ES2819012T3 - Ibat inhibitors for the treatment of liver diseases - Google Patents

Abstract

A compound of Formula II ** (See formula) ** wherein M is CH2 or NH; R1 is H or hydroxy; R2 is H, ** (See formula) ** or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of general cholestasis.

Description

DESCRIPTION

Ibat inhibitors for the treatment of liver diseases

Background of the invention

The ileal bile acid transporter (IBAT ) is the main mechanism for reabsorption of bile acids from the GI tract. Partial or total blockage of this mechanism will lead to a lower concentration of bile acids in the wall of the small intestine, the portal vein, the liver parenchyma, the intrahepatic biliary tree, the extrahepatic biliary tree, including the gallbladder.

Diseases that can benefit from partial or total blockage of the IBAT mechanism may be those that either have a primary pathophysiological defect, or that cause or have symptoms of too high concentration of bile acids in serum and anterior organs. WO 2008/058630 describes the effect of a certain ileal bile acid transport (IBAT) in the treatment of liver disease related to fat disorders.

WO 2004/089350 describes the use of IBAT inhibitors in the treatment of constipation.

European patent EP 1535913 describes the use of 1,4-benzothiazepine derivatives as IBAT inhibitors in the treatment of hyperlipidemia, liver disease caused by cholestasis, obesity, fatty liver and steatohepatitis. WO 03/106482 and WO 03/022286 describe certain 1,5-benzothioazepine and 1,2,5-benzothiadiazepine derivatives as IBAT inhibitors, which are useful in the treatment of hyperlipidemia.

Angulo (Curr. Gastroenterol. Rep. 2002, vol. 4, pp. 37-44) describes the use of ursodeoxycholic acid in patients with liver disease.

The European Association for the Study of the Liver (EASL) has published its clinical practice guidelines for the treatment of cholestatic liver diseases in J. Hepatol. 2009, vol. 51, p. 237-267.

Summary of the invention

The present invention relates to specific IBAT inhibitors as defined in the appended claims for use in the prophylaxis and / or treatment of general cholestasis.

Detailed description of the invention

The present invention is defined in the appended claims. In the present description, IBAT inhibitor compounds of formula (I) are described:

where:

M is CH2, NH

One of R1 and R2 is selected from hydrogen or C1-6 alkyl and the other is selected from C1-6 alkyl;

Rx and Ry are independently selected from hydrogen, hydroxy, amino, mercapto, C 1-6 alkyl, C 1-6 alkoxy, N- (C 1-6 alkyl) amino, N, N- (C 1-6 alkyl) 2 amino, C alkyl ^ S (O) a where a is 0 to 2;

Rz is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkanoyl, C1-6 alkanoyloxy, N- ( C1-6 alkyl) amino, N, N- (C1-6 alkyl) 2-amino, C1-6 alkanoylamino, N- (C1-6 alkyl) carbamoyl, N, N- (C1-6 alkyl) 2carbamoyl, C1-6S alkyl (O) where a is 0 to 2, C1-6 alkoxycarbonyl, N- (C1-6 alkyl) sulfamoyl and N, N- (C1-6 alkyl) 2-sulfamoyl;

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, sulfamoyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, alkoxy C1-4, C1-4 alkanoyl, C1-4 alkanoyloxy, N- (C1-4 alkyl) amino, N, N- (C1-4 alkyl) 2-amino, C1-4 alkanoylamino, N- (C1-4 alkyl) carbamoyl , N, N- (C1-4 alkyl) 2carbamoyl, C1-4Salkyl (O) where a is 0 to 2, C1-4alkoxycarbonyl, N- (C1-4alkyl) sulfamoyl and N, N- (C1-4alkyl) 4) 2sulfamoyl; where R3 and R6 and the other of R4 and R5 can be optionally substituted on the carbon atom with one or more R16;

X is -O-, -N (Ra) -, -S (O) b- or -CH (Ra) -; where Ra is hydrogen or C1-6 alkyl, and b is 0-2;

Ring A is aryl or heteroaryl; where Ring A is optionally substituted with one or more substituents selected from R17;

R7 is hydrogen, C1-4 alkyl, carbocyclyl, or heterocyclyl; where R7 is optionally substituted with one or more substituents selected from R18;

R8 is hydrogen or C1-4 alkyl;

R9 is hydrogen or C1-4 alkyl;

R10 is hydrogen, C1-4 alkyl, carbocyclyl, or heterocyclyl; where R10 is optionally substituted with one or more substituents selected from R19;

R11 is carboxy, sulfo, sulfino, phosphono, -P (O) (ORc) (ORd), -P (O) (OH) (ORc), -P (O) (OH) (Rd) or -P (O ) (ORc) (Rd) where Rc and Rd are independently selected from C1-6 alkyl; or R11 is a group of formula (IB) or (IC):

where:

Y is -N (Rn) -, -N (Rn) C (O) -, -N (Rn) C (O) (CRsR ') vN (Rn) C (O) -, -O- and -S ( O) a-; where a is 0-2, v is 1-2, Rs and R * are independently selected from hydrogen or C1-4 alkyl optionally substituted with R26, and Rn is hydrogen or C1-4 alkyl;

R12 is hydrogen or C1-4 alkyl;

R13 and R14 are independently selected from hydrogen, C1-4 alkyl, carbocyclyl, or heterocyclyl; and when q is 0, R14 can be further selected from hydroxy, where R13 and R14 can be independently optionally substituted with one or more substituents selected from R20;

R15 is carboxy, sulfo, sulfino, phosphono, -P (O) (ORe) (ORf), -P (O) (OH) (ORe), -P (O) (OH) (Re) or -P (O ) (ORe) (Rf), where Re and Rf are independently selected from C1-6 alkyl;

p is 1-3; where the values of R13 can be the same or different;

q is 0-1;

r is 0-3; where the values of R14 can be the same or different;

m is 0-2; where the values of R10 can be the same or different;

n is 1-3; where the values of R7 can be the same or different;

Ring B is a heterocyclyl attached to the nitrogen atom substituted on the carbon atom with a group selected from R, and optionally further substituted on the carbon atom with one or more R; and where if said heterocyclyl attached to the nitrogen atom contains an -NH- moiety, that nitrogen atom may be optionally substituted with a group selected from R25;

R16, R17, and R18 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1- alkanoyl 4, C1-4 alkanoyloxy, N- (C1-4 alkyl) amino, N, N- (C1-4 alkyl) 2-amino, C1-4 alkanoylamino, N- (C1-4 alkyl) carbamoyl, N, N- (alkyl C1-4) 2-carbamoyl, alkyl Ci-4S (O) where a is 0 to 2, Ci-4alkoxycarbonyl, A / - (C i-4 alkyl) sulfamoyl and N, N- (Ci-4 alkyl) 2Sulfamoyl; where R16, R11q7 and J R 21081 pu 2e4den s 26 be substituted or optionally independently on the carbon atom with one or more R21;

R °, R, R, and R are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 alkanoyl, C1-4 alkanoyloxy, N- (C1-4 alkyl) amino, N, N- (C1-4 alkyl) 2-amino, C1-4 alkanoylamino, N- (C1-4 alkyl) carbamoyl, N, N - (C 1-4 alkyl) 2carbamoyl, C 1-4 alkyl (O) where a is 0 to 2, C 1-4 alkoxycarbonyl, N- (C 1-4 alkyl) sulfamoyl, N, N- (C 1-4 alkyl) 2-sulfamoyl , carbocyclyl, heterocyclyl, benzyloxycarbonylamino, sulfo, sulfino, amidino, phosphono, -P (O) (ORa) (ORb), -P (O) (OH) (ORa), -P (O) (OH) (Ra) or -P (O) (ORa) (Rb), where Ra and Rb are independently selected from C1-6 alkyl; where R19, R20, R24 and R26 can be optionally independently substituted on the carbon atom with one or more R22;

R21 and R22 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl , acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl;

R23 is carboxy, sulfo, sulfino, phosphono, -P (O) (ORg) (ORh), -P (O) (OH) (ORg), -P (O) (OH) (Rg) or -P (O ) (ORg) (Rh), where Rg and Rh are independently selected from C1-6 alkyl;

R25 is selected from C1-6 alkyl, C1-6 alkanoyl, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, carbamoyl, N- (C1-6alkyl) carbamoyl, N, N- (C1-6alkyl) carbamoyl, benzyl, benzyloxycarbonyol, benzoyl, and phenylsulfonyl;

or one of its pharmaceutically acceptable salts

for use in the prophylaxis or treatment of liver disease.

The compounds as used in accordance with the invention improve liver tests (serum aminotransferases) and liver histology, and significantly reduce the hydroxyproline content and the number of infiltrating neutrophils, and proliferating hepatocytes and cholangiocytes.

In the literature, IBAT inhibitors are often referred to by different names. It is to be understood that when referring to IBAT inhibitors herein, this term also encompasses compounds known in the literature as: i) Inhibitors of the apical sodium codependent bile acid transporter (ASBT ) of the ileum; ii) Bile Acid Transporter (BAT) inhibitors; iii) inhibitors of the ileum sodium / bile acid countertransporter system; iv) inhibitors of the apical bile acid-sodium cotransporter; v) ileum sodium-dependent bile acid transport inhibitors; vi) Bile Acid Reabsorption Inhibitors (BARI); and vii) Sodium Bile Acid Transporter (SBAT) inhibitors; where they act by inhibiting IBAT.

In the present specification, the term "alkyl" includes both straight and branched chain alkyl groups, but references to individual alkyl groups such as "propyl" are only specific to the straight chain version. For example, "C1-6 alkyl" includes C1-4 alkyl, C1-3 alkyl, propyl, isopropyl, and t-butyl. However, references to individual alkyl groups such as "propyl" are only specific to the straight chain version, and references to individual branched chain alkyl groups such as "isopropyl" are only specific to the branched chain version. A similar convention applies to other radicals, for example, "phenylC 1-6 alkyl" would include phenyC 1-4 alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term "halo" refers to fluorine, chlorine, bromine, and iodine.

When optional substituents are selected from "one or more" groups, this definition is to be understood to include all substituents that are selected from one of the specified groups or substituents that are selected from two or more of the specified groups.

"Heteroaryl" is a fully unsaturated monocyclic or bicyclic ring containing 3-12 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen, which may be, unless otherwise indicated, attached to an atom carbon or nitrogen. Preferably, "heteroaryl" refers to a fully unsaturated monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms, of which at least one atom is selected from nitrogen, sulfur, or oxygen, which may be, unless otherwise indicated, attached to a carbon or nitrogen atom. In another aspect, "heteroaryl" refers to a fully unsaturated monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 8, 9 or 10 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, which may be, unless otherwise indicated, attached to a carbon or nitrogen atom. Examples and suitable values of the term "heteroaryl" are thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyl, and quinolyl. Preferably, the term "heteroaryl" refers to thienyl or indolyl.

