Substituted phenylamino-pyrimidines
View Patent ↗The invention relates to substituted phenylaminopyrimidines, to a process for their preparation and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases in humans and animals, in particular cardiovascular disorders.
1. A compound of the formula (I)
in which
represents a single bond or a double bond,
X represents —NR 6 —, —CR 7 R 8 — or —C(═O)—,
in which
R 6 represents hydrogen or (C 1 -C 3 )-alkyl,
R 7 and R 8 independently of one another represent hydrogen or methyl,
R 1 represents hydrogen, halogen, cyano, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, (C 1 -C 6 )-alkoxycarbonyl or (C 1 -C 6 )-alkylaminocarbonyl,
where alkyl, alkoxycarbonyl and alkylaminocarbonyl for their part may be substituted by hydroxyl, halogen, hydroxycarbonyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, amino, aminocarbonyl, (C 1 -C 6 )-alkylamino or (C 1 -C 6 )-alkylaminocarbonyl,
R 2 represents fluorine or chlorine,
R 3 represents a radical selected from the group consisting of:
hydrogen, hydroxyl, halogen, trifluoromethyl, pentafluoroethyl,
(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 3 -C 8 )-cycloalkyl,
where alkyl, alkoxy and cycloalkyl for their part may be substituted by hydroxyl, hydroxycarbonyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 6 -C 10 )-aryl, —NR 9 R 10 or —C(═O)NR 9 R 10 ,
in which
R 9 and R 10 independently of one another represent hydrogen, (C 1 -C 8 )-alkyl, optionally (C 1 -C 6 )-alkyl-substituted (C 3 -C 6 )-cycloalkyl, optionally halogen-substituted (C 6 -C 10 )-aryl or 5- to 10-membered heteroaryl
or
R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further heteroatom O or N in the ring and which may be substituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkanoyl or (C 1 -C 6 )-alkoxycarbonyl,
(C 6 -C 10 )-aryl, (C 6 -C 10 )-aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, 5- to 10-membered heterocyclyl which is attached via a carbon atom,
where aryl, aryloxy, heteroaryl, heteroaryloxy and heterocyclyl for their part may be substituted by halogen, cyano, nitro, hydroxycarbonyl, amino, trifluoromethyl, optionally hydroxyl-substituted (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkylamino, (C 1 -C 6 )-alkanoyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoylamino, (C 1 -C 6 )-alkoxycarbonylamino or 5- or 6-membered heterocyclyl,
—NR 11 R 12 ,
in which
R 11 and R 12 independently of one another represent hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 8 )-cycloalkyl, (C 6 -C 10 )-aryl or 5- to 10-membered heteroaryl,
where alkyl and cycloalkyl for their part may be substituted by hydroxyl, (C 1 -C 6 )-alkoxy, (C 6 -C 10 )-aryl, 5- to 10-membered heteroaryl or —NR 13 R 14 ,
in which
R 13 and R 14 independently of one another represent hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, (C 6 -C 10 )-aryl or 5- or 6-membered heteroaryl
or
R 13 and R 14 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further heteroatom O or N in the ring and which may be substituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkanoyl or (C 1 -C 6 )-alkoxycarbonyl,
and
where aryl and heteroaryl for their part may be substituted by halogen, hydroxyl, amino, cyano, trifluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkylamino or (C 1 -C 6 )-alkanoylamino,
or
R 11 and R 12 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom O or N in the ring and which may be substituted by fluorine, hydroxyl, hydroxycarbonyl, 5- to 7-membered heterocyclyl which may contain one or two further heteroatoms N and/or O in the ring and which for its part may be substituted by (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxycarbonyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkanoyl, (C 1 -C 4 )-alkoxycarbonyl or —NR 15 R 16 ,
where alkyl for its part may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy or —NR 17 R 18 ,
where
R 17 and R 18 independently of one another represent hydrogen, optionally hydroxyl-substituted (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, (C 6 -C 10 )-aryl or 5- to 6-membered heteroaryl
or
R 17 and R 18 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further heteroatom O or N in the ring and which may be substituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkanoyl or (C 1 -C 6 )-alkoxycarbonyl,
in which
R 15 and R 16 independently of one another represent hydrogen, (C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxycarbonyl, (C 3 -C 8 )-cycloalkyl or (C 1 -C 4 )-alkanoyl
or
R 15 and R 16 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further heteroatom O or N in the ring and which may be substituted by (C 1 -C 6 ) -alkyl, (C 1 -C 6 )-alkanoyl or (C 1 -C 6 )-alkoxycarbonyl,
or
R 11 and R 12 together with the nitrogen atom to which they are attached form a 7- to 12-membered bicyclic or tricyclic heterocycle which is fused or spirocyclic and which may have one or two further heteroatoms from the group consisting of N and O in the ring and which may be substituted by fluorine, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxycarbonyl, (C 1 -C 4 )-alkanoyl or benzyl,
and —C(═O)R 19 ,
in which
R 19 represents (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkylamino or a 5- to 10-membered mono- or bicyclic heterocycle which is attached via a nitrogen atom, which is fused or spirocyclic and which may have one or two further heteroatoms from the group consisting of N and O in the ring,
where alkylamino for its part may be substituted by a 5- or 6-membered heterocycle,
R 4 represents hydrogen, fluorine or chlorine,
R 5 represents hydrogen or (C 1 -C 6 )-alkyl or a salt thereof.
