US2015218146A1PendingUtilityA1
Substituted oxindole derivatives, medicaments containing said derivatives and use thereof
Est. expiryDec 2, 2025(expired)· nominal 20-yr term from priority
Inventors:Thorsten OostWilfried LubischWolfgang WernetWilfried HornbergerLiliane UngerHervé GenesteAstrid Netz
A61P 7/04A61P 7/00A61P 9/00A61P 7/10A61P 7/02A61P 7/12A61P 43/00A61P 9/10A61P 25/20A61P 3/10A61P 25/02A61P 25/24A61P 25/18A61P 25/28A61P 25/22A61P 25/00A61P 25/30A61K 31/427A61K 31/422A61P 13/02A61K 31/496C07D 413/12C07D 417/12A61K 31/454A61P 1/00A61P 11/00A61K 31/4525C07D 401/14A61K 31/551A61P 13/00C07D 413/14C07D 417/14A61K 31/4439A61K 31/5377A61P 1/04C07D 401/12A61P 1/08A61P 1/16A61P 21/02A61P 13/12A61P 13/06
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Claims
Abstract
The invention relates to novel oxindole derivatives of general formula (I), wherein the substituents R 1 , R 2 , A, B, and Y are defined as in Claim 1 . The invention further relates to medicaments containing said derivatives, and use thereof for the prevention and/or treatment of vasopressin-dependent diseases.
Claims
exact text as granted — not AI-modified1 . Compound of general formula (I)
wherein
A is an aromatic, heteroaromatic, partially aromatic, or partially heteroaromatic mono- or bicyclic ring containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms as ring members, and the ring may also contain as ring members 0, 1, 2, 3, or 4 heteroatoms which are the same or different, independently selected from the group comprising nitrogen, oxygen, and sulfur, and which is substituted with the R A 1 radical and which may also be substituted with one, two, or three R A 11 , R A 12 , and/or R A 13 radicals which, independently of one another and independently of their respective occurrence, are selected from the group comprising bromine, chlorine, fluorine, CN, CF 3 , OCF 3 , OCHF 2 , OH, O—C 1 -C 4 alkyl, and C 1 -C 4 alkyl;
R A 1 is selected from the group comprising
C 1 -C 4 alkylene-R A 2 , C 0 -C 3 alkylene-O—C 2 -C 4 alkylene-R A 2 , or C 0 -C 3 alkylene-NR A 3 -C 2 -C 4 alkylene-R A 2 ;
R A 3 is selected from the group comprising hydrogen and C 1 -C 4 alkyl;
R A 2 is selected from the group comprising
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 3 -C 7 cycloalkyl), NH(C 1 -C 4 haloalkyl), N(C 1 -C 4 alkyl)(C 1 -C 4 haloalkyl), and ring R A 4 ;
R A 4 independently of its respective occurrence is selected from the group comprising the particular individual radicals
R A 5 is selected from the group comprising hydrogen, hydroxy, and optionally substituted C 1 -C 4 alkyl;
B is an aromatic, heteroaromatic, partially aromatic, or partially heteroaromatic mono- or bicyclic ring containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 C atoms as ring members, and the ring may also contain as ring members 0, 1, 2, 3, or 4 heteroatoms which are the same or different, independently selected from the group comprising nitrogen, oxygen, and sulfur, and may be substituted with one, two, or three radicals R B 1 , R B 2 , and/or R B 3 which, independently of one another and independently of their respective occurrence, are selected from the group comprising chlorine, bromine, fluorine, CN, CF 3 , OCF 3 , OCHF 2 , OH, O—C 1 -C 4 alkyl, and C 1 -C 4 alkyl;
R 1 is selected from the group comprising 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, and C 2 -C 4 alkynyl;
R 2 is selected from the group comprising hydrogen, C 1 -C 4 alkyl, O—C 1 -C 4 alkyl, chlorine, fluorine, and trifluoromethyl;
Y stands for a radical
wherein
R Y 1 is selected from the group comprising hydrogen and C 1 -C 4 alkyl; and
R Y 2 is selected from the group comprising hydrogen, phenyl, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl,
