KR20130132846A - Ibat inhibitors for treatment of metabolic disorders and related conditions - Google Patents

Abstract

The present invention relates to certain IBAT inhibitors for the prevention or treatment of metabolic syndrome, obesity, disorders of fatty acid metabolism, disorders of glucose use, or disorders involving insulin resistance such as diabetes mellitus type 1 or type 2 diabetes. .

Description

IBAT ATHIBITORS FOR TREATMENT OF METABOLIC DISORDERS AND RELATED CONDITIONS

The present invention relates to certain IBAT inhibitors for the prevention or treatment of metabolic syndrome, obesity, disorders of fatty acid metabolism, disorders of glucose use, or disorders involving insulin resistance such as diabetes mellitus type 1 or type 2 diabetes. .

Obesity is a medical disease that affects millions of people in many countries around the world and is associated with or induces other diseases and disorders. In particular, obesity is an important risk factor for diseases and disorders such as diabetes, hypertension, gallbladder disease, cancer, polycystic ovary disease, and atherosclerosis, Can contribute to elevated levels. In addition, weight gain due to obesity puts strain on the joints, causing arthritis, pain and stiffness. Overeating and obesity have been a problem for the general public. Therefore, there is interest in reducing food intake, weight loss, weight loss, and / or maintaining a healthy weight and lifestyle.

WO10062861 and WO 2008/058630 describe the effect of ileal bile acid transport (IBAT) in the treatment of obesity and diabetes.

The present invention is for the prevention or treatment of metabolic syndrome, obesity, disorders of fatty acid metabolism, disorders of glucose utilization, or disorders involving insulin resistance such as diabetes mellitus type 1 or type 2 diabetes.

The present invention relates to certain IBAT inhibitors for the prevention or treatment of metabolic syndrome, obesity, disorders of fatty acid metabolism, disorders of glucose use, or disorders involving insulin resistance such as diabetes mellitus type 1 or type 2 diabetes. .

The present invention provides for the prevention or treatment of metabolic syndrome, obesity, disorders of fatty acid metabolism, disorders of glucose utilization, or disorders associated with insulin resistance such as diabetes mellitus type 1 or type 2 diabetes.

Degree. One
(A) Schematic overview of the strategies and vectors used to target Slc10a2 wt alleles to obtain Slc10a2 null mice.
(B) Representative immunoblots with specific antibodies to Slc10a2 protein show absent Slc10a2 protein expression in the ileum of Slc10a2-/-mice.
Degree. 2
Mouse The disruption of the ileal BA transporter gene Slc10a2 activates enzymes involved in BA synthesis and inhibits mRNA levels of the liver orphan nuclear receptor SHP. (A) wt, Slc10a2 +/- and Slc10a2-/-mRNA levels of CYP7A1 in livers of animals 11. (B) wt, Slc10a2 +/- and Slc10a2-/-CYP7A1 enzymatic activity of microsomal samples collected from livers of animals . The results shown are the average of both analyzes. (C) Protein levels of CYP7A1 in livers of wt, Slc10a2 +/- and Slc10a2-/-mice found in microsome samples collected by immunoblot with CYP7A1 specific antibody. 20 μg and 40 μg of protein per sample were used, respectively. The results are representative of three separate immunoblots. Note the loading order of the samples. (D) Serum levels of the CYP7A1 activity marker product C4 were analyzed as an indirect measure of CYP7A1 enzymatic activity in the collected serum samples of wt, Slc10a2 +/- and Slc10a2-/-animals. The data represents the average of two separate measurements. (E) Liver mRNA levels of CYP8B1, and (F) Liver SHP mRNA levels of wt, Slc10a2 +/- and Slc10a2-/-mice. mRNA levels for wt mice were normalized to 1. Data is expressed as mean ± standard error (SEM) for mRNA analysis. For AF, wt litters (n = 10), Slc10a2 +/- (n = 9) and Slc10a2-/-(n = 10). p-value <0.05 is denoted by *, p <0.01 is denoted by **.
Degree. 3
Ablation of the Slc10a2 gene leads to low levels of plasma TGs, but not with plasma cholesterol, with simultaneous occurring changes in expression levels of genes related to liver sterols and TG homeostasis. (A) Total plasma cholesterol and TGs from wt, Slc10a2 +/- and Slc10a2-/-mice. (B) Plasma profiles of cholesterol and TGs. (C) FPLC. Represents the mean of all individuals from each group, analyzed from wt, Slc10a2 +/- and Slc10a2-/-animals by Lines, respectively. Lipoprotein fractions are indicated, n = 9-10. (D) HMGCoA reductase mRNA levels and enzymatic activity of livers of wt, Slc10a2 +/- and Slc10a2-/-mice. HMGCoA reductase enzymatic activity was analyzed from microsomal samples collected and averaged of two measurements. (n = 9-10). (E) Liver mRNA levels of the sterol transporters ABCG5 and ABCG8 of wt, Slc10a2 +/- and Slc10a2-/-mice. (F) wt, mRNA levels of SREBP1c and SREBP2 of Slc10a2 +/- and Slc10a2-/-mice. mRNA levels of wt mice were normalized to 1. Data are expressed as mean ± standard error (SEM) for mRNA and total plasma cholesterol and TGs analysis. Wt litters (n = 10), Slc10a2 +/- (n = 9) and Slc10a2-/-(n = 10) for AF. p-value <0.05 is indicated by *.
Degree. 4
Slc10a2-/-mice show lower hepatic TG and cholesterol accumulation compared to wild type with reduced expression of fatty acid synthesis genes according to the sucrose-rich diet. (A) Liver TG and cholesterol content were analyzed from a total of four groups; Wt and Slc10a2-/-mice fed either normal food or sucrose-rich diet (SR) for a period of 2 weeks. (B) mRNA levels of liver of enzymes with fatty acid synthesis from wt or Slc10a2-/-animals, as in (A). (C) Substance for preparing protein of liver cytoplasm and nucleus collected from wt or Slc10a2-/-mice fed with normal food or sucrose-rich (SR) diet using a specific antibody at the N'-terminus of SREBP1. SREBP1 immunoblot was performed on each of the preparations. Antibodies to Lamin were used as loading controls for the nucleus. The blot shown is representative of three separate immunoblots. (D) glucokinase, (GK); Pyruvate kinase, (LPK); And (E) mRNA expression levels of hepatic of glucose-6 phosphodehydrogenase, (G6PDH) and malic enzyme, (ME), and mRNA values in the normal group fed wt group to 1. Normalized. Data are expressed as mean ± standard error (SEM) for mRNA, liver cholesterol and TG analysis. For AD, wt (n = 6), Slc10a2-/-(n = 5), wt + SR (n = 6) and Slc10a2 +/- SR (n = 6). p-value <0.05 is indicated by *.
Degree. 5
Interruption of BA circulation by inhibition of the Slc10a2 protein improves plasma glucose and TGs in ob / ob mice. Ob / ob mice were treated with specific Slc10a2 protein inhibitors (Example 14), or control vehicle, (vehicle) (see experimental methods). (A) fasting (fasting) levels of blood glucose and plasma insulin, (B) plasma total TGs and cholesterol. (C) Liver mRNA levels of FGF21 and CYP7A1. (D) liver cholesterol and TGs. (E) Terminal ileal mRNA levels of FGF15, SHP, IBABP and FXR from ob / ob animals treated with Slc10a2 protein inhibitor. MRNA levels of control vehicle treated animals are normalized to one. Data are shown as mean ± standard error (SEM). p-value <0.05 is indicated by *. P <0.01 is indicated by **.
Degree. 6
Pharmacological inhibition of Slc10a2 leads to altered levels of glucose metabolizing enzymes levels in ob / ob mice and reduced liver SREBP1c mRNA. Ob / ob mice were treated with specific Slc10a2 protein inhibitors, compounds of Example 14, (IBAT inhibitors) or control vehicles, (controls). (See experimental methods). (FIG. 6A) Liver mRNA levels of SREBP1c, and its target genes ACC, FAS, and SCD1. (B) Liver mRNA levels of GK, LPK, G6Pase and PEPCK. MRNA levels of control vehicle treated animals are normalized to one. Data are expressed as mean ± standard error (SEM). p-value <0.05 is indicated by *.
Degree. 7
Pharmacological inhibition of Slc10a2 Induces altered activity of important signal transduction pathways in the ob / ob liver. The activation state of selected kinases, important in glucose and lipid metabolism, was investigated in liver individual protein extracts by phosphorylation site-specific antibodies in Slc10a2 inhibitor treated and control ob / ob mice. (A) Western blot for hepatic pAkt (ser 473), the same membrane was stripped and reprobed with antibody for the total amount of Akt, (B) hepatic pMek1 / 2 (ser 217/221) and Western blot for pErk1 / 2 Thr 202 / Tyr 204), identical membranes were subsequently removed and reprobed with antibodies to total Mek1 / 2 and Erk1 / 2. (C) Western blot for liver pAmpk (Thr 172), the same membrane was removed and reprobed with antibodies to the total amount of Ampk. All membranes were finally reprobed with an antibody against beta-actin. Blots are representative of four individuals performed.
Degree. 8
Of the GLP-1 concentrations in human plasma after daily treatment for two weeks with the compound of Example 14 increase. Both treatment groups increased significantly p ≦ 0.05 compared to 15 mg (n = 12) and 20 mg (n = 9), placebo group (n = 11). Vertical bars indicate standard deviation.
Degree. 9
Percent change in plasma glucose (baseline _ change from the end of treatment, completer population), 10 mg of compound vs. placebo p = 0.13 in patients with glucose ≧ Upper Limit normal (ULN) .

Summary of the Invention

The present invention provides specific ileum effective in the prevention and treatment of metabolic syndrome, obesity, disorders of fatty acid metabolism, disorders of glucose use, disorders related to insulin resistance, diabetes mellitus, type 1 and type 2 diabetes For bile acid transport (IBAT) inhibitors. It is also directed to compositions comprising these IBAT inhibitors, methods of treating the disorders, kits comprising the agents or compositions. Disruption (interference) of bile acid circulation in mice has been shown to improve triglyceride metabolism and normalize increased plasma glucose levels.

Detailed description of the invention

The present invention relates to IBAT inhibitor compounds of formula (I), pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof:

<Formula I>

Where :

M is CH ₂ , NH

One of R ¹ and R ² are hydrogen or C _{1 - 6} alkyl and the other is C _{1 - 6} is selected from alkyl;

R ^x and R ^y is hydrogen, hydroxy, amino, mercapto (mercapto), C _{1 - 6} alkyl, C _{1 - 6} alkoxy, N- (C _{1 - 6} alkyl) amino, N, N- (C _{1 - 6} alkyl) ₂ amino, C _{1 - 6} alkyl, a S (O) _a wherein a is independently selected from which 0-2

R ^z is halo (halo), nitro, (nitro), cyano (cyano),, sulfamoyl, hydroxy, amino, carboxy, carbamoyl, mercapto (sulphamoyl), C _{1 - 6} alkyl, C _{2 - 6} Al alkenyl (alkenyl), C _2-6 alkynyl group (alkynyl), C _{1 - 6} alkanoyl (alkanoyl), C _{1 - 6} alkanoyloxy (alkanoyloxy), N- (C _1-6 alkyl) amino, N, N _- (C ₁ - ₆ alkyl) 2 amino, C _{1 - 6} alkanoylamino, N- (C _{1 - 6} alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _{1 - 6} alkyl S (O) _a wherein a is to be 0 to 2, C _{1 -6} alkoxycarbonyl _{(alkoxycarbonyl), N- (C 1} - 6 alkyl) sulfamoyl and N, N- (C _{1 - 6} alkyl) ₂ sulfamoyl;

v is 0-5;

One of R ⁴ and R ⁵ is a group of formula (IA):

<Formula (IA)>

The other of R ³ and R ⁶ and R ⁴ and R ⁵ is hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{1 - 4} alkoxy, C _{1 - 4} alkanoyl, C _{1 - 4} alkanoyloxy, N- (C _{1 - 4} alkyl) amino , N, N- (C _{1 - 4} alkyl) ₂ amino, C _{1 - 4} alkanoylamino, N- (C _{1 - 4} alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _{1 - 4} alkyl, S (O) _a wherein a is to be 0 to 2, C _{1 - 4} alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _{1 - 4} alkyl ) Is independently selected from ₂ sulfamoyl; Wherein R ³ and R ⁶ and the other of R ⁴ and R ⁵ may be optionally substituted with carbon by one or more R ¹⁶ ;

X is -O-, -N (R ^a ) -, -S (O) _b - or -CH (R ^a ) -; Wherein R ^a is hydrogen or C _{1 - 6} alkyl and b is 0 to 2 and a;

Ring A is aryl or heteroaryl; Then ring A is optionally substituted by one or more substituents selected from R ¹⁷ ;

R ⁷ is hydrogen, C _{1 - 4} alkyl, carbocyclyl (carbocyclyl) or heterocyclyl (heterocyclyl), and; Then R ⁷ is optionally substituted by one or more substituents selected from R ¹⁸ ;

R ⁸ is hydrogen or C 1-4 alkyl;

R ⁹ is hydrogen or C 1-4 alkyl;

R ¹⁰ is hydrogen, C _{1 - 4} alkyl, carbocyclyl or heterocyclyl; Then R ¹⁰ is optionally substituted by one or more substituents selected from R ¹⁹ ;

R ¹¹ is carboxy, sulfo, sulfino, phosphono, P (O) (OR ^c ) (OR ^d ), P (O) (OH) (OR ^c ), P (O ) (OH) (R ^d), or ^{P (O) (oR c)} (R d) , and wherein R ^c and R ^d is c _{1 - 6} are independently selected from alkyl; Or R ¹¹ is a group of formula (IB) or (IC):

<Formula (IB)>

<Formula (IC)>

Where :

Y is -N (R ⁿ )-, -N (R ⁿ ) C (O)-, -N (R ⁿ ) C (O) (CR ^s R ^t ) _v N (R ⁿ ) C (O)-, -O-, and S (O) a; Wherein a is 0-2, v is 1-2 and, R ^s and R ^t is a C ₁ optionally substituted by hydrogen or R ²⁶ _- is independently selected from _4-alkyl, R ⁿ is hydrogen or C _{1 - 4} alkyl;

R ¹² is hydrogen or C _{1 - 4} alkyl and;

R ¹³ and R ¹⁴ are independently selected from hydrogen, C ₁₄ alkyl, carbocyclyl or heterocyclyl; And when q is 0, R ¹⁴ may be further selected from hydroxy, wherein R ¹³ and R ¹⁴ may be optionally substituted independently by one or more substituents selected from R ²⁰ ;

R ¹⁵ is carboxy, sulfo, sulfino, phosphono, P (O) (OR ^e ) (OR ^f ), P (O) (OH) (OR ^e ), P (O) (OH) (R ^e ) or ^{P (O) (OR e)} (R f) wherein R ^e and R ^f is a C _{1 - 6} are independently selected from alkyl;

p is 1-3; Wherein the values of R ¹³ may be the same or different;

q is 0-1;

r is 0-3; Wherein the values of R ¹⁴ may be the same or different;

m is 0-2; Wherein the values of R ¹⁰ may be the same or different;

n is 1-3; Wherein the values of R ⁷ may be the same or different;

Ring B is nitrogen linked heterocyclyl substituted by carbon with one group selected from R ²³ and optionally further substituted with carbon by one or more R ²⁴ ; And wherein when the nitrogen-bonded heterocyclyl comprises an —NH— moiety, the nitrogen may be optionally substituted by a group selected from R ²⁵ ;

R ^16, R ¹⁷ and R ¹⁸ is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{1 - 4} alkoxy, C _{1 - 4} alkanoyl, C _{1 - 4} alkanoyloxy, N- (C _{1 - 4} alkyl) _{amino, N, N- (C 1 -} 4 alkyl) ₂ amino, C _{1 - 4} alkanoylamino, N- (C _{1 - 4} alkyl) _{carbamoyl, N, N- (C 1 -} 4 alkyl) ₂ carbamoyl, C _{1 - 4} alkyl by S (O) _a wherein a is 0 to like a 2, C _{1 - 4} alkoxycarbonyl, N- (C _{1 - 4} alkyl) sulfamoyl and N, N- (C _{1 - 4} alkyl) is independently selected from _2-sulfamoyl; Wherein R ¹⁶ , R ¹⁷ and R ¹⁸ may be optionally substituted independently with carbon by one or more R ²¹ ;

R ^19, R ^20, R ²⁴ and R ²⁶ is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _{1 - 4} alkyl, C ₂₄ alkenyl, C _{2 - 4} alkynyl, C _{1 - 4} alkoxy, C _{1 - 4} alkanoyl, C _{1 - 4} alkanoyloxy, N- (C _{1 - 4} alkyl) _{amino, N, N- (C 1 -} 4 alkyl) _2, amino, C _{1 - 4} alkanoylamino, N- (C _{1 - 4} alkyl) _{carbamoyl, N, N- (C 1 -} 4 alkyl) ₂ carbamoyl, C _{1 - 4} wherein alkyl S (O) _a a is one of 0 to 2, C _{1 - 4} alkoxycarbonyl, N- (C _{1 - 4} alkyl) sulfamoyl, N, N- (C _{1 - 4} alkyl) ₂ sulfamoyl, carbocyclyl, heterocyclyl, Benzyloxycarbonylamino, sulfo, sulfino, amidino, phosphono, P (O) (OR ^a ) (OR ^b ), P (O) (OH) (OR ^a ), P ( ^{O) (OH) (R a} ) or P (O) independently selected from ^{(oR a) (R b)} , wherein R ^a and R ^b is C _{1 - 6} are independently selected from alkyl; Wherein R ¹⁹ , R ²⁰ , R ²⁴ and R ²⁶ may be optionally substituted independently with carbon by one or more R ²² ;

R ²¹ and R ²² are halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl (trifluoromethyl), Trifluoromethoxy (trifluoromethoxy), methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl ( acetyl), formamido, acetylamino, acetoxy, methylamino (methylamino), dimethylamino, N-methylcarbamoyl, N, N-dimethylcarbamoyl, methylthio (methyl thio), methylsulphinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl;

R ²³ is carboxy, sulfo, sulfino, phosphono, P (O) (OR ^g ) (OR ^h ), P (O) (OH) (OR ^g ), P (O) (OH) (R ^g ) or ^{P (O) (OR g)} (R h) and wherein R ^g and R ^h is C _{1 - 6} are independently selected from alkyl;

R ²⁵ is C _{1 - 6} alkyl, C _{1 - 6} alkanoyl, C _{1 - 6} alkylsulfonyl, C _{1 - 6} alkoxycarbonyl, carbamoyl, N- (C _1-6 alkyl) carbamoyl, N, N _- (C ₁ - ₆ alkyl) carbamoyl, benzyl (benzyl), benzyloxycarbonyl, is selected from benzoyl (benzoyl) and phenylsulfonyl (phynylsulphonyl);

It is for the prevention or treatment of metabolic syndrome, obesity, disorders of fatty acid metabolism, impaired glucose use (a glucose impaired), disorders associated with insulin resistance, or diabetes mellitus such as diabetes type 1 or diabetes type 2.

