Claims for Patent: 8,436,180

Summary for Patent: 8,436,180

Title:	Substituted-4-aryl-1,4-dihydro-1,6-naphthyridinamides and use thereof
Abstract:	The present application relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, a process for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially cardiovascular disorders.
Inventor(s):	Barfacker; Lars (Oberhausen, DE), Kolkhof; Peter (Wuppertal, DE), Schlemmer; Karl-Heinz (Wuppertal, DE), Grosser; Rolf (Leverkusen, DE), Nitsche; Adam (Pulheim, DE), Klein; Martina (Heiligenhaus, DE), Munter; Klaus (Wulfrath, DE), Albrecht-Kupper; Barbara (Wulfrath, DE), Hartmann; Elke (Wuppertal, DE)
Assignee:	Bayer Intellectual Property GmbH (Monheim, DE)
Application Number:	12/526,951
Patent Claims:	1. A compound of the formula (I) ##STR00078## in which D is N or C--R.sup.4, in which R.sup.4 is hydrogen, fluorine, trifluoromethyl or (C.sub.1-C.sub.4)-alkyl, Ar is a group of the formula ##STR00079## in which * is the linkage point, R.sup.5 is hydrogen, fluorine, chlorine, cyano, nitro, trifluoromethyl or (C.sub.1-C.sub.4)-alkyl, R.sup.6 is hydrogen or fluorine, R.sup.7 is halogen, (C.sub.1-C.sub.4)-alkyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkoxy or trifluoromethoxy, R.sup.8 is cyano or nitro, R.sup.9 is hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, (C.sub.1-C.sub.4)-alkylthio or di-(C.sub.1-C.sub.4)-alkylamino, it being possible for the alkyl group in said (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy and (C.sub.1-C.sub.4)-alkylthio radicals in each case to be substituted up to three times by fluorine, or phenyl, which may be substituted by halogen, (C.sub.1-C.sub.4)-alkyl or trifluoromethyl, R.sup.10 is hydrogen, halogen or (C.sub.1-C.sub.4)-alkyl, E is CH, C--R.sup.7 or N, and n is the number 0, 1 or 2, it being possible in the case where the substituent R.sup.7 occurs more than once for its meanings to be identical or different, R.sup.1 is (C.sub.1-C.sub.4)-alkyl which may be substituted up to three times by fluorine, R.sup.2 is (C.sub.1-C.sub.6)-alkyl which may be substituted by (C.sub.3-C.sub.7)-cycloalkyl or up to three times by fluorine, or is a group of the formula --SO.sub.2--R.sup.11 in which R.sup.11 is (C.sub.1-C.sub.6)-alkyl, trifluoromethyl, (C.sub.3-C.sub.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.sub.1-C.sub.4)-alkyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkoxy and/or trifluoromethoxy, and R.sup.3 is hydrogen, fluorine, trifluoromethyl or (C.sub.1-C.sub.4)-alkyl, or a salt thereof. 2. A compound of the formula (I) as claimed in claim 1, in which D is C--R.sup.4 in which R.sup.4 is hydrogen, methyl or trifluoromethyl, Ar is a group of the formula ##STR00080## in which * is the linkage point, R.sup.5 is hydrogen, fluorine, chlorine or cyano, R.sup.8 is cyano or nitro, and R.sup.9 is chlorine, bromine, (C.sub.1-C.sub.4)-alkyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkoxy, trifluoromethoxy, (C.sub.1-C.sub.4)-alkylthio or trifluoromethylthio, R.sup.1 is methyl or trifluoromethyl, R.sup.2 is (C.sub.1-C.sub.4)-alkyl, trifluoromethyl or a group of the formula --SO.sub.2--R.sup.11 in which R.sup.11 is (C.sub.1-C.sub.4)-alkyl or trifluoromethyl, and R.sup.3 is hydrogen, methyl or trifluoromethyl, or a salt thereof. 3. A compound of the formula (I) as claimed in claim 1, in which D is C--R.sup.4 in which R.sup.4 is hydrogen or methyl, Ar is a group of the formula ##STR00081## in which * is the linkage point and R.sup.9 is ethyl, methoxy or trifluoromethoxy, R.sup.1 is methyl or trifluoromethyl, R.sup.2 is methyl, ethyl, n-propyl or isopropyl and R.sup.3 is hydrogen or methyl, or a salt thereof. 4. A compound as claimed in claim 1, having one of the following structures: ##STR00082## or a salt thereof. 