"Aryl" is a fully unsaturated monocyclic or bicyclic carbon ring containing 3-12 atoms. Preferably, "aryl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for "aryl" include phenyl or naphthyl. Particularly "aryl" is phenyl.

A "heterocyclyl" is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring, containing 3-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, which may be, unless otherwise indicated , attached to a carbon or nitrogen atom, where a -CH2- group can be optionally replaced by a -C (O) -, or a sulfur ring atom can optionally be oxidized to form the oxides of S. Preferably, a "heterocyclyl" is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing 5 or 6 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, which may be, unless otherwise indicated, attached to a carbon or nitrogen atom, where a -CH2- group may optionally be replaced by a -C (O) -, or a sulfur ring atom may optionally be oxidized to form oxide S / s. Examples and suitable values of the term "heterocyclyl" are thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl, 1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl, 2- oxo-1,3, 4 - (4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo [2.2.1] heptyl, 4 - thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, 1,2,4 - triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyridonyl, quinolyl, and 1-isoquinolonyl.

A "carbocyclyl" is a saturated, partially saturated or unsaturated monocyclic or bicyclic carbon ring containing 3-12 atoms; where a -CH2- group can optionally be replaced by a -C (O) -. Preferably, "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for "carbocyclyl" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl, or 1-oxoindanyl. Particularly "carbocyclyl" is cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or 1-oxoindanyl.

An example of "C 1-6 alkanoyloxy" and "C 1-4 alkanoyloxy" is acetoxy. Examples of "C 1-6 alkoxycarbonyl" and "C 1-4 alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and i-butoxycarbonyl. Examples of "C 1-6 alkoxy" and "C 1-4 alkoxy" include methoxy, ethoxy, and propoxy. Examples of "C 1-6 alkanoylamino" and "C 1-4 alkanoylamino" include formamido, acetamido, and propionylamino. Examples of "C 1-6 alkyl-S (O) a, where a is 0 to 2" and "C 1-4 alkyl-S (O) a, where a is 0 to 2" include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl and ethylsulfonyl. Examples of "C1-6 alkanoyl" and "C1-4 alkanoyl" include C1-3 alkanoyl, propionyl, and acetyl. Examples of "N- (C 1-6 alkyl) amino" and "N- (C 1-4 alkyl) amino" include methylamino and ethylamino. Examples of "N, N- (C ^ am in o alkyl" and "N, N- (C1-4 alkyl) 2amino" include di-N-methylamino, di- (N-ethyl) amino, and N-ethyl- N-methylamino. Examples of "C2-6 alkenyl" and "C2-4 alkenyl" are vinyl, allyl, and 1-propenyl. Examples of "C2-6 alkynyl" and "C2-4 alkynyl" are ethynyl, 1- Propynyl and 2-propynyl Examples of "N- (C 1-6 alkyl) sulfamoyl" and "N- (C 1-4 alkyl) sulfamoyl" are N- (C 1-3 alkyl) sulfamoyl, N- (methyl) sulfamoyl and N- (ethyl) sulfamoyl Examples of "N- (C 1-6 alkyl) 2-sulfamoyl" and "N-C 1-4 -alkyl) 2-sulfamoyl" are N, N- (dimethyl) sulfamoyl and N- (methyl) -N- (ethyl) sulfamoyl. Examples of "N- (C 1-6 alkyl) carbamoyl" and "N- (C 1-4 alkyl) carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl. Examples of ^" N, N- (C 1-6 alkyl) 2 carbamoyl" and "N, N- (C 1-4 alkyl) 2-carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "C 1-6 alkoxycarbonylamino" are ethoxycarbonylamino and i-butoxycarbonylamino. Examples of "^ - (C 1-6 alkyl) ureido" are A / -methylureido and W-ethylureido. Examples of "N- (C 1-6 alkyl) ureido" are N-methylureido and N-ethylureido. Examples of "W, W- (C ^ ure alkyl) are A /, A / -dimethylureido and / V-methyl - ^ - ethylureido. Examples of" ^ - (C1-6 alkyl) -N- ( C 1-6 alkyl ureido are A / -methyl-N-methyl ureido and W-propyl-N ^{-methyl ureido. Examples of "} N , ^ - (C 1-6 alkyl) 2-N- (C 1-6 alkyl) ureido are A /, A / -dimethyl-N-methylureido and W-methyl-W-ethyl-N-propylureido.

A pharmaceutically acceptable salt of a compound is, for example, an acid addition salt of a compound that is sufficiently basic, for example, an acid addition salt with, for example, an organic or inorganic acid, for example acid hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic.

Furthermore, a suitable pharmaceutically acceptable salt of a compound that is sufficiently acidic is an alkali metal salt, for example, a sodium or potassium salt, an alkaline earth metal salt, for example, a calcium or magnesium salt, a salt of ammonium or a salt with an organic base that provides a physiologically acceptable cation, for example, a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

It should also be understood that certain compounds of formula (I) can exist in solvated and unsolvated forms such as, for example, hydrated forms. Formula (I) should be understood to encompass all solvated forms that possess IBAT inhibitory activity.

The preferred values of R1, R2, R3, R4, R5 and R6 are as follows. Such values may be used where applicable to any of the definitions, claims or embodiments defined above or hereinafter.

Preferably R1 and R2 are independently selected from C1-4 alkyl.

More preferably, R1 and R2 are independently selected from ethyl or butyl.

More preferably, R1 and R2 are independently selected from ethyl, propyl, or butyl.

In one case, particularly, R1 and R2 are both butyl.

In a further case, particularly, R1 and R2 are both propyl.

In another case, particularly, one of R1 and R2 is ethyl and the other is butyl.

Preferably, Rx and RY are independently selected from hydrogen or C1-6 alkyl.

More preferably, Rx and RY are both hydrogen.

Preferably, RZ is selected from halo, amino, C1-6 alkyl, C1-6 alkoxycarbonylamino or W- (C1-6 alkyl) ureido.

More preferably, RZ is selected from chloro, amino, f-butyl, f-butoxycarbonylamino or W- (f-butyl) ureido.

Preferably v is 0 or 1.

In one case, more preferably, v is 0.

In one case, more preferably, v is 1.

In one case, preferably, R4 is a group of formula (IA) (as represented above).

In another case, preferably, R5 is a group of formula (IA) (as represented above).

Preferably R3 and R6 are hydrogen.

Preferably, the other of R4 and R5 that is not the group of formula (IA) is selected from halo, C1-4 alkoxy or C1-4 alkyl (O) a, where a is 0 to 2; wherein that R4 or R5 may be optionally substituted on the carbon atom with one or more R16; where R16 is independently selected from hydroxy and N, N- (C1-4alkyl) 2amino.

More preferably, the other of R4 and R5 that is not the group of formula (IA) is selected from bromo, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl; wherein that R4 or R5 may be optionally substituted on the carbon atom with one or more R16; where R16 is independently selected from hydroxy and N, N-dimethylamino.

Particularly, the other of R4 and R5 that is not the group of formula (IA) is selected from bromo, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2- (N, N-dimethylamino) ethylthio or mesyl.

More particularly, the other of R4 and R5 that is not the group of formula (IA) is methylthio. Preferably, the other of R4 and R5 that is not the group of formula (IA) is selected from hydrogen, halo, C ^ alkoxy or C ^ S alkyl (O) a, where a is 0 to 2; wherein that R4 or R5 may be optionally substituted on the carbon atom with one or more R16; where R16 is independently selected from hydroxy, carboxy and N, N- (C 1-4 alkyl) 2 amino.

More preferably, the other of R4 and R5 that is not the group of formula (IA) is selected from hydrogen, bromo, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl; wherein that R4 or R5 may be optionally substituted on the carbon atom with one or more R16; where R16 is independently selected from hydroxy, carboxy, and N, N-dimethylamino.

Particularly, the other of R4 and R5 that is not the group of formula (IA) is selected from hydrogen, bromine, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2- (Ñ, N-dimethylamino) ethylthio or mesyl.

In another case, more preferably, the other of R4 and R5 that is not the group of formula (IA) is selected from hydrogen, chlorine, bromine, methoxy, isopropoxy, methylthio, ethylthio or isopropylthio; wherein that R4 or R5 may be optionally substituted on the carbon atom with one or more R16; where R16 is independently selected from hydroxy, carboxy, and N, N-dimethylamino.

In another case, particularly, the other of R4 and R5 that is not the group of formula (IA) is selected from hydrogen, chlorine, bromine, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio or 2- ( N, N-dimethylamino) ethylthio.

In another case, more particularly, the other of R4 and R5 that is not the group of formula (IA) is bromine or chlorine.

In another case, more particularly, the other of R4 and R5 that is not the group of formula (IA) is methoxy.

In one case, preferably, Ring A is aryl.

Otherwise, preferably, Ring A is heteroaryl.

When Ring A is aryl, preferably Ring A is phenyl.

When Ring A is heteroaryl, preferably, Ring A is thienyl or indolyl.

Preferably Ring A is aryl or heteroaryl; where Ring A is optionally substituted with one or more substituents selected from R17; where R17 is selected from halo, hydroxy, or C1-4 alkyl; where R17 can be optionally substituted on the carbon atom with one or more R21; where R21 is selected from halo.

Preferably X is -O.

More preferably, Ring A is phenyl, thienyl, or indolyl; where Ring A is optionally substituted with one or more substituents selected from halo, hydroxy, or trifluoromethyl.

In particular, Ring A is selected from phenyl, 4-hydroxyphenyl, thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2,3-dihydroxyphenyl or indol-3-yl.

More particularly, Ring A is phenyl.

Otherwise, preferably, Ring A is aryl or heteroaryl; where Ring A is optionally substituted with one or more substituents selected from R17; where R17 is selected from halo, hydroxy, C1-4 alkyl or C1-4 alkoxy; where R17 can be optionally substituted on the carbon atom with one or more R21; where R21 is selected from halo.

In another case, more preferably, Ring A is phenyl, thienyl, or indolyl; where Ring A is optionally substituted with one or more substituents selected from halo, hydroxy, methoxy, or trifluoromethyl.

In another case, particularly, Ring A is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2,3-dihydroxyphenyl or indole-3- ilo.

In a further case, particularly, Ring A is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 2,3- dihydroxyphenyl or indol-3-yl.

Preferably R7 is hydrogen, C1-4 alkyl or carbocyclyl.

More preferably, R7 is hydrogen, methyl or phenyl.

In particular, R7 is hydrogen.

In one case, preferably, R8 is hydrogen.

Otherwise, preferably, R8 is C1-4 alkyl.

In another case, more preferably, R8 is hydrogen or methyl.

In one case, preferably, R9 is hydrogen.

Otherwise, preferably, R9 is C1-4 alkyl.

In another case, more preferably, R9 is hydrogen or methyl.

Preferably R10 is hydrogen.

