Heteroaryloxy-substituted phenylaminopyrimidines as rho-kinase inhibitors
View Patent ↗The invention relates to heteroaryloxy-substituted phenylaminopyrimidines, to methods for the production thereof, and to the use of the same for producing medicaments for the treatment and/or prophylaxis of diseases, especially cardiovascular diseases. The inventive compounds inhibit Rho-Kinase.
1. A compound of the formula
in which
A represents a radical
in which
X represents N or C—H,
Y represents N—R 7 , O or S
in which
R 7 represents hydrogen, benzyl, phenyl, (C 1 -C 6 )-alkyl or (C 3 -C 8 )-cycloalkyl,
where alkyl and cycloalkyl for their part may be substituted by fluorine, hydroxyl, amino, carboxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkylamino or morpholinyl,
Z represents N or C—H,
R 6 represents hydrogen, halogen, trifluoromethyl, (C 1 -C 6 )-alkylamino or W—R 7 ,
in which
W represents NH, O or a bond,
R 7 is as defined above
and
* denotes the point of attachment to the phenolic oxygen,
R 1 and R 2 independently of one another represent hydrogen, halogen or cyano,
R 3 and R 4 independently of one another represent hydrogen, fluorine or chlorine,
R 5 represents a radical selected from the group consisting of:
hydrogen, hydroxyl, halogen, trifluoromethyl,
(C 3 -C 8 )-cycloalkyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy,
where cycloalkyl, alkyl and alkoxy for their part may be substituted by hydroxyl, carboxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 6 -C 10 )-aryl, NR 8 R 9 or C(═O)NR 8 R 9 ,
in which
R 8 and R 9 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 8 and R 9 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, carboxyl, 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 10 R 11
in which
R 10 and R 11 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 15 R 16 ,
in which
R 15 and R 16 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 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,
and
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 10 and R 11 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, carboxyl, 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, optionally hydroxyl-, (C 1 -C 4 )-alkoxy- or NR 17 R 18 -substituted (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkanoyl, (C 1 -C 4 )-alkoxycarbonyl or NR 12 R 13 ,
where
R 12 and R 13 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 12 and R 13 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
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- or 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,
or
R 10 and R 11 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 14 ,
in which
R 14 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, or a salt thereof.
2. The compound as claimed in claim 1
in which
A represents a radical
in which
R 6 represents hydrogen, (C 1 -C 4 )-alkyl or NH—R 7 ,
R 7 represents hydrogen or (C 1 -C 4 )-alkyl
and
* denotes the point of attachment to the phenolic oxygen,
R 1 and R 2 independently of one another represent hydrogen, fluorine or chlorine,
R 3 and R 4 independently of one another represent hydrogen or fluorine,
R 5 represents a radical selected from the group consisting of:
hydrogen, chlorine, (C 3 -C 8 )-cycloalkyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy,
where alkyl and alkoxy for their part may be substituted by hydroxyl, carboxyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, NR 8 R 9 or C(═O)NR 8 R 9 ,
in which
R 8 and R 9 independently of one another represent hydrogen, (C 1 -C 8 )-alkyl, optionally (C 1 -C 4 )-alkyl-substituted (C 3 -C 6 )-cycloalkyl, optionally halogen-substituted phenyl or 5- or 6-membered heteroaryl
or
R 8 and R 9 together with the nitrogen atom to which they are attached form a morpholine, piperazine, piperidine or pyrrolidine ring, where the rings for their part may be substituted by (C 1 -C 4 )-alkyl,
(C 6 -C 10 )-aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl which is attached via a carbon atom,
where aryl, heteroaryl and heterocyclyl for their part may be substituted by halogen, cyano, nitro, carboxyl, amino, trifluoromethyl, optionally hydroxyl-substituted (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkanoyl, (C 1 -C 4 )-alkoxycarbonyl, (C 1 -C 4 )-alkanoylamino, (C 1 -C 4 )-alkoxycarbonylamino or 6-membered heterocyclyl,
NR 10 R 11
in which
R 10 and R 11 independently of one another represent hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 8 )-cycloalkyl, phenyl or 5- or 6-membered heteroaryl,
where alkyl and cycloalkyl for their part may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy, phenyl, 5- or 6-membered heteroaryl or NR 15 R 16 ,
in which
R 15 and R 16 independently of one another represent hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, phenyl or 5- or 6-membered heteroaryl
or
R 15 R 16 together with the nitrogen atom to which they are attached form a morpholine, piperazine, piperidine or pyrrolidine ring, where the rings for their part may be substituted by (C 1 -C 4 )-alkyl,
and
phenyl and heteroaryl for their part may be substituted by fluorine, chlorine, hydroxyl, amino, cyano, trifluoromethyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylamino or (C 1 -C 4 )-alkanoylamino,
or
R 10 and R 11 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, carboxyl, 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, optionally hydroxyl-, (C 1 -C 4 )-alkoxy- or NR 17 R 18 -substituted (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkanoyl, (C 1 -C 4 )-alkoxycarbonyl or NR 12 R 13 ,
where
R 12 and R 13 independently of one another represent hydrogen or (C 1 -C 4 )-alkyl
or
R 12 and R 13 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
R 17 and R 18 independently of one another represent hydrogen, optionally hydroxyl-substituted (C 1 -C 4 )-alkyl or phenyl
or
R 17 and R 18 together with the nitrogen atom to which they are attached form a pyrrolidine ring,
or
R 10 and R 11 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, which may have one or two further hetero atoms from the group consisting of N and O in the ring and which may be substituted by (C 1 -C 4 )-alkyl, (C 1 -C 4 -alkoxycarbonyl, (C 1 -C 4 )-alkanoyl or benzyl,
and C(═O)R 14
in which
R 14 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 heterocyclyl, or a salt thereof.
