KR20000023644A - Novel compounds - Google Patents

Abstract

PURPOSE: Pharmaceutically useful pyrimidine compounds, methods for their preparation, their use as medicaments, and pharmaceutical formulations including them are provided which have anti allergenic and anti-inflammatory activity. CONSTITUTION: The pharmaceutically useful pyrimidine compounds of formula (I), methods for their preparation, their use as medicaments, and pharmaceutical formulations including them are described. The compounds of the formula(1) can form an acid addition salt with an acid such as maleic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, mandelic acid, tartaric acid, and methanesulfonic acid.

Description

Novel Compounds

The present invention relates to pharmaceutically useful compounds, methods for their preparation, their use as medicaments, and pharmaceutical formulations comprising the same.

Certain pyridinocyclohexano-1,3-pyrimidines are known from Heterocycles, 43, 391 (1996) and European Patent Application 0 260 642 A2. 2-aryl substituents are not mentioned. It has now been surprisingly found that a series of structurally distinct quinazoline and pyrimidine derivatives exhibit antiallergic and anti-inflammatory activity.

Therefore, in the first aspect of the present invention,

(In the above formula,

R represents (CH ₂ ) _n , CH = CH, BCH ₂ or CH ₂ B, wherein B is O or S,

n is 1 to 3,

Ar ¹ is halo, nitro, cyano, phenyl, phenylsulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COOH, COO (C _{1- 6} alkyl), CONH ₂ , C _1-6 alkyl substituted with phenyl, or phenyl, wherein all alkyl, alkoxy, alkylthio and alkylsulfinyl groups may be optionally substituted with one or more fluorine atoms Thiazolyl, phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolyl or 2-quinoxarinyl, which may be optionally substituted with the above substituents,

W represents CH, CA or N,

X is CH, CA, N or N ⁺ -O ^- represents,

Y represents CH, CA, N or N ⁺ -O ^- represents,

Z is CH, CA, N or N ⁺ -O ^- represents,

A is optionally selected from hydroxy, halogen, nitro, cyano, phenyl, C _1-6 -thioalkyl, CO ₂ R ¹ , NR ² R ³ , NR ⁴ C (O) R ⁵ , methoxy (CO ₂ R ⁶ Substituted), C _1-6 -alkyl or C _2-6 -alkoxy (the latter two groups are optionally substituted with one or more substituents selected from NH ₂ , hydroxy or CO ₂ R ⁷ ),

R ² represents H or C _1-6 -alkyl, R ³ represents H, C _1-6 -alkyl or CH ₂ Ar ² or R ² and R ³ together with the nitrogen atom to which they are attached pyrrolidinyl Or forms a piperidinyl ring,

R ⁵ represents H, C _1-5 -alkyl or Ar ³ ,

R ¹ , R ⁴ , R ⁶ and R ⁷ independently represent H or C _1-6 -alkyl,

Ar ² and Ar ³ are independently halogen, hydroxy, methoxy (optionally substituted with fluorine), phenoxy, C _2-6 -alkoxy and C _1-6 -alkyl (the following three groups are halogen, hydroxy or Phenyl optionally substituted with one or more substituents selected from C _1-6 -alkyl)

However, (a) X, one of Y and Z is N ⁺ -O ^- when referring to, W, and the other two groups are both represents CH,

(b) when Y represents N and X and Z both represent CH, W can only represent N,

(c) when Z represents CH or N, W represents CH, Y represents CH or CA, X can only represent N,

(d) when W represents N or CH, and X and Z both represent CH, Y can only represent N,

(e) when X represents N or CH, W represents CH, Y represents CH or CA, Z can only represent N,

(f) when only one of X or Z represents N, Y represents CH,

(g) A represents C _2-6 alkoxy substituted with hydroxy, halogen (except fluorine) or NH ₂ , or Ar ¹ , Ar ² or Ar ³ is substituted with halogen (except fluorine) or hydroxy When substituted with C _2-6 -alkoxy, suitably the hydroxy, halogen or NH ₂ substituents are not bonded to the same carbon atom as the oxygen bonded carbon atom,

(h) W, X, Y and Z are all CH and when R is (CH ₂ ) ₂ or OCH ₂ , Ar ¹ is substituted with phenyl)

Or pharmaceutically acceptable derivatives thereof.

Pharmaceutically acceptable derivatives include solvates, salts and N-oxides. For example, compounds of formula I are commonly used as pharmaceutically acceptable acids such as maleic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, mandelic acid, tartaric acid and methanesulfonic acid. Together, acid addition salts can be formed.

Compounds of the present invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the present invention.

The compounds of the present invention may also contain one or more asymmetric carbon atoms and thus exhibit optical and / or diastereoisomers. All diastereomers can be separated using conventional techniques such as, for example, chromatography or fractional crystallization. Various optical isomers may be isolated by isolating racemates or other mixtures of compounds using conventional techniques such as, for example, fractional crystallization or HPLC. Alternatively, preferred optical isomers may be reacted with conventional methods (e.g., by derivatization or salt formation, for example by reacting homochiral acid with a suitable starting material that is optically active under conditions that do not cause racemization). , HPLC, silica phase chromatography, or, in the case of salts, crystallization), to separate the diastereomeric derivatives. All stereoisomers are included within the scope of the present invention.

Alkyl groups, alone or as part of other groups, may be straight or branched chains.

Preferably R represents CH = CH, OCH ₂ or (CH ₂ ) _n , where n is 1, 2 or 3. Most preferably R represents (CH ₂ ) _n where n is 2 or R represents CH = CH.

Preferably Ar ¹ represents thiazolyl optionally substituted with methyl, phenyl optionally substituted with chloro, CF ₃ , CONH ₂ , or methyl, or Ar ¹ is optionally substituted with chloro, CF ₃ , methyl or methoxy Pyridyl or pyridyl N-oxide. If present, substituents of phenyl or pyridyl groups are preferably para to bond with the rest of the molecule. Preferred substituents are halo and C _1-6 alkyl. Most preferably Ar ¹ represents pyridyl substituted with chloro or methyl, in particular 3-pyridyl substituted with methyl.

Preferably, W, X, Y and Z form an optionally substituted phenyl, pyridyl or pyrimidine ring. More preferably W, X, Y and Z are all CH, W is CH, X is N, Y is CH or CA and Z is N; W and Y are both N, X and Z are both CH or one of X, Y or Z is N or N ⁺ -O ^- and the other two are both CH with W. Preferred groups A include C _1-6 alkyl, C _1-6 alkoxy and amino, in particular methyl, methoxy or amino groups.

Most preferred W and Y are both CH, X is CH or N and Z is N.

Preferred compounds of the present invention

2- (4-chlorophenyl) -5,6-dihydro-8-methylpyrimido [4,5-f] quinazolin,

2- (4-chlorophenyl) -5,6-dihydro-8-methoxypyrimido [4,5-f] quinazolin,

2- (4-chlorophenyl) -5,6-dihydropyrimido [5,4-h] quinazoline,

2- (4-chlorophenyl) -5,6-dihydro-pyrido [3,4-h] quinazoline,

2- (4-chlorophenyl) -5,6-dihydro-8-methylthiopyrimido [4,5-f] quinazolin,

2- (4-chlorophenyl) -5,6-dihydropyrimido [4,5-f] quinazolin,

2- (4-chlorophenyl) -5,6-dihydropyrido [3,4-h] quinazolin-8-oxide,

2- (4-chlorophenyl) -5,6-dihydropyrimido [4,5-f] quinazolin-8-amine,

5,6-dihydro-2- (pyridin-3-yl) pyrimido [4,5-f] quinazolin,

5,6-dihydro-2- (pyridin-2-yl) pyrimido [4,5-f] quinazolin,

5,6-dihydro-2- (6-methylpyridin-3-yl) pyrimido [4,5-f] quinazolin,

5,6-dihydro-2- (6-methylpyridin-3-yl-N-oxide) pyrimido [4,5-f] quinazolin-8-amine,

2- (4-chlorophenyl) -6,7-dihydro-5H-pyrido [2,3-i] cycloheptapyrimidine,

2- (4-chlorophenyl) -5,6-dihydropyrido [2,3-h] quinazoline,

2- (pyridin-3-yl) -5,6-dihydropyrido [2,3-h] quinazolin,

2- (6-methylpyridin-3-yl) -5,6-dihydropyrido [2,3-h] quinazolin,

2- (4-chlorophenyl) -5,6-dihydropyrido [2,3-h] quinazolin, 7-oxide,

2- (4-chlorophenyl) -5,6-dihydropyrido [4,3-h] quinazolin,

5,6-dihydro-2- (pyridin-3-yl) -pyrido [4,3-h] quinazolin,

2- (pyridin-3-yl) -pyrido [4,3-h] quinazolin,

2- (4-chlorophenyl) -5,6-dihydropyrido [4,3-h] quinazolin, 9-oxide,

5,6-dihydro-2- (6-methoxypyridin-3-yl) -pyrimido [4,5-f] quinazolin,

2- (6-chloropyridin-3-yl) -5,6-dihydropyrimido [4,5-f] quinazolin,

2- (6-methylpyridin-3-yl) -pyrimido [4,5-f] quinazolin,

2- (4-chlorophenyl) -5H- [1] benzopyrano [4,3-d] pyrimidine,

2- (4-chlorophenyl) -5H-indeno [1,2-d] pyrimidine,

2-phenyl-5H- [1] benzopyrano [4,3-d] pyrimidine,

2-pyridin-4-yl-5H- [1] benzopyrano [4,3-d] pyrimidine,

2- (pyridin-4-yl) -N-oxide-5H- [1] benzopyrano [4,3-d] pyrimidine,

2-pyridin-2-yl-5H- [1] benzopyrano [4,3-d] pyrimidine,

2-pyridin-3-yl-5H- [1] benzopyrano [4,3-d] pyrimidine,

2- (6-methylpyridin-3-yl) -5H- [1] benzopyrano [4,3-d] pyrimidine,

2- (6-chloropyridin-3-yl) -5H- [1] benzopyrano [4,3-d] pyrimidine,

2-pyrazin-2-yl-5H- [1] benzopyrano [4,3-d] pyrimidine,

2- (6-trifluoromethylpyridin-2-yl) -5H- [1] benzopyrano [4,3-d] pyrimidine,

2- (2-methylthiazol-4-yl) -5H- [1] benzopyrano [4,3-d] pyrimidine,

4- (5H- [1] benzopyrano [4,3-d] pyrimidin-2-yl) benzenecarboxamide,

2- (6-methylpyridin-3-yl) -5,6-dihydropyrano [4,3-h] quinazolin,

And pharmaceutically acceptable derivatives thereof.