In one case, preferably, R11 is carboxy, sulfo, sulfino, phosphono, -P (O) (ORc) (ORd), -P (O) (OH) (ORc), -P (O) (OH) (Rd ) or -P (O) (ORc) (Rd), where Rc and Rd are independently selected from C1-6 alkyl.

In another case, preferably, R11 is a group of formula (IB) (as represented above).

Preferably, R11 is carboxy, -P (O) (OH) (ORc) or a group of formula (IB) (as represented above). More preferably, R11 is carboxy, -P (O) (OH) (OEt) or a group of formula (IB) (as depicted above).

In another case, preferably, R11 is carboxy, sulfo, -P (O) (OH) (ORc), where Rc is selected from C1-4 alkyl or a group of formula (IB) (as depicted above).

Preferably Y is -NH- or -NHC (O) -.

More preferably, Y is -NHC (O) -.

In one case, preferably, R12 is hydrogen.

Otherwise, preferably, R12 is C1-4 alkyl.

In another case, more preferably, R12 is hydrogen or methyl.

Preferably R13 is hydrogen, C 1-4 alkyl or carbocyclyl; where R13 is optionally substituted with one or more substituents selected from R20; where R20 is hydroxy.

More preferably, R13 is hydrogen, methyl or phenyl; where R13 is optionally substituted with one or more substituents selected from R20; where R20 is hydroxy.

Particularly, R13 is hydrogen, hydroxymethyl or phenyl.

More particularly, R13 * is hydrogen or hydroxymethyl.

In another case, preferably, R13 * is hydrogen, C1-4 alkyl or carbocyclyl; where R13 is optionally substituted with one or more substituents selected from R20; where R20 is hydroxy, carboxy, carbocyclyl, or amino; where R20 can be optionally substituted on the carbon atom with one or more R22; R22 is hydroxy.

In another case, more preferably, R13 is hydrogen, methyl, ethyl, butyl, or phenyl; where R13 is ^{optionally substituted with one or more substituents selected from R20; where R20 is hydrox22 i, carboxy, phenyl, or amino;} _{where R} 20 _{can be} optionally substituted 22 _{on the carbon atom with one or more R; R is hydroxy.}

In another case, particularly, R13 is hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl or phenyl.

In a further case, preferably, R13 is hydrogen, C1-4 alkyl or carbocyclyl; where R13 is optionally substituted with AnA one or more substituents selected from R20; where R20 is hydroxy, carb AoAxy, c AAarbocyclyl, heterocyclyl, or amino; where R can be optionally substituted on the carbon atom with one or more R; R is hydroxy.

In a further case, more preferably, R13 is hydrogen, methyl, ethyl, butyl or phenyl; where R13 is ^{optionally substituted with one or more substituents selected from R20; where R20 is hydroxy, car20} 2 ^b 2 ^{oxy, phenyl, imidazolyl, or} _{amino; where R can be optionally substituted on the carbon atom with one or more R; R is hydroxy.}

In a further case, particularly, R13 is hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl, imidazol-5-ylmethyl or phenyl.

In yet another case, preferably, R ¹³ is hydrogen, C 1-4 alkyl, carbocyclyl or R ²³ ; where R ¹³ is optionally substituted with one or more substituents selected from R20; where R20 is hydroxy, C ^ S (O) alkyl a, where a is 0, C1-4 alkoxy, amino, carbocyclyl, heterocyclyl, or mercapto; where R20 can be optionally independently substituted on the carbon atom with one or more R; R is selected from hydroxy; and R is carboxy.

In yet another case, more preferably, R ¹³ is hydrogen, methyl, ethyl, butyl or phenyl, or R ²³ ; where R ¹³ is optionally substituted with one or more substituents selected from R20; where R20 is hydroxy, methylthio, methoxy, amino, imidazolyl, or mercapto; where R20 can be optionally independently substituted on the carbon atom with one or more R22; R22 is selected from hydroxy; and R23 is carboxy.

In a further case, particularly, R13 is hydrogen, carboxy, hydroxymethyl, mercaptomethyl, methoxymethyl, methylthiomethyl, 2-methylthioethyl, 4-aminobutyl, 4-hydroxybenzyl, imidazol-5-ylmethyl or phenyl.

In another case, more particularly, R13 is methylthiomethyl, methylsulfonyl or methylsulfonylmethyl.

Preferably R14 is hydrogen.

In another case, preferably, R14 is selected from hydrogen, C1-4 alkyl or carbocyclyl where said C1-4 alkyl or carbocyclyl may be optionally substituted with one or more substituents selected from R20; and R20 is hydroxy.

In another case, more preferably, R14 is selected from hydrogen, methyl, or phenyl; wherein said methyl or phenyl may be optionally substituted with one or more substituents selected from R20; and R20 is hydroxy.

In another case, particularly, R14 is hydrogen, phenyl or hydroxymethyl.

Particularly, R15 is carboxy or sulfo.

In one case, more particularly, R15 is carboxy.

In another case, more particularly, R15 is sulfo.

Preferably, R15 is carboxy, sulfo, -P (O) (ORe) (ORf), -P (O) (OH) (ORe), -P (O) (OH) (Re), or -P (O) ( ORe) (Rf), where Re and Rf are independently selected from C1-4 alkyl.

More preferably, R15 is carboxy, sulfo, -P (O) (ORe) (ORf), -P (O) (OH) (ORe), -P (O) (OH) (Re) or -P (O) (ORe) (Rf), where Re and Rf are independently selected from methyl or ethyl.

Preferably, R15 is carboxy, sulfo, -P (O) (OEt) (OEt), -P (O) (OH) (OEt), -P (O) (OH) (Me) or -P (O) ( OEt) (Me).

Preferably, R15 is carboxy, sulfo, phosphono, -P (O) (ORe) (ORf), -P (O) (OH) (ORe), -P (O) (OH) (Re) or -P (O ) (ORe) (Rf), where Re and Rf are independently selected from C1-4 alkyl, or R15 is a group of formula (IC) (as depicted above).

More preferably, R15 is carboxy, sulfo, phosphono, -P (O) (ORe) (ORf), -P (O) (OH) (ORe), -P (O) (OH) (Re) or -P ( O) (ORe) (Rf), where Re and Rf are independently selected from methyl or ethyl, or R15 is a group of formula (iC) (as depicted above).

Preferably, R15 is carboxy, sulfo, phosphono, -P (O) (OEt) (OEt), -P (O) (Oí-Bu) (Oí-Bu), -P (O) (OH) (OEt), -P (O) (OH) (Me) or -P (O) (OEt) (Me) or R15 is a group of formula (IC) (as represented above).

In one case, preferably, R15 is carboxy.

In another case, preferably, R15 is sulfo.

Otherwise, preferably, R15 is -P (O) (OH) (OEt).

Otherwise, preferably, R15 is -P (O) (OH) (Me).

Otherwise, preferably, R15 is -P (O) (OEt) (Me).

In one case, preferably, R24 is hydrogen.

Otherwise, preferably, R24 is C1-4 alkyl.

Preferably R25 is hydrogen.

Preferably R26 is carboxy.

Preferably p is 1 or 2; where the values of R13 can be the same or different.

In one case, more preferably, p is 1.

Otherwise, more preferably, p is 2; where the values of R13 can be the same or different.

In a further case, more preferably, p is 3; where the values of R13 can be the same or different.

In one case, preferably, q is 0.

Otherwise, preferably, q is 1.

In one case, preferably, r is 0.

In one case, more preferably, r is 1.

Otherwise, more preferably, r is 2; where the values of R14 can be the same or different.

Otherwise, more preferably, r is 3; where the values of R14 can be the same or different.

Preferably m is 0.

Otherwise, preferably, m is 0 or 1.

Preferably n is 1.

Otherwise, preferably, n is 1 or 2.

Preferably, z is 1.

The group of formula (IA), where R7 is hydrogen, methyl or phenyl, n is 1, Ring A is phenyl, thienyl or indolyl; where Ring A is optionally substituted with one or more substituents selected from halo, hydroxy or trifluoromethyl, m is 0 and R9 is carboxy, -P (O) (OH) (ORc) or a group of formula (IB).

The group of formula (IA), where: X is -O-.

Ring A is phenyl, thienyl, or indolyl; where Ring A is optionally substituted with one or more substituents selected from halo, hydroxy, methoxy, or trifluoromethyl;

R7 is hydrogen, methyl or phenyl;

R8 is hydrogen or methyl;

R9 is hydrogen or methyl;

R10 is hydrogen;

m is 0-2, where the values of R10 can be the same or different; and R11 is carboxy, -P (O) (OH) (OEt) or a group of formula (IB) (as depicted in claim 1); The group of formula (IB), where R10 is hydrogen, hydroxymethyl or phenyl, p is 1 or 2; where the values of R10 may be the same or different and R11 is carboxy or sulfo.

The group of formula (IB), where:

R1132 is hydrogen or methyl; 23 1 ₃

R is hydrogen, methyl, ethyl, butyl, or phenyl, or R; where R is optionally substituted with one or more substituents selected from R20; R20 is hydroxy, methylthio, methoxy, amino, imidazolyl, or mercapto; where R20 can be optionally independently substituted on the carbon atom with one or more hydroxy groups; R23 is carboxy; Y is -NH- or -NHC (O) -; R14 is selected from hydrogen, methyl, or phenyl; where methyl or phenyl can be optionally substituted with one or more substituents selected from hydroxy; R15 is carboxy, sulfo, phosphono, -P (O) (ORe) (ORf), -P (O) (OH) (ORe), -P (O) (OH) (Re) or -P (O) ( ORe) (Rf), where Re and Rf are independently selected from methyl or ethyl, or R15 is a group of formula (IC) (as depicted in claim 1); p is 1-3, where the values of R13 can be the same or different;

q is 0-1; Y

r is 0-3, where the values of R14 can be the same or different;

The group of formula (IC), where

R24 is hydrogen;

R25 is hydrogen;

R26 is carboxy; Y

z is 1;

or one of its pharmaceutically acceptable salts.

Also described herein is a compound of formula (I) as illustrated above, where: R1 and R2 are independently selected from ethyl or butyl;

R3 and R6 are hydrogen;

R4 is selected from halo, C1-4 alkoxy, or C1-4 alkyl (O) a, where a is 0 to 2; wherein that R4 can be optionally substituted on the carbon atom with one or more R16; where R16 is independently selected from hydroxy and N, A / - (C ^ am in or alkyl; R5 is a group of formula (IA);

Ring A is aryl or heteroaryl; where Ring A is optionally substituted with one or more substituents selected from R17; where

R17 is selected from halo, hydroxy, or C1-4 alkyl; where R17 can be optionally substituted on the carbon atom with one or more R21; where

R21 is selected from halo;

R7 is hydrogen, C1-4 alkyl or carbocyclyl;

R11 is carboxy, -P (O) (OH) (ORc) or a group of formula (IB) (as represented above);

R13 is hydrogen, C1-4 alkyl or carbocyclyl; where R13 is optionally substituted with one or more substituents selected from R20; where

R20 is hydroxy;

R15 is carboxy or sulfo;

p is 1 or 2; where the values of R13 can be the same or different;

m is 0; Y

n is 1;

or one of its pharmaceutically acceptable salts.

