use of an ibat inhibitor and a bile acid coagulant, and pharmaceutical formulation

专利摘要:
USE OF AN IBAT INHIBITOR AND A BILIARY ACID COAGULANT, PHARMACEUTICAL FORMULATION AND ITS USE, AS WELL AS A KIT. The present invention relates to a combination comprising a substance with an inhibitory effect on the ileal bile acid transport system (IBAT) and at least one other active substance selected from an IBAT inhibitor; an enteroendocrine peptide or enhancer thereof; a dipeptidyl peptidase-IV inhibitor; a biguanidin a; an incretin mimetic; a thiazolidinone; a PPAR agonist; an HMG Co-A reductase inhibitor; a bile acid binder; and a TGR5 receptor modulator; wherein the IBAT inhibitor compound and at least one other active substance are administered simultaneously, consecutively or separately.
公开号:BR112013010705B1
申请号:R112013010705-7
申请日:2011-11-08
公开日:2020-11-17
发明作者:Per-Gôran Gillberg；Hans Graffner；Ingemar Starke
申请人:Albireo Ab；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[1] The present invention relates to a combination comprising a substance with an inhibitory effect on the ileal bile acid transport system (IBAT) and at least one other active substance such as a bile acid binder. BACKGROUND OF THE INVENTION
[2] It is well known that hyperlipidemic conditions associated with high concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interference with the circulation of bile acids within the lumen of the intestinal tract is found to reduce the level of cholesterol. Therapies established to reduce cholesterol concentration involve, for example, treatment with HMG-CoA reductase inhibitors, preferably statins such as simvastin and fluvastine, or treatment with bile acid binders, such as resins. Frequently used weak acid binders are, for example, cholestyramine, colestipol and colesevelam. Someone recently proposed therapy that involves treatment with substances with an inhibitory effect on the ileal bile acid transport system (IBAT).
[3] Bile acid reabsorption from the gastrointestinal tract is a normal physiological process that mainly occurs in the ileum by an active transport mechanism called ileal bile acid transport (IBAT). IBAT inhibitors can be used to treat hypercholesterolemia. See, for example, "Interaction of bile acids and cholesterol with nonsistemic agents having hypocholesterolemic properties", Biochemica et Biophisica Acta, 1210 (1994) 255 - 287. Therefore, the suitable compounds that have such inhibitory IBAT activity are the same useful in the treatment of hyperlipidemic conditions.
[4] Several chemical compounds that have such IBAT activity have been described recently, see, for example, hypolipidemic benzothiazepine compounds described in WO 93/16055 and WO 96/16051; Condensed 1,4-thiazepines described in WO 94/18183; different heterocyclic compounds described in WO 94/18184; and 1,4-benzothiazepine-1,1-dioxides described in WO 96/05188. Besides that; WO 96/08484; bile acid reabsorption inhibitors described in WO 97/33882, WO 98/07449, WO 98/03818, WO 98/40375, WO 99/35135, WO 9964409, WO 99/64410, WO 00/01687, WO 00/47568 , WOOO / 61568, DE 19825804, WO 00/38725, W00038726, WO 00/38727, WOOO / 38728, WOOO / 38729, W001 / 68096, WO 01/66533, WO 02/50051, WO 02/32428, WO 03 / 020710, WO 03/022825, WO 03/022830, WO 03/022286, WO 03/061663, WO 03/091232, WO 03/09106482, WO 04/006899, WO 04/076430, WO 07/009655, WO 07009656, WO 08/058630, EP 864582, EP 489423, EP 549 967, EP 573 848, EP 624 593, EP 624 594, EP 624 595, EP 624 596, EP 0864582, EP 1173205.
[5] In general, pharmaceutical drug substances will be absorbed into the small intestine, and therefore only a small amount will reach the ileum when administered in a conventional oral dosage form. Regardless of the construction of the pharmaceutical dosage form, it should provide contact for the active compound, for example, IBAT inhibitor, with the site of the compound of action in the body, for example, in the ileum. The prior art documents above discuss in general terms the suitable pharmaceutical dosage forms for the IBAT inhibitor compounds described in general. However, none of the documents describes a specific way to obtain a release of the active substance directly to or near the site of action. The contact between the active drug and the site of action can be established in different ways.
[6] Inhibition of bile acid reabsorption from the small intestine performed by an effective IBAT inhibitor can lead to increased levels of bile acids in the lower parts (colon) of the gastrointestinal tract. Such an increase in bile acid concentrations in the distal regions could potentially generate diarrhea and discomfort to the patient. The present invention provides a new method for minimizing the concentration of free bile acids in the colon and thus reducing the potential risk of adverse events by co-administering a bile acid binder together with the IBAT inhibitor. However, the combination of an IBAT inhibitor and a bile acid binder has been previously proposed in the above patent applications that describe the new IBAT inhibitor compounds. The purpose of such previously described combinations was to enhance the effectiveness of cholesterol-lowering therapy. EP1173205 describes that such a combination can be used to minimize a potential risk of diarrhea connected with IBAT inhibitor therapy. BRIEF DESCRIPTION OF THE INVENTION
[7] The purpose of the present invention is to provide a combination for simultaneous, separate or sequential administration, the combination of which comprises an IBAT inhibitor and a bile acid binder. Such a combination will protect the patient from any possible side effect caused by excess bile acids in the colon, such as diarrhea. If the transport of bile acids is blocked by an IBAT inhibitor, bile acids could be deposited in the colon and induce secretory diarrhea as an unwanted side effect caused by treatment with an IBAT inhibitor.
[8] In the combination therapy provided, the bile acid binder, for example, a resin such as cholestyramine, colestipol or colesevelam can be administered in a dosage form with release into the colon of the bile acid binder. A colon release formulation will provide protection from bile acid binder to luminal contents in the most proximal parts of the intestine where bile acid concentrations are high. Such a formulation will prevent the binding of bile acids to the bile acid binder before the formulation reaches the colon. In this way, maximum bile acid binding capacity will be obtained in the colon and any possible gastrointestinal side effect, such as diarrhea, can be avoided. In this way, any additional amount of bile acid presented in the colon due to treatment with the IBAT inhibitor compound would be linked to a bile acid binder in which the bile acid binder is preferably released into the colon, thereby any possible side effects. such as diarrhea are avoided and maximum excretion of bile acids will be achieved (blocking IBAT from IBAT will let more bile acids pass into the colon where they will be bound to bile acid binders which result in no passive absorption of bile acids from the colon). The release of bile acid binders into the colon will decrease the dose needed to archive the pharmacological effects of the binder.
[9] An additional aspect of the invention is that an increased effect can be obtained by binding the unconjugated bile acids in the colon and inhibiting uptake in the colon. This leads to another decrease in bile acid levels and an increase in the use of cholesterol for bile acid synthesis, resulting in lower plasma cholesterol levels.
[10] In addition, the colon's stimulating effect of bile acids is limited, which leads to a decrease in the occurrence of diarrhea. In addition, bile acid salts are eluted to a greater extent without affecting the absorption of lipid-soluble vitamins A, D, E and K in the small intestine. According to one embodiment, an increased efficacy is obtained using an IBAT inhibitor according to Formula (I) or Formula (II) including the compounds of examples 1-14. DETAILED DESCRIPTION OF THE INVENTION
[11] One aspect of the present invention is a combination designed to deliver the bile acid binder to the colon and the IBAT inhibitor to the small intestine, said combination being planned for the administration of the IBAT inhibitor and bile acid binder simultaneously, separately or consecutively. IBAT inhibitor compounds
[12] Suitable active ingredients as IBAT inhibitor compounds in the present invention are those exhibiting activity when evaluating the IBAT inhibiting properties. In the literature, IBAT inhibitors are often referred to by different names. It should be understood that where IBAT inhibitors are referred to here, this term also encompasses compounds known in the literature as: i) ileal apical sodium codependent bile acid transporter (ASBT) inhibitors; ii) bile acid transporter (BAT) inhibitors; iii) ileal bile acid / sodium cotransporter system inhibitors; iv) apical bile-sodium acid transporter inhibitors; v) ileal 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.
[13] Suitable examples of such compounds can be found in the references cited above under the heading "background of the invention and prior art".
[14] Active ingredients particularly suitable as IBAT-inhibiting compounds in the present invention include benzothiazepines, and more particularly benzothiazepines, 1,4-benzothiazepines, 1,5-benzothiazepines, 1,2,5-benzothiadiazepines exhibiting activity when evaluating properties of IBAT inhibition.
[15] In another aspect of the invention, preferred IBAT inhibitors are those in WO 02/50051, WO 03/02286 and WO 03/106482.
[16] Other useful bile IBAT inhibitors are described in WO9932478, WO0168637, W003022804, W00001687 and US 2010/0130472 A1 among these 1- [4- [4 - [(4R, 5R) -3,3-dibutyl-7 - (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxide-1-benzothiepin-5-yl] phenoxy] butyl] 4-aza-1-azoniabicyclo [2.2.2 ] octanomethanesulfonate.
[17] One aspect of the present invention is a combination comprising
[18] A compound of Formula (I)
on what:
[19] M is CH2, NH,
[20] One of R1 and R2 is selected from hydrogen or C-ealkyl, and the other is selected from C-ealkyl;
[21] Rx and Ry are independently selected from hydrogen, hydroxy, amino, mercapto, Ci-βalkyl, Ci-ealoxy, A / - (C-βalkyl) amino, A /, A / - (Ci-ealkyl) 2amino, Ci -6alkylS (O) where a is 0 to 2
[22] Rz is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, Ci-βalkyl, C2-βalkenyl, C2-βalquinyl, Ci-βalcanoila, Ci-βalcanoyloxi, A / - (Ci -βalkyl) amino, N, N- (Ci-βalkyl) 2amino, Ci-βalkanoylamino, A / - (Ci-βalkyl) carbamoyl, N, N- (Ci-βalkyl) 2carbamoyl, Ci-6alkylS (0) is 0 to 2, C-alkoxycarbonyl, A / - (C1-6alkyl) sulfamoyl, and A /, A / - (C1-6alkyl) 2Sulfamoyl;
[23] v is 0-5;
[24] one of R4 and R5 is a Formula (IA) group:
(IA)
[25] R3 and R6 and the other among R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, Ci-4alkyl, C2-4alkenyl, C2-4alquinyl , C-ualkoxy, C1-4alkanoyl, C1-4alkanoyloxy, A / - (C1-4alkyl) amino, A /, A / - (C1-4alkyl) 2amino, C-Malcanoylamino, A / - (Ci-4alkyl) carbamoyl, A /, A / - (C1-4alkyl) 2 carbamoyl, C1-4alkylS (O) a where a is 0 to 2, C1-4 alkoxycarbonyl, / V- (C1-4 alkyl) sulfamoyl, and A /, A / - (C1-4alkyl) 2Sulfamoyl; wherein R3 and R6 and the other one between R4 and R5 can be optionally substituted on carbon by one or more R16;
[26] X is -O-, -N (Ra) -, -S (O) b- or -CH (Ra) -; where Ra is hydrogen or C-i-ealkyl, and b is 0-2;
[27] Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R17;
[28] R7 θ hydrogen, C1-4alkyl, carbocyclyl, or heterocyclyl; where R7 is optionally substituted by one or more substituents selected from R18-
[29] Re θ hydrogen or Ci-4alkyl;
[30] R9 θ hydrogen or Ci-4alkyl;
[31] R10is hydrogen, C-Malquila, carbocyclyl, or heterocyclyl, where R10θ optionally substituted by one or more substituents selected from R ^ θ-
[32] R11 £ carboxy, sulpho, sulfine, phosphono, P (O) (ORc) (ORd), P (O) (OH) (ORC), P (O) (OH) (Rd) or P (O) (ORc) (Rd) θm that Rc and Rd are independently selected from Ci-βalkyl; or R11 is a group of Formula (IB) or (IC):
on what:
[33] Y is -N (Rn) -, -N (Rn) C (O) -, -N (Rn) C (O) (CRsRt) vN (Rn) C (O) -, O and -S ( O) a-; where a is 0-2, v is 1-2, Rs and Rt are independently selected from hydrogen or C1-4alkyl optionally substituted by R26 and Rn is hydrogen or C1-4alkyl;
[34] R12 is hydrogen or Ci-4alkyl;
[35] R13 and R14 are independently selected from hydrogen, C1-4alkyl, carbocyclyl, or heterocyclyl; and when q is 0, R14 can additionally be selected from hydroxy wherein R13 and R14 can independently be optionally substituted by one or more substituents selected from R20;
[36] R15 is carboxy, sulpho, sulfine, phosphono, -P (O) (ORe) (ORf), -P (O) (OH) (ORe), -P (O) (OH) (Re) or - P (O) (ORe) (Rf) where Rθ and Rf are independently selected from Ci.6alkyl;
[37] p is 1-3; wherein the values of R13 can be the same or different;
[38] q is 0-1;
[39] r is 0-3; wherein the values of R14 may be the same or different;
[40] m is 0-2; where Rio values can be the same or different;
[41] n is, -3; wherein the values of R7 may be the same or different;
[42] Ring B is a nitrogen-bonded heterocyclyl substituted on carbon by a group selected from R23, and optionally additionally substituted on carbon by one or more R24; and wherein said nitrogen-bound heterocyclyl contains a portion of -NH-, wherein the nitrogen can be optionally substituted by a group selected from R25;
[43] R16, R17θ pie sθ0j independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamily, C-ualkyl, C2-4alkenyl, C2-4alkynyl, Ci-4alkoxy, Ci- 4alkanoyl, Ci .4alkanoyloxy, A / - (C1-4alkyl) amino, A /, A / - (C1-4alkyl) 2amino, C1-4alkanoylamino, / V- (C1-4alkyl) carbamoyl, A /, A / - (C1-4alkyl) ) 2carbamoyl, C1-4alkylS (O) a where a is 0 to 2, C1-4alkoxycarbonyl, A / - (C1-4alkyl) sulfamoyl, and A /, A / - (Ci-4alkyl) 2 sulfamoyl; wherein R16, R17 and R18 can independently be optionally substituted on carbon by one or more R21;
[44] R19, R20, RMep2θ sθ0jndependently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C-Malkyl, C2-4alkenyl, C2-4alkynyl, Ci-4alkoxy, C- 4alkalkyl, C- 4alkalkyl Malcanoyloxy, / V- (C1-4alkyl) amino, A /, A / - (C1-4alkyl) 2amino, C1-4alkanoylamino, N- (CI-4alkyl) carbamoyl, / V, A / - (C1-4alkyl) 2carbamoyl, C1-4alkylS (O) a where a is 0 to 2, C1-4alkoxycarbonyl, A / - (C1-4alkyl) sulfamoyl, A /, A / - (C1-4alkyl) 2 sulfamoyl, carbocyclyl, heterocyclyl, benzyloxycarbonylamino , sulpho, sulfine, amidine, 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 Ci-βalkyl; wherein R19, R20, R24 and R26 can independently be optionally substituted on carbon by one or more R22;
[45] 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, ally, ethinyl, methoxycarbonyl, formyl, acetyl, formamide, acetylamino, acetoxy, methylamino, dimethylamino, / V-methylcarbamoyl, A /, A / -dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, A / -dimetils;
[46] R23is carboxy, sulpho, sulfine, phosphono, -P (O) (ORg) (ORh), -P (O) (OH) (ORg), -P (O) (OH) (Rg) or -P (O) (OR9) (Rh) where Rg and Rh are independently selected from Ci-θalkyl;
[47] R25 is selected from Ci-θalkyl, Ci-βalkanoyl, Ci-βalkylsulfonyl, Ci-ealcoxycarbonyl, carbamoyl, A / - (C1-6alkyl) carbamoyl, A /, A / - (CI-6 alkyl) carbamoyl, benzyl , benzyloxycarbonyl, benzoyl, and phenylsulfonyl;
[48] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a proparmacode itself; and
[49] (ii) at least one other active substance selected from an IBAT inhibitor; an enteroendocrine peptide or enhancer thereof; a dipeptidyl peptidase-IV inhibitor; a biguanidine; an incretin mimetic; a thiazolidinone; a PPAR agonist; an HMG Co-A reductase inhibitor; a bile acid binder; and a TGR5 receptor modulator; or a pharmaceutically acceptable salt of any one of said active substances;
[50] in which the compound of Formula (I) and at least one other active substance are administered simultaneously, consecutively or separately.
[51] In this report the term "alkyl" includes both straight and branched chain alkyl groups, but references to individual alkyl groups such as "propyl" are specific only to the straight chain version. For example, "Ci-θalkyl", includes Ci-4alkyl, Ci-3alkyl, propyl, isopropyl, and t-butyl. However, references to individual alkyl groups such as 'propyl' are specific only to the straight chain version and references to individual branched chain alkyl groups such as 'isopropyl' are specific only to the branched chain version. A similar convention applies to other radicals, for example "phenylCi-βalkyl", would include phenylC-Malkyl, benzyl, 1-phenylethyl, and 2-phenylethyl. The term "halo" refers to fluorine, chlorine, bromine and iodine.
[52] Where optional substituents are selected from "one or more" groups. It should be understood that this definition includes all substituents that are selected from one of the specified groups or those substituents that are selected from two or more of the specified groups.
[53] "Heteroaryl" is a totally unsaturated, mono- or bicyclic ring containing 3-12 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen, which may, unless otherwise specified, be carbon or bound nitrogen. Preferably "heteroaryl" refers to a totally 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 can less than otherwise. specified manner, be carbon or nitrogen bound. In another aspect of the invention, "heteroaryl" refers to a totally 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 that may, unless otherwise specified, be carbon or nitrogen bound. 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.
[54] "Arila" is a fully unsaturated, mono or bicyclic carbon ring containing 3-12 atoms. Preferably "aryl", it 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. In particular, "aryl" is phenyl.
[55] A "heterocyclyl" is a saturated, partially saturated or unsaturated, mono- or bicyclic ring containing 3-12 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen which may, unless otherwise specified, be bonded carbon or nitrogen, where a -CH2- group can optionally be replaced by a -C (O) - or a ring sulfur atom can optionally be oxidized to form S-oxides. Preferably a "heterocyclyl" is a saturated, partially saturated or unsaturated, mono- or bicyclic ring containing 5 or 6 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen which can, unless otherwise specified, be bonded carbon or nitrogen, where a -CH2- group can optionally be replaced by a -C (O) - or a ring sulfur atom can optionally be oxidized to form S-oxide (s). Examples and suitable values of the term "heterocyclyl" are thiazolidinyl, pyrrolidinyl, pyrrolidinyl, 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, thiomorpholine, 1,1- dioxothiomorfolino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazole pyrazinyl, pyridazinyl, pyridyl, 4-pyridonyl, quinolyl, and 1-isoquinolonyl.
[56] A "carbocyclyl" is a ring of saturated, partially saturated or unsaturated, mono- or bicyclic carbon containing 3-12 atoms; wherein 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.
[57] An example of "Ci-ealcanoyloxy" and "Ci-4alkanoyloxy" is acetoxy. Examples of "Ci-βalkoxycarbonyl", and "Ci-4alcoxycarbonyl", include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of "Ci-eaoxy" and "Ci-4 alkoxy" include methoxy, ethoxy and propoxy. Examples of "Ci-6alkanoylamino" and "C-Malcanooylamino" include formamide, acetamido and propionylamino. Examples of "Ci-6alkylS (O) a where a is 0 to 2" and "Ci-4alkylS (O) a where a is 0 to 2" include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl and ethylsulfonyl, . Examples of "Ci-ealcanoila", and "Ci-4alkanoyl", include Ci-3alkanoyl, propionyl and acetyl. Examples of "A / - (C1-6alkyl) amino" and "A / - (C1-4alkyl) amino" include methylamino and ethylamine. Examples of "A /, A / - (C1-6alkyl) 2amino" and "A /, A / - (C1-4alkyl) 2amino" include di-A / -methylamino, di- (A / -ethyl) amino and A / -ethyl-A / - methylamino. Examples of "C2-6alkenyl", and "C2-4alkenyl", are vinyl, allyl, and 1-propenyl. Examples of "C2-6θlquinyl" and "C2-4alkynyl" are ethynyl, 1-propynyl, and 2-propynyl. Examples of "A / - (C1-6alkyl) sulfamoyl", and "A / - (CI-4 alkyl) -sulfamoyl" are A / - (C1-3alkyl) sulfamoyl, A / - (methyl) sulfamoyl, and A / - (ethyl) -sulfamoyl. Examples of "A / - (C1-6alkyl) 2Sulfamoyl", and "N-4alkyl) 2Sulfamoyl" are N, N- (dimethyl) sulfamoyl, and A / - (methyl) -A / - (ethyl) sulfamoyl. Examples of "N- (C1-6alkyl) -carbamoyl", and "N- (C1-4alkyl) carbamoyl", are methylaminocarbonyl, and ethylaminocarbonyl. Examples of "N, A / - (C1-6alkyl) 2carbamoyl", and "/ V, / V- (C1-4alkyl) 2carbamoyl are dimethylamino-carbonyl and methylethylaminocarbonyl. Examples of" Ci-θalkoxycarbonylamino "are ethoxycarbonylamino and t -butoxycarbonylamino. Examples of "N '- (Ci-6alkyl) ureido" are N'-methylureido and N'-ethylureido. Examples of "N' - (Ci-6alkyl) ureido are N-methylureido and / V-ethylureido. Examples of "N ', N' - (Ci-6alkyl) 2-ureido are A / ', W-dimethylureido and N'-methyl-A /' - ethylureido. Examples of" N '- (Ci-βalkyl) -N - (C1-6alkyl) -ureide are W-methyl- / V-methylureide and M-propyl-N-methylureide. Examples of "N ', N' - (CI-6 alkyl) 2- / V- (C1-6 alkyl) ureido are N ', N'-dimethyl- / V-methylureide and N'-methyl- N'-ethyl- ZV-propylureide.
[58] A pharmaceutically acceptable acceptable salt of a compound of the invention is, for example, an acid addition salt of a compound of the invention that is sufficiently basic, for example, an acid addition salt with, for example, an inorganic acid or organic, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoro-acetic, citric or maleic acid.
[59] In addition, a pharmaceutically suitable acceptable salt of a compound of the invention that is sufficiently acidic is an alkali metal salt, for example, a sodium or potassium salt, an alkaline earth metal salt, for example, a salt of calcium or magnesium, an ammonium salt 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.
[60] A prodrug of any compound mentioned here as an IBAT inhibitor or a compound for use in combination with this is a drug that is disrupted in the human or animal body to produce the compound.
[61] The compounds of Formula (I) can be administered in the form of a prodrug which is disrupted in the human or animal body to produce a compound of Formula (I). Examples of the profárma- include hydrolyzable esters in vivo and hydrolyzable amides in vivo of a compound of Formula (I).
[62] An in vivo hydrolyzable ester of a compound of Formula (I) containing a carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to produce the acid of origin or alcohol. Pharmaceutically acceptable esters suitable for carboxy include, for example, C1-6 alkoxymethyl esters, for example, methoxymethyl, C1-6 alkanoyloxymethyl esters for example, pivaloyloxymethyl, phthalidyl esters, C3-8 cycloalkoxycarbonyloxyCi-6 alkyl esters, for example -hexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example, 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-6 alkoxycarbonyloxyethyl esters, for example, 1-methoxycarbonyloxyethyl, and can be formed on any carboxy group in the compounds of this invention.
[63] An in vivo hydrolyzable ester of a compound of Formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of in vivo hydrolysis of the ester break produces hydroxy group of origin. Examples of a-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of hydrolyzable ester in vivo that forms groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to produce alkyl carbonate esters), dialkylcarbamoyl and N (dialkylaminoethyl) -A / -alkylcarbamoyl carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of benzoyl substituents include morpholino and piperazine attached from a ring nitrogen atom via a methylene group to the 3 or 4 position on the benzoyl ring.
[64] A suitable value for an in vivo hydrolysable amide of a compound of Formula (I) containing a carboxy group is, for example, an A / -C1-6 alkyl or A /, A / -di-C1-6 alkyl amide such as, / V-methyl, A / -ethyl, A / -propyl, A /, A / -dimethyl, A / -ethyl-A / -methyl or / V, A / -diethyl amide.
[65] It should also be understood that certain compounds of Formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention covers all such solvated forms which have IBATi inhibitory activity.
[66] Preferred values for R1, R2, R3, R4, R5 and R6 are as follows. Such values may be used where appropriate with any of the definitions, claims or modalities defined herein earlier or hereinafter.
[67] Preferably, R1 and R2 are independently selected from C1-4 alkyl.
[68] More preferably, R1 and R2 are independently selected from ethyl or butyl.
[69] More preferably, R1 and R2 are independently selected from ethyl, propyl or butyl.
[70] In particular, in one aspect of the invention, R1 and R2 are both butyl.
[71] In particular, in another aspect of the invention R1 and R2 are both propyl.
[72] In particular, in another aspect of the invention one of R1 and R2 is ethyl and the other is butyl.
[73] Preferably, Rx and RY are independently selected from hydrogen or C1-6 alkyl.
[74] More preferably, Rx and RY are both hydrogen.
[75] Preferably, Rz is selected from halo, amino, C1-6 alkyl, C1-6 alkoxycarbonylamino or / V '- (C1-6 alkyl) ureido.
[76] More preferably, Rz is selected from chlorine, amino, t-butyl, t-butoxycarbonylamino or N '- (t-butyl) ureido.
[77] Preferably, v is 0 or 1.
[78] More preferably, in one aspect of the invention, v is 0.
[79] More preferably, in one aspect of the invention, v is 1.
[80] Preferably, in one aspect of the invention, R4 is a group of Formula (IA) (as described above).
[81] Preferably, in another aspect of the invention, R5 is a group of Formula (IA) (as described above).
[82] Preferably, R3 and R6 are hydrogen.
[83] Preferably, the other among R4 and R5, which is not the Formula (IA) group, is selected from halo, Cu alkoxy or Cu alkylS (O) a, where one is 0 to 2; wherein that R4 or R5 can be optionally substituted on carbon by one or more R16; where R16 is independently selected from hydroxy and A /, A / - (CI.4 alkyl) 2 amino.
[84] More preferably, the other among R4θ R5, which is the Formula (IA) group, is selected from bromine, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl; wherein that R4 or R5 can be optionally substituted on carbon by one or more R16- wherein R16 is independently selected from hydroxy and A /, / V-dimethylamino.
[85] In particular, the other among R4 and R5, which is not the Formula (IA) group, is selected from bromine, methoxy, isopropoxy methylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2- (A /, A / -dimethylamino) ethylthio or mesyl.
[86] More particularly, the other among R4 and R5, which is not the Formula (IA) group, is methylthio.
[87] Preferably, the other one from R4 and R5, which is not the Formula (IA) group, is selected from hydrogen, halo, C1-4 alkoxy or C1-4 alkylS (O) a, where one is 0 to 2; wherein that R4 or R5 may be optionally substituted on carbon by one or more R16- wherein R16 is independently selected from hydroxy, carboxy and A /, A / - (CI-4 alkyl) 2 amino.
[88] More preferably, the other among R4 and R5, which is not the Formula (IA) group, is selected from hydrogen, bromine, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl; wherein that R4 or R5 can be optionally substituted on carbon by one or more R16; wherein R16 is independently selected from hydroxy, carboxy and A /, A / -dimethylamino.
[89] Particularly, the other among R4 and R5 that is not the Formula (IA) group, is selected from hydrogen, bromine, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2- ( A /, A / -dimethylamino) ethylthio or mesyl.
[90] In another aspect of the invention, more preferably the other among R4 and R5 which is not the Formula (IA) group is selected from hydrogen, chlorine, bromine, methoxy, isopropoxy, methylthio, ethylthio or isopropylthio; wherein that R4 or R5 can be optionally substituted on carbon by one or more R16; wherein R16 is independently selected from hydroxy, carboxy and A /, / V-dimethylamino.
[91] In another aspect of the invention, particularly the other among R4 and R5 that is not the Formula (IA) group, is selected from hydrogen, chlorine, bromine, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio or 2- (A /, / V-dimethylamino) ethylthio.
[92] In another aspect of the invention, more particularly the other among R4 and R5 that is not the Formula (IA) group, is bromine or chlorine.
[93] In another aspect of the invention, more particularly the other one between R4 and R5 that is not the Formula (IA) group is methoxy.
[94] In one aspect of the invention, preferably Ring A is aryl.
[95] In another aspect of the invention, preferably Ring A is heteroaryl.
[96] When Ring A is aryl, preferably Ring A is phenyl.
[97] When Ring A is heteroaryl, preferably Ring A is ethienyl or indolyl.
[98] Preferably, Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R17; wherein R17 is selected from halo, hydroxy or CMalkyl; wherein R17 can be optionally substituted on carbon by one or more R21; where R21 is selected from halo.
[99] Preferably, X is -O.
[100] More preferably, Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy or trifluoromethyl.
[101] Particularly, Ring A is selected from phenyl, 4-hydroxyphenyl, thien-2-yl, 4-trifluoro-methylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2,3-dihydroxyphenyl or indol-3 -ila.
[102] More particularly, Ring A is phenyl.
[103] In another aspect of the invention, preferably Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R17; wherein R17 is selected from halo, hydroxy, CMalkyl or CM alkoxy; wherein R17 can be optionally substituted on carbon by one or more R21; where R21 is selected from halo.
[104] In another aspect of the invention, more preferably Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl.
[105] In another aspect of the invention, particularly Ring A is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2,3- dihydroxyphenyl or indol-3-yl.
[106] In another aspect of the invention, 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.
[107] Preferably, R7 is hydrogen, CMalkyl or carbocyclic.
[108] More preferably, R7 is hydrogen, methyl or phenyl.
[109] In particular, R7 is hydrogen.
[110] Preferably, in one aspect of the invention, R8 is hydrogen.
[111] Preferably, in another aspect of the invention, R8 is CM alkyl.
[112] More preferably, in another aspect of the invention, R8 is hydrogen or methyl.
[113] Preferably, in one aspect of the invention, R9 is hydrogen.
[114] Preferably, in another aspect of the invention, R9 is CM alkyl.
[115] More preferably, in another aspect of the invention, R9 is hydrogen or methyl.
[116] Preferably, R10 is hydrogen.
[117] Preferably, in one aspect of the invention, R11 is carboxy, sulpho, sulfine, 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.
[118] Preferably, in another aspect of the invention, R11 is a group of Formula (IB) (as described above).
[119] Preferably, R11 is carboxy, -P (O) (OH) (ORC) or a group of Formula (IB) (as described above).
[120] More preferably, R11 is carboxy, -P (O) (OH) (OEt) or a group of Formula (IB) (as described above).
[121] Preferably, in another aspect of the invention, R11 is carboxy, sulfo, -P (O) (OH) (ORC), where Rc is selected from C1-4 alkyl or a group of Formula (IB) ( as described above).
[122] Preferably, Y is -NH- or -NHC (O) -.
[123] More preferably, Y is -NHC (O) -.
[124] Preferably, in one aspect of the invention, R12 is hydrogen.
[125] Preferably, in another aspect of the invention, R12 is C1-4 alkyl.
[126] More preferably, in another aspect of the invention, R12 is hydrogen or methyl.
[127] Preferably, R13 is hydrogen, C1-4 alkyl or carbocyclic; wherein R13 is optionally substituted by one or more substitutes selected from R20; where R20 is hydroxy.
[128] More preferably, R13 is hydrogen, methyl or phenyl; wherein R13 is optionally substituted by one or more substituents selected from R20; where R20 is hydroxy.
[129] In particular, R13 is hydrogen, hydroxymethyl or phenyl.
[130] More particularly, R13 is hydrogen or hydroxymethyl.
[131] Preferably, in another aspect of the invention, R13Q hydrogen, C1-4 alkyl or carbocyclyl; wherein R13 is optionally substituted by one or more substituents selected from R20; wherein R20 is hydroxy, carboxy, carbocyclyl or amino; wherein R20 may be optionally substituted on carbon by one or more R22; R22 is hydroxy.
[132] More preferably, in another aspect of the invention, R13 is hydrogen, methyl, ethyl, butyl or phenyl; wherein R13 is optionally substituted by one or more substituents selected from R2o. wherein R20 is hydroxy, carboxy, phenyl or amino; wherein R20 can be optionally substituted on carbon by one or more R22; R22θ hydroxy.
[133] In particular, in another aspect of the invention, R13 is hydrogen, methyl hydroxide, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl or phenyl.
[134] Preferably, in another aspect of the invention, R12θ hydrogen, C1-4 alkyl or carbocyclyl; wherein R13 is optionally substituted by one or more substituents selected from R20 where R20 is hydroxy, carboxy, carbocyclyl, heterocyclyl or amino; wherein R20 can be optionally substituted on carbon by one or more R22; R22 is hydroxy.
[135] More preferably, in another aspect of the invention R13 is hydrogen, methyl, ethyl, butyl or phenyl; wherein R13 is optionally substituted by one or more substituents selected from R20; wherein R20 is hydroxy, carboxy, phenyl, imidazolyl or amino; wherein R20 can be optionally substituted on carbon by one or more R22; R22 is hydroxy.
[136] In particular, in another aspect of the invention, R13 is hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl, imidazole-5-ylmethyl or phenyl.