IBAT inhibitors used in accordance with the present invention It is possible to reduce the activity of two major kinases, Akt and Mek1 / 2. It is experimentally known that the Akt and Mek1 / 2_Erk1 / 2 pathways are important for hepatic regulation in both glucose metabolism and lipogenesis.

Kinase Akt has proven to be a critical factor in regulating the liver's response to insulin and other circulating factors with the ability to favor glycolysis and lipogenesis. .

The Mek1 / 2_Erk1 / 2 pathway is activated by the FGF receptor 4 / beta-Klotho complex and insulin receptor, known as FGF15 receptors.

IBAT inhibitors used in accordance with the present invention include metabolic syndrome, obesity, disorders of fatty acid metabolism, glucose utilization disorders, disorders in which insulin resistance disorders, diabetes mellitus, type 1 and type 2 diabetes May have improved efficacy.

Furthermore, the substances used according to the invention are effective against high glucose values in serum. Thus, the risk of hypoglycemia is low.

IBAT inhibitors are sometimes referred to in this document in different terms. When reference is made here to IBAT inhibitors, this term is also understood to include compounds known in the literature as follows: i) Apical sodium co-dependent bile acid transporter (ASBT) ) Inhibitors; ii) bile acid transporter (BAT) inhibitors; iii) ileum sodium / bile acid cotransporter system inhibitors; iv) apex sodium-bile acid cotransporter inhibitors; v) ileal sodium-dependent bile acid transport inhibitors; vi) bile acid reuptake (BARI's) inhibitors; And vii) sodium bile acid transporter (SBAT) inhibitors; These are then acted by the suppression of IBAT.

The term "alkyl" used herein includes both straight and branched chain alkyls, but references to individual alkyl groups such as "propyl" are specific to the straight chain form only. For example, "C _{1 - 6} alkyl" is C _{1 - 3} alkyl include, propyl, isopropyl and t- _butyl-4 alkyl, C _1. However, references to individual alkyl groups such as "propyl" are specific to the straight chain form only, and references to individual branched chain alkyl groups such as "isopropyl" are specific to the branched chain form only. There is also a similar manner applicable to other radicals, for example, a "phenyl C _{1 - 6} alkyl" is phenyl C _{1 -} will comprise ₄ alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term "halo" refers to fluoro, chloro, bromo and ioldo.

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

"Heteroaryl" is an unsaturated mono or bicyclic ring, containing 3-12 atoms, wherein at least one valence nitrogen, sulfur EH is selected from oxygen, It can be carbon or nitrogen linked. Preferably "heteroaryl" refers to a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms, which is fully unsaturated, at least one of which is nitrogen, sulfur , Or oxygen, which, unless otherwise specified, can be linked to carbon or nitrogen. In another aspect of the invention “heteroaryl” refers to a monocyclic ring containing 5 or 6 atoms, or a bicyclic ring containing 8, 9 or 10 atoms, which is fully unsaturated, at least of which One atom is selected from nitrogen, sulfur or oxygen, which can be carbon or nitrogen linked unless otherwise specified. Examples and suitable values of the term “heteroaryl” include thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl , Triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridazinyl, pyridyl and quinolyl . Preferably the term “heteroaryl” refers to thienyl or indolyl.

"Aryl" is a fully unsaturated, mono or bicyclic carbon ring containing 3-12 atoms.

Preferably a "aryl" monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for "aryl" include phenyl or naphthyl (naphthyl). Especially "aryl" is phenyl.

"Heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring comprising 3-12 atoms, at least one of which is selected from nitrogen, sulfur or oxygen Unless otherwise specified, it is carbon or nitrogen bonded, the -CH2- group can be optionally replaced by -C (O)-or the ring sulfur atom can be selectively oxidized to form S-oxides have. Preferably "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring comprising 5 or 6 atoms, at least one of which is selected from nitrogen, sulfur or oxygen Which, unless otherwise specified, is carbon or nitrogen bonded, where a —CH 2 — group may be optionally replaced by —C (O) — and the ring sulfur atom is selectively oxidized to S-oxide ( Can be formed). Examples and appropriate values of the term “heterocyclyl” include thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrroli Dioxopyrrolidinyl, benzoxazolinonyl, 1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl, 2-oxo-1,3 , 4- (4-triazolinyl), 2-oxazolidinonyl, 5,6-disideurasilylyl, 1,3-benzodioxolyl, 1, 2,4-oxadiazolyl, 2-azabicyclo [2.2.1] heptyl, 4-thiazolidonyl, morpholino (morpholino), 2- Oxotetrahydrofuranyl, tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl ahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1-dioxo Dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, fi Rollyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pinanyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, Pyridyl, 4-pyridonyl, quinolyl and 1-isoquinolonyl.

A “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring containing 3-12 atoms; At this time, the -CH2- group may be optionally replaced by -C (O)-. Preferably "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values of "carbocyclyl" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexenyl, Phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. In particular "carbocyclyl" is cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or 1-oxoindanyl.

Examples of “C 1-6 alkanoyloxy” and “C 1-4 alkanoyloxy” are acetoxy. Examples of “C 1-6 alkoxycarbonyl” and “C 1-4 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. "C _{1 - 6} alkoxy", and examples of "C _1-4 alkoxy" include methoxy, ethoxy and propoxy. Examples of "C1-6 alkanoylamino" and "C1-4 alkanoylamino" include formamido, acetamido and propionylamino. Examples of _- "C _{1 6} alkyl, S (O) _a wherein a is to be 0 to 2" and "C1-4 alkyl S (O) _a wherein a is to be 0 to 2" are methylthio, ethylthio (ethylthio), methylsulfinyl, ethylsulphinyl, mesyl and ethylsulphonyl. "C _{1 - 6} alkanoyl (alkanoyl)" contains ₃ alkanoyl, propionyl (propionyl), and acetyl (acetyl) _- and _- Examples of "C _{1 4} alkanoyl" are C _1. "N- (C _{1 - 6} alkyl) amino", and _Examples of "N- (C _{1 4} alkyl) amino" include the methylamino and ethylamino. _{"N, N- (C 1 -} 6 alkyl) ₂ amino" and _Examples of "N, N- (C _{1 4} alkyl) ₂ amino" are di -N- methylamino, di - (N- ethyl) amino and N-ethyl-N-methylamino. "C _{2 -6} alkenyl (alkenyl)", and _Examples of "C _{2 4} alkenyl" are vinyl, allyl (allyl) and 1-propenyl (propenyl). "C _{2 - 6} alkynyl group (alkynyl)," and "C _{2 - 4} alkynyl group" in the examples, 1-propynyl (propynyl), and a 2-propynyl ethynyl. "N- (C _{1 - 6} alkyl) sulfamoyl (sulphamoyl)", and _Examples of "N- (C _{1 4} alkyl) sulfamoyl" are N- (C _{1 - 3} alkyl) sulfamoyl, N- (methyl) Sulfamoyl and N- (ethyl) sulfamoyl. "N- (C _{1 - 6} alkyl) 2 sulfamoyl" and "N-4 alkyl) ₂ sulfamoyl" of the examples are N, N- (dimethyl) sulfamoyl and N- (methyl) -N- (ethyl) sulfamic To gather. "N- (C _{1 - 6} alkyl) carbamoyl (carbamoyl)", and _Examples of "N- (C _{1 4} alkyl) carbamoyl" are methylamino and ethylamino carbonyl-carbonyl. "N, N- (C _1-6 alkyl) ₂ carbamoyl" and _{"N, N- (C 1 -} 4 alkyl) ₂ carbamoyl" are the examples of dimethylamino-carbonyl and methyl-ethyl-amino-carbonyl. "C _{1 - 6} alkoxy-carbonyl-amino" in the examples are ethoxycarbonyl and t- butoxycarbonyl-amino-on-a-carbonyl-amino. _{"N '- (C 1 -} 6 alkyl) ureido" are examples of N'- methyl ureido and N'- ethyl urea ear canal. "N-. _- Examples of (C _{1 6} alkyl) urea Ido are N- methyl-ureido is a urea and N- ethyl Ido" N ', N' - ( C 1 - 6 alkyl) 2, examples of the urea Ido are N ' , N'-dimethylureido and N'-methyl-N'-ethylureido. _{"N '- (C 1 -} 6 alkyl) -N- (C _{1 - 6} alkyl), examples of urea Ido are N'- methyl -N- methyl ureido and N'- profile -N- methyl urea ear canal." N ', N' - (C 1 - 6 alkyl) 2-N- examples of the (C _1-6 alkyl) urea Ido are N ', N'- dimethyl -N- methyl ureido and N'- methyl -N' -Ethyl-N-propylureido.

Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, those in which the invention is sufficiently basic as acid-added salts of the compounds, such as inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid. , Acid-added salts with trifluoroacetic acid, citric acid or maleic acid.

Furthermore, suitable pharmaceutically acceptable salts of the compounds of the invention which are sufficiently acidic provide alkali metal salts such as sodium or potassium salts, alkaline earth salts such as calcium or magnesium salts, ammonia salts or physiologically-acceptable cations. Afford salts with organic bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

Prodrugs of any compound mentioned herein as an IBAT inhibitor or compound for use in combination with it are drugs that degrade in the human or animal body to provide the compound.

Examples of prodrugs are in vivo hydrolyzable esters and in vivo hydrolyzable amides of the compound of formula (I).

In vivo hydrolyzable esters of compounds of formula (I) comprising carboxy or hydroxy groups are, for example, hydrolyzed in the human or animal body to produce parent acids or alcohols. And pharmaceutically acceptable esters. Possible suitable pharmaceutically acceptable for the carboxy esters are C _{1 - 6} alkoxymethyl esters, e.g., methoxymethyl, C _{1 - 6} alkanoyloxy ester, e.g. pivaloyl oxymethyl (pivaloyloxymethyl), phthalidyl (phthalidyl) the ester, C _{3 - 8} cycloalkyl-alkoxy-carbonyl-oxy C _{1 - 6} alkyl esters, e.g. 1-oxy-carbonyl-cyclohexyl-ethyl; 1,3-dioxide in solren (dioxolen) -2- methyl O'Neill (onylmethyl) esters for example 5 -Methyl-1,3-dioxolene-2-onylmethyl; And C _{1 - 6} alkoxy-carbonyl-oxy-ethyl ester of example 1-methoxy-comprises a carbonyl-oxy-ethyl, and may be formed at any carboxy group of the compound of the present invention.

In vivo hydrolyzable esters of compounds of formula (I) comprising hydroxy groups include inorganic esters and parent such as phosphate esters and α-acyloxyalkyl ethers. And related compounds as a result of in vivo hydrolysis of ester degradation to provide a hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. The choice of in vivo hydrolyzable ester forming groups for hydroxy is to provide alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (alkyl carbonate esters) ), Dialkylcarbamoyl and N (dialkylaminoethyl) -N-alkylcarbamoyl (to provide carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino bonded to the 3- or 4- position of the benzoyl ring via a ring nitrogen atom through a methylene group.

Suitable values for in vivo hydrolyzable amides of compounds of formula (I) comprising a carboxy group are, for example, N-methyl, N-ethyl, N-propyl, N, N-dimethyl, N-ethyl N-C 1-6 alkyl or N, N-di-C 1-6 alkyl amide, such as -N-methyl or N, N-diethyl amide.

It is understood that certain compounds of formula (I) may exist in unsolvated as well as solvated, such as hydrated forms. The present invention is understood to include all such solvated forms having IBAT inhibitory activity.

Preferred values of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as follows. These values may be used as appropriate with any of the definitions, claims or examples defined before or after this.

Preferably R ¹ and R ² are C _{1 - 4} are independently selected from alkyl.

More preferably R ¹ and R ² are independently selected from ethyl or butyl.

More preferably R ¹ and R ² are independently selected from ethyl, propyl or butyl.

In one aspect of the invention in particular R ¹ and R ² are both butyl.

In a further aspect of the invention in particular both R ¹ and R ² are propyl.

In another aspect of the invention in particular one of R ¹ and R ² is ethyl and the other is butyl.

Preferably, R ^x and R ^Y is hydrogen or C _{1 - 6} are independently selected from alkyl.

More preferably both R ^x and R ^Y are hydrogen.

Preferably R ^Z is halo, amino, C _{1 -} is selected from (C _1-6 alkyl) urea _Ido-6 alkyl, C _{1 - 6} alkoxycarbonyl-amino or N '.

More preferably R ^Z is selected from chloro, amino, t-butyl, t-butoxycarbonylamino or N '-(t-butyl) ureido.

Preferably v is 0 or 1.

In one aspect of the invention, more preferably v is zero.

In one aspect of the invention, more preferably v is 1.

In one aspect of the invention preferably R ⁴ is a group of formula (IA) (as described above).

In another aspect of the invention preferably R ⁵ is a group of formula (IA) (as described above).

Preferably R ³ and R ⁶ are hydrogen.

Preferably R ⁴ and R ⁵ of the other one, not a group of formula (IA) is halo, C _1-4 alkoxy, or C _{1 - 4} wherein alkyl S (O) _a a is selected from those of from 0 to 2 ; Wherein R ⁴ or R ⁵ may be optionally substituted with carbon by one or more R ¹⁶ ; Wherein R ¹⁶ is hydroxy and N, N- _- is independently selected from (C _{1 4} alkyl) ₂ amino.

More preferably the other of R ⁴ and R ⁵ which is not a group of formula (IA) is selected from bromo, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl Become; Wherein R ⁴ or R ⁵ may be optionally substituted with carbon by one or more R ¹⁶ ; Then R ¹⁶ is independently selected from hydroxy and N, N-dimethylamino.

Especially The other of R ⁴ and R ⁵ that is not a group of formula (IA) is bromo, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2- (N, N -Dimethylamino) ethylthio or mesyl.

More particularly, not the group of formula (IA), the other of R ⁴ and R ⁵ is methylthio.

Preferably R ⁴ and R ⁵ of the other one, not a group of formula (IA) is hydrogen, halo, C _{1 -} from which a _4-alkyl S (O) _a wherein a is 0 to 2 _{- 4} alkoxy or C ₁ Selected; Wherein R ⁴ or R ⁵ may be optionally substituted with carbon by one or more R ¹⁶ ; Wherein R ¹⁶ is hydroxy, carboxy and N, N- _- it is independently selected from (C _{1 4} alkyl) ₂ amino.

More preferably another of R ⁴ and R ⁵ which is not a group of formula (IA) is selected from hydrogen, bromo, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl; Wherein R ⁴ or R ⁵ may be optionally substituted with carbon by one or more R ¹⁶ ; Wherein R ¹⁶ is independently selected from hydroxy, carboxy and N, N-dimethylamino.

In particular, the other of R ⁴ and R ⁵ which is not a group of formula (IA) is hydrogen, bromo, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydr Hydroxyethylthio, 2- (N, N-dimethylamino) ethylthio or mesyl.

In another aspect of the invention, more preferably another of R ⁴ and R ⁵ that is not a group of formula (IA) is hydrogen, chloro, bromo, methoxy, isopropoxy, methylthio, ethylthio or iso Selected from propylthio; Wherein R ⁴ or R ⁵ may be optionally substituted with carbon by one or more R ¹⁶ ; Wherein R ¹⁶ is independently selected from hydroxy, carboxy and N, N-dimethylamino.

In another aspect of the invention , in particular , the other of R ⁴ and R ⁵ which is not a group of formula (IA) is hydrogen, chloro, bromo, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, Isopropylthio, 2-hydroxyethylthio or 2- (N, N-dimethylamino) ethylthio.

In another aspect of the invention, more particularly the other of R ⁴ and R ⁵ which is not a group of formula (IA) is bromo or chloro.

In another aspect of the invention, more particularly the other of R ⁴ and R ⁵ which is not a group of formula (IA) is methoxy.

In one aspect of the invention, preferably Ring A is aryl.

In another aspect of the invention, preferably Ring A is heteroaryl.

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

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

Preferably ring A is aryl or heteroaryl; Then ring A is optionally substituted by one or more substituents selected from R ¹⁷ ; Then R ¹⁷ is selected from halo, hydroxy or Cl 4 alkyl; Then R ¹⁷ may be optionally substituted on carbon by one or more R ²¹ ; Then R ²¹ is selected from halo.

Preferably X is -O.