According to the invention,

(a) reacting a compound of formula II with a compound of formula III or a salt thereof, or

(b) for compounds of formula (I) wherein Y is N or CA and A is H, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy, the compound of formula IV is reacted with a compound of formula V,

optionally after step (a) or (b)

Converting the compound of formula I to another compound of formula I,

To form pharmaceutically acceptable derivatives

Also provided is a process for the preparation of a compound of the present invention.

Wherein W, X, Y, Z and R are as defined in formula (I) and L is a leaving group

Ar ¹ C (NH) NH ₂

Wherein Ar is as defined in formula (I)

Wherein W, X, Y, Z and R are as defined in Formula I and L 'is a leaving group

Ar ¹ MgHal

Wherein Hal is Cl or Br and Ar ¹ is as defined in formula (I)

In the compounds of formula II, L is a suitable leaving group, such as OR ⁸ or N (R ⁸ ) ₂ , wherein R is C _1-6 alkyl such as methyl or ethyl. Preferably L is NMe ₂ . The reaction of the compounds of formulas (II) and (III) is suitably carried out in the presence of a base such as sodium methoxide in an organic solvent such as methanol or ethanol. The reaction can be carried out at an elevated temperature, for example at reflux temperature.

For the compound of formula IV, L 'is a leaving group, preferably thioalkyl, specifically thiomethyl. Compounds of formulas (IV) and (V) can be reacted together at ambient temperature in the presence of a suitable catalyst (eg 1,3-bis (disphenylphosphino) propane nickel dichloride) and a suitable organic solvent (eg tetrahydrofuran). .

Compounds of formula II can be prepared by reacting a compound of formula VI with a compound of formula VII.

Wherein W, X, Y, Z and R are as defined in formula (I)

(R ⁹ O) ₂ CHN (R ⁸ ) ₂

Preferred compounds of formula VII (wherein, R ⁸ group are as defined in the R ⁹ group is C _1-6 alkyl, preferably R ⁸ groups are all methyl and R ⁹ groups are both methyl or ethyl Im) is N, N Dimethylformamide dimethyl acetal. Preferably the compound of formula VII is used in excess amount without adding solvent and the reaction is carried out at an elevated temperature, such as reflux temperature.

Compounds of formula II, wherein L is OR ⁸ , are described in Indian J. Chem. Nasipuri et al. 10, 897, (1972) can be prepared similarly to the method described.

Compounds of formula VI are described in, for example, East German Patent 62062; Chem. Pharm. Bull., (1983) 31, 4554; J. Pharm. Soc. Jpn. (1956) 76, 1308; J. Chem. Soc., Perkin Trans. 1 (1984) 2297; and Arch. Pharm., (1961); 294, 759) known or can be obtained using known techniques. For example, compounds of formula (VI) wherein both X and Z are N can be prepared, for example, by reacting a compound of formula (VIII) with a compound of formula (IX) at reflux temperature in the presence of a suitable organic solvent (eg, ethanol). . Compounds of formula VI wherein R is SCH ₂ and W, X, Y and Z are CA / CA can be prepared by dehydration cyclization of the compound of formula X in the presence of a suitable dehydrating agent such as polyphosphoric acid at elevated temperature.

Wherein R is specified in formula (I)

CA (NH) NH ₂

(Wherein A is specified above)

Compounds of formula (VIII) can be prepared by, for example, refluxing

It can be prepared by reacting with N, N-dimethylformamide dimethyl acetal.

Wherein R is specified in formula (I)

Compounds of formula III are either commercially available or readily available using known techniques. For example, a compound of formula III can be prepared by reacting a compound of formula XII with ammonium chloride at about 90 ° C. in the presence of trimethylaluminum and a suitable organic solvent (eg toluene).

Ar ¹ CN

(Wherein Ar ¹ is specified above)

Compounds of formula IV are for example corresponding compounds of formula II at reflux temperature in the presence of a suitable base (e.g. sodium ethoxide) and a suitable organic solvent (e.g. ethanol), wherein Y represents N or CR ^3a , R ^3a is as specified above) can be prepared by reacting with 2-methyl-2-thioshudorea or its hydrohalide salt.

Compounds of formula I can be converted to other compounds of formula I using methods known in the art. For example:

(a) Preparation of a compound of formula (I) wherein R is CH = CH can be carried out using a corresponding compound of formula (I) wherein R is CH ₂ CH ₂ , for example, with a suitable catalyst (e.g. By heating to about 170 ° C. in an inert solvent (eg dimethyl acetamide) in the presence of platinum on carbon).

(b) Preparation of a compound of formula (I) wherein Y is CH and R is (CH ₂ ) _n , for example, comprises a suitable catalyst (eg Raney nickel) and a suitable organic solvent (eg dimethylacetamide) In the presence of about 100 ° C. may be carried out by hydrogenolysis of the corresponding compound of formula I, wherein Y represents CA, wherein A represents C _1-6 thioalkyl.

(c) Preparation of a compound of formula (I) wherein X, Y or Z represents N ⁺ -O ^- and when n represents ¹ , both R ¹ and R ² represent H is suitable oxidizing agents (e.g., In the presence of 3-chloroperbenzoic acid) and a suitable organic solvent (e.g. dichloromethane), by oxidation of the corresponding compound of formula (I, where one of X, Y or Z suitably represents N).

(d) Preparation of a compound of formula (I) wherein Y represents CA, A represents NH ₂ , X and Z both represent N, and R represents (CH ₂ ) _n to produce the corresponding compound of formula I (A Can be carried out by reacting R ¹⁰ SO _2- , wherein R ¹⁰ represents C _1-6 alkyl, with ammonia at elevated temperature in dioxane, for example at about 180 ° C. in spring.

(e) Preparation of a compound of formula (I) wherein A is NR ⁴ C (O) R ⁵ , R ⁴ represents C ^1-6 alkyl and R ⁵ is specified above, for example, is a suitable base (eg, Potassium carbonate) and a suitable organic solvent (e.g., dimethylformamide) can be carried out by reacting the corresponding compound of formula I (R ⁴ represents H) with a compound of formula XIII at room temperature.

R ^4a Hal

(Wherein R ^4a represents C _1-6 alkyl and Hal represents Cl, Br or I)

(f) The preparation of compounds of formula (I) wherein A is NR ⁴ C (O) R ⁵ and R ⁴ and R ⁵ are specified above, for example, can be carried out with a suitable peptide synthesizing agent (e.g. dicyclohexylcarbodiy). The corresponding compound of formula (I) is NR ^2a H (wherein R ^2a is H or C ₁ ) at room temperature in the presence of 4-dimethylaminopyridine and a suitable organic solvent (e.g. dichloromethane or dimethylformamide) _-6 alkyl and coincides with R ⁴ ), by reacting with a compound of formula XIV.

R ⁵ C (O) OH

Wherein R ⁵ is specified above

(g) Preparation of compounds of formula I (A represents NR ² R ³ , R ² represents H or C _1-6 alkyl and R ³ represents C _1-6 alkyl or CH ₂ Ar ² ) For example, at room temperature in the presence of a suitable reducing agent (e.g. borane) and a suitable organic solvent (e.g. tetrahydrofuran) the corresponding compound of formula (A is NR ⁴ C (O) R ⁵ , wherein R ⁴ is As described above, consistent with R ² , R ⁵ as specified above, and when representing Ar ³ , corresponding to Ar ² ).

(h) Preparation of compounds of formula I (A represents NR ² H and R ² represents H or C _1-6 alkyl) is carried out, for example, at reflux in the presence of an aqueous solution of acid (e.g. hydrochloric acid). This can be done by hydrolyzing the corresponding compound of I (A represents NR ⁴ C (O) CH ₃ and R ⁴ is as specified above and coincides with R ² ).

(i) a compound of formula I (A represents NR ² R ³ and R ² and R ³ represent C _1-6 alkyl or together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl ring The preparation of C) can be carried out by, for example, zinc chloride and the appropriate compound of formula (I represents NH ₂ ) at room temperature in the presence of a suitable organic solvent (e.g. methanol) and a suitable reducing agent (e.g. sodium To novolohydride).

R ^x CHO

(Wherein R ^x represents C _1-5 alkyl or HC (O) Z ¹ , wherein Z ¹ represents C _2-3 alkylene)

(j) Preparation of the compound of formula (I) represents cyano), for example, the reaction of the corresponding compound of formula I (A represents bromine) at reflux temperature in the presence of N-methylpyrrolidone By reaction with I).