3. The compound as claimed in claim 1
in which
A represents a radical
in which
R 6 represents hydrogen or methyl
and
* denotes the point of attachment to the phenolic oxygen,
R 1 and R 2 independently of one another represent hydrogen, fluorine or chlorine,
R 3 and R 4 represent hydrogen,
R 5 represents a radical selected from the group consisting of:
hydrogen, chlorine, cyclohexyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy,
where alkyl and alkoxy for their part may be substituted by hydroxyl, carboxyl, (C 1 -C 4 )-alkoxy, methyloxycarbonyl, ethyloxycarbonyl, NR 8 R 9 or C(═O)NR 8 R 9 ,
in which
R 8 and R 9 independently of one another represent hydrogen, (C 1 -C 8 )-alkyl, cyclopropyl, optionally methyl-substituted cyclopentyl or optionally fluorine-substituted phenyl
or
R 8 and R 9 together with the nitrogen atom to which they are attached form a piperidine, 2-methylpiperidine or 2,6-dimethylpiperidine ring,
phenyl, pyridyl, pyrrolyl, piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-yl,
where phenyl, pyridyl and pyrrolyl for their part may be substituted by fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, methyl, hydroxymethyl, methoxy, dimethylamino or morpholinyl,
and
piperidin-3-yl, piperidin-4-yl and pyrrolidin-2-yl for their part may be substituted by methyl, ethyl, n-propyl, isopropyl, methylcarbonyl or ethylcarbonyl,
NR 10 R 11
in which
R 10 and R 11 independently of one another represent hydrogen, (C 1 -C 4 )-alkyl, 3-hydroxypropyl, 2-hydroxycyclohexyl, 2-aminocyclohexyl, phenyl, pyridyl or pyrazolyl,
where phenyl and pyridyl for their part may be substituted by chlorine, hydroxyl, amino, cyano, methyl or methoxy,
or
R 10 and R 11 together with the nitrogen atom to which they are attached form a piperazine, 3-methylpiperazine, 3,5-dimethylpiperazine, 4-isobutylpiperazine, morpholine, pyrrolidine, 3-aminopyrrolidine, 3-methylaminopyrrolidine, 3-(N,N-dimethylamino)pyrrolidine, 2-aminomethylpyrrolidine, 3-hydroxypyrrolidine, 2-hydroxymethylpyrrolidine or 2-methoxymethylpyrrolidine ring or a radical
in which
* denotes the point of attachment to the pyrimidine ring,
and C(═O)R 14
in which
R 14 represents methoxy, piperidinyl-N-ethylamino, piperidinyl or piperazinyl,
or a salt thereof.
4. A process for preparing compounds as defined in claim 1 , characterized in that either
[A] compounds of the formula (II)
in which
A, R 1 , R 2 , R 3 and R 4 are as defined in claim 1
are reacted with compounds of the formula (III)
R 5 —X 1 (III),
in which
R 5 is as defined in claim 1 and
X 1 represents hydrogen, B(OH) 2 or a boronic acid ester such as
or
[B] compounds of the formula (IV)
in which
R 5 is as defined in claim 1
are reacted with compounds of the formula (V)
in which
A, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 .
5. A pharmaceutical composition comprising a compound as defined in claim 1 in combination with an inert nontoxic pharmaceutically acceptable auxiliary.
6. A method for the treatment of erectile dysfunction in a human or animal, comprising administering to said human or animal, a cardiovascularly effective amount of a compound as defined in claim 1 .