2. The compound of the formula (I) as claimed in claim 1 , in which
represents a double bond,
X represents —NR 6 —, —CH 2 — or —C(═O)—,
in which
R 6 represents hydrogen or methyl,
R 1 represents hydrogen, fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, methyl, ethyl, hydroxyethyl, methoxyethyl, cyclopropyl, (C 1 -C 6 )-alkoxycarbonyl or (C 1 -C 6 )-alkylaminocarbonyl,
where alkoxycarbonyl and alkylaminocarbonyl for their part may be substituted by hydroxyl, hydroxycarbonyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, amino, aminocarbonyl, (C 1 -C 6 )-alkylamino or (C 1 -C 6 )-alkylaminocarbonyl,
R 2 represents fluorine or chlorine,
R 3 represents a radical selected from the group consisting of:
hydrogen, hydroxyl, halogen, trifluoromethyl, pentafluoroethyl,
(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 3 -C 8 )-cycloalkyl,
where alkyl, alkoxy and cycloalkyl for their part may be substituted by hydroxyl, hydroxycarbonyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 6 -C 10 )-aryl, —NR 9 R 10 or —C(═O)NR 9 R 10 ,
in which
R 9 and R 10 independently of one another represent hydrogen or (C 1 -C 8 ) -alkyl
or
R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further heteroatom O or N in the ring and which may be substituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkanoyl or (C 1 -C 6 )-alkoxycarbonyl,
phenyl, 5- or 6-membered heteroaryl, 5- to 10-membered heterocyclyl which is attached via a carbon atom,
where phenyl, heteroaryl and heterocyclyl for their part may be substituted by halogen, cyano, nitro, hydroxycarbonyl, amino, trifluoromethyl, optionally hydroxyl-substituted (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkyl-amino, (C 1 -C 6 )-alkanoyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoylamino or (C 1 -C 6 )-alkoxycarbonylamino,
—NR 11 R 12 ,
in which
R 11 and R 12 independently of one another represent hydrogen, (C 1 -C 6 ) -alkyl, (C 3 -C 8 )-cycloalkyl, (C 6 -C 10 )-aryl or 5- to 10-membered heteroaryl,
where alkyl and cycloalkyl for their part may be substituted by hydroxyl,
(C 1 -C 6 )-alkoxy, (C 6 -C 10 )-aryl or 5-to 10-membered heteroaryl,
and
where aryl and heteroaryl for their part may be substituted by halogen, hydroxyl, amino, cyano, trifluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 ) -alkoxy, (C 1 -C 6 )-alkylamino or (C 1 -C 6 )-alkanoylamino,
or
R 11 and R 12 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom O or N in the ring and which may be substituted by fluorine, hydroxyl, hydroxycarbonyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkanoyl or (C 1 -C 4 )-alkoxycarbonyl,
and —C(═O)R 19 ,
in which
R 19 represents (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkylamino or a 5-to 10-membered mono- or bicyclic heterocycle which is attached via a nitrogen atom, which is fused or spirocyclic and which may have one or two further heteroatoms from the group consisting of N and O in the ring,
where alkylamino for its part may be substituted by a 5- or 6-membered heterocycle,
R 4 represents hydrogen, fluorine or chlorine,
R 5 represents hydrogen or methyl,
or a salt thereof.
3. The compound of the formula (I) as claimed in claim 1 , in which
represents a double bond,
X represents —NR 6 —, —CH 2 — or —C(═O)—,
in which
R 6 represents hydrogen or methyl,
R 1 represents hydrogen, fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, methyl, ethyl, hydroxyethyl, methoxyethyl or cyclopropyl,
R 2 represents fluorine or chlorine,
R 3 represents a radical selected from the group consisting of:
hydrogen, hydroxyl, halogen, trifluoromethyl, pentafluoroethyl,
(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 3 -C 8 )-cycloalkyl,
where alkyl, alkoxy and cycloalkyl for their part may be substituted by hydroxyl, (C 1 -C 6 )-alkoxy or —NR 9 R 10 ,
in which
R 9 and R 10 independently of one another represent hydrogen or (C 1 -C 8 )-alkyl
or
R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further heteroatom O or N in the ring and which may be substituted by (C 1 -C 3 ) -alkyl or (C 1 -C 3 )-alkanoyl,
phenyl and 5- or 6-membered heteroaryl,
where phenyl and heteroaryl for their part may be substituted by halogen, amino or trifluoromethyl,
R 4 represents hydrogen, fluorine or chlorine,
R 5 represents hydrogen or methyl,
or a salt thereof.
4. The compound of the formula (I) as claimed in claim 1 in which
represents a double bond,
X represents —NH— or —CH 2 —,
R 1 represents hydrogen, chlorine or methyl,
R 2 represents fluorine,
R 3 represents a radical selected from the group consisting of hydrogen, halogen, trifluoromethyl, optionally halogen-substituted phenyl and pyridine,
R 4 represents hydrogen or fluorine,
R 5 represents hydrogen,
or a salt thereof.
5. A process for preparing a compound of the formula (I) as defined in claim 1 , characterized in that
a compound of the formula (II)
in which
, X, R 1 , R 2 , R 4 and R 5 are as defined in claim 1
are reacted with a compound of the formula (III)
in which
R 3 is as defined in claim 1 , which, if X represents a CH 2 group, may be followed by an oxidation to give the corresponding keto group —C(═O)— or a methylation to give the corresponding mono- or dimethyl compound [—CH(CH 3 )— or —C(CH 3 ) 2 —].
6. A pharmaceutical composition, comprising a compound of the formula (I) as defined in claim 1 in combination with a further active compound.
7. A pharmaceutical composition, comprising a compound of the formula (I) as defined in claim 1 in combination with an inert nontoxic pharmaceutically acceptable auxiliary.
8. A method for the treatment of erectile dysfunction in a human or an animal comprising administering to said human or animal an effective amount of a compound of formula (I) as define in claim 1 .
9. A method for the treatment of hypertension in a human or an animal comprising administering to said human or animal an effective amount of a compound of formula (I) as define in claim 1 .