US2019367516A1PendingUtilityA1
Positive allosteric modulators of muscarinic m2 receptor
Est. expiryJun 9, 2035(~8.9 yrs left)· nominal 20-yr term from priority
Inventors:Henrik TellerAlexander StraubMarkus BrechmannThomas MüllerMark MeininghausKatrin Nowak-ReppelHanna TinelKlaus MünterDaniela FliegnerThomas MondritzkiMelissa Boultadakis ArapinisTobias MarquardtAlexandros VakalopoulosAnne-Sophie RebstockMatthias Beat Wittwer
A61P 13/12A61K 31/5377C07D 519/00C07D 471/04A61P 9/00A61P 9/04A61K 45/06A61K 31/4545A61K 31/4375A61K 31/496A61P 9/12A61K 31/513
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Claims
Abstract
The present application relates to positive allosteric modulators of the muscarinic M2 receptor, especially to novel 7-substituted 1-arylnaphthyridine-3-carboxamides, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular disorders and/or renal disorders.
Claims
exact text as granted — not AI-modified1 : A compound of formula (I)
in which
R 1 is NR 4 R 5 ,
in which
R 4 is hydrogen, methyl, (C 2 -C 4 )-alkyl or (C 3 -C 6 )-cycloalkyl,
where (C 2 -C 4 )-alkyl may be substituted by hydroxyl or up to trisubstituted by fluorine
and
R 5 is (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, 3- to 6-membered saturated heterocyclyl or (C 1 -C 4 )-alkylsulphonyl,
where (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl and 3- to 6-membered saturated heterocyclyl may be up to trisubstituted, identically or differently, by methyl, difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy and cyano, and additionally up to tetrasubstituted by fluorine,
or
R 4 and R 5 together with the nitrogen atom to which they are bonded form a saturated or partially unsaturated, 3- to 6-membered monocyclic or 6- to 10-membered bicyclic heterocycle which may contain one or two further, identical or different heteroatoms from the group of N, O, S, SO and/or SO 2 as ring members,
where the 3- to 6-membered monocyclic and the 6- to 10-membered bicyclic heterocycle may each be substituted by 1 to 5 substituents independently selected from the group of (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl, oxo, (C 1 -C 3 )-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, (C 1 -C 3 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 3 )-alkylaminocarbonyloxy, —NHC(═O)R 22A and —CH 2 NHC(═O)R 22B , and additionally up to tetrasubstituted by fluorine, in which
R 22A and R 22B independently represent (C 1 -C 3 )-alkyl or cyclopropyl, and
in which (C 1 -C 4 )-alkyl may be mono- or disubstituted, identically or differently, by hydroxyl and (C 1 -C 3 )-alkoxy, and up to tetrasubstituted by fluorine,
R 2 is a group of the formula
in which
* marks the bonding site to the nitrogen atom of the amide moiety,
R 6A is hydrogen or (C 1 -C 4 )-alkyl,
R 6B is hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, trifluoromethyl, methoxymethyl or trifluoromethoxymethyl,
R 7 is (C 1 -C 4 )-alkyl, cyclopropyl or cyclobutyl,
where (C 1 -C 4 )-alkyl may be up to pentasubstituted and cyclopropyl and cyclobutyl up to tetrasubstituted by fluorine,
Y 1 is —(CH 2 ) k —, —CF 2 —, —O—CH 2 —, —CH 2 —O— or —CH 2 —O—CH 2 —,
in which
k is 0, 1, 2 or 3,
R 8 is up to penta-fluorine-substituted (C 1 -C 2 )-alkyl or trifluoromethoxymethyl,
L 1 is a bond or a group of the formula —C(R 9A R 9B )—(C(R 10A R 10B )) m —,
in which
m represents 0 or 1,
R 9A represents hydrogen or methyl,
R 9B represents hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl,
R 10A and R 10B independently represent hydrogen or methyl,
Ar 2 is phenyl,
where phenyl may be mono- to trisubstituted, identically or differently, by fluorine, chlorine, (C 1 -C 3 )-alkyl, difluoromethoxymethyl, trifluoromethoxymethyl and/or trifluoromethyl,
or
is a 5- to 10-membered bicyclic or tricyclic carbocycle,
where the 5- to 10-membered bicyclic or tricyclic carbocycle may be up to trisubstituted, identically or differently, by (C 1 -C 3 )-alkyl and trifluoromethyl, and additionally up to tetrasubstituted by fluorine,
Ar 1 is a group of the formula
in which
** marks the bonding site to the nitrogen atom,
R 3A is fluorine, chlorine or trifluoromethyl,
R 3B is hydrogen or fluorine,
and
R 3C is hydrogen, fluorine or chlorine.
