Substituted benzimidazolone derivatives, medicaments comprising them and their use
View Patent ↗The present invention relates to novel benzimidazolone derivatives of the general formula (I) in which the substituents R 1 , R 2 , R 3 , A 1 , A 2 , and B are as defined in claim 1 , medicaments comprising these, and the use thereof for the prophylaxis and/or treatment of vasopressin-dependent diseases.
1. A method for the treatment of a vasopressin-dependent disease selected from the group consisting of anxiety disorders, depressive disorders, and hyponatremia, the method comprising administering to a subject in need thereof a compound of the general formula (I),
in which
A 1 is hydrogen, in each case optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkenyl or C 1 -C 4 -alkylene-phenyl, or
an aromatic, heteroaromatic, partly aromatic or partly heteroaromatic mono- or bicyclic ring having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms as ring members, which may besides additionally comprise 0, 1, 2, 3 or 4 identical or different heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur as ring members, and which may be substituted by one, two or three radicals R A 11 , R A 12 and/or R A 13 which are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, bromine, chlorine, iodine, fluorine, CN, CF 3 , OCF 3 , OCHF 2 , OH, COOH, CO—NH 2 , NH 2 , NH—CO—NH, or in each case optionally substituted C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, O—C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkenyl, C 1 -C 4 -alkylene-aryl, NH—(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl)-C 1 -C 4 —NH—C 1 -C 4 -alkylene-NH—(C 1 -C 6 -alkyl), C 1 -C 4 -alkylene-N(C 1 -C 6 -alkyl)-C 1 -C 4 -alkylene-OH, C 1 -C 4 alkylene-O—C 1 -C 6 -alkyl, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl, CO—NH(C 1 -C 6 -alkyl), C 1 -C 6 -alkyl)-NH—CO—C 1 -C 6 -alkyl, NH—CO—N(C 1 -C 6 -alkyl) 2 , and N(C 1 -C 6 -alkyl)-CO—C 1 -C 6 -alkyl;
A 2 is hydrogen or in each case optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 6 -alkynyl or C 3 -C 6 -cycloalkyl,
or where the radicals A 1 and A 2 may form together with the carbon atom to which they are bonded an in each case optionally substituted 3- to 7-membered carbocyclic ring (spiro linkage) which may additionally comprise a heteroatom as ring member selected from the group consisting of 0, S and NR A 14 in which R A 14 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, aryl and C 1 -C 4 -alkylene-aryl, and where the ring formed in this way may be substituted by one, two or three radicals R A 11 , R A 12 and/or R A 13 which may independently of one another and independently of their respective occurrence assume the aforementioned meanings;
B is an aromatic, heteroaromatic, partly aromatic or partly heteroaromatic mono- or bicyclic ring having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms as ring members, which may additionally comprise 0, 1, 2, 3 or 4 identical or different heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur as ring members, and which may be substituted by one, two or three radicals R B 1 , R B 2 and/or R B 3 , where R B 1 , R B 2 and R B 3 are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, chlorine, bromine, fluorine, CN, CF 3 , OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CF 3 , OCH 2 —CHF 2 , OH, and in each case optionally substituted O—C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl and C 2 -C 4 -alkynyl;
R 1 is selected from the group consisting of hydrogen, bromine, chlorine, fluorine, iodine, CN, CF 3 , OCF 3 , OCHF 2 , O—C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, C 2 -C 4 -alkynyl, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), NO 2 , NHCHO, NHCO(C 1 -C 4 -alkyl) and NHCONH 2 ;
R 2 is selected from the group consisting of hydrogen, and in each case optionally substituted C 1 -C 4 -alkyl, O—C 1 -C 4 -alkyl, chlorine, fluorine, difluoromethyl (CHF 2 ) and trifluoromethyl;
R 3 is a radical (X)—(Y), where
X is CO, SO 2 or (C═NH),
Y is selected from the group consisting of OH, NH 2 , NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), NH(C 2 -C 4 -alkylene-OH), N(C 1 -C 4 -alkyl)(C 2 -C 4 -alkylene-OH), NH(C 2 -C 4 -alkylene-O—C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 2 -C 4 -alkylene-O—C 1 -C 4 -alkyl), NH(C 3 -C 7 -cycloalkyl), N(C 1 -C 4 -alkyl)(C 1 -C 7 -cyclo-alkyl), NH(C 1 -C 4 -haloalkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 -haloalkyl), N(R 5 )(C 1 -C 4 -alkylene)-R Y 3 , and radical R Y 1 ;