(k) Preparation of compounds of formula I (A represents fluorine) when W, X, Y and Z are all CH, for example 170 in the presence of a suitable organic solvent (e.g. 1,2-dichlorobenzene) By heating to < RTI ID = 0.0 > C, < / RTI > reacting the compound of formula XVI with sodium tetrafluoroborate or, alternatively, when the counter ion is tetrafluoroborate, the preparation of such compounds of formula I is carried out with a suitable organic solvent (e.g. 1,2-dichlorobenzene) can be carried out by heating the diazonium salt to 170 ° C.

Wherein R and Ar ¹ are as specified above

(l) Preparation of compounds of formula I (A represents nitro) when W, X, Y and Z are all CH, is carried out above at room temperature, for example in the presence of copper powder and a suitable solvent (e.g. water). This can be done by reacting the diazonium salt of formula XVI with sodium nitrite.

(m) The preparation of compounds of formula I (A represents chlorine) when W, X, Y and Z are all CHs is those of formula XVI as defined above by, for example, warming in a suitable solvent (e.g. aqueous ethanol solution). This can be done by reacting the diazonium salt with copper chloride (I).

(o) The preparation of compounds of formula I (A represents iodine) when W, X, Y and Z are all CHs is as defined above for example by warming in a suitable solvent (e.g. This can be done by reacting the diazonium salt with copper chloride (I).

(p) Preparation of the compound of formula I (A represents NH ₂ ) reduces the corresponding compound of formula I (A represents nitro) by heating to a reflux temperature, for example, in a suitable solvent (e.g. aqueous ethanol solution). Can be done.

(q) Preparation of the compound of formula I (A represents CO ₂ H) hydrolyzes the corresponding compound of formula I (A represents cyano) under appropriate conditions, for example by refluxing in the presence of 50% sulfuric acid. Can be done.

(r) Preparation of compounds of formula I (A represents CO ₂ R ¹ and R ¹ represents C _1-6 alkyl) comprises compounds of formula XVII, and suitable acid or base catalysts or activators (e.g. In the presence of onyl), by esterifying the corresponding compound of formula (A represents CO ₂ H).

R ^1a OH

Wherein R ^1a represents C _1-6 alkyl

(s) The preparation of compounds of formula (I) represents, for example, the presence of a suitable Lewis acid (e.g. boron tribromide or aluminum tribromide) and a suitable organic solvent (e.g. dichloromethane or ethanethiol) Can be carried out by hydrolyzing the corresponding compound of formula I (A represents C _1-6 alkoxy) between 0 and -78 ° C.

(t) Preparation of compounds of formula I (A represents C _1-6 alkoxy) may be carried out at room temperature in the presence of a base (e.g. sodium hydride) and a suitable organic solvent (e.g. dimethylformamide) This can be done by reacting the corresponding compound (A represents hydroxy) with a compound of formula XVIII.

R'Hal

Wherein R 'represents C _1-6 alkyl and Hal is specified above

(u) Preparation of compounds of formula I (A represents C _1-6 alkyl) can be carried out, for example, with suitable catalyst systems (e.g. palladium on activated carbon and triphenylphosphine or dichloro (triphenylphosphine) palladium, chloride Heated to reflux in the presence of lithium and 2,6-di-t-butyl-4-methylphenol and an appropriate organic solvent (eg dimethylformamide or dioxane), or alternatively an appropriate activator (eg , Trifluoromethanesulfonic anhydride) can be used to react the corresponding compound of formula I (A represents hydroxy) with a compound of formula XIX by activating the OH group.

R '(R ") ₃ Sn

Wherein R ″ represents C _1-4 alkyl and R ′ is specified above

(v) Preparation of compounds of formula I (A represents phenyl) is carried out, for example, in the presence of cesium fluoride and tetrakis (triphenylphosphine) palladium (0) and a suitable organic solvent (e.g. dimethoxyethane) By refluxing can be carried out by reacting the corresponding compound of formula I (A represents bromine) with phenylboric acid.

(w) a compound of formula I (A represents methoxy substituted with CO ₂ R ⁶ or C _2-6 alkoxy substituted with CO ₂ R ⁷ , R ⁶ and / or R ⁷ suitably C _1- Preparation of ₆ alkyl) corresponds to, for example, the corresponding compound of formula I (A represents hydroxy) at room temperature in the presence of a suitable base (e.g. potassium carbonate) and a suitable organic solvent (e.g. dimethylformamide). ) May be reacted with a compound of formula XX,

R ^y OC (O) Z ² Hal

(Wherein Z ² represents C _1-6 alkylene, R ^y represents C _1-6 alkyl, Hal is as specified above, and the alkylene group which Z ² may represent is straight or branched)

(x) The preparation of compounds of formula I (A represents C _1-6 alkoxy substituted with CO ₂ H) can be carried out, for example, with suitable hydrolysing agents (eg lithium hydroxide) and suitable organic / aqueous solvent systems. This can be done by hydrolyzing the corresponding compound of formula (I) at room temperature in the presence of (eg tetrahydrofuran / water).

The other starting compounds mentioned above are commercially available and are well known in the literature or are available using known techniques. The novel intermediate compounds described above form further two sides of the present invention.

Compounds of the invention can be isolated from the reaction mixture using conventional techniques.

It will be understood by those skilled in the art that the functional groups of the intermediate compounds in the process steps described above need to be protected by protecting groups. Protection of the functional groups can be made before all process steps described above. The protecting group can be removed after the reaction step or at the end of the reaction process using techniques well known to those skilled in the art. The use of protecting groups is fully described in JWF McOmie's "Protective Groups in Organic Chemistry", Plenum Press (1973), and "Protective Groups in Organic Synthesis", 2nd edition, TW Greene & PGM Wutz, Wiley-Interscience (1991). It is.

The compounds of the present invention are useful because they have pharmaceutical activity. The present invention therefore provides a compound of formula (I) for use in therapy.

Specifically, the compounds of the present invention have allergic and anti-inflammatory activity, as described, for example, in the experiments below.

Therefore, the compounds of the present invention are allergic to airways such as asthma (e.g. bronchial asthma, allergic asthma, endogenous asthma, exogenous and acute asthma), specifically chronic or chronic asthma (e.g. terminal asthma and airway hypersensitivity), bronchitis, etc. And for use in the treatment of inflammatory diseases.

In addition, the compounds of the present invention include acute rhinitis; Allergic rhinitis; Atrophic rhinitis; Chronic rhinitis including casein rhinitis, hypertrophic rhinitis, purulent rhinitis and dry rhinitis; Drug rhinitis; Membranous rhinitis including croupous, fibrillar, and mucosal rhinitis; Adenoid rhinitis; Seasonal rhinitis including rhinitis nervosa (hay fever); And all conditions characterized by inflammation of the nasal mucous membranes, such as vasculitis rhinitis, are effective in the treatment of diseases including inflammation / allergy, such as rhinitis.

The compounds of the present invention may also be used for chronic allergic diseases, atopic dermatitis, dermatitis eosinophilia, eosinophilic fasciitis, hyper IgE syndrome, spring conjunctivitis, systemic lupus erythematosus, thyroiditis, leprosy la, sedentary syndrome, chronic graft versus host disease, severe It is effective for use in the treatment of myasthenia gravis, idiopathic thrombocytopenia purpura.

The compounds of the present invention are also active in the prevention and treatment of acquired immunodeficiency syndrome (AIDS), in the prevention of chronic rejection of tagase grafts mediated by humoral immunity, and in the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. .

Of the above indications, in the prevention of asthma, especially asthma, and rhinitis, the use of the compounds of the present invention is most particularly of interest in seasonal rhinitis including allergic rhinitis and rhinitis (hay fever).

According to a further aspect of the present invention, allergic, comprising administering to a person suffering from or susceptible to such a disease, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, as specified above Or methods of treating or preventing inflammatory diseases.

In a further aspect of the invention, the formula (I) in the manufacture of a medicament for the treatment or prophylaxis of said diseases, in particular asthma and rhinitis, most particularly seasonal rhinitis including allergic rhinitis and rhinitis (hay fever) The use of a compound or a pharmaceutically acceptable derivative thereof is provided.

Administration of the compounds of the invention may be local (eg, by inhalation to the lungs). The compounds of the present invention can be inhaled as dry powders that can be indented or nonindented.

In non-indented powder compositions, the active ingredient in finely divided form can be used in admixture with a large size pharmaceutically acceptable inert carrier.

The composition may alternatively be pressurized and include, for example, a compressed gas, such as nitrogen, or a liquefied gas propellant. In such pressurized compositions, the active ingredient is preferably finely separated. The indented composition may also include a surface active agent. Indented compositions can be prepared by conventional methods.

The compounds of the present invention may be administered systemically (eg by oral administration to the gastrointestinal tract). The active ingredient can be combined with known adjuvants, diluents or carriers using conventional techniques to prepare tablets or capsules for oral administration to the gastrointestinal tract.

Examples of suitable adjuvants, diluents or carriers for oral administration in the form of tablets, capsules and dragees include sugars such as microcrystalline cellulose, calcium phosphate, diatomaceous earth, lactose, dextrose or mannitol, talc, stearic acid, starch, Sodium bicarbonate and / or gelatin.

According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof, as specified above, together with a pharmaceutically acceptable adjuvant, diluent or carrier.

Suitable dosages for topical or oral administration range from 0.01 to 30 mg kg ⁻¹ day ⁻¹ , for example 0.3 mg kg ⁻¹ day ⁻¹ .

It will be understood by those skilled in the art that certain functional groups of the compounds of the present invention may be protected using appropriate protecting groups to form "protected derivatives" of the compounds of the present invention. It will also be appreciated that even if such protected derivatives do not have pharmaceutical activity, they may be administered and then metabolized in the body to form pharmaceutically active compounds of the present invention. Such derivatives can therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds of formula I are included within the scope of the present invention.