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

Ring A in particular is phenyl, 4-hydroxyphenyl, thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2,3-dihydroxy Oxyphenyl or indol-3-yl.

More particularly ring A is phenyl.

In another aspect of the invention, preferably Ring A is aryl or heteroaryl; Then ring A is optionally substituted by one or more substituents selected from R ¹⁷ ; Wherein R ¹⁷ is halo, hydroxy, C _{1 - 4} alkoxy group is selected from _{- 4} alkyl or C _1; Then R ¹⁷ may be optionally substituted on carbon by one or more R ²¹ ; Then R ²¹ is selected from halo.

In another aspect of the invention, more preferably Ring A is phenyl, thienyl or indolyl; Then ring A is optionally substituted by one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl.

In another aspect of the invention, particularly ring A is phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl , 2,3-dihydroxyphenyl or indol-3-yl.

In a further aspect of the invention, particularly Ring A is phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluoro Rophenyl, 4-fluorophenyl, 2,3-dihydroxyphenyl or indol-3-yl.

Preferably, R ⁷ is hydrogen, C _{1 - 4} alkyl or a carbocyclyl (carbocyclyl).

More preferably R ⁷ is hydrogen , methyl or phenyl.

Especially R ⁷ is hydrogen.

In one aspect of the invention, preferably R ⁸ is hydrogen.

In yet another aspect of the invention, preferably R ⁸ is C _{1 - 4} is alkyl.

In another aspect of the invention, more preferably R ⁸ is hydrogen or methyl.

In one aspect of the invention, preferably R ⁹ is hydrogen.

In yet another aspect of the invention, preferably R ⁹ is C _{1 - 4} is alkyl.

In another aspect of the invention, more preferably R ⁹ is hydrogen or methyl.

Preferably R ¹⁰ is hydrogen.

In one aspect of the invention, preferably R ¹¹ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^c ) (OR ^d ), -P (O) (OH) (OR ^c ), and -P (O) (OH) ( R d) or ^{-P (O) (oR c)} (R d), wherein R ^c and R ^d is C _{1 - 6} are independently selected from alkyl.

In another aspect of the invention, preferably R ¹¹ is a group of formula (IB) (as described above).

Preferably R ¹¹ is carboxy, —P (O) (OH) (OR ^c ) or a group of formula (IB) (as described above).

More preferably R ¹¹ is carboxy, —P (O) (OH) (OEt) or a group of formula (IB) (as described above).

In yet another aspect of the invention, preferably R ¹¹ is carboxy, sulfo, -P (O) (OH) (OR c) , and wherein R ^c is C _{1 - 4} alkyl, or selected from a group of formula (IB) (As described above).

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

More preferably Y is -NHC (O)-.

In one aspect of the invention, preferably R ¹² is hydrogen.

In yet another aspect of the invention, preferably R ¹² is C _{1 - 4} is alkyl.

In another aspect of the invention, more preferably R ¹² is hydrogen or methyl.

Preferably R ¹³ is hydrogen, C _{1 - 4} alkyl, carbocyclyl, and; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; Wherein R ²⁰ is hydroxy.

More preferably R ¹³ is hydrogen, methyl or phenyl; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; Wherein R ²⁰ is hydroxy.

In particular R ¹³ is hydrogen, hydroxymethyl or phenyl.

More particularly R ¹³ is hydrogen or hydroxymethyl.

In yet another aspect of the invention, preferably R ¹³ is hydrogen, C _{1 - 4} alkyl, carbocyclyl, and; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; Then R ²⁰ is hydroxy, carboxy, carbocyclyl or amino; Then R ²⁰ may be optionally substituted by carbon by one or more R ²² ; R ²² is hydroxy.

In another aspect of the invention, more preferably R ¹³ is hydrogen, methyl, ethyl, butyl or phenyl; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; Then R ²⁰ is hydroxy, carboxy, phenyl or amino; Then R ²⁰ may be optionally substituted by carbon by one or more R ²² ; R ²² is hydroxy.

In another aspect of the invention, in particular, R ¹³ is hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl or phenyl.

In naahgan aspect of the invention, preferably R ¹³ is hydrogen, C _{1 - 4} alkyl, carbocyclyl, and; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; Then R ²⁰ is hydroxy, carboxy, carbocyclyl, heterocyclyl or amino; Then R ²⁰ may be optionally substituted by carbon by one or more R ²² ; R ²² is hydroxy.

In a further aspect of the invention, more preferably R ¹³ is hydrogen, methyl, ethyl, butyl or phenyl; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; Wherein R ²⁰ is hydroxy, carboxy, phenyl, imidazolyl or amino; Then R ²⁰ may be optionally substituted by carbon by one or more R ²² ; R ²² is hydroxy.

In a further aspect of the invention, in particular R ¹³ is hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl, imidazol-5-ylmethyl or phenyl.

In a further another aspect of the invention, preferably R ¹³ is hydrogen, C _{1 - 4} alkyl, carbocyclyl or R ²³ a; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; Wherein R ²⁰ is hydroxy, C _{1 - 4} alkyl, S (O) _a wherein a is to be a 0, C _{1 - 4} alkoxy, amino, carbocyclyl, heterocyclyl or mercapto gt; Then R ²⁰ may be optionally substituted independently with carbon by one or more R ²² ; R ²² is selected from hydroxy; And R ²³ is carboxy.

In another further aspect of the invention, more preferably R ¹³ is hydrogen, methyl, ethyl, butyl or phenyl or R ²³ ; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; Wherein R ²⁰ is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; Then R ²⁰ may be optionally substituted independently with carbon by one or more R ²² ; R ²² is selected from hydroxy; And R ²³ is carboxy.

In another further aspect of the invention, in particular, R ¹³ is hydrogen, carboxy, hydroxymethyl, mercaptomethyl, methoxymethyl, methylthiomethyl, 2-methylthioethyl, 4-aminobutyl, 4-hydroxy Oxybenzyl, imidazol-5-ylmethyl or phenyl.

In other aspects more particularly R ¹³ is methylthiomethyl, methylsulfinylmethyl or methylsulfonylmethyl.

Preferably, R ¹⁴ is hydrogen.

In yet another aspect of the invention, preferably R ¹⁴ is selected from hydrogen, C ₁₄ alkyl or carbocyclyl; At this time, the C _{1 - 4} alkyl or carbocyclyl is optionally may be substituted by one or more substituents selected from R ^20; And R ²⁰ is hydroxy.

In another aspect of the invention, more preferably R ¹⁴ is selected from hydrogen, methyl or phenyl; Wherein said methyl or phenyl may be optionally substituted by one or more substituents selected from R ²⁰ ; And R ²⁰ is hydroxy.

In another aspect of the invention , in particular, R ¹⁴ is hydrogen, phenyl or hydroxymethyl.

In particular R ¹⁵ is carboxy or sulfo.

In one aspect of the invention , more particularly R ¹⁵ is carboxy.

In another aspect of the invention, more particularly R ¹⁵ is sulfo.

Preferably, R ¹⁵ is carboxy, sulfo, -P (O) (OR ^e ) (OR ^f ), -P (O) (OH) (OR ^e ), -P (O) (OH) (R ^e ) or -P ( ^{O) (OR e) (R} f) wherein R ^e and R ^f is a C _{1 - 4} are independently selected from alkyl.

More preferably R ¹⁵ is carboxy, sulfo, -P (O) (OR ^e ) (OR ^f ), -P (O) (OH) (OR ^e ), -P (O) (OH) (R ^e ) or -P (O) (OR ^e ) ( R ^f ) where R ^e and R ^f are independently selected from methyl or ethyl.

Preferably R ¹⁵ is carboxy, sulfo, -P (O) (OEt) (OEt), -P (O) (OH) (OEt), -P (O) (OH) (Me) or -P (O (OEt) (Me).

Preferably, R ¹⁵ is carboxy, sulfo, phosphono, -P (O) (OR ^e ) (OR ^f ), -P (O) (OH) (OR ^e ), -P (O) (OH) (R ^e ) or ^{-P (O) (oR e)} (R f) wherein R ^e and R ^f is a C _{1 - 4} are independently selected from alkyl, R ¹⁵ is a group of formula (IC) (as described above).

More preferably R ¹⁵ is carboxy, sulfo, phosphono, -P (O) (OR ^e ) (OR ^f ), -P (O) (OH) (OR ^e ), -P (O) (OH) ( R ^e ) or —P (O) (OR ^e ) (R ^f ) wherein R ^e and R ^f are independently selected from methyl or ethyl or R ¹⁵ is a group of formula (IC) (as described above) .

Preferably, R ¹⁵ is 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 R ¹⁵ is a group of formula (IC) (as described above).

In one aspect of the invention, preferably R ¹⁵ is carboxy.

In another aspect of the invention, preferably R ¹⁵ is sulfo.

In another aspect of the invention, preferably R ¹⁵ is -P (O) (OH) (OEt).

In another aspect of the invention, preferably R ¹⁵ is -P (O) (OH) (Me).

In another aspect of the invention, preferably R ¹⁵ is -P (O) (OEt) (Me).

In one aspect of the invention, preferably R ²⁴ is hydrogen.

In another aspect of the invention, preferably R ²⁴ is C 1-4 alkyl.

Preferably, R ²⁵ is hydrogen.

Preferably R ²⁶ is carboxy.

Preferably p is 1 or 2; In this case, the values of R ¹³ may be the same or different.

In one aspect of the invention, more preferably p is 1.

In another aspect of the invention, more preferably p is 2; In this case, the values of R ¹³ may be the same or different.

In a further aspect of the invention, more preferably p is 3; In this case, the values of R ¹³ may be the same or different.

In one aspect of the invention, preferably q is zero.

In a further aspect of the invention, preferably q is one.

In one aspect of the invention, preferably r is zero.

In one aspect of the invention, more preferably r is 1.

In another aspect of the invention, more preferably r is 2; In this case, the values of R ¹⁴ may be the same or different.

In a further aspect of the invention, more preferably r is 3; In this case, the values of R ¹⁴ may be the same or different.

Preferably, m is zero.

In another aspect of the invention, preferably m is 0 or 1.

Preferably n is 1.

In another aspect of the invention, preferably n is 1 or 2.

Preferably z is 1.

Group of (IA), wherein R ⁷ is hydrogen, methyl or phenyl, n is 1 and 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 R ⁹ is carboxy, -P (O) (OH) (OR ^c ) Or a group of formula (IB).

Wherein: X is -0-.

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

R ⁷ is hydrogen, methyl or phenyl;

R ⁸ is hydrogen or methyl;

R ⁹ is hydrogen or methyl;

R ¹⁰ is hydrogen;

m is 0-2, wherein the values of R ¹⁰ may be the same or different; And R ¹¹ is carboxy, —P (O) (OH) (OEt) or a group of formula (IB) (as described in claim 1); A group of formula (IB) wherein R ¹⁰ is hydrogen, hydroxymethyl or phenyl and p is 1 or 2; Wherein the values of R ¹⁰ may be the same or different and R ¹¹ is carboxy or sulfo.

Wherein a group of formula (IB):

R ¹² is hydrogen or methyl;

R ¹³ is hydrogen, methyl, ethyl, butyl or phenyl or R ²³ ; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; R ²⁰ is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; Then R ²⁰ may be optionally substituted independently of carbon by one or more hydroxy; R ²³ is carboxy; Y is -NH- or -NHC (O)-; R ¹⁴ is selected from hydrogen, methyl or phenyl; Wherein said methyl or phenyl may be optionally substituted by one or more substituents selected from hydroxy; R ¹⁵ is carboxy, sulfo, phosphono, -P (O) (ORe) (ORf), -P (O) (OH) (ORe), -P (O) (OH) (Re) or -P (O (OR ^e ) (R ^f ) wherein R ^e and R ^f are independently selected from methyl or ethyl or R ¹⁵ is a group of formula (IC) (as described in claim 1);

p is 1-3 and the values of R ¹³ can be the same or different;

q is 0-1; And

r is 0-3 wherein the values of R ¹⁴ can be the same or different;

The values of formula (IC)

R ²⁴ is hydrogen;

R ²⁵ is hydrogen;

R ²⁶ is carboxy; And

z is 1;

Or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.

therefore In a further aspect of the invention there is provided a compound of formula (I) as described above wherein:

R ¹ and R ² are independently selected from ethyl or butyl;

R ³ and R ⁶ are hydrogen;

R ⁴ is halo, C ^{1 - 4} alkoxy or C _{1 - 4} alkyl S (O) _a wherein a is selected from those of from 0 to 2; Wherein R ⁴ may be optionally substituted with carbon by one or more R ¹⁶ ; Wherein R ¹⁶ is hydroxy and N, N- (C _{1 - 4} alkyl) is independently selected from _2-amino;

R ⁵ is a group of formula (IA);

Ring A is aryl or heteroaryl; Then ring A is optionally substituted by one or more substituents selected from R ¹⁷ ; At this time

R ¹⁷ is halo, hydroxy or C _{1 -} is selected from _4-alkyl; Then R ¹⁷ may be optionally substituted on carbon by one or more R ²¹ ; At this time

R ²¹ is selected from halo;

R ⁷ is hydrogen, C 1-4 alkyl or carbocyclyl;

R ¹¹ is carboxy, —P (O) (OH) (OR ^c ) or a group of formula (IB) (as described above);

R ¹³ is hydrogen, C _{1 - 4} alkyl, carbocyclyl, and; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; At this time

R ²⁰ is hydroxy;

R ¹⁵ is carboxy or sulfo;

p is 1 or 2; Wherein the values of R ¹³ may be the same or different;

m is 0; And

n is 1;

Or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.

In a further aspect of the invention, therefore, a compound of formula (I) as described above is provided, wherein:

R ¹ and R ² are both butyl or one of R ¹ and R ² is ethyl and the other is butyl;

R ⁴ is methylthio;

R ⁵ is a group of formula (IA) (as described above);

R ³ and R ⁶ are hydrogen;

Ring A is phenyl;

R ⁷ is hydrogen;

R ¹¹ is a group of formula (IB) (as described above);

R ¹³ is hydrogen or hydroxymethyl;

R ¹⁵ is carboxy or sulfo;

p is 1 or 2; Wherein the values of R ¹³ may be the same or different;

m is 0;

n is 1;

Or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.

In a further further aspect of the invention, therefore, there is provided a compound of formula (I) as described above, wherein:

R ¹ and R ² are independently selected from ethyl or butyl;

R ³ and R ⁶ are hydrogen;

R ⁴ is halo, C _{1 - 4} alkoxy or C _{1 - 4} alkyl S (O) _a wherein a is selected from those of from 0 to 2; Wherein R ⁴ may be optionally substituted with carbon by one or more R ¹⁶ ; Wherein R ¹⁶ is hydroxy and N, N- (C _{1 - 4} alkyl) is independently selected from _2-amino;

R ⁵ is a group of formula (IA);

Ring A is aryl or heteroaryl; Then ring A is optionally substituted by one or more substituents selected from R ¹⁷ ;

R ⁷ is hydrogen, C _{1 - 4} alkyl, carbocyclyl, and;

R &lt; ⁸ &gt; is hydrogen or methyl;

R ⁹ is hydrogen or methyl;

R ¹¹ is carboxy, —P (O) (OH) (OR ^c ) or a group of formula (IB) (as described above);

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

R ¹² is hydrogen or methyl;

R ¹³ is hydrogen, C _{1 - 4} alkyl, carbocyclyl, and; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ;

R ¹⁴ is hydrogen;

R ¹⁵ is carboxy or sulfo;

R ¹⁷ is halo, hydroxy, C _{1 - 4} alkoxy group is selected from _{- 4} alkyl or C _1; Then R ¹⁷ may be optionally substituted on carbon by one or more R ²¹ ;

R ²⁰ is hydroxy, carboxy, carbocyclyl or amino; Then R ²⁰ may be optionally substituted by carbon by one or more R ²² ;

R ²¹ is selected from halo;

R ²² is hydroxy;

p is 1-3; Wherein the values of R ¹³ may be the same or different;

q is 0-1;

r is 0-3; Wherein the values of R ¹⁴ may be the same or different; And then if q is 1, r is not 0;

m is 0-2; And

n is 1-3;

Or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.

