Granted Patent
B2
US 12,187,690 · App. 18/164,185 · Granted Jan 7, 2025
Benzothiadiazepine compounds and their use as bile acid modulators
Inventors:
Per-Göran Gillberg (Åsbro, SE); Jan Mattsson (Kullavik, SE); Ingemar Starke (Gothenburg, SE); Santosh S. Kulkarni (Bangalore, IN)
Assignee:
Albireo AB
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Abstract
The invention relates to 1,2,5-benzothiadiazepine derivatives of formula (I). These compounds are bile acid modulators having apical sodium-dependent bile acid transporter (ASBT) and/or liver bile acid transport (LBAT) inhibitory activity. The invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases.
Claims (278)
1. A compound of formula (I-b)
or a pharmaceutically acceptable salt thereof,
wherein
R 2 is methyl, ethyl, n-propyl or n-butyl;
R 3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, cyano, trifluoromethyl, methoxy, and trifluoromethoxy;
R 4 is selected from the group consisting of fluoro, chloro, bromo, hydroxy, cyano, methoxy, ethoxy, methylthio, ethylthio and dimethylamino; and
R 5A is selected from the group consisting of hydrogen, halogen, hydroxy, amino and methyl.
2. The compound of claim 1 , wherein R 3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy and methoxy; and
R 4 is selected from the group consisting of fluoro, chloro, bromo, methoxy, ethoxy, methylthio, ethylthio and dimethylamino.
3. The compound of claim 1 , wherein R 2 to R 5A are as indicated in the table below:
TABLE 1
R 2
R 3
R 4
R 5A
CH 3
H
SCH 3
H
CH 3
F
SCH 3
H
CH 3
OCH 3
SCH 3
H
CH 3
OH
SCH 3
H
CH 3
Cl
SCH 3
H
CH 3
H
SCH 3
OH
CH 3
F
SCH 3
OH
CH 3
OCH 3
SCH 3
OH
CH 3
OH
SCH 3
OH
CH 3
Cl
SCH 3
OH
CH 3
H
N(CH 3 ) 2
H
CH 3
F
N(CH 3 ) 2
H
CH 3
OCH 3
N(CH 3 ) 2
H
CH 3
OH
N(CH 3 ) 2
H
CH 3
Cl
N(CH 3 ) 2
H
CH 3
H
N(CH 3 ) 2
OH
CH 3
F
N(CH 3 ) 2
OH
CH 3
OCH 3
N(CH 3 ) 2
OH
CH 3
OH
N(CH 3 ) 2
OH
CH 3
Cl
N(CH 3 ) 2
OH
CH 2 CH 3
H
SCH 3
H
CH 2 CH 3
F
SCH 3
H
CH 2 CH 3
OCH 3
SCH 3
H
CH 2 CH 3
OH
SCH 3
H
CH 2 CH 3
Cl
SCH 3
H
CH 2 CH 3
H
SCH 3
OH
CH 2 CH 3
F
SCH 3
OH
CH 2 CH 3
OCH 3
SCH 3
OH
CH 2 CH 3
OH
SCH 3
OH
CH 2 CH 3
Cl
SCH 3
OH
CH 2 CH 3
H
N(CH 3 ) 2
H
CH 2 CH 3
F
N(CH 3 ) 2
H
CH 2 CH 3
OCH 3
N(CH 3 ) 2
H
CH 2 CH 3
OH
N(CH 3 ) 2
H
CH 2 CH 3
Cl
N(CH 3 ) 2
H
CH 2 CH 3
H
N(CH 3 ) 2
OH
CH 2 CH 3
F
N(CH 3 ) 2
OH
CH 2 CH 3
OCH 3
N(CH 3 ) 2
OH
CH 2 CH 3
OH
N(CH 3 ) 2
OH
CH 2 CH 3
Cl
N(CH 3 ) 2
OH
CH 2 CH 2 CH 2 CH 3
H
SCH 3
H
CH 2 CH 2 CH 2 CH 3
F
SCH 3
H
CH 2 CH 2 CH 2 CH 3
OCH 3
SCH 3
H
CH 2 CH 2 CH 2 CH 3
OH
SCH 3
H
CH 2 CH 2 CH 2 CH 3
Cl
SCH 3
H
CH 2 CH 2 CH 2 CH 3
H
SCH 3
OH
CH 2 CH 2 CH 2 CH 3
F
SCH 3
OH
CH 2 CH 2 CH 2 CH 3
OCH 3
SCH 3
OH
CH 2 CH 2 CH 2 CH 3
OH
SCH 3
OH
CH 2 CH 2 CH 2 CH 3
Cl
SCH 3
OH
CH 2 CH 2 CH 2 CH 3
H
N(CH 3 ) 2
H
CH 2 CH 2 CH 2 CH 3
F
N(CH 3 ) 2
H
CH 2 CH 2 CH 2 CH 3
OCH 3
N(CH 3 ) 2
H
CH 2 CH 2 CH 2 CH 3
OH
N(CH 3 ) 2
H
CH 2 CH 2 CH 2 CH 3
Cl
N(CH 3 ) 2
H
CH 2 CH 2 CH 2 CH 3
H
N(CH 3 ) 2
OH
CH 2 CH 2 CH 2 CH 3
F
N(CH 3 ) 2
OH
CH 2 CH 2 CH 2 CH 3
OCH 3
N(CH 3 ) 2
OH
CH 2 CH 2 CH 2 CH 3
OH
N(CH 3 ) 2
OH
CH 2 CH 2 CH 2 CH 3
Cl
N(CH 3 ) 2
OH
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3 , wherein R 2 is CH 2 CH 3 or CH 2 CH 2 CH 2 CH 3 .