The invention is illustrated in more detail by the following examples.

Example 1

2- (4-chlorophenyl) -5,6-dihydro-8-methylpyrimido [4,5-f] quinazoline

6,7-Dihydro-2-methylquinazolin-5 (8H) -one (East Patent 62 062; 530 mg) and dimethylformamide dimethylacetal (1 ml) are heated to reflux for 35 minutes. The reaction is cooled to ambient temperature and the volatiles are evaporated. The residue is dissolved in ethanol (2 ml), then 4-chlorophenylbenzamidine hydrochloride (130 mg) and sodium methoxide (25 mg) are added and the solution is heated to reflux for 75 minutes. The solvent is evaporated and the residue is dissolved in ethyl acetate (25 ml). The ethyl acetate solution is washed with water (twice) and brine, then dried, filtered and evaporated. Chromatography eluting with ethyl acetate gives the title compound (48 mg).

MS (EI) 308/310 (M ⁺ )

mp 186-187 ℃

¹ H NMR (DMSO) δ 2.69 (3H, s), 3.10 (4H, s), 7.61 (2H, d), 8.52 (2H, d), 8.84 (1H, s), 9.49 (1H, s).

Example 2

2- (4-chlorophenyl) -5,6-dihydro-8-methoxypyrimido [4,5-f] quinazoline

6,7-dihydro-2-methoxyquinazolin-5 (8H) -one (East patent 62 062; 1.0 g) and dimethylformamide dimethylacetal (2 ml) followed by 4-chlorophenylbenzamidine hydroyo Prepared according to the method of example 1 above using odide (1.6 g) and sodium methoxide (300 mg) to afford the title compound (550 mg).

MS (EI) 324/326 (M ⁺ )

mp 192 ℃

¹ H NMR (DMSO) δ 3.07 (4H, s), 4.00 (3H, s), 7.59 (2H, d), 8.50 (2H, d), 8.78 (1H, s), 9.42 (1H, s).

Example 3

2- (4-chlorophenyl) -5,6-dihydropyrimido [5,4-h] quinazoline

5,6-dihydroquinazolin-8 (7H) -one (Chem. Pharm. Bull., (1983) 31, 4554; 180 mg) and dimethylformamide dimethylacetal (1 ml) followed by 4-chlorophenylbenz Prepared according to the method of example 1 above using amidine hydroiodide (350 mg) and sodium methoxide (70 mg) to afford the title compound (24 mg).

MS (APCI) 294/296 ((MH) ^- )

mp 190 ℃

¹ H NMR (DMSO) δ3.07 (4H, s), 7.64 (2H, d), 8.50 (2H, d), 8.91 (1H, s), 8.98 (1H, s), 9.32 (1H, s).

Example 4

2- (4-chlorophenyl) -5,6-dihydropyrimido [3,4-h] quinazoline

6,7-dihydroisoquinolin-5 (8H) -one (J. Pharm. Soc. Jpn. (1956) 76, 1308; 900 mg) and dimethylformamide dimethylacetal (2 ml) followed by 4-chlorophenyl Prepared according to the method of Example 1 above using benzamidine hydroiodide (1.75 g) and sodium methoxide (340 mg) to afford the title compound (700 mg).

MS (APCI) 294/296 ((M + H) ⁺ )

mp 160-162 ℃

¹ H NMR (DMSO) δ3.02 (4H, s), 7.62 (2H, d), 8.25 (1H, d), 8.51 (2H, d), 8.66 (1H, d), 8.69 (1H, s), 8.89 (1 H, s).

Example 5

2- (4-chlorophenyl) -5,6-dihydro-8-methylthiopyrimido [4,5-f] quinazoline

6,7-dihydro-2-methylthioquinazolin-5 (8H) -one (East Patent 62 062; 1.0 g) and dimethylformamide dimethylacetal (2 ml), followed by 4-chlorophenylbenzamidine hydroyo Prepared according to the method of Example 1 above using odide (1.45 g) and sodium methoxide (278 mg) to afford the title compound (526 mg).

MS (APCI) 341/343 ((M + H) ⁺ )

mp> 200 ℃

¹ H NMR (DMSO) δ 2.59 (3H, s), 3.08 (4H, s), 7.58 (2H, d), 8.49 (2H, d), 8.79 (1H, s), 9.40 (1H, s).

Example 6

2- (4-chlorophenyl) -5,6-dihydropyrimido [4,5-f] quinazoline

2- (4-chlorophenyl) -5,6-dihydro-8-methylthiopyrimido [4,5-f] quinazoline in dimethylacetamide (30 ml) (see Example 5 above; 200 mg) ) And Raney nickel (10 g) are heated at 100 ° C. for 2 hours. The reaction mixture is cooled and filtered. Nickel is washed with dimethylacetamide and the filtrate is concentrated. The residue is purified by chromatography eluting with dichloromethane: ethyl acetate (1: 1), followed by reverse phase HPLC eluting with an aqueous solution of an ammonium acetate: methanol mixture, and finally recrystallized from an aqueous methanol solution to give the title compound (57 mg). Get

MS (EI) 294/296 (M ⁺ )

mp 157-158 ℃

¹ H NMR (DMSO) δ 3.15 (4H, s), 7.60 (2H, d), 8.53 (2H, d), 8.88 (1H, s), 9.21 (1H, s), 9.61 (1H, s).

Example 7

2- (4-chlorophenyl) -5,6-dihydropyrido [3,4-h] quinazolin-8-oxide

2- (4-chlorophenyl) -5,6-dihydropyrido [3,4-h] quinazoline (see Example 4 above) 220 mg is dissolved in dichloromethane (20 ml). 3-chloroperbenzoic acid (230 mg) is added and the reaction is stirred overnight. The reaction is quenched with sodium metabisulfite solution and then diluted with excess dichloromethane. The reaction mixture is washed with sodium bicarbonate solution and then dried, filtered and evaporated. The residue is recrystallized from THF: isohexane and then recrystallized from toluene to give the title compound (93 mg).

MS (APCI) 310/312 ((M + H) ⁺ )

mp 245 ℃

¹ H NMR (DMSO) δ 2.98 (4H, m), 7.60 (2H, d), 8.26 (1H, dd), 8.30 (1H, d), 8.36 (1H, d), 8.49 (2H, d), 8.82 (1 H, s).

Example 8

2- (4-chlorophenyl) -5,6-dihydropyrimido [4,5-f] quinazolin-8-amine

(a) 2- (4-chlorophenyl) -5,6-dihydro-8-methylsulfonylpyrimido [4,5-f] quinazoline

2- (4-chlorophenyl) -5,6-dihydro-8-methylthiopyrimido [4,5-f] quinazoline (see Example 5 above; 260 mg) was dissolved in chloroform (20 ml) and m-chloroperbenzoic acid (430 mg) is added. The reaction is stirred overnight and then quenched with sodium metabisulfite solution. The organic layer is evaporated and the residue is partitioned between ethyl acetate and sodium bicarbonate solution. The ethyl acetate phase is washed with aqueous sodium bicarbonate solution followed by brine, dried, filtered and evaporated to give the subtitle compound (200 mg).

MS (APCI) 373/375 ((M + H) ⁺ ), MS (ESI) 373/375 ((M + H) ⁺ )

mp 255 ℃

¹ H NMR (DMSO) δ3.19 (2H, t), 3.37 (2H, t), 3.43 (3H, s), 7.50 (2H, d), 8.47 (2H, d), 8.78 (1H, s), 9.77 (1 H, s).

(b) 2- (4-chlorophenyl) -5,6-dihydropyrimido [4,5-f] quinazolin-8-amine

2- (4-chlorophenyl) -5,6-dihydro-8-methylsulfonylpyrimido [4,5-f] quinazoline (from step (a); 80 mg) was converted to dioxin (15 ml). In water and add ammonia solution (density 0.88; 10 ml). The mixture is heated to 100 ° C. for 2 hours in spring. The volatiles are evaporated and the residue is purified by chromatography eluting with a dioxane: isohexane mixture, followed by reverse phase HPLC eluting with an aqueous solution of ammonium acetate: methanol mixture. The appropriate fractions are freeze dried to afford the title compound (15 mg).

MS (APCI) 310/312 ((M + H) ⁺ )

mp 273-275 ℃

¹ H NMR (DMSO) δ 2.86 (2H, t), 2.99 (2H, t), 7.33 (2H, br s), 7.57 (2H, d), 8.47 (2H, d), 8.65 (1H, s) , 9.13 (1 H, s).

Example 9

5,6-dihydro-2- (pyridin-3-yl) pyrimido [4,5-f] quinazoline

(a) 5,6-dihydro-8-methylthio-2- (pyridin-3-yl) pyrimido [4,5-f] quinazoline

6,7-dihydro-2-methylthioquinazolin-5 (8H) -one (German patent, 62 062; 1.0 g) and dimethylformamide dimethylacetal (2 ml), followed by 3-pyridylamidine hydrochloride (1.0 g) and sodium methoxide (460 mg) were prepared according to the method of Example 1 to obtain the subtitle compound (800 mg).

MS (APCI) 308 ((M + H) ⁺ )

¹ H NMR (DMSO) δ 2.60 (3H, s), 3.08 (4H, brs), 7.55 (1H, dd), 8.71 (1H, dd), 8.77 (1H, ddd), 8.83 (1H, s), 9.45 (1 H, s), 9.61 (1 H, d).