wherein R Y 1 and R Y 2 combined, together with the atom to which they are bonded, may also form a 4-, 5-, 6-, or 7-membered saturated or unsaturated carbocyclic ring containing a nitrogen atom, and the ring may contain one or two substituents R Y 6 and/or R Y 7 which, independently of one another and independently of their respective occurrence, are selected from the group comprising fluorine, OH, O—C 1 -C 4 alkyl, phenyl, and C 1 -C 4 alkyl; or when R Y 6 and R Y 7 occupy adjacent positions, R Y 1 and R Y 2 together with the respective C atom to which they are bonded may form a condensed substituted or unsubstituted benzene ring;
R Y 3 is selected from the group comprising hydrogen and methyl;
R Y 4 is a saturated, partially saturated, or unsaturated ring containing 1, 2, 3, 4, 5, or 6 C atoms as ring members, and the ring may also contain as ring members 1, 2, 3, or 4 heteroatoms which are the same or different, independently selected from the group comprising nitrogen, oxygen, and sulfur, and which may be substituted with one or two radicals R Y 8 and/or R Y 9 , where R Y 8 and R Y 9 independently of one another and independently of their respective occurrence are selected from the group comprising chlorine, bromine, fluorine, CN, OH, O—C 1 -C 4 alkyl, and C 1 -C 4 alkyl;
and tautomeric forms, prodrugs, and physiologically tolerable salts of the referenced compounds of general formula (I).
2 . Compound of general formula (I) according to claim 1 , wherein
A is a ring selected from the group comprising benzene, benzo[1,3]dioxol, thiophene, and pyridine, and is substituted with the R A 1 radical and may also be substituted with one or two R A 11 and/or R A 12 radicals which independently of one another and independently of their respective occurrence are selected from the group comprising chlorine, fluorine, hydroxy, methoxy, ethoxy, propoxy, methyl, ethyl, and propyl; R A 1 is selected from the group comprising C 1 -C 4 alkylene-R A 2 , O—C 2 -C 4 alkylene-R A 2 , NR A 3 -C 2 -C 4 alkylene-R A 2 , and CH 2 —NR A 3 -C 2 -C 4 alkylene-R A 2 ; R A 3 is selected from the group comprising hydrogen and C 1 -C 4 alkyl; R A 2 is selected from the group comprising
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), and ring R A 4 ;
R A 4 independently of its respective occurrence is selected from the group comprising the particular individual radicals
R A 5 is selected from the group comprising hydrogen and C 1 -C 4 alkyl;
B is an aromatic or heteroaromatic mono- or bicyclic ring containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 C atoms as ring members, and the ring may also contain as ring members 0, 1, 2, 3, or 4 heteroatoms which are the same or different, independently selected from the group comprising nitrogen, oxygen, and sulfur, and may be substituted with one or two radicals R B 1 and/or R B 2 , wherein R B 1 and R B 2 are independently selected from the group comprising chlorine, fluorine, CN, OH, O—C 1 -C 4 alkyl, and C 1 -C 4 alkyl;
R 1 is selected from the group comprising hydrogen, chlorine, fluorine, CN, methoxy, and methyl;
R 2 is selected from the group comprising hydrogen, chlorine, fluorine, and methyl;
Y stands for a radical
wherein
R Y 1 is selected from the group comprising hydrogen and C 1 -C 4 alkyl; and
R Y 2 is selected from the group comprising hydrogen, phenyl, and C 1 -C 4 alkyl;
wherein R Y 1 and R Y 2 combined, together with the respective atom to which they are bonded, may also form a 5- or 6-membered saturated or unsaturated carbocyclic ring containing a nitrogen atom, and the ring may contain a substituent R Y 6 selected from the group comprising C 1 -C 4 alkyl, O—C 1 -C 4 alkyl, fluorine, and OH;
R Y 3 is hydrogen;
R Y 4 is a 5-membered or 6-membered heteroaromatic ring containing 1, 2, 3, 4, or 5 C atoms as ring members, and the ring may also contain as ring members 1, 2, 3, or 4 heteroatoms which are the same or different, and which are independently selected from the group comprising nitrogen, oxygen and sulfur, and may optionally be substituted with a R Y 8 radical, wherein R Y 8 , independently of its occurrence, is selected from the group comprising C 1 -C 4 alkyl;
and tautomeric forms, prodrugs, and physiologically tolerable salts of the referenced compounds of general formula (I).