R Y 1 is selected independently of its respective occurrence from the group consisting of the respective individual radicals mentioned below
where n is independently of its occurrence the integer 1 or 2,
where the aforementioned radicals may independently of one another each have one or two substituents R Y 12 and/or R Y 13 which are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, fluorine, OH, in each case optionally substituted O—C 1 -C 4 -alkyl, phenyl and C 1 -C 4 -alkyl;
R Y 11 is a radical selected from the group consisting of hydrogen, in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl;
R Y 2 is a radical selected from the group consisting of hydrogen, in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl, C 1 -C 4 -alkylene-phenyl, C 1 -C 4 -haloalkyl, C 3 -C 7 -cycloalkyl, pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, imidazole, pyrazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, triazole, 1,3,5-triazine, tetrazole, (C 2 -C 4 -alkylene)-R Y 3 and ring radical R Y 22 , where
R Y 22 is selected independently of its respective occurrence from the group consisting of the respective individual radicals
where the aforementioned radicals may independently of one another in each case have one or two substituents R Y 222a and/or R Y 223a which are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, fluorine, OH and in each case optionally substituted O—C 1 -C 4 -alkyl, phenyl and C 1 -C 4 -alkyl;
R Y 221 is a radical selected from the group consisting of hydrogen, and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 1 -C 4 -alkylene-phenyl, in particular hydrogen, and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and C 1 -C 6 -alkynyl;
R Y 3 is a radical selected from the group consisting of hydrogen, NH 2 , N(R Y 3a )R Y 3b , NH(C 2 -C 4 -alkylene)-R Y 8 , N(R Y 7 )(C 2 -C 4 -alkylene)-R Y 8 , N(R Y 7 )R Y 9 , N(R Y 7 )CH 2 R Y 9 , a radical R Y 33 , a radical CH 2 R Y 33 and an aromatic radical, selected from phenyl, pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, triazole, 1,3,5-triazine and tetrazole, the aromatic radical being substituted or carrying 1 or 2 substitutens R Y 331 and/or R Y 332 , where
R Y 33 is independently of its respective occurrence a radical selected from the group consisting of the respective individual radicals
where n is independently of its occurrence the integer 1 or 2,
where the aforementioned radicals R 33 may independently of one another in each case have one or two substituents R Y 331 and/or R Y 332 ;
R Y 331 , R Y 332 are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, fluorine, OH, and in each case optionally substituted O—C 1 -C 4 -alkyl, phenyl and C 1 -C 4 -alkyl;
R Y 333 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 3a is a radical selected from the group consisting of hydrogen, and in each case optionally substituted C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 3b is a radical selected from the group consisting of in each case optionally substituted C 1 -C 6 -alkyl and C 1 -C 4 -alkylene-phenyl;
R Y 5 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 4 -alkyl;
R Y 6 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 7 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 8 is a radical selected from the group consisting of OH, NH 2 , and in each case optionally substituted NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 alkyl), NH(C 2 -C 4 -alkylene-OH), N(C 1 -C 4 -alkyl)(C 2 -C 4 -alkylene-OH), NH(C 2 -C 4 -alkylene-O—C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 2 -C 4 alkylene-O—C 1 -C 4 -alkyl), NH(C 3 -C 7 -cycloalkyl), N(C 1 -C 4 -alkyl)(C 3 -C 7 -cycloalkyl), NH(C 1 -C 4 haloalkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 -haloalkyl), O—C 1 -C 4 -alkyl, and the ring radical R Y 81 , where
R Y 81 is a radical independently of its respective occurrence selected from the group consisting of the respective individual radicals
R Y 9 is a 5- or 6-membered heteroaromatic radical having 2, 3, 4 or 5 carbon atom as ring members and 1, 2 or 3 heteroatoms, selected from 0, S and N, wherein the 5- or 6-membered heteroaromatic radical may be unsubstituted or may have one or two substituents R Y 331 and/or R Y 332 ;
the tautomeric, enantiomeric and/or diastereomeric forms thereof, and the physiologically tolerated salts of the aforementioned compound or compounds;
with the proviso that R 1 ≠H (is not hydrogen) when A 1 =A 2 =hydrogen;
and with the proviso that R 1 is halogen, cyano, or in each case optionally substituted C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl when A 1 =A 2 =hydrogen.