and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides or salts thereof.
2 : The compound according to claim 1 ,
in which R 1 is NR 4 R 5 ,
in which
R 4 is hydrogen or methyl,
and
R 5 is (C 1 -C 4 )-alkyl or methylsulphonyl,
where (C 1 -C 4 )-alkyl may be up to disubstituted by hydroxyl and additionally up to trisubstituted by fluorine,
or
R 4 and R 5 together with the nitrogen atom to which they are bonded form a saturated or partially unsaturated, 4- to 6-membered monocyclic or 6- to 10-membered bicyclic heterocycle which may contain one or two further heteroatoms from the group of N, O, S, SO and SO 2 as ring member,
where the 4- to 6-membered monocyclic and the 6- to 10-membered bicyclic heterocycle may each be substituted by 1 to 5 substituents independently selected from the group of (C 1 -C 3 )-alkyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, cyano, methoxycarbonyl, aminocarbonyl and monomethylaminocarbonyloxy, and additionally up to tetrasubstituted by fluorine,
R 2 is a group of the formula
in which
* marks the bonding site to the nitrogen atom of the amide moiety,
R 6A is hydrogen or methyl,
R 6B is hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, trifluoromethyl or trifluoromethoxymethyl,
R 7 is (C 1 -C 4 )-alkyl, cyclopropyl or cyclobutyl,
where (C 1 -C 4 )-alkyl may be up to pentasubstituted by fluorine,
Y 1 is —(CH 2 ) k —, —CF 2 —, —O—CH 2 —, —CH 2 —O— or —CH 2 —O—CH 2 —,
in which
k is 0, 1, 2 or 3,
R 8 is methyl, trifluoromethyl or 2,2,2-trifluoroethyl,
L 1 is a bond or a group of the formula —CR 9A R 9B —,
in which
R 9A represents hydrogen or methyl,
R 9B represents hydrogen, methyl, trifluoromethyl or trifluoromethoxymethyl,
Ar 2 is phenyl,
which may be mono- or disubstituted, identically or differently, by fluorine, chlorine, methyl and/or trifluoromethyl,
R 11 , R 12 and R 23 are each independently hydrogen, fluorine, methyl, ethyl or trifluoroethyl,
n is the number 1 or 2,
where, if one of the substituents R 11 , R 12 or R 23 occurs twice in each case, its definitions may independently be the same or different,
Ar 1 is a group of the formula
in which
** marks the bonding site to the nitrogen atom,
R 3A is fluorine, chlorine or trifluoromethyl,
R 3B is hydrogen or fluorine
and
R 3C is hydrogen, fluorine or chlorine
and the salts, solvates and solvates of the salts thereof.