Also described herein is a compound of formula (I) as illustrated above, where: R1 and R2 are both butyl, or one of R1 and R2 is ethyl and the other is butyl;

R4 is methylthio;

R5 is a group of formula (IA) (as represented above);

R3 and R6 are hydrogen;

Ring A is phenyl;

R7 is hydrogen;

R11 is a group of formula (IB) (as represented above);

R13 is hydrogen or hydroxymethyl;

R15 is carboxy or sulfo;

p is 1 or 2; where the values of R13 can be the same or different;

m is 0;

n is 1;

or one of its pharmaceutically acceptable salts.

Also described herein is a compound of formula (I) as illustrated above, where: R1 and R2 are independently selected from ethyl or butyl;

R3 and R6 are hydrogen;

R4 is selected from halo, C1-4 alkoxy or C ^ S O alkyl a, where a is 0 to 2; wherein that R4 can be optionally substituted on the carbon atom with one or more R16; where R16 is independently selected from hydroxy and N, A / - (C ^ a m ino alkyl; R5 is a group of formula (IA);

Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted with one or more substituents selected from R17;

R7 is hydrogen, C1-4 alkyl or carbocyclyl;

R8 is hydrogen or methyl;

R9 is hydrogen or methyl;

R11 is carboxy, -P (O) (OH) (ORc) or a group of formula (IB) (as represented above);

X is -NH- or -NHC (O) -;

R12 is hydrogen or methyl;

R13 is hydrogen, C1-4 alkyl or carbocyclyl; where R13 is optionally substituted with one or more substituents selected from R20;

R14 is hydrogen;

R15 is carboxy or sulfo;

R17 is selected from halo, hydroxy, C1-4 alkyl or C1-4 alkoxy; where R17 can be optionally substituted on the carbon atom with one or more R21;

R20 is hydroxy, carboxy, carbocyclyl, or amino; where R20 can be optionally substituted on the carbon atom with one or more R22;

R21 is selected from halo;

R22 is hydroxy;

p is 1-3; where the values of R13 can be the same or different.

q is 0-1;

r is 0-3; where the values of R14 can be the same or different; and where, if q is 1, r is not 0;

m is 0-2; Y

n is 1-3;

or one of its pharmaceutically acceptable salts.

Also described herein is a compound of formula (I) as illustrated above, where: R1 and R2 are independently selected from C1-4 alkyl;

Rx and Ry are both hydrogen;

Rz is selected from halo, amino, C1-6 alkyl, C1-6 alkoxycarbonylamino or / V- (C1-6 alkyl) ureido;

v is 0 or 1;

R3 and R6 are hydrogen;

one of R4 and R5 is a group of formula (IA) (as depicted above) and the other is selected from hydrogen, halo, C ^ alkoxy or C ^ alkyl (O) a, where a is 0 to 2; wherein that R4 or R5 may be optionally substituted on the carbon atom with one or more R16; where R16 is independently selected from hydroxy, carboxy, and N, N- (C ^ to min o alkyl; X is -O-;

R7 is hydrogen, methyl or phenyl;

R8 is hydrogen or methyl;

Ring A is aryl or heteroaryl 'where Ring A is optionally substituted with one or more substituents selected from R17; where R17 is selected from halo, hydroxy, C1-4 alkyl or C1-4 alkoxy; where R17 can be optionally substituted on the carbon atom with one or more R21; where

R21 is selected from halo;

R9 is hydrogen or methyl;

R10 is hydrogen;

R11 is carboxy, -P (O) (OH) (ORc), where Rc is selected from C1-4 alkyl or a group of formula (IB) (as depicted above);

R12 is hydrogen or methyl;

Y is -NH- or -NHC (O) -;

R is hydrogen, C1-4 alkyl, carbocyclyl, or R; where R is optionally substituted with one or more substituents selected from R20; where R20 is hydroxy, C ^ S (O) alkyl a, where a is 0, C1-4 alkoxy, amino, carbocyclyl, heterocyclyl, or mercapto; where R20 can be optionally independently substituted on the carbon atom with one or more R22; R22 is selected from hydroxy; and R23 is carboxy;

R14 is selected from hydrogen, C1-4 alkyl or carbocyclyl; wherein said C1-4 alkyl or carbocyclyl may be optionally substituted with one or more substituents selected from R20; and R20 is hydroxy;

R15 is carboxy, sulfo, phosphono, -P (O) (ORe) (ORf), -P (O) (OH) (ORe), -P (O) (OH) (Re) or -P (O) ( ORe) (Rf), where Re and Rf are independently selected from C1-4 alkyl, or R15 is a group of formula (IC) (as depicted above);

R24 is hydrogen;

R25 is hydrogen;

R26 is carboxy;

p is 1-3; where the values of R13 can be the same or different;

q is 0-1;

r is 0-3; where the values of R14 can be the same or different;

m is 0-2; where the values of R10 can be the same or different;

n is 1-2; where the values of R7 can be the same or different;

z is 0-1; where the values of R25 can be the same or different;

or one of its pharmaceutically acceptable salts.

In another case, the preferred compounds are any one of the examples or a pharmaceutically acceptable salt thereof.

In a first aspect, the invention relates to a compound of formula II

where

M is CH2 or NH;

R1 is H or hydroxy;

R2 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH (CH3) 2, -CH2CH (CH ^, -CH (CH3) CH2CH3, -CH2OH, -CH2OCH3, -CH (OH) CH3, -CH2SCH3 or -CH2CH2SCH3;

for use in the prophylaxis or treatment of general cholestasis.

Examples of useful substances according to the invention are:

1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -a- [A / - (carboxymethyl) carbamoyl) benzyl} carbamoylmethoxy) -2,3,4 , 5-tetrahydro-1,2,5-benzothiadiazepine,

1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(ph) -a- [W - ((S) -1-carboxyethyl) carbamoyl) benzyl} carbamoylmethoxy) -2 , 3,4,5-tetrahydro-1,5-benzothiazepine,

1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((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- (W - {(R) -a- [W - ((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- (W - {(R) -a- [A / - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,

1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((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- (W - {(R) -a- [W - ((S) -1-carboxy-2-methylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,

1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(fi) -a- [A / - ((S) -1-carboxy-2- (fi) - 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- (W - {(R) -a- [W - ((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- (W - {(R) -a- [W - ((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- (W - {(R) -a- [W - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine,

1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((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- (W - {(ph) -a- [W - ((S) -1-carboxy-2-methylpropyl) 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- (W - {(R) -1'-phenyl-1 '- [W- (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy) -2.3 .4.5- tetrahydro-1,5-benzothiazepine.

Compounds of formula (II) may have chiral and / or geometric isomeric centers ( E and Z isomers), and it is to be understood that the invention encompasses all such optical isomers, diastereoisomers, and geometric isomers that possess IBAT inhibitory activity.

The invention relates to each and every one of the tautomeric forms of the compounds of formula (II) that possess IBAT inhibitory activity.

The invention also relates to optical and / or geometric isomers of the compounds of the invention, pure or as a mixture, in all proportions, of the compounds of formula II, and those specifically mentioned and the possible tautomeric forms.

In certain embodiments, the compounds described herein have one or more chiral centers. As such, all stereoisomers are contemplated herein. In various embodiments, the compounds described in the present disclosure are present in racemic or optically active forms. The compounds of the present invention should be understood to encompass racemic, optically active, regioisomeric, and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. The preparation of optically active forms is accomplished in any suitable way, including by way of example, by resolution of the racemic form by recrystallization techniques, by synthesis of optically active starting materials, by chiral synthesis, or by chromatographic separation using a single phase. chiral stationary. In some embodiments, mixtures of one or more isomers are used as the therapeutic compound described herein. In certain embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is accomplished by any means including, by way of example, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, and the like.

The compounds can exist in free acid or free base form, or in a pharmaceutically acceptable salt form. In certain embodiments, a compound described herein exists in an unsolvated or solvated form, where the solvated forms comprise any pharmaceutically acceptable solvent, eg, water, ethanol, and the like.

The invention also relates to a composition comprising at least one IBAT inhibitor of Formula (II), for use in the prophylaxis and / or treatment of general cholestasis.

An IBAT inhibitor of Formula II can be used in conjunction with at least one other therapeutically active compound as described herein, in the preparation of a medicament for the prophylactic and / or therapeutic treatment of general cholestasis.

Liver disease

Liver disease is defined in the present description as any disease dependent on bile acids (BA, Bile Acid) produced in the liver and in organs related thereto, such as the portal vein of the pancreas, the liver parenchyma, the biliary tree. intrahepatic, extrahepatic biliary tree and gallbladder.

The ileal bile acid transporter (IBAT ) is the main mechanism for reabsorption of bile acids from the GI tract. Partial blockage of this mechanism will lead to a lower concentration of bile acids in the wall of the small intestine, the portal vein, the liver parenchyma, the intrahepatic biliary tree, the extrahepatic biliary tree, and in the gallbladder. Diseases that can benefit from partial or total blockage of the IBAT mechanism may be those that have a primary pathophysiological defect, or that cause or have symptoms of excessively high concentration of bile acids in serum and anterior organs.

Examples of liver diseases described in the present description include liver parenchyma; an inherited metabolic disorder of the liver; Biler's syndrome; a primary defect of bile acid (BA) synthesis such as cerebrotendinous or xanthomatosis; a secondary defect such as Zellweger syndrome, neonatal hepatitis, cystic fibrosis, liver manifestations, AS (Alagilles syndrome), CIFP (Familial Progressive Intrahepatic Cholestasis), autoimmune hepatitis, primary biliary cirrhosis (PBC), liver fibrosis, liver disease nonalcoholic fatty liver, NAFLD / NASH, portal hypertension, general cholestasis such as in jaundice due to drugs or pregnancy, intrahepatic and extrahepatic cholestasis such as inherited forms of cholestasis such as CIFP1, primary sclerosing cholangitis, gallstones and choledocholithiasis, tumor malignant causing obstruction of the biliary tree, symptoms (itching, pruritus) due to cholestasis / jaundice, pancreatitis, chronic autoimmune liver disease leading to progressive cholestasis or itching of cholestatic liver disease.

Other examples of liver diseases described in the present disclosure include a liver disorder or liver-related condition, fatty liver, hepatic steatosis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, acute fatty liver, pregnancy-induced fatty liver, hepatitis induced drug, iron overload disorders, liver fibrosis, liver cirrhosis, hepatoma, viral hepatitis and problems related to tumors and neoplasms of the liver, biliary tract and pancreas.

Combination with other active substances

Further described herein is an IBAT inhibitor according to Formula (I) or Formula (II) as defined above, in combination with at least one other therapeutically active substance. The at least one other therapeutically active substance can be an IBAT inhibitor compound.