2. The method of claim 1 , wherein the compound of the formula (I) has a binding affinity Ki for the vasopressin V1b receptor subtype of less than about 100 nM.
3. The method of claim 1 , wherein the compound of the formula (I) has a binding affinity Ki for the vasopressin V1b receptor subtype of between about 10 nM and about 100 nM.
4. The method of claim 1 , wherein the compound of the formula (I) has a binding affinity Ki for the vasopressin V1b receptor subtype of less than or equal to about 10 nM.
5. The method of claim 1 , wherein the method comprises administering an effective amount of a compound of formula (I), or of a physiologically tolerated salt thereof, to a subject that is a mammal.
6. A method for the treatment of a vasopressin-dependent disease selected from the group consisting of hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemias of the heart, disorders of the renal system, edemas, renal vasospasm, necrosis of the renal cortex, hypokalemia, Schwartz-Bartter syndrome, disorders of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers, emesis, emesis occurring during chemotherapy, travel sickness, diabetes insipidus, nocturnal enuresis, and incontinence, or for delaying micturition, the method comprising administering to a subject in need thereof a compound of the general formula (I),
in which
A 1 is hydrogen, in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkenyl or C 1 -C 4 -alkylene-phenyl, or
an aromatic, heteroaromatic, partly aromatic or partly heteroaromatic mono- or bicyclic ring having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms as ring members, which may besides additionally comprise 0, 1, 2, 3 or 4 identical or different heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur as ring members, and which may be substituted by one, two or three radicals R A 11 , R A 12 and/or R A 13 which are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, bromine, chlorine, iodine, fluorine, CN, CF 3 , OCF 3 , OCHF 2 OH, COOH, CO—NH 2 , NH 2 , NH—CO—NH 2 or in each case optionally substituted C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, O—C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkenyl, C 1 -C 4 -alkylene-aryl, NH—(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl)-C 1 -C 4 —NH 2 , C 1 -C 4 -alkylene-NH—(C 1 -C 6 -alkyl), C 1 -C 4 -alkylene-N(C 1 -C 6 -alkyl)-C 1 -C 4 -alkylene-OH, C 1 -C 4 alkylene-O—C 1 -C 6 -alkyl, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl, CO—NH(C 1 -C 6 -alkyl), CO—N(C 1 -C 6 -alkyl) 2 , NH—CO—C 1 -C 6 -alkyl, NH—CO—N(C 1 -C 6 -alkyl) 2 , and N(C 1 -C 6 -alkyl)-CO—C 1 -C 6 -alkyl;
A 2 is hydrogen or in each case optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 6 -alkynyl or C 3 -C 6 -cycloalkyl,
or where the radicals A 1 and A 2 may form together with the carbon atom to which they are bonded an in each case optionally substituted 3- to 7-membered carbocyclic ring (spiro linkage) which may additionally comprise a heteroatom as ring member selected from the group consisting of O, S and NR A 14 in which R A 14 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, aryl and C 1 -C 4 -alkylene-aryl, and where the ring formed in this way may be substituted by one, two or three radicals R A 11 , R A 12 and/or R A 13 which may independently of one another and independently of their respective occurrence assume the aforementioned meanings;
B is an aromatic, heteroaromatic, partly aromatic or partly heteroaromatic mono- or bicyclic ring having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms as ring members, which may additionally comprise 0, 1, 2, 3 or 4 identical or different heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur as ring members, and which may be substituted by one, two or three radicals R B 1 , R B 2 and/or R B 3 , where R B 1 , R B 2 and R B 3 are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, chlorine, bromine, fluorine, CN, CF 3 , OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CF 3 , OCH 2 —CHF 2 , OH, and in each case optionally substituted O—C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl and C 2 -C 4 -alkynyl;