[137] Preferably, in another aspect of the invention, R13 is hydrogen, CM alkyl, carbocyclyl or R23; wherein R13 is optionally substituted by one or more substituents selected from R20; where R20 is hydroxy, C1-4 alkylS (O) a, where a is 0, C1-4 alkoxy, amino, carbocyclyl, heterocyclyl or mercapto; wherein R20 can independently be optionally substituted on carbon by one or more R22; R22 is selected from hydroxy; and R23θ carboxy.
[138] More preferably, in another aspect of the invention, R13 is hydrogen, methyl, ethyl, butyl or phenyl or R23; wherein pi3 is optionally substituted by one or more substituents selected from R20; wherein R20 is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; wherein R20 can independently be optionally substituted on carbon by one or more R22; R22 is selected from hydroxy; and R23 is carboxy.
[139] In particular, in another aspect of the invention, R13 is hydrogen, carboxy, methyl hydroxide, mercaptomethyl, methoxymethyl, methylthiomethyl, 2-methylthioethyl, 4-aminobutyl, 4-hydroxybenzyl, imidazole-5-ylmethyl or phenyl.
[140] More particularly in another aspect R13 is methylthiomethyl, methylsulfinylmethyl or methylsulfonylmethyl.
[141] Preferably, R14 is hydrogen.
[142] Preferably, in another aspect of the invention, R14 is selected from hydrogen, C1-4 alkyl or carbocyclyl; wherein said CMalkyl or carbocyclyl can be optionally substituted by one or more substituents selected from R20; and R20 is hydroxy.
[143] More preferably, in another aspect of the invention, R14θ selected from hydrogen, methyl or phenyl; wherein said methyl or phenyl may be optionally substituted by one or more substituents selected from R20; and R20 is hydroxy.
[144] In particular, in another aspect of the invention, R14 is hydrogen, phenyl or hydroxymethyl.
[145] In particular, R15 is carboxy or sulfo.
[146] More particularly in one aspect of the invention, Ris θ carboxy.
[147] More particularly in another aspect of the invention, Risulfo.
[148] Preferably, R15 θ 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 Ci-4alkyl.
[149] More preferably, Ris is carboxy, sulfo, -P (O) (ORe) (ORf), -P (O) (OH) (ORe), -P (O) (OH) (Re) or -P (O) (ORθ) (Rf), where Re and Rf are independently selected from methyl or ethyl.
[150] Preferably, R15 is carboxy, sulfo, -P (O) (OEt) (OEt), - P (O) (OH) (OEt), -P (O) (OH) (Me) or -P (O ) (OEt) (Me).
[151] Preferably, R15 θ 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 described above).
[152] More preferably, R15is carboxy, sulfo, phosphono, - P (O) (ORe) (ORf), -P (O) (OH) (ORe), -P (O) (OH) (Re) or - P (O) (ORθ) (Rf), where Re and Rf are independently selected from methyl or ethyl or R15 is a group of Formula (IC) (as described above).
[153] Preferably, R15is carboxy, sulfo, phosphono, - P (O) (OEt) (OEt), -P (O) (Ot-Bu) (Ot-Bu), -P (O) (OH) (OEt ), -P (O) (OH) (Me) or -P (O) (OEt) (Me) or R15 is a group of Formula (IC) (as described above).
[154] Preferably, in one aspect of the invention, R15 is carboxy
[155] Preferably, in another aspect of the invention, R15θ sulfo
[156] Preferably, in another aspect of the invention, Ris is P (O) (OH) (OEt).
[157] Preferably, in another aspect of the invention, Ris P (O) (OH) (Me).
[158] Preferably, in another aspect of the invention, Ris is P (O) (OEt) (Me).
[159] Preferably, in one aspect of the invention, R24θ hydrogen.
[160] Preferably, in another aspect of the invention, R24θ C-M alkyl.
[161] Preferably, R25 is hydrogen.
[162] Preferably, R26θ carboxy.
[163] Preferably, p is 1 or 2; wherein the values of R13 can be the same or different.
[164] More preferably, in one aspect of the invention, p is 1.
[165] More preferably, in another aspect of the invention, p is 2, where the values of R13 can be the same or different.
[166] More preferably, in another aspect of the invention, p is 3; wherein the values of R13 can be the same or different.
[167] Preferably, in one aspect of the invention, q is 0.
[168] Preferably, in another aspect of the invention, q is 1.
[169] Preferably, in one aspect of the invention, r is 0.
[170] More preferably, in one aspect of the invention, r is 1.
[171] More preferably, in another aspect of the invention, r is 2, where the values of R14 can be the same or different.
[172] More preferably, in another aspect of the invention, r is 3; wherein the values of R14 can be the same or different.
[173] Preferably, m is 0.
[174] Preferably, in another aspect of the invention, m is 0 or 1.
[175] Preferably, n is 1.
[176] Preferably, in another aspect of the invention, n is 1 or 2.
[177] Preferably, z is 1.
[178] The Formula (IA) group, where R7 is hydrogen, methyl or phenyl, n is 1, Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by 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) .
[179] the Formula (IA) group where: X is -0-.
[180] Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl;
[181] R7 £ hydrogen, methyl or phenyl;
[182] R8 £ hydrogen or methyl;
[183] R9 θ hydrogen or methyl;
[184] R10θ hydrogen;
[185] rn 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 described in claim 1); The Formula (IB) group, where R10 is hydrogen, hydroxymethyl or phenyl, p is 1 or 2; wherein the values of R10 can be the same or different and R11 is carboxy or sulfo.
[186] The Formula (IB) group in which:
[187] R12θ hydrogen or methyl;
[188] R13is hydrogen, methyl, ethyl, butyl or phenyl or R23; where R13 is optionally substituted by one or more substituents selected from R20; R20 is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; wherein R20 can independently be optionally substituted on carbon by one or more hydroxy; R23 is carboxy, Y is -NH- or -NHC (O) -; R14 is selected from hydrogen, methyl or phenyl; wherein said methyl or phenyl can be optionally substituted by one or more substituents selected from hydroxy; Ris is carboxy, sulfo, phosphono, -P (O) (ORe) (ORf), - P (O) (OH) (ORe), -P (O) (OH) (Rθ) or -P (O) ( ORθ) (Rf), in which Re and Rf are selected are independently selected from methyl or ethyl or R15 is a group of Formula (IC) (as described in claim 1);
[189] foot 1-3, where the values of R13 can be the same or different;
[190] q0-0; and
[191] aft 0-3, in which the values of R14 can be the same or different;
[192] The Formula (CI) group, in which
[193] R24 is hydrogen;
[194] R25 is hydrogen;
[195] R26 is carboxy; and
[196] Zé1;
[197] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[198] Therefore, in another aspect of the invention, a compound of Formula (I) is provided as described above, wherein:
[199] R1 and R2 are independently selected from ethyl or butyl;
[200] R3 and R6 are hydrogen;
[201] R4 is selected from halo, CM alkoxy or CM alkylS (O) a, where a is 0 to 2; wherein that R4 may be optionally substituted on carbon by one or more R16; wherein R16 is independently selected from hydroxy and A /, A / - (CM alkyl) 2amino;
[202] R5 θ a group of Formula (IA);
[203] Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R17; on what
[204] R17 is selected from halo, hydroxy or CMalkyl, where R17 can be optionally substituted on carbon by one or more R21; on what
[205] R21 is selected from the halo;
[206] R7 is hydrogen, CMalkyl or carbocyclyl;
[207] R11 is carboxy, -P (O) (OH) (ORC) or a group of Formula (IB) (as described above);
[208] R13is hydrogen, CMalkyl or carbocyclyl; wherein R13θ optionally substituted by one or more substituents selected from R20; on what
[209] R20θ hydroxy;
[210] R1Sθ carboxy or sulfo;
[211] P is 1 or 2; wherein the values of R13 can be the same or different;
[212] mé0; and
[213] right1;
[214] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[215] Therefore, in another aspect of the invention, a compound of Formula (I) is provided as described above, wherein:
[216] Ri and R2 are both butyl or one of R1 and R2 is ethyl and the other is butyl;
[217] R4 is methylthio;
[218] RSθ a group of Formula (IA) (as described above);
[219] R3 eR6S £ 0 hydrogen;
[220] Ring A is phenyl;
[221] R7 is hydrogen;
[222] R11θ a group of Formula (IB) (as described above);
[223] R13 θ hydrogen or hydroxymethyl;
[224] Ris θ carboxy or sulfo;
[225] P is 1 or 2; wherein the values of R13 can be the same or different;
[226] m is 0;
[227] right1;
[228] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[229] Therefore, in a further aspect of the invention, a compound of Formula (I) is provided as described above wherein:
[230] R1 and R2 are independently selected from ethyl or butyl;
[231] R3 and R6 are hydrogen;
[232] R4 is selected from halo, C-Malcoxy or C1-4 alkylS (O) a, where a is 0 to 2; wherein that R4 may be optionally substituted on carbon by one or more R16; wherein R16 is independently selected from hydroxy and / V, / V- (C1-4 alkyl) 2amino;
[233] R5 is a group of Formula (IA);
[234] Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R17;
[235] R7 is hydrogen, C1-4 alkyl or carbocyclyl;
[236] Re θ hydrogen or methyl;
[237] R9 is hydrogen or methyl;
[238] R11θ carboxy, -P (O) (OH) (ORC) or a group of Formula (IB) (as described above);
[239] X is -NH- or -NHC (O) -;
[240] R12 θ hydrogen or methyl;
[241] R13 is hydrogen, C1-4 alkyl or carbocyclyl; wherein R13 is optionally substituted by one or more substituents selected from R20;
[242] R14 θ hydrogen;
[243] Ris θ carboxy or sulfo;
[244] R17θ selected from halo, hydroxy, C1-4 alkyl or C1-4 alkoxy; in qUeRV p0 (je be optionally substituted in carbon by one or more R21;
[245] R2o θ hydroxy, carboxy, carbocyclyl or amino; wherein R20 can be optionally substituted on carbon by one or more R22;
[246] R21 is selected from halo;
[247] R22 is hydroxy;
[248] foot 1-3; wherein the values of R13 can be the same or different.
[249] q is 0-1;
[250] r is 0-3; wherein the values of R14 can be the same or different; and where q is 1, r is not 0;
[251] m0-2; and
[252] ne1-3;
[253] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[254] Therefore, in another further aspect of the invention, a compound of Formula (I) is provided as described above wherein:
[255] R1θ R2 are independently selected from C-Malquila;
[256] Rxθ Ry are both hydrogen;
[257] Rz is selected from halo, amino, Ci-β alkyl, Ci-θ alkoxycarbonylamino or A / '- (Ci-6 alkyl) ureido;
[258] v is 0 or 1;
[259] R3 θ Rβ S3Q hydrogen;
[260] one of R4 and R5 is a group of Formula (IA) (as described above), and the other is selected from hydrogen, halo, CM alkoxy or CM alkylS (O) a, where a is 0 to 2 ; wherein that R4 or R5 can be optionally substituted on carbon by one or more R16; wherein R16 is independently selected from hydroxy, carboxy and A /, A / - (CI-4 alkyl) 2amino;
[261] Xé-0-;
[262] R7 θ hydrogen, methyl or phenyl;
[263] Rβ θ hydrogen or methyl;
[264] Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R17; wherein R17 is selected from halo, hydroxy, CM alkyl or C1-4 alkoxy; wherein R17 can be optionally substituted on carbon by one or more R21; where R21 is selected from halo;
[265] R9 is hydrogen or methyl;
[266] R10 is hydrogen;
[267] R11 is carboxy, -P (O) (OH) (ORC), where Rc is selected from C1-4 alkyl or a group of Formula (IB) (as described above);
[268] R12 is hydrogen or methyl;
[269] Yé-NH-or-NHC (O) -;
[270] R13 θ hydrogen, C1-4 alkyl, carbocyclyl or R23; wherein R13 is optionally substituted by one or more substituents selected from R20; where R20 is hydroxy, CM alkylS (O) a, where a is 0, C1-4 alkoxy, amino, carbocyclyl, heterocyclyl or mercapto; wherein R20 can independently be optionally substituted on carbon by one or more R22; R22 is selected from hydroxy; and R23 is carboxy;
[271] Ru θ selected from hydrogen, C1-4 alkyl or carbocyclyl; wherein said C1-4 alkyl or carbocyclyl can be optionally substituted by one or more substituents selected from R20; and R20θ hydroxy;
[272] Ris θ carboxy, sulfo, phosphono, -P (O) (ORe) (ORf), - P (O) (OH) (ORθ), -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 described above);
[273] R24 θ hydrogen;
[274] R25 £ hydrogen;
[275] R26 &carboxy;
[276] p is 1-3; where the values of Ria can be the same or different;
[277] qéO-1;
[278] r is 0-3, where the values of R14 can be the same or different;
[279] m is 0-2; where the values of R1θ can be the same or different;
[280] n is 1-2; wherein the values of R7 can be the same or different;
[281] z is 0-1; wherein the values of R25 can be the same or different;
[282] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[283] In another aspect of the invention, preferred compounds of the invention are any of the Examples or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
[284] One aspect of the present invention is a combination comprising
[285] a compound of Formula II
on what
[286] M is -CH2OU NH;
[287] R1 is H or OH; and
[288] R2 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH (CH3) 2, -CH2CH (CH3) 2, -CH (CH3) CH2CH3, -CH2OH, CH2OCH3, -CH (0H) CH3, -CH2SCH3, or -CH2CH2-S-CH3; or a pharmaceutically acceptable salt thereof; and
[289] at least one other active substance selected from an IBAT inhibitor; an enteroendocrine peptide or enhancer thereof; a dipeptidyl peptidase-IV inhibitor; a biguanidine; an incretin mimetic; a thiazolidinone; a PPAR agonist; an HMG Co-A reductase inhibitor; a bile acid binder; and a TGR5 receptor modulator; or a pharmaceutically acceptable salt of any one of said active substances;
[290] wherein the compound of Formula (II) and at least one other active substance is administered simultaneously, sequentially or separately.
[291] One aspect of the present invention is a combination comprising
[292] a compound selected from
[293] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 - (/ V - {(R) -a - [/ V- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1. 2. 5-benzothiadiazepine;
[294] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -a- [A / '- ((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;
[295] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -α- [A / - ((S) -1-carboxypropyl) carbamoyl ] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
[296] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -a- [A / - ((R) -1 -carboxy-2 -methylthioethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
[297] 1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -a- [A / - ((S) -1-carboxypropyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
[298] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (Δ / - {(R) -α - [/ / - ((R) -1-carboxi- 2-methylthio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
[299] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -α- [A / - ((S) -1-carboxy-2 -methylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
[300] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -α - [/ V - ((S) -1-carboxy-2 - (R) -hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
[301] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -α - [/ V - ((S) -1 -carboxybutyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
[302] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -α- [A / - ((S) -1-carboxyethyl) carbamoyl ] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
[303] 1,1-Dioxo-3, 3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -α- [A / '- ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;
[304] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -α - [/ V - ((S) -1-carboxyethyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
[305] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [A / - ((S) -1 -carboxy-2- methylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
[306] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -1 '-phenyl-1 [/ V- (carboxymethyl) carbamoyl] methyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;
[307] or a pharmaceutically acceptable salt of any such compound; and
[308] at least one other active substance selected from an IBAT inhibitor; an enteroendocrine peptide or enhancer thereof; a dipeptidyl peptidase-IV inhibitor; a biguanidine; an incretin mimetic; a thiazolidinone; a PPAR agonist; an HMG Co-A reductase inhibitor; a bile acid binder; and a TGR5 receptor modulator; or a pharmaceutically acceptable salt of any one of said active substances;
[309] wherein the compound of Formula (I) and at least one other active substance are administered simultaneously, sequentially or separately.
[310] Compounds of Formula (I) may have chiral centers and / or geometric isomeric centers (E and Z isomers), and it should be understood that the invention encompasses all such optical diastereoisomers and geometric isomers, which have IBAT inhibitory activity.
[311] The invention relates to any and all tautomeric forms of the compounds of Formula (1) that have IBAT inhibitory activity.
[312] The invention also lists all possible isomers of the compounds of the invention such as optical and / or geometric, pure or as a mixture, in all proportions, of said compounds of Formulas I and II, and those specifically mentioned and the possible tautomeric forms.
[313] In certain embodiments, the compounds described herein have one or more chiral centers. As such, all stereoisomers are considered here. In various embodiments, the compounds described herein are present in optically active or racemic forms. It should be understood that the compounds of the present invention encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof, which have the therapeutically useful properties described herein. The preparation of optically active forms is obtained in any suitable manner, including by means of a non-limiting example, by resolving the racemic form by recrystallization techniques, by synthesis of optically active starting materials, by chiral synthesis, or by chromatographic separation using a 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. The resolution of compounds and isomers thereof is achieved by any means, including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, and the like. Compounds for use in combination with an IBAT inhibitor compound of the invention. Bile acid binders (bile acid scavengers, resins) [314] The following bile acid binders can be used according to the invention.
[315] Cholestyramine, a hydrophilic polyacrylic quaternary ammonium anion exchange resin, which is known to be effective in lowering blood cholesterol levels. Cholestyramine, and various compositions, including cholestyramine, are described, for example, in U.S. Pat. British Nos. 929,391 and 1,286,949; and U.S. 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 Novofarm, USA Inc (Questrans Light), Upsher-Smith (PREVALITE (D) and Apothecon. When used herein, "cholestyramine" includes any such composition comprising cholestyramine, or pharmaceutically acceptable salts thereof. Questrans® .
[316] Questran Light Questrans Light (cholestyramine) is an FDA approved non-absorbable uranium binding resin for the treatment of hypercholesterolemia.
[317] An amine polymer that has a first substituent, attached to a first amine of the amine polymer, which includes a hydrophobic aliphatic portion and a second substituent, attached to a second amine of the amine polymer, which includes an amine-containing portion aliphatic quaternary as described in USP 5,693,675 and 5,607,669.
[318] The salt of an alkylated and cross-linked polymer, which comprises the reaction product of: (a) one or more cross-linked polymers, or salts and copolymers thereof, which have a repeated unit selected from the group consisting of: (NR-CH2CH2) 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 C1- group C8 alkyl; (b) at least one aliphatic alkylating agent, said reaction product characterized by the fact that: (i) at least some of the nitrogen atoms in said repeating units not reacted with said alkylating agent; (ii) less than 10 mol percent of the nitrogen atoms in said repeating units that react with said alkylating agent, which forms quaternary ammonium units; and (iii) a fixed positive charge and one or more counterions, such as Colesevelam and colesevelam hydrochloride
[319] Bile acid binders suitable for such a combination therapy are resins, such as cholestyramine and cholestipol. 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, which comprises only a bile acid binder. By a low dose of bile acid binder, any possible side effect caused by the patient's poor tolerance to the therapeutic dose could likewise be avoided.
[320] Another useful bile acid binder is a water-insoluble non-toxic polymeric amine, which has a molecular weight in excess of 3,000, having the property of binding at least 30% of the available glycolic acid within 5 minutes, when exposed to an aqueous solution of an equal weight of said acid, having an inert polymer backbone for digestive enzymes, and having a water content greater than 65% after equilibration with air at 100% relative humidity, egg, colestipol described in USP 3,383,281,
[321] In another aspect of the invention, a suitable bile acid binder is one of cholestyramine, colestipol or colesevelam.
[322] A preferred aspect of the present invention is the use of co-lesevelam as the bile acid binder. Other active compounds for use in combination with an IBAT inhibitor compound of the invention.
[323] According to a further aspect of the present invention, a combination treatment is provided which comprises administering an effective amount of an IBAT inhibitor compound or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder, in which the formulation is designed to release the bile acid binder into the colon, with simultaneous, sequential or separate administration of one or more of the following agents selected from: Statins
[324] In another aspect of the invention, an IBAT inhibitor compound, for example, a compound of Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, administered in combination with an HMG Co-A reductase inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable HMG Co-A reductase inhibitors, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, are statins well known in the art. Particular statins are flu-vastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivas-tatin, bervastatin, dalvastatin, mevastatin and (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl ( methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxyhept-6-enoic (rosuvastatin), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. A particular statin is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. A more particular statin is atorvastatin calcium salt. Another particular statin is (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5- dihydroxyhept-6-enoic (rosuvastatin), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. Other particular statins are rosuvastatin and pitavastatin calcium salt (HMG CoA reductase inhibitor).
[325] In a further aspect of the invention, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, can be administered in combination with an HMG Co-A inhibitor reductase, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and / or a bile acid binder, thereby avoiding a possible risk of excess bile acids in the colon, caused by inhibition of the system of transport of ileal bile acid. An excess of bile acids in the visceral contents can cause diarrhea. Thus, the present invention also provides a treatment for a possible side effect, such as diarrhea in patients during therapy, which comprises the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a profárma-co of the same.
[326] An HMG CoA reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, by its action, will decrease the endogenous cholesterol available for bile acid synthesis and will have an effect additive in combination with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in reducing lipid.
[327] A CETP (cholesteryl ester transfer protein) inhibitor, for example, those referenced and described in WO 00/38725 page 7 line 22-page 10, line 17 which are incorporated herein by reference.
[328] A cholesterol absorption antagonist, for example, azetidinones such as SCH 58235 and those described in US 5,767,115 which are incorporated herein by reference;
[329] MTP (microsomal transfer protein) inhibitor, for example, those described in Science, 282,751-54,1998 which are incorporated herein by reference;
[330] A derivative of fibric acid; for example, clofibrate, genfibrozil, fenofibrate, ciprofibrate and bezafibrate;
[331] A nicotinic acid derivative, for example, nicotinic acid (niacin), acipimox and niceritrol;
[332] A phytosterol compound, for example, stanols;
[333] Probucol;
[334] An anti-obesity compound, for example, orlistat (EP129,748) and sibutramine (GB 2,184,122 and US 4,929,629);
[335] 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 al-fa blocker / mixed adrenergic beta, an adrenergic stimulant, calcium channel blocker, a diuretic or a vasodilator;
[336] Insulin;
[337] Sulphonylureas including glibenclamide and / or tolbutamide;
[338] Biguanides;
[339] The other active compound may be a biguanide, which can reduce blood glucose levels and / or plasma. Examples of biguanides include and are not limited to buformin, metformin, fenformin, proguanil, or the like.
[340] Acarbose;
[341] or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or vehicle to a homeothermal animal, such as a man in need of such therapeutic treatment. ACE inhibitors
[342] Particular ACE inhibitors or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, including active metabolites that can be used in combination with a compound of Formula (I) include, but are not limited to, the following compounds: alacepril, alatriopril, altiopril calcium, ancovine, benazepril, benazepril hydrochloride, benazeprilate, benzoilcap-topril, captopril, captopril-cysteine, captopril-glutathione, ceranapril, cepranopril, ceronapril, ceronapril, ceronapril, ceronapril, delapril, delapril-diacid, enalapril, enalaprilate, enapril, epicaptopril, foroxymitin, fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinopril sodium, fosinoprilate, fosinoprylic acid, glycopril, hemorphine, indiumprilpril, librapril, imraprilpril, libraprilpril, imraprilpril, librapril, imrapril A, lyciumin B, mixanpril, moexipril, moexiprilate, moveltipril, muracein A, muracein B, murine C, pentopril, perindopril, perindoprilate, pivalopri l, pivopril, quina-phi, cl the rat of quinapril rat, quinaprilate, ramipril, ramiprilate, spirapril, spirapril hydrochloride, spiraprilate, spiropril, spiropril hydrochloride, temocapril, temocapril hydrochloride, teprotida, trandola, trandola, trandola, trandola, trandola, trandola, trandola, utibapril, zabicipril, zabiciprilate, zofenopril and zofenoprilate. Preferred ACE inhibitors for use in the present invention are ramipril, ramiprilate, lisinopril, enalapril and enalaprilate. Most preferred ACE inhibitors for use in the present invention are ramipril and ramiprilate. Anqiotensin II antagonists
[343] Preferred angiotensin II antagonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof for use in combination with a compound of Formula (I) include, but are not limited to, the compounds: candesartan, candesartan cilexetil , losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan. Particularly preferred angiotensin II antagonists or pharmaceutically acceptable derivatives thereof for use in the present invention are candesartan and candesartan cilexetil.
[344] PPAR alpha and / or gamma and / or delta agonists.
[345] In another aspect of the invention, the IBAT inhibitor compound, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, can be administered in combination with a PPAR alpha and / or gamma agonist , or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha and / or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs 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 which are all incorporated herein by reference. In particular, a PPAR alpha and / or gamma agonist refers to WY-14643, clofibrate, fenofibrate, bezafibrate, GW 9578, troglitazone, pioglitazone, rosiglitazone, eglite-zone, proglitazone, BRL-49634, KRP-297, JTT-501, JTT-501 , SB 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433.
[346] Particularly a PPAR alpha and / or gamma agonist refers to (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid and pharmaceutically acceptable salts thereof.
[347] Other useful active substances may be antidiabetics, hypoglycemic active ingredients, cholesterol absorption inhibitors, PPAR delta agonsites, fibrates, MTP inhibitors, bile acid absorption inhibitors, polymeric bile acid inhibitors, LDL receptor inducers , ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, stenotase synthetase inhibitors, lipoprotein antagonists, HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, thiazolidinediones alpha-glucosidase inhibitors, active ingredients that act in the ATP-dependent potassium channel of beta cells, glycogen phosphorylase inhibitors, glucagon receptor antagonists, glucokinase activators, gluconeogenesis inhibitors, fructose-1,6- inhibitors bisphosphatase, glucose transporter 4 modulators, glutamine-fructose-6-phosphate amidotransferase inhibitors, ini dipeptidylpeptidase IV binders, 11-beta-hydroxysteroid dehydrogenase 1 inhibitors, protein tyrosine phosphatase 1B inhibitors, sodium-dependent glucose transporter modulators 1 or 2, GPR40 modulators, hormone-sensitive lipase inhibitors, acetyl inhibitors -CoA carboxylase, phosphoenolpyruvate carboxycin inhibitors, glycogen-synthase kinase-3 beta inhibitors, protein kinase C beta inhibitors, endothelin-A receptor antagonists, I kappa kinase inhibitors, glucocorticoid receptor modulators, agonists CART, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, BP CRF antagonists, urocortin agonists, beta 3 agonists, CB1 receptor antagonists, MSH agonists ( melanocyte-stimulating hormone), CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and noradrenergic compounds, 5HT agonists, besine, galanine antagonists, growth hormones, growth hormone releasing compounds, HRT agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase / amylase inhibitors , PPAR modulators, RXR modulators or TR-beta agonists or amphetamines.
[348] Examples of delta PPAR agonists are GW-501516 (501516, GSK-516, GW-516, GW-1516; a peroxisome proliferator-activated delta receptor (PPAR) agonist and several other compounds developed from GW-501516 , including GI-262570, GW-0072, GW-7845 and GW-7647.
[349] According to one modality, the IBAT inhibitor can be combined with one or more of Atreleutone, Eprotiroma, Los-mapimode, Ezetimibe (SCH58235), Bezafibrato, Fenofibrato, Vares-pladibe, Darapladibe, Lomitapida, Implitapida, Rosiglitazona, Dalcetra- pibe, Anacetrapibe, Lorcasserina, Dapagliflozina, Canagliflozina, Sergliflozina, ASP-1941, Orlistate, Exenatida, Liraglutida, Taspoglutida, Tulaglutida, Pranlintida, Lixisenatida, Albiglutona, Sizlitazitaz, Lazisazitaz, Lizazitazitaz, Lizazitazitaz, Lizazitazitaz, Lizazitazin glitazar, Bromocriptine, Tesofensina, Alogliptina, Vildagliptina, Saxa- gliptina, Sitagliptina, Denagliptina, Gemigliptina, Linagliptina, Dutoglip-tina, Teneligliptina, LC-150444, que Laropiprant liberate niacin, ezetimibe de Rosvastatin, ezetimibe and Rosvastatin. Atorvastatin ezetimibe.
[350] Combinations with Tredaptive, Vitorina and Certriade can be used
[351] According to one embodiment, the IBAT inhibitors of the present invention are combined with at least one other active substance selected from dipeptidyl peptidase-IV inhibitors, statins, PPAR y agonist, statins and bile acid binders in any combination.
[352] According to one embodiment, the IBAT inhibitors of the present invention are combined with at least one DPPIV, at least one PPAR y agonist, such as Sitagliptin and Pioglitazone.
[353] According to another embodiment, the IBAT inhibitors of the present invention are combined with at least one statin, for example, Sitagliptin and Simvastatin and at least one DPPIV.
[354] In certain examples, the use of the compounds reduces or inhibits the recycling of bile acid salts in the gastrointestinal tract. In some embodiments, bile transport inhibitors are non-systemic compounds. In other embodiments, bile acid transporter inhibitors are systemic compounds. In certain embodiments, the bile transport inhibitors described here enhance L-cell secretion of enteroendocrine peptides. In certain instances, increased L-cell secretion of enteroendocrine peptides is associated with induction of satiety and / or reduced food intake (caloric intake) and subsequent weight loss. In some embodiments, increased L-cell secretion of enteroendocrine peptides is associated with a reduction in blood glucose levels and / or plasma in a hyperglycemic individual. In some instances, increased L-cell secretion of enteroendocrine peptides is associated with increased insulin sensitivity.
[355] Provided here are methods for treating obesity or diabetes, comprising contacting the distal ileum of an individual in need thereof with an IBAT inhibitor of the invention. In some types of methods, contacting the distal ileum of an individual in need of it with an IBAT a inhibitor. reduces food intake in the individual; B. induces satiety in the individual; ç. reduces blood glucose and / or plasma levels in the individual; d. treats a metabolic disorder in the individual; and. reduces the individual's weight; f. stimulates L cells in the individual's distal gastrointestinal tract; g. increases the concentration of bile acids and their salts in the vicinity of L cells in the individual's distal gastrointestinal tract; H. enhances the secretion of enteroendocrine peptide in the individual; or i. any combination of them.
[356] According to one embodiment, the IBAT inhibitor can be combined with one or more of any of the other compounds mentioned above.
[357] In some embodiments, the IBAT inhibitor is not systemically absorbed. In some other embodiments, the IBAT inhibitor is systemically absorbed.