Incretins and hormones produced by L cells

The at least one other therapeutically active substance can be an incretin or a hormone produced by L cells.

In one case, the at least one other therapeutically active substance is an L-cell endocrine peptide enhancer such as a GLP-1 enhancer. Examples of a GLP-1 enhancer are GLP-1, a GLP-1 secretion enhancer, a GLP-1 degradation inhibitor, or a combination thereof.

In one case, the L-cell endocrine peptide enhancer is a GLP-2 enhancer such as GLP-2, an enhancer of GLP-2 secretion, an inhibitor of GLP-2 degradation, or a combination thereof. .

In one case, the L-cell endocrine peptide enhancer is a PYY enhancer such as an oxynomodulin enhancer.

Incretin Mimetics

In one case, the at least one other therapeutically active substance is an incretin mimetic such as exenatide (Byetta®).

Also described is an oral combination of an IBAT inhibitor of Formula (I) or Formula (II) as described herein and a DPP-IV inhibitor.

Enteroendocrine peptides

In one case, the at least one other therapeutically active substance is an enteroendocrine peptide such as GLP-1 or GLP-1 analogs, eg, Taspoglutide® (Ipsen) or the like.

Combination therapy with an IBAT inhibitor and a DPP-IV inhibitor

In one case, the at least one other therapeutically active substance is a DPP-IV inhibitor.

Also described is a combination of an IBAT inhibitor and metformin and / or sitagliptin (Janumet®) and / or DPP-IV inhibitors suitable for use with the methods described herein, including, but not limited to, (2S) -1 - {2 - [(3-hydroxy-1-adamantyl) amino] -acetyl} pyrrolidine-2-carbonitrile (vildagliptin), (3fí) -3-amino-1 - [9- (trifluoromethyl) - 1,4,7,8-tetrazabicyclo [4.3.0] nona-6,8-dien-4-yl] -4- (2,4,5-trifluorophenyl) butan-1 -one (sitagliptin), (1 S , 3S, 5S) -2 - [(2S) -2-amino-2- (3-hydroxy-1-adamantyl) acetyl] -2-azabicyclo [-3.1.0] hexane-3-carbonitrile (saxagliptin) and 2 - ({6 - [(3R) -3-aminopiperidin-1-yl] -3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl} methyl) benzonitrile (alogliptin).

TGR5 receptor modulators

In one case, the at least one other therapeutically active substance is a TGR5 agonist. TGR5 modulators (eg, agonists) include, but are not limited to, the compounds described in W or 2008/091540, W or 2008/067219 and US Application No. 2008/0221161.

Thiazolidinediones

In one case, the at least one other therapeutically active substance is a thiazolidinedione such as Rosiglitazone (Avandia), Pioglitazone (Actos), Troglitazone (Rezulin), MCC-555, rivoglitazone, ciglitazone or the like.

Combination therapy with an IBAT inhibitor, a biliary diversion, and a DPP-IV inhibitor

Also described is the administration of an IBAT inhibitor of Formula (I) or Formula (II), as described herein, in combination with a DPP-IV inhibitor and / or a biliary bypass. Examples of biliary shunts include, but are not limited to, shunts described in WO 2007/0050628.

As used in the present description, the term "additive effect" describes the combined effect of two (or more) pharmaceutically active agents that is equal to the sum of the effect of each agent administered alone. A synergistic effect is one in which the combined effect of two (or more) pharmaceutically active agents is greater than the sum of the effect of each agent administered alone. Any suitable combination of an ASBTI with one or more of the other active ingredients mentioned above and optionally with one or more other pharmacologically active substances is contemplated within the scope of the methods described herein.

In some embodiments, the particular choice of compounds depends on the diagnosis of the treating physicians and their judgment of the individual's condition and the appropriate treatment protocol. The compounds are optionally administered concurrently (eg, simultaneously, essentially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder or condition, the individual's condition, and choice. actual of the compounds used. In certain cases, the determination of the order of administration and the number of repetitions of administration of each therapeutic agent during a treatment protocol is based on an evaluation of the disease being treated and the condition of the individual.

In some embodiments, the therapeutically effective doses vary when the drugs are used in combination treatments. Methods for experimentally determining therapeutically effective doses of drugs and other agents for use in combination treatment regimens are described in the literature.

In some embodiments of the combination therapies described herein, the doses of the co-administered compounds vary depending on the type of co-drug used, the specific drug used, the disease or condition being treated, and so on. Furthermore, when administered in conjunction with one or more biologically active agents, the compound provided herein is optionally administered either simultaneously with the biologically active agent (s) or sequentially. In certain cases, if administered sequentially, the treating physician will decide the appropriate order of the therapeutic compound described herein in combination with the additional therapeutic agent.

The multiple therapeutic agents (at least one of which is a therapeutic compound described herein) are optionally administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are optionally provided in a single unitized form or in multiple forms (by way of example only, either as a single pill or as two separate pills). In certain cases, one of the therapeutic agents is optionally administered in multiple doses. In other cases, both are optionally administered as multiple doses. If not administered simultaneously, the time between multiple doses is any suitable time, for example, from more than zero weeks to less than four weeks. Furthermore, the combination of methods, compositions and formulations is not limited to the use of just two agents; The use of multiple therapeutic combinations (including two or more compounds described herein) is also envisioned.

In certain embodiments, a dosage regimen for treating, preventing, or ameliorating the condition (s) for which relief is sought is modified according to a variety of factors. These factors include the disorder suffered by the subject, as well as the subject's age, weight, sex, diet, and medical condition. Thus, in various embodiments, the dosage regimen actually employed varies and deviates from the dosage regimens set forth herein.

In some embodiments, the pharmaceutical agents that make up the combination therapy described herein are provided in a combined dosage form or in separate dosage forms for substantially simultaneous administration. In certain embodiments, the pharmaceutical agents that make up the combination therapy are administered sequentially, with any therapeutic compound being administered by a regimen that allows for two-step administration. In some embodiments, the two-step administration regimen allows sequential administration of the active agents or separate administration of the separate active agents. In certain embodiments, the time period between multiple administration steps ranges, for example, from a few minutes to several hours, depending on the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile of the pharmaceutical agent.

Also disclosed are IBAT inhibitor compounds described herein in combination with at least one bile acid binder, eg, a resin such as cholestyramine, colestipol, and colesevelam.

Bile acid binders (bile acid sequestrants, resins)

It is disclosed that an IBAT inhibitor of Formula (I) or Formula (II), as defined above, can be administered in the form of a pharmaceutical formulation that also comprises at least one bile acid binder, said formulation being designed to deliver the bile acid binder in the colon and IBAT inhibitor in the small intestine.

Examples of useful bile acid binders are cholestyramine, which is a hydrophilic polyacrylic quaternary ammonium anion exchange resin known to be effective in lowering blood cholesterol levels. Cholestyramine, and various compositions including cholestyramine, are described, for example, in British Patent Nos. 929,391 and 1,286,949; and US Patent Nos. 3,383,281; 3,308,020; 3,769,399; 3,846,541; 3,974,272; 4,172,120; 4,252,790; 4,340,585; 4,814,354; 4,874,744; 4,895,723; 5,695,749; and 6,066,336. Cholestyramine is commercially available from Novopharm, USA Inc. (Questrans Light), Upsher-Smith (PREVALITE (D) and Apothecon. As used herein, "cholestyramine" includes any such composition comprising cholestyramine or Pharmaceutically acceptable salts thereof These are also called Questrans ™.

Questran Light Questrans Light (cholestyramine) is a non-absorbable anion-binding resin approved by the FDA for the treatment of hypercholesterolemia.

An amine polymer having a first substituent, attached to a first amine of the amine polymer, that includes a hydrophobic aliphatic moiety, and a second substituent, attached to a second amine of the amine polymer, that includes a quaternary amine-containing moiety aliphatic as described in USP 5,693,675 and 5,607,669. The salt of an alkylated and cross-linked polymer comprising the reaction product of: (a) one or more cross-linked polymers, or salts and copolymers thereof, having a repeating unit selected from the group consisting of: (NR-C ^ CH2) n (2) and (NR-CH2CH2-NR-CH2CH2-NR-CH2CHOH-CH2) n (3), where n is a positive integer and each R, independently, is H or a C _{1- alkyl group} EC; (b) at least one aliphatic alkylating agent, said reaction product being characterized in that: (i) at least some of the nitrogen atoms of said repeating units did not react with said alkylating agent; (ii) less than 10 mole percent of the nitrogen atoms of said repeating units reacted with said alkylating agent to form quaternary ammonium units; and (iii) a fixed positive charge and one or more counter ions, such as Colesevelam and Colesevelam hydrochloride.

Useful bile acid binders are resins, such as cholestyramine and colestipol. An advantage is that the dose of bile acid binder could be kept lower than the therapeutic dose for the treatment of cholesterol in a single treatment comprising only one bile acid binder. A low dose of bile acid binder could also avoid any possible side effects caused by poor tolerance of the patient to the therapeutic dose.

Another useful bile acid binder is a non-toxic, water-insoluble polymeric amine having a molecular weight greater than 3,000, which has the property of binding at least 30% of the available glycocholic acid within 5 minutes when exposed to an aqueous solution of an equal weight of said acid, which has a polymer backbone inert to digestive enzymes, and which has a water content greater than 65% after equilibration with air at 100% relative humidity, for example, colestipol described in the document USP 3,383,281.

In one case, a suitable bile acid binder is one of cholestyramine, colestipol, or colesevelam.

In only one case, colesevelam is used as a bile acid binder.

The compositions may further comprise statins, for example, an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

Also disclosed is a combined oral pharmaceutical formulation comprising an IBAT inhibitor compound of Formula (I) or Formula (II), as defined above, or a pharmaceutically acceptable salt thereof, and a bile acid binder, or a salt. pharmaceutically acceptable thereof, said formulation being designed to deliver the bile acid binder in the colon and the IBAT inhibitor in the small intestine.

Also disclosed is a pharmaceutical formulation comprising a core of a bile acid binder formulated for release in the colon, surrounded by an outer layer comprising an IBAT inhibitor of Formula (I) or Formula (II), as defined above, and formulated for immediate release or delayed release in the distal jejunum or proximal ileum.

Statins

It is disclosed that an IBAT inhibitor compound, for example, a compound of Formula (I) or Formula (II), as defined above, or a pharmaceutically acceptable salt thereof, can be administered in association with an inhibitor of HMG Co- A reductase, or pharmaceutically acceptable salts thereof. Suitable HMG Co-A reductase inhibitors or pharmaceutically acceptable salts thereof are statins well known in the art. Particular statins are fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, bervostatin, dalvastatin, mevastatin, and (£) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino acid ] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxyhept-6-enoic acid (rosuvastatin) or a pharmaceutically acceptable salt thereof. A particular statin is atorvastatin or a pharmaceutically acceptable salt thereof. A more particular statin is a calcium salt of atorvastatin. A further particular statin is (£) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5- acid. dihydroxyhept-6-enoic acid (rosuvastatin) or a pharmaceutically acceptable salt thereof. Other particular statins are the calcium salt of rosuvastatin and pitavastatin (HMG CoA reductase).

