Triazolo and tetrazolo pyrimidine derivatives as HNE inhibitors for treating COPD

1. A compound of formula (I)

in which

A represents CH

Y represents C—R 7 or N in which

R 7 represents hydrogen, (C 1 -C 6 )-alkyl, amino or a group of the formula —NH—C(═O)—R 8 or —NH—SO 2 —R 8 in which

R 8 represents (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl or phenyl,

where (C 1 -C 6 )-alkyl may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy, (C 3 -C 6 )-cycloalkyl or phenyl and up to three times by fluorine

and where

the cycloalkyl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of (C 1 -C 4 )-alkyl and up to two times by fluorine

and

the phenyl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, difluoromethoxy and trifluoromethoxy,

Z represents N

R 1 represents hydrogen

or

represents a group of the formula —S(O) n —R 20 in which

R 20 represents (C 1 -G 6 )-alkyl

and

N represents the number 0, 1 or 2,

R 2 represents cyano or a group of the formula —C(═O)—R 21 , —C(═O)—O—R 21 or —C(═O)—NH—R 21 in which

R 21 represents hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-alkenyl or (C 3 -C 6 )-cycloalkyl,

where (C 1 -C 6 )-alkyl and (C 3 -C 6 )-cycloalkyl for their part may be substituted up to two times by identical or different substituents from the group consisting of hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, mono- and di-(C 1 -C 4 )-alkylamino and in (C 1 -C 6 )-alkyl and (C 3 -C 6 )-cycloalkyl in each case one CH 2 group may be replaced by an oxygen atom provided this results in a chemically stable compound,

R 3 represents methyl or ethyl

or

R 2 and R 3 are attached to one another and together form a fused group of the formula

in which

* denotes the point of attachment to the 5-position, marked in formula (I), of the dihydropyrimidine ring

and

** denotes the point of attachment to the 6-position, marked in formula (I), of the dihydropyrimidine ring

and

R 22 represents hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 6 )-cycloalkyl,

where (C 1 -C 6 )-alkyl may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy, aminocarbonyl, aminocarbonylamino, (C 1 -C 4 )-acylamino or (C 3 -C 6 )-cycloalkyl,

R 4 represents nitro or trifluoromethyl

and

R 5 represents hydrogen, fluorine or chlorine,

or a salt thereof.

2. The compound of claim 1 in which

A represents CH,

Y represents C—R 7 or N,

in which

R 7 represents hydrogen, amino or a group of the formula —NH—C(═O)—

R 8 or —NH—SO 2 —R 8 in which

R 8 represents (C 1 -C 4 )-alkyl or (C 3 -C 6 )-cycloalkyl,

where (C 1 -C 4 )-alkyl may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy or (C 3 -C 6 )-cycloalkyl and up to three times by fluorine

and

the cycloalkyl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of (C 1 -C 4 )-alkyl and up to two times by fluorine,

Z represents N,

R 1 represents hydrogen, or a group of the formula —SO 2 —R 20 in which

R 20 represents (C 1 -C 4 )-alkyl

R 2 represents cyano or a group of the formula —C(═O)—R 21 or —C(═O)—O—R 21 or

C(═O)—NH—R 21 in which

R 21 represents hydrogen, methyl, ethyl or 2-hydroxyethyl,

R 3 represents methyl,

R 4 represents trifluoromethyl

and

R 5 represents hydrogen,

or

R 2 and R 3 are attached to one another and together form a fused group of the formula

in which

* denotes the point of attachment to the 5-position, marked in formula (I), of the dihydropyrimidine ring

and

** denotes the point of attachment to the 6-position, marked in formula (I), of the dihydropyrimidine ring

and

R 22 represents hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 6 )-cycloalkyl, where (C 1 -C 6 )-alkyl may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy;

or a salt thereof.