R 1 is selected from the group consisting of hydrogen, bromine, chlorine, fluorine, iodine, CN, CF 3 , OCF 3 , OCHF 2 , O—C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, C 2 -C 4 -alkynyl, NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), NO 2 , NHCHO, NHCO(C 1 -C 4 -alkyl) and NHCONH 2 ;
R 2 is selected from the group consisting of hydrogen, and in each case optionally substituted C 1 -C 4 -alkyl, O—C 1 -C 4 -alkyl, chlorine, fluorine, difluoromethyl (CHF 2 ) and trifluoromethyl;
R 3 is a radical (X)—(Y), where
X is CO, SO 2 or (C═NH),
Y is selected from the group consisting of OH, NH 2 , NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), NH(C 2 -C 4 -alkylene-OH), N(C 1 -C 4 -alkyl)(C 2 -C 4 -alkylene-OH), NH(C 2 -C 4 -alkylene-O—C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 2 -C 4 -alkylene-O—C 1 -C 4 -alkyl), NH(C 3 -C 7 -cycloalkyl), N(C 1 -C 4 -alkyl)(C 1 -C 7 -cyclo-alkyl), NH(C 1 -C 4 -haloalkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 -haloalkyl), N(R Y 5 )(C 1 -C 4 -alkylene)-R Y 3 , and radical R Y 1 ;
R Y 1 is selected independently of its respective occurrence from the group consisting of the respective individual radicals mentioned below
where n is independently of its occurrence the integer 1 or 2,
where the aforementioned radicals may independently of one another each have one or two substituents R Y 12 and/or R Y 13 which are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, fluorine, OH, in each case optionally substituted O—C 1 -C 4 -alkyl, phenyl and C 1 -C 4 -alkyl;
R Y 11 is a radical selected from the group consisting of hydrogen, in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl;
R Y 2 is a radical selected from the group consisting of hydrogen, in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl, C 1 -C 4 -alkylene-phenyl, C 1 -C 4 -haloalkyl, C 3 -C 7 -cycloalkyl, pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, imidazole, pyrazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, triazole, 1,3,5-triazine, tetrazole, (C 2 -C 4 -alkylene)-R Y 3 and ring radical R Y 22 , where
R Y 22 is selected independently of its respective occurrence from the group consisting of the respective individual radicals
where the aforementioned radicals may independently of one another in each case have one or two substituents R Y 222a and/or R Y 223a which are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, fluorine, OH and in each case optionally substituted O—C 1 -C 4 -alkyl, phenyl and C 1 -C 4 -alkyl;
R Y 221 is a radical selected from the group consisting of hydrogen, and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 1 -C 4 -alkylene-phenyl, in particular hydrogen, and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl;
R Y 3 is a radical selected from the group consisting of hydrogen, NH 2 , N(R Y 3a )R Y 3b , NH(C 2 -C 4 -alkylene)-R Y 8 , N(R Y 7 )(C 2 -C 4 -alkylene)-R Y 8 , N(R Y 7 )R Y 9 , N(R Y 7 )CH 2 R Y 9 , a radical R Y 33 , a radical CH 2 R Y 33 and an aromatic radical, selected from phenyl, pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, triazole, 1,3,5-triazine and tetrazole, the aromatic radical being substituted or carrying 1 or 2 substitutens R Y 331 and/or R Y 332 , where
R Y 33 is independently of its respective occurrence a radical selected from the group consisting of the respective individual radicals
where n is independently of its occurrence the integer 1 or 2,
where the aforementioned radicals R 33 may independently of one another in each case have one or two substituents R Y 331 and/or R Y 332 ;
R Y 331 , R Y 332 are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, fluorine, OH, and in each case optionally substituted O—C 1 -C 4 -alkyl, phenyl and C 1 -C 4 -alkyl;
R Y 333 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 3a is a radical selected from the group consisting of hydrogen, and in each case optionally substituted C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 3b is a radical selected from the group consisting of in each case optionally substituted C 1 -C 6 -alkyl and C 1 -C 4 -alkylene-phenyl;