Therefore, a compound of formula (I) as described above is provided wherein:

R ¹ and R ² are C _{1 - 4} are independently selected from alkyl;

R ^x and R ^y are both hydrogen;

R ^z is selected from halo, amino, C _{1 - 6} alkyl, C _{1 - 6} alkoxycarbonyl or amino-N _'- (C ₁ - ₆ alkyl) is selected from urea Ido;

v is 0 or 1;

R ³ and R ⁶ are hydrogen;

R ⁴ and R ⁵ either is a (as defined above), a group is of formula (IA) and the other is hydrogen, halo, C _{1 - 4} alkoxy or C _{1 - 4} alkyl, S (O) _a a wherein a is 0 2 to 2; Wherein R ⁴ or R ⁵ may be optionally substituted with carbon by one or more R ¹⁶ ; Wherein R ¹⁶ is hydroxy, carboxy and N, N- (C _{1 - 4} alkyl) is independently selected from _2-amino;

X is -0-

R ⁷ is hydrogen, methyl or phenyl;

R &lt; ⁸ &gt; is hydrogen or methyl;

Ring A is aryl or heteroaryl; Then ring A is optionally substituted by one or more substituents selected from R ¹⁷ ; Wherein R ¹⁷ is halo, hydroxy, C _{1 - 4} alkoxy group is selected from _{- 4} alkyl or C _1; Then R ¹⁷ may be optionally substituted on carbon by one or more R ²¹ ; Then R ²¹ is selected from halo;

R ⁹ is hydrogen or methyl;

R ¹⁰ is hydrogen;

R ¹¹ is carboxy, -P (O) (OH) (OR c) wherein R ^c is a C _{1 -} (as defined above) selected from the group of the _4-alkyl or formula (IB), and;

R ¹² is hydrogen or methyl;

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

R ¹³ is hydrogen, C _{1 - 4} alkyl, carbocyclyl or R ²³ a; Then R ¹³ is optionally substituted by one or more substituents selected from R ²⁰ ; Wherein R ²⁰ is hydroxy, C _{1 - 4} alkyl, S (O) _a wherein a is to be a 0, C _{1 - 4} alkoxy, amino, carbocyclyl, heterocyclyl or mercapto gt; Then R ²⁰ may be optionally substituted independently with carbon by one or more R ²² ; R ²² is selected from hydroxy; And R ²³ is carboxy;

R ¹⁴ is selected from hydrogen, C ₁₄ alkyl or carbocyclyl; At this time, the C _{1 - 4} alkyl or carbocycle may be optionally substituted by one or more substituents selected from R ²⁰ rilneun; And R ²⁰ is hydroxy;

R ¹⁵ is carboxy, sulfo, phosphono, -P (O) (ORe) (OR ^f ), -P (O) (OH) (OR ^e ), -P (O) (OH) (R ^e ) or- P (O) (oR ^e) (R ^f) wherein R ^e and R ^f is a C _{1 - 4} are independently selected from alkyl, R ¹⁵ is a group of formula (IC) (as defined above);

R ²⁴ is hydrogen;

R ²⁵ is hydrogen;

R ²⁶ is carboxy;

p is 1-3; Wherein the values of R ¹³ may be the same or different;

q is 0-1;

r is 0-3; Wherein the values of R ¹⁴ may be the same or different;

m is 0-2; Wherein the values of R ¹⁰ may be the same or different;

n is 1-2; Wherein the values of R ⁷ may be the same or different;

z is 0-1; Wherein the values of R ²⁵ may be the same or different;

Or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.

One aspect of the invention is a compound of Formula (II),

&Lt;

At this time

M is CH ₂ or NH

R ¹ is H or hydroxy

R ² is H, CH 3, -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) ₂ ,- CH (CH ₃ ) CH ₂ CH ₃ , —CH ₂ OH, —CH ₂ OCH ₃ , —CH (OH) CH ₃ , —CH ₂ SCH ₃ , —CH ₂ CH ₂ SCH ₃ ;

It is for use in the prevention or treatment of metabolic syndrome.

In one aspect of the invention said metabolic syndrome is a disorder of fatty acid metabolism.

In one aspect of the invention the disorder of fatty acid metabolism is obesity.

One aspect of the invention is a compound of Formula (II),

&Lt;

At this time

M is CH ₂ or NH

R 1 is H or hydroxy

R2 is H, CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) ₂ ,- CH (CH ₃ ) CH ₂ CH ₃ , —CH ₂ OH, —CH ₂ OCH ₃ , —CH (OH) CH ₃ , —CH ₂ SCH ₃ , —CH ₂ CH ₂ SCH ₃ ;

It is for use in the prevention and treatment of glucose use disorders.

In one aspect of the invention, the glucose utilization disorder is a disorder involving insulin resistance.

In one aspect of the invention, the glucose utilization disorder is diabetes mellitus type 1.

In one aspect of the invention, the glucose utilization disorder is diabetes mellitus type 2.

Examples of useful materials according to the invention are as follows:

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylme Methoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines (1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine),

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxyethyl) carba Moyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 -(N-{(R) -α- [N '-((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine),

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl ] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio -8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine) ,

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thioethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines (1,1-Dioxo-3,3-dibutyl-5- phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methylthioethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro -1,2,5-benzothiadiazepine),

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (1,1-Dioxo-3,3-dibutyl-5- phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro- 1,2,5-benzothiadiazepine),

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines (1,1-Dioxo-3, 3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methylthio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine),

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines (1,1-Dioxo-3,3-dibutyl-5-phenyl -7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro- 1,2,5-benzothiadiazepine),

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2- ( R) -hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines (1,1-Dioxo -3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2- (R) -hydroxypropyl) carbamoyl]- 4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine),

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxybutyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (1,1-Dioxo-3,3-dibutyl-5- phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxybutyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro- 1,2,5-benzothiadiazepine),

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl ] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio -8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine) ,

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxypropyl) cover Moyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (1,1-Dioxo-3,3-dibutyl-5-phenyl- 7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1 , 5-benzothiazepine),

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (1,1-Dioxo-3,3-dibutyl-5- phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro- 1,2,5-benzothiadiazepine),

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines (1,1-Dioxo-3,3- dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2, 3,4,5-tetrahydro-1,2,5-benzothiadiazepine), and

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -1'-phenyl-1 '-[N'-(carboxymethyl) carba Moyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (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).

In another aspect of the invention, preferred compounds of the invention are any one of the examples or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.

Compounds of formula (I) or formula (II) may have chiral centers and / or geometric isomeric centers (E- and Z-isomers), and it It is understood to include the use of all such optical, diastereomers and geometric isomers with IBAT inhibitory activity according to the invention. The present invention is directed to any and all tautomeric forms of the compound of formula (1) having IBAT inhibitory activity.

The invention also relates to all possible isomers of the invention, especially those mentioned and possible tautomeric forms, as optical and / or geometric, pure or mixtures of all ratios of the compounds of the formulas (I) and (II).

In certain embodiments, the compounds described herein have one or more chiral centers. Commonly speaking stereoisomers are to be expected here. In various embodiments, the compounds described herein exist in optically active or racemic forms. Compounds of the invention are understood to include racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof having the pharmaceutically useful properties described herein. Preparation of the optically active form is accomplished in any suitable manner, which is by way of non-limiting examples and by resolution of the racemic form by recrystallization techniques, from the optically-active starting material By synthesis of chiral or by chromatographic separation using a chiral stationary phase. In some embodiments mixtures of one or more isomers are used as the therapeutic compound described herein. In certain embodiments, the compounds described herein include one or more chiral centers. These compounds are prepared by any means, which include enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. The resolution of these compounds and isomers is achieved by any means, which means that such chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, etc., are by way of non-limiting examples. Include.

In another aspect of the invention, preferred compounds of the invention are any one or more of pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.

One aspect of the invention relates to the prevention of metabolic syndrome, obesity, disorders of fatty acid metabolism, disorders of glucose use, disorders related to insulin resistance, comprising diabetes mellitus according to the invention and Therapeutic composition.

It is also intended for the manufacture of drugs or pharmaceutical compositions for the treatment of metabolic syndrome, obesity, disorders of fatty acid metabolism, disorders involving glucose use, disorders associated with insulin resistance, diabetes mellitus, type 1 and type 2 diabetes. To the use of a substance or composition according to the invention.

According to the invention having the formulas I and II IBAT inhibitors are one or The above magnetic field may be combined with one other active substance. The agonist may be another substance having an IBAT inhibitory effect.

Combination therapy with other agents Combination Treatment )

In certain instances, Provided herein are combination compositions and / or treatments comprising a combination comprising any compound described herein and another agent that can be an L-cell endocrine peptide enhancer ( combination) compositions and / or treatments.

In one example, The L-cell endocrine peptide enhancer is a PYY enhancer. Enhanced secretion of PYY can provide a reduction in hunger. The L-cell endocrine peptide enhancer may be an oxyntomodulin enhancer. In some embodiments, enhanced secretion of auxintomodulin inhibits meal-stimulated gastric secretion.

Another useful L-cell endocrine peptide enhancer is the GLP-1 enhancer. Examples of GLP-1 enhancers are such as GLP-1, GLP-1 secretion enhancers, GLP-1 degradation inhibitors, or a combination thereof. In certain examples, enhanced GLP-1 concentrations provide a reduction in food intake and / or a reduction in gastric emptying in human subjects.

The L-cell endocrine peptide enhancer can also be a GLP-2 enhancer such as a GLP-2, GLP-2 secretion enhancer, a GLP-2 degradation inhibitor, and the like. Or combinations thereof. According to one example, enhanced GLP-2 secretion inhibits gastric emptying and reduces intestinal permeability and / or enhanced GLP-2 secretion inhibits gastric acid secretion. Enhanced GLP-2 secretion may also reduce or prevent inflammation (gastrointestinal enteritis) in the gastrointestinal tract and / or regenerate and / or heal wounds in gastrointestinal tissues (eg, For example, radiation enteritis.

In some embodiments, the other agonist modulates bile acid receptors in the gastrointestinal lumen and / or other organs. In some embodiments, the other agonist significantly or partially agonizes bile acid receptors in the gastrointestinal tract (eg, TGR5 receptors or Farnesoid-X receptors). Another Agonist In some embodiments, the additional therapeutic agent may be a bile acid analog. In certain embodiments the additional therapeutic agent is a TGR5 agonist. Administration of a TGR5 agonist in combination with any of the compounds described herein can enhance the secretion of enteroendocrine peptides from L-cells. TGR5 modulators (eg agents) are described in WO 2008/091540, WO 2008/067219 and US Application No. Include, but are not limited to, compounds described in 2008/0221161.

In some examples, Another agonist is biguanide. Biguanides can reduce blood and / or plasma glucose levels. Examples of biguanides include, but are not limited to, metformin, phenformin, buformin, proguanil, or the like.

In some embodiments, the other agonist is selected from enteroendocrine peptides. They may reverse insulin resistance and lower blood and / or plasma glucose levels. Examples of enteroendocrine peptides include, but are not limited to, GLP-1 or GLP-1 analogs or the like, such as Taspoglutide.RTM. (Ipsen).

In another example, the other agent is Thiazolidinedione. Thiazolidinediones can reverse insulin resistance or lower blood and / or plasma glucose levels. Examples of thiazolidinediones include Rosiglitazone (Avandia), Pioglitazone (Actos), Troroglitazone (Rezulin), MCC-555, Riboglitazone, ciglitazone or ciglitazone These include, but are not limited to.

In some embodiments, the additional therapeutic agent is an incretin mimetic, which may mimic increased pancreatic response in response to ingestion of food, and in some embodiments, any of the compounds described herein Administration of incretin mimetic in combination with of lowers blood and / or plasma glucose levels. Examples of incretin mimetics include, but are not limited to, exenatide (Byetta.RTM.).

One treatment currently used for the treatment of diabetes is a subcutaneous injection of Exenatide (Byetta.RTM.). In some embodiments, an oral combination of an IBAT inhibitor and a DPP-IV inhibitor is the same or more effective than the injection of exenatide in reducing plasma glucose levels. In some embodiments, oral combinations of IBAT inhibitors and DPP-IV inhibitors reduce or eliminate the discomfort associated with injection of glucose-lowering drugs.

According to the invention the IBAT inhibitor is Can be used with DPP-IV inhibitors. In some embodiments, the other agonist inhibits degradation of L-cell enteroendocrine peptides. In certain embodiments, the other agonist is a DPP-IV inhibitor. Administration of an IBAT inhibitor to an individual in need thereof may enhance the secretion of GLP-1. Administration of a DPP-IV inhibitor in combination with an IBAT inhibitor can reduce or inhibit the degradation of GLP-1, thereby extending the therapeutic benefit of enhanced levels of GLP-1. In some embodiments, administration of an IBAT inhibitor reduces the weight of the subject. In this way, administration of an IBAT inhibitor in combination with a DPP-IV inhibitor can reduce the subject's weight.

DPP-IV inhibitors include (2S) -1- {2-[(3-hydroxy-1-adamantyl) amino] acetyl} -pyrrolidine-2-carbonitrile (vildagliptin), ( 3R) -3-amino-1- [9- (trifluoromethyl) -1,4,7,8-tetrazabicyclo [4.3.0] nona-6,8--dien-4-yl] -4 -(2,4,5-trifluorophenyl) butan-1-one (sitagliptin), (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 ( alogli ptin)).

Another standard of care for the treatment of diabetes is a combination of metformin and cytagliptin (Janumet.RTM.). At a dose of 0,3-300 mg / kg metformin in combination with 30 mg / kg of cytaglipthione, a reduction in plasma glucose concentrations is induced from 3 hours to about 6 hours after dosing. In some embodiments, the combination of IBAT inhibitor and cytagliptin maintains reduced plasma glucose concentrations for a longer time compared to the combination of metformin and cytagliptin. In some embodiments, the IBAT inhibitor treatment eliminates side effects associated with metformin treatment and / or DPP-IV inhibitor treatment.

In some examples of any of the methods described herein, administration of an ASBT inhibitor described herein, in combination with a DPP-IV inhibitor, may result in GLP of blood and / or plasma of the subject prior to administration of the IBAT inhibitor in combination with the DPP-IV inhibitor. Increase the GLP-1 level in the blood and / or plasma of an individual from about 1.5 times to about 30 times compared to the −1 level.

In some embodiments, a drug following administration of an ASBT inhibitor described herein in combination with a DPP-IV inhibitor as compared to the blood and / or plasma GLP-1 levels of an individual prior to administration of the IBAT inhibitor in combination with a DPP-IV inhibitor An increase in GLP-1 levels from 2 to about 3 times is associated with antidiabetic effects and / or reduced food intake and / or induction of satiety and / or weight loss.

In some examples of any of the methods described herein, administration of an IBAT inhibitor in combination with a DPP-IV inhibitor is compared to a reduction in glucose levels in blood and / or plasma by administration of metformin in combination with a DPP-IV inhibitor. Reduce sugar levels in the blood and / or plasma for a longer period of time (eg, at least 24 hours).

In some examples of any of the methods described herein, the administration of a single dose of a compound according to the invention in combination with a DPP-IV inhibitor may be performed in the blood following the administration of a single dose of metformin in combination with a DPP-IV inhibitor. Or reduced blood levels of blood and / or plasma when compared to a decrease in glucose levels in plasma 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 Duration for at least 30 hours, at least 36 hours or at least 48 hours.

According to one example, the administration of the IBAT inhibitor in combination with the DPP-IV inhibitor is compared to the sugar levels in the blood and / or plasma when compared to the glucose levels in the blood and / or plasma prior to the administration of the IBAT inhibitor in combination with the DPP-IV inhibitor. May reduce levels by at least 20%.

In some examples of any of the methods described herein, administration of the IBAT inhibitor in combination with the DPP-IV inhibitor is compared to glucose levels in the blood and / or plasma prior to administration of the IBAT inhibitor in combination with the DPP-IV inhibitor , Reduce sugar levels of blood and / or plasma by at least 30%, such as at least 50%, such as at least 20%, eg, at least 40%.

According to one example of the invention, administration of an IBAT inhibitor in combination with a DPP-IV inhibitor results in a higher GLP-in the blood and / or plasma of the subject as compared to the blood and / or plasma GLP-1 levels of the normal subject. Causes 1 level. In some examples of any of the methods described herein, administration of the IBAT inhibitor in combination with the DPP-IV inhibitor may be directed to GLP-1 in blood and / or plasma in the subject being treated with metformin and / or DPP-IV inhibitor. Compared to the level, it results in higher levels of GLP-1 in blood and / or plasma in the subject.

In some embodiments, the IBAT inhibitor is administered in combination with a DPP-IV inhibitor and / or biliary shunt. Biliary shunts may be selected from the shunts described in WO 2007/0050628, incorporated herein by reference. Biliary shunts may transfer bile acids into the distal ileum and / or 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. This increase in the concentration of bile acids in the vicinity of L-cells In some embodiments, the secretion of GLP-1 from L-cells, thereby reducing satiety and / or hunger and / or weight loss and / or decreasing plasma glucose levels or their To derive any combination.

Other Agonists and IBAT inhibitors are used so that the combination is present in a therapeutically effective amount. For example, IBAT inhibitors and other agonists (eg, DPP-IV inhibitors) are each used in therapeutically effective amounts. When there are additional or synergistic effects, these can be used in subclinical therapeutically effective amounts, respectively.

In some embodiments, the use of a combination of other active ingredients and IBAT inhibitors described herein may be therapeutically effective if the combined use is therapeutically effective because of their addition or synergistic effects. Present in an effective amount, and the other includes combinations when present in a subclinical therapeutically effective amount. As used herein, the term "additive effect" refers to two (or more) pharmaceutically active agents that are equal to the sum of the effects when each substance is provided alone. Indicates a combined effect. A synergistic effect refers to the combined effect of two (or more) pharmaceutical actives, which is greater than the sum of the effects when each substance is provided alone. Any suitable combination of ASBTIs with the other active ingredients described above and optionally one or more other pharmaceutically active substances is contemplated as being within the scope of the methods described herein.

Methods for experimentally determining therapeutically-effective doses of drugs and other agents for use in combination treatment regimens are described herein.

The compounds may be administered simultaneously, for example simultaneously, essentially simultaneously or within the same treatment protocol or in succession, depending on the disease, disorder or nature of the disease, the condition of the individual and the actual selection of the compound used. Can be.

The multiple therapeutic agents are optionally administered in any order or simultaneously. If at the same time, the combination therapies are optionally provided in a single, integrated form or multiple forms, such as a single pill or two separate pills. In certain embodiments one of the therapeutic agents is optionally given in multiple doses. In other examples, both are optionally given in combination doses. If not at the same time, the timing between the multiple doses may be, for example, from more than two days to less than four weeks. In addition, the combination methods, compositions and formulations are not limited to the use of only two agents. The use of a plural therapeutic shovels is also expected to include two or more of the agonists described herein.