(b) 5,6-dihydro-2- (pyridin-3-yl) pyrimido [4,5-f] quinazoline

5,6-dihydro-8-methylthio-2- (pyridin-3-yl) pyrimido [4,5-f] quinazolin (from step (a) above; 800 mg) and Raney nickel (10 g) Prepared according to the method of Example 6 above using the title compound (110 mg).

MS (APCI) 262 ((M + H) ⁺ )

mp 187-188 ℃

¹ H NMR (DMSO) δ 3.16 (4H, s), 7.59 (1H, dd), 8.74 (1H, dt), 8.83 (1H, dt), 8.92 (1H, s), 9.22 (1H, s), 9.65 (1 H, d), 9.67 (1 H, s).

Example 10

5,6-dihydro-2- (pyridin-2-yl) pyrimido [4,5-f] quinazoline

(a) 5,6-dihydro-8-methylthio-2- (pyridin-2-yl) pyrimido [4,5-f] quinazoline

6,7-dihydro-2-methylthioquinazolin-5 (8H) -one (German patent, 62 062; 1.0 g) and dimethylformamide dimethylacetal (3.5 ml) followed by 2-pyridylamidine hydrochloride (0.81 g) and sodium methoxide (460 mg) were prepared according to the method of Example 1 to obtain a subtitle compound (1.0 g).

MS (APCI) 308 ((M + H) ⁺ )

¹ H NMR (DMSO) δ 2.60 (3H, s), 3.11 (4H, m), 7.54 (1H, td), 8.00 (1H, td), 8.51 (1H, d), 8.78 (1H, dd), 8.88 (1 H, s), 9.36 (1 H, s).

(b) 5,6-dihydro-2- (pyridin-2-yl) pyrimido [4,5-f] quinazolin

5,6-dihydro-8-methylthio-2- (pyridin-2-yl) pyrimido [4,5-f] quinazolin (from step (a) above; 1.0 g) and Raney nickel (13 g) Prepared according to the method of Example 6 above using the title compound (260 mg).

MS (APCI) 262 (M + H)

mp 177-179 ℃

¹ H NMR (DMSO) δ 3.18 (4H, s), 7.55 (1H, br dd), 8.00 (1H, td), 8.53 (1H, d), 8.79 (1H, br d), 8.94 (1H, s ), 9.21 (1 H, s), 9.55 (1 H, s).

Example 11

5,6-dihydro-2- (pyridin-3-yl-N-oxide) -pyrimido [4,5-f] quinazoline

5,6-dihydro-2- (pyridin-3-yl) pyrimido [4,5-f] quinazolin (see Example 9 above; 60 mg) was dissolved in dichloromethane (10 ml) and m- Chloroperbenzoic acid (100 mg) is added. The reaction is stirred for 130 minutes and then quenched with sodium metabisulfite solution. The organic phase is washed with sodium bicarbonate solution, dried and evaporated. The residue is purified by chromatography and then purified by HPLC eluting with a dichloromethane: methanol mixture to give the title compound (20 mg).

MS (APCI) 278 ((M + H) ⁺ )

¹ H NMR (DMSO) δ3.17 (4H, s), 7.60 (1H, t), 8.38 (2H, t), 8.94 (1H, s), 9.12 (1H, br s), 9.22 (1H, s) , 9.69 (1 H, s).

Example 12

5,6-dihydro-2- (6-methylpyridin-3-yl) pyrimido [4,5-f] quinazoline

(a) 6-methyl-3-pyridylamidine hydrochloride

Trimethylaluminum (2M in hexane; 15 ml) is added to a vigorously stirred suspension of ammonium chloride (1.65 g) in toluene (25 ml) cooled in an ice bath. The cooling bath is removed and the reaction is brought to room temperature. 6-Methyl-pyridine-3-carbonitrile (1.18 g) is added and the reaction is heated to 90 ° C. overnight. The reaction is cooled to room temperature and then methanol is added dropwise. The mixture is poured into a slurry of alumina (25 g) in chloroform (225 ml). Methanol (100 ml) is added and the slurry is stirred for 30 minutes. The mixture is filtered, the solid is washed with methanol and the combined filtrates are concentrated to give the subtitle compound (2.78 g) contaminated with ammonium chloride.

MS (APCI) 136 ((M + H) ⁺ )

¹ H NMR (DMSO) δ 2.57 (3H, s), 7.35 (4H, brs), 7.50 (1H, d), 8.19 (1H, dd), 8.89 (1H, d).

(b) 5,6-dihydro-8-methylthio-2- (6-methylpyridin-3-yl) pyrimido [4,5-f] quinazoline

6,7-dihydro-2-methylthioquinazolin-5- (8H) -one (German Patent 62 062; 1.0 g) and dimethylformamide dimethylacetal (3 ml) followed by 6-methyl-3-pyridyl Amidine (hydrochloride (from step (a) above) is liberated as follows: hydrochloride is added to saturated sodium bicarbonate solution (excess), the solution is evaporated, the resulting residue is extracted with ethanol and ethanol is extracted Filtration and then evaporation to give free base (0.60 g)) and sodium methoxide (230 mg) were prepared according to the method of example 1 above to obtain the subtitle compound (1.10 g).

MS (APCI) 322 ((M + H) ⁺ )

¹ H NMR (DMSO) δ2.55 (3H, s), 2.58 (3H, s), 3.08 (4H, s), 7.41 (1H, d), 8.66 (1H, dd), 8.80 (1H, s), 9.43 (1 H, s), 9.47 (1 H, d).

(c) 5,6-dihydro-2- (6-methylpyridin-3-yl) pyrimido [4,5-f] quinazoline

5,6-dihydro-8-methylthio-2- (6-methylpyridin-3-yl) pyrimido [4,5-f] quinazolin (from step (b) above; 1.10 g) and Raney nickel ( 11.7 g) is prepared according to the method of Example 6 above to obtain the title compound (110 mg).

MS (APCI) 276 ((M + H) ⁺ )

mp 157-158 ℃

¹ H NMR (DMSO) δ2.57 (3H, s), 3.15 (4H, s), 7.43 (1H, d), 8.70 (1H, dd), 8.88 (1H, s), 9.21 (1H, s), 9.51 (1 H, sd), 9.63 (1 H, s).

Example 13

5,6-dihydro-2- (6-methylpyridin-3-yl-N-oxide) -pyrimido [4,5-f] quinazolin-8-amine

(a) 5,6-dihydro-2- (6-methylpyridin-3-yl-N-oxide) -8-methylsulfonylpyrimido [4,5-f] quinazoline

5,6-dihydro-8-methylthio-2- (6-methylpyridin-3-yl) -pyrimido [4,5-f] quinazolin (see Example 12 (b) above; 500 mg) And 3-chloroperbenzoic acid (900 mg) are dissolved in dichloromethane (30 ml) and stirred at room temperature for 2 hours. The reaction is quenched with sodium metabisulfite solution. The reaction mixture is partitioned between dichloromethane and aqueous sodium bicarbonate solution and the aqueous layer is extracted with dichloromethane, then the organic phase is combined, dried, filtered and evaporated to give the subtitle compound (270 mg).

MS (APCI) 370 ((M + H) ⁺ )

¹ H NMR (CDCl ₃ ) δ2.63 (3H, s), 3.22 (2H, t), 3.38 (2H, t), 3.45 (3H, s), 7.43 (1H, d), 8.28 (1H, dd) , 8.81 (1 H, s), 9.42 (1 H, d), 9.75 (1 H, s).

(b) 5,6-dihydro-2- (6-methylpyridin-3-yl-N-oxide) -pyrimido [4,5-f] quinazolin-8-amine

5,6-dihydro-2- (6-methylpyridin-3-yl-N-oxide) -8-methylsulfonylpyrimido [4,5-f] quinazolin (from step (a) above; 210 mg) and 0.88 density ammonia solution (6 ml) were prepared according to the method of Example 8 above to obtain the title compound (75 mg).

MS (APCI) 307 ((M + H) ⁺ )

mp> 250 ° C

¹ H NMR (DMSO) δ2.44 (3H, s), 2.86 (2H, t), 3.02 (2H, t), 7.37 (2H, br s), 7.65 (1H, d), 8.22 (1H, dd) , 8.68 (1 H, s), 9.09 (1 H, d), 9.16 (1 H, s).

Example 14

2- (4-chlorophenyl) -6,7-dihydro-5H-pyrido [2,3-i] cycloheptapyrimidine

6,7,8,9-tetrahydrocycloheptapyridin-5 (5H) -one (J. Chem. Soc., Perkin Trans. 1 (1984) 2297; 600 mg) and dimethylformamide dimethylacetan (5 ml ), Followed by 4-chlorophenylbenzamidine hydroiodide (640 mg) and sodium methoxide (180 mg) according to the method of Example 1 above to afford the title compound (526 mg).

MS (APCI) 308/310 ((M + H) ⁺ )

mp 143-145 ℃

¹ H NMR (DMSO) δ 2.37 (2H, quin), 2.57 (2H, t), 2.75 (2H, t), 7.54 (1H, dd), 7.60 (2H, d), 8.22 (1H, dd), 8.47 (2H, d), 8.65 (1H, dd), 8.87 (1H, s).

Example 15

2- (4-chlorophenyl) -5,6-dihydropyrido [2,3-h] quinazoline

6,7-dihydroquinazolin-5 (8H) -one (Arch. Pharm. (1961) 294, 759; 150 mg) and dimethylformamide dimethylacetal (0.5 ml) followed by 4-chlorophenylbenzamidine hydro Prepared according to the method of example 1 above using chloride (152 mg) and sodium methoxide (43 mg) to afford the title compound (82 mg).