[358] In some embodiments, the methods described above also include the administration of a second agent selected from a DPP-IV inhibitor, a biguanide, an accretin mimetic, a thiazolidinedione, GLP-1 or an analogue thereof, and a TGR5 agonist. In some embodiments, the second agent is a DPP-IV inhibitor.
[359] In some methods, the individual is obese or morbidly overweight. In some modalities of the methods, the individual is a diabetic individual. In some fashion methods, the individual is a non-diabetic individual.
[360] In some embodiments, provided here are methods for the treatment of obesity and / or diabetes, comprising administering a therapeutically effective amount of a combination of an IBAT inhibitor and a DPP-IV inhibitor to an individual in need of themselves. In some embodiments, provided herein are methods for the treatment of obesity and / or diabetes, comprising administering a therapeutically effective amount of a combination of an IBAT inhibitor and a TGR5 agonist to an individual in need thereof. In some embodiments, provided here are methods for treating obesity and / or diabetes, comprising administering a therapeutically effective amount of a combination of an IBAT inhibitor and a thiazolidinedione to an individual in need thereof. In some embodiments, provided herein are methods for the treatment of obesity and / or diabetes comprising administering a therapeutically effective amount of a combination of an IBAT inhibitor and an incretin mimic to an individual in need thereof. In some embodiments, provided herein are methods for the treatment of obesity and / or diabetes, comprising administering a therapeutically effective amount of a combination of an IBAT and GLP-1 inhibitor or an analogue to an individual in need thereof. In some embodiments, provided here are methods for the treatment of obesity and / or diabetes, comprising administering a therapeutically effective amount of a combination of an IBAT INHIBITOR and a biguanide to an individual in need thereof.
[361] In some modalities, the methods described here reduce food intake (caloric intake) in an individual in need. In some modalities, the methods described here induce satiety in an individual in need of them. In some embodiments, the methods described here treat metabolic disorders in an individual in need. In some embodiments, the methods described here reduce the weight of an individual in need. In some embodiments, the methods described here stimulate L cells in the distal gastrointestinal tract of an individual in need. In some embodiments, the methods described increase the concentration of bile acid and its salts in the vicinity of L cells in an individual's distal gastrointestinal tract.
[362] Provided here are methods for reducing food intake in an individual in need thereof, comprising administering an IBAT inhibitor to an individual in need of which the IBAT inhibitor is delivered or released non-systemically in the distal ileum. of the individual.
[363] Provided here are methods for reducing circulating plasma or blood glucose levels in an individual in need thereof, including administering an IBAT inhibitor to an individual in need thereof in which the IBAT inhibitor is delivered or released. not systemically in the individual's distal ileum.
[364] Provided here are methods of increasing insulin secretion in an individual in need thereof, comprising administering an IBAT inhibitor to an individual in need of it in which the IBAT inhibitor is distributed or released systemically in the ileum. distal of the individual.
[365] In some embodiments, the methods described here enhance the secretion of enteroendocrine peptide in an individual in need. In some of these embodiments, the enteroendocrine peptide is GLP-1, GLP-2, PYY, oxintomodulin or a combination thereof.
[366] In some modalities, contacting an individual's distal ileus in need of it with an IBAT inhibitor increases the level of GLP-1 in the individual's blood and / or plasma by about 2 times, to about 6 times the level of GLP-1 in the individual's blood and / or plasma before contacting the individual's distal ileum with the IBAT inhibitor.
[367] In some modalities, contacting an individual's distal ileus in need of it with an IBAT inhibitor reduces the individual's blood glucose and / or plasma level by at least 30% compared to the blood glucose level. and / or plasma of the individual before contacting the individual's distal ileum with the IBAT inhibitor.
[368] In some modalities, contacting an individual's distal ileus in need of it with an IBAT inhibitor keeps blood and / or plasma glucose levels reduced in the individual for at least 24 hours compared to glucose levels in the blood and / or plasma in the subject before contacting the subject's distal ileum with the IBAT inhibitor.
[369] In some embodiments, the IBAT inhibitor is administered orally. In some embodiments, the IBAT inhibitor is administered as an ileal pH-sensitive release formulation that distributes the IBAT inhibitor to an individual's distal ileum and / or colon and / or rectum. In some embodiments, the IBAT inhibitor is administered as an enterically coated formulation.
[370] In some embodiments of the methods described above, the IBAT inhibitor is a compound of Formula I as described herein. In some embodiments of the methods described above, the IBAT inhibitor is a compound of Formula II as described herein.
[371] In some modalities of the methods described above, the IBAT inhibitor is administered before eating food. In some modalities of the methods described above, the IBAT inhibitor is administered less than about 60 minutes before eating food. In some modalities of the methods described above, the IBAT inhibitor is administered less than about 30 minutes before eating food. In some modalities of the methods described above, the IBAT inhibitor is administered after eating food.
[372] Provided here are methods for preventing and / or treating congestive heart failure, ventricular dysfunction, toxic hypervolemia, polycystic ovary syndrome, inflammatory bowel disease, impaired bowel integrity, short bowel syndrome, gastritis, peptic ulcer, or irritable bowel disease comprising contacting the distal ileum of an individual in need of it with an IBAT inhibitor. In some embodiments, the methods also comprise administering a DPP-IV inhibitor, a TGR5 agonist, a biguanide, an incretin mimetic, or GLP-1 or an analog thereof. Provided here are methods for the prevention and / or treatment of radiation enteritis, comprising contacting the distal ileum of an individual in need of it with an IBAT inhibitor. In some embodiments, the methods also comprise administration of a DPP-IV inhibitor, a TGR5 agonist, a biguanide, an incretin mimetic, or GLP-1 or an analog thereof.
[373] Provided here are the compositions for reducing caloric intake in an individual in need thereof comprising an IBAT inhibitor, and a pharmaceutically acceptable carrier, in which the IBAT inhibitor is distributed or released not systemically in the distal ileum of the individual. Provided here are compositions for reducing circulating blood and / or plasma glucose levels in an individual in need thereof comprising an IBAT inhibitor, and a pharmaceutically acceptable carrier, in which the IBAT inhibitor is delivered or released non-systemically in the distal ileum of the individual. Provided here are compositions for increasing insulin secretion in an individual in need thereof comprising an IBAT inhibitor, and a pharmaceutically acceptable carrier, in which the IBAT inhibitor is delivered or released non-systemically in the individual's distal ileum. In any of the above-mentioned embodiments, the compositions also comprise a DPP-IV inhibitor, a TGR5 agonist, a biguanide, an incretin mimetic, or GLP-1 or an analog thereof.
[374] Supplied here, in some embodiments, are IBAT inhibitors to reduce food intake (caloric intake) or to reduce circulating blood or plasma glucose levels where the IBAT inhibitor is not systemically absorbed after oral administration . In some of such embodiments, the IBAT inhibitor is a compound of Formula I, II, as described herein. In some of these modalities, the IBAT inhibitor is prevented from being absorbed in the stomach by its presence in a formulation that releases into the ileum. In some of these embodiments, the IBAT inhibitor is administered in combination with a second therapeutic agent selected from a DPP-IV inhibitor, a biguanide, a thiazolidinedione, an incretin mimetic, GLP-1 or an analogue thereof, or a TGR5 agonist.
[375] All substances mentioned here can be used including IBAT inhibitors and other active substances can likewise be used in the form of pharmaceutically acceptable salts and esters where applicable.
[376] Incretins and hormones produced by L cells
[377] In one embodiment, the other active substances may be Incretins and / or hormones produced by L cells.
[378] In some embodiments, the additional therapeutic agent is an L cell endocrine peptide enhancer. In some instances, the L cell endocrine peptide enhancer is a GLP-1 enhancer. In some embodiments, the GLP- 1 is GLP-1, a GLP-1 secretion enhancer, a GLP-1 degradation inhibitor, and the like, or a combination thereof. In certain instances, the enhanced GLP-1 concentration provides a reduction in food intake and / or a reduction in gastric emptying in human subjects.
[379] In some embodiments, an L-cell endocrine peptide enhancer is a GLP-2 enhancer. In certain examples, the GLP-2 enhancer is GLP-2, a GLP-2 secretion enhancer, a GLP-2 degradation inhibitor, and the like, or a combination thereof. In certain instances, enhanced GLP-2 secretion inhibits gastric emptying and reduces intestinal permeability. In some instances, enhanced GLP-2 secretion inhibits gastric acid secretion. In some instances, enhanced GLP-2 secretion reduces or prevents inflammation in the gastrointestinal tract (gastrointestinal enteritis). In some instances, enhanced secretion of GLP-2 regenerates and / or heals the injury to gastrointestinal tissues (eg, radiation enteritis).
[380] In some examples, the L-cell endocrine peptide enhancer is a PYY enhancer. In some instances, enhanced PYY secretion provides a reduction in the feeling of hunger. In some examples, the L-cell endocrine peptide enhancer is an oxintomodulin enhancer. In some instances, enhanced oxytomodulin secretion inhibits gastric secretion stimulated by the meal.
[381] Incretin mimetics
[382] In some embodiments, the additional therapeutic agent is an incretin mimetic. In some modalities, an mimic of incredulous increases the response of the pancreas to food intake. In some examples, administration of an incretin mimetic in combination with any of the compounds described herein decreases blood glucose levels and / or plasma. Examples of incretin mimetics include and are not limited to exenatide (Bietta.RTM.).
[383] One therapy currently used for treatment is a subcutaneous injection of exenatide (Bietta.RTM.). In some embodiments, an oral combination of an IBAT inhibitor and a DPP-IV inhibitor is equally or more effective than an injection of exenatide in reducing plasma glucose levels. In some embodiments, an oral combination of an IBAT inhibitor and a DPP-IV inhibitor reduces or eliminates the discomfort associated with injections of glucose-lowering drugs.
[384] Enteroendocrine Peptides
[385] In some embodiments, the additional therapeutic agent is an enteroendocrine peptide. In some modalities, enteroendocrine peptides reverse insulin resistance and decrease blood glucose levels and / or plasma. Examples of enteroendocrine peptides that are administered as additional therapeutic agents include and are not limited to GLP-1 or GLP-1 analogs such as Taspoglutide.RTM. (Ipsen), or the like. Combination Therapy with IBAT Inhibitor and DPP-IV Inhibitor
[386] In specific embodiments, the additional therapeutic agent inhibits the degradation of L-cell enteroendocrine peptides. In certain embodiments, the additional therapeutic agent is a DPP-IV inhibitor. In certain examples, administration of an IBAT inhibitor to an individual in need of it enhances the secretion of GLP-1; administration of a DPP-IV inhibitor in combination with the IBAT inhibitor reduces or inhibits the degradation of GLP-1 from this mod, prolonging the therapeutic benefit of enhanced levels of GLP-1. In some embodiments, administration of an IBAT inhibitor reduces an individual's weight. In some embodiments, administration of an IBAT inhibitor in combination with a DPP-IV inhibitor reduces an individual's weight.
[387] Another therapy is a combination of metformin and sitagliptin (Janumet.RTM.). At doses of 0, 3, 30, 100, than 300 mg / kg of metformin in combination with 30 mg / kg of sitagliptiona, reductions in plasma glucose concentrations are observed from 3 hours to about 6 hours post-dose. In some embodiments, a combination of an IBAT inhibitor and sitagliptin keeps plasma glucose concentrations reduced for a longer duration of time (for example, at least 24 hours) compared to a combination of metformin and sitagliptin (about 6 hours). In some instances, IBAT inhibitor therapy eliminates the side effects associated with metformin therapy and / or DPP-IV inhibitor therapy.
[388] DPP-IV inhibitors suitable for use with the methods described here include and are not limited to (2S) -1- {2 - [(3-hydroxy-1-adamantyl) amino] acetyl} pyrrolidine-2-carbonitrile (viladagliptin), (3R) -3- amino-1- [9- (trifluoromethyl) -1,4,7,8-tetrazabicyclo [4.3.0] ninth-6.8 - dien-4-yl] -4 - (2,4,5-trifluorophenyl) butan-1-one (sitagliptin), (1S, 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-dihydropyrimidi-n-1 (2H) -yl} methyl) benzonitrile (alogliptin).
[389] In some embodiments of any of the methods described here, administration of an ASBT inhibitor described here in combination with a DPP-IV inhibitor increases the level of GLP-1 in an individual's blood and / or plasma by about 1.1 times, about 30 times compared to the level of GLP-1 in the blood and / or plasmid individual before administration of the IBAT inhibitor in combination with the DPP-IV inhibitor. In some embodiments of any of the methods described here, administration of an ASBT inhibitor described here in combination with a DPP-IV inhibitor increases the level of GLP-1 in an individual's blood and / or plasma by about 1.1 time, about 20 times compared to the individual's blood and / or plasma GLP-1 level prior to administration of the IBAT inhibitor in combination with the DPP-IV inhibitor. In some embodiments of any of the methods described here, administration of an ASBT inhibitor described here in combination with a DPP-IV inhibitor increases the level of GLP-1 in an individual's blood and / or plasma by about 1.5 time, about 10 times compared to the level of GLP-1 in the subject's blood and / or plasma prior to administration of the IBAT inhibitor in combination with the DPP-IV inhibitor. In some embodiments of any of the methods described here, administration of an ASBT inhibitor described here in combination with a DPP-IV inhibitor increases the level of GLP-1 in an individual's blood and / or plasma by about 2 times, about 8 times compared to the individual's blood and / or plasma GLP-1 level prior to administration of the IBAT inhibitor in combination with the DPP-IV inhibitor. In some embodiments of any of the methods described here, administration of an ASBT inhibitor described here in combination with a DPP-IV inhibitor increases the level of GLP-1 in an individual's blood and / or plasma by about 2 times, about 6 times compared to the level of GLP-1 in the subject's blood and / or plasma prior to administration of the IBAT INHIBITOR in combination with the DPP-IV inhibitor. In some instances, an increase in the level of GLP-1 from about 2 times to about 3 times following the administration of an ASBT inhibitor described here in combination with a DPP-IV inhibitor compared to the level of GLP-1 in the blood and / or plasma of the individual prior to administration of the IBAT INHIBITOR in combination with the DPP-IV inhibitor may be used. In some instances, an increase in the level of GLP-1 from about 3 times to about 8 times the administration of an ASBT inhibitor described here in combination with a DPP-IV inhibitor compared to the level of GLP-1 in the blood and / or plasma of the subject prior to administration of the IBAT inhibitor in combination with a DPP-IV inhibitor can be used.
[390] In certain embodiments of any of the methods described here, administration of an IBAT inhibitor in combination with a DPP-IV inhibitor reduces blood sugar and / or plasma levels by at least 20%, at least 30% at least 40%, at least 50% at least 60%, at least 70% or at least 80% compared to blood and / or plasma sugar levels prior to administration of the IBAT inhibitor in combination with a DPP inhibitor -IV. In some embodiments of any of the methods described here, administration of an IBAT inhibitor in combination with a DPP-IV inhibitor reduces blood sugar and / or plasma levels by at least 20% compared to blood sugar levels and / or plasma prior to administration of the IBAT inhibitor in combination with a DPP-IV inhibitor. In some embodiments of any of the methods described here, administration of an IBAT inhibitor in combination with a DPP-IV inhibitor reduces blood sugar and / or plasma levels by at least 30% compared to blood sugar levels and / or plasma prior to administration of the IBAT inhibitor in combination with a DPP-IV inhibitor. In some embodiments of any of the methods described here, administration of an IBAT inhibitor in combination with a DPP-IV inhibitor reduces blood sugar and / or plasma levels by at least 40% compared to blood sugar levels and / or plasma prior to administration of the IBAT INHIBITOR in combination with a DPP-IV inhibitor.
[391] In some embodiments of any of the methods described here, administration of an IBAT inhibitor in combination with a DPP-IV inhibitor reduces blood sugar and / or plasma levels over a longer period of time (for example , at least 24 hours) compared to the reduction in blood sugar and / or plasma levels when administering metformin in combination with a DPP-IV inhibitor. In some embodiments of any of the methods described here, administration of a single dose of an IBAT inhibitor in combination with a DPP-IV inhibitor sustains reduced blood and / or plasma sugar levels for at least 6 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 24 hours, at least 30 hours, at least 36 hours or at least 48 hours compared to the reduction in sugar levels in blood and / or plasma when taking a single dose of metformin in combination with a DPP-IV inhibitor.
[392] In some embodiments of any of the methods described here, administration of an IBAT inhibitor in combination with a DPP-IV inhibitor results in higher levels of GLP-1 in an individual's blood and / or plasma compared to levels of GLP-1 in the blood and / or plasma of a normal individual. In some embodiments of any of the methods described here, administration of an IBAT inhibitor in combination with a DPP-IV inhibitor results in higher levels of GLP-1 in an individual's blood and / or plasma compared to the levels of GLP -1 in the blood and / or plasma of an individual undergoing therapy with metformin and / or a DPP-IV inhibitor. TGR5 Receiver Modulators
[393] In some instances, the additional therapeutic agent modulates bile acid receptors in the gastrointestinal lumen. In some embodiments, the additional therapeutic agent agonizes or partially agonizes bile acid receptors (for example, TGR5 receptors or Farnesoide-X receptors) in the gastrointestinal tract. In some embodiments, the additional therapeutic agent is a bile acid analogue. In certain instances the additional therapeutic agent is a TGR5 agonist. In certain examples, administration of a TGR5 agonist in combination with any of the compounds described here enhances the secretion of L-cell enteroendocrine peptides (eg, TGR5 modulators) include, and are not limited to, the compounds described in WO 2008 / 091540, WO 2008/067219 and US Application No. 2008/0221161. Thiazolidinediones
[394] In some embodiments, the additional therapeutic agent is thiazolidinedione. In some instances, thiazolidinediones reverses insulin resistance and lowers blood glucose levels and / or plasma. Examples of thiazolidinediones include and are not limited to Rosiglitazone (Avandia), Pioglitazone (Actos), Troglitazone (Rezulin), MCC-555, rivoglitazone, ciglitazone or the like. Combination therapy with IBAT I inhibitor, Biliary Bypass and DPP-IV inhibitor
[395] In some embodiments, an IBAT INHIBITOR is administered in combination with a DPP-IV inhibitor and / or a bile bypass. Examples of bile derivations include and are not limited to derivations described in WO 2007/0050628, the description of bile derivations described herein, is incorporated herein by reference. In some of these modalities, a bile bypass moves bile acid into the distal ileum and / or the rectum and / or the colon, thereby increasing the concentration of bile acids in the vicinity of L cells present in the distal portion of the gastrointestinal tract. In some instances, such an increase in the concentration of bile acids in the vicinity of L cells, increases L-cell secretion of GLP-1, thereby inducing satiety and / or reduction in hunger and / or weight loss and / or reduction in plasma glucose levels or any combination thereof.
[396] An IBAT inhibitor and a second active ingredient are used, such that the combination is present in a therapeutically effective amount. That therapeutically effective amount arises from the use of a combination of an IBAT inhibitor and the other active ingredient (for example, a DPP-IV inhibitor) in which each is used in a therapeutically effective amount, or due to the additive or synergistic effects that arise from combined use, each can also be used in a subclinical therapeutically effective amount, that is, an amount that, if used alone, provides reduced efficacy for the therapeutic purposes noted here, as long as the combined use is therapeutically effective. In some embodiments, the use of a combination of an IBAT inhibitor and any other active ingredient as described herein, encompasses combinations where the IBAT inhibitor or the other active ingredient is present in a therapeutically effective amount, and the other is present in a subclinical therapeutically effective amount, provided that the combined use is therapeutically effective, due to its additive or synergistic effects. When used herein, 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 produced 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 produced alone. Any suitable combination of an ASBIT with one or more of the other active ingredients mentioned above and optionally with one or more other pharmacologically active substances is considered to be within the scope of the methods described herein.
[397] In some embodiments, the particular choice of compounds depends on the diagnosis of the attending physicians and their judgment of the individual's condition and the appropriate treatment protocol. The compounds are optionally administered concurrently (for example, simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder or condition, the condition of the individual, and the current choice of compounds used. In certain instances, determining the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is the basis for an assessment of the disease to be treated and the condition of the individual.
[398] In some embodiments, therapeutically effective dosages vary when drugs are used in treatment combinations. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature.
[399] In some modalities of the combination therapies described herein, the dosages of the co-administered compounds vary depending on the type of co-drug used, the specific drug used, the disease or condition to be treated and so on. In addition, when co-administered with one or more biologically active agents, the compound provided herein is optionally administered simultaneously with the biologically active agent (s), or sequentially. In certain instances, if administered sequentially, the attending physician will decide on the appropriate sequence of therapeutic compound described herein in combination with the additional therapeutic agent.
[400] Multiple therapeutic agents (at least one of which is a therapeutic compound described herein) are optionally administered in any order or even simultaneously. In the case of simultaneously, multiple therapeutic agents are optionally supplied in a unified, single, or multiple form (by way of example only, or as a single pill or as two separate pills). In certain examples, one of the therapeutic agents is optionally given as multiple doses. In other examples, they are optionally also given as multiple doses. In the case of non-simultaneous, timing between multiple doses is any suitable timing, for example, from more than zero weeks to less than four weeks. In addition, the methods of combination, compositions and formulations will not be limited to the use of just two agents; the use of multiple therapeutic combinations in the same way is considered (including two or more compounds described herein).
[401] In certain modalities, a dosage regimen to treat, prevent or improve the condition (s) for which relief is sought, is modified according to a variety of factors. These factors include the disorder from which the individual suffers, as well as the age, weight, sex, diet and medical condition of the individual. Thus, in various modalities, the dosage regimen actually employed varies and differs from the dosage regimens mentioned here.
[402] 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 intended for substantially simultaneous administration. In certain embodiments, the pharmaceutical agents that make up combination therapy are administered sequentially, with any therapeutic compound being administered by a regimen that requires two-stage administration. In some embodiments, the two-step administration regime requires sequential administration of active agents or administration that is separate from separate active agents. In certain embodiments, the time period between multiple administration steps varies, by way of non-limiting 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. Diseases
[403] One or more of the IBAT inhibitor compounds of the invention possibly and together with one or more of any of the active compounds mentioned for use in combination with an IBAT inhibitor compound of the invention, can be used. undergoing prophylactic or therapeutic treatment of dyslipidemic conditions and disorders such as hyperlipidemia, hypertriglyceridemia, hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (high VLDL), hyperkylomicronemia, hypolipoproteinemia, hypercholesterolemia (hyperlipoproteinemia) and hyperlipoproteinemia (hyperlipoproteinemia). In addition, these compounds are expected to be useful for the prevention and treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hyperactive thrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart disease, cardiovascular disease, myocardial infarction , angina pectoris, peripheral vascular diseases, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocyte, macrophage and / or monocyte infiltrate, thickening , medial thinning, infectious and surgical trauma and vascular thrombosis, stroke and transient ischemic attacks; gallstones, diarrhea.
[404] Fatty acid metabolism disorders and glucose utilization disorders, disorders in which insulin resistance is involved. Diabetes mellitus, especially type 2 diabetes, including prevention of the sequelae associated with it. Particular aspects in this context are hyperglycemia, improvement in insulin resistance, improvement in glucose tolerance, protection of pancreatic beta cells, prevention of macro- and microvascular disorders. Dyslipidemias and their sequelae such as, for example, atherosclerosis, coronary heart disease, cerebrovascular disorders, etc., especially those (but not restricted to them) that are characterized by one or more of the following factors: high plasma triglyceride concentrations, post-plasma triglyceride concentrations -prandial foods, low concentration of HDL cholesterol, low concentrations of apoA lipoprotein, high concentrations of LDL cholesterol, small dense LDL cholesterol particles, high concentrations of apoB lipoprotein, desaturation index (for example, 18: 1 ratio / 18: 0n-9, 16: 1/16: 0 n-7 or 18: 1n-9 + 16: 1n-7/16: 0 fatty acids). Various other conditions that may be associated with metabolic syndrome or X syndrome, such as: increased waist circumference dyslipidemia (eg, hypertriglyceridemia and / or low HDL) insulin resistance, hypercoagulability, hyperuricemia, microalbuminemia, thrombosis, hypercoagulable and prothrombotic states - cos (arterial and venous), high blood pressure, heart failure such as, for example (but not restricted to them), following myocardial infarction, hypertensive heart disease or cardiomyopathy. Liver disorders and conditions related to them, fatty liver, fatty liver, non-alcoholic hepatitis, non-alcoholic steatoepatitis (NASH), alcoholic hepatitis, acute fatty liver, pregnancy fatty liver, drug-induced hepatitis, iron overload disorders, liver fibrosis , liver cirrhosis, hepatoma, viral hepatitis. Disorders and conditions of the skin and those associated with polyunsaturated fatty acids, eczema, acne, psoriasis, formation of keloid scarring or prevention of other diseases related to mucous membrane fatty acid composition. Primary or secondary hypertriglyceridemia, hyperlipoproteinemias, apolipoprotein deficiency (for example, apoCII or apoE deficiency). Diseases or conditions related to neoplastic cell proliferation, cancer of benign or malignant tumors, neoplasia, metastasis, carcinogenesis. Diseases or conditions related to neurological, psychiatric or immune disorders or conditions. Other diseases or conditions in which inflammatory reactions or cell differentiation may, for example, be involved are: atherosclerosis such as, for example (but not restricted to), coronary sclerosis including angina pectoris or myocardial infarction, stroke, stroke ischemic cerebral vascular disease and transient ischemic attack (TIA), peripheral occlusive disease, vascular restenosis or reocclusion, chronic inflammatory bowel diseases, such as, for example, Crohn's disease and ulcerative colitis, pancreatitis, sinusitis, other inflammatory conditions, retinoopathy , ischemic retinopathy, adipose cell tumors, lipomatous carcinomas, such as, for example, liposarcomas, solid tumors and neoplasms, such as, for example (but not restricted to them), carcinomas of the gastrointestinal tract, liver, biliary tract and pancreas, endocrine tumors, carcinomas of the lungs, kidneys and urinary tract, genital tract, prostate carcinomas, et c., acute and chronic myeloproliferative disorders and lymphomas, angiogenesis, neurodegenerative disorders, Alzheimer's disease, multiple sclerosis, Parkinson's disease, erythematous-squamous dermatoses, such as, for example, psoriasis, acne vulgaris, other disorders skin conditions and dermatological conditions that are modulated by PPAR, eczema and neurodermatitis, dermatitis such as, for example, seborrheic dermatitis or photodermatitis, keratitis and keratoses, such as, for example, seborrheic keratoses, senile keratoses, actinic keratoses, photoin keratoses - follicular keratosis or keratosis, keloids and prophylaxis of keloids, warts, including condylomata or condylomata acuminate, viral infections of human papilloma (HPV) such as, for example, venous papilloma, viral warts such as, for example, contagious mollusc, leukemia coplaquia, papular dermatoses, such as, for example, lichen planus, skin cancer, such as, for example, basal cell carcinomas, melanomas or lymph cutaneous T cell cells, localized benign epidermal tumors, such as, for example, keratoderma, epidermal nevus, chilblains, high blood pressure, syndrome X, polycystic ovary syndrome (PCOS), asthma, cystic fibrosis, osteoarthritis, lupus erythematosus (LE ) or inflammatory rheumatic disorders, such as, for example, rheumatoid arthritis, vasculitis, emaciation (cachexia), gout, ischemia / reperfusion syndrome, acute respiratory distress syndrome (ARDS), viral diseases and infections, lipodystrophy and lipodystrophy conditions, too to treat adverse drug effects (for example, after taking HIV drugs or tumors), myopathies and lipid myopathies (such as carnitine palmitoyltransferase I or II deficiency).
[405] One aspect of the present invention is a combination, as described herein, for use in the prophylactic or therapeutic treatment of liver disease. Examples of liver diseases where a combination as described herein can be useful, include liver parenchyma; a metabolic disorder inherited from the liver; Byler syndrome; a primary defect in bile acid (BA) synthesis, such as cerebro-tendinous, or xanthomatosis; a secondary defect, such as Zellweger syndrome, neonatal hepatitis, cystic fibrosis, liver manifestations, ALGS (Alagilles syndrome), PFIC (progressive intraepathic familial cholestasis, autoimmune hepatitis, primary biliary cirrhosis (PBC), liver fibrosis, adipose liver disease non-alcoholic, NAFLD / NASH, portal hypertension, general cholestasis, as in jaundice due to drugs during pregnancy, intra and extraepathic cholestasis, such as hereditary forms of cholestasis, such as PFIC1, primary sclerosing cholangitis, gallstones and choledocholithiasis, obstruction causing malignancy of the biliary tree, symptoms (itching, itching) due to cholestasis / jaundice, pancreatitis, chronic autoimmune liver disease that leads to progressive cholestasis, or itching of cholestatic liver disease; a liver disorder or a condition hepatic-related, fatty liver, fatty liver, non-alcoholic steatoepatitis (NASH), alcoholic hepatitis, acute fatty liver, liver pregnancy fat, drug-induced hepatitis, iron overload disorders, liver fibrosis, liver cirrhosis, hepatoma, viral hepatitis and problems related to tumors and neoplasms of the liver and biliary tract. Medicinal and pharmaceutical use of the invention.
