Claims for Patent: 7,132,416

Summary for Patent: 7,132,416

Title:	Benzothiazepine and benzothiazepine derivatives with ileal bile acid transport (IBAT) inhibotory activity for the treatment hyperlipidaemia
Abstract:	The present invention relates to compounds of formula (I) wherein Rv, R1, R2, Rx, Ry, M, Rz, v, R3, R4, R5 and R6 are as defined within; pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their 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.
Inventor(s):	Ingemar Starke, Mikael Ulf Johan Dahlstrom, David Blomberg, Suzanne Alenfalk, Tore Skjaret, Malin Lemurell
Assignee:	Kreos Capital IV UK Ltd
Application Number:	US10/488,870
Patent Claims:	1. A compound of formula (I): wherein: Rv is selected from hydrogen or C1-6alkyl; One of R1 and R2 are selected from hydrogen, C1-6alkyl or C2-6alkenyl and the other is selected from C1-6alkyl or C2-6alkenyl; Rx and Ry are independently selected from hydrogen, hydroxy, amino, mercapto, C1-6alkyl, C1-6alkoxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkylS(O)a wherein a is 0 to 2; M is selected from —N— or —CH—; Rz is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl and N,N-(C1-6alkyl)2sulphamoyl; v is 0–5; one of R4 and R5 is a group of formula (IA): 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 R16; X is —O—, —N(Ra)—, —S(O)b— or —CH(Ra)—; wherein Ra is hydrogen or C1-6alkyl and b is 0–2; Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R17; R7 is hydrogen, C1-4alkyl, carbocyclyl or heterocyclyl; wherein R7 is optionally substituted by one or more substituents selected from R18; R8 is hydrogen or C1-4alkyl; R9 is hydrogen or C1-4alkyl; R10 is hydrogen, C1-4alkyl, carbocyclyl or heterocyclyl; wherein R10 is optionally substituted by one or more substituents selected from R19; R11 is carboxy, sulpho, sulphino, phosphono, —P(O)(ORc)(ORd), —P(O)(OH)(ORc), —P(O)(OH)(Rd) or —P(O)(ORc)(Rd) wherein Rc and Rd are independently selected from C1-6allkyl; or R11 is a group of formula (IB) or (IC): R19, R20, R24 and R26 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, N,N-(C1-4alkyl)2sulphamoyl, carbocyclyl, heterocyclyl, benzyloxycarbonylamino, (C1-4alkyl)3silyl, sulpho, sulphino, amidino, 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; wherein R19, R20, R24 and R26 may be independently optionally substituted on carbon by one or more R22; R21 and R22 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, tifluoromethoxy, 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; R23 is carboxy, sulpho, sulphino, phosphono, —P(O)(ORg)(ORh), —P(O)(OH)(ORg), —P(O)(OH)(Rg) or —P(O)(ORg)(Rh) wherein Rg and Rh are independently selected from C1-6alkyl; R25 is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein “heteroaryl” is a totally unsaturated, mono or bicyclic ring containing 3–12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked; wherein a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3–12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a CH2 group can optionally be replaced by a C(O) or a ring sulphur atom may be optionally oxidised to form the S oxides; and wherein a “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3–12 atoms; wherein a CH2 group can optionally be replaced by a C(O); or a pharmaceutically acceptable salt thereof. 2. A compound of formula (I) as claimed in claim 1 wherein Rv is hydrogen or a pharmaceutically acceptable salt thereof. 3. A compound of formula (I) as claimed in claim 1 wherein R1 and R2 are both butyl or a pharmaceutically acceptable salt thereof. 4. A compound of formula (I) as claimed in claim 1 wherein Rx and Ry are both hydrogen or a pharmaceutically acceptable salt thereof. 5. A compound of formula (I) as claimed in claim 1 wherein M is —N— or a pharmaceutically acceptable salt thereof. 6. A compound of formula (I) as claimed in claim 1 wherein v is 0 or a pharmaceutically acceptable salt thereof. 7. A compound of formula (I) as claimed in claim 1 wherein R3 and R6 are hydrogen or a pharmaceutically acceptable salt thereof. 8. A compound of formula (I) as claimed in claim 1 wherein R4 is bromo, methyl or methylthio or a pharmaceutically acceptable salt thereof. 9. A compound of formula (I) as claimed in claim 1 wherein R5 is a group of formula (IA) (as depicted in claim 1) wherein: X is —O—; Ring A is phenyl optionally substituted by one or more substituents selected from R17; n is 1; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; m is 0; R11 is carboxy, a group of formula (IB) (as depicted above) or a group of formula (IC) (as depicted above) wherein: R12 is hydrogen or C1-4alkyl; p is 1 or 2; R13 is hydrogen or C1-6alkyl optionally substituted by R20 wherein R20 is hydroxy, carbamoyl, amino, benzyloxycarbonylamino, C1-4alkylS(O)a wherein a is 0 or (C1-4alkyl)3silyl; R14 is hydrogen or hydroxy or C1-6alkyl; wherein R14 may be optionally substituted by one or more substituents selected from R20; Y is —N(Rn)C(O)— wherein Rn is hydrogen; q is 0 or 1; r is 0 or 1; R15 is carboxy or sulpho; R17 is hydroxy; and R20 is selected from hydroxy; Ring B is pyrrolidin-1-yl or azetidinyl substituted on carbon by one group selected from R23, and optionally additionally substituted on carbon by one or more R24; wherein R23 is carboxy and R24 is hydroxy; or a pharmaceutically acceptable salt thereof. 