Aryl-or heteroaryl-substituted pyrido[2,3-d] pyrimidines and pharmaceutical compositions of the same
View Patent ↗The present application relates to novel aryl- or heteroaryl-substitued pyrido[2,3-d] pyrimidines of formula (I), pharmaceuitical compositions of the same, and a process for their preparation. Formula(I) is: wherein Ar is an aryl or heteroaryl substituent, and R 1 , R 2 , R 3 , Ar, D, and E are as defined in the specification. Compounds and compositions of the present invention can be used in the treatment and/or prophylaxis of various disorders in humans and animals, including aldosteronism, high blood pressure, chronic heart failure, the sequelae of a myocardial infarction, cirrhosis of the liver, renal failure, and stroke.
1. A compound of the formula (I)
in which
D is C—R 4 in which
R 4 is hydrogen, (C 1 -C 6 )-alkyl, trifluoromethyl, (C 1 -C 6 )-alkoxy, trifluoromethoxy, (C 1 -C 6 )-alkylthio, amino, mono-(C 1 -C 6 )-alkylamino or di-(C 1 -C 6 )-alkylamino,
E is N,
Ar is a group of the formula
in which
* is the linkage point,
R 6 is hydrogen or halogen,
R 7 is methyl or ethyl,
R 8 is hydrogen, fluorine, chlorine, cyano, nitro, trifluoromethyl or (C 1 -C 4 )-alkyl,
R 9 is hydrogen or fluorine,
R 10 is halogen, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy or trifluoromethoxy,
R 11 is cyano,
R 12 is hydrogen, halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio or di-(C 1 -C 4 )-alkylamino, it being possible for the alkyl group in said (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy and (C 1 -C 4 )-alkylthio radicals in each case to be substituted up to three times by fluorine, or
phenyl, which may be substituted by halogen, (C 1 -C 4 )-alkyl or trifluoromethyl,
R 13 is hydrogen, halogen or (C 1 -C 4 )-alkyl,
G is CH, C—R 10 or N, and
n is the number 0, 1 or 2,
it being possible in the case where the substituent R 10 occurs more than once for its meanings to be identical or different,
R 1 is cyano, nitro or a group of the formula —C(═O)—R 14 or —C(═O)—O—R 15 in which
R 14 is (C 1 -C 6 )-alkyl which may be substituted by (C3-C7)-cycloalkyl or once to three times by fluorine, or phenyl which may be substituted by halogen, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy or trifluoromethoxy, or (C 3 -C 7 )-cycloalkyl,
and
R 15 is (C 1 -C 6 )-alkyl which may be substituted by (C 3 -C 7 )-cycloalkyl or once to three times by fluorine, or (C 3 -C 7 )-cycloalkyl,
R 2 is (C 1 -C 4 )-alkyl, trifluoromethyl, cyclopropyl, cyclobutyl, (C 1 -C 4 )-alkoxy or (C 1 -C 4 )-alkylthio,
and
R 3 is (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, trifluoromethoxy, (C 1 -C 6 )-alkylthio, or a group of the formula —O—SO 2 —R 16 ,
where said (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy and (C 1 -C 6 )-alkylthio radicals may in each case be substituted by (C 3 -C 7 )-cycloalkyl,
and
R 16 is (C 1 -C 6 )-alkyl, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, phenyl or 5- or 6-membered heteroaryl having up to two heteroatoms from the series N, O and/or S,
it being possible for phenyl and heteroaryl in turn each to be substituted once or twice, identically or differently, by halogen, cyano, nitro, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy and/or trifluoromethoxy,
and the salts, thereof.
2. The compound of claim 1 , in which
D is C—R 4 in which
R 4 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino,
E is N,
Ar is a group of the formula
in which
* is the linkage point,
R 8 is hydrogen, fluorine, chlorine or cyano,
R 10 is fluorine, chlorine, methyl or ethyl,
R 11 is cyano,
R 12 is chlorine, bromine, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, (C 1 -C 4 )-alkylthio or trifluoromethylthio, and
n is the number 0 or 1,
R 1 is cyano, acetyl, trifluoroacetyl or a group of the formula —C(═O)—O—R 15 in which
R 15 is (C 1 -C 4 )-alkyl which may be substituted by (C 3 -C 5 )-cycloalkyl or once to three times by fluorine, or (C 3 -C 5 )-cycloalkyl,
R 2 is methyl or trifluoromethyl, and
R 3 is (C 1 -C 4 )-alkoxy, trifluoromethoxy or a group of the formula —O—SO 2 —R 16 in which
R 16 is (C 1 -C 4 )-alkyl, trifluoromethyl, (C 3 -C 6 )-cycloalkyl, phenyl or thienyl,
where phenyl and thienyl in turn may each be substituted once or twice, identically or differently by fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy and/or trifluoromethoxy,
and the salts thereof.
