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CN-116744935-B - Benzazepine compound, preparation method and medical application thereof

CN116744935BCN 116744935 BCN116744935 BCN 116744935BCN-116744935-B

Abstract

Benzazepine compounds A compound and its preparation method and medicinal application are provided. In particular to a compound shown in a formula II-1 or a formula VIII-1, a pharmaceutical composition containing the compound and medical application thereof. Said benzazepine The compounds can be used for treating diseases related to vasopressin receptors, in particular hypertension, heart diseases and the like.

Inventors

  • ZHU LINGJIAN
  • SHI JIANYU
  • JI CHANGJIN
  • DONG BANGJIE
  • HUANG JIAN

Assignees

  • 上海森辉医药有限公司
  • 上海盛迪医药有限公司
  • 江苏恒瑞医药股份有限公司

Dates

Publication Date
20260512
Application Date
20220210
Priority Date
20210210

Claims (14)

  1. 1. A compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, , Wherein, the Q is Wherein: l 1 is- (CH 2 ) m -, said- (CH 2 ) -optionally being replaced by O; L 2 is- (CH 2 ) n -; m is selected from 0,1, 2, 3; n is selected from 2,3,4, 5; x is selected from O; R 1 is selected from C 1-6 alkyl; R 2 is selected from C 1-6 alkyl; R 3 is selected from C 1-6 alkyl.
  2. 2. The compound of formula II-1 according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is-CH 2 -O-.
  3. 3. The compound of formula II-1 according to claim 1, wherein L 1 is- (CH 2 ) m -, m is 0, or a pharmaceutically acceptable salt thereof.
  4. 4. A compound of formula II-1 according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein L 2 is- (CH 2 ) 2 -.
  5. 5. The compound of formula II-1 according to claim 4, wherein R 1 is selected from C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.
  6. 6. The compound of formula II-1 according to claim 5, wherein R 2 is selected from C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.
  7. 7. A compound of formula II-1 according to claim 5 or 6, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1-3 alkyl.
  8. 8. The compound of formula II-1 or a pharmaceutically acceptable salt thereof according to claim 1, Wherein, the X is O; L 1 is- (CH 2 ) m -, m is 0, or L 1 is-CH 2 -O-; L 2 is- (CH 2 ) n -, n is selected from 2 and 3; R 1 is selected from methyl, ethyl, n-propyl, isopropyl; R 2 is selected from methyl, ethyl, n-propyl, isopropyl; R 3 is selected from methyl, ethyl, n-propyl, isopropyl.
  9. 9. The compound of formula II-1 according to claim 8, wherein R 1 is selected from methyl, R 2 is selected from methyl, and R 3 is selected from methyl, or a pharmaceutically acceptable salt thereof.
  10. 10. A compound of formula II-1 according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , 。
  11. 11. an isotopic substitution of the compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, which isotopic substitution is deuterium atom substitution.
  12. 12. A pharmaceutical composition comprising at least one compound of formula II-1 according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, or an isotopically substituted compound according to claim 11, and a pharmaceutically acceptable excipient.
  13. 13. Use of a compound of formula II-1 according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or an isotopically substituted compound according to claim 11, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the prevention and/or treatment of vasopressin receptor related diseases.
  14. 14. Use of a compound of formula II-1 according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or an isotopic substitution according to claim 11, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the prevention and/or treatment of oedema, ascites, heart failure, renal dysfunction, vasopressin abnormal secretion syndrome, hyponatremia.

Description

Benzazepine compound, preparation method and medical application thereof Technical Field The present disclosure relates to a benzazepine, which belongs to the field of medicineA method for preparing the same, a composition and medical application. Background Vasopressin is a nine peptide hormone secreted primarily by the posterior pituitary gland that acts via the vascular V l receptor and the renal V 2 receptor subtype. The V 2 receptor present in the kidney stimulates adenylate cyclase to achieve a urine-producing effect. The vasopressin receptor antagonist has very wide application, and can be used for treating diseases such as hypertension, congestive heart failure, liver cirrhosis, renal failure, cerebral edema and the like. Benzazepine compoundsClass is a class of small molecule vasopressin V 2 receptor antagonists, tolvaptan (Tolvaptan) is the first such compound to be marketed. Tolvaptan inhibits the binding of vasopressin to the receptor of the manifold V 2, so that aquaporin-2 cannot migrate to the surface of the cell membrane, inhibits urine concentration, increases free water drainage without sodium drainage, and achieves the diuretic effect (J Clin Med,2014,3 (4): 1276-1290). In animal experiments, tolvaptan has diuretic effect on rats and dogs, and compared with furan aniline, can significantly increase the clearance of electrolyte and water, and increase the concentration of sodium ions (Circulation, 2003,107,690-2696). The other two clinical experiments in patients with hyponatremia caused by Congestive Heart Failure (CHF) and liver cirrhosis show that the compound has good tolerance, can quickly and effectively raise the concentration of sodium ions in serum, has no side effects such as dry mouth, thirst feeling and the like, and does not need to limit water intake. Is suitable for clinically significant hypervolemic hyponatremia and normvolemic hyponatremia, including heart failure, liver cirrhosis and antidiuretic hormone secretion disorder Syndrome (SIADH) (J.sinensis, 2010,19 (10): 819-822). Tolvaptan is a known compound, which has been disclosed in U.S. patent No. 5,258,510, the structure of which is shown below: However, administration is limited due to its low water solubility, insufficient intestinal absorption, and the like. WO2009001968A discloses that it can be used as a blood vessel vasopressin antagonists is a benzazepine of (2) The derivatives of tolvaptan are studied. In addition, CN101346390a discloses a novel phosphate derivative of tolvaptan, useful for improving its water solubility. Disclosure of Invention In one aspect, the present disclosure provides a compound of formula I-1 or a pharmaceutically acceptable salt thereof, Wherein: Is an amino acid residue, or R 1 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl are optionally substituted with A; R 2 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl are optionally substituted with A; Or R 1 and R 2 together with the N atom to which they are attached form a 3-to 12-membered heterocyclic group containing 1 to 3 heteroatoms, said 3-to 12-membered heterocyclic group being optionally further substituted with A; A is selected from H, -COOH, -NH 2, -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, said-NH 2、C1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl optionally being substituted with R 4; R 4 is selected from halogen, -NH 2、-OH、C1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl. In an alternative embodiment, the present disclosure provides a compound of formula I-1, or a pharmaceutically acceptable salt thereof, wherein,Is an amino acid residue selected from the group consisting of alanine, arginine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, glycine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, valine. In an alternative embodiment, the present disclosure provides a compound of formula I-1, or a pharmaceutically acceptable salt thereof, wherein,Is an amino acid residue, and the amino acid residue is glutamic acid. In alternative embodiments, the present disclosure provides compounds of formula I-1, or pharmaceutically acceptable salts thereof, wherein R 1 and R 2 together with the N atom to which they are attached form a 3-8 membered heterocyclyl containing 1-3 heteroatoms, the 3-8 membered heterocyclyl optionally being substituted with A, A being selected from H, -COOH, -NH 2, -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, the-NH 2、C1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl optionally being substituted with R 4, and R 4 being selected from halogen, -NH 2、-OH、C1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl. In alternative embodiments, the present disclosure provides compounds of f