3 : The compound according to claim 1 ,
in which R 1 is NR 4 R 5 ,
in which
R 4 is hydrogen or methyl,
and
R 5 is methyl, isopropyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl or 2-hydroxypropyl,
or
is a 4- to 6-membered monocyclic or 6- to 8-membered bicyclic heterocycle which is bonded via a nitrogen atom and is of the formula
in which
*** marks the bonding site to the carbon atom of the pyridine ring,
the ring Q 1 is a group of the formula
in which
# 1 and # 2 mark the bonding site to the carbon atom of the pyrrolidine ring, and
Y 7 is —CF 2 — or —CHR 15 —,
in which
R 15 represents methoxymethyl,
and
R 16 is hydroxyl,
R 13A is fluorine, hydroxyl, hydroxymethyl, methyl, trifluoromethyl or methoxy,
R 13D is hydrogen, fluorine, methyl, hydroxyl, hydroxymethyl, methoxy or difluoromethoxy,
R 13E is hydrogen, fluorine, methyl, hydroxyl, hydroxymethyl or methoxy,
R 13F is fluorine, methyl, hydroxyl, hydroxymethyl or cyano,
R 13G is fluorine or hydroxyl,
R 13H is hydrogen, methyl, hydroxymethyl, aminocarbonyl or methoxycarbonyl,
R 13J is oxo, hydroxymethyl or difluoromethyl,
R 13K is hydrogen, methyl or 2-hydroxyethyl,
R 13L is hydrogen or methyl,
R 13M is ethyl, 2-hydroxyethyl or cyano,
R 13N is hydrogen or ethyl,
R 13O is hydrogen or hydroxyl,
R 14 is methyl, methoxycarbonyl or aminocarbonyl,
q is the number 0, 1 or 2,
r is the number 0, 1, 2 or 3,
s is the number 0 or 1,
t is the number 0, 1, 2, 3 or 4,
where, in the case that the substituents R 13A , R 13D , R 13E , R 13F , R 13G , R 13J and R 13L occur more than once, the definitions thereof may each be the same or different,
R 2 is a group of the formula
in which
* marks the bonding site to the nitrogen atom of the amide moiety,
R 6A is hydrogen or methyl,
R 6B is methyl, ethyl, cyclopropyl, trifluoromethyl or trifluoromethoxymethyl,
R 7 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-methylprop-1-yl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl or cyclopropyl,
R 8 is 2,2,2-trifluoroethyl,
L 1 is a bond or a group of the formula —CR 9A R 9B —,
in which
R 9A represents hydrogen or methyl,
R 9B represents hydrogen, methyl, trifluoromethyl or trifluoromethoxymethyl,
Ar 2 is phenyl,
which may be mono- or disubstituted, identically or differently, by fluorine, chlorine, methyl and/or trifluoromethyl,
R 11 is hydrogen, fluorine or methyl,
R 12A is hydrogen, fluorine, methyl, ethyl or trifluoromethyl,
R 12B is hydrogen or fluorine,
R 23 is hydrogen, fluorine or trifluoromethyl,
and
Ar 1 is a group of the formula
in which
** marks the bonding site to the nitrogen atom,
R 3A is fluorine or chlorine,
R 3B is hydrogen or fluorine,
and
R 3C is hydrogen, fluorine or chlorine
and the salts, solvates and solvates of the salts thereof.
4 : The compound according to claim 1 ,
in which R 1 is a group of the formula
in which
*** marks the bonding site to the carbon atom of the pyridine ring,
R 13DA is hydrogen or methyl,
R 13EA is hydroxyl or hydroxymethyl,
R 13EB is methyl or hydroxymethyl,
R 13EC is hydrogen or methyl,
R 13LA is hydrogen or methyl,
R 2 is a group of the formula
in which
* marks the bonding site to the nitrogen atom of the amide moiety,
R 6B is trifluoromethoxymethyl,
R 7A is methyl, ethyl, trifluoromethyl or cyclopropyl,
R 7B is trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl,
R 7C is methyl or ethyl,
R 19 is chlorine,
and
Ar 1 is a group of the formula
in which
** marks the bonding site to the nitrogen atom,
R 3A is fluorine or chlorine, and
R 3C is hydrogen or fluorine,
and the salts, solvates and solvates of the salts thereof.
5 : The compound according to claim 1 ,
in which R 1 is a group of the formula
in which
* ** marks the bonding site to the carbon atom of the pyridine ring,
R 2 is a group of the formula
in which
* marks the bonding site to the nitrogen atom of the amide moiety,
R 7A is ethyl, trifluoromethyl or cyclopropyl,
R 7B is trifluoromethyl,
R 7C is methyl or ethyl,
and
Ar 1 is a group of the formula
in which
** marks the bonding site to the nitrogen atom,
and the salts, solvates and solvates of the salts thereof.