It is also disclosed that the compound of Formula (I) or Formula (II), as defined above, or a pharmaceutically acceptable salt thereof, can be administered in association with an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt. thereof, and / or a bile acid binder thus avoiding a possible risk of excess bile acids in the colon caused by inhibition of the ileum bile acid transport system. An excess of bile acids in the visceral content can cause diarrhea.

An HMG CoA-reductase inhibitor, or a pharmaceutically acceptable salt thereof, by its action will reduce the endogenous cholesterol available for the synthesis of bile acids and will have an additive effect in combination with a compound of Formula (I) or Formula ( II), as defined above, or a pharmaceutically acceptable salt thereof, on lipid lowering.

The composition may further comprise a PPAR alpha and / or gamma agonist, or a pharmaceutically acceptable salt thereof.

A CETP (cholesteryl ester transfer protein) inhibitor, for example, referred to and described in WO 00/38725 page 7 line 22, page 10 line 17.

A cholesterol absorption antagonist, for example azetidinones such as SCH 58235 and those described in US 5,767,115;

an MTP (microsomal transfer protein) inhibitor, for example, those described in Science, 282,751-54, 1998; a derivative of fibric acid; for example, clofibrate, gemfibrozil, fenofibrate, ciprofibrate, and bezafibrate;

a derivative of nicotinic acid, for example, nicotinic acid (niacin), acipimox and niceritrol;

a phytosterol compound, for example stanols;

probucol;

an anti-obesity compound, for example orlistat (EP 129,748) and sibutramine (GB 2,184,122 and US 4,929,629);

An antihypertensive compound, for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergic blocker, an alpha adrenergic blocker, a beta adrenergic blocker, an alpha / beta adrenergic blocker mixed, an adrenergic stimulant, a calcium channel blocker, a diuretic, or a vasodilator;

Insulin;

Sulfonylureas, including glibenclamide and / or tolbutamide.

Biguanides

In some embodiments, the additional therapeutic agent is a biguanide. In some cases, biguanides lower blood and / or plasma glucose levels. Examples of biguanides include and are not limited to metformin, buformin, phenformin, proguanil, or the like.

The acarbose; or a pharmaceutically acceptable salt thereof, optionally, together with a pharmaceutically acceptable diluent or carrier for a warm-blooded animal, such as a human in need of such therapeutic treatment.

Angiotensin II antagonists

Preferred angiotensin II antagonists, or pharmaceutically acceptable salts thereof, for use in combination with a compound of Formula (I) include the compounds: candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan . Particularly preferred angiotensin II antagonists or pharmaceutically acceptable derivatives thereof are candesartan and candesartan cilexetil.

PPAR alpha and / or gamma and / or delta agonists or a pharmaceutically acceptable salt thereof.

It is also disclosed that the IBAT inhibitor compound, or a pharmaceutically acceptable salt thereof, can be administered in association with a PPAR alpha and / or gamma agonist, or pharmaceutically acceptable salts thereof. Suitable PPAR alpha and / or gamma agonists, or pharmaceutically acceptable salts thereof, are well known in the art. These include the compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996, 39 , 665, "Expert Opinion on Therapeutic Patents", 10 (5), 623-634 (in particular, the compounds described in the patent applications listed on page 634) and J Med Chem, 2000, 43, 527. In particular, A PPAR alpha and / or gamma agonist refers to WY-14643, Clofibrate, Fenofibrate, Bezafibrate, GW 9578, Troglitazone, Pioglitazone, Rosiglitazone, Eglitazone, Proglitazone, BRL-49634, KRP-297, JTT-501, SBT 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433.

Particularly, a PPAR alpha and / or gamma agonist refers to (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid and the pharmaceutically acceptable salts thereof.

It is also disclosed that the compound of Formula (I) or Formula (II), as defined above, can be used together with one or more antidiabetics, hypoglycemic active principles, cholesterol absorption inhibitors, PPAR delta agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein (a) antagonists, HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, active substances that act on the ATP-dependent potassium channel of beta cells , glycogen phosphorylase inhibitors, glucagon receptor antagonists, glucokinase activators, gluconeogenesis inhibitors , fructose-1,6-bisphosphatase inhibitors, glucose transporter 4 modulators, glutamine-fructose-6-phosphate amidotransferase inhibitors, dipeptidylpeptidase IV inhibitors, 11-beta-hydroxysteroid dehydrogenase 1 inhibitors, protein tyrosine phosphatase 1B, sodium-dependent glucose transporter 1 or 2 modulators, GPR40 modulators, hormone-sensitive lipase inhibitors, acetyl-CoA carboxylase inhibitors, phosphoenolpyruvate carboxykinase inhibitors, glycogen synthase inhibitors beta kinase-3, protein kinase C beta inhibitors, endothelin-A receptor antagonists, I kappaB kinase inhibitors, glucocorticoid receptor modulators, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, beta 3 agonists, CB1 receptor antagonists, MSH (melanocyte stimulating hormone), CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone releasing compounds, agonists TRH, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, PPAR modulators, RXR modulators, or TR-beta or amphetamine agonists.

It is disclosed that an IBAT inhibitor of Formula (I) or Formula (II), as defined above, can be administered in combination with a second therapeutic agent selected from a DPP-IV inhibitor, a thiazolidinedione, or an analog of the itself, or a TGR5 agonist.

It is disclosed herein that the IBAT inhibitor compounds described herein may be combined with or used in combination with one or more of the following therapeutic agents in any combination: insulin, insulin mimetics, DPP-IV inhibitors, or modulators. by TGR5.

Other active substances to be combined with one or more IBAT inhibitors of the invention can be selected from one or more of the following substances:

ursodeoxycholic acid; nor-ursodeoxycholic acid; rifampicin and related rifampicin derivatives as described in US 3,342,810; opiate antagonists, such as naloxone and naltrexone; serotonin antagonists such as 5-HT3 receptor antagonists and 5-HT2 antagonists, eg, trazodone, nefazodone, amoxapine, clozapine; antihistamines such as brompheniramine, chlorpheniramine dimenhydrate, diphenhydramine, doxylamine, loratadine cetirizine; serotonin reuptake inhibitors, such as citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, lindalpine, paroxetine, sertraline, zimelidine; corticosteroids, such glucocorticoids and mineralocorticoids, for example, those selected from hydrocortisone (cortisol), cortisone and acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone and aceterone acetate (desoxycortisone), and aceterone DOCtate (desolate).

Examples of PPAR agonists are GW-501516 (501516, GSK-516, GW-516, GW-1516; a peroxisome proliferation activated receptor (PPAR) -delta agonist, and various other compounds developed from GW -501516, including GI-262570, GW-0072, GW-7845 and GW-7647.

It is described that the IBAT inhibitor can be combined with one or more of otorleuton, eprothyroid, losmapimod, ezetimibe (SCH58235), bezafibrate, fenofibrate, varespladib, darapladib, lomitapide, implitapide, rosiglitazin, dalcetragliflozin, dalcetragliflozin, serpagliflozifin, serpagliflozifin, serpagliflozin , ASP-1941, orlistat, pioglitazone, sodelglitazar, netglitazone, indeglitazar, naveglitazar, lobeglitazone, aleglitazar, bromocriptine, tesofensin, monoamine, alogliptin, vildagliptin, saxagliptin, sitagliptin, denagliptin, dutogliptin, litoptin teneligliptin, LC-150444, laropiprant, extended-release niacin, simvastatin ezetimibe, rosuvastatin fenofibrate, rosuvastatin ezetimibe, and atorvastatin ezetimibe.

Combinations with Tredaptive, Vytorin, and Certriad can be used.

According to one embodiment, the IBAT inhibitor can be combined with one or more of any of the other compounds mentioned above.

It is disclosed that IBAT inhibitors can be combined with at least one other active substance selected from dipeptidyl peptidase-IV inhibitors, PPAR agonists, and statins and bile acid binders in any combination.

It is disclosed that IBAT inhibitors can be combined with at least one DPPIV, at least one PPAR agonist, and such as sitagliptin and pioglitazone.

It is disclosed that IBAT inhibitors can be combined with at least one DPPIV and at least one statin, eg, sitagliptin and simvastatin.

Another active substance that can be combined with the IBAT inhibitors of the invention is ursodeoxycholic acid.

Carriers and excipients

The compositions of the invention may also comprise a pharmaceutically acceptable diluent or carrier.

Pharmaceutical compositions can be formulated as is known in the art using one or more physiologically acceptable carriers including, for example, excipients and depending on the selected route of administration.

A carrier includes, in some embodiments, a pharmaceutically acceptable excipient, and is selected based on compatibility with the compounds described herein, such as, compounds of any of Formula I and II, and the properties of the release profiles of the desired dosage form.

Exemplary carrier materials include, for example, binders, suspending agents, disintegrating agents, bulking agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents.

Pharmaceutical compositions and carriers are described, for example, in "Remington: The Science and Practice of Pharmacy", Nineteenth Ed. (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., "Pharmaceutical Dosage Forms", Marcel Decker, New York, N.Y., 1980; and "Pharmaceutical Dosage Forms and Drug Delivery Systems", Seventh Ed. (Lippincott Williams and Wilkins 1999).

A mixture of a compound of Formula I and II, and possibly also other active compounds mentioned herein, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents and / or other excipients can be formulated into a composition. In certain embodiments, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to an individual who has a disease, disorder, or condition to be treated. In specific embodiments, the individual is a human. The compounds described herein are used alone or in combination with one or more additional therapeutic agents.

In certain embodiments, the pharmaceutical formulations described in the present disclosure are administered to an individual in any manner, including one or more of multiple routes of administration, such as, by way of example, oral, parenteral routes of administration, (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal or transdermal.

The pharmaceutical compositions described herein are formulated as a dosage form. As such, in some embodiments, the present disclosure provides a dosage form comprising a compound described herein, suitable for administration to an individual. In certain embodiments, suitable dosage forms include, by way of example, aqueous, liquid oral dispersions, gels, syrups, elixirs, slurries, suspensions, solid dosage forms, aerosols, controlled release formulations, fast melt formulation, effervescent formulations. , lyophilized formulations, tablets, powders, pills, lozenges, capsules, delayed-release formulations, prolonged-release formulations, pulsed-release formulations, multiparticulate formulations, and mixed immediate-release and controlled-release formulations.