[406] In accordance with another aspect of the invention there is provided an oral pharmaceutical Formulation comprising an IBAT-inhibiting compound or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof and a bile acid binder, wherein the formulation is designed to release the bile acid binder into the colon for use in producing an inhibitory effect of IBAT in a warm-blooded animal, such as man.
[407] According to another aspect of the invention an oral pharmaceutical formulation is provided comprising an IBAT-inhibiting compound or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug of the same and a bile acid binder, and at least one of other active compounds mentioned above and a bile acid binder of the invention in which the formulation is designed to release the bile acid binder into the colon for use in producing an inhibitory effect of IBAT in a warm-blooded animal, such as man.
[408] According to another aspect of the invention there is provided an oral pharmaceutical formulation comprising an IBAT-inhibiting compound or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof and a bile acid binder, wherein the formulation is designed to release the bile acid binder into the colon for use in the prophylaxis or treatment of any of the medical indications mentioned here in a warm-blooded animal, such as man.
[409] According to another aspect of the invention there is provided an oral pharmaceutical formulation comprising an IBAT-inhibiting compound or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof and a bile acid binder, and at least one of the other active compounds mentioned above and a bile acid binder of the invention in which the formulation is designed to release the bile acid binder into the colon for use in the prophylaxis or treatment of any of the medical indications mentioned herein in a warm-blooded animal, such as like the man.
[410] According to another aspect of the invention there is provided an oral pharmaceutical formulation comprising an IBAT-inhibiting compound or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof and a bile acid binder, wherein the formulation is designed to release the bile acid binder into the colon for use in the preparation of a pharmaceutical product for use in the prophylaxis or treatment of any of the medical indications mentioned herein in a warm-blooded animal, such as man.
[411] According to another aspect of the invention there is provided an oral pharmaceutical formulation comprising an IBAT-inhibiting compound or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof and a bile acid binder, and at least one of the other active compounds mentioned above and a bile acid binder of the invention in which the formulation is designed to release the bile acid binder into the colon for use in the preparation of a pharmaceutical product for use in the prophylaxis or treatment of any of the medical indications mentioned herein in a warm-blooded animal, such as man.
[412] In a further aspect of the invention, a method of treating any of the medical conditions mentioned herein is provided in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a IBAT-inhibiting compound or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of a bile acid binder.
[413] In a further aspect of the invention, a method of treating any of the medical conditions mentioned herein is provided in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a IBAT-inhibiting compound or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, and at least one of the other active compounds mentioned above, in simultaneous, sequential or separate administration with an effective amount of a bile acid binder . Pharmaceutical Formulations
[414] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable vehicles including, for example, excipients and auxiliaries that facilitate the processing of active compounds in preparations that are suitable for pharmaceutical use. In certain embodiments, appropriate formulation is dependent on the chosen administration routine. A summary of pharmaceutical compositions described here is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (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 Edition. (Lippincott Williams & Wilkins 1999).
[415] A pharmaceutical composition, as used herein, refers to a mixture of a compound described here, such as, for example, a compound of Formulas I and II and possibly also other active compounds mentioned here, with other chemical components, such as such as vehicles, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or other excipients. In certain cases, the pharmaceutical composition facilitates the administration of the compound to an individual or cell. In certain embodiments of practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to an individual having a disease, disorder, or condition to be treated. In specific modalities, the individual is a human being. As described herein, the compounds described herein are either used individually or in combination with one or more additional therapeutic agents.
[416] In certain embodiments, the pharmaceutical formulations described here are administered to an individual in any way, including one or more of the multiple administration routines, such as, by way of non-limiting example, oral or oral administration routines.
[417] In certain embodiments, a pharmaceutical composition described here includes one or more compounds described here as an active ingredient in the form of a free acid or free base, or in a pharmaceutically acceptable salt form. In some embodiments, the compounds described here are used as an N-oxide. In some situations, a compound described here exists as tautomers. All tautomers are included in the scope of compounds shown here. In certain embodiments, a compound described herein exists in an unsolvated or solvated form, wherein the solvated forms comprise any pharmaceutically acceptable solvent, for example, water, ethanol, and the like. The solvated forms of the compounds shown here are also considered to be described here.
[418] According to the invention, the IBAT inhibitor and the bile acid binder can be administered simultaneously, separately or sequentially. According to the invention, the IBAT inhibitor and bile acid binder can be formulated in separate formulations with the IBAT inhibitor formulation which releases the drug immediately or delayed in the distal jejunum or proximal ileum and the bile acid binder formulation. releasing the drug into the colon.
[419] According to the invention, the IBAT inhibitor and the bile acid binder can be combined in a formulation with the bile acid binder in the core and formulated for release into the colon and the IBAT inhibitor and an outer layer formulated for immediate or delayed release in the distal jejunum or proximal ileum.
[420] According to one embodiment, a new dosage regimen is provided by administering an IBAT inhibitor of the invention once a day and a bile acid binder once, twice or three times a day.
[421] According to one embodiment, the IBAT inhibitor and bile acid binder are administered together once, twice or three times a day.
[422] According to one embodiment, the IBAT inhibitor is administered in a formulation that releases it into the small intestine.
[423] According to one embodiment, the bile acid binder is administered in a formulation that releases it into the colon.
[424] One aspect of the present invention is a pharmaceutical combination formulation, comprising:
[425] an inner core comprising a bile acid binder;
[426] a layer of colon release over the nucleus;
[427] an IBAT inhibition layer on top of the said colon release layer; and
[428] an external protective coating
[429] In, however, one aspect of the invention, the IBAT inhibitor layer comprises a compound of Formula II
II
[430] M is -CH2OU NH;
[431] R1 is H or OH; and
[432] R2 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH (CH3) 2, -CH2CH (CH3) 2, -CH (CH3) CH2CH3, -CH2OH, CH2OCH3, -CH (0H) CH3, -CH2SCH3, or -CH2CH2-S-CH3; or a pharmaceutically acceptable salt thereof.
[433] In the dosage regimen or the aforementioned formulations, the acid binder can be colesvelam and the IBAT inhibitor a compound of Formula I, II or the 14 examples below.
[434] Dosage forms with different release regimes can be constructed in different ways, for example, as described in the following. Release in distal jejunum or ileum and / or colon
[435] In certain embodiments, a dosage form comprises a matrix (for example, a matrix comprising hypermolesterol) that provides 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 sensitive to pH (for example, an MMX.TM. matrix from Cosmo Pharmaceuticals) and provides controlled release of an active agent into the ileum and / or colon. Examples of such pH sensitive polymers suitable for controlled release include and are not limited to polyacrylic polymers (for example, anionic polymers of methacrylic acid and / or esters of methacrylic acid, for example, polymers of Carbopol.R ™) which comprise acidic groups (for example, -COOH, -SO3H) and swell at basic intestinal pH (for example, pH about 7 to about 8). In some embodiments, a suitable dosage form for controlled release into the distal ileum comprises microparticulate active agent (for example, micronized active agent). In some embodiments, a non-enzymatically degrading poly (dl-lactide-co-glycolide) (PLGA) nucleus is suitable for releasing an IBAT inhibitor to the distal ileum. In some embodiments, a dosage form comprising an IBAT inhibitor is coated with an enteric polymer (eg, Eudragit.RTM. S-100 (CAS number: 25086 - 15 - 1), cellulose acetate phthalate, polyvinylacetate phthalate , hydroxypropylmethylcellulose phthalate, anionic polymers of methacrylic acid, methacrylic acid esters or the like) for specific site release to the ileum and / or colon. In some embodiments, bacterially activated systems are suitable for targeted delivery to the ileum. Examples of activated microflora systems include dosage forms comprising amylose, pectin, galactomannan, and / or azo hydrogels and / or glycoside conjugates (e.g., 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-xylopyranidasidase or the like.
[436] A controlled delay time can be activated by changes in pH, differences in redox potential or metabolic luminal changes in the gastrointestinal tract as described in Aliment Pharmacol Ther 1997, 11 (suppl 3): 109-115. Such a controlled delay time can be obtained, for example, by a programmed disintegration of the formulation due to erosion, dissolution or in general by components present in the formulation that interact with the environment in the gastrointestinal tract. Preferably, the drug release from the dosage form can be activated by varying the pH between the jejunum and the ileum.
[437] Alternatively, the drug release from the dosage form can be controlled chronographically to obtain the above specified time limits, such as, for example, described in European Patent Application, Publication No. EP-A-0384642.
[438] In accordance with another aspect of the invention, a continuous release formulation can be constructed by any known principle, such as corrosion or non-corrosion matrices, layers of membrane coating or by diffusion or drug delivery, osmotically directed. Suitable techniques for the construction of such formulations are described, for example, in M. E. Aulton, Pharmaceutics, The Science of dosage form design. (1988).
[439] In the present invention, an IBAT inhibitor compound is combined with a bile acid binder thereby avoiding a possible risk of excess bile acids in the colon caused by inhibition of the ileal bile acid transport system. An excess of bile acids in the visceral contents can cause diarrhea. Accordingly, the present invention also provides a treatment for a possible side effect such as diarrhea in patients during therapy that comprises IBAT inhibitor compounds.
[440] Bile acid binders suitable for such a combination therapy are resins, such as cholestirmine, colestipol or collectable. An advantage is that the dose of the bile acid binder could be kept below the therapeutic dose for the treatment of cholesterolemia in the only treatment that comprises only a bile acid binder. By a low dose of bile acid binder, any possible side effects caused by the patient's lower tolerance to the therapeutic dose that can likewise be avoided.
[441] The bile acid binder is administered in a dosage form with release in the colon, that is, distribution of the active dose of bile acid binder in the colon. A possible risk of receiving an excess of bile acid in the colon by treatment with an IBAT inhibitor can be avoided by co-administering a bile acid binder with release in the colon. In this way, any excess bile acid in the colon, with a possible risk of causing diarrhea, will be bonded to a resin. The dose of the bile acid binder can be kept low due to an effective use of the dose by such a release in the colon. The distribution in the colon of the bile acid binder can be obtained by a formulation comprising a core containing the bile acid binder and optionally pharmaceutically acceptable excipients, and a coating of the said core with a release membrane adapted for colonic delivery. Technologies for obtaining such a distribution of drugs to the colon are, for example, described in Drug development and Industrial Pharmacy 1997, 23: 893-913.
[442] According to one embodiment, the invention relates to a composition comprising one or more IBAT inhibitors of the invention and cholestyramine and / or colesevelam and / or cholestipol.
[443] According to one embodiment, the invention relates to a composition comprising one or more of the compounds of Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 and cholestyramine and / or colesevelam and / or colestipol.
[444] According to another embodiment, the invention relates to a composition comprising one or more of the compounds among 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -1 '-phenyl-1' - [N- (carboxymethyl) -carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 5) and cholestyramine and / or colesevelam and / or colestipol.
[445] According to another embodiment, the invention relates to a composition comprising one or more of the compounds among 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (A / - {(R) -a - [/ / - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2 , 5-benzothiadiazepine (Example 13), and cholestyramine and / or colesevelam and / or colestipol.
[446] According to another embodiment, the invention relates to a composition comprising one or more of the compounds among 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- { (R) -1 '-phenyl-1' - [N- (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 14) and cholestyramine and / or colesevelam and / or cholestipol. Preparation of core material
[447] The core material for the units, ie the tablets or individual pellets can be constituted according to different principles. The core material can be homogeneous or heterogeneous. The core containing the active ingredient can be formulated differently such as monolithic tablets, capsules, granules, pellets, other particles or crystals.
[448] With a homogeneous core material is meant, which has a homogeneous distribution of the active substance throughout the core material.
[449] Depending on whether the IBAT inhibitor and the bile acid binder are formulated separately or combined, the active substances are optionally mixed with additional components to obtain the preferred handling and processing properties and an appropriate concentration of the active substance in the final mixture. . Such components can be binders, surfactants, lubricants, glidants, fillers, additives or other pharmaceutically acceptable ingredients, alone or in mixtures.
[450] Said core material can be produced by direct compression of the mixed ingredients, or by granulation of the ingredients followed by compression of the granular material.
[451] In direct compression, the ingredients are mixed and pressed using ordinary tablet preparation equipment.
[452] For granulation, there are numerous alternatives to granulation procedures mentioned in the literature, dry methods like roller compaction (Chilsonator) and wet methods using granulation solutions with and without the addition of binders. A variant of wet methods is to prepare spray granulation in a fluid bed.
[453] For wet granulation methods, organic solvents, aqueous solutions or pure water can be used to prepare the granulation solutions. Due to environmental considerations, pure water is preferred, if possible due to the composition of the mixture.
[454] Homogeneous core particles can likewise be prepared by techniques such as dry or wet grinding, freeze grinding, air jet micronization, spray drying, spray cooling, controlled crystallization, supercritical crystallization, solvent evaporation by emulsion and solvent extraction by emulsion.
[455] The core material can likewise be produced by extrusion / spheronization, ball-forming or compression, using different process equipment.
[456] The size of the formulated core materials is approximately between 2 and 20 mm, preferably between 3 and 15 mm for a tablet preparation, and between 0.001 and 4 mm, preferably between 0.001 and 2 mm for a pellet preparation .
[457] The core material manufactured can also be layered with additional ingredients that comprise the active substance and / or be used for another process.
[458] Alternatively, the core material may be heterogeneous with an inner zone, for example, a seed or sphere, not containing the active substance. A layer comprising the active substance, and optionally pharmaceutically acceptable excipients, surrounds this seed or sphere.
[459] The seed or sphere can be soluble or insoluble. Optionally, the seed or sphere (inner area) can be covered with an inert layer to prepare a smooth surface before the layer containing the active substance is applied over the seed / sphere.
[460] Insoluble seeds / spheres may comprise different oxides, celluloses, organic polymers and other materials, alone or in mixtures. Water-soluble seeds / spheres can comprise different inorganic salts, sugars and other materials, alone or in mixtures. The size of the seeds can vary between approximately 0.1 and 2 mm. Layered seeds with the matrix containing the active substance are produced in layered powder or solution / suspension using, for example, granulation or spray coating / layered equipment. Processes for applying release modification membranes
[461] A release modification membrane can be applied to the core material, either a monolithic tablet, multiple units, or a hard or soft gelatin capsule, by layering or coating procedures on suitable equipment such as coating pans. , coating granulators or in a fluidized bed mechanism using water and / or organic solvents for the coating process. Likewise, powder coating principles can be applied. Another possibility is to apply the coating by microencapsulation techniques such as co-storage, emulisification with subsequent removal of the solvent by extraction or evaporation, ionotropic freezing or freezing.
[462] Such modifying release membranes can be applied to the core material comprising the IBAT inhibitor for delivery to the distal small intestine and optionally likewise can be applied to the bile acid binder for delivery to the colon. Pharmaceutical additives
[463] Modifying release coatings can be obtained by one or more, separately or in compatible combinations of pharmaceutically acceptable ingredients, in carefully titrated amounts to achieve the planned release properties. Like the delayed release coating layer, the following pH sensitive polymers can be applied; for example, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, polyvinyl acetate phthalate, cellulose acetate trimelite, carboxymethyl ethyl cellulose, shellac or other (s ) polymer (s) of the appropriate enteric coating layer. The coating layer may likewise be composed of film-forming polymers being sensitive to other luminous components of the pH, such as bacterial degradation or a component that has such sensitivity when it is mixed with another film-forming polymer. Examples of such components that provide delayed release to planned regions are; polymers comprising azo bond (s), polysaccharides such as pectin and its salts, galactomannans, amylose and chondroitin, disulfide polymers and glycosides.
[464] The delayed release coating or an additional coating of the formulation may contain other film-forming polymers and are not sensitive to luminous conditions for technical reasons or chronographic control of drug release. Materials to be used for such a purpose include, but are not limited to; sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and others, used alone or in mixtures.
[465] Additives such as dispersants, dyes, pigments, additional polymers, for example, poly (ethylacrylate, methylmethacrylate), non-stick agents and defoamers can likewise be included in the coating layer. Other compounds can be delayed to increase the density of the film and decrease the diffusion of acidic gastric juices in the core material.
[466] The coating layers can likewise contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties. Such plasticizers are, for example, but not restricted to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, glycerol monoesters, polysorbates or other plasticizers and mixtures thereof. The amount of plasticizer is preferably optimized for each Formula, in relation to the selected polymer (s) ^), selected plasticizer (s) and the applied amount of the said polymer (s) ).
[467] In preparing the tablets, as cores containing monolithic drug for subsequent coating with a modified release membrane or as a matrix for multiple coated units, additional ingredients may be needed to obtain the appropriate technical properties such as binders, de-disintegrants, bulking agents, glidants, lubricants, and coating agents with no effect on drug release such as water-soluble polymers, non-stick agents, dyes, pigments and waxes. Ingredients well known for such use are, for example, described in "Handbook of pharmaceutical excipients", 2nd edition, 1994, Pharmaceutical Press, London. Preparation of final dosage forms
[468] Coated units can be filled in hard gelatin capsules or mixed with tablet excipients, such as fillers, binders, disintegrants, lubricants and other pharmaceutically acceptable additives, and be compressed into tablets. The pressed tablet is optionally coated with film-forming agents to obtain a smooth tablet surface and in the same way enhance the mechanical stability of the tablet during packaging and transportation. Such a tablet coating, which can be applied to a multiple unit tablet or a conventional tablet, can also comprise additives such as non-stick agents, dyes and pigments or other additives to improve the appearance of the tablet.
[469] Drugs suitable for the new formulations are composed of an IBAT inhibitor as described in the documents discussed above, hereby incorporated by reference.
[470] The IBAT inhibitor compound may alternatively be a low-permeability drug as defined in the Biopharmatics-Classification System proposed by the FDA.
[471] A combination therapy according to the invention should preferably comprise the administration simultaneously, separately or consecutively of an IBAT inhibitor compound and a bile acid binder. The IBAT inhibitor may preferably be formulated for delivery to the ileum and the bile acid binder may preferably be the formulation for release to the colon. Dosage
[472] An appropriate unit dose will vary with respect to the patient's body weight, condition and severity of the disease. The dose will also depend on whether it should be used for prophylaxis or to treat severe conditions, as well as the administration routine. The daily dose can be administered as a single dose or divided into two or more unit doses. An orally administered daily dose of an IBAT inhibitor is preferably within 0.1 - 5,000 mg, for example 0.01-1000 mg, such as 0.1-800 mg, more preferably 1 - 500 mg, for example, 100 - 400 mg.
[473] A pharmaceutical formulation according to the present invention with a targeted distribution in the gastrointestinal tract provides a reduced systemic exposure, as can be measured by the area under the plasma concentration of drug versus time curve (AUC), while maintaining or even increasing the therapeutic effect, as for example, measured by the reduction of serum cholesterol.
[474] 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 4, 3, 2 or less than 1 g. Suitable ranges can be 0.1-5 g, 0.5-4 g, 1-3 g, 2-4 g, 2-3 g per day. A colon-release dosage form of bile acid binder can be constructed by any of the principles described above for delayed-release formulations.
[475] One tablet can consist of an inner core of 1- 1000 mg, for example, 200-800 mg, 50-400 mg, 10-200 mg or 20-80 mg of acid binder in a colonic distribution formulation ca and an external slide with 1-100 mg, 5-50 mg for example, 1-20 mg of an IBAT inhibitor.
[476] The daily dose of IBAT inhibitor and / or bile acid binder can be administered as a single dose or can be divided into one, two, three or more single doses.
[477] Dosing three times a day with 400 mg of colesevelam in a colonic release formulation will produce adequate bile acid binding in the colon, just as the total luminal volume is expected to be about 100 ml_, which is in line with an accepted pharmacokinetic calculation volume of 250 to 300 ml_ for the small intestine. The recommended total daily dose of colesevelam to block bile acid absorption in the total human intestine is 3750 mg / day.
[478] The dose predicted to treat constipation with Example 14 is 10 mg / day, when the total effectiveness in decreasing bile acids in the human body is targeted, a total dose of 20 mg / day is predicted to be adequate, which will induce colonic side effects according to table 2. The tablet will consist of an inner core of 400 mg of colesevelam in a colonic distribution formulation and an outer layer with 7 mg of Example 14 or 0.7 mg of Examples 5, 8 or 13 in a form of immediate release.
[479] The invention also considers a method of treatment and / or prophylaxis of hypercholesterolemia, in a homothermic animal, such as man, in need of such treatment and / or prophylaxis, which comprises administering an effective amount of a composition according to any of claims 1-14.
[480] In accordance with another aspect of the present invention, a kit is provided which comprises a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a binder of bile acid.
[481] The invention also envisages a kit comprising an IBAT inhibitor compound, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder in the same or separate pharmaceutical formulation possibly in the same way an instruction for use.
[482] The following Examples considered are intended to illustrate, but in no way limit the scope of the invention. All references cited herein are hereby incorporated by reference in their entirety.
[483] The term "comprising" when used herein, should be understood to include, but not be limited to, the items declared. Example 1
[484] 1,1 - D ioxo-3,3-di butyl l-5-fe ni l-7-methyl Iti o-8- (N - {(R) -α- [N - (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 696.89.
[485] This compound is prepared as described in Example 2 of WO3022286. Example 2
[486] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N '- ((S) -1-carboxyethyl) -carbamoyl ] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine, Mw. 709.92.
[487] This compound is prepared as described in Example 2 of WO03106482. Example 3
[488] 1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxypropyl) -carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 724.94.
[489] This compound is prepared as described in Example 6 of WO3022286. Example 4
[490] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((R) -1 -carboxy-2-methylthioethyl ) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 757.01.
[491] This compound is prepared as described in Example 7 of WO3022286. Example 5
[492] 1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1 -carboxypropyl) -carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 740.94.
[493] This compound is prepared as described in Example 29 of WO3022286. Example 6
[494] 1.1 - D ioxo-3,3-di buti l-5-fe ni l-7-methyl Iti o-8- (N - {(R) -α- [N - ((R) - 1-carboboxy-2-methylthio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 773.00.
[495] This compound is prepared as described in Example 30 of WO3022286. Example 7
[496] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1 -carboxy-2-methylpropyl ) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 738.97.
[497] This compound is prepared as described in Example 15 of WO3022286. Example 8
[498] 1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1 -carboxy-2- ( R) -hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 756.94.
[499] This compound is prepared as described in Example 26 of WO3022286. Example 9
[500] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxybutyl) -carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 754.97.
[501] This compound is prepared as described in Example 28 of WO3022286. Example 10
[502] 1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1 -
carboxyethyl) -carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 710.91.
[503] This compound is prepared as described in Example 5 of WO3022286. Example 11
[504] 1.1 - D ioxo-3,3-dibut i l-5-phen i l-7-methylthio-8- (N - {(R) -a- [N '- ((S) - 1-carboxypropyl) -carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine, Mw. 739.95.
[505] This compound is prepared as described in Example 1 of WO3022286. Example 12
[506] 1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxyethyl) carbamoyl] - 4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 726.91.
[507] This compound is prepared as described in Example 11 of WO3022286. Example 13
[508] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxy-2-methylpropyl ) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 754.97.
[509] This compound is prepared as described in Example 27 of WO3022286. Example 14
[510] 1,1 -Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1 '-phenyl-1' - [N '- (carboxymethyl) -carbamoyl ] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine, Mw. 695.90.
[511] This compound is prepared as described in Example 43 of W00250051. Example 15: Pharmaceutical Effect Inhibitori Bad effect (%)
[512] ISBT Hu HEK Uptake SPA 13203 IBAT HUM Ileal Bile Acid Transporter Human HEK Glycocholic acid Uptake Radiometric - SPA Inhibitor IC50 (nM) was determined for the compounds of examples 1-14 Test system
[513] Animals
[514] Mouse species; ApoE knockout strain; Subspecies C57BL / 6; Female Gender; Total number of animals 70; Body weight range 20 g to 22 g; Supplier Mollegaard’s Breeding (Skensved, Denmark); Identification method ID cards (barcode).
[515] Acclimatization: At least one week in the Laboratory Section; Animal Resource in AstraZeneca; Housing conditions: Kept five in five in cages (Makrolon III, 7 dm2) in an environment with regulated temperature (22 ° C), relative humidity (40% to 60%) and a 12/12 hour light / dark cycle . Diet: Free access to R3 pellets (Lactamin, Vadstena, Sweden) during accommodation and trial period. Water: Free access to tap water during accommodation and trial period.
[516] Fodder: Spray the aspen wood forage (Tapvei, Finland). Experimental procedures
[517] The animals were orally administered 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 13: 00 hours on the experimental day. Thirty minutes later, a trace amount of 75SeHCAT (75Se-homo-tauro-cholic acid) (0.1 mCi per 0.1 mL per mouse) was administered orally to each mouse. Twenty-four hours after 75SeHCAT administration, the animals were exterminated by CO2 inhalation. At sacrifice, the gallbladder and the entire intestine were removed, and feces during the 24-hour period after the administration of 75SeHCAT were collected for each mouse. The gamma radioactivities of 75SeHCAT in faeces and gallbladder-intestine were counted separately by 1282 CompuGamma CS Gamma counter (Wallacy, Turku, Finland). The stability, as well as the amount of 75SeHCAT administered to each mouse, was controlled with an additional 75SeHCAT aliquot that follows the same experimental process as other samples tested in the study. Data analysis
[518] The sum of the stool gamma and gallbladder-bowel counts was considered to be the total recovered 75SeHCAT, which was calculated on average around 85% of the total 75SeHCAT administered to each mouse. Of the radioactivity recovered from 75SeHCAT, the percentage of 75SeHCAT detected in the faeces was considered as the excretion of faeces while that in the gallbladder-intestine as retention of the body. The inhibitory effect of the compound of Example 14 on the intestinal absorption of 75SeHCAT was calculated following the 75SeHCAT retention and fecal excretion, and the ED50 of the compound was calculated following the dose-effect curve. Results
[519] The inhibitory effect of average IBAT (%) in one dose (pmol / kg): 0.156 was determined for the compounds of examples 1-14 and is reported in Table 1Table 1


