Benzazepine compounds, preparation method therefor and pharmaceutical use thereof
Benzazepine compounds, a preparation method therefor and pharmaceutical use thereof. Specifically, the present invention relates to a compound represented by formula II-1 or formula VIII-1, a pharmaceutical composition containing same, and pharmaceutical use thereof. The benzazepine compounds can be used for treating diseases associated with vasopressin receptors, in particular hypertension, heart disease, etc.
1 . A compound of formula II-1 or a pharmaceutically acceptable salt thereof,
wherein,
Q is
wherein:
L 1 is —(CH 2 ) m —, and the —(CH 2 )— is optionally replaced by a heteroatom selected from the group consisting of O, S and N;
L 2 is —(CH 2 ) n —, and the —(CH 2 )— is optionally replaced by a heteroatom selected from the group consisting of O, S and N;
m is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6;
n is selected from the group consisting of 1, 2, 3, 4, 5 and 6;
the —(CH 2 )— of L 2 is optionally substituted with A;
X is selected from the group consisting of O and S;
R 1 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl and 3-12 membered heterocyclyl; the C 1-6 alkyl, C 3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with group B;
R 2 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl and 3-12 membered heterocyclyl; the C 1-6 alkyl, C 3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with group B;
R 3 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl and 3-12 membered heterocyclyl; the C 1-6 alkyl, C 3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with group B;
or R 1 and R 2 or R 2 and R 3 , together with the N atom to which they are attached, form a 3-12 membered heterocyclyl group containing 1-3 heteroatoms; the 3-12 membered heterocyclyl group is optionally substituted with group B;
A is selected from the group consisting of H, —COOH, —NH 2 , —OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, —COR 4 , —NHCOR 4 and —OCOR 4 ; the —NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with R 4 ;
R 4 is selected from the group consisting of halogen, —NH 2 , —OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-12 membered heterocyclyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with one or more groups selected from the group consisting of —COOH, —NH 2 , —OH, halogen, cyano, nitro, oxo, C 1-6 alkyl and C 1-6 alkoxy;
group B is selected from the group consisting of H, —COOH, —NH 2 , —OH, halogen, cyano, nitro and oxo.
2 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 1 , wherein X is O.
3 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 2 , wherein n is selected from the group consisting of 2, 3, 4 and 5.
4 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 2 , wherein m is selected from the group consisting of 0, 1, 2, 3, 4 and 5.
5 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 2 , wherein A is selected from the group consisting of H, —COOH, —NH 2 , —OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-12 membered heterocyclyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with R 4 ;
R 4 is selected from the group consisting of halogen, —NH 2 , —OH and C 1-6 alkyl.
6 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 5 , wherein L 1 is —CH 2 —O—, or L 1 is —(CH 2 ) m —, and m is 0.
7 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 6 , wherein L 2 is —(CH 2 ) 2 —.
8 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 7 , wherein R 1 is C 1-3 alkyl.
9 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 8 , wherein R 2 is C 1-3 alkyl.
10 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 8 , wherein R 3 is C 1-3 alkyl.
11 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 1 ,
wherein,
X is O;
L 1 is —(CH 2 ) m —, and m is 0; or L 1 is —CH 2 —O—;
L 2 is —(CH 2 ) n —, and n is selected from the group consisting of 2 and 3;
R 1 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl;
R 2 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl; and
R 3 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.
12 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 11 , wherein the compound is selected from the group consisting of:
13 . An isotopically substituted form of the compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the isotopic substitution is a substitution with a deuterium atom.
14 . A pharmaceutical composition comprising at least one compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient.
15 . A method for treating hypertension, edema, abdominal dropsy, heart failure, renal dysfunction, syndrome of inappropriate vasopressin secretion, cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory insufficiency, polycystic kidney disease, cerebral infarction or myocardial infarction in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 14 .
16 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 3 , wherein n is selected from the group consisting of 2 and 3.
17 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 4 , wherein m is selected from the group consisting of 0, 1, 2 and 3.
18 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 5 , wherein A is selected from the group consisting of H, —COOH, —NH 2 , —OH, halogen, cyano and nitro.
19 . The compound of formula II-1 or the pharmaceutically acceptable salt thereof according to claim 11 ,
wherein,
R 1 is methyl, R 2 is methyl, and R 3 is methyl.