3 . Compound of general formula (I) according to claim 1 or 2 , wherein
A is a benzene ring which is substituted with the R A 1 radical and which may also be substituted with an R A 11 radical;
R A 11 is selected from the group comprising chlorine, fluorine, methoxy, ethoxy, propoxy, methyl, and ethyl;
R A 1 is a radical selected from the group comprising the particular individual radicals
B is a ring selected from the group comprising benzene, pyridine, thiophene, and quinoline, and the ring may be substituted in each case with one or two radicals R B 1 and/or R B 2 , wherein R B 1 and R B 2 are independently selected from the group comprising chlorine, fluorine, CN, methyl, ethyl, hydroxy, methoxy, and ethoxy;
R 1 is selected from the group comprising hydrogen, chlorine, fluorine, CN, methoxy, and methyl;
R 2 is selected from the group comprising hydrogen, chlorine, and fluorine;
Y is a radical selected from the group comprising the particular individual radicals
R Y 4 is a radical selected from the group comprising 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, and tetrazole;
R Y 6′ is selected from the group comprising the radicals hydrogen, fluorine, and OH;
and tautomeric forms, prodrugs, and physiologically tolerable salts of the referenced compounds of general formula (I).
4 . Compound of general formula (I) according to one of claims 1 through 3 , wherein
A is selected from the group comprising the particular individual radicals
R A 1 is a radical selected from the group comprising the particular individual radicals
B is a ring selected from the group comprising the particular individual radicals
wherein
R B 1 and R B 2 , independently of one another and independently of their respective occurrence, are selected from the group comprising hydrogen, chlorine, fluorine, CN, methyl, ethyl, methoxy, and ethoxy;
R 1 is selected from the group comprising chlorine, fluorine, methoxy, and CN;
R 2 is selected from the group comprising hydrogen, chlorine, and fluorine;
Y is selected from the group comprising the particular individual radicals
R Y 4 is selected from the group comprising the particular individual radicals
and tautomeric forms, prodrugs, and physiologically tolerable salts of the referenced compounds of general formula (I).
5 . Compound of general formula (I) according to one of claims 1 through 4 , wherein
A is a radical selected from the group comprising the particular individual radicals
R A 1 is a radical selected from the group comprising the particular individual radicals
B is a radical selected from the group comprising the particular individual radicals
R 1 is selected from the group comprising chlorine, fluorine, and CN;
R 2 is selected from the group comprising hydrogen, chlorine, and fluorine;
Y is a radical selected from the group comprising the particular individual radicals
and tautomeric forms, prodrugs, and physiologically tolerable salts of the referenced compounds of general formula (I).
6 . Compound of general formula (I) according to one of claims 1 through 5 , wherein
A is a radical selected from the group comprising′ the particular individual radicals
R A 1 is a radical selected from the group comprising the particular individual radicals
B stands for a radical
R 1 is selected from the group comprising chlorine and CN;
R 2 is selected from the group comprising hydrogen and chlorine;
Y is a radical selected from the group comprising the particular individual radicals
and tautomeric forms, prodrugs, and physiologically tolerable salts of the referenced compounds of general formula (I).