10. A compound of formula (I) as claimed in claim 1 wherein: Rv is hydrogen; R1 and R2 are both butyl; Rx and Ry are both hydrogen; M is —N—; v is 0; R3 and R6 are hydrogen; R4 is bromo, methyl or methylthio; and R5 is N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxyethyl) carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxy-2-carbamoyl-ethyl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-{(R)-α-[N-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxy-3 -methylbutyl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-(1-(S)-1-carboxy-2-(S)-2-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy, N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxy-4-aminobutyl)carbamoyl]benzyl}carbamoylmethoxy, N-((R)-α-{N-[(S)-1-carboxy-4-(benzyloxycarbonylamino)butyl]carbamoyl}benzyl)carbamoylmethoxy, N-[(R)-α-((S)-2-carboxypyrrolidin-1-ylcarbonyl)benzyl]carbamoylmethoxy, N-{(R)-α-[N-(carboxymethyl)-N-methylcarbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-(1-(R)-2-(R)-1-carboxy-1-hydroxyprop-2-yl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-(sulphomethyl)carbamoyl]benzyl}carbamoylmethoxy, N-((R)-α-carboxybenzyl)carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[2-(S)-2-(carboxy)-4-(R)-4-(hydroxy)pyrrolidin-1-ylcarbonyl]benzyl}carbamoylmethoxy, N-{(R)-α-[2-(S)-2-(carboxy)azetidin-1-ylcarbonyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-{(S)-1-[N-((S)-1-carboxyethyl)carbamoyl]ethyl}carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-((R)-1-carboxy-3,3-dimethylbutyl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-((S)-1-carboxy-3,3-dimethylbutyl)carbamoyl]benzyl}carbamoylmethoxy, N-{(R)-α-[N-((R)-1-carboxy-3,3-dimethylbutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy, N-((R)-α-{N-[(S)-1-carboxy-2-(trimethylsilyl)ethyl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy or N-((R)-α-{N-[(R)-1-carboxy-2-(trimethylsilyl)ethyl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy; or a pharmaceutically acceptable salt thereof. 11. A compound of formula (I) as claimed in claim 1 selected from: 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; and 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; or a pharmaceutically acceptable salt thereof. 12. A process for preparing a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof which process comprises of: Process 1): for compounds of formula (I) wherein X is —O—, —NRa or —S—; reacting a compound of formula (IIa) or (IIb): with a compound of formula (III): wherein L is a displaceable group; Process 2): reacting an acid of formula (IVa) or (IVb): or an activated derivative thereof; with an amine of formula (V): Process 3): for compounds of formula (I) wherein R11 is a group of formula (IB); reacting a compound of formula (I) wherein R11 is carboxy with an amine of formula (VI): Process 4) for compounds of formula (I) wherein one of R4 and R5 are independently selected from C1-6alkylthio optionally substituted on carbon by one or more R17; reacting a compound of formula (VIIa) or (VIlb): wherein L is a displaceable group; with a thiol of formula (VIII): Rm—H (VIII) wherein Rm is C1-6alkylthio optionally substituted on carbon by one or more R16; Process 5): for compounds of formula (I) wherein R11 is carboxy, deprotecting a compound of formula (IXa): wherein Rp together with the —OC(O)— group to which it is attached forms an ester; Process 6): for compounds of formula (I) wherein R11 is a group of formula (IB) and R15 is carboxy, deprotecting a compound of formula (Xa): wherein Rp together with the —OC(O)— group to which it is attached forms an ester; or Process 7): for compounds of formula (I) wherein R11 is a group of formula (IB) and N(Rn)C(O)—; reacting an acid of formula (XIa): or an activated derivative thereof; with an amine of formula (XII): 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. 13. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, in association with a pharmaceutically-acceptable diluent or carrier. 14. A compound selected from the group consisting of: 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; and 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; or a pharmaceutically acceptable salt thereof. 15. A compound selected from the group consisting of: a compound of formula (IXa): a compound of formula (IXb): a compound of formula (Xa): and a compound of formula (Xb): wherein, in each said compound, Rv, R1, R2, M, Rx, Ry, Rz, R3, R4, R5, R6, X, Ring A, R7, R8, R9, R10, R11, Y, R12, R13, R14, R15, p, q, r, m, n, Ring B, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25 and R26 are as defined in claim 1, and Rp is C1-6alkyl or phenylC1-6alkyl; or a pharmaceutically acceptable salt thereof.