In the combination therapies described herein, the agonists may be provided in a combined dosage form or in separate dosage forms intended primarily for simultaneous administration. In some embodiments, the active compounds are administered continuously with the therapeutic compound administered by therapy with two-step administration. In some embodiments, a two-step dosing regimen refers to continuous administration of active agents or spatially-separated administration of discrete active agents. In certain embodiments, depending on the properties of each pharmaceutical agent, such as efficacy, solubility, bioavailability, plasma half-life, and kinetic profile of the agent, from several minutes to several minutes, The time period between multiple dosing steps up to time varies.

In certain instances, the treatment of the disease (s), prevention, or treatment capacity to improve, for example, are modified according to the age, weight, sex, diet and suffer a disability objects, including the medical condition of the object. In this way, in various examples, the dosage regimen actually employed may differ from the dosage regimens described herein.

In certain embodiments, IBAT inhibitors The compounds described herein are combined with or in combination with one or more of the following: any combination of insulin, insulin-mematics, incretin mimetics, GLP-1 or analogs thereof, GLP-2 or analogs thereof, auxintomodulin, PYY, DPP-IV inhibitors, or TGR5 modulators.

The present invention also relates to IBAT inhibitors in combination with at least one bile acid binder which is a resin such as, for example, cholestyramine (cholestyramine), cholestipol and colesevelam. will be.

Bile acid  Binders ( Bile acid Metal Ion Blocker ( sequestrants ), Resins)

The following bile acid binders can be used in accordance with the present invention.

Cholestyramine hydrophilic polyacrylic quaternary ammonium anion exchange resin, which is known to be effective in reducing blood cholesterol levels, and various compositions, including cholestyramine, and cholestyramine, are described, for example, in British Patent No. . 929,391 and 1,286, 949; And US Patent Nos. 3,383, 281; 3,308, 020; 3,769, 399; 3,846, 541; 3,974, 272; 4,172, 120; 4,252, 790; 4,340, 585; 4,814, 354; 4,874, 744; 4,895, 723; 5,695, 749; And 6,066, 336. Cholestyramine is commercially available from Novopharm, USA Inc (Questrans Light), Upsher-Smith (PREVALITE (D) and Apothecon. As used herein, "cholestyramine" refers to cholestyramine, or a pharmaceutical thereof. Or any such composition that includes, in principle, acceptable salts, these are also referred to as Questrans ^™ .

Questran Light Questrans Light (cholestyramine) is an FDA-approved non-hygroscopic anionic binding resin for the treatment of anionic binding resin hypercholesterolemia.

To the first substituent that binds to the first amine of the amine polymer comprising a hydrophobic aliphatic moiety, and to the second amine of the amine polymer comprising an aliphatic quaternary amine-comprising moiety, as described in SP 5,693,675 and 5,607,669. An amine polymer having a second substituent to bond.

Salts of alkylated and crosslinked polymers comprising the following reaction products: (a) one or more crosslinked polymers, or salts thereof having repeat units selected from the group consisting of And copolymers: (NR-CH2CH2) n (2) and (NR-CH2CH2-NR-CH2CH2-NR-CH2CHOH-CH2) n (3) when n is a positive integer, each R is, independently, H Or a C1-C8 alkyl group; (b) at least one aliphatic alkylating agent, said reaction product characterized by: (i) at least some nitrogen atoms in said repeating unit not reacted with said alkylating agent; (ii) less than 10 mole percent nitrogen atoms in the repeating units reacted with the alkylating agent to form quaternary ammonium units; And (iii) fixed positive charges and one or more counter ions, such as Colesevelam and Colesevelam hydrochloride.

Suitable bile acid binders for such combination therapies are resins such as cholestyramine and cholestipol. One advantage is that the dose of the bile acid binder can be kept lower than the therapeutic dose of the cholesterol cholesterolaemia in a single treatment comprising only the bile acid binder. Any possible side effects caused by the patient's low resistance to the therapeutic dose by the low dose of the bile acid binder can also be avoided.

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

In a further aspect of the invention, a suitable bile acid binder is one of cholestyramine, cholestipol or cholesevelam.

A preferred aspect of the present invention is the use of Colesevelam as a bile acid binder.

According to a further further aspect of the present invention there is provided a combination therapy comprising the administration of an effective amount of an IBAT inhibitor compound or a pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs thereof, and bile acid binders,

The formulations are then designed to deliver the bile acid binder to the colon with simultaneous, continuous or separate administration of one or more of the following materials selected from:

Statins

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 salts or prodrugs thereof, is HMG Co-A Reductase inhibitors, or pharmaceutically acceptable salts, solvates, solvates of these salts, or prodrugs thereof. Suitable HMG Co-A reductase inhibitors, pharmaceutically acceptable salts, solvates, solvates of these salts or prodrugs thereof are statins well known in the art. Certain statins include fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin, dalvastatin, Mevastatin and (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S ), 3,5-dihydroxyhept-6-enoic acid (Rosuvastatin), or a pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs thereof. Particular statins are atorvastatin, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. More particular statin is the atorvastatin calcium salt. Further particular statins are (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxycept-6-enoic acid (Rosuvastatin), or a pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs thereof. Other specific statins are Rosuvastatin calcium salt and pitavastatin. In a further aspect of the invention, the compounds of formula (I), or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are HMG Co-A reductase inhibitors, or pharmaceutically acceptable salts , Solvates, solvates of such salts or prodrugs thereof, and / or bile acid binders can be administered, thereby avoiding possible risks of excess bile acid in the colon caused by inhibition of the ileal bile acid transport system. Excess of bile acids in the intestinal contents can cause diarrhea. In this way, the present invention also provides for the treatment of possible side effects such as diarrhea in a patient during treatment comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof. .

HMG CoA-reductase inhibitors, or pharmaceutically acceptable salts, solvates, solvates of these salts, or their prodrugs, by its action reduce endogenous cholesterol and lower lipids available for the synthesis of cholesterol available for the bile acids In combination with a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof.

A CETP (cholesteryl ester transfer protein) inhibitors such as those described and referred to in WO 00/38725, page 7-10, page 10, line 17, which are incorporated herein by reference;

Cholesterol absorption antagonists such as azetidinones, such as those described in SCH 58235 and US 5,767,115, which are incorporated herein by reference;

MTP (microsomal transfer protein) inhibitors such as those described in Science, 282,751-54,1998, incorporated herein by reference;

Fibric acid derivatives; Such as clofibrate, gemfibrozil, fenofibrate, ciprofibrate and bezafibrate;

Nicotinic acid derivatives such as nicotinic acid (niacin), acipimox and niceritrol;

A phytosterol compound such as stanols;

Probucol;

Anti-obesity compounds such as orlistat (EP 129,748) and sibutramine (GB 2,184,122 and US 4,929,629);

Antihypertensive compounds such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, adrenergic blockers, alpha adrenergic blockers, beta adrenergic blockers, mixed alpha / beta adrenergic blockers , Stimulants of adrenergic action, calcium channel blockers, diuretics or vasodilators;

insulin;

Sulphonylureas, including glibenclamide and / or tolbutamide.

Acarbose;

Or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier in a warm blooded animal such as a human being in need of such therapeutic treatment.

ACE  Inhibitors

Certain ACE inhibitors or pharmaceutically acceptable salts, solvates, solvates of these salts, or the like, including active metatabolites, which may be used in combination with the compound of formula (I) Prodrugs include, but are not limited to, the following compounds: alacepril, alatriopril, altiopril calcium, ancovenin, benazepril , Benazepril hydrochloride, benazeprilat, benzoylcaptopril, benzoylcaptopril, captopril, captopril-cysteine, captopril-glutathione, ceranapril, cerranoapril ceranopril, ceronapril, cirazapril, cilazaprilat, delapril, delapril-diacid, enalapril, enal Raff Enalaprilat, enapril, epicaptopril, foroxymithine, phosphenopril, fosfenopril, fosenopril sodium, posinopril sodium, fosinopril , Fosinopril sodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4, idrapril, imidapril ( imidapril, indolapril, indolapril, indolaprilat, ribenzapril, licinopril, lyciumin A, rishmin B, mixanpril, mother Exipril, moexipril, moexiprilat, moveltipril, murasin A, murasin B, murasin C, pentopril, perindopril ), Perindoprilat, pivalopril, pivopril, quinapril, quinapril, quinapril hydrochloride, Naprillat (quinaprilat), ramipril, ramiprilat, ramiprilat, spirapril, spirapril richloride, spiraprilat, spiraprill, spiropril, spiropril hydrochloride, temocapril (temocapril), temocapryl hydrochloride, teprotide, trandolapril, trandolaprilat, utidolapril, zabicipril, zabicipril, zabiciprilat (zabiciprilat), zofenopril and zofenoprilat. Preferred ACE inhibitors for use in the present invention are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors for use in the present invention are ramipril and ramiprilat.

Angiotensin II antagonists

Preferred angiotensin II antagonists, pharmaceutically acceptable salts, solvates, solvates of these salts or prodrugs thereof for use in combination with a compound of formula (I) include, but are not limited to: No: candesartan, candesartan cilexetil, losartan, valsartan, ilbesartan, tasosartan, telmisartan and telmisartan Eprosartan. Preferred angiotensin II antagonists or pharmaceutically acceptable derivatives thereof, especially for use in the present invention, are candesartan and candesartan cilexetil.

PPAR alpha and / or gamma and / or delta agents or pharmaceutically acceptable salts thereof.

In another aspect of the invention, the IBAT inhibitor compound, or pharmaceutically acceptable salts, solvates, solvates of such salts, or prodrugs thereof, comprises PPAR alpha and / or gamma and / or delta agents, or pharmaceutically It may be administered in combination with acceptable salts, solvates, solvates of these salts or their prodrugs. Suitable PPAR alpha and / or gamma and / or delta agents, pharmaceutically acceptable salts, solvates, solvates of these salts or prodrugs thereof are well known in the art. These are all incorporated herein by reference, 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 certain the compounds described in the patent applications listed on page 634) and compounds described in J Med Chem, 2000,43,527. In particular, PPAR alpha and / or gamma agonists include WY-14643, clofibrate, fenofibrate, benzafibrate, GW 9578, troglitazone, pioglitazone, rosiglitazone, eglitazone, proglitazone ), BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433.

Especially PPAR alpha and / or gamma agonists are (S) -2-ethoxy-3- [4- (2- {4- methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid and pharmaceutically acceptable thereof Indicates possible salts.

Diabetes drugs, hypoglycemic active ingredients, cholesterol absorption inhibitors, PPAR delta agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, polymer bile acid adsorbents, LDL receptor inducers Inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoproteins (a) antagonists, HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors Active ingredients that act on ATP-dependent potassium channels of beta cells, glycogen phosphorylase inhibitors, glucagon receptor antagonists, activin of glucokinase Activators, inhibitors of gluconeogenesis, inhibitors of fructose-1,6-bisphosphatase, inhibitors of glucose transporter 4, glutamine-fructose-6-phosphate amidotrans Inhibitors of amidasetransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of 11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosin phosphatase 1B , Modulators of sodium-dependent glucose transporter 1 or 2, modulators of GPR40, inhibitors of hormone-sensitive lipases, inhibitors of acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvate carboxykinase, Inhibitors of glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta, endothelin-A receptor antagonists, inhibitors of I kappaB kinase, glue Modulators of the cocorticoid receptor, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists , Beta 3 agonists, CB1 receptor antagonists, MSH (melaninite-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and noradrenergic Compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators , Leptin agonists, DA agonists (bromocriptine, Doprexin), lipase / amylase inhibitors, PPAR modulators, RXR modulators or TR-beta-agonists or amphetamines.

Examples of PPAR delta agonists include GW-501516 (501516, GSK-516, GW-516, GW-1516; peroxysome proliferator-activated receptor (PPAR) -delta agonists, and several developed from GW-501516 And other compounds, including GI-262570, GW-0072, GW-7845 and GW-7647.

According to one example IBAT inhibitors are Atreleuton (5-LO) Eprotirome (THR-beta), Lossapimod (p38MAPK), Ezetimibe (Ezetimibe) (SCH58235) (NPC1L1) Benzafibrate, Fenofibrate, Varespladib, (sPLA2), Darapladib, (LpPLA2), Lomitapide, Implitapide, Logiglatazone, Dalset Dalcetrapib, Anacetrapib, Lorcaserin, Dapagliflozin, Canagliflozin, Sergliflozin, ASP-1941 , Olistat, Exenatide, Liraglutide, Taspogluted, Tulaglutide, Pramlintide, Lixisenatide, Albiglutide, Fioglitazone , Sodelglitazar, Netoglitazone, Indeglitazar, Naveglitazar litazar, Lobeglitazone, Alleglitazar, Bromocriptine, Tesofensine Monoamine, Allogliptin, Bildagliptin, Saxagliptin, Citagliptin Denagliptin, Gemigliptin, Linagliptin, Dutogliptin, Tenegligliptin, LC-150444, Laropiprant Extended It can be combined with one or more of release niacin, simvastatin ezetimibe, Rosuvastatin fenofibrate, rosuvastatin ezetimibe and Atorvastatin ezetimibe.

Treaptive® (laropiprant), Vitorin® (Ezetimibe / Simvastatin) and Certriad (Rosuvastatin calcium and fenofibric acid) ) May be used in combination therapy.

In one example, the IBAT inhibitor can be combined with one or more of the aforementioned compounds.

According to one example, the IBAT inhibitor of the present invention may be combined with at least one other agonist selected from dipeptidyl peptidase-IV-inhibitors, PPAR y agents, statins and bile acid binders.

In one example, the IBAT inhibitors used in accordance with the present invention may be combined with at least one DPPIV, at least one PPAR γ agent, such as cytagliptin and Pioglitazon.

According to one example, the IBAT inhibitor used according to the invention is combined with at least one DPPIV and at least one statin, for example cytagliptin and simvastatin.

According to one example The at least one other material is Dipeptidyl peptidase-IV inhibitors such as biguanides such as cytagliptin and; Incretin mimetic, thiazolidinone, GLP-1 or analogs thereof, and TGR5 agonists. At least one other substance having an IBAT inhibitory effect is metformin and non-absorbable sodium dependent bile transport inhibitors such as 1- [4- [4-[(4R, 5R) -3,3-dibutyl- 7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothien-5-yl] phenoxy] butyl] 4-aza -1-azoniabicyclo [2.2.2] octane methane sulfonate.

The compositions of the present invention further comprise statins such as HMG Co-A reductase inhibitors, or pharmaceutically acceptable salts, solvates, solvates of such salts, or prodrugs thereof in combination with a pharmaceutically acceptable diluent or carrier. It may include.

According to one example, the present invention relates to a composition comprising one or more IBAT inhibitors of the invention and cholestyramin and / or cholesevelam and / or cholestipol.

According to one example the present invention provides compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 and cholestyramine and / or Colesevelam and And / or to a composition comprising cholestipol.

According to another example, the present invention relates to 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 5) and cholestyramine and / or colese To a composition comprising one or more of the compounds of belam and / or cholestipol.

According to another example, the present invention relates to 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S)- 1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example 13 And, and one or more of the compounds of cholestyramine and / or cholesevelam and / or cholestipol.

According to another example, the present invention relates to 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 cholesevelam And / or to one or more of the compounds of cholestipol.

The use of a substance or combination of the present invention reduces or inhibits the recycling of bile salts in the gastrointestinal tract. Bile transport inhibitors can be non-systematic and systemic compounds. They can enhance L-cell secretion of enteroendocrine peptides. In certain embodiments, increased L-cell secretion of enteroendocrine peptides is associated with induction of satiety and / or reduction of food intake and subsequent weight loss. In some embodiments, increased L-cell secretion of enteroendocrine peptides is associated with a decrease in blood and / or plasma glucose levels in an individual that is hyperglycaemic. In some embodiments, increased L-cell secretion of enteroendocrine peptides is associated with increased insulin sensitivity. The present invention relates to a method of treating obesity or diabetes, comprising contacting the terminal ileum of an individual in need thereof with an IBAT inhibitor as described herein.

In the examples of the present invention, it is brought into contact with the terminal ileum of the object as IBAT inhibitor reduces food intake, inducing satiation, reduce the serum and / or plasma glucose levels, treating a metabolic disorder, reduce weight, It can stimulate L-cells in the distal gastrointestinal tract, increase the concentration of bile acids and their salts in the vicinity of L-cells in the distal gastrointestinal tract and / or enhance the enteroendocrine peptide secretion of the individual.

In one example of the invention, the IBAT inhibitor as disclosed herein is a second agent selected from DPP-IV inhibitors, biguanides, incretin mimetic, thiazolidinedione, GLP-1 or analogs thereof, and TGR5 agonists It is administered together with.

Individuals for treatment as disclosed herein can be obese or overweight individuals, diabetic individuals or non-diabetic individuals.

The compounds and compositions as disclosed herein can be used for the treatment of obesity and / or diabetes, whereby a therapeutically effective amount of a combination of an IBAT inhibitor and a DPP-IV inhibitor is administered to a subject in need of such treatment. do. For the treatment of obesity and / or diabetes, therapeutically effective amounts of a combination of IBAT inhibitors and TGR5 agonists can be administered to a subject in need of such treatment. One example of the invention is a method of treating obesity and / or diabetes wherein a therapeutically effective amount of a combination of at least one other agonist such as an IBAT inhibitor and thiazolidinedione is administered to a subject in need of such treatment. do. Also contemplated are methods of treating obesity and / or diabetes comprising administering to a subject in need thereof a therapeutically effective amount of a combination of an IBAT inhibitor and an incretin mimic. Obesity and / or diabetes can be treated according to the invention by administering to a subject in need thereof a therapeutically effective amount of a combination of an IBAT inhibitor and GLP-1 or an analog thereof. Obesity and / or diabetes can be treated by administration to a subject in need of such treatment in a therapeutically effective amount of a combination of an IBAT inhibitor and biguanide.