3. The compound of claim 1 in which

A represents CH,

Y represents C—R 7 or N,

in which

R 7 represents amino or a group of the formula —NH—C(═O)—R 8 in which

R 8 represents (C 1 -C 4 )-alkyl or (C 3 -C 6 )-cycloalkyl,

where (C 1 -C 4 )-alkyl may be substituted by hydroxyl, methoxy, ethoxy or (C 3 -C 6 )-cycloalkyl and up to three times by fluorine and

the cycloalkyl groups mentioned may be substituted up to two times by methyl and up to two times by fluorine,

Z represents N,

R 1 represents hydrogen, methyl sulfonyl or trifluoromethyl-sulfonyl,

R 2 represents cyano, acetyl, ethoxycarbonyl, carboxyl, or aminocarbonyl

R 3 represents methyl,

R 4 represents trifluoromethyl

and

R 5 represents hydrogen,

or a salt thereof.

4. The compound of claim 1 , wherein

A represents CH,

Y represents C—R 7 or N,

whererein,

R 7 represents amino or a group of the formula —NH—C(═O)—R 8 in which

R 8 represents (C 3 -C 6 )-cycloalkyl,

[where the cycloalkyl groups mentioned may be substituted up to two times by methyl and up to two times by fluorine,]

Z represents N,

R 1 represents hydrogen,

R 2 represents cyano, acetyl, ethoxycarbonyl, carboxyl, or aminocarbonyl,

R 3 represents methyl,

or

R 2 and R 3 are attached to one another and together form a fused group of the formula

in which

* denotes the point of attachment to the 5-position, marked in formula (I), of the dihydropyrimidine ring

and

** denotes the point of attachment to the 6-position, marked in formula (I), of the dihydropyrimidine ring

and

R 22 represents (C 1 -C 6 )-alkyl,

where (C1-C6)-alkyl is substituted by (C1-C4)-alkoxy,

R 4 represents trifluoromethyl

and

R 5 represents hydrogen,

or a salt thereof.

5. The compound of claim 1 , selected from the group consisting of:

6. A compound of the formula:

7. A pharmaceutical composition comprising a compound of claim 1 and at least one inert non-toxic pharmaceutically acceptable excipient.

8. The pharmaceutical composition of claim 7 further comprising at least one active compound selected from the group consisting of a kinase inhibitor, a stimulator and activator of soluble guanylate cyclase, a prostacyclin analog, an endothelin receptor antagonist, a phosphodiesterase inhibitor, a beta-adrenergic receptor agonist, an anticholinergic, and a glucocorticoid.

9. A process for preparing a compound of claim 1 , comprising reacting a compound of formula (II)

in which A, R 1 , R 2 and R 3 each have the meanings given in claim 1 ,

in the presence of a base with a compound of formula (III)

in which Y and Z have the meanings given in claim 1 ,

to give an intermediate of formula (IV)

in which A, Y, Z, R 1 , R 2 and R 3 each have the meanings given above, cyclizing the intermediate of formula (IV) in situ or in a separate acid-catalyzed reaction step to give a compound of formula (V)

in which A, Y, Z, R 1 , R 2 and R 3 each have the meanings given above,

coupling the compound of formula (V) in the presence of a copper(II) catalyst and a base

with a phenylboronic acid of formula (VI)

in which R 4 and R 5 have the meanings given in claim 1 , to give the compound of formula (I).

10. The process of claim 9 , wherein more than one enantiomer or diastereomer of a compound of formula (I) is produced, the process further comprising a step of separating the enantiomers or diastereomers.

11. The process of claim 9 , wherein the compound of formula (I) is converted with an appropriate (i) solvents and/or (ii) bases or acids into a salt thereof.

12. A method for the treatment of pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), of chronic-obstructive pulmonary diseases (COPD), of acute lung injury (ALI), of acute respiratory distress syndrome (ARDS), of bronchiectasis, of Bronchiolitis obliterans, of pulmonary emphysema, of alpha-1 antitrypsin deficiency (AATD) and of cystic fibrosis (CF) comprising administering to a human or animal in need thereof an effective amount of a compound of claim 1 .