7 . Compound of general formula (I) according to one of claims 1 through 6 , wherein the radicals A, B, Y, R 1 , and R 2 in each case independently have one of the meanings stated in claims 1 through 6 , and wherein the R 2 radical is bonded at the 6-position of the oxindole ring structure.
8 . Compound of general formula (I) according to one of claims 1 through 7 , wherein the radicals A, B, Y, R 1 , and R 2 in each case independently have one of the meanings stated in claims 1 through 6 , and wherein the R 1 and R 2 radicals have the following meanings:
1) R 1 ═Cl or CN, and R 2 ═H;
or
2) R 1 ═Cl, and R 2 =6-Cl;
and tautomeric forms, prodrugs, and physiologically tolerable salts of the referenced compounds of general formula (I).
9 . Compound of general formula (I) according to claim 1 , wherein the radicals A, B, R 1 , and R 2 in each case independently have one of the meanings stated in claims 1 through 8 , and
Y stands for the radical
and tautomeric forms, prodrugs, and physiologically tolerable salts of the referenced compounds of general formula (I).
10 . Compound of general formula (I) according to claim 1 , wherein the radicals A, B, R 1 , and R 2 in each case independently have one of the meanings stated in claims 1 through 8 , and
Y stands for the radical
and tautomeric forms, prodrugs, and physiologically tolerable salts of the referenced compounds of general formula (I).
11 . Compound of general formula (I) according to claim 1 , wherein the radicals A, B, R 1 , and R 2 in each case independently have one of the meanings stated in claims 1 through 8 , and
Y stands for the radical
and tautomeric forms, prodrugs, and physiologically tolerable salts of the referenced compounds of general formula (I).
12 . Compound of general formula (I) according to claim 1 , wherein the radicals A, B, R 1 , and R 2 in each case independently have one of the meanings stated in claims 1 through 8 , and
Y stands for the radical
and tautomeric forms, prodrugs, and physiologically tolerable salts of the referenced compounds of general formula (I).
13 . Compound of general formula (I.a)
wherein the radicals R 1 , R 2 , R A 2 , R A 11 , R B 1 , R Y 1 , and R Y 2 have one of the meanings stated in claims 1 through 12 , and X stands for O or S; and tautomeric forms, prodrugs, and physiologically tolerable salts of compounds of formula (I.a).
14 . Compound of general formula (I) or (I.a) according to one of claims 1 through 13 , wherein the Y radical on the C atom bearing the R Y 4 radical has the S configuration, and the carbon atom in the 3-position on the oxindol-2-one structure has either the R or the S configuration.
15 . Compound of general formula (I) or (I.a) according to one of claims 1 through 14 , wherein the compound is present in the form of the levorotatory stereoisomer with respect to the free base.
16 . Compound of general formula (I) or (I.a) according to one of claims 1 through 15 , wherein the compounds have a binding affinity Ki for the vasopressin receptor subtype V1b of less than approximately 100 nM, preferably between approximately 10 nM and approximately 100 nM, particularly preferably less than or equal to approximately 10 nM.
17 . Compound of general formula (I) or (I.a) according to one of claims 1 through 16 for use as a medicament.
18 . Medicament containing at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
19 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment and/or prevention of at least one vasopressin-dependent disease, and/or for producing a medicament for the treatment and/or prevention of at least one vasopressin-dependent disease.
20 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment and/or prevention of at least one disease selected from the group comprising diabetes insipidus, enuresis nocturna, incontinence, diseases characterized by blood clotting abnormalities, and/or for delaying urination, and/or for producing a medicament for the treatment and/or prevention of at least one of the referenced diseases.
21 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment and/or prevention of at least one disease selected from the group comprising hypertonia, pulmonary hypertonia, cardiac insufficiency, myocardial infarction, coronary spasm, unstable angina, percutaneous transluminal coronary angioplasty (PTCA), cardiac ischemia, disorders of the renal system, edema, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, disorders of the gastrointestinal tract, gastric vasospasm, cirrhosis of the liver, ulcers of the stomach and intestine, emesis, emesis occurring during chemotherapy, and/or travel sickness, and/or for producing a medicament for the treatment and/or prevention of at least one of the referenced diseases.