The present invention further relates to a method of reducing food intake in a subject in need thereof, which comprises administering an IBAT inhibitor that is delivered or released non-systemically in the terminal ileum of the subject.

Reduction of food and calories in the subject Or induction of satiety can be performed with the methods of the present invention. As such metabolic disorders can be treated and body weight can be reduced in the subject. In some embodiments, the methods described herein stimulate L-cells of the terminal gastrointestinal tract of an individual. In some embodiments, the methods increase the concentration of bile acid and its salts in the vicinity of L-cells in the terminal gastrointestinal tract of the individual.

Circulating in the object Blood or plasma glucose levels It can be reduced as the administration of an IBAT inhibitor to the subject, wherein the IBAT inhibitor is delivered or released non-systemically in the terminal ileum of the subject.

In addition, insulin secretion can be increased in a subject comprising administration of the IBAT inhibitor, wherein the IBAT inhibitor is delivered or released non-systemically in the terminal ileum of the subject.

In the examples of the invention Wherein the enteroendocrine peptide is for example GLP-1, GLP-2, PYY, auxintomodulin, or a combination thereof, and the methods described herein enhance enteroendocrine peptide secretion.

The terminal ileum of an individual can be tailored in contact with an IBAT inhibitor, and the blood and / or plasma GLP-1 levels of the individual are determined in the blood and / or plasma of the individual prior to contact with the terminal ileum of the individual and the IBAT inhibitor. It can be increased from about 2 times to about 7 times the GLP-1 level.

In embodiments of the invention, contacting the IBAT inhibitor with the terminal ileal of the subject is at least 20%, at least 30%, or as compared to glucose levels in the blood and / or plasma of the subject prior to contacting the BAT inhibitor with the terminal ileal of the subject or At least 40%, to reduce the blood and / or plasma glucose levels in the individual. This reduction may be maintained for at least 12 or at least 24 hours as compared to glucose levels in the blood and / or plasma of the subject prior to contacting the IBAT inhibitor with the terminal ileum of the subject.

IBAT inhibitors as described herein may be administered orally as ileal release agents that deliver IBAT inhibitors to the terminal ileum, colon and / or rectum of an individual. In some embodiments, the IBAT inhibitor is administered as an enterically coated formulation.

In some examples as described above, the IBAT inhibitor is a compound of Formula I or Formula II as described above.

The compounds and compositions used in accordance with the present invention may be administered less than about 30 minutes or less than about 60 minutes prior to ingestion of food. They may also be given after ingestion of food.

Inflammatory bowel disease, impaired bowel condition, short bowel syndrome, gastritis, gastric ulcer, or irritable colon, comprising contacting an IBAT inhibitor with the terminal ileum of an individual in need thereof For prevention and / or treatment of syndrome, congestive heart failure, ventricular dysfunction, toxic hypervolemia and / or polycystic ovary syndrome . In some embodiments, the methods further comprise administration of a DPP-IV inhibitor, a TGR5 agonist, biguanide, incretin mimetic, or GLP-1 or an analog thereof. Provided herein are methods of radiation prophylaxis and / or treatment comprising contacting an IBAT inhibitor with the terminal ileum of its individual. In some embodiments, the methods further comprise administration of a DPP-IV inhibitor, a TGR5 agonist, biguanide, incretin mimetic, or GLP-1 or an analog thereof.

The compounds and compositions as described herein can be used to reduce calorie intake in a subject, wherein the IBAT inhibitor as described herein is delivered or released non-systemically in the terminal ileum of the subject. In this way, compositions for reducing circulating blood and / or plasma glucose levels in an individual may comprise an IBAT inhibitor, and a pharmaceutically acceptable carrier, wherein the IBAT inhibitor is delivered non-systemically in the terminal ileum of the individual. do. Provided herein are compositions for increasing insulin secretion, which include an IBAT inhibitor, and a pharmaceutically acceptable carrier, wherein the IBAT inhibitor is delivered or released non-systemically in the terminal ileum of an individual. In any of the examples mentioned above, the compositions may further comprise a DPP-IV inhibitor, a TGR5 agonist, biguanide, incretin mimetic, or GLP-1 or an analog thereof.

In some embodiments the IBAT inhibitors and compositions comprising them are used for reducing food intake (calorie intake) or for reducing circulating blood or plasma glucose levels, wherein the IBAT inhibitor is a system after oral administration. It is not absorbed. In some of these examples, the IBAT inhibitor is prevented from being absorbed in the stomach by its presence in the formulation that releases it in the ileum. In some of these examples, the IBAT inhibitor is administered in combination with a second therapeutic agent selected from a DPP-IV inhibitor, biguanide, thiazolidinedione, incretin mimetic, GLP-1 or an analog thereof, or a TGR5 agonist .

According to one example, the present invention relates to IBAT inhibitor compounds or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs and / or bile acid binders or pharmaceutically acceptable salts, solvates, solvates of such salts. Or a combination oral pharmaceutical formulation comprising a prodrug thereof, wherein the formulation is designed to deliver the IBAT inhibitor to the bile acid binder and the small intestine in the colon, wherein the combined formulation is the IBAT inhibitor and It is intended for simultaneous, separate or continuous administration of the bile acid binder.

In one example The acid binder is It is made of a separate formulation with the IBAT inhibitor formulation that releases the drug immediately or delayed in the terminal jejunum or proximal ileum and the bile acid binder formulation that releases the drug in the colon.

In one example, the formulation comprises a core comprising a bile acid binder made for release in the colon, surrounded by an outer layer comprising an IBAT inhibitor, and for immediate release or delayed release in the terminal jejunum or proximal ileum. (core).

Pharmacologic and Pharmaceutical Use of the Invention

According to another feature of the invention Provided are oral pharmaceutical preparations comprising IBAT inhibitor compounds or pharmaceutically acceptable salts, solvates, solvates of such salts, or prodrugs and bile acid binders thereof, wherein the preparations inhibit IBAT in warm blooded animals, such as humans It is designed to deliver a bile acid binder to the colon for use in the production of effects.

According to another feature of the invention Oral pharmaceutical preparations comprising an IBAT inhibitor compound or a pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs and bile acid binders thereof and at least one of the other active compounds mentioned above and bile acid binders disclosed herein An agent is provided, wherein the agent is designed to deliver a bile acid binder to the colon for use in the prevention or treatment of any of the medical indications mentioned herein in a warm blooded animal, such as a human.

According to another feature of the invention there is provided an oral pharmaceutical preparation comprising an IBAT inhibitor compound or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug and bile acid binder thereof, wherein the preparation is a human In warm-blooded animals such as is designed to deliver a bile acid binder to the colon for use in the prevention or treatment of any of the medical indications mentioned herein.

According to another feature of the invention there is provided at least one of an IBAT inhibitor compound or a pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs and bile acid binders thereof, and other active compounds mentioned above and Oral pharmaceutical formulations are provided comprising a bile acid binder, wherein the formulation is designed to deliver a bile acid binder to the colon for use in the prevention or treatment of any of the medical indications mentioned herein in a warm blooded animal, such as a human. do.

According to another feature of the invention Provided are oral pharmaceutical formulations comprising an IBAT inhibitor compound or a pharmaceutically acceptable salt, solvate, solvate of such salts, or prodrugs and bile acid binders thereof, wherein the formulation is used herein in a warm blooded animal, such as a human It is designed to deliver a bile acid binder to the colon for use in the manufacture of a pharmaceutical for use in the prophylaxis or treatment of any of the mentioned medical indications.

According to another feature of the invention IBAT inhibitor compounds or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs and bile acid binders thereof, and at least one of the other active compounds mentioned above and bile acid binders as disclosed herein Oral pharmaceutical formulations are provided wherein the formulation delivers a bile acid binder to the colon for use in the manufacture of a pharmaceutical for use in the prevention or treatment of any of the medical indications mentioned herein in a warm blooded animal, such as a human. It is designed to.

In one embodiment of the invention, such as a human, provided in a warm-blooded animal, method of any of the treatment of a medical disease mentioned herein is, thus IBAT inhibitor compound or a pharmaceutically acceptable salt, solvate, of such salts the solvent Effective amounts of the compounds or their prodrugs are administered simultaneously, continuously or separately, in combination with effective amounts of bile acid binders to the subject in need of such treatment.

In one embodiment of the invention, provided with a human and the like, of any of the treatment of a medical condition referred to herein in a warm-blooded animal, method and, thus IBAT inhibitor compound or a pharmaceutically acceptable salt, solvate, such salts solvates Or an effective amount of their prodrugs, and at least one of the other active compounds mentioned above, is administered simultaneously, continuously or separately, in combination with an effective amount of a bile acid binder to the subject in need of such treatment.

Formulations ( Dosage form )

Pharmaceutical compositions can be made as a dosage form. The formulations may comprise a compound of formula I or a compound of formula II for proper administration to a subject.

Suitable formulations are, by way of non-limiting examples, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral formulations, aerosols, controlled Release formulations, melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees Capsule capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations. do.

Pharmaceutical solid dosage forms include additional therapeutic compounds as described herein and compatible carriers, binders, fillers, suspensions, flavors, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers Optionally including one or more pharmaceutically acceptable additives such as wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoams, antioxidants, preservatives, or one or more combinations thereof can do. In some aspects, film coating is provided around the formulation of a compound of Formula (I) or Formula (II) using a standard coating process, such as described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one example, the compound as described herein is in a form in which some or all of the particles or particles of the compound are coated. In certain embodiments, some or all of the particles of the compound as described herein are microencapsulated. In some examples, particles of a compound as described herein are not microencapsulated and not coated. Pharmaceutical compositions can be made as known in the art using one or more physiologically acceptable carriers, which, for example, allow processing into preparations suitable for pharmaceutical use of the active compounds. Additives and auxiliaries. In certain embodiments, the appropriate formulation is dependent upon the route of administration chosen. An overview of pharmaceutical compositions and carriers is described, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical formulations, Marcel Decker, New York, NY, 1980; And Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

The pharmaceutical preparations may be administered orally, parenterally (eg, intravenously, subcutaneously, intramuscularly), intranasally, buccal, topical, rectal, by way of non-limiting examples. The subject is administered to the subject in any manner, including one or more of multiple routes of administration, such as rectal, or transdermal routes of administration.

IBAT inhibitors of formula (I) or formula (II) are used in the manufacture of medicaments for the prevention and / or therapeutic treatment of obesity and / or diabetes. In a subject in need of such treatment, the method of treating any of the diseases or disorders described herein may be administered to the subject in therapeutically effective amounts of at least one IBAT inhibitor described herein, or a pharmaceutically acceptable Administration of pharmaceutical compositions comprising a salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate thereof.

Formulations that allow for controlled release of active agents in terminal jejunum, proximal ileum, terminal ileum and / or colon are also within the scope of the present invention. In some embodiments, the formulation comprises a polymer that is pH sensitive, eg, an MMX® matrix from Cosmo Pharmaceuticals, which allows for controlled release of the active agent in the ileum and / or colon. Examples of such pH sensitive polymers suitable for controlled release are polyacrylic polymers (eg anionic polymers of methacrylic acid and / or methacrylic acid esters, eg acidic groups (eg- COOH, -SO3H) and swell at the intestinal basic pH (e.g. pH of about 7 to about 8), including Carbopol.® polymers Cas number 9063-87-0; 600-07-7 It is not limited to this. In some embodiments, formulations suitable for controlled release in terminal ileum include microparticulate active agents (eg micronized active agents). In some examples, the non-enzymatically degrading poly (dl-lactide-co-glycolide) (PLGA) core is suitable for delivery of IBAT to the terminal ileum. In some embodiments, formulations comprising IBAT may be enteric polymers (eg, Eudragit.® S-100, Cas number 25086, for site specific delivery to the ileum and / or colon. -15-1), cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, anionic polymers of methacrylic acid, methacrylic acid esters or the like). In some embodiments, bacterially activated systems are suitable for targeted delivery to the ileum. Examples of micro-flora activated systems include glycoside conjugates (eg, conjugates of pectin, galactomannan, and / or Azo hydrogels and / or active agent). Formulations comprising D-galactoside, beta-D-xylopyranoside or the like). Examples of gastrointestinal micro-flora enzymes include, for example, D-galactosidase, beta-D-glucosidase, alpha-L-arabinofuranosidase, beta-D-xylpyranosidase bacterial glycosidases, such as xylopyranosidase or the like. Coated The units may be filled into hard gelatin capsules or mixed with tablet additives such as fillers, binders, disintegrants, lubricants and other pharmaceutically acceptable additives. Can be compressed into tablets. The compressed tablet is optionally covered with a film former to obtain a smooth surface of the tablet and further enhance the tablet's mechanical stability during packaging and transportation. Such tablet coatings, which may be applied to multiple unit tablets or conventional tablets, may include additives such as anti-tacking agents, colorants and pigments or other additives to improve tablet appearance. Can be.

According to the invention The combination therapy should preferably include the administration of concurrent, isolated or continuous IBAT inhibitor compounds and bile acid binders. The IBAT inhibitor may preferably be made for ileal delivery, and the bile acid binder may preferably be an agent for colonic release.

Volume( Dosage )

Appropriate unit doses of the IBAT inhibitor compounds of Formula I or Formula II vary with regard to the weight, condition, and severity of the disease of the patient. The dose also depends on the route of administration and whether it is used for prophylaxis or treatment. The daily dose may be administered as a single dose or divided into one, two, three or more unit doses. The daily dose administered orally of the IBAT inhibitor is preferably within 0.1-1000 mg, more preferably 1-100 mg.

Pharmaceutical formulations according to the invention with targeted delivery to the gastrointestinal tract provide for reduced systemic exposure, as measured by, for example, a decrease in serum cholesterol, which maintains or even increases the therapeutic effect, while As measured by plasma concentration versus time curve (AUC) bottom region or 7α-hydroxy-4-cholsten-3-one (C4).

Combinations comprising IBAT inhibitors and bile acid binders may include low daily amounts of bile acid binders, such as up to 5 g, more preferably up to 2 g of resin. Formulations with colonic release of bile acid binders can be made by any of the above principles for delayed release formulations.

Combinations comprising IBAT inhibitors and bile acid binders may comprise low daily amounts of bile acid binders, such as up to 5 g, more preferably up to 4 g, up to 3 g, or up to 2 g or up to 1 g of the resin. have. Suitable daily doses of bile acid binders may be 0.1-5 g, 0.5-4 g, 1-3 g, 2-4 g, 2-3 g. Formulations with colonic release of bile acid binders can be made by any of the above principles for delayed release formulations.

The tablet may contain 1-1000 mg, for example 200-800 mg, 50-400 mg, 10-200 mg or 20-80 mg of the inner binder of the acid binder and 1-100 mg, 5-50 mg in the colon delivery formulation. For example, an outer lamina with 1-20 mg of the IBAT inhibitor as described herein.

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

The IBAT inhibitor can be administered once a day and the acid inhibitor once, twice or three times a day. In one example, the IBAT inhibitor and the bile acid binder are administered in combination once, twice or three times a day.

In one example of the present invention, the bile acid binder is Colesevelam.

The recommended daily total dose of Colesevelam to block bile acid absorption in human gut can be up to 3750 mg / day.

The invention also relates to a method of treating and / or preventing obesity or diabetes in a warm blooded animal, such as a human, whereby an effective amount of a compound, composition or combination described herein is directed to a subject in need of such treatment and / or prevention. Administered.

A method of treating any of the diseases or disorders described herein of an individual may comprise at least one IBAT inhibitor, or a pharmaceutically acceptable salt, as described herein, in a therapeutically effective amount for said individual. Administration of a pharmaceutical composition comprising an acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate thereof.

Furthermore, the present invention also relates to the kit instructions for use and optionally comprising a compound or composition according to the invention.

Of other useful compounds of the invention Examples

All references described herein are incorporated herein by reference in their entirety.

The expression "comprising" as used herein is to be understood to include, but not limited to, the items mentioned.

Example  One

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylme Methoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines, Mw. 696,89.

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

Example  2

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxyethyl) cover Moyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine, Mw. 709,92.

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

Example  3

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl ] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines, Mw. 724,94.

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

Example  4

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thioethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines, Mw. 757,01.

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

Example  5

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines, Mw. 740,94.

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

Example  6

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines, Mw. 773,00.

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

Example  7

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines, Mw. 738,97.

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

Example  8

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2- ( R) -hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines, Mw. 756,94.

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

Example  9

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxybutyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines, Mw. 754,97.

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

Example  10

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl ] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines, Mw. 710,91.

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

Example  11

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxypropyl) cover Moyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine, Mw. 739,95.

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

Example  12

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines, Mw. 726,91.

This compound is prepared as described in Example 11 of WO3022286.

Example  13

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines, Mw. 754,97.

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

Example  14

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -1'-phenyl-1 '-[N'-(carboxymethyl) carba Moyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine, Mw. 695,90.

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

Example  15 Pharmaceutical Effect Average Inhibitory Effect (%)

ISBT Hu HEK Intake SPA 13203 IBAT HUM President Bile Acid Transporter Human HEK Glycocholic Acid Intake Radiation-SPA Inhibitor IC50 Average IC50 (nM) was determined for the compounds of Examples 1-14 .

Test system

Animals:

Species mice; Strain ApoE knock out; Substrain C57BL / 6; Sex females; Total number of animals 70; Body weight range 20 g to 22 g; Supplier Mollegaard's Breeding (Skensved, Denmark); Recognition method ID cards (bar code).

Adaptation : at least one week in the laboratory section; Animal AstraZeneca's Resource; Breeding conditions: Keep 5 in cage (Makrolon III, 7 dm 2) Relative humidity (40% to 60%) and 12/12 hours light / dark cycle in a room with controlled temperature (22 ° C.). Diet: Free access to R3 pellets (Lactamin, Vadstena, Sweden) during breeding and experimentation. Water: Free access to tap water during breeding and testing.