Example 16
[520] A Phase llb, Double-blind, Place-Bo Controlled, Multi-Center, Dose Discovery, Effectiveness and Safety of a Dose Range of Example 14 compound in about 200 patients with Chronic Idiopathic Constipation , where patients were treated for 56 days, was performed. The patients were male or non-pregnant female> 20 years old and <80 years old, having a body mass index (BMI)> 18.5, but <35.
[521] All patients with adverse events of diarrhea and type abdominal pain related to the compound of Example 14 in table 2.Table 2 Number of patients with diarrhea and abdominal pain in a treatment study for Chronic Idiopathic Constipation

[522] Contradictory patients who also receive 400mg colonic release 3 times a day of "colesevelam" showed little increase in the two bile acid-dependent side effects generated from the colon.
[523] Thus, the compound of Example 14 in combination with the bile acid binder "colesevelam" has been shown to effectively block the bile acid side effects generated from the colon. Example 17
[524] A formulation for delayed release of the IBAT inhibitor having the following composition is prepared: Substance quantity / capsule (mg) IBAT-inhibiting compoundExample 14 10Beads not Parallel 500 Ethyl cellulose 2Hydroxypropylmethyl cellulose 10Eudragit L100-55 (CAS No. 25212-88- 8) 25 Triethyl citrate 2.4
[525] The active drug is dissolved together with ethyl cellulose and hydroxypropyl cellulose, in 99% ethanol.
[526] The mixture is then sprayed onto the non-paryl spheres, in a fluidized bed mechanism. After that, the pellets are dried and aerated to remove residual ethanol. The Eudragit L100-55 dispersion with the addition of triethyl citrate is then sprayed onto the drug beads in a fluidized bed mechanism. Subsequently, the coated beads are filled into hard gelatin capsules after drying and sifting. Example 18
[527] A formulation for delayed release of the IBAT inhibitor that has the following composition is prepared: Ingredient quantity / tablet (mg) IBAT-inhibiting compound Example 14 10 Silicon dioxide 200Povidone K-25 20Eudragit FS30D (CAS No. 26936 - 24 - 3) Microcrystalline cellulose 250Sodium stearyl fumarate 5
[528] The active drug is suspended in water and sprayed on the silicon dioxide cores of a predefined size in a fluidized bed mechanism. The drug pellets are dried in an oven at 40 ° C for 24 h. After that, a layer of Povidone K-25 is applied over the beads of an ethanolic solution in a fluidized bed mechanism. A final Eudragit FS30D dispersion coating is then 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
[529] A combination tablet comprising an IBAT inhibitor of Formula (I) or Formula (II) as described above, and co-develop, having an immediate release of the IBAT inhibitor and release into the colon of the bile acid binder, is Guantanity ingredient / tablet (mg)