R Y 5 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 4 -alkyl;
R Y A is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 7 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 8 is a radical selected from the group consisting of OH, NH 2 , and in each case optionally substituted NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) (C 1 -C 4 -alkyl), NH(C 2 -C 4 -alkylene-OH), N(C 1 -C 4 -alkyl)(C 2 -C 4 -alkylene-OH), NH(C 2 -C 4 -alkylene-O—C 1 -C 4 alkyl), N(C 1 -C 4 -alkyl)(C 2 -C 4 -alkylene-O—C 1 -C 4 -alkyl), NH(C 3 -C 7 -cycloalkyl), N(C 1 -C 4 -alkyl)(C 3 -C 7 -cycloalkyl), NH(C 1 -C 4 haloalkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 -haloalkyl), O—C 1 -C 4 -alkyl, and the ring radical R Y 81 , where
R Y 81 is a radical independently of its respective occurrence selected from the group consisting of the respective individual radicals
R Y 9 is a 5- or 6-membered heteroaromatic radical having 2, 3, 4 or 5 carbon atom as ring members and 1, 2 or 3 heteroatoms, selected from the group consisting of O, S and N, wherein the 5- or 6-membered heteroaromatic radical may be unsubstituted or may have one or two substituents R Y 331 and/or R Y 332 ;
the tautomeric, enantiomeric and/or diastereomeric forms thereof, and the physiologically tolerated salts of the aforementioned compound or compounds;
with the proviso that R 1 —H (is not hydrogen) when A 1 =A 2 =hydrogen;
and with the proviso that R 1 is halogen, cyano, or in each case optionally substituted C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl when A 1 =A 2 =hydrogen.
7. The method of claim 6 , wherein the compound of the formula (I) has a binding affinity Ki for the vasopressin V1b receptor subtype of less than about 100 nM.
8. The method of claim 6 , wherein the compound of the formula (I) has a binding affinity Ki for the vasopressin V1b receptor subtype of between about 10 nM and about 100 nM.
9. The method of claim 6 , wherein the compound of the formula (I) has a binding affinity Ki for the vasopressin V1b receptor subtype of less than or equal to about 10 nM.
10. The method of claim 6 , wherein the method comprises administering an effective amount of a compound of formula (I), or of a physiologically tolerated salt thereof, to a subject that is a mammal.
11. A method for the treatment of a vasopressin-dependent disease selected from the group consisting of memory impairments, Alzheimer's disease, psychoses, psychotic disorders, Cushing's syndrome, sleep disorders, schizophrenia, vasomotor symptoms, and thermoregulatory dysfunctions, the method comprising administering to a subject in need thereof a compound of the general formula (I),
in which
A 1 is hydrogen, in each case optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkenyl or C 1 -C 4 -alkylene-phenyl, or
an aromatic, heteroaromatic, partly aromatic or partly heteroaromatic mono- or bicyclic ring having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms as ring members, which may besides additionally comprise 0, 1, 2, 3 or 4 identical or different heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur as ring members, and which may be substituted by one, two or three radicals R A 11 , R A 12 and/or R A 13 which are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, bromine, chlorine, iodine, fluorine, CN, CF 3 , OCF 3 , OCHF 2 , OH, COOH, CO—NH 2 , NH 2 , NH—CO—NH, or in each case optionally substituted C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, O—C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkenyl, C 1 -C 4 -alkylene-aryl, NH—(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl)-C 1 -C 4 —NH 2 , C 1 -C 4 -alkylene-NH—(C 1 -C 6 -alkyl), C 1 -C 4 -alkylene-N(C 1 -C 6 -alkyl)-C 1 -C 4 -alkylene-OH, C 1 -C 4 alkylene-O—C 1 -C 6 -alkyl, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl, CO—NH(C 1 -C 6 -alkyl), CO—N(C 1 -C 6 -alkyl)-NH—CO—C 1 -C 6 -alkyl, NH—CO—N(C 1 -C 6 -alkyl) 2 , N(C 1 -C 6 -alkyl)-CO—C 1 -C 6 -alkyl;