3. The compound of claim 1 , in which
D is C—R 4 in which
R 4 is hydrogen, amino, methoxy or methylthio,
E is N,
Ar is a group of the formula
in which
is the linkage point and
R 12 is ethyl, methoxy or trifluoromethoxy,
R 1 is cyano, acetyl, methoxycarbonyl or ethoxycarbonyl,
R 2 is methyl or trifluoromethyl, and
R 3 is (C 1 -C 3 )-alkoxy or a group of the formula —O—SO 2 —R 16 in which
R 16 is (C 1 -C 3 )-alkyl,
and the salts thereof.
4. A process for preparing compounds of the formula (I-B)
in which Ar, R 1 , R 2 and R 4 have the meanings indicated in claim 1 ,
and
R 3B is (C 1 -C 6 )-alkoxy or (C 1 -C 6 )-alkylthio, each of which may be substituted by (C 3 -C 7 )-cycloalkyl, or is trifluoromethoxy, or a group of the formula —O—SO 2 —R 16 in which R 16 has the meaning indicated in claim 1 ,
comprising:
condensing a compound of the formula (II)
in which Ar has the meaning indicated in claim 1 ,
with a compound of the formula (XI)
in which R 1 and R 2 have the meanings indicated in claim 1 ,
to give a compound of the formula (XII)
in which Ar, R 1 and R 2 each have the meanings indicated above, and either
[B-1] reacting the compound of formula XII in an inert solvent with a compound of the formula (XIII)
in which R 3B and R 4 have the meanings indicated in claim 1 , or
[B-2] reacting the compound of formula (XII) in an inert solvent with a compound of the formula (XIV)
in which R 4 has the meaning indicated in claim 1 ,
to give a compound of the formula (XV)
in which Ar, R 1 , R 2 and R 4 each have the meanings indicated above, and either:
alkylating the compound of formula (XV) in an inert solvent, optionally, in the presence of a base, with a compound of the formula (VIII) or a trialkyloxonium salt of the formula (IX)
in which
R 17 is (C 1 -C 6 )-alkyl which may be substituted by (C 3 -C 7 )-cycloalkyl, or is trifluoromethyl,
R 17A is methyl or ethyl,
Q is a leaving group, and
Z 13 is a non-nucleophilic anion,
to give compounds of the formula (I-B 1)
in which Ar, R 1 , R 2 , R 4 and R 17 each have the meanings indicated above, or reacting the compound of formula (XV) in an inert solvent in the presence of a base with a compound of the formula (X)
in which R 16 has the meaning indicated in claim 1 , to give a compound of the formula (I-B2)
in which Ar, R 1 , R 2 , R 4 and R 16 each have the meanings indicated above, wherein a racemate or diastereomeric mixture of compounds of formula (I-B), (I-B 1) or (I-B2) is optionally produced and separated by methods known to the skilled worker into their enantiomers and/or diastereomers, and/or
wherein the compound of formula (I-B), (I-B 1) or (I-B2) is optionally reacted with the appropriate (i) solvent and/or (ii) base or acid to produce the solvates, salts and/or solvates of the salts thereof.
5. A pharmaceutical composition comprising a compound of the formula (I) as defined in claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.
6. The pharmaceutical composition of claim 5 , further comprising at least one active ingredient selected from the group consisting of an ACE inhibitor, a renin inhibitor, an angiotensin II receptor antagonist, a beta-blocker, acetylsalicylic acid, a diuretic, a potassium supplement, a calcium antagonist, a statin, a digitalis (digoxin) derivative, a calcium sensitizer, a nitrate, and an antithrombotic.