CoreColesevelam hydrochloride 400Microcrystalline cellulose 150Hydroxypropyl methyl cellulose 50Colloidal silicon dioxide 10Magnesium stearate 5Colon release layerEudragit FS30DPlasACRYL T20 (Protective cellulose inhibitor 12Hydrolytic inhibitor 6Hydrate inhibitor) two
[530] Colesevelam hydrochloride, microcrystalline cellulose and colloidal silicon dioxide are mixed and granulated with hydroxypropyl methyl cellulose, dissolved in water. The granules are dried and mixed with magnesium stearate and compressed into tablets. The EUDRAGIT FS30D dispersion and water are agitated in PlasACRYL T20 and sprayed on the core tablets using a suitable coating machine. The IBAT inhibitor coating suspension is prepared by mixing the IBAT inhibitor, hydroxypropyl methyl cellulose and croscarmellose sodium in water and sprayed on the tablet cores with the colon release layer using a suitable coating machine. Finally, the solution of the protective layer of hydroxypropylmethyl cellulose, and polyethylene glycol is sprayed onto the tablets using a suitable coating machine. Example 20
[531] A Colesevelam colon release tablet that has the following composition is prepared:

Ingredient amount / tablet (mg) CoreColesevelam 400 hydrochlorideMicrocrystalline cellulose 150Hydroxypropyl methyl cellulose 50Colloidal silicon dioxide 10Magnesium stearate 5Colon release layerAmylose 30Eudragit S100 60Triethyl citrate 6Glycerol monostearate 3
[532] Colesevelam hydrochloride, microcrystalline cellulose and colloidal silicon dioxide are mixed and granulated with hydroxypropyl methyl cellulose dissolved in water. The granules are dried and mixed with magnesium stearate and compressed into tablets. Amylose, Eudragit 100, triethyl citrate and glycerol monoesterate are dissolved in suitable solvents and sprayed onto the tablet cores using a suitable coating machine. Example 21
[533] This study is carried out on 4 male beagle dogs (weight approximately 10 kg). A commercially available diet, Teklad 2021 from Harlan Teklad-Europa, Blacktorn, England, is offered twice daily in portions of 175 g per animal with an equal amount of water added.
[534] Animals are trained in procedures using a commercially available diet, GLP-Diet from Dechra Veterinary Pro-ducts, Denmark, as a reward. The amount used per animal is minimal and is not recorded.
[535] On dosing days (Days 1 and 4), animals are offered 50 g of LPG diet during the rectal dosing procedure and the remaining meal (125 g) was administered 1 hour after the rectal dosing procedure.
[536] The substance of Example 5 (30 mg / kg, 5 mL / kg of 20% v / v suspension of propylene glycol in purified water) is administered by oral dosing according to the most recent body weight data. All groups receive the substance of Example 5 orally in combination with rectal administration of cholestyramine or placebo.
[537] Rectal administration of cholestyramine (1.2-2.2 g total, 12 mL suspension in water) and a placebo formulation (exploration gel) are used to comply with the planned human route of administration. Cholestyramine and placebo are administered by rectal catheterization using a 40 cm flexible plastic tube (unomedical "feeding tube") to apply the test substances to the proximal part of the colon. Treatment is performed on Day 1 and Day 4.
[538] Following each dosing occasion, all animals are monitored continuously for a period of 6 hours. The number of defecations is counted. Stool consistency is assessed using the Bristol Stool form Scale (seven-degree scale; reduced 1, separate hard pieces, like walnuts (hard to pass); highest 7, watery, no solid, totally liquid pieces). The amount of stools passed for each defecation event is marked according to the following classification system: 1-minimal, 2-mild, 3-moderate, 4- marked.
[539] Count data is analyzed with the t test. Significant intergroup differences are detected, the subsequent identification of the groups is performed with the unilateral t test. For all tests, the level of significance is defined as p <0.05.
[540] The placebo and cholestyramine groups provide an average Bristol form Scale (BSS) of 6.7 + -0.3, 5.3 + -0.6, (mean + -EM), respectively. This difference is statistically significant at the level of significance p <0.05. The placebo group has watery stools, as expected, the cholestyramine group has more solid stools.
[541] The placebo and cholestyramine group pass the following amount of feces according to the scale above for each defecation event and provide an average value of 3.5 + -0.6, 2.3 + -0 , 8, (mean + - SEM), respectively. This difference is not statistically significant at the level of significance p <0.05. The placebo-treated group passes more stools compared to the cholestyramine group, even if it is not significant. Both BSS parameters and "amount of stool passage" indicate that the cholestiramin group has lower free bile acid concentrations within the colon compared to the placebo group. Since bile acids in the colon have a laxative effect, this experiment confirms that a release in the colon of bile acid binders works according to the invention.