5. The compound of claim 4 , wherein R 2 is CH 2 CH 3 .
6. The compound of claim 4 , wherein R 2 is CH 2 CH 2 CH 2 CH 3 .
7. A compound:
3-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo-1,2,5-thiadiazepin-8-yl)oxy) propanoic acid, or a pharmaceutically acceptable salt thereof.
8. A compound:
(R)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy) propanoic acid, or a pharmaceutically acceptable salt thereof.
9. A compound:
3-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoic acid, or a pharmaceutically acceptable salt thereof.
10. A compound:
(R)-3-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoic acid, or a pharmaceutically acceptable salt thereof.
11. A compound:
3-((3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy) propanoic acid, or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
13. A method for treating a cholestatic liver disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
14. The method according to claim 13 , wherein the cholestatic liver disease or disorder is selected from the group consisting of: primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome (ALGS), biliary atresia, pruritus due to cholestasis, and non-alcoholic steatohepatitis (NASH).
15. The method according to claim 14 , wherein the cholestatic liver disease or disorder is primary biliary cirrhosis (PBC).
16. The method according to claim 14 , wherein the cholestatic liver disease or disorder is primary sclerosing cholangitis (PSC).
17. The method according to claim 14 , wherein the cholestatic liver disease or disorder is pruritus due to cholestasis.
18. The method according to claim 14 , wherein treatment of the cholestatic liver disease or disorder decreases the level of serum bile acids in the subject.
19. The method according to claim 13 , wherein the subject is an adult subject.
20. The method according to claim 13 , wherein the subject is a pediatric subject.
Assignments (12)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: GILLBERG, PER-GÖRAN; MATTSSON, JAN; STARKE, INGEMAR
To: ALBIREO AB
Reel/Frame 066742/0481 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: GILLBERG, PER-GÖRAN; STARKE, INGEMAR; MATTSSON, JAN
To: ALBIREO AB
Reel/Frame 066742/0583 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: GILLBERG, PER-GÖRAN; STARKE, INGEMAR; MATTSSON, JAN
To: ALBIREO AB
Reel/Frame 066742/0716 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: GILLBERG, PER-GÖRAN; MATTSSON, JAN; STARKE, INGEMAR
To: ALBIREO AB
Reel/Frame 066742/0726 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: KULKARNI, SANTOSH S.
To: SYNGENE INTERNATIONAL LTD
Reel/Frame 066742/0765 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: KULKARNI, SANTOSH S.
To: SYNGENE INTERNATIONAL LTD
Reel/Frame 066742/0803 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: KULKARNI, SANTOSH S.
To: SYNGENE INTERNATIONAL LTD
Reel/Frame 066742/0807 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: KULKARNI, SANTOSH S.
To: SYNGENE INTERNATIONAL LTD
Reel/Frame 066742/0837 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: SYNGENE INTERNATIONAL LTD
To: ALBIREO AB
Reel/Frame 066742/0872 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: SYNGENE INTERNATIONAL LTD
To: ALBIREO AB
Reel/Frame 066742/0875 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: SYNGENE INTERNATIONAL LTD
To: ALBIREO AB
Reel/Frame 066742/0951 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 12, 2024
From: SYNGENE INTERNATIONAL LTD
To: ALBIREO AB
Reel/Frame 066742/0954 →
Priority Claims (3)
IN 201911004690
· Feb 6, 2019
· national
SE 1950464-6
· Apr 12, 2019
· national
IN 201911049981
· Dec 4, 2019
· national
Continuity (4)
Continuation
PCTEP2020052942
· Feb 6, 2020
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