MS (APCI) 294/6 ((M + H) ⁺ )

mp 133-134 ℃

¹ H NMR (d6-DMSO) δ3.15 (m, 4H), 7.50 (dd, 1H), 7.60 (d, 2H), 8.50 (d, 2H), 8.65 (dd, 1H), 8.75 (dd, 1H ), 8.85 (s, 1 H).

Example 16

2- (pyridin-3-yl) -5,6-dihydropyrido [2,3-h] quinazoline

6,7-dihydroquinolin-5 (8H) -one (Arch. Pharm. (1961) 294, 759; 150 mg) and dimethylformamide dimethylacetal (0.5 ml), followed by 3-amidinopyridine hydrochloride (125 mg) and sodium methoxide (43 mg) were prepared according to the method of Example 1 above to obtain the title compound (47 mg).

MS (APCI) 261 ((M + H) ⁺ )

mp 101-102 ℃

¹ H NMR (d6-DMSO) δ3.15 (m, 4H), 7.50 (dd, 1H), 7.60 (dd, 1H), 8.65 (dd, 1H), 8.75 (d, 1H), 8.80 (m, 2H ), 8.90 (s, 1 H), 9.65 (s, 1 H).

Example 17

2- (6-methylpyridin-3-yl) -5,6-dihydropyrido [2,3-h] quinazoline

6,7-dihydroquinolin-5 (8H) -one (Arch. Pharm. (1961) 294, 759; 400 mg) and dimethylformamide dimethylacetal (2 ml) followed by 6-methyl-3-pyridylami Prepared according to the method of Example 1 above using Dean hydrochloride (see Example 12 (a) above; 300 mg) and sodium methoxide (120 mg) to afford the title compound (225 mg).

MS (APCI) 275 ((M + H) ⁺ )

mp 114-145 ℃

¹ H NMR (d6-DMSO) δ 2.60 (s, 3H), 3.15 (m, 4H), 7.40 (d, 1H), 7.50 (dd, 1H), 8.60-8.70 (m, 2H), 8.75 (dd , 1H), 8.85 (s, 1H), 9.50 (s, 1H).

Example 18

2- (4-chlorophenyl) -5,6-dihydropyrido [2,3-h] quinazolin, 7-oxide

According to the method of Example 11, 2- (4-chlorophenyl) -5,6-dihydropyrido [2,3-h] quinazoline (see Example 15; 60 mg) was added to 3-chloroperbenzoic acid. Oxidation with (85 mg) gives the title compound (29 mg).

MS (APCI) 310/2 ((M + H) ⁺ )

mp 208-209 ℃

¹ H NMR (d6-DMSO) δ3.10 (t, 2H), 3.25 (t, 2H), 7.50 (t, 1H), 7.60 (d, 2H), 8.35 (d, 1H), 8.45 (d, 1H ), 8.50 (d, 2H), 8.90 (s, 1H).

Example 19

2- (4-chlorophenyl) -5,6-dihydropyrido [4,3-h] quinazoline

6,7-dihydroisoquinolin-8- (5H) -one (J. Pharm. Soc.Jpn., (1956) 76, 1308; 400 mg) dimethylformamide dimethylacetal (2 ml), 4-chlorobenz Prepared according to the method of example 1 above using amidine hydrochloride (475 mg) and sodium methoxide (135 mg) to afford the title compound (175 mg).

MS (APCI) 294/6 ((M + H) ⁺ )

mp 152-153 ℃

¹ H NMR (d6-DMSO) δ3.02 (s, 4H), 7.43 (d, 1H), 7.61 (d, 2H), 8.53 (d, 2H), 8.63 (d, 2H), 8.83 (s, 1H ), 9.51 (s, 1 H).

Example 20

5,6-dihydro-2- (pyridin-3-yl) -pyrido [4,3-h] quinazoline

6,7-dihydroisoquinolin-8- (5H) -one (J. Pharm. Soc.Jpn., (1956) 76, 1308; 400 mg) dimethylformamide dimethylacetal (2 ml), 3-amidino Prepared according to the method of example 1 above using pyridine hydrochloride (390 mg) and sodium methoxide (135 mg) to afford the title compound (124 mg).

MS (APCI) 261 ((M + H) ⁺ )

mp 151-152 ℃

¹ H NMR (d6-DMSO) δ3.04 (s, 4H), 7.43 (d, 1H), 7.57-7.62 (m, 1H), 8.63 (d, 1H), 8.73 (dd, 1H), 8.80 (dt , 1H), 8.86 (s, 1H), 9.54 (s, 1H), 9.63 (d, 1H).

Example 21

2- (pyridin-3-yl) -pyrido [4,3-h] quinazoline

The title compound is isolated from the previous example.

MS (APCI) 259 ((M + H) ⁺ )

mp 243-244 ℃

¹ H NMR (d6-DMSO) δ7.59-7.63 (dd, 1H), 7.98 (d, 1H), 8.04 (d, 1H), 8.23 (d, 1H), 8.7 (dd, 1H), 8.92 (d , 1H), 9.01-9.05 (m, 1H), 9.72 (s, 1H), 9.87 (d, 1H), 10.59 (s, 1H).

Example 22

2- (4-chlorophenyl) -5,6-dihydropyrido [4,3-h] quinazolin, 9-oxide

2- (4-chlorophenyl) -5,6-dihydropyrido [4,3-h] quinazoline (see Example 19 above; 290 mg) was added to 3-chloroperbenzoic acid according to the method of Example 7. Oxidation with (285 mg) affords the title compound (107 mg).

MS (APCI) 310/2 ((M + H) ⁺ )

mp 228-230 ℃

¹ H NMR (d6-DMSO) δ3.01 (bs, 4H), 7.48 (d, 1H), 7.60 (d, 2H), 8.30 (dd, 1H), 8.51 (d, 2H), 8.89 (s, 1H ), 8.99 (s, 1 H).

Example 23

5,6-dihydro-2- (6-methoxypyridin-3-yl) -pyrimido [4,5-f] quinazoline

(a) 6-methoxypyridin-3-ylamidine hydrochloride

Prepared according to the method of Example 12 (a) above using trimethylaluminum (9.5 ml of 2M solution), ammonium chloride (1.10 g) and 6-methoxypyridine-3-carbonitrile (1.218 g) to obtain a subsidiary compound ( 2.02 g; containing ammonium chloride).

MS (APCI) 152 ((M + H) ⁺ )

¹ H NMR (DMSO) δ 3.95 (3H, s), 7.06 (1H, d), 8.14 (1H, dd), and 8.69 (1H, d).

(b) 5,6-dihydro-2- (6-methoxypyridin-3-yl) pyrimido [4,5-f] quinazoline

6,7-dihydroquinazolin-5 (8H) -one (German patent 62 062; 151 mg), dimethylformamide dimethylacetal (0.75 ml), 6-methoxypyridin-3-ylamidine (excess sodium Dissolved in aqueous bicarbonate solution and then evaporated to free from hydrochloride (430 mg; from step (a) above) to obtain a solid, titrated with ethanol, filtered and evaporated) and sodium methoxide (54 mg) Prepared according to the method of Example 1 above to afford the title compound (89 mg).

mp 212-213.5 ° C

MS (APCI) 292 ((M + H) ⁺ )

¹ H NMR (DMSO) δ 3.15 (4H, s), 3.96 (3H, s), 6.99 (1H, d), 8.74 (1H, dd), 8.86 (1H, s), 9.21 (1H, s), 9.30 (1 H, d) and 9.65 (1 H, s).

Example 24

2- (6-chloropyridin-3-yl) -5,6-dihydropyrimido [4,5-f] quinazoline

(a) 6-chloropyridin-3-ylamidine hydrochloride

Prepared according to the method of Example 12 (a) using trimethylaluminum (4.5 ml of 2 M solution), ammonium chloride (0.54 g) and 6-chloropyridine-3-carbonitrile (0.75 g) to obtain a subtitle compound ( 0.85 g; containing ammonium chloride).

MS (APCI) 156/158 ((M + H) ⁺ )

¹ H NMR (DMSO) δ 7.84 (1H, d), 8.26 (1H, dd), and 8.83 (1H, d).

(b) 5,6-dihydro-2- (6-chloropyridin-3-yl) pyrimido [4,5-f] quinazoline

6,7-dihydroquinazolin-5 (8H) -one (German patent 62 062; 145 mg), dimethylformamide dimethylacetal (1.5 ml) and 6-chloropyridin-3-ylamidine (excess sodium ratio Dissolved in aqueous carbonate solution and then evaporated to give a solid, which was prepared according to the method of example 1 above using solids extracted with ethanol, filtered and evaporated to give the title compound (62 mg).

mp 186-198 ℃

MS (APCI) 296/298 ((M + H) ⁺ )

¹ H NMR (DMSO) δ 3.17 (4H, s), 7.71 (1H, d), 8.87 (1H, dd), 8.93 (1H, s), 9.22 (1H, s), 9.46 (1H, d) and 9.68 (1 H, s).

Example 25

2- (6-methylpyridin-3-yl) -pyrimido [4,3-f] quinazoline

5,6-dihydro-2- (6-methylpyridin-3-yl) pyrimido [4,3-f] quinazolin (50 mg; see Example 12 above) and N, N-dimethylacetamide ( 5 ml) and 5% palladium on carbon (5 mg) in cyclohexane (5 ml) are heated at 170 ° C. for 18 hours. The mixture is cooled and then filtered to evaporate. Chromatography eluting the residue with 9: 1 ethyl acetate: methanol and RP-HPLC eluting with an ammonium acetate: methanol mixture and then the fractions are lyophilized to give the title compound (18 mg).

mp 187-190 ℃

MS (APCI) 274 ((M + H) ⁺ )

¹ H NMR (DMSO) δ2.62 (3H, s), 7.53 (1H, d), 8.12 (1H, d), 8.57 (1H, d), 8.97 (1H, dd), 9.66 (1H, s), 9.76 (1 H, d), 9.86 (1 H, s), 10.74 (1 H, s).