权利要求:
Claims (28)
[0001]
1. Use of an IBAT inhibitor, selected from the group consisting of: 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [ N - (((S) -1 - caroboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; e1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1 '-phenyl-1' - [N '- (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine, or a pharmaceutically acceptable salt thereof, and a bile acid scavenger, the bile acid coagulant being formulated for release into the colon, the said use being characterized by the fact that it is for the preparation of a combination for simultaneous, separate or sequential administration, for the treatment of a liver disease ,.
[0002]
2. Use, according to claim 1, characterized by the fact that liver disease is selected from the group consisting of primary biliary cirrhosis (PBC); progressive familial intrahepatic cholestasis (PFIC); Alagilles syndrome (ALGS); primary sclerosing cholangitis (PSC); non-alcoholic steatohepatitis (NASH); pruritus of cholestatic liver disease; general cholestasis; jaundice during pregnancy; non-alcoholic fatty liver disease (NAFLD) and hepatoma.
[0003]
3. Use, according to claim 1, characterized by the fact that the liver disease is primary biliary cirrhosis (PBC).
[0004]
4. Use, according to claim 1, characterized by the fact that liver disease is pro-progressive family intrahepatic cholestasis (PFIC).
[0005]
5. Use, according to claim 1, characterized by the fact that the liver disease is Alagille syndrome (ALGS).
[0006]
6. Use according to claim 1, characterized by the fact that the liver disease is primary sclerosing cholangitis (PSC).
[0007]
7. Use, according to claim 1, characterized by the fact that liver disease is non-alcoholic steatohepatitis (NASH).
[0008]
8. Use, according to claim 1, characterized by the fact that liver disease is itchy from cholestatic liver disease.
[0009]
9. Use according to claim 1, characterized by the fact that liver disease is general cholestasis.
[0010]
10. Use, according to claim 1, characterized by the fact that liver disease is jaundice during pregnancy.
[0011]
11. Use, according to claim 1, characterized by the fact that liver disease is non-alcoholic fatty liver disease (NAFLD).
[0012]
12. Use according to claim 1, characterized by the fact that the liver disease is hepatoma.
[0013]
13. Use according to any one of claims 1 to 12, characterized in that the combination is prepared to deliver the IBAT inhibitor in the small intestine and the bile acid scavenger in the colon.
[0014]
14. Use according to any one of claims 1 to 13, characterized by the fact that the bile acid scavenger is cholestyramine, colestipol or colesevelam.
[0015]
15. Pharmaceutical formulation, characterized by the fact that it comprises: an IBAT inhibitor, as defined in claim 1, and a bile acid scavenger, the bile acid drying agent being at the center and formulated to be released into the colon, and the IBAT inhibitor is in the outer layer, prepared for immediate release or for delayed release in the distal jejunum or proximal ileum, for use in the manufacture of a drug to treat liver disease.
[0016]
16. Formulation, according to claim 15, characterized by the fact that liver disease is selected from the group consisting of primary biliary cirrhosis (PBC); progressive familial intrahepatic cholestasis (PFIC); Alagilles syndrome (ALGS); primary sclerosing cholangitis (PSC); non-alcoholic steatohepatitis (NASH); pruritus of cholestatic liver disease; general cholestasis; jaundice during pregnancy; non-alcoholic fatty liver disease (NAFLD) and hepatoma.
[0017]
17. Formulation, according to claim 15, characterized by the fact that the liver disease is primary biliary cirrhosis (PBC).
[0018]
18. Formulation according to claim 15, characterized by the fact that liver disease is progressive familial intrahepatic cholestasis (PFIC).
[0019]
19. Formulation, according to claim 15, characterized by the fact that the liver disease is Alagille syndrome (ALGS).
[0020]
20. Formulation according to claim 15, characterized by the fact that the liver disease is primary sclerosing cholangitis (PSC).
[0021]
21. Formulation according to claim 15, characterized by the fact that the liver disease is non-alcoholic steatohepatitis (NASH).
[0022]
22. Formulation according to claim 15, characterized by the fact that liver disease is itchy from cholestatic liver disease.
[0023]
23. Formulation according to claim 15, characterized by the fact that liver disease is general cholestasis.
[0024]
24. Formulation according to claim 15, characterized by the fact that liver disease is jaundice during pregnancy.
[0025]
25. Formulation according to claim 15, characterized by the fact that liver disease is non-alcoholic fatty liver disease (NAFLD).
[0026]
26. Formulation according to claim 15, characterized by the fact that the liver disease is hepatoma.
[0027]
27. Formulation according to any one of claims 15 to 26, characterized in that it comprises: (i) an internal nucleus comprising a bile acid scavenger; (ii) a colon release layer over the nucleus; ( iii) an IBAT inhibitor layer on top of said colon release layer; and (iv) an external protective coating.
[0028]
28. Formulation according to any one of claims 15 to 27, characterized in that the bile acid scavenger is cholestyramine, colestipol or colesevelam.

