoneal injection ( i . p .) of lipolysaccharid ( lps ). the treatment by the compounds of the invention or the carrier is administrated by oral route in male wistar rats , 30 min . before lps injection . the rats are sacrificed 90 min . after lps stimulation , the blood is harvested on edta and tnfα concentration is measured in each plasma sample . the results obtained from some of the compounds of the current invention are presented in the table below . chen , y . l ., the vraux , v ., giroud , j . p . and chauvelot - moachon l . ( 1994 ). anti - tumor necrosis factor properties of non - peptide drugs in acute - phase responses . eur . j . pharmacol ., 271 ( 2 - 3 ), 319 - 27 . prabhakar , u ., lipshutz , d ., o &# 39 ; leary barthus , j ., slivjak , j ., smith iii e . f ., lee , j . c . and esser k . m . ( 1994 ). characterization of camp - dependent inhibition of lps - induced tnfα production by rolipram , a specific phosphodiesterase iv ( pde iv ) inhibitor . int . j . immunopharmacol ., 16 ( 10 ), 805 - 816 . the studies undertaken from this experimental model aim to evaluate inhibitory effect of the compounds of the invention on the rush of inflammatory cells and in particular of eosinophils in the opening of trachea - bronchial shaft in rat . the eosinophils play a major role in asthma physiopathology in human by releasing on the level of pulmonary parenchyma some pro - inflammatory mediators like leukotriens , proteins and specific enzymes ( ecp , epo , mbp ) and cytokins . the massive recruitment of this cellular type air passages in asthmatic patient leads to a progressive degradation of pulmonary tissue explaining bronchial hyperactivity , chronic disease and exacerbation in the absence of treatment . this model uses brown norway rats , whose particularity is to produce , like atopic patients , immunoglobulin e ( ige ) rates in response to a sensibilization by antigen . the protocol used involves two sensibilizations to ovalbumin at fourteen days interval then a challenge seven days later with ovalbumin aerosol . forty - eight hours after the antigenic challenge , the animals undergo a bronchoalveolar wash under anesthesia in order to harvest inflammatory cells infiltrate in lung . these cells are then counted and differentiated according to morphological criteria . the products of the invention are administrated by oral route , 1 hour before the antigenic challenge . most of the preferred compounds of the current invention tested in this model have also demonstrated an excellent activity . the studies undertaken from this experimental protocol aim to evaluate modulating effect of the compounds of the invention on the rush of pro - inflammatory cells ( precocious phase ) in the opening of trachea - bronchial shaft in mouse . this cellular rush is consecutive to stimulation simulating a bacterial infection ( bacterial lipopolysaccharid or lps ). this precocious inflammatory step results from events combination among which the main ones are synthesis and release of stimulating ( tnfαi ) and chimiotactic ( il - 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