1,5-Benzothiazepines and their use as hypolipidaemics
AssigneeAstraZeneca AB
InventorsIngemar Starke, Mickael Dahlstrom, David Blomberg
Life of this patent
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Abstract
The present invention relates to compounds of formula (I) wherein R1 and R2 are independently selected from C1-6alkyl; one of R4 and R5 is a group of formula (IA): R3, R6, R7, R8, R9, R10 and R11 and the other of R4 and R5 are as defined within, pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and there use as ileal bile acid transport (IBAT) inhibitors for the treatment of hyperlipidaemia. Processes for their manufacture and pharmaceutical compositions containing them are also described.
Claims21
A compound of formula (I):
- 81
- wherein:
- R1and R2 are independently selected from C1-6alkyl;
- one of R4 and R5 is a group of formula (IA):
- 82
- R3 and R6 and the other of R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, N—(C1-4alkyl)amino, N,N—(C1-4alkyl)2amino, C1-4alkanoylamino, N—(C1-4alkyl)carbamoyl, N,N—(C1-4alkyl)2carbamoyl, C1-4alkylS(O)a wherein a is 0 to 2, C1-4alkoxycarbonyl, N—(C1-4alkyl)sulphamoyl and N,N—(C1-4alkyl)2sulphamoyl;
- wherein R3 and R6 and the other of R4 and R5 may be optionally substituted on carbon by one or more R14;
- R7 is carboxy, sulpho, sulphino, phosphono, —P(O)(ORa)(ORb), P(O)(OH)(ORa), —P(O)(OH)(Ra) or P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-6alkyl;
- or R7 is a group of formula (IB):
- 83
- R8 and R9 are independently hydrogen, C1-4alkyl or a saturated cyclic group, or R8 and R9 together form C2-6alkylene;
- wherein R8 and R9 or R8 and R9 together may be independently optionally substituted on carbon by one or more substituents selected from R15;
- and wherein if said saturated cyclic group contains an —NH— moiety, that nitrogen may be optionally substituted by one or more R20;
- R10 is hydrogen or C1-4alkyl;
- wherein R10 is optionally substituted on carbon by one or more substituents selected from R24;
- R11 is hydrogen, C1-4alkyl, carbocyclyl or heterocyclyl;
- wherein R11 is optionally substituted on carbon by one or more substituents selected from R16;
- and wherein if said heterocyclyl contains an —NH— moiety, that nitrogen maybe optionally substituted by one or more R21;
- R12 is hydrogen or C1-4alkyl, carbocyclyl or heterocyclyl;
- wherein R12 is optionally substituted on carbon by one or more substituents selected from R17;
- and wherein if said heterocyclyl contains an —NH— moiety, that nitrogen may be optionally substituted by one or more R22;
- R13 is carboxy, sulpho, sulphino, phosphono, —P(O)(ORc)(ORd), —P(O)(OH)(ORc), —P(O)(OH)(Rc) or —P(O)(ORc)(Rd) wherein Rc and Rd are independently selected from C1-6alkyl;
- m is 1-3;
- wherein the values of R8 and R9 may be the same or different;
- n is 1-3;
- wherein the values of R11 may be the same or different;
- p is 1-3;
- wherein the values of R12 may be the same or different;
- R14 and R16 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, N—(C1-4alkyl)amino, N,N—(C1-4alkyl)2amino, C1-4alkanoylamino, N—(C1-4alkyl)carbamoyl, N,N—(C1-4alkyl)2carbamoyl, C1-4alkylS(O)a wherein a is 0 to 2, C1-4alkoxycarbonyl, N—(C1-4alkyl)sulphamoyl and N,N—(C1-4alkyl)2sulphamoyl;
- wherein R14 and R16 may be independently optionally substituted on carbon by one or more R18;
- R15 and R17 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, N—(C1-4alkyl)amino, N,N—(C1-4alkyl)2amino, C1-4alkanoylamino, N—(C1-4alkyl)carbamoyl, N,N—(C1-4alkyl)2carbamoyl, C1-4alkylS(O)a wherein a is 0 to 2, C1-4alkoxycarbonyl, N—(C1-4alkyl)sulphamoyl and N,N—(C1-4alkyl)2sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, —P(O)(ORe)(ORf), —P(O)(OH)(ORe), —P(O)(OH)(Re) or —P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-6alkyl;
- wherein R15 and R17 may be independently optionally substituted on carbon by one or more R19;
- and wherein if said heterocyclyl contains an —NH— moiety, that nitrogen may be optionally substituted by one or more R23;
- R18, R19 and R25 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;
- R20, R21, R22, R23 and R26 are independently C1-4alkyl, C1-4alkanoyl, C1-4alkylsulphonyl, sulphamoyl, N—(C1-4alkyl)sulphamoyl, N,N—(C1-4alkyl)2sulphamoyl, C1-4alkoxycarbonyl, carbamoyl, N—(C1-4alkyl)carbamoyl, N,N—(C1-4alkyl)2carbamoyl, benzyl, phenethyl, benzoyl, phenylsulphonyl and phenyl;
- R24 is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, N—(C1-4alkyl)amino, N,N—(C1-4allyl)2amino, C1-4alkanoylamino, N—(C1-4alkyl)carbamoyl, N,N—(C1-4alkyl)2carbamoyl, C1-4alkylS(O)a wherein a is 0 to 2, C1-4alkoxycarbonyl, N—(C1-4alkyl)sulphamoyl and N,N—(C1-4alkyl)2sulphamoyl, carbocyclyl, heterocyclyl;
- wherein R24 may be independently optionally substituted on carbon by one or more R25;
- and wherein if said heterocyclyl contains an —NH— moiety, that nitrogen may be optionally substituted by one or more R26;
- or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
A process for preparing a compound of the formula (I) which comprises of:
- Process 1):
- oxidising a benzothiazepine of formula (II):
- 84
- Process 2):
- reacting an alcohol of formula (IIIa) or (IIIb):
- 85
- with a compound of formula (IV):
- 86
- wherein L is a displaceable group;
- Process 3):
- reacting an acid of formula (Va) or (Vb):
- 87
- or an activated derivative thereof;
- with an amine of formula (VI):
- 88
- Process 4):
- for compounds of formula (I) wherein R7 is a group of formula (IB);
- reacting an acid of formula (VIIa) or (VIIb):
- 89
- or an activated derivative thereof;
- with an amine of formula (IX):
- 90
- and thereafter if necessary or desirable:
- i) converting a compound of the formula (I) into another compound of the formula (I);
- ii) removing any protecting groups;
- iii) forming a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug.
A compound of formula (Va), (Vb), (VIIa) or (VIIb) or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof:
- 91
A compound of the formula (Va), (Vb), (VIIa) or (VIIb), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in claim 19 for use as a medicament.
A compound of formula (Va), (Vb), (VIIa) or (VIIb), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in claim 19 for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such as man.
The use of a compound of the formula (Va), (Vb), (VIIa) or (VIIb), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in claim 19 in the manufacture of a medicament for use in the production of an IBAT inhibitory effect in a warm-blooded animal, such as man.
Dependencies are inferred from the claim text.