A 2 is hydrogen or in each case optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 6 -alkynyl or C 3 -C 6 -cycloalkyl,
or where the radicals A 1 and A 2 may form together with the carbon atom to which they are bonded an in each case optionally substituted 3- to 7-membered carbocyclic ring (spiro linkage) which may additionally comprise a heteroatom as ring member selected from the group consisting of 0, S and NR A 14 in which R A 14 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, aryl and C 1 -C 4 -alkylene-aryl, and where the ring formed in this way may be substituted by one, two or three radicals R A 11 , R A 12 and/or R A 13 which may independently of one another and independently of their respective occurrence assume the aforementioned meanings;
B is an aromatic, heteroaromatic, partly aromatic or partly heteroaromatic mono- or bicyclic ring having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms as ring members, which may additionally comprise 0, 1, 2, 3 or 4 identical or different heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur as ring members, and which may be substituted by one, two or three radicals R B 1 , R B 2 and/or R B 3 , where R B 1 , R B 2 and R B 3 are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, chlorine, bromine, fluorine, CN, CF 3 , OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CF 3 , OCH 2 —CHF 2 , OH, and in each case optionally substituted O—C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl and C 2 -C 4 -alkynyl;
R 1 is selected from the group consisting of hydrogen, bromine, chlorine, fluorine, iodine, CN, CF 3 , OCF 3 , OCHF 2 , and in each case O—C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl and C 2 -C 4 -alkynyl; NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), NO 2 , NHCHO, NHCO(C 1 -C 4 -alkyl) or NHCONH 2 ;
R 2 is selected from the group consisting of hydrogen, and in each case optionally substituted C 1 -C 4 -alkyl, O—C 1 -C 4 -alkyl, chlorine, fluorine, difluoromethyl (CHF 2 ) and trifluoromethyl;
R 3 is a radical (X)—(Y), where
X is CO, SO 2 or (C═NH),
Y is selected from the group consisting of
OH, NH 2 , NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), NH(C 2 -C 4 -alkylene-OH), N(C 1 -C 1 -alkyl)(C 2 -C 4 -alkylene-OH), NH(C 2 -C 4 -alkylene-O—C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 2 -C 4 -alkylene-O—C 1 -C 4 -alkyl), NH(C 1 -C 7 -cycloalkyl), N(C 1 -C 1 -alkyl)(C 1 -C 7 -cyclo-alkyl), NH(C 1 -C 4 -haloalkyl), N(C 1 -C 4 -alkyl)(C 1 -C 1 -haloalkyl), N(R Y 5 )(C 1 -C 4 -alkylene)-R Y 3 , and radical R Y 1 ;
R Y 1 is selected independently of its respective occurrence from the group consisting of the respective individual radicals mentioned below
where n is independently of its occurrence the integer 1 or 2,
where the aforementioned radicals may independently of one another each have one or two substituents R Y 12 and/or R Y 13 which are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, fluorine, OH, in each case optionally substituted O—C 1 -C 4 -alkyl, phenyl and C 1 -C 4 -alkyl;
R Y 11 is a radical selected from the group consisting of hydrogen, in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl;
R Y 2 is a radical selected from the group consisting of hydrogen, in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl, C 1 -C 4 alkylene-phenyl, C 1 -C 4 -haloalkyl, C 3 -C 1 -cycloalkyl, pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, imidazole, pyrazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, triazole, 1,3,5-triazine, tetrazole, (C 2 -C 4 -alkylene)-R Y 3 and ring radical R Y 22 , where
R Y 22 is selected independently of its respective occurrence from the group consisting of the respective individual radicals
where the aforementioned radicals may independently of one another in each case have one or two substituents R Y 222a and/or R Y 223a which are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, fluorine, OH and in each case optionally substituted O—C 1 -C 4 -alkyl, phenyl and C 1 -C 4 -alkyl;