Experimental procedure

remind Animals were treated with vehicle (n = 3) or the compound of Example 14 (0.156 (n = 3), 0.625 (n = 3) or 2.5 μmol / kg (n = 3) at 13:00 on the day of the experiment). ) Orally. After 30 minutes, a trace amount of 75SeHCAT (75Se-homo-tauro-cholic acid) (0.1 mCi per 0.1 mL per mouse) was given orally to each mouse. 24 hours after 75SeHCAT administration, the animals were killed by CO 2 inhalation. At the time of sacrifice, the gallbladder and total intestines were removed and feces were collected for each mouse for 24 hours after 75SeHCAT administration. Gamma radioactivity of 75SeHCAT in the feces and gallbladder-intestine was counted separately by a 1282 CompuGamma CS gamma counter (Wallac oy, Turku, Finland). Stability, including the amount of 75SeHCAT administered to each mouse, was controlled with additional 75SeHCAT subsamples following the same experimental procedure as the other tested samples in the study.

Data Analysis

The sum of gamma counts from both the stool and the gallbladder-intestine was thought to be a total recovered 75SeHCAT, which averaged about 85% of the total 75SeHCAT administered to each mouse. Of the recovered radioactivity of 75SeHCAT, the percentage of 75SeHCAT detected in the stool was considered to be the excretion of feces against it in the gallbladder-intestine as body retention. The inhibitory activity of the compound of Example 14 for absorption of 75SeHCAT intestines was calculated according to the 75SeHCAT body retention and excretion of the excretion, and the ED 50 of the compound was estimated according to the dose-effect curve.

Results

Dose (μmol / kg): Average% IBAT inhibitory activity at 0.156 was determined for the compounds of Examples 1-14 and is reported in Table 1.

Example  16

Interruption of the bile acid circulation by inhibition of the bile acid transporter Slc 10a2 improves triglyceride metabolism and normalizes plasma glucose levels.

Experimental methods

Animals

Slc10a2 +/- and Slc10a2-/-mice are described below and described in Dawson, Haywood, Craddock, Wilson, Tietjen, Kluckman, Maeda Parks. Made in AstraZeneca R & D, Molndal, as described in J Biol Chem 2003; 278: 33920-7.

Slc10a2  Locus Targeted

mouse The targeting vector used to modify the Slc10a2 locus was a friendly gift from P. Dawson, previously described by Dawson et. Al 2003. In short, it is an inverted Neo (neomycin phosphotransferase) cassette that is driven off from the phosphoglycerate kinase (PGK) promoter to the ~ 14kb 5 'homology arm and the 1.6kb 3' homology site. It is composed. The targeting vector has the correct targeting of Intron 2, Exon 3, Intron 3, and the Slc10a2 gene (see FIG. 1A). B, BamHI; H, designed to cause most of its 5 'end of exon 4 replaced by the Neo cassette to inactivate HaeIII. After linearization the targeting construct was electroporate into R1 ES cells, and neomycin-resistant clones were collected in G-418-containing (300 μg / ml) medium. Of the 400 G418-resistant clones screened, two targeted clones were identified using PCR screening for the short arm and then confirmed by Southern analysis. The primers used for the detection of the target allele are forward primers located in the inverted Neo cassette and reverse primers located downstream of the forearm (5'-cgtactggggcatagaatctttgc-3 '). It was. The same reverse primer was combined with forward primers of intron 3 (5'-ctcttcctatgaagctaaaggggc-3 ') for detection of wild type alleles. One positive clone was expanded and injected into C57Bl / 6 blastocysts to create chimeric mice. Chimeric males were backcrossed with C57Bl / 6 females, and the genotypes of offspring were performed from tail biopsies by PCR and Southern. To confirm that the target SLC10A2 allele caused a null mutation, the entire RNA was 8-10 weeks old homozygous, heterozygous using TRIzol Reagent according to the manufacturer's instructions (Invitrogen, Paisley, UK). (heterozygous), and kidneys and intestines of wild type litters. cDNA was synthesized using Super-script II Rnase H-Reverse Transcriptase and random hexamer primers (Invitrogen, Paisley, UK). TaqMan real-time PCR using ABI PRISM 7700 Sequence Detector system (Applied Biosystems, Warrington, UK) This was done. All samples were performed three times and data were normalized using mouse acidic ribosome phosphoprotein PO (M36B4) as an internal control. The TaqMan primers and probes for SLC10A2 are: 5'-accacttgctccacactgctt-3 '(forward), 5'-acccacatcttggtgtagacga-3' (reverse) and 5'-ccttggaatgatgcctctttgcctc-3 '(probe).

A diet enriched in sucrose (D12329, Research Diets, NJ) with drinking water supplemented with 10% fructose was used for high carbohydrate experiments. Animals had free access to a two week diet. Control animals receiving standard mouse food and tap water. Male ob / ob animals were from Taconic, DK. Ob / ob animals were gavaged for 11 days with specific Slc10a2 inhibitors, compounds of Example 14 or control vehicles. Animals had free access to food and water. All animal care and experiments were performed in accordance with the standards of humane animal care approved and accepted by the Ethics Committee of the University of Goteborg.

Plasma analysis

Blood is centrifuged, and the plasma is compared to total cholesterol and trisleyides (TGs) using IL TestTM Cholesterol 181618-10 and TG 181610-60 kits from the Monarch 2000 system (IL Scandinavia, Gothenburg, Sweden). Analyzed. Lipoprotein cholesterol profiles were obtained by separation of 10 μl of plasma using a micro fast protein liquid chromatography (FPLC) system to make lipoprotein profiles 15. Plasma insulin levels were analyzed using the Rodent Insulin RIA Kit (Linco, St. Charles, MI). Total plasma glucose was analyzed using the IL test (IL Scandinavia, Gothenburg, Sweden) on the Monark 2000 system. Blood glucose was determined using a Bayer Elite Glucometer (Bayer diagnostics, Germany). Plasma free fatty acids were analyzed using a commercial 3 NEFA kit (Wako Chemicals USA Inc. Richmond, Virginia). Serum levels of 7α-hydroxy-4-cholesten-3-one (C4) were used as an indirect measure of CYP7A1 activity and analyzed in collected or individual plasma samples by high pressure liquid chromatography.

Enzymatic  Active

HMGCoA reductase and CYP7A1 enzymatic activities were analyzed in liver microsomes as described.

RNA  Extraction and Quantitative Real-time PCR

Total RNA was extracted from frozen livers or terminal ileum using TRIzol reagent (Invitrogen, Carlsbad, Calif.). The RNA was DNase-treated with RQ1 Dnase (Promega, Madison, Wis.).

cDNA synthesis and quantitative real-time PCR were performed with HPRT as endogenous control (18). Primer and probe information is available on request.

Liver protein and Immunoblotting

Ligand blots using 125I-labeled rabbit β-VLDL are described in Rudling, Norstedt, Olivercrona, Reihner, Gustavsson, Angelin. Proc. Natl. Acad. Sci. USA 1992; 89: 6983-7, was used to detect liver LDL receptors. SR-BI between Galman, Angelin, Rudling. Analysis was by immunoblot using rodent specific rabbit polyclonal antibodies (Novus Biologicals Inc., Littleton, CO) as described in Endocrinology 2002; 143: 1809-16. Cyp7a1 protein levels were determined by CYP7A1 Lundasen, Liao, Angelin, Rudling. J. Biol. Chem. 2003; 278: 43224-43228) were analyzed in protein samples of liver microsomes by immunoblot using rabbit polyclonal antibodies directed against the C-terminus. To detect the SREBP1 protein, cytoplasmic and nuclear protein preparations of the liver were prepared according to the manufacturer's instructions: Complete protease inhibitor (Roche), 1 mM phenyl-methylsulfonyl fluoride, 0.5 mM leupetin, 5 μg / ml carpa It was carried out using a phosphate inhibitor I (Biomol, NE-PER reagent (Pierce), including PA.) 50 μg and 25 μg of liver and protein fractions of the cytoplasm and nucleus, respectively, were found in NuPage Bis-Tris gels (Invitrogen). Were electrophoresed and transported to nitrocellulose membranes, the membranes were blocked with 5% skim milk powder and the N 'of SREBP1 at 1.5 μg / mL in 5% skim milk powder at room temperature for 2 hours. -HRP conjugated goat anti-mouse F (ab) 2 antibody (Pierce) was incubated with the raised mouse monoclonal antibody against the end (Labvision Corporation, CA). Supersignal reagent (Pierce) and Fuji BAS 1800 analyzer (F uji Photo Film Co.) Total liver protein homogenates were frozen by homogenization using polytron to analyze liver proteins phosphorylated by Western blot. Prepared from tissue, then 20 mM Tris-HCl, pH 7,4, 1% Triton X-100, 10% glycerol, 150 mM NaCl, 2 mM EDTA, 25 mM betaglycerophosphate, 20 mM sodium fluoride, 1 mM sodium orthovanadate, 2 mM sodium pyrophosphate, 1 mM benzamidine, 1 mM phenyl-methylsulfonyl fluoride, 0.5 mM leupeptin, complete proteinase inhibitor (Roche) Sonicate in buffer and then centrifuge at 14000 rpm in microcentrifuge and recover the supernatant. 50 μg protein was loaded onto NuPage Bis-Tris gels (Invitrogen) and transported to nitrocellulose membranes. The membranes were blocked in Starting Block-PBS (Pierce), and incubated in + 4C overnight at + 4C, incubated in 3% BSA with phosphorylation site specific antibodies, pAkt1, pErk1 / 2, pMek1 / 2, pAmpk, It is then stripped with Restore (Pierce), reprobed with antibodies that detect the total amount of Akt1, Mek1 / 2, Erk1 / 2, and Ampk, finally removed, and gel loading Reprobe with antibody against beta-actin (Abcam) to confirm. Antibodies against kinases were purchased from Cell Signaling Technology, Inc. Blots were developed as described above.

liver TGs  And determination of cholesterol

Liver cholesterol was determined as described above, and liver TGs were determined using an extracted and commercially available kit (Roche Applied Science, Indianapolis).

Statistics

Data shows mean +/- SEM. The significance of the differences between the groups tested was tested with 1-way ANOVA and post-hoc comparisons according to Dunnett using GraphPad PrismSoftware. The importance between groups for the study on ob / ob mice was tested by Student's t-test.

Results

Slc10a2 -/-Mice Making

The making of Slc10a2-/-mice was performed as detailed in the FIG. 1 experimental methods. Southern blotting, quantitative real-time PCR and immunoblotting confirmed adequate targeting and lack of Slc10a2 expression in null mice (FIG. 1 and not shown). Slc10a2-/-animals are viable and fertile. Abnormalities in behavior, overall appearance, or survival were not seen and were consistent with those previously recorded in Dawson et al. 2003.

cock Slc10a2 +/- and Slc10a2 -/-On mice Increased BA  synthesis

A recognized response to disrupting the enterohepatic circulation of bile acids (Bas) is the induced synthesis of BAs (2,6-8,22). Indeed, there was ˜7-fold induction in Slc10a2-/ − mice when rate-limiting enzymes in liver mRNA levels for CYP7A1, synthesis of BAs, were analyzed by quantitative real-time PCR (qrtPCR) (FIG. 2A). There was also a clear but less pronounced (˜3-fold) increase in CYP7A1 mRNA in Slc10a2 +/− mice. When tested in collected microsomes, consistent with CYP7A1 mRNA increase, the enzymatic activity and the many proteins of CYP7A1 were higher in both Slc10a2 +/− and − / − mice (FIGS. 2B and 2C). The CYP7A1 reaction product 7α-hydroxy-4-cholsten-3-one (C4) present in blood serum has been demonstrated as an accurate marker of CYP7A1 enzyme activity (16). Analysis of serum collected from both heterologous and homozygous animals showed higher serum C4 levels when compared to control animals (FIG. 2D). With the observed increase in CYP7A1, mRNA levels for 12 alphahydroxylase, CYP8B1, were also dose dependently induced (FIG. 2E). When the circulation of BAs is disturbed, the amount of available ligand of BA receptor FXR in the liver nucleus decreases. Along with this, reduced liver mRNA levels of the FXR target gene, Small Heterodimer Partner (SHP), and a suppressor of CYP7A1 gene transcription were found in heterologous and homozygous mice with the most dramatic changes in the latter group. (Fig. 2F).

Slc10a2 +/- and Slc10a2 -/-Lowered Plasma in Mice TGs

Plasma total TGs were up to 22% in Slc10a2 +/− mice compared to controls and Significantly decreased by 35% in Slc10a2-/-mice (FIG. 3A). The plasma cholesterol and TG lipoprotein profiles were then analyzed by Fast Perform Liquid Chromatography (FPLC) (FIGS. 3B and C). The plasma cholesterol profiles did not differ significantly between controls and isotype animals. However, larger changes were found in the plasma TG profiles of these mice (FIG. 3C). In Slc10a2 +/- mice, TGs were reduced in LDL, whereas in Slc10a2-/-mice, TGs were decreased in both VLDL- and LDL (FIG. 3C). Plasma glucose and insulin, however, did not change in the Slc10a2-/-animals of this experiment (not shown).

BA  Adaptation of Liver Cholesterol Metabolism to Deficiency

There was no change in liver expression of the LDL-receptor or the HDL-receptor SR-BI at either mRNA n and protein levels (data not shown). The increased demand of cholesterol as a substrate for CYP7A1 in the livers of Slc10a2 +/- and Slc10a2-/-mice, based on the analysis of samples of collected microsomes, with a 2-fold increase in heteromorphism and a 3.5-fold increase in homologous animals, It was reflected in the increased enzymatic activity of HMG CoA reductase in the liver (FIG. 3D). The increase in hepatic HMGCoA reductase mRNA levels had a similar pattern, although small differences were observed between groups (FIG. 3D). Gene expression of the sterol transporters ABCG5 and ABCG8 in the liver was inhibited by 50% in a gene-dose dependent manner (FIG. 3E). Following the discovery of HMG CoA reductase, the liver levels of SREBP2 mRNA increased in both Slc10a2 +/- and Slc10a2-/-mice (FIG. 3F). Interestingly, the regulation of the SREBP1c gene in the liver showed the opposite pattern, with reduced mRNA levels in heterologous and homozygous mice compared to the controls, in a gene-dose dependent manner (FIG. 3F).

Liver TG  Production SLC10A2 Inhibited in mice

To further explore TG metabolism in this animal model of BA uptake, to increase substrate availability, for two weeks, the Slc10a2-/-and wt control animals received a sucrose-rich diet (SRdiet), Animals received food as a control. There was no significant difference between Slc10a2-/-and each wt control group in any of the diet types used, neither in plasma glucose, insulin or food intake (data not shown). Similarly, densitometric x-ray analysis (DEXA) showed no significant changes in the body composition of Slc10a2-/-animals when compared to wt controls (not shown). The liver TG content tended to be lower in Slc10a2-/-mice fed regular chow (FIG. 4A). This difference was even more evident in the SR diet; In wt animals hepatic TGs increased by 120%, whereas in Slc10a2-/-animals this increase was blunted (FIG. 4A). In addition, liver cholesterol was lower in Slc10a2-/-mice fed the SR diet compared to wt controls fed this diet (FIG. 4A). Because lower liver TG levels in Slc10a2-/-mice may be due to decreased fatty acid synthesis, mRNA levels of ACL, ACC, FAS and SCD1 by qRT PCR were measured. Gene expression of these enzymes was reduced in livers of Slc10a2-/-animals (FIG. 4B); This finding was more pronounced when animals were challenged with the SR diet. The transcription factor SREBP1c is critical for optimal activation of most genes of fatty acid synthesis pathways 23. Protein expression of SREBP1c (mature and precursor forms) was reduced in Slc10a2-/-mice, as assessed by Western blot for protein fractions of the cytoplasm and nucleus with antibodies to the N'-terminus of SREBP1c (FIG. 4C).

BA  Circulation chaos disruption ) Is Glucose  Manipulation changes the expression of related genes

TG synthesis in the liver depends on the substrate flow of the glycolytic pathway, and in this way the activity and gene expression of glucose metabolizing enzymes. MRNA levels of hepatic glycolytic enzyme glucokinase (GK) did not change in Slc10a2-/-animals compared to wt controls of both food and SR diets (FIG. 4D). However, mRNA levels of liver pyruvate kinase (LPK) were reduced by 30% in Slc10a2-/-for chow (FIG. 4D). Interestingly, feeding the SR diet in Slc10a2-/-mice results in 4.3-fold upregulation of LPK mRNA from basal levels, and in modal 1.8-fold stimulation under the same conditions in wt control animals. There was this. The determination of the NADPH generating enzyme glucose-6-phosphate dehydrogenase (G6PDH) mRNA was increased in Slc10a2-/-animals as compared to the normal (normal) food wt mice. (Fig. 4E). Feeding the SR diet resulted in a 3-fold increase in G6PDH mRNA in wt mice whereas only a minor 60% increase in Slc10a2-/-mice (FIG. 4E). Therefore, it was interesting to determine whether the gene expression of the malic enzyme (ME), and also the portion of the NADPH generating step that converts malate to pyruvate, was altered in Slc10a2-/-livers. Degree. As shown in 4E, ME mRNA tended to decrease in Slc10a2-/-mice, the usual food, and increased to a similar degree in wt and Slc10a2-/-animals during the SR diet.

ob Of ob  In mice Slc10a2 Suppression of Increased  Liver FGF21 mRNA With plasma glucose and TGs Decreases.