22 . Use of at least one compound of general formula (I) or (La) according to one of claims 1 through 16 for the treatment of affective disorders, and/or for producing a medicament for the treatment of affective disorders.
23 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment of anxiety disorders and/or stress-related anxiety disorders, and/or for producing a medicament for the treatment of anxiety disorders and/or stress-related anxiety disorders.
24 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment of memory disorders and/or Alzheimer's disease, and/or for producing a medicament for the treatment of memory disorders and/or Alzheimer's disease.
25 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment of psychoses and/or psychotic disorders, and/or for producing a medicament for the treatment of psychoses and/or psychotic disorders.
26 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment of Cushing's syndrome or other stress-related diseases, and/or for producing a medicament for the treatment of Cushing's syndrome or other stress-related diseases.
27 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment of sleep disorders, and/or for producing a medicament for the treatment of sleep disorders.
28 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment of depressive conditions, and/or for producing a medicament for the treatment of depressive conditions.
29 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment of vasomotor symptoms and/or thermoregulatory malfunctions, such as “hot flush” symptoms, for example.
30 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment and/or prevention of dependencies caused by drugs, medicaments, and/or other factors, for the treatment and/or prevention of stress resulting from withdrawal from one or more of the dependency-causing factors, and/or for the treatment and/or prevention of stress-induced relapse into the dependencies caused by drugs, medicaments, and/or other factors.
31 . Use of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 for the treatment and/or prevention of schizophrenia and/or psychosis.
32 . Method for the treatment and/or prevention of at least one condition selected from the group comprising diabetes insipidus, enuresis nocturna, incontinence, diseases characterized by blood clotting abnormalities, and/or for delaying urination, in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
33 . Method for the treatment and/or prevention of at least one condition selected from the group comprising hypertonia, pulmonary hypertonia, cardiac insufficiency, myocardial infarction, coronary spasm, unstable angina, percutaneous transluminal coronary angioplasty (PTCA), cardiac ischemia, disorders of the renal system, edema, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, disorders of the gastrointestinal tract, gastric vasospasm, cirrhosis of the liver, ulcers of the stomach and intestine, emesis, emesis occurring during chemotherapy, and/or travel sickness in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
34 . Method for the treatment and/or prevention of affective disorders in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
35 . Method for the treatment of anxiety disorders and/or stress-related anxiety disorders in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
36 . Method for the treatment of memory disorders and/or Alzheimer's disease in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
37 . Method for the treatment of psychoses and/or psychotic disorders in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
38 . Method for the treatment of Cushing's syndrome in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
39 . Method for the treatment of sleep disorders in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
40 . Method for the treatment of depressive conditions in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
41 . Method for the treatment and/or prevention of vasomotor symptoms and/or thermoregulatory malfunctions, such as “hot flush” symptoms, for example, in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
42 . Method for the treatment and/or prevention of dependencies caused by drugs, medicaments, and/or other factors, for the treatment and/or prevention of stress resulting from withdrawal from one or more of the dependency-causing factors, and/or for the treatment and/or prevention of stress-induced relapse into the dependencies caused by drugs, medicaments, and/or other factors, in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
43 . Method for the treatment and/or prevention of schizophrenia and/or psychosis in a patient, characterized in that the patient is administered an effective quantity of at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 .
44 . Method according to one of claims 19 through 43 , characterized in that the patient is a mammal, preferably a human being or a nonhuman mammal or a nonhuman transgenic mammal.
45 . Method for preparing at least one compound of general formula (I) or (I.a) according to one of claims 1 through 16 , characterized in that said compound may be prepared by a competent person skilled in the art and having knowledge of the technical teaching of the invention for carrying out and/or analogously carrying out method steps known as such.Join the waitlist — get patent alerts
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