R Y 221 is a radical selected from the group consisting of hydrogen, and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 1 -C 4 -alkylene-phenyl, in particular hydrogen, and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl;
R Y 3 is a radical selected from the group consisting of hydrogen, NH 2 , N(R Y 3a )R Y 3b , NH(C 2 -C 4 -alkylene)-R Y 8 , N(R Y 7 )(C 2 -C 4 -alkylene)-R Y 8 , N(R Y 7 )R Y 9 , N(R Y 7 )CH 2 R Y 9 , a radical R Y 33 , a radical CH 2 R Y 33 and an aromatic radical, selected from phenyl, pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, triazole, 1,3,5-triazine and tetrazole, the aromatic radical being substituted or carrying 1 or 2 substitutens R Y 331 and/or R Y 332 , where
R Y 33 is independently of its respective occurrence a radical selected from the group consisting of the respective individual radicals
where n is independently of its occurrence the integer 1 or 2,
where the aforementioned radicals R 33 may independently of one another in each case have one or two substituents R Y 331 and/or R Y 332 ;
R Y 331 , R Y 332 are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, fluorine, OH, and in each case optionally substituted O—C 1 -C 4 -alkyl, phenyl and C 1 -C 4 -alkyl;
R Y 333 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 3a is a radical selected from the group consisting of hydrogen, and in each case optionally substituted C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 3b is a radical selected from the group consisting of in each case optionally substituted C 1 -C 6 -alkyl and C 1 -C 4 -alkylene-phenyl;
R Y 5 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 4 -alkyl;
R Y A is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 7 is a radical selected from the group consisting of hydrogen and in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl and C 1 -C 4 -alkylene-phenyl;
R Y 8 is a radical selected from the group consisting of OH, NH 2 , and in each case optionally substituted NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 alkyl), NH(C 2 -C 4 -alkylene-OH), N(C 1 -C 4 -alkyl)(C 2 -C 4 -alkylene-OH), NH(C 2 -C 4 -alkylene-O—C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl)(C 2 -C 4 -alkylene-O—C 1 -C 4 -alkyl), NH(C 3 -C 7 -cycloalkyl), N(C 1 -C 4 -alkyl)(C 3 -C 7 -cycloalkyl), NH(C 1 -C 4 haloalkyl), N(C 1 -C 4 -alkyl)(C 1 -C 4 -haloalkyl), O—C 1 -C 4 -alkyl, and the ring radical R Y 81 , where
R Y 81 is a radical independently of its respective occurrence selected from the group consisting of the respective individual radicals
R Y 9 is a 5- or 6-membered heteroaromatic radical having 2, 3, 4 or 5 carbon atom as ring members and 1, 2 or 3 heteroatoms, selected from 0, S and N, wherein the 5- or 6-membered heteroaromatic radical may be unsubstituted or may have one or two substituents R Y 331 and/or R Y 332 ;
the tautomeric, enantiomeric and/or diastereomeric forms thereof, and the physiologically tolerated salts of the aforementioned compound or compounds;
with the proviso that R 1 —H (is not hydrogen) when A 1 =A 2 =hydrogen;
and with the proviso that R 1 is halogen, cyano, or in each case optionally substituted C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl when A 1 =A 2 =hydrogen.
12. The method of claim 11 , wherein the compound of the formula (I) has a binding affinity Ki for the vasopressin V1b receptor subtype of less than about 100 nM.
13. The method of claim 11 , wherein the compound of the formula (I) has a binding affinity Ki for the vasopressin V1b receptor subtype of between about 10 nM and about 100 nM.
14. The method of claim 11 , wherein the compound of the formula (I) has a binding affinity Ki for the vasopressin V1b receptor subtype of less than or equal to about 10 nM.
15. The method of claim 11 , wherein the method comprises administering an effective amount of a compound of formula (I), or of a physiologically tolerated salt thereof, to a subject that is a mammal.