Although serum glucose in Slc10a2-/-mice did not change, these animals were hypolipidemic. Therefore, it was evaluated whether beneficial effects could be obtained in ob / ob mice, a model in which chronically elevated plasma glucose and TGs were elevated. Ob / ob mice were treated with specific Slc2a10 inhibitors or compounds of Example 14 for 11 days. Fasting levels of glucose were reduced by 30% in drug-treated ob / ob mice compared to vehicle treated animals (FIG. 5A). Similarly, this treatment reduced fasting insulin levels by 50% in drug-treated animals. In addition, the total plasma TG levels decreased by 73% in the drug-treated controls, whereas total plasma cholesterol tended to increase slightly (16%) (FIG. 5B). It was previously discovered that mRNA levels of the hormone FGF21 in ob / ob livers increased 10-fold, compared to that of wt animals. Lundasen, Hunt, Nilsson, Sanyal, Angelin, Alexson, Rudling. 2007 Biochem. Biophys. Res. Commun 2007; 2: 437-440). In addition, administration of exogenous FGF21 reduces serum TGs, insulin and glucose Kharitonenkov, Shiyanova, Koester, Ford, Micanovic, Galbreath, Sandusky, Hammond, Moyers, Owens, Gromada, Brozinick, Hawkins, Wroblewski, Li, Mehrbod , Jaskunas, Shanafelt. J. Clin. Invest 2005; 115 :, 1627-1635. Interestingly, liver mRNA expression of FGF21 was doubled in mice treated with Slc10a2 inhibitors (FIG. 5C). As expected, liver mRNA levels of CYP7A1 were increased in drug-treated mice (FIG. 5C). No differences were seen between the inhibitor-treated and control animals when the liver cholesterol and TG contents were analyzed (FIG. 5D). To identify Slc10a2 blockade, mRNA levels of the FXR target genes FGF15, SHP and IBABP were analyzed in samples from terminal ileum; They were all significantly reduced in response to treatment, as would be expected from the reduced influx of BAs into the terminal ileum (FIG. 5E). Gene expression for FXR did not change in terminal ileum following Slc10a2 protein inhibitor treatment (FIG. 5E).

ob Of ob  Ileum in mice Slc10a2 Suppression of SREBP1c  And its in the liver target  Reduce genes

Since dysregulated SREBP1c has been published as a major determinant of increased lipogenic response in ob / ob liver, ultimately leading to decreased hepatic insulin sensitivity, leading to hepatic SREBP1c mRNA expression Was analyzed next and was three of its target genes. Significantly reduced mRNA levels of SREBP1c were observed in response to treatment, consistent with the reduced SREBP1c levels observed in both Slc10a2-/-mice under both basal and SR diet tests (FIG. 6A). In addition, mRNA levels of SREBP1c liver target genes ACC and FAS were strongly reduced to 50% and 80%, respectively (FIG. 6A). However, the SCD1 mRNA levels did not change significantly when compared to vehicle-treated controls (FIG. 6A).

Slc10a2 Inhibitor Treated ob Of ob  Liver in mice Glucose  Altered expression of metabolic genes

Next, expression levels of enzymes important for glucose handling in livers of ob / ob mice treated with the compound of Example 14 were studied. Degree. As shown in 6B, mRNA levels for GK, the first stage of glycolysis, increased in treated mice, consistent with decreased blood glucose levels. However, in contrast, mRNA for glycolytic gene LPK was reduced by 30% (FIG. 6B). Similar results for LPK mRNA were also found in Slc10a2-/-livers (FIG. 4D). In addition, expression of the gluconeogenic genes G6Pase and PEPCK (Fig. 6B) was analyzed and consistent with the discovery of reduced blood glucose levels in these animals, they all decreased even in the inhibitor treated mice. Was found.

Slc10a2 Suppression of ob Of ob  From mouse to mouse Akt  And Mek1 / 2 reduces activity.

Further, in order to study the molecular mechanisms underlying the observed changes in gene transcription in livers in inhibitor-treated ob / ob mice, the activity of major kinase signaling pathways known to be important in liver regulation of both glucose metabolism and lipogenesis. Was tested. Akt is a decisive factor in the regulation of the liver's response to insulin and other circulatory factors with the ability to favor glycolysis and fat production, and has been demonstrated to inhibit luconeogenesis with food intake. Induction of SREBP 1c transcription by insulin is dependent on the Akt pathway Hegarty, Bobard, Hainault, Ferre, Bossard, Foufelle. Proc. Natl.Acad. Sci. USA. 2005; 102: 2: 791-796. When Akt activity is assessed by phosphospecific antibodies, reduced serine 473 phosphorylation is noted in liver lysates of inhibitor-treated animals (FIG. 7A). Another kinase pathway activated by the FGF receptor 4 / beta-Klotho complex, known as the insulin receptor and FGF15 receptors, is the Mek1 / 2_Erk1 / 2 pathway. Interestingly, it has also been found that these important kinases show reduced activation in ob / ob livers by treatment with Slc10a2 inhibitors.

Conclusions

Disruption of the hepatic circulation of bile acids (BA) increases cholesterol metabolism, thereby stimulating liver cholesterol synthesis from acetate. Subsequent reductions in the acetate pool of liver can alter Trisleyeride (TG) and glucose metabolism. This was explored in mice genetically deficient (Slc10a2) and Slc10a2 inhibitor Example 14 ob / ob mice treated with the compound of the ileal sodium BA transporter. Plasma TG levels were reduced in Slc10a2 deficient mice and, when tested with a sucrose-rich diet, were observed from mRNA levels for key enzymes of fatty acid synthesis, ACL, ACC, FAS, SCD1. As shown, there was a reduced response in liver TG production. This effect is paralleled by reduced induction of mature SREBP1c. Consistently, pharmacological inhibition of Slc10a2 in diabetic ob / ob mice reduced serum glucose, insulin and TGs, as well as liver mRNA levels of SREBP1c and its target genes ACC and FAS. In addition, when major metabolic signal transduction intermediates in the liver were studied, the Mek1 / 2-Erk1 / 2 pathway was found to blunt in ob / ob mice after treatment with Slc10a2 inhibitors with Akt. It became. It is concluded that ablation of Slc10a2 reduces liver SREBP1c activity and serum TGs, and also reduces glucose and insulin levels in the diabetic ob / ob model. Therefore, targeting Slc10a2 may be a strategy to treat hypertriglyceridemia and diabetes.

Example  17

The effect of the compounds as described herein gives an increase in glucagon-like peptide-1 (GLP1) and also has an effect on insulin secretion.

In double-blind, placebo-controlled studies of 36 female patients with random, functional constipation, placebo, 15 mg of the compound according to Example 14, or 20 mg of the compound according to Example 14 It was administered orally once a day for 14 consecutive days and the glucagon-like peptide-1 (GLP-1) was evaluated. For the differences, the model was aonva (analysis for variance) for differences versus treatment. Analyzes for 15 mg versus placebo and 20 mg versus placebo, with analysis for non-placebo versus placebo, were statistically performed. The results are shown in Figure 8.

Example  18

In satisfying a range of phase IIb, double blind, random, placebo-controlled, Multi-centre, dose-finding, efficacy and doses of the substance according to Example 14, chronic (Chronic) Idiopathic Constipation and also patients with glucose levels above the Upper limit of normal (ULN) were treated for 56 days. The patient was a male or non-pregnant female, age ≧ 20 years old, age ≦ 80 years, and body mass index (BMI) ≧ 18.5 or <35. When comparing the baseline value of glucose concentration to the end of treatment, the concentrations of patients with higher levels of glucose than ULN showed a significant decrease from dose of 10 mg to 36% after 56 days of treatment with the compound of Example 14 (Table 2, FIG. 9). Contradictory patients with lower or equivalent values for ULN did not show any significant changes with the material according to Example 14.

The p-values were obtained from baseline values as covariates in the covariance analysis and model of the by-demographic group as treatment group, demographic group and fixed factors. There was no adjustment for multiple comparisons.

In this way, the material according to Example 14 was found to lower high glucose values in plasma, while normal values were hardly affected.

Example  19

Formulations for the delayed release of IBAT inhibitors with the following compositions are prepared:

matter Volume / Capsule ( mg )

IBAT Inhibitor Compound

Example 14 10

Non-Parail Spheres 500

Ethyl cellulose 2

Hydroxypropylmethyl cellulose 10

Eudragit L100-55 CAS 25212-88-8 25

Triethyl Citrate 2.4

The active drug is dissolved with ethyl cellulose and hydroxypropyl cellulose in 99% ethanol. This mixture is then sprayed onto non-pareil spheres in a fluidized bed apparatus. Afterwards, the pellets are dried and vented to remove residual ethanol. The Eudragit L100-55 dispersion with triethyl citrate is then sprayed onto the drug beads of the fluidized bed apparatus. Thereafter, the coated beads are filled into hard gelatin capsules after drying and sieving.

Example  20

Formulations for delayed release of IBAT inhibitors with the following compositions can be prepared:

Ingredient amount / tablet (mg)

IBAT Inhibitor Compound

Example 14 10

Silicon dioxide 200

Povidone K-25 20

Eudragit FS30D CAS 26936_ 24_3 30

Microcrystalline Cellulose 250

Sodium stearyl fumarate 5

The active drug is suspended in water and silicon dioxide cores of predetermined size in a fluidized bed apparatus. Sprayed onto the bed. Drug pellets are dried in an oven at 40 ° C. for 24 hours. Thereafter, a layer of Povidone K-25 is applied on the beads from the ethanol solution of the fluid bed apparatus. The final coating of the Eudragit FS30D dispersion is then applied to the fluidized bed. The coated beads are mixed with microcrystalline cellulose and sodium stearyl fumarate in a mixer and then pressed into a tablet.

Example  21

An IBAT inhibitor-colesevelam combination tablet is prepared having immediate release of an IBAT inhibitor and colonic release of a bile acid binder, having the following composition:

ingredient amount/ Tablet  ( mg )

core

Colesevelam Hydrochloride 400

Microcrystalline Cellulose 150

Hydroxypropyl methyl cellulose 50

Colloidal Silicon Dioxide 10

Magnesium Stearate 5

Colon release layer

Eudragit FS30D 60

PlasACRYL T20 (CAS No 123-94-4) 6

IBAT  Inhibitor layer

IBAT Inhibitors Example 14 7

Hydroxypropylmethyl cellulose 12

Croscarmellose Sodium 6

Protective coating

Hydroxypropylmethyl cellulose 12

Polyethylene glycol 2

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. EUDRAGIT FS30D dispersion and water are mixed with PlasACRYL T20 (CAS number 123-94-4) and sprayed onto core tablets using a suitable coating machine. The IBAT inhibitor coating suspension is prepared by mixing IBAT inhibitor, hydroxypropyl methyl cellulose and croscarmellose sodium in water and sprayed onto tablet cores with a colon release layer using a suitable coating machine. Finally a protective coating solution of hydroxypropylmethyl cellulose and polyethylene glycol is sprayed onto the tablets using an appropriate coating machine.

Example  22

A Colesevelam colon release tablet is prepared having the following composition:

Ingredient amount / tablet (mg)

core

Colesevelam Hydrochloride 400

Microcrystalline Cellulose 150

Hydroxypropyl methyl cellulose 50

Colloidal Silicon Dioxide 10

Magnesium Stearate 5

Colon release layer

Amylose 30

Eudragit S100 60

Triethyl citrate 6

Glycerol Monostearate 3

Colesevelam hydrochloride, microcrystalline cellulose and colloidal silicon dioxide are mixed and dissolved in water Granulated with hydroxypropyl methyl cellulose. The granules are dried, mixed with magnesium stearate and pressed into tablets. Amylose, Eudragit 100, triethylcitrate and glycerol monostearate are dissolved in a suitable solvent and sprayed onto the tablet core using a suitable coating machine.

Claims (20)

Compounds of formula (II) for the prevention and treatment of metabolic syndrome and / or glucose utilization disorders:
<Formula II>

At this time
M is -CH ₂ or NH;
R &lt; ¹ &gt; is H or OH; And
R ² is H, CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ OH, CH ₂ OCH ₃ , -CH (OH) CH ₃ , -CH ₂ SCH ₃ , or -CH ₂ CH ₂ -S-CH ₃ .
Compounds of formula (II) for the prevention or treatment of glucose utilization disorders:
<Formula II>

At this time
M is -CH ₂ or NH;
R &lt; ¹ &gt; is H or OH; And
R ² is H, CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) ₂ , —CH (CH ₃ ) CH ₂ CH ₃ , —CH ₂ OH, CH ₂ OCH ₃ , —CH (OH) CH ₃ , —CH ₂ SCH ₃ , or —CH ₂ CH ₂ —S—CH ₃ .
The method of claim 1,
The metabolic syndrome is a compound impaired in fatty acid metabolism.
The method of claim 3, wherein
Said disorder being obese.
3. The method of claim 2,
The glucose use disorder is a disordered compound associated with insulin resistance.
6. The method of claim 5,
The disorder is diabetes mellitus type 1.
6. The method of claim 5,
The disorder is diabetes mellitus type 2.
8. The method according to any one of claims 1 to 7,
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylme Methoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxyethyl) cover Moyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl ] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thioethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2- ( R) -hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxybutyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl ] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxypropyl) cover Moyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines; And
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -1'-phenyl-1 '-[N'-(carboxymethyl) carba Moyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine
&Lt; / RTI &gt;
A pharmaceutical composition comprising a compound of formula (II) for the prevention or treatment of a glucose use disorder and / or a glucose use disorder:

<Formula II>

At this time
M is -CH ₂ or NH;
R &lt; ¹ &gt; is H or OH; And
R ² is H, CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ OH, CH ₂ OCH ₃ , -CH (OH) CH ₃ , -CH ₂ SCH ₃ , or -CH ₂ CH ₂ -S-CH ₃ .
(i) a compound of formula II:
<Formula II>

At this time
M is -CH ₂ or NH;
R &lt; ¹ &gt; is H or OH; And
R ² is H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ OH, CH ₂ OCH ₃ , -CH (OH) CH ₃ , -CH ₂ SCH ₃ , or -CH ₂ CH ₂ -S-CH ₃ ; and
(ii) IBAT inhibitors; Enteroendocrine peptides or enhancers thereof; Dipeptidyl peptidase-IV inhibitors; Biguanide; Incretin mimetic; Thiazolidinones; PPAR agonists; HMG Co-A Reductase Inhibitors; Bile acid binders; And at least one other agonist selected from TGR5 receptor modulators; Or a pharmaceutically acceptable salt of any one of the foregoing agents
&Lt; / RTI &gt;
The method of claim 10,
The compound of formula (II)
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (carboxymethyl) carbamoyl] -benzyl} carbamoyl Methoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxyethyl) cover Moyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl ] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thioethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2- ( R) -hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxybutyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl ] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxypropyl)- Carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines; And
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -1'-phenyl-1 '-[N'-(carboxymethyl) carba Moyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine
Combination selected from.
The method according to claim 10 or 11,
Wherein said at least one other agonist is a bile acid binder.
13. The method of claim 12,
And said bile acid binder is cholestyramine, cholestipol or cholesevelam.
The method according to claim 10 or 11,
The at least one other agonist is a HMG Co-A reductase inhibitor.
The method of claim 14,
The HMG Co-A reductase inhibitor is a statin combination.
Use of a compound according to formula (II) for the manufacture of a medicament for the prevention or treatment of metabolic syndrome and / or glucose use disorders:

<Formula II>

At this time
M is -CH ₂ or NH;
R &lt; ¹ &gt; is H or OH; And
R ² is H, CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) ₂ , —CH (CH ₃ ) CH ₂ CH ₃ , —CH ₂ OH, CH ₂ OCH ₃ , —CH (OH) CH ₃ , —CH ₂ SCH ₃ , or —CH ₂ CH ₂ —S—CH ₃ .
Use of a compound according to formula (II) for the manufacture of a medicament for the prevention or treatment of glucose utilization disorders and / or glucose utilization disorders:

<Formula II>

At this time
M is -CH ₂ or NH;
R &lt; ¹ &gt; is H or OH; And
R ² is H, CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) ₂ , —CH (CH ₃ ) CH ₂ CH ₃ , —CH ₂ OH, CH ₂ OCH ₃ , —CH (OH) CH ₃ , —CH ₂ SCH ₃ , or —CH ₂ CH ₂ —S—CH ₃ .
A method for the treatment and / or prophylaxis of metabolic syndrome and / or glucose utilization disorders wherein the compound of formula II is administered to a subject in need of such treatment:

<Formula II>

At this time
M is -CH ₂ or NH;
R &lt; ¹ &gt; is H or OH; And
R ² is H, CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) ₂ , —CH (CH ₃ ) CH ₂ CH ₃ , —CH ₂ OH, CH ₂ OCH ₃ , —CH (OH) CH ₃ , —CH ₂ SCH ₃ , or —CH ₂ CH ₂ —S—CH ₃ .
A method of treating and / or preventing glucose using disorders and / or glucose using disorders, wherein the compound of formula II is administered to a subject in need of such treatment:

<Formula II>

At this time
M is -CH ₂ or NH;
R &lt; ¹ &gt; is H or OH; And
R ² is H, CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) ₂ , —CH (CH ₃ ) CH ₂ CH 3, —CH ₂ OH, CH ₂ OCH ₃ , —CH (OH) CH ₃ , —CH ₂ SCH ₃ , or —CH ₂ CH ₂ —S—CH ₃ .
20. The method according to claim 18 or 19,
The compound
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylme Methoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxyethyl) cover Moyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl ] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thioethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2- ( R) -hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxybutyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl ] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxypropyl) cover Moyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines; And
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -1'-phenyl-1 '-[N'-(carboxymethyl) carba Moyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine
Selected from any one of.

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