The solid dosage forms described herein include an additional therapeutic compound described herein and one or more compatible pharmaceutically acceptable additives such as a carrier, binder, bulking agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moisturizing agent, plasticizer, stabilizer, penetration enhancer, wetting agent, agent antifoam, antioxidant, preservative, or one or more combinations thereof. In some aspects, using conventional coating procedures, such as those described in "Remington's Pharmaceutical Sciences", 20th Edition (2000), a film coating is provided around the formulation of the compound of Formula I-II. In one embodiment, a compound described herein is in the form of a particle, and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of a compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are uncoated.

Dosage forms

Solid dosage forms can optionally include additional therapeutic compounds and one or more compatible pharmaceutically acceptable additives such as a carrier, binder, bulking agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moisturizing agent, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoam agent, antioxidant, preservative, or one or more combinations thereof. In some aspects, using conventional coating procedures, such as those described in "Remington's Pharmaceutical Sciences", 20th Edition (2000), a film coating is provided around the formulation of the compound of Formula I-II. In one embodiment, a compound described herein is in the form of a particle, and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of a compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are uncoated.

A dosage form comprises a matrix that allows the controlled release of an active agent in the distal jejunum, proximal ileum, distal ileum, and / or the colon. In some embodiments, a dosage form comprises a polymer that is pH sensitive (eg, a MMX. ™ matrix from Cosmo Pharmaceuticals) and allows for the controlled release of an active agent in the ileum and / or the colon. Examples of such pH-sensitive polymers suitable for controlled release include, and are not limited to, polyacrylic polymers (eg, anionic polymers of methacrylic acid and / or esters of methacrylic acid, eg, Carbopol.R ™ polymers (number CAS 9063-87-0), which comprise acidic groups (eg, -COOH, -SO3H) and swell at the basic pH of the intestine (eg, pH from about 7 to about 8). In some embodiments, a form A suitable dosage form for controlled release in the distal ileum comprises microparticulate active agent (eg, micronized active agent). In some embodiments, a nonenzymatic degradation poly (dl-lactide-co-glycolide) (PLGA) core is suitable for delivery of an IBAT to the distal ileum In some embodiments, a dosage form comprising an IBAT is coated with an enteric polymer (eg, Eudragit.R ™ S-100 (CAS number: 25086-15-1), acetate -cellulose phthalate, polyvinyl phthalate, hydroxypropylmethylcellulose phthalate, anionic methacrylic acid polymers, methacrylic acid esters or the like) for site-specific delivery in the ileum and / or colon. In some embodiments, bacterially activated systems are suitable for delivery directed to the ileum. Examples of microflora activated systems include dosage forms comprising pectin, galactomannan, and / or azohydrogels and / or glycoside conjugates (eg, D-galactoside, beta-D-xylopyranoside conjugates, or the like) of the active agent. Examples of gastrointestinal microflora enzymes include bacterial glycosidases such as, for example, D-galactosidase, beta-D-glucosidase, alpha-L-arabinofuranosidase, beta-D-xylopyranosidase, or the like.

The coated units can be filled into hard gelatin capsules or mixed with tablet excipients, such as fillers, binders, disintegrants, lubricants, and other pharmaceutically acceptable additives, and compressed into tablets. Optionally, the compressed tablet is covered with film-forming agents, obtaining a smooth surface of the tablet and also enhancing the mechanical stability of the tablet during packaging and transport. Such a tablet coating, which can be applied over a multi-unit tablet or a conventional tablet, may further comprise additives such as anti-tack agents, colorants and pigments or other additives to improve the appearance of the tablet.

Suitable drugs for the new formulations are IBAT inhibitor compounds such as those described in the documents mentioned above.

The IBAT inhibitor compound could alternatively be a low permeability drug as defined in the FDA's proposed biopharmaceutical classification system.

A combination therapy as described herein should preferably comprise the simultaneous, separate or sequential administration of an IBAT inhibitor compound and a bile acid binder. The IBAT inhibitor could preferably be formulated for delivery to the ileum and the bile acid binder could preferably be a colon release formulation.

Dose

The compound of Formula (II), or a pharmaceutically acceptable salt thereof, will normally be administered to a warm-blooded animal at a unit dose within the range of 5-5000 mg per square meter of body area of the animal, i.e., about 0.1 to 100 mg or 0.01 to 50 mg, and this usually provides a therapeutically effective dose. A unit dose form such as a tablet or capsule will usually contain, for example, 1-250 mg of active ingredient. Preferably, a daily dose in the range 1-50 mg is employed. In another case, a daily dose in the range of 0.02-20 mg is employed. However, the daily dose will necessarily vary depending on the host treated, the particular route of administration, and the severity of the disease being treated.

Consequently, the optimal dose can be determined by the medical professional treating any particular patient.

The size of the dose required for therapeutic or prophylactic treatment will necessarily vary depending on the host treated, the route of administration and the severity of the disease being treated. A unit dose in the range of, for example, 1 to 100, preferably 1 to 50 is contemplated. The daily dose can be administered as a single dose or divided into one, two, three or more unit doses.

A pharmaceutical formulation according to the present invention with a delivery directed to the gastrointestinal tract provides a reduced systemic exposure, as measured by the Area Under the Curve (AUC) of drug plasma concentration versus time or 7a - hydroxy-4-cholesten-3-one (C4), while maintaining or even enhancing the therapeutic effect, as measured, for example, by lowering serum cholesterol.

A combination therapy comprising an IBAT inhibitor and a bile acid binder preferably comprises a low daily dose of the bile acid binder, such as less than 5 g of a resin, and more preferably, less than 2 g. A colon release dosage form of the bile acid binder could be constructed by any of the principles described above for delayed release formulations.

A combination therapy comprising an IBAT inhibitor and a bile acid binder may comprise a low daily dose of the bile acid binder, such as less than 5 g of a resin, and more preferably, less than 4, 3, 2 or less than 1 g. Suitable ranges can be 0.1 to 5 g, 0.5 to 4 g, 1 to 3 g, 2 to 4 g, 2 to 3 g per day. A colon release dosage form of the bile acid binder could be constructed by any of the principles described above for delayed release formulations.

A tablet may consist of an inner core of 1 to 1000 mg, for example 200 to 800 mg, 10 to 400 mg, 10 to 200 mg or 20 to 80 mg of acid binder in a delivery formulation in the colon and an outer lamina with 1 to 100 mg, 5 to 50 mg, eg, 1 to 20 mg of an IBAT inhibitor.

The daily dose of IBAT inhibitor and / or bile acid binder can be administered as a single dose or divided into one, two, three or more unit doses.

Dosing three times daily with 400 mg of colesevelam in a colonic-release formulation will provide adequate bile acid binding in the colon, as the total lumen volume is expected to be approximately 100 mL, which is consistent with an accepted pharmacokinetic calculation volume of 250 to 300 ml for the small intestine. The total recommended daily dose of colesevelam to block the absorption of bile acids in the total intestine of humans is 3750 mg / day.

The following contemplated examples are intended to illustrate the invention.

The term "comprising", as used herein, should be understood to include, but is not limited to, stated articles.

Example 1

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(ph) -a- [W- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5 -tetrahydro-1,2,5-benzothiadiazepine, MW. 696.89.

This compound is prepared as described in Example 2 of WO3022286.

Example 2

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2 , 3,4,5-tetrahydro-1,5-benzothiazepine, PM. 709.92.

This compound is prepared as described in Example 2 of WO03106482.

Example 3

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1-carboxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2 , 3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw 724.94.

This compound is prepared as described in Example 6 of WO3022286.

Example 4

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((R) -1-carboxy-2-methylthioethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, MW. 757.01.

This compound is prepared as described in Example 7 of WO3022286.

Example 5

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, MW. 740.94.

This compound is prepared as described in Example 29 of WO3022286.

Example 6

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -a- [A / - ((ph) -1-carboxy-2-methylthio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, MW. 773.00.

This compound is prepared as described in Example 30 of WO3022286.

Example 7

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1-carboxy-2-methylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, MW. 738.97.

This compound is prepared as described in Example 15 of WO3022286.

Example 8

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1-carboxy-2- (R) -hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, MW. 756.94.

This compound is prepared as described in Example 26 of WO3022286.

Example 9

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1-carboxybutyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, MW. 754.97.

This compound is prepared as described in Example 28 of WO3022286.

Example 10

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2 , 3,4,5-tetrahydro-1,2,5-benzothiadiazepine, PM. 710.91.

This compound is prepared as described in Example 5 of WO3022286.

Example 11

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine, Mw 739.95.

This compound is prepared as described in Example 1 of WO3022286.

Example 12

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1-carboxyethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, MW. 726.91. This compound is prepared as described in Example 11 of WO3022286.

Example 13

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4 -hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, MW. 754.97.

This compound is prepared as described in Example 27 of WO3022286.

Example 14

1.1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -1'-phenyl-1 '- [W- (carboxymethyl) carbamoyl) methyl} carbamoylmethoxy) -2 , 3,4,5-tetrahydro-1,5-benzothiazepine, PM. 695.90.

This compound is prepared as described in Example 43 of WO0250051.

Example 15

Average inhibitory effect of the pharmaceutical effect (%)

The mean IC50 (nM) of the IC50 of the radiometric SPA inhibitor, the glycolic acid uptake in human HEK, the ileum bile acid transporter SPA 13203 IBAT HUM and the HEK Hu uptake of ISBT were determined for the compounds of the Examples 1-14.

Test system

Animals

Species: mouse; Strain: ApoE inactivated; Substrain: C57BL / 6; Sex: female; Total number of animals: 70; Body weight range: 20g to 22g; Supplier: Mollegaard’s Breeding (Skensved, Denmark); Identification method: ID cards (barcode).

Acclimatization: At least one week in the laboratory section; Animal resources at AstraZeneca; Housing conditions: five by five are kept in cages (Makrolon III, 7 dm2) in a room with regulated temperature (22 0C), relative humidity (40% to 60%) and a 12/12 light / dark cycle hours. Diet: free access to R3 granules (Lactamin, Vadstena, Sweden) during accommodation and the experimental period. Water: free access to running water during the accommodation and the experimental period.

Bed: granular bed of poplar wood (Tapvei, Finland).

Experimental procedures

The animals received orally vehicle (n = 3) or the compound of Example 14 (0.156 (n = 3), 0.625 (n = 3) or 2.5 pmol / kg (n = 3)) at 1:00 p.m. o'clock on the experimental day. Thirty minutes later, each mouse orally received a trace amount of 75SeHCAT (75Se-homo-tauro-cholic acid) (0.1 mCi per 0.1 ml per mouse). Twenty-four hours after administration of 75SeHCAT, the animals were sacrificed by CO2 inhalation. At sacrifice, the entire gallbladder and intestines were removed, and feces were collected for the 24 hour period after 75SeHCAT administration for each mouse. The gamma radioactivities of 75SeHCAT in the stool and in the gallbladder-intestine were counted separately using a 1282 CompuGamma CS gamma counter (Wallac oy, Turku, Finland). Stability, as well as the amount of 75SeHCAT administered to each mouse, was monitored with an additional 75SeHCAT aliquot following the same experimental process as the other samples tested in the study.