Example 26

2- (4-chlorophenyl) -5H- [1] benzopyrano [4,3-d] pyrimidine

(a) 2,3-dihydro-3- (N, N-dimethylaminomethylene) -4H-1-benzopyran-4-one

N, N-dimethylformamide dimethyl acetal (2 ml) is added to 4-chromanone (1 g) and heated at 110 ° C. for 105 minutes. The residue is concentrated during cooling to give the subtitle compound (1.3 g).

MS (EI) 203 (M ⁺ )

¹ H NMR (CDCl ₃ ) δ3.13 (6H, s), 5.25 (2H, s), 6.90 (1H, d), 7.00 (1H, t), 7.60 (1H, s), 7.97 (1H, d) .

(b) 2- (4-chlorophenyl) -5H- [1] benzopyrano [4,3-d] pyrimidine

Sodium methoxide (143 mg) and 4-chlorobenzamidine hydrochloride (730 mg) were added to 2,3-dihydro-3- (N, N-dimethylaminomethylene) [1] benzopyran in ethanol (10 ml). 4-one (510 mg; from step (a) above) is added to the suspension. During cooling the product is crystallized from the reaction mixture and collected by filtration. Purification by chromatography eluting with 8: 1: 1 isohexane: dichloromethane: ethyl acetate gives the title compound (200 mg).

mp 149 ℃

MS (EI) 294,296 (M ⁺ )

¹ H NMR (DMSO) 5.39 (2H, s), 7.07 (1H, d), 7.21 (1H, t), 7.51 (1H, t), 7.62 (2H, d), 8.34 (1H, d), 8.51 ( 2H, d), 8.78 (1H, s).

Example 27

2- (4-chlorophenyl) -5H-indeno [1,2-d] pyrimidine

(a) 2- (N, N-dimethylaminomethylene) indanon

A subtitle compound is prepared from indan-1-one similarly to the method described in Example 26 (a).

MS (APCI) 188 ((M + H) ⁺ )

¹ H NMR (CDCl ₃ ) 3.19 (6H, s), 3.89 (2H, s), 7.38 (1H, t), 7.44-7.50 (2H, m), 7.54 (1H, s) and 7.85 (1H, d) .

(b) 2- (4-chlorophenyl) -5H-indeno [1,2-d] pyrimidine

The title compound is prepared from 2- (N, N-dimethylaminomethylene) indanon (from step (a) above) according to the method described in Example 26 (b).

mp 187-192 ℃

MS (ESI) 279/281 ((M + H) ⁺ )

¹ H NMR (DMSO) 4.09 (2H, s), 7.56-7.67 (4H, m), 7.78 (1H, d), 8.19 (1H, d), 8.54 (2H, d), 9.07 (1H, s).

Example 28

The following examples are prepared according to the method used in Examples 26 and 27 (see table):

Example name m.p. MS NMR (DMSO-d ₆ ) δ 28 2-phenyl-5H- [1] benzopyrano- [4,3-d] pyrimidine 113 260 5.38 (2H, s), 7.07 (1H, d), 7.23 (1H, t), 7.49 (1H, t), 7.53 (3H, m), 8.34 (1H, d), 8.50 (2H, d), 8.77 (1H, s) 29 2-pyridin-4-yl-5H- [1] benzopyrano [4,3-d] pyrimidine 145-6 262 (M + H) ⁺ 5.42 (2H, s), 7.07 (1H, d), 7.22 (1H, t), 7.53 (1H, t), 8.36 (3H, d), 8.80 (2H, d), 8.85 (1H, s) 30 2- (pyridin-4-yl) -N-oxide-5H- [1] benzopyrano [4,3-d] pyrimidine 225-8 278 (M + H) ⁺ 5.40 (2H, s), 7.07 (1H, d), 7.21 (1H, t), 7.52 (1H, t), 8.36 (5H, m), 8.81 (1H, s) 31 2-pyridin-2-yl-5H- [1] benzopyrano [4,3-d] pyrimidine 124-5 262 (M + H) ⁺ 5.40 (2H, s), 7.07 (1H, d), 7.22 (1H, t), 7.5-7.6 (2H, m), 8.00 (1H, t), 8.30 (1H, d), 8.50 (1H, d) , 8.80 (1H, d) 8.84 (1H, s) 32 2-pyridin-3-yl-5H- [1] benzopyrano [4,3-d] pyrimidine 130 262 (M + H) ⁺ 5.41 (2H, s), 7.07 (1H, d), 7.23 (1H, t), 7.52 (1H, t), 7.59 (1H, dd), 8.35 (1H, d), 8.74 (1H, d), 8.77 (1H, d), 8.82 (1H, s) 33 2- (6-methylpyridin-3-yl-5H- [1] benzopyrano [4,3-d] pyrimidine 132 276 (M + H) ⁺ 2.57 (3H, s), 5.39 (2H, s), 7.07 (1H, d), 7.21 (1H, t), 7.44 (1H, d), 7.52 (1H, t), 8.35 (1H, d), 8.67 (1H, d), 8.78 (1H, s), 9.49 (1H, s) 34 2- (6-chloropyridin-3-yl-5H- [1] benzopyrano [4,3-d] pyrimidine 193-5 296/298 (M + H) ⁺ 5.40 (2H, s), 7.06 (1H, d), 7.20 (1H, t), 7.52 (1H, t), 7.71 (1H, d), 8.34 (1H, d), 8.81 (2H, m), 9.41 (1H, s) 35 2-pyrazin-2-yl-5H- [1] benzopyrano [4,3-d] pyrimidine 138-147 262 (M + H) ⁺ 5.43 (2H, s), 7.06 (1H, d), 7.20 (1H, t), 7.52 (1H, t), 8.30 (1H, d), 8.82 (1H, s), 8.86 (2H, s), 9.65 (1H, s) 36 2- (6-trifluoromethylpyridin-2-yl-5H- [1] benzopyrano [4,3-d] pyrimidine 124-5 330 (M + H) ⁺ 5.45 (2H, s), 7.08 (1H, d), 7.22 (1H, t), 7.53 (1H, t), 8.31 (1H, d), 8.43 (1H, dd), 8.70 (1H, d), 8.89 (1H, s), 9.19 (1H, d) 37 2- (2-methylthiazol-4-yl-5H- [1] benzopyrano [4,3-d] pyrimidine 140 282 (M + H) ⁺ 2.77 (3H, s), 5.37 (2H, s), 7.06 (1H, d), 7.20 (1H, t), 7.50 (1H, t), 8.27 (1H, d), 8.46 (1H, s), 8.73 (1H, s) 38 4- (5H- [1] benzopyrano [4,3-d] pyrimidin-2-yl) benzenecarboxamide 283 304 (M + H) ⁺ 5.40 (2H, s), 7.07 (1H, d), 7.22 (1H, t), 7.53 (2H, br t), 8.04 (2H, d), 8.13 (1H, br s), 8.37 (1H, d) , 8.56 (2H, d), 8.81 (1H, s)

Example 29

2- (6-methylpyridin-3-yl) -5,6-dihydropyrido [4,3-h] quinazoline

6,7-dihydroisoquinolin-8- (5H) -one (J. Pharm. Soc., 76 1308; 500 mg) and dimethylformamide dimethylacetal (3 ml) followed by 6-methyl-3-pyridyl Prepared according to the method of example 1 above using amidine (450 mg) and sodium methoxide (160 mg) to afford the title compound (160 mg) after chromatography.

MS (APCI) 275 ((M + H) ⁺ )

mp 176-8 ℃

¹ H NMR (d6-DMSO) δ2.57 (s, 3H), 3.02 (m, 4H), 7.42 (s, 1H), 7.44 (d, 1H), 8.63 (d, 1H), 8.69 (dd, 1H ), 8.83 (s, 1 H), 9.50 (d, 1 H), 9.52 (s, 1 H).

Pharmacy data

Experiment A

Chronic graft versus host experiment

The pharmacological activity of the compounds of the present invention is described in Clin. J. Doutrelepont et al. Exp. Immunol., 1991., vol. 83, 133-6; Inhibition of chronic graft-versus-host (c-GVH) disease in the mouse] method. Experimental compounds are administered to rats subcutaneously as suspension in saline with TWEEN-80 daily for 21 days.

Experiment B

Inhibition of eosinophilia

The effects of the compounds of the invention on inflammatory cells in the rat lung are described in Brussels et al., Clin. Exp. Allergy 1994, 24, 73-80] is measured according to the method adopted. Measurement of eosinophilic peroxidase as an indication for eosinophil numbers is described by Cehng et al., J. Pharmacol. Exp. Ther., 1993, 264, 922-929.

Male Balb / c mice are sensitized with an egg albumin / Al (OH) ₃ mixture.

Compound administration is initiated 14 days after sensitization. The compound is administered daily orally or subcutaneously as a suspension or solution (depending on the dosage and solubility of the compound) in 5% Tween 80.

After 17 days of sensitization and 1 hour after 4 doses of compound, mice are placed in a windshield chamber sprayed with a solution of egg albumin (2% w / v). Allow the mouse to inhale egg albumin for 30-40 minutes. This test is repeated daily at the same time for an additional 3 or 7 days.

In the case of a 4 day test, an additional test with egg albumin is given 4 hours after the first dose on the last day of administration.

The next day the animals are slaughtered and the inhibition of the next parameter is measured by comparison with the control animal.