类似技术:

---

公开号 | 公开日 | 专利标题

---

BR112013010705B1|2020-11-17|use of an ibat inhibitor and a bile acid coagulant, and pharmaceutical formulation

---

US10011633B2|2018-07-03|IBAT inhibitors for the treatment of liver diseases

---

WO2012064268A1|2012-05-18|Ibat inhibitors for treatment of metabolic disorders and related conditions

---

AU2014262173A1|2014-11-27|A pharmaceutical combination comprising an IBAT inhibitor and a bile acid binder

---

ES2819012T3|2021-04-14|Ibat inhibitors for the treatment of liver diseases

同族专利:

---

公开号 | 公开日

---

SG190433A1|2013-06-28|

---

CN105287604A|2016-02-03|

---

CN105287604B|2019-07-09|

---

US20170182115A1|2017-06-29|

---

JP2013545739A|2013-12-26|

---

JP6097695B2|2017-03-15|

---

RU2619215C2|2017-05-12|

---

HK1189500A1|2014-06-13|

---

WO2012064267A1|2012-05-18|

---

KR20130135264A|2013-12-10|

---

ZA201303059B|2015-10-28|

---

EP2637646A4|2014-03-19|

---

PT2637646T|2016-08-17|

---

AU2011326872B2|2014-09-11|

---

EP2637646A1|2013-09-18|

---

AU2011326872C1|2015-02-19|

---

CN103228270A|2013-07-31|

---

MY180164A|2020-11-24|

---

MX2013005112A|2013-08-29|

---

CN103228270B|2016-02-10|

---

AU2011326872A1|2013-04-11|

---

IL225603A|2017-09-28|

---

CA2815698C|2019-04-30|

---

RU2013126119A|2014-12-20|

---

CA2815698A1|2012-05-18|

---

US20150031637A1|2015-01-29|

---

DK2637646T3|2016-08-29|

---

US20200330545A1|2020-10-22|

---

US20130236541A1|2013-09-12|

---

EP2637646B1|2016-05-11|

---

MX345040B|2017-01-16|

---

KR101890960B1|2018-09-28|

---

BR112013010705A2|2016-08-09|

---

IL225603D0|2013-06-27|

---

ES2586956T3|2016-10-19|

---

PL2637646T3|2017-01-31|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

BE580490A|1958-07-15|1960-01-08|Merck & Co Inc|Compositions and methods for lowering the cholesterol content of the blood|

---

US3383281A|1961-09-22|1968-05-14|Merck & Co Inc|Method for binding bile acids in vivo|

---

US3308020A|1961-09-22|1967-03-07|Merck & Co Inc|Compositions and method for binding bile acids in vivo including hypocholesteremics|

---

NL7017227A|1969-12-27|1971-06-29|

---

GB1348642A|1970-10-15|1974-03-20|Howard A N|Hypocholesterolaemic compositions|

---

US3769399A|1971-03-05|1973-10-30|L Hagerman|Intestinal bile acid binding process and compositions|

---

US3974272A|1972-09-01|1976-08-10|Merck & Co., Inc.|Palatable cholestyramine coacervate compositions|

---

US4252790A|1974-10-23|1981-02-24|Interx Research Corporation|Method for treating gastric ulcer-prone patients|

---

GB1566609A|1977-03-10|1980-05-08|Reckitt & Colmann Prod Ltd|Pharmaceutical compositions containing cholestyramine and alginic acid|

---

IT1106718B|1978-12-21|1985-11-18|Alfa Farmaceutici Spa|PHARMACOLOGICALLY ACTIVE SALONIZED ANIONIC RESIN BASED COMPOSITIONS|

---

CA1247547A|1983-06-22|1988-12-28|Paul Hadvary|Leucine derivatives|

---

GB8531071D0|1985-12-17|1986-01-29|Boots Co Plc|Therapeutic compound|

---

GB2184122B|1985-12-17|1989-10-18|Boots Co Plc|N,n-dimethyl-1-[1-cyclobutyl]-3-methyl butylamine hydrochloride monohydrate|

---

US4895723A|1986-09-08|1990-01-23|Amer And Company|Cholestyramine compositions and method for preparation thereof|

---

US4814354A|1986-09-26|1989-03-21|Warner-Lambert Company|Lipid regulating agents|

---

GB8903564D0|1989-02-16|1989-04-05|Rashid Abdul|Drug dispensing device|

---

US4874744A|1989-03-13|1989-10-17|University Of Cincinnati|Method of using melanocyte stimulating hormone as dermatis treatment|

---

IL100240A|1990-12-06|1995-10-31|Hoechst Ag|Bile acid derivatives process for their preparation and use of these compounds as pharmaceuticals|

---

NZ245503A|1991-12-20|1995-11-27|Hoechst Ag|Polymers containing bile acids; pharmaceuticals and preparatory methods|

---

GB9203347D0|1992-02-17|1992-04-01|Wellcome Found|Hypolipidaemic compounds|

---

IT1257793B|1992-05-18|1996-02-13|PHARMACEUTICAL COMPOSITION BASED ON BILIARY ACIDS IN MICROGRANULES WITH CONTROLLED RELEASE|

---

ES2111092T3|1992-06-12|1998-03-01|Hoechst Ag|DERIVATIVES OF BILIAR ACIDS, PROCEDURE FOR THE PREPARATION AND USE OF THESE COMPOUNDS AS MEDICINES.|

---

IL108634D0|1993-02-15|1994-05-30|Wellcome Found|Hypolipidaemic heterocyclic compounds, their prepatation and pharmaceutical compositions containing them|

---

IL108633A|1993-02-15|1998-07-15|Wellcome Found|Hypolipidaemic benzothiazepine derivatives their preparation and pharmaceutical compositions containing them|

---

DE4314583A1|1993-04-29|1994-11-03|Astra Chem Gmbh|Composition containing colestyramine and process for its preparation|

---

EP0624593A3|1993-05-08|1995-06-07|Hoechst Ag|Bile acid derivates, a method for their production and their use as medicines.|

---

TW289757B|1993-05-08|1996-11-01|Hoechst Ag|

---

TW289021B|1993-05-08|1996-10-21|Hoechst Ag|

---

TW289020B|1993-05-08|1996-10-21|Hoechst Sktiengesellschaft|

---

US5631365A|1993-09-21|1997-05-20|Schering Corporation|Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents|

---

US5607669A|1994-06-10|1997-03-04|Geltex Pharmaceuticals, Inc.|Amine polymer sequestrant and method of cholesterol depletion|

---

TW474813B|1994-06-10|2002-02-01|Geltex Pharma Inc|Alkylated composition for removing bile salts from a patient|

---

ZA956647B|1994-08-10|1997-02-10|Wellcome Found|Hypolipidaemic compounds.|

---

US5994391A|1994-09-13|1999-11-30|G.D. Searle And Company|Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake|

---

AU700557B2|1994-09-13|1999-01-07|Monsanto Company|Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake|

---

GB9423172D0|1994-11-17|1995-01-04|Wellcom Foundation The Limited|Hypolipidemic benzothiazepines|

---

US6069167A|1996-01-16|2000-05-30|University Technology Corporation|Use of antioxidant agents to treat cholestatic liver disease|

---

DE69734100D1|1996-03-11|2005-10-06|G D Searle Llc St Louis|BENZOTHIEPINES WITH INPUT AS INHIBITORS OF ILEUMGALLIC ACID TRANSPORT AND TAUROCHOLATE RECORDING|

---

EP0912861B1|1996-07-24|2000-11-29|Zumtobel Staff GmbH|Adapter for a retaining means used to secure a built-in lamp in a mounting hole, or retaining means or built-in lamp provided with such an adapter|

---

DE19633268A1|1996-08-19|1998-02-26|Hoechst Ag|Polymeric bile acid absorption inhibitors with simultaneous bile acid adsorber action|

---

IL131872D0|1997-03-11|2001-03-19|Searle & Co|Composition comprising an ileal bile acid transport inhibiting benzothiepines and hmg co-a reductase inhibitors|

---

EP0864582B1|1997-03-14|2003-06-04|Aventis Pharma Deutschland GmbH|Hypolipidemic 1,4-benzothiazepine-1,-dioxides|

---

SE9702305D0|1997-06-17|1997-06-17|Astra Ab|New thiazolidinedione, oxazolidinedione and oxadiazolidinedione derivatives|

---

US6066336A|1997-09-29|2000-05-23|Bristol-Myers Squibb Company|Cholesterol-lowering tablets|

---

ES2195428T3|1997-12-19|2003-12-01|Searle & Co|METHOD FOR PREPARING OXIDES OF TETRAHYDROBENZOTIEPIN ENRICHED ENANTIOMETRICALLY.|

---

GB9800428D0|1998-01-10|1998-03-04|Glaxo Group Ltd|Chemical compounds|

---

SE9801992D0|1998-06-04|1998-06-04|Astra Ab|New 3-aryl-2-hydroxypropionic acid derivative I|

---

SE9801990D0|1998-06-04|1998-06-04|Astra Ab|New 3-aryl propionic acid derivatives and analogs|

---

MA26634A1|1998-06-04|2004-12-20|Astra Ab|NOVEL 3-ARYL PROPIONIC ACID DERIVATIVES AND THE LIKE|

---

DE19825804C2|1998-06-10|2000-08-24|Aventis Pharma Gmbh|1,4-Benzothiepin-1,1-dioxide derivatives, processes for their preparation and medicaments containing these compounds|

---

JP2002533413A|1998-12-23|2002-10-08|ジー．ディー．サールエルエルシー|Combination of ileal bile acid transport inhibitors and fibric acid derivatives for cardiovascular applications|

---

BR9916486A|1998-12-23|2002-02-05|Searle Llc|Combinations of bile acid transport inhibitors in the ileum and cholesterol ester transfer protein inhibitors for cardiovascular indications|

---

AU776953B2|1998-12-23|2004-09-30|G.D. Searle Llc|Combinations of ileal bile acid transport inhibitors and bile acid sequestring agents for cardiovascular indications|

---

KR20010102963A|1998-12-23|2001-11-17|윌리암스 로저 에이|Combinations of ileal bile acid transport inhibitors and nicotinic acid derivatives for cardiovascular indications|

---

CZ20012344A3|1998-12-23|2002-01-16|G. D. Searle Llc|Combination for cardiovascular indications|

---

WO2000047568A2|1999-02-12|2000-08-17|G.D. Searle Llc|1,2-benzothiazepines for the treatment of hyperlipidemic diseases|

---

DE19916108C1|1999-04-09|2001-01-11|Aventis Pharma Gmbh|1,4-Benzothiazepine-1,1-dioxide derivatives substituted with sugar residues, process for their preparation and their use|

---

SE9901387D0|1999-04-19|1999-04-19|Astra Ab|New pharmaceutical foromaulations|

---

GB9919413D0|1999-08-18|1999-10-20|Zeneca Ltd|Chemical compounds|

---

GB9919411D0|1999-08-18|1999-10-20|Zeneca Ltd|Chemical compounds|

---

TW574193B|1999-12-03|2004-02-01|Astrazeneca Ab|Novel phenalkyloxy-phenyl derivatives, pharmaceutical composition containing the same and their uses|

---

SE0000772D0|2000-03-08|2000-03-08|Astrazeneca Ab|Chemical compounds|

---

AU4011501A|2000-03-10|2001-09-24|Pharmacia Corp|Method for the preparation of tetrahydrobenzothiepines|

---

US20020061888A1|2000-03-10|2002-05-23|Keller Bradley T.|Combination therapy for the prophylaxis and treatment of hyperlipidemic conditions and disorders|

---

FR2812886B1|2000-08-08|2002-11-08|Assist Publ Hopitaux De Paris|SCREENING FOR A NEW HEPATIC SYNDROME AND ITS APPLICATIONS|

---

SE0003766D0|2000-10-18|2000-10-18|Astrazeneca Ab|Novel formulation|

---

EG26979A|2000-12-21|2015-03-01|Astrazeneca Ab|Chemical compounds|

---

DE10131715B4|2001-06-29|2010-03-18|Sms Siemag Aktiengesellschaft|Apparatus for the continuous casting of liquid metals, in particular of steel, with a continuous casting mold arranged on a swing frame|

---

GB0121337D0|2001-09-04|2001-10-24|Astrazeneca Ab|Chemical compounds|

---

GB0121622D0|2001-09-07|2001-10-31|Astrazeneca Ab|Chemical compounds|

---

GB0121621D0|2001-09-07|2001-10-31|Astrazeneca Ab|Chemical compounds|

---

RU2305681C2|2001-09-08|2007-09-10|Астразенека Аб|Benzothiadiazepine derivatives and method for production thereof |

---

CA2460330A1|2001-09-12|2003-03-20|Jung Min Park|Method for the preparation of crystalline tetrahydrobenzothiepines|

---

GB0201850D0|2002-01-26|2002-03-13|Astrazeneca Ab|Therapeutic treatment|

---

GB0209467D0|2002-04-25|2002-06-05|Astrazeneca Ab|Chemical compounds|

---

GB0213669D0|2002-06-14|2002-07-24|Astrazeneca Ab|Chemical compounds|

---

GB0216321D0|2002-07-13|2002-08-21|Astrazeneca Ab|Therapeutic treatment|

---

CA2497345C|2002-08-28|2008-10-14|Asahi Kasei Pharma Corporation|Novel quaternary ammonium compounds|

---

US7312208B2|2002-08-28|2007-12-25|Asahi Kasei Pharma Corporation|Quaternary ammonium compounds|

---

GB0304194D0|2003-02-25|2003-03-26|Astrazeneca Ab|Chemical compounds|

---

US7670624B2|2004-01-29|2010-03-02|Astella Pharma Inc.|Gastrointestinal-specific multiple drug release system|

---

WO2006121861A2|2005-05-05|2006-11-16|Microbia, Inc.|Biphenylazetidinone cholesterol absorption inhibitors|

---

DE102005033100B3|2005-07-15|2007-01-25|Sanofi-Aventis Deutschland Gmbh|Novel 1,4-benzothiazepine-1,1-dioxide derivative with improved properties, drugs containing this compound and methods for their preparation|

---

DE102005033099A1|2005-07-15|2007-01-18|Sanofi-Aventis Deutschland Gmbh|Novel 1,4-benzothiazepine 1,1-dioxide derivative with improved properties, process for its preparation, medicines containing it and its use|

---

EP1948280A4|2005-10-24|2011-07-06|Andrew Young|Biliary/pancreatic shunt device and method for treatment of metabolic and other diseases|

---

DE102006053637B4|2006-11-14|2011-06-30|Sanofi-Aventis Deutschland GmbH, 65929|Novel fluorine-substituted 1,4-benzothiepine-1,1-dioxide derivatives, pharmaceutical compositions containing them and their use|

---

US20090035306A1|2006-11-29|2009-02-05|Kalypsys, Inc.|Quinazolinone modulators of tgr5|

---

CN101679476B|2007-01-19|2014-05-07|英特塞普特医药品公司|23-substituted bile acids as TGR5 modulators and methods of use thereof|

---

US20080221161A1|2007-02-09|2008-09-11|Kalypsys, Inc.|Heterocyclic modulators of tgr5 for treatment of disease|

---

CN102316872B|2008-11-26|2016-12-21|萨蒂奥根制药公司|Treatment obesity and the bile acid recycling inhibitors of diabetes|

---

RU2619215C2|2010-11-08|2017-05-12|Альбирео Аб|Pharmaceutical combination comprising ibat-inhibitor and bile acid binder|

---

WO2012064268A1|2010-11-08|2012-05-18|Albireo Ab|Ibat inhibitors for treatment of metabolic disorders and related conditions|DE19903701C5|1999-01-30|2006-12-14|Asahi Kasei Kabushiki Kaisha|Process for producing a thermoplastic molded body containing carbon fibers|

---

CN102316872B|2008-11-26|2016-12-21|萨蒂奥根制药公司|Treatment obesity and the bile acid recycling inhibitors of diabetes|

---

EP2995317A1|2010-05-26|2016-03-16|Satiogen Pharmaceuticals, Inc.|Bile acid recycling inhibitors and satiogens for treatment of diabetes, obesity, and inflammatory gastrointestinal conditions|

---

WO2012064268A1|2010-11-08|2012-05-18|Albireo Ab|Ibat inhibitors for treatment of metabolic disorders and related conditions|

---

RS60901B1|2010-11-08|2020-11-30|Albireo Ab|Ibat inhibitors for the treatment of liver diseases|

---

RU2619215C2|2010-11-08|2017-05-12|Альбирео Аб|Pharmaceutical combination comprising ibat-inhibitor and bile acid binder|

---

KR102051030B1|2011-10-28|2019-12-02|루메나 파마수티컬즈, 인코포레이티드|Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases|

---

JO3301B1|2013-04-26|2018-09-16|Albireo Ab|Crystal modifications of elobixibat|

---

CA2952406A1|2014-06-25|2015-12-30|Ea Pharma Co., Ltd.|Solid formulation and method for preventing or reducing coloration thereof|

---

WO2015199146A1|2014-06-25|2015-12-30|味の素株式会社|Solid preparation and method for stabilizing same|

---

EP3012252A1|2014-10-24|2016-04-27|Ferring BV|Crystal modifications of elobixibat|

---

CN105520919A|2015-12-28|2016-04-27|青岛海之星生物科技有限公司|Colestipol slow release capsule and preparation method thereof|

---

CN105456219A|2015-12-28|2016-04-06|青岛海之星生物科技有限公司|Colestipol sustained release tablet and preparation method thereof|

---

US10441604B2|2016-02-09|2019-10-15|Albireo Ab|Cholestyramine pellets and methods for preparation thereof|

---

US10441605B2|2016-02-09|2019-10-15|Albireo Ab|Oral cholestyramine formulation and use thereof|

---

EP3413877B1|2016-02-09|2021-04-07|Albireo AB|Oral cholestyramine formulation and use thereof|

---

JP6954927B2|2016-02-09|2021-10-27|アルビレオ・アクチボラグ|Oral cholestyramine preparation and its use|

---

US10786529B2|2016-02-09|2020-09-29|Albireo Ab|Oral cholestyramine formulation and use thereof|

---

ES2784446T3|2016-02-09|2020-09-25|Albireo Ab|Cholestyramine microgranules and methods for their preparation|

---

RU2020109469A3|2017-08-09|2022-01-14|

---

US10793534B2|2018-06-05|2020-10-06|Albireo Ab|Benzothiaazepine compounds and their use as bile acid modulators|

---

KR20210024032A|2018-06-20|2021-03-04|알비레오 에이비|Crystalline variant of odebiccibat|

---

US11007142B2|2018-08-09|2021-05-18|Albireo Ab|Oral cholestyramine formulation and use thereof|

---

US10722457B2|2018-08-09|2020-07-28|Albireo Ab|Oral cholestyramine formulation and use thereof|

---

US10975045B2|2019-02-06|2021-04-13|Aibireo AB|Benzothiazepine compounds and their use as bile acid modulators|

---

US10941127B2|2019-02-06|2021-03-09|Albireo Ab|Benzothiadiazepine compounds and their use as bile acid modulators|

---

US11014898B1|2020-12-04|2021-05-25|Albireo Ab|Benzothiazepine compounds and their use as bile acid modulators|

---

US11225466B2|2019-12-04|2022-01-18|Albireo Ab|Benzothiadiazepine compounds and their use as bile acid modulators|

---

US11267794B2|2019-12-04|2022-03-08|Albireo Ab|Benzothiaazepine compounds and their use as bile acid modulators|

---

US11111224B2|2019-12-04|2021-09-07|Albireo Ab|Benzothiaazepine compounds and their use as bile acid modulators|

---

US11180465B2|2019-12-04|2021-11-23|Albireo Ab|Benzothiaazepine compounds and their use as bile acid modulators|

法律状态:
2016-09-20| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 5A ANUIDADE. PAGAR RESTAURACAO. |

---

2016-11-22| B08H| Application fees: decision cancelled [chapter 8.8 patent gazette]|Free format text: REFERENTE AO DESPACHO 8.6 NA RPI 2385 DE 20/09/2016 |

---

2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

---

2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2018-07-31| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

---

2019-02-19| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

---

2019-12-17| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

---

2020-05-26| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2020-11-10| B09X| Republication of the decision to grant [chapter 9.1.3 patent gazette]|

---

2020-11-17| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 08/11/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US41095510P| true| 2010-11-08|2010-11-08|

---

US61/410,955|2010-11-08|

---

SE1051164|2010-11-08|

---

SE1051164-0|2010-11-08|

---

US41491510P| true| 2010-11-18|2010-11-18|

---

US61/414,915|2010-11-18|

---

PCT/SE2011/051336|WO2012064267A1|2010-11-08|2011-11-08|A pharmaceutical combination comprising an ibat inhibitor and a bile acid binder|

---