Analysis of data

The sum of the gamma counts of both the stool and the gallbladder-intestine was considered the total recovered 75SeHCAT, which turned out to be, on average, approximately 85% of the total 75SeHCAT administered to each mouse. Of the radioactivity recovered from 75SeHCAT, the percentage of 75SeHCAT detected in the feces was considered as faecal excretion, while that detected in the gallbladder-intestine was considered as body retention. The inhibitory effect of the compound of Example 14 on intestinal absorption of 75SeHCAT after fecal excretion and body retention of 75SeHCAT was calculated, and the ED50 of the compound was estimated following the dose-effect curve.

Results

The mean inhibitory effect of IBAT (%) was determined at a dose (pmol / kg): 0.156 for the compounds of Examples 1-14 and is presented in Table 1.

Table 1

Example 16

In vivo animal model of primary sclerosing cholangitis (PSC)

Genetic mice with targeted alteration of the multidrug resistant Mdr2 ( Abcb4) gene encoding a canalicular phospholipid lipase ( Mdr2 - / - mice) spontaneously develop sclerosing cholangitis with macroscopic and microscopic features of human primary sclerosing cholangitis. The injury to the bile duct of these mice is linked to a defective bile phospholipid secretion that produces an increase in the concentration of free non-micellar bile acids that subsequently cause damage to the epithelial cells of the bile duct (cholangiocyte). pericholangitis, periductal fibrosis with ductular proliferation, and finally sclerosing cholangitis. The gene expression profile has revealed remarkable similarities between Mdr2-l- and human CEP. In analogy to the mouse model Mdr2 - / - sclerosing cholangitis, defects resistant protein multidrug MDR3 / ABCB4 (the human orthologue of Mdr2 / ABCB4 rodent) play a role in the pathogenesis of various cholangiopathy in humans. MDR3 variants play a role as a modifying gene in the pathogenesis of various cholangiopathies such as PSC, primary biliary cirrhosis (PBC), and adult idiopathic ductopenia / biliary fibrosis.

Mdr2 - / - mice received doses of the compound of Example 14 orally by gavage for 2-4 weeks, and controls received vehicle in the same way. Serum liver tests, liver histology, and fibrosis were investigated. The compound of Example 14 improves liver tests, liver histology, and fibrosis.

Example 17

A formulation for the delayed release of the IBAT inhibitor is prepared having the following composition: Substance Can

IBAT inhibitor compound

Example 14 10

Non-granulated spheres 500

Ethylcellulose 2

Hydroxypropylmethylcellulose 10

Eudragit L100-55, CAS No: 25212-88-8 25

2.4 triethyl citrate

The IBAT inhibitor compound of Example 14 is dissolved together with ethylcellulose and hydroxypropylcellulose in 99% ethanol. The mixture is then sprayed onto the non-granulated spheres in a fluidized bed apparatus. After that, the granules are dried and aerated to remove residual ethanol. Then, the Eudragit L100-55 dispersion with addition of triethyl citrate is sprayed onto the drug beads in a fluidized bed apparatus. Subsequently, the coated beads are loaded into hard gelatin capsules after drying and sieving.

Example 18

A formulation for the delayed release of the IBAT inhibitor is prepared having the following composition: Ingredient Amount / tablet (mg)

IBAT inhibitor compound

Example 14 10

Silicon dioxide 200

Povidone K-25 20

Eudragit FS30D, CAS No. #: 26936-24-3 30

Microcrystalline cellulose 250

Sodium stearyl fumarate 5

The IBAT inhibitor compound of Example 14 is suspended in water and sprayed onto silicon dioxide cores of a predefined size in a fluidized bed apparatus. The drug granules are dried in an oven at 40 ° C for 24 h. After that, a layer of povidone K-25 is applied on the beads from an ethanolic solution in a fluidized bed apparatus. Thereafter a dispersion topcoat of Eudragit FS30D is applied in a fluidized bed. The coated beads are mixed with microcrystalline cellulose and sodium stearyl fumarate in a mixer and subsequently compressed into tablets.

Example 19

A combination tablet of IBAT inhibitor and colesevelam is prepared with immediate release of the IBAT inhibitor and release in the colon of the bile acid binder having the following composition: Ingredient Quantity / tablet (mg)

Core

Colesevelam Hydrochloride 400

Microcrystalline Cellulose 150

Hydroxypropylmethylcellulose 50

Colloidal Silicon Dioxide 10

Magnesium stearate 5

Release layer in the colon

Eudragit FS30D 60

PlasACRYL T20, CAS No. 123-94-4 6

IBAT inhibitor layer

IBAT inhibitor Example 14 7

Hydroxypropylmethylcellulose 12

Croscarmellose sodium 6

Protective coating

Hydroxypropylmethylcellulose 12

Polyethylene glycol 2

Colesevelam hydrochloride, microcrystalline cellulose and colloidal silicon dioxide are mixed and granulated with hydroxypropylmethylcellulose dissolved in water. The granules are dried and mixed with magnesium stearate, and compressed to give tablets. The EUDRAGIT FS30D dispersion and water are stirred in the PlasACRYL T20, and sprayed onto the core tablets using a suitable coating machine. The IBAT inhibitor coating suspension is prepared by mixing the IBAT inhibitor, hydroxypropylmethylcellulose and croscarmellose sodium in water, and sprayed onto the tablet cores with the release layer in the colon using a suitable coating machine. Finally, the hydroxypropylmethylcellulose and polyethylene glycol protective coating solution is sprayed onto the tablets using a suitable coating machine.

Example 20

A colonic release tablet of colesevelam is prepared having the following composition:

Ingredient Amount / tablet (mg)

Core

Colesevelam Hydrochloride 400

Microcrystalline Cellulose 150

Hydroxypropylmethylcellulose 50

Colloidal Silicon Dioxide 10

Magnesium stearate 5

Release layer in the colon

Amylose 30

Eudragit S100 60

Triethyl citrate 6

Glycerol monostearate 3

Colesevelam hydrochloride, microcrystalline cellulose and colloidal silicon dioxide are mixed and granulated with hydroxypropylmethylcellulose dissolved in water. The granules are dried and mixed with magnesium stearate, and compressed to give tablets. Amylose, Eudragit 100, triethyl citrate and glyceryl monostearate are dissolved in suitable solvents and sprayed onto the tablet cores using a suitable coating machine.

Claims (12)

A compound of Formula II where M is CH2 or NH; R1 is H or hydroxy; R2 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH (CH3) 2, -CH2CH (CH3) 2, -CH (CH3 ) CH2CH3, -CH2OH, -CH2OCH3, -CH (OH) CH3, -CH2SCH3 or -CH2CH2SCH3; or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of general cholestasis. The compound for use according to Claim 1, wherein the compound of Formula II is selected from the group consisting of: 1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(ph) -a- [W- (carboxymethyl) carbamoyl) benzyl} carbamoylmethoxy) -2.3.4.5- tetrahydro-1 2,5-benzothiadiazepine; 1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(ph) -a- [W - ((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2.3 .4.5- tetrahydro-1,5-benzothiazepine; 1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((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- (A / - {(phi) -a- [W - ((phi) -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- (A / - {(ph) -a- [A / - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(ph) -a- [Á / - ((ph) -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- (A / - {(ph) -a- [Á / - ((S) -1-carboxy-2-methylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(ph) -a- [W - ((S) -1-carboxy-2- (ph) -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- (A / - {(ph) -a- [Á / - ((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- (W - {(ph) -a- [W - ((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- (Á / - {(ph) -a- [A / - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((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- (A / - {(ph) -a- [A / - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; Y 1.1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(ph) -1'-phenyl-1 '- [W- (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy) -2.3 .4.5- tetrahydro-1,5-benzothiazepine or one of its pharmaceutically acceptable salts. The compound for use according to claim 1 or 2, wherein the compound of Formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) - a- [W - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2.3.4.5- tetrahydro-1, 2,5-benzothiadiazepine or one of its pharmaceutically acceptable salts. The compound for use according to claim 1 or 2, wherein the compound of Formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) - 1'-phenyl-1 '- [W- (carboxymethyl) -carbamoyl] methyl} carbamoylmethoxy) -2. 3. 4.5- tetrahydro-1,5-benzothiazepine or one of its pharmaceutically acceptable salts. 5. The compound 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a- [W - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of general cholestasis. 6. The compound 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -1'-phenyl-1 '- [N- (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine, or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of general cholestasis. 7. The compound for use according to any one of claims 1 to 6, wherein the general cholestasis is intrahepatic or extrahepatic cholestasis. The compound for use according to any one of claims 1 to 6, wherein the general cholestasis is jaundice due to drugs or jaundice of pregnancy. 9. A pharmaceutical composition comprising a compound of Formula (II)

where M is CH2 or NH; R1 is H or hydroxy; R2 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH (CH ^, -CH2CH (CH3) 2, -CH (CH3) CH2CH3, -CH2OH, -CH2OCH3, -CH (OH) CH3, -CH2SCH3 or -CH2CH2SCH3; or one of its pharmaceutically acceptable salts, for use in the prophylaxis or treatment of general cholestasis. The pharmaceutical composition for use according to claim 9, wherein the compound of Formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(fi ) -a- [A / - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2.3.4.5- tetrahydro-1,2,5-benzothiadiazepine or a pharmaceutically acceptable salt thereof. The pharmaceutical composition for use according to claim 9, wherein the compound of Formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -1'-phenyl-1 '- [W- (carboxymethyl) -carbamoyl] methyl} carbamoylmethoxy) -2.3.4.5- tetrahydro-1,5-benzothiazepine or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical combination for simultaneous or sequential administration, comprising a compound of Formula II

where M is CH2 or NH; R1 is H or hydroxy; R2 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH (CH3) 2, -CH2CH (CH3) 2, -CH (CH3) CH2CH3, -CH2OH, -CH2OCH3, -CH (OH) CH3, - CH2SCH3 or -CH2CH2SCH3; or one of its pharmaceutically acceptable salts, and ursodeoxycholic acid, for use in the prophylaxis or treatment of general cholestasis. A pharmaceutical combination for simultaneous or sequential administration, comprising a compound of Formula II

where M is CH2 or NH; R1 is H or hydroxy; R2 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH (CH3) 2, -CH2CH (CH3) 2, -CH (CH3) CH2CH3, -CH2OH, -CH2OCH3, -CH (OH) CH3, - CH2SCH3 or -CH2CH2SCH3; or one of its pharmaceutically acceptable salts, and nor-ursodeoxycholic acid, for use in the prophylaxis or treatment of general cholestasis. The pharmaceutical combination for use according to claim 12, wherein the compound of Formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -a - [W - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine or a pharmaceutically acceptable salt thereof. The pharmaceutical combination for use according to claim 12, wherein the compound of Formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(fí) -1 '-phenyl-1' - [W- (carboxymethyl) -carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine or a pharmaceutically acceptable salt thereof.