(1) Increase in the number of inflammatory cells, especially eosinophils in bronchoalveolar lavage (after 4 days of administration)

(2) Accumulation of eosinophils in lung tissue as measured by an increase in eosinophilic peroxidase in homogenized lung tissue.

(3) Increase in antibody values (IgE, IgG1 and IgG2a) present in serum obtained from whole blood.

Certain compounds of the invention exhibit activity in chronic graft versus host and inhibition of eosinophilia with an ED _{50 ′} in the range of 0.1-10 mg / kg.

Claims (14)

Compounds of formula (I), or pharmaceutically acceptable derivatives thereof. <Formula I> (In the above formula, R represents (CH ₂ ) _n , CH = CH, BCH ₂ or CH ₂ B, wherein B is O or S, n is 1 to 3, Ar ¹ is halo, nitro, cyano, phenyl, phenylsulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COOH, COO (C _{1- 6} alkyl), CONH ₂ , C _1-6 alkyl substituted with phenyl, or phenyl, wherein all alkyl, alkoxy, alkylthio and alkylsulfinyl groups may be optionally substituted with one or more fluorine atoms Thiazolyl, phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolyl or 2-quinoxalinyl, which may be optionally substituted with the above substituents, W represents CH, CA or N, X is CH, CA, N or N ⁺ -O ^- represents, Y represents CH, CA, N or N ⁺ -O ^- represents, Z is CH, CA, N or N ⁺ -O ^- represents, A is optionally selected from hydroxy, halogen, nitro, cyano, phenyl, C _1-6 -thioalkyl, CO ₂ R ¹ , NR ² R ³ , NR ⁴ C (O) R ⁵ , methoxy (CO ₂ R ⁶ Substituted), C _1-6 -alkyl or C _2-6 -alkoxy (the latter two groups are optionally substituted with one or more substituents selected from NH ₂ , hydroxy or CO ₂ R ⁷ ), R ² represents H or C _1-6 -alkyl, R ³ represents H, C _1-6 -alkyl or CH ₂ Ar ² or R ² and R ³ together with the nitrogen atom to which they are attached pyrrolidinyl Or forms a piperidinyl ring, R ⁵ represents H, C _1-5 -alkyl or Ar ³ , R ¹ , R ⁴ , R ⁶ and R ⁷ independently represent H or C _1-6 -alkyl, Ar ² and Ar ³ are independently halogen, hydroxy, methoxy (optionally substituted with fluorine), phenoxy, C _2-6 -alkoxy and C _1-6 -alkyl (the following three groups are halogen, hydroxy or Phenyl optionally substituted with one or more substituents selected from C _1-6 -alkyl). However, (a) X, one of Y and Z is N ⁺ -O ^- when referring to, W, and the other two groups are both represents CH, (b) when Y represents N and X and Z both represent CH, W can only represent N, (c) when Z represents CH or N, W represents CH, Y represents CH or CA, X can only represent N, (d) when W represents N or CH and X and Z both represent CH, then Y can only represent N, (e) when X represents N or CH, W represents CH, Y represents CH or CA, Z can only represent N, (f) when only one of X or Z represents N, Y represents CH, (g) A represents C _2-6 alkoxy substituted with hydroxy, halogen (except fluorine) or NH ₂ , or Ar ¹ , Ar ² or Ar ³ is substituted with halogen (except fluorine) or hydroxy When substituted with C _2-6 -alkoxy, suitably the hydroxy, halogen or NH ₂ substituents are not bonded to the same carbon atom as the oxygen bonded carbon atom, (h) W, X, Y and Z are all CH and when R is (CH ₂ ) ₂ or OCH ₂ , Ar ¹ is substituted with phenyl) 3. The compound of claim 1, wherein R is CH═CH, OCH ₂ or (CH ₂ ) _n , wherein n is 1, 2 or 3. 4. The compound of claim 1, wherein Ar ¹ is optionally substituted with methyl; Phenyl optionally substituted with chloro; CF ₃ ; CONH ₂ ; Or methyl or pyridyl or pyridyl N-oxide, wherein Ar ¹ is optionally substituted with CF ₃ , methyl or methoxy. The compound of any of claims 1-3 wherein W, X, Y and Z are all CH. 4. The compound of claim 1, wherein W is CH, X is N, Y is CH or CA, and Z is N. 5. The compound of any one of claims 1-3, wherein W and Y are both N and X and Z are both CH. The compound of any one of claims 1-3, wherein one of X, Y or Z is N or N ⁺ -O ^- and the other two are both CH together with W. The compound of claim 5, wherein A is C _1-6 alkyl, C _1-6 alkoxy and amino. The method of claim 1, 2- (4-chlorophenyl) -5,6-dihydro-8-methylpyrimido [4,5-f] quinazolin, 2- (4-chlorophenyl) -5,6-dihydro-8-methoxypyrimido [4,5-f] quinazolin, 2- (4-chlorophenyl) -5,6-dihydropyrimido [5,4-h] quinazoline, 2- (4-chlorophenyl) -5,6-dihydropyrido [3,4-h] quinazoline, 2- (4-chlorophenyl) -5,6-dihydro-8-methylthiopyrimido [4,5-f] quinazolin, 2- (4-chlorophenyl) -5,6-dihydropyrimido [4,5-f] quinazolin, 2- (4-chlorophenyl) -5,6-dihydropyrido [3,4-h] quinazolin-8-oxide, 2- (4-chlorophenyl) -5,6-dihydropyrimido [4,5-f] quinazolin-8-amine, 5,6-dihydro-2- (pyridin-3-yl) pyrimido [4,5-f] quinazolin, 5,6-dihydro-2- (pyridin-2-yl) pyrimido [4,5-f] quinazolin, 5,6-dihydro-2- (6-methylpyridin-3-yl) pyrimido [4,5-f] quinazolin, 5,6-dihydro-2- (6-methylpyridin-3-yl-N-oxide) pyrimido [4,5-f] quinazolin-8-amine, 2- (4-chlorophenyl) -6,7-dihydro-5H-pyrido [2,3-i] cycloheptapyrimidine, 2- (4-chlorophenyl) -5,6-dihydropyrido [2,3-h] quinazoline, 2- (pyridin-3-yl) -5,6-dihydropyrido [2,3-h] quinazolin, 2- (6-methylpyridin-3-yl) -5,6-dihydropyrido [2,3-h] quinazolin, 2- (4-chlorophenyl) -5,6-dihydropyrido [2,3-h] quinazolin, 7-oxide, 2- (4-chlorophenyl) -5,6-dihydropyrido [4,3-h] quinazolin, 5,6-dihydro-2- (pyridin-3-yl) -pyrido [4,3-h] quinazolin, 2- (pyridin-3-yl) -pyrido [4,3-h] quinazolin, 2- (4-chlorophenyl) -5,6-dihydropyrido [4,3-h] quinazolin, 9-oxide, 5,6-dihydro-2- (6-methoxypyridin-3-yl) -pyrimido [4,5-f] quinazolin, 2- (6-chloropyridin-3-yl) -5,6-dihydropyrimido [4,5-f] quinazolin, 2- (6-methylpyridin-3-yl) -pyrimido [4,5-f] quinazolin, 2- (4-chlorophenyl) -5H- [1] benzopyrano [4,3-d] pyrimidine, 2- (4-chlorophenyl) -5H-indeno [1,2-d] pyrimidine, 2-phenyl-5H- [1] benzopyrano [4,3-d] pyrimidine, 2-pyridin-4-yl-5H- [1] benzopyrano [4,3-d] pyrimidine, 2- (pyridin-4-yl) -N-oxide-5H- [1] benzopyrano [4,3-d] pyrimidine, 2-pyridin-2-yl-5H- [1] benzopyrano [4,3-d] pyrimidine, 2-pyridin-3-yl-5H- [1] benzopyrano [4,3-d] pyrimidine, 2- (6-methylpyridin-3-yl) -5H- [1] benzopyrano [4,3-d] pyrimidine, 2- (6-chloropyridin-3-yl) -5H- [1] benzopyrano [4,3-d] pyrimidine, 2-pyrazin-2-yl-5H- [1] benzopyrano [4,3-d] pyrimidine, 2- (6-trifluoromethylpyridin-2-yl) -5H- [1] benzopyrano [4,3-d] pyrimidine, 2- (2-methylthiazol-4-yl) -5H- [1] benzopyrano [4,3-d] pyrimidine, 4- (5H- [1] benzopyrano [4,3-d] pyrimidin-2-yl) benzenecarboxamide, 2- (6-methylpyridin-3-yl) -5,6-dihydropyrido [4,3-h] quinazolin, And pharmaceutically acceptable derivatives thereof. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable derivative thereof, for use as a pharmaceutical. A pharmaceutical formulation which is a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable derivative thereof. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable derivative thereof, for use in the treatment of allergy or inflammatory disease. (a) reacting a compound of formula II with a compound of formula III or a salt thereof, or (b) for compounds of formula (I) wherein Y is N or CA and A is H, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy, reacting a compound of formula IV with a compound of formula V, optionally after step (a) or (b) Converting the compound of formula I to another compound of formula I, To form pharmaceutically acceptable derivatives A process for preparing a compound of formula (I) comprising. <Formula II> Wherein W, X, Y, Z and R are as defined in formula (I) and L is a leaving group <Formula III> Ar ¹ C (NH) NH ₂ Wherein Ar is as defined in formula (I) <Formula IV> Wherein W, X, Y, Z and R are as defined in Formula I and L 'is a leaving group <Formula V> Ar ¹ MgHal Wherein Hal is Cl or Br and Ar ¹ is as defined in formula (I) A compound of formula (II) as defined in claim 13.