5. A compound as claimed in claim 1, having one of the following structures: ##STR00083## ##STR00084## or a salt thereof. 6. A process for preparing compounds of the formula (I) as defined in claim 1, comprising reacting a compound of the formula (II) ##STR00085## in which Ar has the meaning indicated in claim 1, in an inert solvent, optionally, in the presence of an acid, an acid/base combination and/or a dehydrating agent, with a compound of the formula (III) ##STR00086## in which R.sup.1 has the meaning indicated in claim 1, and T is allyl or 2-cyanoethyl, to give a compound of the formula (IV) ##STR00087## in which Ar, T and R.sup.1 each have the meanings indicated above, condensing the compound of formula (IV) in an inert solvent with a compound of the formula (V) ##STR00088## in which D and R.sup.3 have the meanings indicated in claim 1, to give a compound of the formula (VI) ##STR00089## in which Ar, D, T, R.sup.1 and R.sup.3 each have the meanings indicated above, alkylating a compounds of the formula (VI) in an inert solvent, optionally, in the presence of a base, with a compound of the formula (VII) or a trialkyloxonium salt of the formula (VIII) ##STR00090## in which R.sup.12 is (C.sub.1-C.sub.6)-alkyl which may be substituted by (C.sub.3-C.sub.7)-cycloalkyl or up to three times by fluorine, R.sup.12A is methyl or ethyl, X is a leaving group such as, for example, halogen, mesylate, tosylate or triflate, and Y.sup.- is a non-nucleophilic anion such as, for example, tetrafluoroborate, or in the presence of an acid with a trialkyl orthoformate of the formula (IX) ##STR00091## in which R.sup.12A has the meaning indicated above, to give a compounds of the formula (X-A) ##STR00092## in which Ar, D, T, R.sup.1, R.sup.3 and R.sup.12 each have the meanings indicated above, or reacting the compounds of the formula (VI) in an inert solvent in the presence of a base with a compound of the formula (XI) ##STR00093## in which R.sup.11 has the meaning indicated in claim 1, to give a compound of the formula (X-B) ##STR00094## in which Ar, D, T, R.sup.1, R.sup.3 and R.sup.11 each have the meanings indicated above, eliminating the ester group T in the compounds of the formula (X-A) or (X-B) to give a carboxylic acids of the formula (XII) ##STR00095## in which Ar, D, R.sup.1, R.sup.2 and R.sup.3 each have the meanings indicated in claim 1, then converting the compound of formula (CII) with 1,1'-carbonyldiimidazole into the imidazolides of the formula (XIII) ##STR00096## in which Ar, D, R.sup.1, R.sup.2 and R.sup.3 each have the meanings indicated above, and reacting the compound of formula (XIII) in an inert solvent, optionally in the presence of an auxiliary base, with ammonia to give an amide of the formula (I), optionally, separating compounds of the formula (I) produced as described above by method known to the skilled worker into their enantiomers and/or diastereomers, and, optionally, converting the compound of formula (I) with an appropriate (i) solvent and/or (ii) base or acid into a salt thereof. 7. 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. 8. The pharmaceutical composition of claim 7 further comprising one or more further active ingredients selected from the group consisting of ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, beta-blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis (digoxin) derivatives, calcium sensitizers, nitrates and antithrombotics. 9. The pharmaceutical composition as claimed in claim 7 for the treatment of aldosteronism, high blood pressure, chronic heart failure, the sequelae of a myocardial infarction, cirrhosis of the liver, renal failure and stroke. 10. A compound having the following structure: ##STR00097## or a salt thereof.