6 : A process for preparing a compound of formula (I) according to claim 1 , wherein
[A] a compound of the formula (II)
in which R 2 and Ar 1 are as defined in claim 1 ,
and
Hal is fluorine, chlorine, bromine or iodine,
is reacted with a compound of the formula (III)
R 1 —H (III)
in which R 1 is as defined in claim 1 ,
to give the carboxamide of the formula (I)
in which R 1 , R 2 and Ar 1 are as defined in claim 1 , or
[B] a compound of the formula (IV)
in which R 1 and Ar 1 are as defined in claim 1 ,
is reacted with a compound of the formula (V)
R 2 —NH 2 (V)
in which R 2 is as defined in claim 1 ,
to give the compound of the formula (I)
in which R 1 , R 2 and Ar 1 are as defined in claim 1 ,
and wherein the compound of formula (I) is optionally separated into enantiomers and/or diastereomers and/or converted with the appropriate (i) solvents and/or (ii) bases or acids to their solvates, salts and/or solvates of the salts.
7 : A compound of formula (II)
R 2 is a group of the formula
in which
* marks the bonding site to the nitrogen atom of the amide moiety,
R 6A is hydrogen or (C 1 -C 4 )-alkyl,
R 6B is hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, trifluoromethyl, methoxymethyl or trifluoromethoxymethyl,
R 7 is (C 1 -C 4 )-alkyl, cyclopropyl or cyclobutyl,
where (C 1 -C 4 )-alkyl may be up to pentasubstituted and cyclopropyl and cyclobutyl up to tetrasubstituted by fluorine,
Y 1 is —(CH 2 ) k —, —CF 2 —, —O—CH 2 —, —CH 2 —O— or —CH 2 —O—CH 2 —,
in which
k is 0, 1, 2 or 3,
R 8 is up to penta-fluorine-substituted (C 1 -C 2 )-alkyl or trifluoromethoxymethyl,
L 1 is a bond or a group of the formula —C(R 9A R 9B )—(C(R 10A R 10B )) m —,
in which
m represents 0 or 1,
R 9A represents hydrogen or methyl,
R 9B represents hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl,
R 10A and R 10B independently represent hydrogen or methyl,
Ar 2 is phenyl,
where phenyl may be mono- to trisubstituted, identically or differently, by fluorine, chlorine, (C 1 -C 3 )-alkyl, difluoromethoxymethyl, trifluoromethoxymethyl and/or trifluoromethyl,
or
is a 5- to 10-membered bicyclic or tricyclic carbocycle,
where the 5- to 10-membered bicyclic or tricyclic carbocycle may be up to trisubstituted, identically or differently, by (C 1 -C 3 )-alkyl and trifluoromethyl, and additionally up to tetrasubstituted by fluorine,
Ar 1 is a group of the formula
in which
** marks the bonding site to the nitrogen atom,
R 3A is fluorine, chlorine or trifluoromethyl,
R 3B is hydrogen or fluorine,
and
R 3C is hydrogen, fluorine or chlorine,
and
Hal is fluorine, chlorine, bromine or iodine.
8 : A compound of formula (IV)
in which
R 1 is NR 4 R 5 ,
in which
R 4 is hydrogen, methyl, (C 2 -C 4 )-alkyl or (C 3 -C 6 )-cycloalkyl,
where (C 2 -C 4 )-alkyl may be substituted by hydroxyl or up to trisubstituted by fluorine
and
R 5 is (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, 3- to 6-membered saturated heterocyclyl or (C 1 -C 4 )-alkylsulphonyl,
where (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl and 3- to 6-membered saturated heterocyclyl may be up to trisubstituted, identically or differently, by methyl, difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy and cyano, and additionally up to tetrasubstituted by fluorine,
or
R 4 and R 5 together with the nitrogen atom to which they are bonded form a saturated or partially unsaturated, 3- to 6-membered monocyclic or 6- to 10-membered bicyclic heterocycle which may contain one or two further, identical or different heteroatoms from the group of N, O, S, SO and/or SO 2 as ring members,
where the 3- to 6-membered monocyclic and the 6- to 10-membered bicyclic heterocycle may each be substituted by 1 to 5 substituents independently selected from the group of (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl, oxo, (C 1 -C 3 )-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, (C 1 -C 3 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 3 )-alkylaminocarbonyloxy, —NHC(═O)R 22A and —CH 2 NHC(═O)R 22B , and additionally up to tetrasubstituted by fluorine, in which
R 22A and R 22B independently represent (C 1 -C 3 )-alkyl or cyclopropyl, and
in which (C 1 -C 4 )-alkyl may be mono- or disubstituted, identically or differently, by hydroxyl and (C 1 -C 3 )-alkoxy, and up to tetrasubstituted by fluorine, and
Ar 1 is a group of the formula
in which
** marks the bonding site to the nitrogen atom,
R 3A is fluorine, chlorine or trifluoromethyl,
R 3B is hydrogen or fluorine,
and
R 3C is hydrogen, fluorine or chlorine.
9 . (canceled)
10 : A method for treatment and/or prophylaxis of diseases, comprising administering to a patient in need thereof a compound according to claim 1 .
11 : A method for treatment and/or prophylaxis of heart failure, coronary heart disease, atrial and ventricular arrhythmia, renal failure and nephropathy, comprising administering to a patient in need thereof a compound according to claim 1 .
12 : A pharmaceutical combination comprising a compound according to claim 1 in combination with one or more further active ingredients selected from the group consisting of active hypotensive ingredients, active antiarrhythmic ingredients, vasopressin receptor antagonists, PDE 5 inhibitors, platelet aggregation inhibitors, sGC activators and sGC stimulators.
13 : A pharmaceutical composition comprising a compound according to claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.
14 : A method for treatment and/or prophylaxis of heart failure, coronary heart disease, atrial and ventricular arrhythmia, renal failure and nephropathy, comprising administering to a patient in need thereof a pharmaceutical combination according to claim 12 .
15 . (canceled)
16 : A method for treatment and/or prophylaxis of cardiovascular disorders and/or renal disorders, comprising administering a positive allosteric modulator of the muscarinic M2 receptor to a patient in need thereof.
17 : The method of claim 16 , wherein the positive allosteric modulator of the muscarinic M2 receptor has subtype selectivity for the M2 receptor over the various muscarinic acetylcholine receptors in terms of the positive allosteric effect.
18 : The method of claim 16 , wherein the positive allosteric modulator of the muscarinic M2 receptor has, within a concentration range of 1 μM-10 μM, an identical or higher selectivity for the muscarinic M2 receptor than for the muscarinic M4 receptor, and
wherein the selectivity is determined as the quotient of the respective modulator-related allosteric shift in the EC 50 value of the ACh dose-response curve for the M2 receptor relative to the M4 receptor.
19 : The method of claim 16 , wherein the positive allosteric modulator of the muscarinic M2 receptor has, within a concentration range of 5 μM-20 μM, a selectivity at least 4 times higher for the muscarinic M2 receptor than for the muscarinic M1 receptor,
and wherein the selectivity is determined as the quotient of the respective modulator-related allosteric shift in the EC 50 value of the ACh dose-response curve for the M2 receptor relative to the M1 receptor.
20 : The method of claim 16 , wherein the positive allosteric modulator of the muscarinic M2 receptor comprises a 1-arylnaphthyridine-3-carboxamide structure.
21 : A method for treatment and/or prophylaxis of heart failure, coronary heart disease, atrial and ventricular arrhythmia, renal failure and nephropathy, comprising administering a pharmaceutical composition according to claim 13 to a patient in need thereof.Join the waitlist — get patent alerts
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